Tarascon Adult
Endocrinology
Pocketbook
Marc J. Laufgraben, MD, MBA, FACE, FACP
Associate Professor of Medicine,
Cooper Medical School of Rowan University and Chief,
Division of Endocrinology, Cooper University Hospital, Camden, NJ
Geetha Gopalakrishnan, MD
Associate Professor of Medicine
Director of Fellowship Program in Diabetes and Endocrinology
Alpert Medical School of Brown University, Providence, RI
48565_FM_i-xx.indd i
5/3/13 8:19 PM
World Headquarters
Jones & Bartlett Learning
5 Wall Street
Burlington, MA 01803
978-443-5000
info@jblearning.com
www.jblearning.com
Jones & Bartlett Learning books and products are available through most bookstores and online booksellers.
To contact Jones & Bartlett Learning directly, call 800-832-0034, fax 978-443-8000, or visit our website,
www.jblearning.com.
Substantial discounts on bulk quantities of Jones & Bartlett Learning publications are available to
corporations, professional associations, and other qualified organizations. For details and specific
discount information, contact the special sales department at Jones & Bartlett Learning via the above
contact information or send an email to specialsales@jblearning.com.
Copyright © 2014 by Jones & Bartlett Learning, LLC, an Ascend Learning Company
All rights reserved. No part of the material protected by this copyright may be reproduced or utilized in
any form, electronic or mechanical, including photocopying, recording, or by any information storage and
retrieval system, without written permission from the copyright owner.
The content, statements, views, and opinions herein are the sole expression of the respective authors
and not that of Jones & Bartlett Learning, LLC. Reference herein to any specific commercial product,
process, or service by trade name, trademark, manufacturer, or otherwise does not constitute or imply
its endorsement or recommendation by Jones & Bartlett Learning, LLC and such reference shall not be
used for advertising or product endorsement purposes. All trademarks displayed are the trademarks of
the parties noted herein. Tarascon Adult Endocrinology Pocketbook is an independent publication and has
not been authorized, sponsored, or otherwise approved by the owners of the trademarks or service marks
referenced in this product.
There may be images in this book that feature models; these models do not necessarily endorse, represent,
or participate in the activities represented in the images. Any screenshots in this product are for educational and instructive purposes only. Any individuals and scenarios featured in the case studies throughout
this product may be real or fictitious, but are used for instructional purposes only.
The authors, editor, and publisher have made every effort to provide accurate information. However, they
are not responsible for errors, omissions, or for any outcomes related to the use of the contents of this
book and take no responsibility for the use of the products and procedures described. Treatments and
side effects described in this book may not be applicable to all people; likewise, some people may require
a dose or experience a side effect that is not described herein. Drugs and medical devices are discussed
that may have limited availability controlled by the Food and Drug Administration (FDA) for use only in
a research study or clinical trial. Research, clinical practice, and government regulations often change
the accepted standard in this field. When consideration is being given to use of any drug in the clinical
setting, the health care provider or reader is responsible for determining FDA status of the drug, reading
the package insert, and reviewing prescribing information for the most up-to-date recommendations on
dose, precautions, and contraindications, and determining the appropriate usage for the product. This is
especially important in the case of drugs that are new or seldom used.
Production Credits
Executive Publisher: William Brottmiller
Senior Acquisitions Editor: Nancy Anastasi Duffy
Production Assistant: Alex Schab
Digital Marketing Manager: Jennifer Sharp
Manufacturing and Inventory Control Supervisor: Amy Bacus
Composition: CAE Solutions Corp.
Cover Design: Kristin E. Parker
Rights & Photo Research Assistant: Ashley Dos Santos
Cover Image: Courtesy of National Library of Medicine
Printing and Binding: Cenveo Publisher Services
Cover Printing: Cenveo Publisher Services
To order this product, use ISBN:
978-1-4496-4856-5
6048
Printed in the United States of America
17 16 15 14 13 10 9 8 7 6 5 4 3 2 1
48565_FM_i-xx.indd ii
5/3/13 8:19 PM
CONTRIBUTORS LIST
Shabina Ahmed, MD Johns Hopkins University, Division of Endocrinology
and Metabolism, Baltimore, MD
Erik K Alexander, MD Brigham and Women’s Hospital, Boston, MA
Bradley Anawalt, MD University of Washington Medical Center, Seattle, WA
Jennifer A Argumedo, MD Texas Diabetes Institute, San Antonio, TX
Stephen L Atkin FRCP, PhD Head, Academic Endocrinology, Diabetes
and Metabolism, Hull York Medical School, Michael White Centre,
Hull, UK
Richard J Auchus, MD MEND/Internal Medicine, University of Michigan,
Ann Arbor, MI
Theingi Aung, MD The Oxford Centre for Diabetes, Endocrinology, and
Metabolism The Churchill Hospital, Oxford, UK
Nupur Bahl, MD Rhode Island Hospital, E. Providence, RI
Guiseppe Barbesino, MD Massachusetts General Hospital, Boston, MA
Geetha Bhat, MD Cooper University Hospital, Division of Endocrinology,
Cherry Hill, NJ
Harikrashna Bhatt, MD Rhode Island Hospital, E. Providence, RI
Charlotte M Boney, MD Rhode Island Hospital, Department of Pediatrics,
Providence, RI
George A Bray, MD Boyd Professor, Chief, Division of Clinical Obesity
and Metabolism Professor, Pennington Biomedical Research Center, Baton
Rouge, LA
Gregory A Brent, MD UCLA, Department of Medicine, Los Angeles, CA
M Luiza Caramori, MD, MSc, PhD University of Minnesota, Department of
Medicine, Division of Endocrinology and Diabetes, Minneapolis, MN
Harold E Carlson, MD Professor of Medicine and Division Head, Stony
Brook University School of Medicine, Department of Endocrinology, Stony
Brook, NY
Kenneth Chen, MD Women and Infants’ Hospital of Rhode Island,
Providence, RI
Vicky Cheng, MD Rhode Island Hospital, E. Providence, RI
David S Cooper, MD The Johns Hopkins University School of Medicine,
Division of Endocrinology, Baltimore, MD
Mark S Cooper, MD Queen Elizabeth Hospital, Department of Endocrinology,
Birmingham, UK
Glenn R Cunningham, MD Baylor College of Medicine, Houston, TX
48565_FM_i-xx.indd iii
5/3/13 8:19 PM
iv
Contributors List
Guari Dhir, MD Temple University Hospital, Philadelphia, PA
Kevin Donohue, DO Thomas Jefferson University Hospital, Department of
Endocrinology, Philadelphia, PA
Diana R Engineer, MD Baylor College of Medicine, Houston, TX
Azeez Farooki, MA Memorial Sloan-Kettering Cancer Center, New York, NY
Mark N Feinglos, MD Duke University Medical Center, Durham, NC
Natali Franzblau, MD Cooper University Hospital, Department of OB/
Gyn, Camden, NJ
Neil Gittoes, MD Queen Elizabeth Hospital, Department of Medicine,
Birmingham, UK
Ole-Petter Hamnvik Brigham and Women’s Hospital, Boston, MA
Amir H Hamrahian, MD Cleveland Clinic, Department of Endocrinology,
Cleveland, OH
Anthony Heaney, MD Gonda Diabetes Center, Los Angeles, CA
Mark Herman, MD Beth Israel Deaconess Medical Center, Boston, MA
Silvio E Inzucchi, MD Yale University, New Haven, CT
Serge Jabbour, MD, FACE, FACP Thomas Jefferson University Hospital,
Department of Endocrinology, Philadelphia, PA
William Jeffcoate, MRCP Consultant Endocrinologist, Diabetologist,
Nottingham University Hospitals, Department of Diabetes and Endocrinology,
Nottingham, UK
Tessey Jose, MD Yale University, New Haven, CT
Rajesh M Kabadi, MD Cooper University Hospital, Camden, NJ
Niki Karavitaki, MD The Oxford Centre for Diabetes, Endocrinology, and
Metabolism The Churchill Hospital, Oxford, UK
Laurence Katznelson, MD Professor of Medicine and Neurosurgery,
Stanford University, Stanford, CA
Steven Kaufman, MD Cooper University, Department of Endocrinology,
Cherry Hill, NJ
Aliya Khan, MD Professor of Clinical Medicine, McMaster University,
Oakville, ON, Canada
Maryam Khan, MD Cooper University Hospital, Division of Endocrinology,
Camden, NJ
Jaya Kothapolly, MD Cooper University Hostipal, Willingboro, NJ
Matthew H Kulke, MD Dana-Farber Cancer Institute, Boston, MA
Andre Lacroix, MD Centre hospitalier de l’Universite de Montreal
(CHUM), Division of Endocrinology, Montreal, QC, Canada
David Wing-Hang Lam, MD Mount Sinai School of Medicine, New York, NY
Rebecca Leboeuf, MD CHUM Hospital Notre-Dame, Montreal, QC, Canada
Lillian F Lien, MD Duke University Medical Center, Durham, NC
48565_FM_i-xx.indd iv
5/3/13 8:19 PM
Contributors List
v
Ivana Lukacova-Zib, MD Rhode Island Hospital, E. Providence, RI
Eleftheria Maratos-Flier, MD Beth Israel Deaconess Medical Center,
Boston, MA
Jane V Mayrin, MD Einstein Medical Center, Elkin Park, PA
Rebecca McEachern Clinical Assistant Professor of Pediatrics, Pediatric
Endocrinology of Rhode Island, Providence, RI
Anna Milanesi, MD, PhD Cedars-Sinai Medical Center, Division of
Endocrinology, Los Angeles, CA
Mark E Molitch, MD Martha Leland Sherwin Professor of Endocrinology,
Northwestern University Feinburg School of Medicine, Division of
Endrocrinology, Metabolism and Molecular Medicine, Chicago, IL
Farah Morgan, MD Cooper University Hospital, Division of Endocrinology,
Diabetes and Metabolism, Cherry Hill, NJ
Harmeet Singh Narula, MD Assistant Professor of Clinical Medicine,
Stony Brook University School of Medicine, Department of Endocrinology,
Stony Brook, NY
Lawrence Nelson, MD National Institutes of Health (NIH), Bethesda, MD
Benjamin O’Donnell, MD Rhode Island Hospital, E. Providence, RI
Catherine J Owen, MRCP, PhD Royal Victoria Infirmary, Department of
Pediatric Endocrinology, New Castle upon Tyne, UK
Karel Pacak, MD, PhD, DSc Head, Section on Medical
Neuroendocrinology, National Institutes of Health (NIH), Bethesda, MD
Kevin M Panalone, MD Cleveland Clinic, Department of Endocrinology,
Cleveland, OH
Mohammed Zohair Rahman, MD McMaster University, Oakville, ON,
Canada
J Bruce Redmon, MD University of Minnesota, Minneapolis, MN
Raymond R Russell, MD Yale University, New Haven, CT
Chad D Sagnella, MD Resident, Yale University School of Medicine,
Emergency Medicine, New Haven, CT
Thokhukat Sathyapalan, MD, FRCP Michael White Centre for Diabetes
and Endocrinology, Hull, UK
Urvi Shah, MD Eunice Kennedy Shriver NICHD/NIH, Bethesda, MD
Jennifer Sipos, MD Ohio State University, Columbus, OH
Elias S Siraj, MD Temple University Hospital, Philadelphia, PA
Robert J Smith Professor of Medicine, Alpert Medical School of Brown
University, Providence, RI
Michael Stowasser, MD Endocrine Hypertension Research Centre,
University of Queensland School of Medicine, Brisbane, Queensland,
Australia
48565_FM_i-xx.indd v
5/3/13 8:19 PM
vi
Contributors List
Vin Tangpricha, MD Associate Professor, Emory College, Atlanta, GA
Pamela Taxel, MD Associate Professor of Medicine, University of
Connecticut Health Center, Farmington, CT
Joseph R Tucci, MD, FACP, FACE Roger Williams Medical Center,
Providence, RI
Joseph G Verbalis, MD Chief of the Division of Endocrinology and
Metabolism, Georgetown University, Washinton, DC
Wendy Vitek, MD University of Rochester Medical Center, Rochester, NY
Perry J Weinstock, MD Cooper University Hospital, Camden, NJ
Hilary Whitlatch, MD Rhode Island Hospital, E. Providence, RI
Robert T Yanagisawa, MD Program Director, Clinical Fellowship in
Encrinology, Diabetes, and Bone Diseases, Mount Sinai School of Medicine,
New York, NY
Kevin CJ Yuen, MD Oregon Health and Science University, Portland, OR
48565_FM_i-xx.indd vi
5/3/13 8:19 PM
CONTENTS
Abbreviations in Text
xiv
SECTION I: PITUITARY
1 Pituitary Essentials
Basic Facts
Pituitary Control
Pituitary Function
References
2 Hypopituitarism
Background
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Hormone Replacement
References
3 Prolactinemia
and Prolactinoma
Pathophysiology of
Hyperprolactinemia
and Prolactinomas
Clinical Presentation
Diagnostic Evaluation
Treatment
Follow-Up
Pregnancy
References
4 Acromegaly
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Management
References
5 Growth Hormone
Deficiency in Adults
Pathophysiology
Clinical Presentation
Laboratory Evaluation
Imaging
Management
References
6 Pituitary Incidentalomas,
Nonfunctioning Pituitary
Adenomas, and
Craniopharyngiomas
Pituitary Incidentalomas
Nonfunctioning Pituitary
Adenomas
1
3
3
3
5
6
7
7
7
7
9
9
11
48565_FM_i-xx.indd vii
13
13
13
14
15
16
16
17
19
19
19
20
21
24
25
25
25
26
29
29
30
31
31
32
Craniopharyngiomas
References
7 Hypoosmolality and the
Syndrome of Inappropriate
Antidiuretic Hormone
Secretion
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Classification of
Hypoosmolality
by ECF Volume Status
Syndrome of Inappropriate
Antidiuretic Hormone
Secretion (SIADH)
References
8 Diabetes Insipidus
Definition
Etiologies
Clinical Manifestations
Diagnosis
References
SECTION II: THYROID
9 Thyroid Essentials and
Thyroid Function Tests
Anatomy
Histology
Physiology
References
10 Thyrotoxicosis
and Hyperthyroidism
Etiology and Pathophysiology
Clinical Presentation
Diagnosis
Management Options
Thyroid Storm: Diagnosis
and Management
Subclinical Hyperthyroidism
References
11 Hypothyroidism
Background
Diagnosis
Treatment
Subclinical Hypothyroidism
Myxedema Coma
References
34
36
37
37
37
38
38
39
42
43
43
43
43
44
45
47
49
49
49
49
52
53
53
54
54
57
60
60
61
63
63
64
65
66
66
67
5/3/13 8:19 PM
viii Contents
12 Nonthyroidal Illness
Syndrome
Background
Pathophysiology
Diagnostic Evaluation
Management
References
13 Drugs Affecting Thyroid
Function and Thyroid
Hormone Replacement
General Comments
Drugs Affecting Thyroid
Absorption
Drugs Affecting Thyroid
Hormone Metabolism
Drugs Directly Affecting
Thyroid Function
Drugs Causing Central
Hypothyroidism
References
14 Thyroid Nodule
Evaluation
Epidemiology and
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Management
References
15 Papillary and Follicular
Thyroid Carcinoma
Definition
Epidemiology
Risk Factors
Pathogenesis
Pathological Features
Clinical Presentation
and Diagnosis
Prognosis
Tumor Node Metastasis
(TNM) Classification
Initial Treatment of DTC
Long-Term Management
Management of Persistent/
Recurrent Disease
References
16 Medullary Thyroid
Cancer
Pathophysiology
Clinical Presentation
Diagnosis
Clinical Features
Staging
Therapy
48565_FM_i-xx.indd viii
69
69
69
70
71
71
73
73
73
74
75
77
78
79
79
79
80
81
82
85
85
85
85
86
86
87
87
88
89
90
91
92
93
93
94
94
95
95
95
Follow-Up
References
17 Anaplastic Thyroid
Cancer and Poorly
Differentiated Thyroid
Cancer
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Management
Surgery
External Radiation Therapy
References
18 Thyroid Disorders
in Pregnancy
Hypothyroidism in Pregnancy
Etiology and Pathophysiology
Clinical Presentation
Screening for Hypothyroidism
in Pregnancy
Laboratory Evaluation
Diagnosis
Management
Hyperthyroidism in
Pregnancy
Etiology and Pathophysiology
Clinical Presentation
Laboratory Evaluation
Diagnosis
Management
Thyroid Nodules and
Thyroid Cancer
Etiology and Pathophysiology
Clinical Presentation
Diagnosis and Management
History of Thyroid Cancer
Postpartum Thyroiditis
Etiology and Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Treatment and Monitoring
References
SECTION III: ADRENAL
19 Adrenal Essentials
Anatomy
Histology
Hormone Synthesis
Regulation of Adrenal
Function
Function of Adrenal
Hormones
References
96
96
97
97
97
98
100
100
100
102
103
103
103
103
103
104
104
104
105
105
106
106
106
107
107
107
108
108
109
109
109
109
109
110
110
111
113
113
113
113
114
115
116
5/3/13 8:19 PM
Contents ix
20 Adrenal Insuffi ciency
Causes of Adrenal
Insufficiency
Diagnosis of AI
Chronic Treatment of AI
Acute Adrenal Crisis
Conditions That May
Require an Adjustment
in HC Dosing
Patient Education and
“Sick Day Management”
Critical Illness-Related
Corticosteroid Insufficiency
(“Relative AI”)
References
21 Cushing’s Syndrome
Background
Diagnostic Strategy
Standard Diagnostic Tests
for Cushing’s Syndrome
Differential Diagnosis
of Cushing’s Syndrome
Basics of Management
of Major Causes of
Cushing’s Syndrome
References
22 Primary Aldosteronism
Clinical Presentation
Screening: Plasma
Aldosterone/Renin
Ratio (ARR) Testing
Confirmatory Testing Options
Subtype Differentiation
Management
References
23 Pheochromocytoma
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Management
Malignant
Pheochromocytomas
Follow-Up
Acknowledgments
References
24 Congenital Adrenal
Hyperplasia
Pathophysiology
Types of CAH
Clinical Presentation
Diagnostic Evaluation
Management
References
48565_FM_i-xx.indd ix
117
117
118
119
120
120
120
121
121
123
123
124
125
126
127
129
131
131
131
132
133
134
134
135
135
136
137
140
141
141
141
142
143
143
144
144
145
145
148
25 Adrenal Incidentaloma
Introduction
Assessment for Hormone
Hypersecretion
Pheochromocytoma
Subclinical Cushing’s
Syndrome
Primary Aldosteronism
Differentiating Benign
and Malignant Adrenal
Masses
Natural History and
Follow-Up of Patients with
Adrenal Incidentalomas
References
26 Adrenocortical
Carcinoma
Epidemiology and
Pathophysiology
Clinical Presentation
Initial Therapy and Surgical
Approach
Pathological Evaluation
Adjuvant Mitotane or
Radiotherapy and
Follow-Up
Advanced Disease
Mitotane Effect on Endocrine
Function
References
SECTION IV: CALCIUM AND BONE
27 Calcium Metabolism
Essentials
Maintenance of Overall
Calcium Balance
PTH
Vitamin D
Calcitonin
References
28 Hypercalcemia
Incidence
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Management
References
29 Hyperparathyroidism
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Management
References
149
149
149
149
150
150
151
153
153
155
155
155
157
157
157
158
158
159
161
163
163
164
165
167
167
169
169
169
170
170
172
173
175
175
176
176
178
179
5/3/13 8:19 PM
x
Contents
30 Hypocalcemia
Pathophysiology
Specific Causes
Clinical Presentation
Laboratory Testing
Management
References
31 Vitamin D Defi ciency
Pathophysiology
Prevalence of Vitamin D
Deficiency
Risk Factors for Vitamin D
Deficiency
Clinical Presentation
Diagnosis
Management
References
32 Osteoporosis
Epidemiology
Definition
Bone Metabolism
Risk Factors
Screening
Treatment
References
33 Paget’s Disease of Bone
(Osteitis Deformans)
Etiology
Pathophysiology
Clinical Presentation
Physical Examination
Diagnostic Evaluation
Management
Assessment of Therapeutic
Response
References
SECTION V: REPRODUCTION
34 Male Reproduction
Essentials
Testes
Reproductive Outflow
Tract
Sexual Differentiation
Neuroendocrine
Regulation
References
35 Gynecomastia
Clinical Presentation
Diagnostic Evaluation
Management
References
48565_FM_i-xx.indd x
181
181
181
182
182
183
184
185
185
185
185
186
186
186
187
189
189
189
190
191
191
191
193
195
195
195
195
196
196
197
198
198
199
201
201
202
202
203
204
205
206
206
207
207
36 Testosterone
Defi ciency in Men
Prevalence
Pathophysiology
Etiology
History
Physical Exam
Chronic Conditions with
High Prevalence of
Hypogonadism
Assays/Tests
Diagnosis
Potential Risks of Androgen
Replacement
References
37 Male Infertility
Definition of Infertility
Pathophysiology of Male
Infertility
Clinical Presentation
Diagnostic Evaluation
Diagnostic Imaging
Treatment of Male
Infertility
References
38 Female Reproduction
Essentials
Development of the Female
Reproductive Tract
in the Embryo
Puberty
Hormones of the Menstrual
Cycle
Normal Menstrual Cycle
Menopause
References
39 Polycystic Ovary
Syndrome (PCOS)
Background
Definitions
Symptoms
Signs
Investigations
Imaging
General Management
of PCOS
Approach to Hirsutism
in PCOS
Approach to Menstrual
Irregularity in PCOS
Approach to Infertility
in PCOS
References
209
209
209
210
211
211
211
212
212
213
216
217
217
217
218
218
219
219
220
221
221
221
221
224
224
226
227
227
227
227
228
228
229
229
230
231
231
231
5/3/13 8:19 PM
Contents xi
40 Hirsutism
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Management
References
41 Adult-Onset Primary
Ovarian Insuffi ciency
(POI)
Definition
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Management
Acknowledgments
References
42 Female Infertility
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Management
References
233
233
233
235
236
238
239
239
239
239
240
241
243
244
245
245
246
246
247
249
SECTION VI: DIABETES,
METABOLISM, AND OBESITY
251
43 Endocrine Pancreas
and Fuel Metabolism
Essentials
253
References
256
44 Diabetes Mellitus
257
Background
257
Pathophysiology
of Type 1 DM
257
Clinical Presentation
of Type 1 DM
257
Pathophysiology
of Type 2 DM
257
Clinical Presentation
of Type 2 DM
258
Pathophysiology and
Clinical Presentation
of Other Forms of DM
258
American Diabetes
Association (ADA) Criteria
for DM Screening in Adults 259
ADA Criteria for the
Diagnosis of DM
259
Additional Laboratory
Testing for the Diagnosis
and Management of
Glycemia in DM
260
Pharmaceutical Options for
Diabetes Management
261
48565_FM_i-xx.indd xi
45
46
47
48
Glycemic Management in
Type 1 Diabetes:
Initiating Outpatient
Regimens
264
Glycemic Management
in Type 2 Diabetes:
ADA Guidelines
265
References
266
Maturity Onset Diabetes
of the Young
267
Pathophysiology
267
Clinical Presentation
267
Diagnostic Evaluation
267
Management
268
References
270
Hyperglycemic Emergencies:
Diabetic Ketoacidosis (DKA)
and the Hyperosmolar
Hyperglycemic State
(HHS)
271
Pathophysiology
271
Typical Precipitating Factors 272
Evaluation
272
Commonly Seen Laboratory
Abnormalities
273
Management
273
Complications of
Management
274
Resolution of the
Hyperglycemic Crisis
275
Transition from IV Insulin
Infusion
275
References
276
Hypoglycemia in Patients
with Diabetes
277
Definition
277
Symptoms of Hypoglycemia 277
Classification of
Hypoglycemia in
Patients with Diabetes
277
Etiologies of Hypoglycemia
in Diabetes
277
Hypoglycemia-Associated
Autonomic Failure (HAAF) 278
Acute Treatment of
Hypoglycemia in
Diabetes
279
Prevention of Hypoglycemia
in Diabetes
279
References
280
Diabetic Retinopathy
281
Pathophysiology
281
Clinical Presentation
281
5/3/13 8:19 PM
xii
Contents
Diagnostic Evaluation
Management
References
49 Diabetic Nephropathy
Epidemiology
Risk Factors
Pathophysiology
Clinical Presentation
Diagnostic Evaluation
Management
References
50 Distal Symmetric
Polyneuropathy
Pathophysiology
Clinical Presentation
Screening and Monitoring
of Distal Symmetric
Polyneuropathy (DSPN)
Management of DSPN
References
51 Cardiovascular Disease
in Type 2 Diabetes
Diabetes and Cardiovascular
Risk: Overview
Pathophysiology
Glycemic Control
Hypertension Management
Dyslipidemia
Lipid Guidelines
Antiplatelet Therapy
Coronary Heart Disease
(CHD) Screening
Management of DM in Acute
Coronary Syndrome
References
52 Diabetes in Pregnancy
Classification
Risk Factors for GDM
Diagnosis of GDM
Preconception Care of Women
with Preexisting Diabetes
Management of Diabetes
in Pregnancy
Special Prenatal
Considerations for
Diabetic Patients
Postnatal Care
References
53 Glycemic Issues in
Hospitalized Patients
For Hospitalized Patients
Outside the ICU
48565_FM_i-xx.indd xii
281
282
283
285
285
285
285
286
286
287
288
289
289
289
54
55
289
290
290
293
56
293
293
294
297
298
298
299
300
300
301
303
303
303
303
304
304
305
305
306
307
307
57
For Patients in ICUs
References
Prediabetes and Diabetes
Prevention
Pathophysiology
Clinical Presentation
Associated Conditions
Recommendations for
Delay of DM Type 2
Management of CVD
in Prediabetes
Treatment Goals with
Pharmacologic Therapy
References
Diabetic Foot Disease
Diabetic Foot Ulceration
and Infection
Charcot
Neuroosteoarthropathy
(CN; the Charcot Foot)
References
Hypoglycemia Disorders
Defined by Whipple’s Triad
Symptoms
Classification of
Hypoglycemias in Adults
Diagnosis
Imaging (Localizing Studies)
Treatment
References
Lipid Essentials
Lipid Profile Reflects the
Lipoproteins Carrying
Cholesterol and Triglyceride
Plasma Lipoproteins Are
Determined by 3 Interrelated
Pathways
References
58 Lipid Disorders
Lipid Components
Classification of Total
Cholesterol and LDL
Cholesterol
Common Pharmacologic
Therapies
References
59 Essentials of Adipose
Tissue Endocrinology
Types of Adipose Tissue
Endocrine Regulation of
Lipid Storage and Release
in Adipocytes
309
310
311
311
311
311
312
312
312
313
315
315
317
319
321
321
321
321
322
323
323
324
325
325
326
329
331
331
331
335
338
339
339
339
5/3/13 8:19 PM
Contents
Adipose Tissue Derived
Efferent Signals
Leptin
Adiponectin
Obesity
Adipose Tissue Endocrinology
in Obesity
Lipodystrophies
References
60 Obesity Management
Pathophysiology
Diagnosis
Clinical Presentation
Treatment
References
61 Metabolic Syndrome
Introduction
Prevalence
Diagnosis
Clinical Presentation
Laboratory Testing
Treatment
References
SECTION VII: MISCELLANEOUS
62 Pancreatic Neuroendocrine
Tumors and Carcinoid
Syndrome
Pathophysiology
Clinical Presentation
Diagnosis
General Management
Approach
48565_FM_i-xx.indd xiii
340
340
340
341
341
342
342
343
343
343
344
345
347
349
349
349
350
350
350
350
351
353
355
355
356
357
358
Treatment of Symptoms
of Hormonal
Hypersecretion by
Tumor Type
Treatment of Patients with
Hepatic-Predominant
Metastatic Disease
Systemic Treatment Options
for Tumor Control
References
63 Autoimmune
Polyglandular Syndromes
and Multiple Endocrine
Neoplasias
Autoimmune Polyglandular
Syndromes (APS)
Autoimmune Polyglandular
Syndromes Type 2
(APS2)
Autoimmune Polyglandular
Syndromes Type 1
(APS1)
Multiple Endocrine
Neoplasias (MEN)
Clinical Presentation
of MEN-1
Clinical Presentation
of MEN-2
Diagnosis of MEN-1
Diagnosis of MEN-2
Management of MEN
References
Index
xiii
358
359
359
360
361
361
361
364
365
365
366
367
367
368
368
369
5/3/13 8:19 PM
xiv
Abbreviations in Text
ABBREVIATIONS IN TEXT
5-HIAA
11OHD
17-OHP
17OHD
18FDG
21OHD
25-OHD
3betaHSDD
4d CT
ABCA1
ABG
ACC
ACCF
ACEI
ACOG
ACTH
ADA
ADH
AFC
AGE
AGHD
AHA
AI
AIRE
AIT
AITD
AMH
APECED
APS-1
APS(1/2)
AR
ARB
ARR
ASA
ATC
ATD
IPSS
AUS
AVP
AVPR
AZF
BMD
BMI
BP
48565_FM_i-xx.indd xiv
5-hydroxyindole acetic acid
11-hydroxylase deficiency
17-hydroxyprogesterone
17-hydroxylase/17, 20-lyase deficiency
18-fluorodeoxyglucose
21-hydroxylase deficiency
25-hydroxy Vitamin D
3beta-hydroxysteroid dehydrogenase deficiency
four-dimensional computed tomography
ATP-binding cassette transport A1
arterial blood gas
adrenocortical carcinoma
American College of Cardiology Foundation
angiontensin-converting enzyme inhibitor
American College of Obstetrics & Gynecology
adrenocorticotropic hormone
American Diabetes Association
antidiuretic hormone
antral follicle counts
advanced glycation end products
adult-onset growth hormone deficiency
American Heart Association
adrenal insufficiency
“autoimmune regulator” gene
amiodarone-induced hyperthyroidism
autoimmune thyroid disease
antimullerian hormone
autoimmunepolyendocrinopathy-candidiasis-ectodermal
dystrophy syndrome
autoimmune polyendocrine syndrome, type 1
autoimmune polyglandular syndrome (type 1/2)
androgen receptor
angiotensin (II) receptor blocker
aldosterone/renin ratio
aspirin
anaplastic thyroid cancer
antithyroid drugs
International Prognostic Scoring System
atypia of undetermined significance
arginine vasopressin
arginine vasopressin receptor
azoospermic factor [AZFa/b/c]
bone mineral density
body mass index
blood pressure
5/3/13 8:19 PM
Abbreviations in Text xv
BPH
BUN
BWL
C-peptide
Ca
CAD
CAH
cAMP
CaSR
CBC
CBG
CBT
CCH
CDC
CE
CEA
CETP
CFRD
CGA
CGRP
CHD
CHF
ClCM
CMC
CN
CNS
COPD
CPA
Cr
CRH
CST
CT
CTR
CTx
CVA
CVD
D1/D2/D3
DA
dDAVP
DEXA
DHEA-s
DHEA
DHT
DHT
DIT
DKA
48565_FM_i-xx.indd xv
benign prostatic hyperplasia
blood urea nitrogen
behavioral weight loss
connecting peptide
calcium
coronary artery disease
congenital adrenal hyperplasia
cyclic AMP
calcium-sensing receptor
complete blood cell count
corticosteroid-binding globulin
cognitive behavioral therapy
C-cell hyperplasia
US Centers for Disease Control and Prevention
cholesterol ester
carcinoembryonic antigen
cholesterol ester transport protein
cystic fibrosis-related diabetes
chromagranin A
calcitonin gene-related peptide
coronary heart disease
congestive heart failure
chloride
chylomicron
chronic mucocutaneous candidiasis
Charcot neuroosteoarthropathy
central nervous system
chronic obstructive pulmonary disease
cyproterone acetate
creatinine
corticotrophin-releasing hormone
cosyntropin stimulation test
computed tomography
calcitonin receptor
C-terminal telopeptide
cerebrovascular accident
cardiovascular disease
Type 1/2/3 deiodinase
dopamine
desmopressin
dual-energy X-ray absorptiometry
DHEA-sulphate
dehydroepiandrosterone
dihydrotestosterone
dihydrotestosterone
diiodotyrosine
diabetic ketoacidosis
5/3/13 8:19 PM
xvi
Abbreviations in Text
DM
DOR
DPP-4
DRE
DSD
DSP
DSPN
DST
DTC
EBRT
ECF
ECG
EDP
Epi
ESRD
FA
FAI
FAP
FC
FDA
FDG
FFA
FGF
FHH
FLUS
FNA
FRAX
FSH
FT4
FTC
FTI
FTO
FXPOI
GCK
GD
GDM
GFR
GH
GHD
GHRH
GIP
GLP-1
GnRH
GO
Gs/Gq
HAAF
HAART
48565_FM_i-xx.indd xvi
diabetes mellitus
diminished ovarian reserve
dipeptidyl peptidase-4
digital rectal exam
disorders of sex development
diastolic blood pressure
distal symmetric polyneuropathy
dexamethasone suppression test
differentiated thyroid cancer
external beam radiation therapy
extracellular fluid
electrocardiogram
etoposide, doxorubicin, and cisplatin
epinephrine
end-stage renal disease
fludrocortisone acetate
free androgen index
familial adenomatous polyposis
free cholesterol
U.S. Food and Drug Administration
fluorodeoxyglucose
free fatty acid
fibroblast growth factor
familial hypercalciuric hypercalcemia
follicular lesion of undertermined significance
fine needle aspiration
WHO Fracture Risk Assessment Tool
follicular stimulating hormone
free thyroxine
follicular thyroid carcinoma
free thyroxine index
fat mass and obesity
fragile X-associated primary ovarian insufficiency
glucokinase
Graves’ disease
gestational diabetes mellitus
glomerular filtration rate
growth hormone
growth hormone deficiency
growth hormone−releasing hormone
gastric inhibitory peptide
glucagon-like peptide 1
gonadotropin-releasing hormone
Graves’ ophthalmolophathy
7-transmembrane G-protein-coupled receptor
hypoglycemia-associated autonomic failure
highly active antiretroviral therapy
5/3/13 8:19 PM
Abbreviations in Text xvii
HC
hCG
HCO3
HCTZ
HDDST
HDL-/LDL-C
HDL
HIV
HL
HLA
HNF-1alpha
HPA
HPT
HSG
HSL
HT
HU
IADSPG
iCa2+
ICSI
ICU
IDL
IFG
IGF-1
IgG
IGT
IL-1
IL-6
IM
IMRT
INSL3
IPF-1
IPSS
ITT
IUI
IV
IVF
JNC
LADA
LAR
LCAH
LCAT
LDL
LDLR
LFT
LH
48565_FM_i-xx.indd xvii
hydrocortisone
human chorionic gonadotropin
bicarbonate
hydrochlorothiazide
high-dose dexamethasone suppression test
high-/low-density lipoprotein cholesterol
high-density lipoprotein
human immunodeficiency virus
hepatic lipase
human leukocyte antigen
hepatocyte nuclear factor 1alpha
hypothalamic-pituitary-adrenal
hypothalamic-pituitary thyroid
hysterosalpingogram
hormone-sensitive lipase
Hashimoto’s thyroiditis
Hounsfield units
International Association of Diabetes
in Pregnancy Study Groups
ionized calcium concentration
intracytoplasmic sperm injection
intensive care unit
intermediate density lipoprotein
impaired fasting glucose
insulin like growth factor 1
immunoglobulin G
impaired glucose tolerance
interleukin 1
interleukin 6
intramuscularly
intesnsity-modulated radiation therapy
insulin-like factor 3
insulin promoter factor-1
inferior petrosal sinus sampling
insulin tolerance test
intrauterine unsemination
intravenously
in vitro fertilization
Joint National Committee
latent autoimmune diabetes of the adult
long-acting release
lipoid congenital adrenal hyperplasia
lecithin cholesterol acyltransferase
low-density lipoprotein
LDL receptor
liver function test
luteinizing hormone
5/3/13 8:19 PM
xviii Abbreviations in Text
LOH
LPL
LT4
M-CSF
MAPK
MC4R
MCT8
MEN-1
METS
MI
MIBG
MIT
Mg2+
MMI
MN
MNT
MODY
MRI
MTC
NCCAH
NCEP
NE
NET
Nf1
NGSP
nHDL
NIH
NIPHS
NIS
NPO
NSAIDs
NSTEMI
NTIS
NTx
OCP
ODS
OGTT
OPG
PAD
PCOS
PDTC
PET
PG
PGB
PHPT
PI
48565_FM_i-xx.indd xviii
loss of heterozygosity
lipoprotein lipase
levothyroxine
Macrophage-Colony Stimulatin Factor
mitogen-activated protein kinase pathway
melanocortin 4 receptor
monocarboxylate transporter
multiple endocrine neoplasia type 1
[MEN/MEN1/MEN2/MEN-1/MEN-2]
Metabolic Equivalent of Tasks
myocardial infarction
mateiodobenzylguanidine
monoiodotyrosine
magnesium concentration
methimazole
metanephrine
medical nutrition therapy
maturity-onset diabetes of the young
magnetic resonance imaging
medullary thyroid cancer
nonclassic congenital adrenal hyperplasia
National Cholesterol Education Program
norepinephrine
neuroendocrine tumor
neurofibromatosis type 1
National Glycohemoglobin Standardization Program
nascent HDL
National Institutes of Health
noninsulinoma pancreatogenous hypoglycemia syndrome
sodium/iodide symporter
nil per os (nothing by mouth)
nonsteroidal anti-inflammatory drugs
non-ST elevation myocardial infarction
nonthyroidal illness syndrome
N-terminal telopeptide
oral contraceptive pill
osmotic demyelination syndrome
oral glucose tolerance test
osteoprotegrin
peripheral arterial disease
polycystic ovary syndrome
poorly differentiated thyroid cancer
positron emission tomography
plasma glucose
postgastric bypass
primary hyperparathyroidism
pituitary incidentaloma
5/3/13 8:19 PM
Abbreviations in Text xix
PKA
PMCA
POCT
POI
POMC
POMC
PORD
PPARgamma
PPI
PPN
PPNAD
PRA
PRL
PSA
PTC
PTH
PTHrP
PTH-1R
PTU
RAI
RAIU
RANKL
RBC
RET
RET
rhTSH
RIA
RMR
RT
SBP
SCA-POI
SCS
SDHB/D
SDS
SHG
SIADH
SLE
SPEP
SQ
SR-B1
SRS
SRY
SSKI
STD
STEMI
STI
SUV
48565_FM_i-xx.indd xix
protein kinase A
plasma membrane calcium ATPase
point-of-care testing
primary ovarian insufficiency
proopiomelanocortin
proopiomelanocortin
P450-oxioreductase deficiency
peroxisome proliferator-activated receptor gamma
proton pump inhibitors
peripheral parenteral nutrition
primary pigmented nodular adrenocortical disease
plasma renin activity
prolactin
prostate specific antigen
papillary thyroid carcinoma
parathyroid hormone
PTH related peptide
parathyroid hormone 1 receptor
propylthiouracil
radioactive iodine
radioactive iodine uptake
receptor activator of nuclear factor kappa-B ligand
red blood cell count
rearranged during transfection
rearranged during transfection
recombinant-human TSH
radioimmunoassay
resting metabolic rate
radiation therapy
systolic blood pressure
steroidogenic cell autoimmune primary ovarian insufficiency
subclinical Cushing’s syndrome
succinate dehydrogenase subunits B and D
standard deviations
saline sonohysterogram
syndrome of inappropriate antidiuretic hormone secretion
systemic lupus erythematosus
serum protein electrophoresis
subcutaneous
scavenger receptor B-1
stereotactic radiosurgery
sex-determining region of the Y chromosome
supersaturated potassium iodide
sexually transmitted diseases
ST elevation myocardial infarction
soft tissue infection
Standard Uptake Value
5/3/13 8:19 PM
xx
Abbreviations in Text
T3
T4
TART
TB
TBG
TBG
TC
TDD
TESA
TFT
TG
Tg
TgAb
TGF
THRbeta
THRT
TKI
TNF
TNM
TPN
TPO
TRAb
TRBII
TRH
TSH
TSI
TTF1
TVUS
UA
UAE
UPEP
USDA
USP
UTI
UVB
VDBP
VDR
VEGF
VHL
VIP
VIPoma
VLDL
VTE
WC
WHO
Yq
48565_FM_i-xx.indd xx
triiodothyronine
thyroxine
testicular adrenal rest tissue
tuberculosis
thyroid binding golobulin
thyroid hormone binding globulin
total cholesterol
total daily dose
testicular extraction sperm aspiration
thyroid function test
triglycerides
thyroglobulin
thyroglobulin antibodies
transforming growth factor
thyroid hormone receptor beta
thyroid hormone replacement therapy
tyrosine-kinase inhibitor
tumor necrosis factor
tumor node metastasis
total parenteral nutrition
thyroid peroxidase
TSH-receptor antibodies
thyroid receptor binding inhibitor immunoglobulin
thyrotrophin-releasing hormone
thyroid stimulating hormone
thyroid-stimulating immunoglobulin
thyroid transcription factor-1
transvaginal ultrasound
unstable angina
urinary albumin excretion
urine protein electrophoresis
US Department of Agriculture
United States Pharmacopeia
urinary tract infection
photolysis
vitamin D–binding protein
vitamin D receptor
vascular endothelial growth factor
Von Hippel-Lindau syndrome
vasoactive intestinal peptide
neoplasm secreting vasoactive intestinal peptide
very low-density lipoprotein
venous thromboembolism
waist circumference
World Health Organization
long arm of the Y chromosome
5/3/13 8:19 PM
SECTION I: PITUITARY
48565_ST01_001-046.indd 1
5/1/13 9:35 PM
1 ■ PITUITARY ESSENTIALS
Anthony Heaney, MD
BASIC FACTS
• Comprises an anterior lobe (2/3), the posterior lobe (1/3), and vestigial
intermediate lobe
• Situated within the sella turcica that forms the bony roof of the
sphenoid sinus
• Above is the dural diaphragma sella through which the pituitary stalk
connects to the median eminence of the hypothalamus
• Laterally are bone (lower portion) and dura (upper portion) separating
it from the cavernous sinuses through which the 3rd, 4th, and 6th
cranial nerves and internal carotid arteries run
• Development
anterior pituitary (adenohypophysis) forms from Rathke’s
° The
pouch, an ectodermal invagination anterior to the roof of the oral
cavity formed by the 4th to 5th week of gestation
posterior pituitary (neurohypophysis) arises from neural
° The
ectoderm associated with third ventricle development
posterior pituitary consists of axons from cells in the supra° The
optic and paraventricular nuclei of the hypothalamus
• Gland volume enlarges during menstrual cycle and pregnancy
• Blood supply
arterial blood supply is provided from the inferior
° Systemic
hypophyseal arteries that are branches from the cavernous internal
carotid and posterior communicating arteries
portal vessels, originating from infundibular plexuses
° Hypophyseal
and within the pituitary stalk, together with contractile internal capillaries (“gomitoli”) provide both antegrade and retrograde blood flow
■ Ensures bidirectional flow of hypothalamic-pituitary hormonal signals
° Venous drainage: inferior petrosal sinuses
PITUITARY CONTROL
• Control of anterior and pituitary hormone release is depicted in Figure 1-1
• Three tiers of complex intracellular signals control pulsatile release
of the two posterior and six anterior pituitary hormones
and thirst areas of the brain (posterior pituitary)
° Osmoreceptors
and specific hypothalamic-derived releasing hormones (corticotrophinreleasing hormone [CRH], growth hormone–releasing hormone
[GHRH], gonadotrophin-releasing hormone [GnRH], thyrotrophinreleasing hormone [TRH]) arrive via the portal system to act
48565_ST01_001-046.indd 3
5/1/13 9:35 PM
48565_ST01_001-046.indd 4
+
Stress rresponse
esspon
nsse
ns
Homeostasis
stasis
iss
Cortisol
Co
C
ortisoll
ACTH
ACT
A
T
TH
S
SMS
Protein
P
i synthesis
y h i
Thermogenesis
Th
i
T4 & T3
Thyrotroph
ph
+
TRH
Spermatogenesis
Sperrmatttog
S
gge
Testes
Teste
T
eess
Testosterone
Testo
T
oosstte
IInhibin
nhib
bin
b
Ovulation
Ovaries
Estrogen
Progesterone
FS
F
SH
S
H & LH
+ FSH
+
Gonadotroph
Gooonad
G
dootttro
d
+
G
GnRH
+
SMS
Cell proliferation
Linear growth
LGF-1
GH
Somatotroph
+
GHRH
Lactation
+
Prolactin
Lactotroph
+
Dopamine
+
Paturition
Lactation
+
Oxytocin
+
Thirst center
Osmoreceptor
BP
Vomiting
Water balance
ADH
+
FIGURE 1.1 General control of anterior and posterior pituitary function. CRH, corticotrophin releasing hormone; ACTH, adrenocorticotrophin;
TRH, thyrotrophin releasing hormone; SMS, somatostatin; TSH, thyroid stimulating hormone; GnRH, gonadotrophin releasing hormone; FSH,
follicle stimulating hormone; LH, luteinizing hormone; GHRH, growth hormone releasing hormone; GH, growth hormone; IGF-1, insulin-like
growth factor-1; ADH, antidiuretic hormone.
Action
Target
hormone
+
CRH
Corticotroph
p
ph
Tissue Target
Trophic
Hormone
Pituitary
HYPOTHALAMUS
4
Pituitary Essentials
5/1/13 9:35 PM
Pituitary Function
°
°
5
directly on G-protein coupled surface receptors on anterior pituitary
cells (anterior pituitary)
Pituitary-derived growth factors (fibroblast growth factor [FGF],
vascular endothelial growth factor [VEGF], transforming growth
factors [TGFs]) and cytokines (tumor necrosis factor [TNF],
interleukin-6 [IL-6]) act in paracrine and autocrine fashion to
regulate pituitary cell growth and hormone secretion
End-organ derived hormones act primarily in negative feedback
manner to regulate anterior pituitary hormone release (e.g., cortisol
on adrenocorticotropic hormone [ACTH]-producing corticotroph,
insulin-like growth factor-1 [IGF-1] on growth hormone [GH]producing somatotroph)
PITUITARY FUNCTION
• Posterior pituitary hormones
° Oxytocin
■ Role: regulates parturition, lactation, reproductive behavior
■ Control of release: nipple stimulation, birth canal distension
■ Miscellaneous: oxytocin receptor widely expressed in central nervous
system (CNS) and influences reproductive behavior in some species
° Vasopressin
■ Role: regulation of water balance, potent pressor, ACTH secretagogue, coagulation regulator
■ Control of release: osmotic status, blood pressure (BP)/
circulatory volume, nausea and emesis
■ Miscellaneous: osmoreceptors within the brain but in direct
contact with the circulation via local gaps in blood-brain barrier
interact with vasculature baroreceptors and central thirst
mechanisms to regulate water balance
• Anterior pituitary cells and hormones
Somatotrophs
° ■ Hormone: GH
■ Role: linear and organ growth
■ Control of release
• Stimulatory: GHRH and ghrelin
• Inhibitory: somatostatin
■ Miscellaneous
• Somatotrophs make up ~50% of anterior pituitary cells
• Acidophilic cells, mostly located in lateral wings of anterior lobe
° Lactotrophs
■ Hormone: prolactin (PRL)
■ Role: lactation
■ Control of release
• Inhibitory: dopamine (DA)
■ Miscellaneous: only pituitary cell under negative tonic control
48565_ST01_001-046.indd 5
5/1/13 9:35 PM
6
Pituitary Essentials
°
°
°
°
Mammosomatotrophs
■ Hormone: both PRL and GH
■ Role: linear and organ growth and lactation
■ Control of release
• Stimulatory: GHRH
• Inhibitory: somatostatin, DA
■ Miscellaneous
• Indistinguishable from somatotrophs by conventional histology
• Ultrastructural immunocytology demonstrates both GH
(usually intense) and PRL (less prominent) in the same cell,
frequently in same secretory granule
Corticotrophs
■ Hormone: ACTH; also other derivatives of proopiomelanocortin
(POMC) including melanocyte-stimulating hormone, lipotrophic
hormone, and endorphins
■ Role: cell metabolism and homeostasis
■ Control of release
• Stimulatory: CRH
• Inhibitory: cortisol
■ Miscellaneous: basophilic staining
Thyrotrophs
■ Hormone: thyroid-stimulating hormone (TSH)
■ Role: thermogenesis
■ Control of release
• Stimulatory: TRH
• Inhibitory: T4 and T3
Gonadotrophs
■ Hormone: FSH and LH
■ Role: regulate sex steroid synthesis and ovulation/
spermatogenesis
■ Control of release
• Stimulatory: GnRH
• Inhibitory: sex steroids
■ Miscellaneous: follicular stimulating hormone (FSH)/luteinizing
hormone (LH)-expressing gonadotrophs equal in female fetus, LH
gonadotrophs predominate in male fetus
REFERENCES
Anderson E, Haymaker W. Breakthroughs in hypothalamic and pituitary
research. Prog Brain Res, 1974;41:1–60.
Melmed S, ed. The Pituitary. 2nd ed. Malden, MA: Wiley-Blackwell; 2002.
Wass J, Shalet S, eds. The Oxford Textbook of Endocrinology & Diabetes.
New York, NY: Oxford University Press; 2002.
48565_ST01_001-046.indd 6
5/1/13 9:35 PM
2 ■ HYPOPITUITARISM
Theingi Aung, MD and Niki Karavitaki, PhD, FRCP
BACKGROUND
• Clinical syndrome of partial or complete deficiency of anterior and/or
posterior pituitary hormones due to pituitary or hypothalamic disorders
• Incidence 4.2 per 100,000 per year; prevalence 45.5 cases per 100,000
people
PATHOPHYSIOLOGY
Causes of hypopituitarism
• Pituitary/parapituitary tumors
adenoma, craniopharyngioma, meningioma, glioma,
° Pituitary
Rathke’s cleft cyst, chordoma, metastasis (e.g., breast, lung)
• Surgery in the area of the pituitary gland
• Radiotherapy (pituitary, cranial, nasopharyngeal)
• Pituitary infarction/hemorrhage (apoplexy)
• Sheehan’s syndrome (postpartum pituitary necrosis)
• Subarachnoid hemorrhage
• Head trauma/traumatic brain injury
• Empty sella syndrome
• Infiltrative lesions
lymphocytic hypophysitis, hemochromatosis,
° Sarcoidosis,
histiocytosis
• Infection
° Tuberculosis (TB), pituitary abscess, meningitis, encephalitis
• Isolated hypothalamic-releasing hormone deficits
° Kallman’s syndrome
• Genetic causes
° Mutations of genes including HESX-1, LHX3, LHX4, PROP-1, POU1F1
CLINICAL PRESENTATION
• The clinical manifestations of hypopituitarism depend mainly on the
underlying disease, as well as the type and degree of the hormonal
deficits
• Tumors in the sellar region with suprasellar or lateral extension may be
associated with visual deterioration, headaches, and ophthalmoplegia
due to damage to cranial nerves (III, IV, or VI) within the cavernous
sinus
48565_ST01_001-046.indd 7
5/1/13 9:35 PM
8
Hypopituitarism
• Presentation of hypopituitarism varies from subclinical (diagnosed
only following hormonal investigations) to acute onset requiring hospital admission; ACTH, TSH, and antidiuretic hormone (ADH) deficiency
are potentially life-threatening, whereas FSH/LH and GH deficiencies
are associated with chronic morbidity
• In most etiologies, the development of hormone deficiencies follows a
particular pattern with GH and LH/FSH being affected first followed by
TSH and ACTH secretion
TABLE 2.1 Manifestations of Defi cient Hormones
Defi cient Hormone
Manifestations
ACTH
• Weakness, tiredness, weight loss, anorexia, dizziness,
postural hypotension, syncope, nausea, vomiting,
diarrhea
• In contrast to primary adrenal insufficiency, no
hyperpigmentation
• Hypoglycemia, anemia
• Fatigue, lethargy, constipation, menstrual irregularities,
dry skin, hair loss, coarsening of voice, cold intolerance,
weight gain, inability to concentrate, periorbital edema,
prolonged relaxation of deep tendon reflexes, coarse
facial appearance, hypothermia, bradycardia, pallor
• Reduced libido, infertility, menstrual irregularities,
erectile dysfunction, dyspareunia, testicular atrophy
• Decreased muscle mass
• Osteoporosis
• Failure to thrive and short stature in children
• In adults, fatigue, reduced exercise capacity, impaired
psychological well-being, reduced lean body mass,
dyslipidaemia, premature atherosclerosis
• Failure of lactation
• Polyuria, nocturia, polydipsia
• Hypernatraemia
TSH
LH/FSH
GH
PRL
ADH
48565_ST01_001-046.indd 8
5/1/13 9:35 PM
Hormone Replacement 9
DIAGNOSTIC EVALUATION
TABLE 2.2 Hormonal Assessment for Pituitary Hypofunction
Hormone
Defi ciency
Basal Hormone Tests*
Dynamic Testing*
ACTH
8 AM serum cortisol and plasma
ACTH
Cosyntropin stimulation test, insulin
tolerance test, glucagon test, or
metyrapone test
TSH
LH/FSH
Serum TSH, FT4, FT3
Serum LH and FSH with 8 AM
testosterone in males or
estradiol in females
Serum IGF-1
GH
ADH
Paired urine and plasma
osmolality, blood urea, and
electrolytes
Insulin tolerance test, glucagon
test, or GHRH + Arginine test
Water deprivation test
* Results should be interpreted according to the cutoff values of each laboratory.
• Other investigations
investigations to exclude functioning pituitary adenomas
° Hormonal
(e.g., prolactinoma)
MRI or CT to detect anatomical abnormalities
° Pituitary
(e.g., tumors)
■ Biopsy of lesion sometimes needed for definitive diagnosis
HORMONE REPLACEMENT
• See also chapters on individual hormone deficiency syndromes
• For ACTH deficiency
any acute medical emergency, immediate hydrocortisone
° In
(HC; 100 mg intramuscularly [IM] or intravenously [IV])
with HC 20 mg daily in divided doses or prednisone
° Replacement
5 mg daily: recommendation includes replacement with the smallest possible dose of HC that is acceptable to patient and compatible with normal vitality to avoid overreplacement
adjustment (two- to threefold) during moderate illness
° Dose
(e.g., fever >37.5°C)
HC
injections
if major stress (e.g., major surgery)
° Patients shouldsystematically
have a medical alert bracelet and medical
° identification card
of replacement assessed by checking for manifestations
° Adequacy
of steroid deficiency or excess
48565_ST01_001-046.indd 9
5/1/13 9:35 PM
10 Hypopituitarism
• For TSH deficiency
with levothyroxine (LT4; mean dose 1.6 mcg/Kg of
° Replacement
body weight)
Exclude
and
treat
concomitant ACTH deficiency before starting
° thyroxine (T4) replacement
to avoid adrenal crisis
free T4 (FT4) levels in the upper half of the reference range;
° Target
TSH levels not useful marker of replacement
• For FSH/LH deficiency
testosterone replacement
° Males:
■ Multiple forms: targets for serum testosterone depend on the
preparation
■ Main contraindication = prostate cancer
■ Do not start therapy in patients with palpable prostate nodule
or induration, haematocrit >50%, untreated severe obstructive
sleep apnea, severe lower urinary tract symptoms, or uncontrolled heart failure, or in those desiring fertility
■ Monitor hematocrit, prostate specifi c antigen (PSA), and digital
rectal exam
■ Alternatively, gonadotropin therapy is required for fertility
Females:
replacement therapy in premenopausal women
° ■ Multiplehormonal
options
■ Absolute contraindications: vaginal bleeding of unclear etiology,
active thromboembolism, active endometrial cancer, breast
cancer
■ Relative contraindications: history of endometrial cancer, family
or past history of thromboembolism, ischemic heart disease,
cerebrovascular disease, active liver disease, dyslipidemia
■ Alternatively, gonadotropin therapy is required for fertility
• For GH deficiency
start with low dose of 150−300 mcg/day and titrate according
° Adults:
to clinical response; side effects and IGF-I levels: maximum dose
1 mg daily
active malignancy, benign intracranial
° Contraindications:
hypertension, preproliferative/proliferative retinopathy
effects: headaches, benign intracranial hypertension,
° Adverse
carpal tunnel syndrome, arthralgia, myalgia, insulin resistance,
hyperglycemia
• For ADH deficiency (diabetes insipidus)
oral (0.3−1.2 mg/day) or intranasal (10−40 mcg/day)
° Desmopressin
divided in 1−4 doses
Monitor
for
polyuria/polydipsia
and serum sodium, urine and
° plasma osmolalities
48565_ST01_001-046.indd 10
5/1/13 9:35 PM
References
11
REFERENCES
Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with
androgen deficiency syndromes: an Endocrine Society clinical practice
guideline. J Clin Endocrinol Metab, 2010;95(6):2536−59.
Grossman AB. Clinical review: the diagnosis and management of central
hypoadrenalism. J Clin Endocrinol Metab 2010;95(11):4855−63.
Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML; Endocrine
Society. Evaluation and treatment of adult growth hormone deficiency:
an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab,
2011;96(6):1587−609.
Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, Stalla GK, Ghigo E.
Hypopituitarism. Lancet, 2007;369(9571):1461−70.
48565_ST01_001-046.indd 11
5/1/13 9:35 PM
48565_ST01_001-046.indd 12
5/1/13 9:35 PM
3 ■ PROLACTINEMIA AND PROLACTINOMA
Mark E. Molitch, MD
PATHOPHYSIOLOGY OF HYPERPROLACTINEMIA AND PROLACTINOMAS
• Inhibition of PRL secretion by DA predominates over hypothalamic stimulation; PRL levels rise when there is interference with this inhibition
of DA receptors by drugs (neuroleptics, atypical antipsy° Blockade
chotics, metoclopramide, verapamil, methyldopa)
° Lesions interrupting hypothalamic or portal vessel DA pathways
• Stimulation of afferent pathways from breast to hypothalamus result
in increased PRL
stimulation (sexual, nipple rings)
° Nipple
° Chest wall irritation (burns, trauma, cancer)
• Other causes: hypothyroidism (due to TRH stimulation of PRL release),
renal insufficiency
• Prolactinomas: benign neoplasms (very rarely malignant) of pituitary
lactotrophs
sporadic and rarely familial
° Usually
<10 mm; PRL levels usually <100 ng/ml, rarely
° Microadenomas:
cause hypopituitarism
≥10 mm; can be very large with very high PRL levels
° Macroadenomas:
■ Can cause mass effects
■ Can be locally invasive of surrounding bone, brain
• Other pituitary adenomas co-secreting PRL: GH- and ACTH-secreting
adenomas
• Idiopathic
CLINICAL PRESENTATION
• Pathophysiology: hyperprolactinemia suppresses hypothalamic GnRH
pulsatile secretion, causing hypogonadotropic hypogonadism
TABLE 3.1 Symptoms Due to Hyperprolactinemia
Women
Amenorrhea
Galactorrhea
Infertility
Decreased libido
Osteopenia
48565_ST01_001-046.indd 13
Men
Erectile dysfunction
Galactorrhea (rare)
Infertility
Decreased libido
Osteopenia
5/1/13 9:35 PM
14
Prolactinemia and Prolactinoma
• Symptoms due to mass effects
field defects if tumor compresses optic chiasm
° Visual
if tumor invades cavernous sinus
° Ophthalmoplegias
Hypopituitarism
if tumor compresses other pituitary cells or stalk
° Headaches
°
• Physical examination
fields defects by confrontation
° Visual
° Galactorrhea
Signs
of
(decreased hair, muscle bulk)
° Testicularhypogonadism
atrophy
° Other evidence
of hypopituitarism (see Chapter 2, Hypopituitarism)
°
DIAGNOSTIC EVALUATION
• PRL levels
caused by drugs and other nonprolactinoma causes, usually
° If<150
ng/mL
levels usually <200 ng/mL
° Microprolactinomas:
Macroprolactinomas:
levels usually >200 ng/mL; can be
° >20,000 ng/mL
■ PRL level generally proportional to tumor size
■ Special caution: in some two-site PRL assays, patients with
very large prolactinomas and very high PRL levels may appear to
have PRL levels that are normal or only modestly elevated, thus
mimicking a large, nonfunctioning adenoma due to saturation of
the assay antibodies
• PRL levels should always be remeasured at 1:100 dilution
PRL
elevations may be due to macroprolactin, which is a
° high mild
molecular weight PRL aggregate with immunoglobulins with
diminished biologic potency
■ Macroprolactinemia usually found in patients with equivocal
symptoms
■ Detect by precipitating complex with polyethylene glycol
• If PRL levels in supernatant >70% of the upper limit of normal
for assay, patient can be assumed to have true hyperprolactinemia and not an elevation due simply to macroprolactin
■ When PRL elevation due to macroprolactin alone, no treatment
necessary
• Imaging
If
no
obvious cause by history and exam, then image with MRI with
° contrast
° CT with direct coronal cuts gives less detail
• Visual fields
° If tumor abuts optic chiasm, do formal visual field testing
48565_ST01_001-046.indd 14
5/1/13 9:35 PM
Treatment 15
TREATMENT
• Observation
has microadenoma or idiopathic hyperprolactinemia
° Ifandpatient
presents with nonbothersome galactorrhea and has normal
estrogen/testosterone levels, he/she can simply be followed with
periodic PRL levels
patients with amenorrhea but not interested in fertility may
° Similar
be treated with estrogen replacement
• DA agonists
agonists normalize PRL levels, correct amenorrhea-galactorrhea,
° DA
and decrease tumor size by more than 50% in 80−90% of patients
Cabergoline
° bromocriptinemore efficacious and better tolerated than
use cabergoline even if visual field defects, as long as visual
° Can
acuity is not threatened by rapid progression or recent tumor
hemorrhage
of patients whose PRL levels normalize and tumors
° 40−50%
shrink can eventually be tapered off cabergoline without tumor
reexpansion
50% of patients resistant to bromocriptine will respond to
° About
cabergoline
15−20% of prolactinomas are resistant to cabergoline
° About
■ Important to ensure compliance and to be certain that the
underlying lesion is a prolactinoma and not some other cause
of hyperprolactinemia
■ Most patients resistant to standard doses of cabergoline
respond to larger doses
• Doses >3 mg/day may be associated with cardiac valvular
abnormalities
• Echocardiographic monitoring should be used in patients
taking >2 mg/week
• Transsphenoidal surgery
Initial
remission rates 70−80% for microprolactinomas and
° 25−40%
for macroadenomas
recurrence rates of 20%
° Long-term
Complications
of hypopituitarism, infections, and bleeding are
° minimal, but increase
proportionately with tumor size
for large tumors rarely curative and much higher
° Craniotomy
complication rates
• Radiation therapy (RT), usually stereotactic, reserved for patients with
macroadenomas not responding to either medical or surgical treatment
often causes hypopituitarism, developing gradually
° Irradiation
over years
48565_ST01_001-046.indd 15
5/1/13 9:35 PM
16 Prolactinemia and Prolactinoma
FOLLOW-UP
• Goals of treatment
PRL levels or at least bring them to levels at which
° Normalize
gonadal/reproductive/sexual function is normalized
Decrease
tumor
size
°
• Once PRL levels reach normal or near-normal, levels can be monitored
every 3−6 months for first year and then every 6−12 months thereafter
• Tumor size monitored by MRI
once maximal size reduction documented, further
° Macroadenomas:
scans may not be necessary as long as PRL levels are being monitored
necessity of second MRI scan is debatable if PRL
° Microadenomas:
levels are monitored
Extremely
rare
for
to increase in size without there being a
° significant increasea tumor
in PRL levels
field abnormalities should be repeated until normal or stable
° Visual
and then do not need to be repeated
PREGNANCY
• DA agonists needed for ovulation and stopped once pregnancy is
diagnosed
such fetal exposure, there are no risks for fetal malformations
° With
or other adverse pregnancy outcomes
■ Safety database for bromocriptine is eightfold larger than that
for cabergoline
° DA agonists are then reinstituted when breastfeeding is completed
• Symptomatic growth occurs in 23% of macroprolactinomas and 3%
of microprolactinomas in second or third trimester due to stimulatory
effect of high estrogen levels of pregnancy and withdrawal of the DA
agonist
field testing each trimester with macroadenomas but only if
° Visual
symptomatic with microadenomas
resonance imaging (MRI) scans (without gadolinium)
° Magnetic
if visual field defects or severe headaches when a therapeutic
intervention is contemplated
evidence of significant symptoms and tumor growth, patient
° When
should be restarted on a DA agonist
■ Transsphenoidal surgical decompression can be done if there is
an unsatisfactory response to the DA agonist
■ Delivery of the baby can be done if the pregnancy is suffi ciently
advanced
levels may rise during pregnancy when there is no tumor size
° PRL
change and some tumors enlarge without an associated rise in
PRL; therefore, measurement of PRL during pregnancy should not
be carried out
48565_ST01_001-046.indd 16
5/1/13 9:35 PM
References
17
REFERENCES
Casanueva FF, Molitch ME, Schlechte JA, et al. Guidelines of the Pituitary
Society for the diagnosis and management of prolactinomas. Clin
Endocrinol (Oxf), 2006;65(2):265−73.
Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of
hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin
Endocrinol Metab, 2011;96(2):273−88.
Storgaard H, Jensen CB, Vaag AA, Vølund A, Madsbad S. Insulin secretion after short- and long-term low-grade free fatty acid infusion in
men with increased risk of developing type 2 diabetes. Metabolism,
2003;52(7):885−94.
48565_ST01_001-046.indd 17
5/1/13 9:35 PM
48565_ST01_001-046.indd 18
5/1/13 9:35 PM
4 ■ ACROMEGALY
Laurence Katznelson, MD
PATHOPHYSIOLOGY
• Normal
is secreted in pulses by the pituitary gland, mostly during night
° GH
stimulates and somatostatin inhibits GH secretion
° GHRH
stimulates hepatic production of IGF-1
° GH
° Both GH and IGF-1 have metabolic and growth properties
• In acromegaly
producing somatotroph pituitary tumor is the cause in most cases
° GH
a macroadenoma (greater than 1 cm)
° Usually
cases of ectopic GHRH or GH production by neuroendocrine
° Rare
tumors
tumors usually sporadic with rare familial cases, such as
° Pituitary
multiple endocrine neoplasia type 1 (MEN-1)
GH causes liver to overproduce IGF-1
° Excess
GH and IGF-1 cause metabolic disturbances and somatic
° Excess
growth
CLINICAL PRESENTATION
• History and examination
features are due to high serum levels of GH and IGF-1
° Clinical
effects of GH and IGF-1 include insulin antagonism
° Metabolic
and lipolysis
can cause local mass effects including loss of
° Macroadenomas
peripheral vision through optic chiasmal compression, ophthalmoplegia through cavernous sinus involvement, and hypopituitarism through compression of the normal pituitary gland
usually present for 6−12 years prior to diagnosis
° Disease
■ The disease is insidious, and patients rarely present with
complaint of somatic overgrowth
■ In women, the disease is often considered during an evaluation
for oligo/amenorrhea
■ In men, the disease is often considered during evaluation of
headache
48565_ST01_001-046.indd 19
5/1/13 9:35 PM
20
Acromegaly
°
°
Signs and symptoms
■ Headache, excess sweating, joint aches (diffuse), fatigue
■ Somatic overgrowth: large hands (history of rings that need to be
cut), enlarged feet (increasing shoe size), carpal tunnel syndrome
■ Sleep apnea syndrome
■ Glucose intolerance, frank diabetes mellitus type 2
■ Hypertension
■ Hypertrophic cardiomyopathy
• Diastolic and systolic dysfunction in early disease
• Congestive, dilated cardiomyopathy with advanced disease
■ Hypopituitarism: hypothyroidism, adrenal insuffi ciency (AI),
hypogonadism (oligo/amenorrhea in premenopausal women,
sexual dysfunction with testosterone deficiency in men)
Physical exam
■ Vital signs reveal hypertension
■ Deep “acromegalic” voice
■ Thickening of skin
■ Enlargement of hands and feet (thickening of hand volume and
heel pad)
■ Head with frontal bossing (protruding frontal bones), coarse
features (thickened facial skin), furrowing of brow skin
■ Prognathism (enlarged and widened jaw), jaw malocclusion and
overbite, macroglossia
■ Nodular thyroid goiter
■ Skin tags, especially about neck
■ Gynecomastia in men, galactorrhea in women
■ Testicular atrophy
■ Neurologic exam: ophthalmopathy, visual field defects (temporal),
Tinel’s sign for carpal tunnel syndrome, radiculopathy
DIAGNOSTIC EVALUATION
• Laboratory testing performed in a patient with clinical suspicion of
disease
• Biochemical testing to determine GH and IGF-1 hypersecretion
• Specific testing
levels
° IGF-1
■ Random IGF-1 level is single best test: elevated in acromegaly
■ IGF-1 is an integrated marker of GH secretion
■ IGF-1 levels do not vary with food intake, time of day, or exercise
■ IGF-1 levels are normalized for age and gender
levels
° GH
■ Measurement of GH useful in situations with equivocal serum
IGF-1 levels
■ GH secretion affected by food, exercise, stress, and sleep, and
may be elevated with uncontrolled diabetes mellitus and liver
disease
48565_ST01_001-046.indd 20
5/1/13 9:35 PM
Management 21
Random GH levels are not generally useful for diagnosis, unless
very high, and are usually not relied upon for biochemical
confirmation
■ Oral glucose tolerance test (OGTT): normal GH less than 1 ng/ml
■ For OGTT, 75 g of glucose, then GH measured q 30 min for
2 hours, but other protocols include measurements at 1 and
2 hours only
Additional laboratory testing
■ PRL (commonly co-secreted)
■ Assessment of hypopituitarism (FT4 for hypothyroidism, cortisol
evaluation for AI, serum testosterone in men for gonadal
function)
Imaging
■ Imaging used to determine source of GH hypersecretion
■ MRI scan is the most sensitive test for identifying a pituitary
adenoma
■ The tumor is a macroadenoma (>1 cm) in at least 75% of cases
■ Imaging can determine tumor extension, including presence of
extrasellar involvement, such as in the cavernous sinus
■ If there is suprasellar extension and tumor touches or compresses the optic chiasm, then visual field testing should be
performed
■ If the MRI scan is normal, there may still be a microadenoma
(<1 cm) in the pituitary gland, but need to consider ectopic
secretion of GHRH or GH by a neuroendocrine tumor
• Perform abdominal and chest imaging
• Consider octreoscan to search for ectopic neuroendocrine
tumor
■
°
°
MANAGEMENT
• Goals: normalize biochemical GH and IGF-1 levels, improve medical
comorbidities, improve signs and symptoms, reduce tumor burden,
prevent premature mortality
• Surgery is primary mode of therapy and can rapidly normalize GH
levels, reduce tumor bulk, and reverse local mass effects
• Medical and RT used in an adjuvant role for patients with residual
disease following surgery
• Primary medical therapy in lieu of surgery may be used in a patient
with a tumor that may not be cured with surgery (i.e., cavernous sinus
involvement) and without chiasmal effects
• Surgery
approach most common
° Transsphenoidal
■ Surgery with endoscopy frequently performed
■ Craniotomy indicated in patients with tumors that have extensive
extrasellar involvement that cannot be resected via the transsphenoidal approach
48565_ST01_001-046.indd 21
5/1/13 9:35 PM
22
Acromegaly
°
Rapidity to perform surgery depends on degree of clinical signs and
symptoms, and presence of local mass effects
is unclear whether preoperative medical therapy may be useful to
° Itimprove
surgical outcome for macroadenomas
Preoperative
therapy may be indicated to improve medical
° comorbidities,medical
such as sleep apnea syndrome, prior to surgery
surgery, measure day 1 postoperative fasting serum
° Following
GH level
■ If less than 1 ng/ml postop in a patient with elevated level
preop, then surgery may have been successful
■ Repeat IGF-1 level 8−12 weeks following surgery to gauge
success
■ Repeat OGTT may be useful at 8−12 weeks if the IGF-1 is
borderline
• Medical therapy
Usually
used in an adjuvant role following incomplete surgery
° Three types
medications: Somatostatin analogues, DA agonists,
° GH receptor ofantagonist
■ Somatostatin analogues most commonly used given excellent
response in majority of subjects
■ GH receptor antagonist usually recommended in patients with
incomplete response to somatostatin analogue
■ DA agonists may be used in patients with modest disease and in
situations in which cost is a limiting factor
■ Can be used alone or in combination
analogues
° Somatostatin
■ Octreotide LAR (long-acting release) and lanreotide autogel:
similar efficacy and side effect profiles
■ Normalizes IGF-1 in approximately 55% of patients
■ Doses based on serum IGF-1 levels drawn after 60−90 days
■ Octreotide LAR (10, 20, 30 mg) administered as monthly IM
injections, usually starting at 20 mg monthly
• A two-week trial of short acting SQ octreotide at 50−100 mcg
TID is recommended to assess tolerance, but most clinicians
offer 1−2 doses only of short-acting octreotide prior to LAR dose
■ Lanreotide autogel (60, 90, and 120 mg) administered as
monthly deep SQ injection at doses usually starting at 90 mg
■ Side effects: GI upset with diarrhea, gallstones, bradycardia,
fatigue, hair loss, hyperglycemia
DA
agonists (bromocriptine, cabergoline)
° ■ Oral
administration, and less expensive than other medical
therapies
■ Cabergoline better tolerated and better effi cacy than bromocriptine with normal IGF-1 achieved in up to 40%
■ Dose titrated to normalize IGF-1 levels
■ Side effects: GI upset, dizziness, stuffy nose, headache
48565_ST01_001-046.indd 22
5/1/13 9:35 PM
Management
°
°
23
GH receptor antagonist (pegvisomant)
■ Blocks GH at its receptor without effect at the primary tumor
■ Normalizes IGF-1 value in >90% of cases
■ GH should not be measured on pegvisomant as level will
increase
■ Administered as daily (10, 15, 20 mg) or weekly SQ injections
and titrated to normalize IGF-1 levels
■ Side effects: abnormal liver function tests (LFTs), flulike
syndrome, local skin reactions, local lipohypertrophy
■ Tumor growth uncommon
Combination therapy
■ Addition of DA agonist or pegvisomant to somatostatin analogue
can be considered in patients with incomplete response (i.e.,
elevated IGF-1 levels, tumor growth)
• RT
°
Adjuvant role after incomplete surgery and/or incomplete medical
therapy response
fractionated versus stereotactic radiosurgery (SRS)
° Conventional
gamma knife, CyberKnife, or proton beam radiation; SRS indicated
if there is minimum distance between tumor and optic chiasm
take up to 5−10 years for efficacy
° May
therapy indicated until IGF-1 normalizes
° Medical
normalize IGF-1 in approximately half of patients without need
° May
for medical therapy
effects include hypopituitarism, risk of secondary neoplasm,
° Side
cerebrovascular atherosclerosis
• Management of medical comorbidities
surveillance and management of type 2 diabetes
° Aggressive
mellitus (type 2 DM), hypertension, hyperlipidemia
to assess for colon polyps and malignancy
° Colonoscopy
study to detect sleep apnea syndrome
° Sleep
Consider
corrective
jaw surgery once GH/IGF-1 levels normalized
°
TABLE 4.1 Testing for Acromegaly
Test
IGF-1
OGTT (75 g)
MRI scan to evaluate for pituitary
adenoma
Visual field testing if adenoma
compresses optic chiasm
48565_ST01_001-046.indd 23
Comments
Elevated level consistent with disease
Trough GH >1 ng/ml is abnormal
5/1/13 9:35 PM
24
Acromegaly
TABLE 4.2 Medical Therapy Options
Class
Somatostatin
analogs
Dopamine
agonists
GH receptor
antagonist
Name
Route
Octreotide LAR Intramuscular
Effi cacy
55%
Lanreotide
autogel
Cabergoline
Deep
subcutaneous
Oral
55%
Bromocriptine
Pegvisomant
Oral
Subcutaneous
8%
>90%
39%
Side Effects
GI upset/diarrhea,
gallstones,
hyperglycemia,
bradycardia,
hair loss
GI upset,
headache,
dizziness, nasal
stuffiness
Abnormal
LFTs, flulike
symptoms,
local skin
reactions, and
lipohypertrophy
REFERENCES
Bevan JS. Clinical review: The antitumoral effects of somatostatin analog
therapy in acromegaly. J Clin Endocrinol Metab, 2005;90(3):1856–63.
Giustina A, Chanson P, Bronstein MD, et al. A consensus on criteria for cure
of acromegaly. J Clin Endocrinol Metab, 2010;95(7):3141−8.
Katznelson L, Atkinson JL, Cook DM, et al. American Association of Clinical
Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis
and Treatment of Acromegaly—2011 update: executive summary. Endocr
Pract, 2011;17(4):636−46.
Melmed S, Colao A, Barkan A, et al. Guidelines for acromegaly management:
an update. J Clin Endocrinol Metab, 2009;94(5):1509−17.
48565_ST01_001-046.indd 24
5/1/13 9:35 PM
5 ■ GROWTH HORMONE DEFICIENCY IN ADULTS
Kevin C.J. Yuen, MD
PATHOPHYSIOLOGY
• Growth hormone deficiency (GHD) in adults affects 1−3/10,000 people
annually
• As GH levels decline with aging, important to distinguish between
age-related physiological decline in GH levels and pathological GH
deficiency that usually has an identifiable cause
• Causes of GHD in adults
lesions in the pituitary and hypothalamus: benign (e.g.,
° Mass
pituitary adenomas, craniopharyngiomas, cysts) and malignant
(e.g., metastases from breast, lung) tumors
of hypothalamic and pituitary lesions (e.g., surgery and/
° Treatment
or irradiation)
ltrative diseases (e.g., lymphocytic hypophysitis, sarcoidosis,
° Infi
histiocytosis)
Head
trauma/vascular injury (e.g., subarachnoid hemorrhage,
° Sheehan
syndrome)
(e.g., hemorrhage into the pituitary gland)
° Apoplexy
diseases (e.g., PIT-1, PROP-1, LHX3/4, HESX-1, PITX-2
° Genetic
mutations)
(meningitis, encephalitis, tuberculous meningitis)
° Infections
(e.g., childhood-onset GHD that persists in adulthood
° Idiopathic
without structural pituitary lesion and no other pituitary hormone
deficiencies)
CLINICAL PRESENTATION
• History: inquire about history of hypothalamic-pituitary disease,
cranial irradiation, childhood-onset GHD, head trauma, CNS infections,
underlying autoimmune endocrine disease that may affect the pituitary
gland, and unexplained osteopenia
48565_ST01_001-046.indd 25
5/1/13 9:35 PM
26
Growth Hormone Defi ciency in Adults
• Physical exam: as the symptoms of GHD are nonspecific, physical
examination is usually unrevealing
TABLE 5.1 Signs, Symptoms, and Clinical Features of AGHD
Symptoms
• Increased body fat
• Reduced muscle bulk,
muscle strength, and
physical fitness
• Impaired psychological
well-being
mood,
° Depressed
reduced energy,
reduced vitality,
reduced physical
stamina, poor
motivation, and
increased social
isolation
Signs
Clinical Features
• Overweight, with
predominantly central
obesity
• Poor muscular
development
• Reduced exercise
performance
• Thin, dry skin
• Depressed affect
• Peak GH response to
hypoglycemia <3 μg/L
• Low or low normal (<0
IGF-I SDS) serum IGF-I
levels
• Hyperlipidemia (↑ LDL
cholesterol and ↓ HDL
cholesterol)
• Reduced lean body
mass/increased fat
mass
• Increased fasting insulin
levels
• Reduced bone mineral
density
LABORATORY EVALUATION
• Serum IGF-I levels ≤2 standard deviations (SDS) is suggestive of GHD,
and a provocative test is required to confirm the diagnosis
48565_ST01_001-046.indd 26
5/1/13 9:35 PM
Laboratory Evaluation
27
TABLE 5.2 Diagnosis of AGHD Based on Recommendations From Various
Consensus Guidelines
GH Research
Society 2007
Number of
• None if ≥3
Tests to
pituitary
Establish
hormone
Diagnosis
deficiencies and
low IGF-I
• 1 test in
adults with
hypothalamicpituitary disease
and ≥1 pituitary
hormone
deficiency
• 2 tests in adults
with idiopathic
GHD
• 1 test in
reconfirmation of
COGHD
Test of Choice ITT
Alternative
• GHRH and
Test (in
arginine
order of
• Glucagon
preference)
GH Cutoff
• ITT <5 ng/ml
Levels
• GHRH and
arginine
– BMI <25,
<11 ng/ml
– BMI 25–30,
<8 ng/ml
– BMI ≥25,
<4 ng/ml
• Glucagon
<3 ng/ml
American Association
of Clinical Endocrinologists 2009
• None if ≥3
pituitary hormone
deficiencies and
low IGF-I
• 1 test in adults with
hypothalamicpituitary disease
• 1 test in
reconfirmation of
COGHD ≥1 month
after stopping GH
ITT
• GHRH and arginine
• Glucagon
• Arginine
Endocrine Society
2011
• None if ≥3
pituitary hormone
deficiencies and
low IGF-I
• 1 test in adults
with hypothalamicpituitary disease
and ≥1 pituitary
hormone deficiency
• 2 tests in adults
with idiopathic
GHD
• 1 test in
reconfirmation of
COGHD ≥1 month
after stopping GH
ITT
• GHRH and arginine
• Glucagon
• ITT <5 ng/ml
• ITT <5 ng/ml
• GHRH and arginine • GHRH and arginine
– BMI <25,
– BMI <25,
<11 ng/ml
<11 ng/ml
– BMI 25–30,
– BMI 25–30,
<8 ng/ml
<8 ng/ml
– BMI ≥25,
– BMI ≥25,
<4 ng/ml
<4 ng/ml
• Glucagon <3 ng/ml • Glucagon <3 ng/ml
• Arginine <0.4 ng/ml
• The insulin tolerance test (ITT) is the gold standard test but contraindicated in elderly patients and in patients with a history of coronary
artery disease (CAD), cerebrovascular disease, or seizure disorders
• Alternative tests include GHRH and arginine (currently GHRH analogue
is unavailable in the United States), glucagon, or arginine alone
48565_ST01_001-046.indd 27
5/1/13 9:35 PM
28
Growth Hormone Defi ciency in Adults
TABLE 5.3 Provocative Dynamic Tests for GH Secretion in Adults
Test
ITT
GHRH and
arginine
Glucagon
Arginine
48565_ST01_001-046.indd 28
Timing of
samples
Administration (min)
Advantages
Disadvantages
0.05−0.15 U/
0, 15, 30, 60, Gold standard Caution in patients
kg IV; glucose
75, 90, 120;
test, able
with previous head
levels must fall alternatively to test HPA
injury, patients aged
<40 mg/dl
at 0, 30, 45, axis in
>60 yr, patients
60, 90
addition to
with hypoglycemic
GH secretion symptoms, and
patient discomfort;
contraindicated
in patients with a
history of coronary
artery disease,
cerebrovascular
disease, or seizure
disorders
GHRH 1 μg/
0, 15, 30, 60 Safer than
GHRH not widely
kg IV at time
(up to 90);
the ITT with
available, may
0 followed by
alternatively validated
cause facial
arginine
at 0, 30, 60, cutpoints
flushing or metallic
0.5 mg/kg IV
90, 120
based
taste; arginine
over 30 mins
on BMI,
contraindicated in
(max 30 g)
applicable
liver or renal disease
to wider
patient
population
1 mg IV for
0, 30, 60,
Safer than
Less effective GH
body weight
90, 120,
ITT with
stimulant, less
<90 kg and
150, 180;
validated
discriminatory than
1.5 mg IV for
alternatively cutpoints,
the ITT, high rate of
body weight
at 0, 90,
applicable to nausea and vomiting
≥90 kg
120, 150,
wider patient
180, 210,
population
240
0.5 mg/kg IV
0, 15, 30,
Safer
Least established test,
>30 mins
45, 60;
than ITT,
less discriminatory
(max 30 g)
alternatively applicable
than the ITT,
at 0, 30, 60, to wider
contraindicated in
90, 120
patient
liver or renal disease
population
5/1/13 9:35 PM
Management 29
IMAGING
• MRI of the hypothalamic-pituitary area is recommended for all
patients once biochemical evidence of GHD is confirmed
MANAGEMENT
• Goals of GH replacement therapy
GH to restore serum IGF-I levels in the upper half of the
° Replace
reference range
abnormalities associated with GHD
° Correct
■ Improve body composition (↓ fat mass, ↑ lean body mass)
■ Improve metabolism (lipid profile, insulin sensitivity)
■ Improve muscle function and exercise tolerance
■ Improve bone mineral density (BMD)
■ Improve quality of life
• Contraindications to GH replacement therapy: active malignancy,
benign intracranial hypertension, proliferative diabetic retinopathy
TABLE 5.4 Recommendations for GH Replacement Therapy in AGHD
Starting dose:
• Age <30 yrs: 0.4−0.5 mg/day (may be higher for pediatric transition patients)
• Age 30−60 years: 0.2−0.3 mg/day
• Age >60 years: 0.1−0.2 mg/day
Use lower GH doses (0.1−0.2 mg/day) in patients with glucose intolerance
Dose titration: At one- to two-month intervals, increase dose in increments of
0.1−0.2 mg/day based on clinical response, serum IGF-I levels, side effects, and
individual considerations such as glucose intolerance; aim for serum IGF-I levels
≥0 to +2 SDS unless side effects are significant
Monitoring: At six-month intervals once maintenance doses are achieved. Monitoring
should include clinical evaluation, anthropometric measurements, assessment of
side effects, and measurement of serum IGF-I and fasting glucose levels. Lipid profile
should be measured every 12 months, quality of life measurements every 6−12 months.
If the initial bone DEXA scan is abnormal, repeat at two-year intervals. If pituitary
microadenomas or postsurgery residual pituitary tumor is still present, periodic
MRIs should be undertaken. Higher GH doses are required in women on oral, but not
transdermal, estrogens. Patients on concurrent cortisol and thyroid hormone replacement
may need dose adjustments after starting GH replacement therapy.
Length of GH therapy: The appropriate length of GH therapy is unclear; if benefits are
achieved, treatment should continue; if no apparent or objective benefi ts of treatment
are achieved after at least 2 years, discontinuing GH therapy may be considered
48565_ST01_001-046.indd 29
5/1/13 9:35 PM
30
Growth Hormone Defi ciency in Adults
• Adverse effects tend to be dose-dependent and transient
adverse effects are fluid retention and arthralgia
° Common
reductions are usually required
° Dose
Initiating
GH replacement therapy at low doses and slowly titrating
° the dose upwards
may prevent these events
Transition from pediatric to adult care
• Patients with childhood structural hypothalamic-pituitary damage
(e.g., craniopharyngioma), three or more pituitary hormone deficiencies, or genetic defects do not require additional GH stimulation
testing as they enter into adulthood
these patients, GH replacement can be continued but lower adult
° In
GH doses should be employed titrated based on serum IGF-I levels
• Patients with isolated idiopathic GHD should be retested with two
tests (e.g., ITT and glucagon test)
to retest patients ≥1 month after stopping GH at the time
° Important
of linear growth completion
Patients
who
remain GH-deficient in adulthood should be consid° ered for resumption
of GH replacement therapy
■ Initiation and maintenance GH doses in these patients are
usually greater than those used in typical GHD in adults, and
should not be based on weight or body surface area but on
serum IGF-I levels
REFERENCES
Cook DM, Yuen KC, Biller BM, Kemp SF, Vance ML; American Association
of Clinical Endocrinologists. American Association of Clinical
Endocrinologists medical guidelines for clinical practice for growth
hormone use in growth hormone-deficient adults and transition patients–
2009 update. Endocr Pract, 2009;15(Suppl 2):1−29.
Ho KK; 2007 GH Deficiency Consensus Workshop Participants. Consensus
guidelines for the diagnosis and treatment of adults with GH deficiency II:
a statement of the GH Research Society in association with the European
Society for Pediatric Endocrinology, Lawson Wilkins Society, European
Society of Endocrinology, Japan Endocrine Society, and Endocrine Society
of Australia. Eur J Endocrinol, 2007;157(6):695−700.
Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML; Endocrine
Society. Evaluation and treatment of adult growth hormone deficiency:
an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab,
2011;96(6):1587−609.
48565_ST01_001-046.indd 30
5/1/13 9:35 PM
6 ■ PITUITARY INCIDENTALOMAS,
NONFUNCTIONING PITUITARY
ADENOMAS, AND CRANIOPHARYNGIOMAS
Geetha Bhat, MD and Marc J. Laufgraben, MD
PITUITARY INCIDENTALOMAS
Background
• Definition
pituitary incidentaloma (PI) is a lesion in the pituitary gland
° Athat
is discovered on an imaging study performed for an unrelated
indication, in a patient without overt signs and symptoms of
pituitary disease
are <1 cm
° Microincidentalomas
Macroincidentalomas are ≥1 cm
°
• Prevalence
of PI at autopsy is ~10%
° Prevalence
of PI on MRI varies but is likely similar to autopsy
° Prevalence
all PI are <1 cm
° Nearly
■ Lesions ≥1 cm typically present clinically rather than incidentally
• Differential diagnosis
are pituitary adenomas
° ~90%
■ Vast majority are nonfunctional
■ Of functional tumors, prolactinomas and GH-secreting adenomas
are most common
are craniopharyngioma or Rathke’s cleft cysts
° ~9%
various disorders including aneurysm, metastatases, inflam° ~1%:
matory or infiltrative diseases, pituitary hyperplasia, germ cell
tumors, meningioma
Evaluation
• Although PIs are by definition discovered during an imaging study for
an unrelated indication, all patients with PI should undergo a careful
history and physical exam with attention to signs and symptoms
of pituitary hyperfunction, pituitary hypofunction, and neurologic
symptoms related to mass effect
• All patients with PI diagnosed by CT should undergo gadoliniumenhanced MRI with fine cuts of the sella unless contraindicated
48565_ST01_001-046.indd 31
5/1/13 9:35 PM
32 Pituitary Incidentalomas, Nonfunctioning Pituitary Adenomas
• Visual field testing is recommended for all patients with PI that
compress, abut, or approach the optic chiasm
• Screening for hyperfunction
level should be measured in all patients
° PRL
■ In patients with macroincidentalomas, PRL <200 may be due to
stalk compression rather than a PRL-secreting tumor
■ For large (>3 cm) macroadenomas, perform 1:100 dilution of
sample to exclude “hook effect”
should be measured in all patients
° IGF-1
■ Acromegaly may be clinically subtle and early diagnosis and
treatment may improve patient outcomes
for Cushing’s syndrome or other pituitary hyperfunction
° Screening
if clinically indicated
• Screening for hypopituitarism
routinely for all patients with macroincidentalomas
° Recommended
■ Some experts also recommend routine testing for large
(6−9 mm) microincidentalomas
■ Microincidentalomas ≤5 mm are very unlikely to cause
hypopituitarism, though testing is indicated if there is clinical
suspicion
Typical
testing includes AM cortisol, TSH and FT4, and IGF-1
° Testosterone
° symptoms may be measured in men, especially those with sexual
premenopausal women, an abnormal menstrual history provides
° In
evidence of gonadal dysfunction; in postmenopausal woman, low LH
and FSH indicate gonadotroph dysfunction, though this information
is not likely to alter management
Management
• For patients with hormonal hypersecretion
DA agonist therapy (see Chapter 3, Prolactinemia
° Prolactinomas:
and Prolactinoma)
For
other
hormone-secreting
tumors: neurosurgical resection
°
• For patients with hormonally inactive tumors
pituitary adenomas: see next section
° Nonfunctioning
° Craniopharyngioma: see Craniopharyngiomas section, page 34
NONFUNCTIONING PITUITARY ADENOMAS
Presentation and natural history
• Nonfunctioning microadenomas (<1 cm)
present as PI
° Most
° Significant growth over time is unusual
48565_ST01_001-046.indd 32
5/1/13 9:35 PM
Nonfunctioning Pituitary Adenomas
33
• Nonfunctioning macroadenomas (≥1 cm)
present clinically with
° Most
■ Signs or symptoms of mass effect
• Headache
• Visual field deficits from optic chiasm compression
• Ophthalmoplegia from invasion of cavernous sinus causing
compression of cranial nerves
■ Signs or symptoms of hormonal dysfunction
• Hyperprolactinemia (PRL above normal but <200) from stalk
compression
• Hypopituitarism
~20−25%
of nonfunctioning macroadenomas will grow over
° long-term follow-up
Management
• Nonfunctioning microadenoma
approach is surveillance without intervention
° Usual
■ Repeat MRI in one year, then again in 1−2 years, and then at
increasing intervals (or consider stop testing)
consider surgery if patient has unremitting headache,
° Can
but response is variable and improvement cannot be
guaranteed
• Nonfunctioning macroadenomas
is recommended for
° Surgery
■ Patients with tumors compressing or abutting the optic chiasm
or optic nerves
■ Patients with tumors causing opthalmoplegia or other neurologic
problems
■ Patients with worsening headache
■ Patients with tumors that grow signifi cantly during follow-up or
approach the optic chiasm
can be considered for
° Surgery
■ Patients with hypopituitarism
• Hypopituitarism may improve after resection but cannot be
guaranteed
■ Women who are planning pregnancy who have tumors close to
the optic chiasm
• Increased levels of estrogen in pregnancy may induce tumor
growth resulting in chiasmal compression
beam RT is usually reserved for patients with significant or
° External
enlarging tumor remnant after surgery
DA
agonists
° ■ Can be considered to lower PRL in patients with symptomatic
hyperprolactinemia from stalk effect who would otherwise not
need surgery
48565_ST01_001-046.indd 33
5/1/13 9:35 PM
34 Pituitary Incidentalomas, Nonfunctioning Pituitary Adenomas
Have shown some efficacy in reducing tumor volume in uncontrolled studies
• Can be considered for patients with nonfunctioning macroadenomas for whom surgery would be recommended but who
cannot or will not have surgery
• Can be considered as an alternative to external beam radiation therapy in patients with significant or enlarging tumor
remnant after surgery
Somatostatin analogues are less effective than DA agonists for
reducing the size of nonfunctioning macroadenomas, but can be
considered in patients who are not surgical candidates and who do
not respond to DA agonist therapy
For patients who do not require surgical intervention, surveillance
is recommended
■ Repeat MRI in 6 months, then yearly for 3 years, then at increasing intervals
■ Consider repeat evaluation for hypopituitarism at appropriate follow-up intervals, particularly if tumor grows or patient
develops new signs or symptoms
■ Repeat VF testing if tumor grows toward the chiasm
■ Patients should be educated on the symptoms of pituitary
apoplexy and should seek medical attention immediately if such
symptoms occur
■
°
°
CRANIOPHARYNGIOMAS
Background
• Rare benign epithelial tumors arising along the path of the craniopharyngeal duct from remnants of Rathke’s pouch
• Occurs in a bimodal age distribution: peaks at 5−15 years old in
children and 50−74 years old in adults
• Located mainly in the sellar and parasellar region
are suprasellar or both suprasellar and intrasellar
° 95%
majority of tumors are cystic or mixed cystic-solid
° The
Half
of
contain calcifications
° Majoritycraniopharyngiomas
2−4 cm at diagnosis
° Can exertarepressure
effects on multiple structures including visual
° pathways, brain parenchyma,
ventricular system, blood vessels,
and hypothalamus and pituitary
48565_ST01_001-046.indd 34
5/1/13 9:35 PM
Craniopharyngiomas 35
Presentation and evaluation
• Signs and symptoms
differs depending on pattern of growth (i.e., what
° Presentation
structures are effected)
Most
common
° ■ Headaches presenting symptoms are
■ Nausea/vomiting
■ Visual problems
■ Growth failure in children
■ Hypogonadism in adults
• Radiologic evaluation
MRI:
best study to define relationship of tumor to other structures
° Computed
(CT): useful for indentifying calcifications
° and cystic tomography
components
diagnosis includes other cystic lesions of the sellar/
° Differential
parasellar area including Rathke’s cleft cyst and cystic pituitary
adenoma
• Laboratory evaluation
majority of patients have some aspect of compromised pituitary
° The
function
All
patients
should have evaluation for hypopituitarism (including
° diabetes insipidus
if suggested by symptoms) with deficits treated
as appropriate
Management
• Surgery is the primary treatment modality
• Lifelong radiologic surveillance is necessary for patients with gross
total resection, as recurrence is common
• Adjuvant radiotherapy is recommended for patients with residual tissue on postoperative imaging or who recur during surveillance
also be considered as primary therapy for small biopsy-proven
° May
craniopharyngiomas that are not causing compressive symptoms
• Repeat surgery can be considered for acute pressure effects or
life-threatening growth of solid components, but rarely achieves total
removal and is associated with increased perioperative morbidity and
mortality
• Multiple modalities have been employed to control cystic components,
included repeated aspiration, brachytherapy, or intracystic bleomycin
• New problems may occur as a result of tumor growth or recurrence,
surgery, RT, or the use of other treatment modalities
should be monitored for the development of new pituitary
° Patients
deficits, new visual compromise, and hypothalamic disorders
including hyperphagia and obesity (“hypothalamic obesity”),
behavioral problems, and loss of control of body temperature
48565_ST01_001-046.indd 35
5/1/13 9:35 PM
36 Pituitary Incidentalomas, Nonfunctioning Pituitary Adenomas
REFERENCES
Colao A, Di Somma C, Pivonello R, Faggiano A, Lombardi G, Savastano S.
Medical therapy for clinically non-functioning pituitary adenomas. Endocr
Relat Cancer, 2008;15(4):905−15.
Fernández-Balsells MM, Murad MH, Barwise A, et al. Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review
and metaanalysis. J Clin Endocrinol Metab, 2011;96(4):905−12.
Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an
endocrine society clinical practice guideline. J Clin Endocrinol Metab,
2011;96(4):894−904.
Jane JA Jr, Laws ER Jr. The management of non-functioning pituitary adenomas. Neurol India, 2003;51(4):461−5.
Karavitaki N, Cudlip S, Adams CB, Wass JA. Craniopharyngiomas. Endocr
Rev, 2006;27(4):371−97.
Karavitaki N, Wass JA. Craniopharyngiomas. Endocrinol Metab Clin North Am,
2008;37(1):173−93.
Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas.
Endocrinol Metab Clin North Am, 2008;37(1):151−71.
Orija IB, Weil RJ, Hamrahian AH. Pituitary incidentaloma. Best Pract Res Clin
Endocrinol Metab, 2012;26(1):47−68.
48565_ST01_001-046.indd 36
5/1/13 9:35 PM
7 ■ HYPOOSMOLALITY AND THE SYNDROME
OF INAPPROPRIATE ANTIDIURETIC HORMONE
SECRETION
Joseph G. Verbalis, MD
PATHOPHYSIOLOGY
• Hypoosmolality indicates an excess of total body water relative to total
body solute
• Imbalances between body water and solute can be generated either by
depletion of body solute more than body water, or by dilution of body
solute from increases in body water more than body solute
• Most hypoosmolar states include components of both solute depletion
and water retention, but this general concept provides a framework for
understanding hypoosmolar disorders
CLINICAL PRESENTATION
• Clinical manifestations of hyponatremia are largely neurological, and
primarily reflect brain edema resulting from osmotic water shifts into
the brain
• Symptoms range from nonspecific such as headache and confusion,
to more severe manifestations such as decreased sensorium, coma,
seizures, and death
• Significant CNS symptoms generally do not occur until the serum [Na+]
falls below 125 mmol/L, and the severity of symptoms can be roughly
correlated with the degree of hypoosmolality
• Individual variability is marked, and for any patient the level of
serum [Na+] at which symptoms will appear cannot be accurately
predicted
other than the severity of the hypoosmolality also affect the
° Factors
degree of neurological dysfunction, the most important is the time
course over which hypoosmolality develops: rapid development of
severe hypoosmolality frequently causes marked neurological symptoms, whereas gradual development over several days or weeks
is often associated with relatively mild symptomatology despite
profound degrees of hypoosmolality
• Underlying neurological and metabolic disorders (hypoxia, hypercapnia,
acidosis, hypercalcemia, etc.) also affect the level of hypoosmolality at
which symptoms appear
48565_ST01_001-046.indd 37
5/1/13 9:35 PM
38
Hypoosmolality and the Syndrome
DIAGNOSTIC EVALUATION
• Careful history (especially concerning medications)
• Physical examination with emphasis on clinical assessment of the
extracellular fluid (ECF) volume status and thorough neurologic
evaluation
• Laboratory analysis
of serum or plasma electrolytes, glucose, blood urea
° Measurement
nitrogen (BUN), creatinine and uric acid
Calculated
and/or
directly measured plasma osmolality
° Determination of simultaneous
urine electrolytes and osmolality
°
CLASSIFICATION OF HYPOOSMOLALITY BY ECF VOLUME STATUS
• Decreased ECF volume (hypovolemia)
detectable hypovolemia indicates solute depletion
° Clinically
isotonic or hypotonic fluid losses can cause hypoosmolality if
° Even
water or hypotonic fluids are subsequently ingested or infused
urine sodium concentration (UNa) suggests a nonrenal cause
° Aoflow
solute depletion, whereas a high UNa suggests renal causes of
solute depletion
° Diuretic use is the most common cause of hypovolemic hypoosmolality
• Normal ECF volume (euvolemia)
disorder causing hypoosmolality can present with a volume sta° Any
tus that appears normal by standard methods of clinical evaluation
presence of normal or low BUN and uric acid concentrations are
° The
helpful laboratory correlates of relatively normal ECF volume
Low
mmol/L) suggests depletional hypoosmolality second° ary toUNaECF(<30
losses with subsequent volume replacement by water or
other hypotonic fluids
High UNa (>30 mmol/L) generally indicates a dilutional hypoosmo° lality
such as the syndrome of inappropriate antidiuretic hormone
secretion
• Increased ECF volume (hypervolemia)
detectable hypervolemia indicates whole body sodium
° Clinically
excess
Hypoosmolality
in these patients suggests a relatively decreased
° intravascular volume
and/or pressure leading to water retention as
a result of elevated plasma arginine vasopressin (AVP) levels and
decreased distal delivery of glomerular filtrate to the kidneys
usually have a low UNa because of secondary hyperaldoste° Patients
ronism, but under certain conditions the UNa may be elevated (e.g.,
diuretic therapy)
failure and cirrhosis are the most common causes of hyper° Heart
volemic hypoosmolality
48565_ST01_001-046.indd 38
5/1/13 9:35 PM
Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) 39
SYNDROME OF INAPPROPRIATE ANTIDIURETIC
HORMONE SECRETION (SIADH)
• The clinical criteria necessary to diagnose SIADH remain as initially
defined by Bartter and Schwartz in 1967
presence of hyponatremia with a correspondingly low plasma
° The
osmolality (i.e., hypotonic hyponatremia)
inappropriately elevated urine osmolality (>100 mOsm/kg H2O)
° An
euvolemia (i.e., absence of signs of volume depletion or
° Clinical
retention)
Na+ >30 mEq/L
° UNormal
renal, adrenal, and thyroid function
°
• Many different disorders are associated with SIADH, which can be
divided into four major groups: tumors, CNS disorders, drug effects,
and pulmonary diseases
Treatment
• Current therapies for managing SIADH in hospitalized patients
saline
° Isotonic
■ Treatment of choice for hypovolemic hyponatremia (patients
who either have clinical signs of hypovolemia, or in whom a spot
UNa+ is <30 mmol/L)
■ Ineffective for dilutional hyponatremias such as SIADH; administration of isotonic saline to a euvolemic patient may worsen
hyponatremia and/or cause fluid overload
Hypertonic
° ■ Patients saline
with severe neurological symptoms should be treated
promptly with hypertonic solutions, typically 3% NaCl ([Na+] =
513 mmol/L)
■ The infusion rate of 3% NaCl (mL/h) can be estimated by
multiplying the patient’s weight (kg) by desired correction rate
(mmol/L/h)
• An alternative option is administration of a 100-mL bolus of
3% NaCl, repeated once if no clinical improvement
restriction
° Fluid
■ Most widely accepted treatment for patients with chronic
hyponatremia
■ Restrict all fluids to 500 ml less than the 24-hour urine output
■ Serum [Na+] increases slowly (1–2 mmol/L/day) even with
severe fluid restriction
■ Often poorly tolerated because of associated increased thirst
■ Should not be used with hypovolemic patients
■ Difficult in patients with high urine osmolalities secondary
to high AVP levels; if the sum of urine Na+ and K + exceeds
the serum [Na+], most patients will not respond to a fluid
restriction since electrolyte-free water clearance will be
difficult to achieve
48565_ST01_001-046.indd 39
5/1/13 9:35 PM
40
Hypoosmolality and the Syndrome
°
°
°
Demeclocycline
■ Can be used when patients find fluid restriction unacceptable
■ Initial dose is 300 mg twice a day (BID); titrate upward to
1200 mg/day as needed
■ Can cause nephrotoxicity in patients with heart failure or
cirrhosis
Urea
■ Induces osmotic diuresis and augments free water excretion
■ Effective doses for treatment of hyponatremia are 30–60 g daily
in divided doses
■ Use limited because there is no United States Pharmacopeia
(USP) formulation and it is associated with poor palatability
■ Mild azotemia can be seen but rarely reaches clinically signifi cant levels
Arginine vasopressin receptor (AVPR) antagonists
■ Antagonists of the AVP V2 (antidiuretic) receptor (“vaptans”) are
approved by the U.S. Food and Drug Administration (FDA) for the
treatment of euvolemic and hypervolemic hyponatremia
■ AVPR antagonists produce electrolyte-free water excretion
(“aquaresis”) without affecting renal sodium and potassium
excretion
■ Serum [Na+] is signifi cantly increased within 24–48 hours,
which is considerably faster than the effects of fluid restriction
(which can take many days)
■ Increased renal fluid excretion can cause or worsen hypotension
in patients with hypovolemic hyponatremia so vaptans are
contraindicated in these patients
■ Conivaptan is available only as an intravenous preparation and
is given as a 20-mg loading dose over 30 min, followed by a
continuous infusion of 20 or 40 mg
• The 20-mg continuous infusion is used for the first 24 h to
gauge the initial response; if the correction of serum [Na+] is
felt to be inadequate (e.g., <5 mmol/L), then the infusion rate
can be increased to 40 mg/day
• Therapy is limited to a maximum duration of 4 days because
of drug-interaction effects with other agents metabolized by
CYP3A4 isoenzymes
• Most common adverse effects include injection-site reactions,
which are generally mild and usually do not lead to treatment
discontinuation, headache, thirst, and hypokalemia
■ Tolvaptan is available as an oral preparation that can be used for
both short- and long-term treatment of hyponatremia
• Similar to conivaptan, tolvaptan must be initiated in the
hospital so that the rate of correction can be monitored
carefully
48565_ST01_001-046.indd 40
5/1/13 9:35 PM
Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) 41
• Patients with a serum [Na+] <125 mmol/L are eligible for
therapy with tolvaptan as primary therapy; if the serum [Na+]
is ≥125 mmol/L, tolvaptan therapy is only indicated if the
patient has symptoms that could be attributed to the hyponatremia and the patient is resistant to fluid restriction
• Starting dose is 15 mg on the first day, and can be titrated
to 30 mg and 60 mg at 24-hour intervals if the serum [Na+]
remains <135 mmol/L or the increase in serum [Na+] has
been ≤5 mmol/L in the previous 24 hours
• Patients should not be on a fluid restriction when tolvaptan
is initiated
• Reported side effects include dry mouth, thirst, increased
urinary frequency, dizziness, nausea, orthostatic hypotension,
and liver injury
■ Hyponatremia treatment guidelines for hospitalized patients
with SIADH are based on their presenting symptoms summarized
as in Figure 7-1
• Monitoring serum [Na+] in hospitalized patients with SIADH
frequency of serum [Na+] monitoring is dependent on both the
° The
severity of the hyponatremia and the therapy chosen
rapid correction of serum [Na+] can cause damage to the
° Overly
myelin sheath of nerve cells, resulting in central pontine myelinolysis, also called the osmotic demyelination syndrome (ODS)
FIGURE 7.1 Hyponatremia treatment algorithm
48565_ST01_001-046.indd 41
5/1/13 9:35 PM
42
Hypoosmolality and the Syndrome
°
°
°
°
°
Maximal recommended rates of correction are 12 mmol/L within
24 hours or 18 mmol/L within 48 hours; this should be reduced to
8 mmol/L for any 24-hour period in patients with risk factors for
development of osmotic demyelination (severely low serum [Na+],
malnutrition, alcoholism, or hypokalemia)
Patients undergoing active treatment with hypertonic saline for
level 1 or 2 symptomatic hyponatremia should have frequent
monitoring of serum [Na+] and ECF volume status (every 2−4 hours)
to ensure that the serum [Na+] does not exceeded the recommended
levels during the active phase of correction
Patients treated with vaptans for level 2 or 3 symptoms should have
serum [Na+] monitored every 6−8 hours during the active phase of
correction, which will generally be the first 24−48 hours of therapy
In patients with a stable level of serum [Na+] treated with fluid
restriction or therapies other than hypertonic saline, measurement of serum [Na+] daily is generally sufficient, since levels will
not change that quickly in the absence of active therapy or large
changes in fluid intake or administration
If the correction exceeds recommended limits, administer sufficient
water, either orally or as IV D5W, to bring the overall correction
below desired limits
REFERENCES
Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med, 2007;356(20):2064−72.
Schrier RW, ed. Diseases of the Kidney and Urinary Tract. 7th ed. Philadelphia,
PA: Lippincott Williams & Wilkins, 2001.
Verbalis JG. Control of brain volume during hypoosmolality and hyperosmolality. Adv Exp Med Biol. 2006;576:113−29.
Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia
treatment guidelines 2007: expert panel recommendations. Am J Med, 2007;
120(11 Suppl 1):S1−21.
48565_ST01_001-046.indd 42
5/1/13 9:35 PM
8 ■ DIABETES INSIPIDUS
Vicky Cheng, MD and Geetha Gopalakrishnan, MD
DEFINITION
• Characterized by the excretion of large volumes of dilute urine
(>2.5−3.0 mL/kg body weight per hour, specific gravity <1.005, urine
osmolality <200 mOsm/kg H2O)
• Types of DI
diabetes insipidus: inadequate secretion of AVP from the
° Central
hypothalamus/posterior pituitary
Nephrogenic
diabetes insipidus: impaired response of the kidney
° to AVP
polydipsia: excess intake of water leads to suppression of
° Primary
AVP; it is typically psychogenic in nature
ETIOLOGIES
TABLE 8.1 Etiologies of Diabetes Insipidus
Central DI
• Congenital (congenital malformations;
autosomal dominant AVP-neurophysin
gene mutation)
• Autoimmune (lymphocytic hypophysitis)
• Drugs (alcohol, diphenylhydantoin)
• Granulomatous disease (sarcoidosis,
histiocytosis)
• Infectious (meningitis, encephalitis)
• Tumors (craniopharyngioma, metastatic
pituitary tumors)
• Trauma (neurosurgery, head injury)
• Vascular (cerebral hemorrhage,
infarction)
Nephrogenic DI
• Congenital (X-linked recessive AVP V2
receptor gene mutations; autosomal
dominant/recessive aquaporin-2 water
channel gene mutations)
• Drugs (lithium, demeclocyline,
cisplatin, methoxyflurane)
• Electrolyte disorders (hypercalcemia,
hypokalemia)
• Infiltrative (sarcoidosis, amyloidosis)
• Renal disease (chronic renal failure,
obstructive uropathy)
• Vascular (sickle cell disease or trait)
CLINICAL MANIFESTATIONS
• Polyuria, polydipsia
• Craving for cold water
• Signs and symptoms of dehydration, depending on whether the patient
has intact thirst mechanism and is able to drink fluids
48565_ST01_001-046.indd 43
5/1/13 9:35 PM
44
Diabetes Insipidus
DIAGNOSIS
• Rule out osmotic diuresis from hyperglycemia or fluid overload
• Polyuria (urine volume >3L in 24 hours)
• Dilute urine (specific gravity <1.005, urine osmolality <200 mOsm/
kg H2O)
• Serum osmolality and sodium
patients with DI present with normal serum sodium and
° Most
osmolality if they are able to maintain oral intake of fluids, elevated
serum osmolality and sodium are only noted in patients who are
unable to drink to thirst
patients with diabetes insipidus (DI) have high or high° Typically,
normal serum sodium and osmolality; in primary polydipsia, serum
sodium and osmolality are typically in the low end of normal range
• Water deprivation test
testing to differentiate central DI from nephrogenic DI
° Provocative
in patients with intact thirst mechanism
■ Fluids are withheld to promote dehydration which is a potent
stimulus for maximal AVP secretion
■ Measure urine volume and osmolality every 1 hour and serum
sodium and osmolality every 2 hours until any of the following
occur
• Serum Na is ≥146 mEq/L
• Urine osmolality reaches a plateau (3 consecutive urines with
<10% differences)
• Body weight decreases by 3%
• Patient develops cardiovascular instability (i.e., low BP or
tachycardia)
■ After one of the above criteria is reached, blood is drawn for
AVP level and the patient is given AVP (5 U) or dDAVP (1 μg) SQ;
measure urine osmolality and urine volume every 30 minutes for
the next 2 hours
Interpretation
test results
° ■ Patients withof central
DI will have low or “inappropriately normal”
AVP levels whereas those with nephrogenic DI will have elevated
levels
■ Patients with central DI will have a ≥50% increase in urine
osmolality after dDAVP administration
■ Patients with nephrogenic DI will have a <10% increase in urine
osmolality after dDAVP administration
■ Patients with primary polydipsia are usually eunatremic
and have <10% increases in urine osmolality after dDAVP
administration; plasma AVP levels are appropriate to the plasma
osmolality
48565_ST01_001-046.indd 44
5/1/13 9:35 PM
References
45
Treatment
• Central DI
of any preexisting water deficits
° Correction
recording of fluid intake and output
° Accurate
Desmospressin
acetate (dDAVP): synthetic analogue of AVP, it is
° the drug of choice;
available in parenteral (1−2 μg), oral (0.1 or
0.2 mg), and nasal (10 μg) formulations
Other
agents
that
can
be considered in DI especially if partial
° deficit (i.e., some circulating
AVP present)
■ Thiazide diuretics: by causing modest hypovolemia, thiazide
diuretics increase the absorption of salt and water in the
proximal tubule
■ Chlorpropamide: an oral hypoglycemic agent; potentiates the
action of AVP in the kidney
■ Carbamazepine: enhances renal sensitivity to AVP
■ Clofibrate: increases secretion of AVP
■ Nonsteroidal anti-inflammatory drugs (NSAIDs): inhibit the renal
synthesis of prostaglandins, which are AVP antagonists
• Nephrogenic DI
Correction
any preexisting fluid deficits
° Correction of
of electrolyte disturbances (e.g., hypercalcemia,
° hypokalemia)
of any drugs that may be causing nephrogenic DI
° Discontinuation
diuretics: most effective therapy
° Thiazide
Other
agents
that
can be considered include NSAIDs, chlor° propamide, carbamazepine,
and clofibrate
• Primary polydipsia
Behavior
modifi
cation
°
REFERENCES
Loh JA, Verbalis JG. Disorders of water and salt metabolism associated with
pituitary disease. Endocrinol Metab Clin North Am, 2008;37(1):213−34.
Makaryus AN, McFarlane SI. Diabetes insipidus: diagnosis and treatment of a
complex disease. Cleve Clin J Med, 2006;73(1):65−71.
Verbalis JG. Diabetes insipidus. Rev Endocr Metab Disord, 2003;4(2):177–85.
48565_ST01_001-046.indd 45
5/1/13 9:35 PM
48565_ST01_001-046.indd 46
5/1/13 9:35 PM
SECTION II: THYROID
48565_ST02_047-110.indd 47
5/1/13 9:34 PM
48565_ST02_047-110.indd 48
5/1/13 9:34 PM
9 ■ THYROID ESSENTIALS AND THYROID
FUNCTION TESTS
Shabina R. Ahmed, MD and David S. Cooper, MD
ANATOMY
• Butterfly-shaped organ that lies under the sternothyroid and sternohyoid muscles
• Composed of left and right lobes joined by an isthmus; occasionally
a pyramidal lobe sits on top of the isthmus, can be palpable in Graves’
disease
• Surrounded by a thin, fibrous capsule attached to the cricoid cartilage
and superior tracheal rings
• The recurrent laryngeal nerves run posteriorly to the gland and the
parathyroid glands sit behind the superior and middle portions of
each lobe
• Highly vascular, supplied by the superior and inferior thyroid arteries
HISTOLOGY
• The thyroid gland is made up of individually functioning units called
follicles
by simple cuboidal epithelium
° Lined
with a glycoprotein complex called thyroglobulin (Tg), or
° Filled
colloid
• Epithelium produces thyroid hormone (T4 and T3) within the colloid,
where it is also stored
• The basement membrane of the follicles contain neuroendocrine
secretory cells called C cells, which have a pale granular cytoplasm
and secrete calcitonin
PHYSIOLOGY
• Thyroid hormone is comprised of two iodinated thyronine residues
bonded by an ether linkage
• Thyroid hormone synthesis requires several steps that are dependent
upon iodine (a key structural component of thyroid hormone), the
sodium/iodide symporter (NIS), thyroid peroxidase (TPO), pendrin,
and Tg
48565_ST02_047-110.indd 49
5/1/13 9:34 PM
50
Thyroid Essentials and Thyroid Function Tests
• Trapping and iodide transport: iodide from the circulation is transported
into the follicular cell via NIS at the basal membrane of the thyroid
NIS is regulated by TSH; iodide also regulates NIS; when
° Normally
iodine ↑, NIS expression and activity ↓
■ In Graves’ disease, NIS is stimulated by TSH receptor-stimulating
antibodies
is an iodide/chloride transporter at the apical membrane
° Pendrin
and positions iodide to act as a substrate for hormonogenesis
■ Patients with mutations in the pendrin gene develop Pendred’s
syndrome, with congenital deafness, goiter, and defective iodide
organification
• Organification: iodide is oxidized at the apical-colloid membrane by
endogenously generated hydrogen peroxide in a reaction catalyzed by
TPO. Oxidized iodide is then bound to tyrosine residues within Tg, a
large glycoprotein with multiple tyrosyl sites.
• Coupling: TPO also catalyzes the coupling of two iodotyrosyl residues
within Tg to form monoiodotyrosine (MIT) and diiodotyrosine (DIT); two
DITs couple to form T4 and one MIT and one DIT couple to form T3
antithyroid drugs (ATDs) methimazole (MMI) and propothio° The
uracil (PTU) are competitive inhibitors of TPO and work to block
synthesis of T4 and T3
• Storage of hormone: iodinated Tg containing T4 and T3 is secreted into
the follicular lumen and makes up the bulk of colloid
• Proteolysis and secretion of thyroid hormone
reenters the thyrocyte via micropinocytosis of colloid
° Thyroglobulin
droplets
droplets fuse with lysosomes, causing the release of T4 and
° Colloid
T3, and deiodination of MIT and DIT
Most
of
Tg is proteolyzed; some is released in the serum or
° recycledthe
into the follicular lumen
• Intrathyroidal deiodination of T4: 5’-deiodinase is present in the
peripheral tissues to convert T4 to the biologically active T3, but it also
is present within the thyroid itself
• The thyroid is controlled by the hypothalamus and pituitary. TRH
produced by the hypothalamus stimulates the pituitary to release TSH
or thyrotropin. In turn, TSH acts on thyroid follicular cells to promote
all the steps in thyroid hormone synthesis and release. T4 and T3
inhibit TRH and TSH secretion, so that serum TSH levels increase in
hypothyroidism and decrease in hyperthyroidism.
48565_ST02_047-110.indd 50
5/1/13 9:34 PM
Physiology 51
TABLE 9.1 Use and Interpretation of Thyroid Function Tests
Test
TSH
Use
Thyroid Function Tests
Interpretation
• Anterior pituitary
• ↑ suggests primary hypothyroidism;
hormone; stimulates
rarely pituitary TSHoma or thyroid
release of thyroid hormone
hormone resistance
and growth of gland
• ↓ suggests hyperthyroidism; rarely
central hypothyroidism
• Very sensitive test; can
effectively diagnose hypo- • May be difficult to interpret in
nonthyroidal illness, pregnancy,
or hyperthyroidism in most
patients on high-dose
cases
glucocorticoids or dopamine
Total thyroxine • Measures bound and free
(T4)
T4 and T3 concentrations
• >99% of thyroid hormone
is bound to thyroid
hormone binding globulin
• ↑ suggests hyperthyroidism
• ↓ suggests hypothyroidism
• May not accurately assess thyroid
hormone status: many medications
and clinical conditions may alter
TBG and affect total T4 levels
FT4
• Measures bioactive T4
levels
• ↑ indicates hyperthyroidism
• ↓ indicates hypothyroidism
• Preferrable over free thyroxine index
Total T3
• Measures bound and free
T3 levels
• Useful in patients with
hyperthyroidism
Free T3
• Measures bioactive T3
levels
• Useful in patients with
hyperthyroidism
Thyroid
hormone
binding
globulin
(TBG)
• Binds T4 and T3
• Causes of ↑ TBG
○ Drugs (estrogen, oral
contraceptives, tamoxifen,
heroin, methadone,
5-fluorouracil)
○ Pregnancy
○ Acute hepatitis
○ Congenital
○ Acute intermittent porphyria
• Causes of ↓ TBG
○ Drugs (androgens,
glucocorticoids, slow-release
nicotinic acid)
○ Severe illness or malnutrition
○ Chronic liver disease
○ Protein-losing states (e.g.,
nephritic syndrome)
○ Congenital
(continues)
48565_ST02_047-110.indd 51
5/1/13 9:34 PM
52
Thyroid Essentials and Thyroid Function Tests
TABLE 9.1 (continued )
Thyroid Function Tests
Interpretation
Test
T3 resin
uptake
(T3RU)
Use
• An indirect measure of
the binding capacity of
patient’s serum proteins
(measures unoccupied
T4-binding sites)
• Used in conjunction with
serum T4
• ↑ T3RU: hyperthyroidism, low TBG
states
• ↓ T3RU: hypothyroidism, high TBG
states
Free thyroxine
index (FTI)
• Product of serum T4 and
T3RU
• Corrects for changes
in binding protein
concentration
• Highly correlated with free T4
REFERENCES
Bizhanova A, Kopp P. Minireview: The sodium-iodide symporter NIS
and pendrin in iodide homeostasis of the thyroid. Endocrinology,
2009;150(3):1084−90.
Gardner DG, Shoback D. Greenspan’s Basic & Clinical Endocrinology. 8th ed.
New York, NY: McGraw Hill; 2007.
Hall JE, Nieman LK, eds. Handbook of Diagnostic Endocrinology. Totowa, NJ:
Humana Press; 2003.
Moore KL, Dalley AF. Clinically Oriented Anatomy. 4th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 1999.
Pesce L, Bizhanova A, Caraballo JC, et al. TSH regulates pendrin membrane
abundance and enhances iodide efflux in thyroid cells. Endocrinology,
2012;153(1):512−21.
Young B, Heath JW. Wheater’s Functional Histology: A Text and Colour Atlas.
4th ed. Philadelphia, PA: Churchill Livingstone; 2000.
48565_ST02_047-110.indd 52
5/1/13 9:34 PM
10 ■ THYROTOXICOSIS AND
HYPERTHYROIDISM
Anna Milanesi, MD, PhD and Gregory A. Brent, MD
ETIOLOGY AND PATHOPHYSIOLOGY
• Thyrotoxicosis is the clinical condition resulting from an excess of
circulating thyroid hormones from any of a number of etiologies
• Some endocrinologists use the term hyperthyroidism only when there
is increased synthesis of thyroid hormones by the thyroid gland, but
most use the term hyperthyroidism to refer to any condition with
excess thyroid hormone
TABLE 10.1 Causes of Thyrotoxicosis
Etiology
Graves’ disease
Toxic adenoma or toxic goiter
Silent subacute thyroiditis
Painful subacute thyroiditis
(De Quervain’s or subacute
granulomatous thyroiditis)
TSH-secreting pituitary
adenoma
Iodine
Pathophysiology
Stimulating antibody that recognizes the TSH
receptor
Autonomous thyroid hormone production (often due
to somatic activating mutation of TSH-receptor
gene)
Thyroid inflammation and release of preformed
hormone with positive thyroid autoantibodies (antiTPO), most common in the postpartum period
Thyroid inflammation and release of preformed
hormone following a viral infection
TSH-stimulated thyroid growth and thyroid hormone
production and secretion
“Jod-Basedow,” excess thyroid hormone secretion,
usually in the setting of multinodular goiter
Medications (e.g., amiodarone, Varied
interferon)
Trophoblastic disease
High levels of hCG bind and stimulate TSH-receptor
to stimulate thyroid hormone production
Struma ovarii
Ectopic thyroid hormone production from ovarian
teratom
Factitious thyrotoxicosis
Ingestion of exogenous thyroxine (T4), triiodothyronine
(T3), or products containing T4 and/or T3
Thyroid hormone resistance
Mutation of the thyroid hormone receptor-beta gene
48565_ST02_047-110.indd 53
5/1/13 9:34 PM
54
Thyrotoxicosis and Hyperthyroidism
CLINICAL PRESENTATION
• The clinical features of hyperthyroidism can be dramatic with manifestations across many organ systems; however, a proportion of patients,
especially the elderly or those with more mild disease, may present
with few symptoms
palpitations, increased heart rate, increased
° Cardiovascular:
cardiac output, increased contractility, atrial fibrillation, congestive
heart failure (CHF), cardiovascular collapse and death
muscle: proximal muscle weakness, generalized fatigue,
° Skeletal
muscular atrophy
tremor, irritability, nervousness, insomnia, psychosis,
° Neurological:
altered mental status, lethargy, and coma
Gonadal:
irregular
menstrual cycles, reduced libido, increased
° circulating sex hormone-binding
globulin and reduced levels of
free sex hormones
Bone:
increased
bone
turnover,
ostopenia/osteoporosis,
and
° fracture
weight loss, sweating
° Metabolic:
° Gastrointestinal: vomiting, diarrhea
• Disease-associated symptoms and signs
thyroid enlargement, thyroid bruit in anterior neck
° Graves’disease:
with auscultation, thyroid-associated orbitopathy (soft-tissue
swelling and inflammation, exophthalmos, proptosis, lid lag),
dermopathy and acropachy
multinodular goiter: thyroid enlargement, venous compression
° Toxic
syndrome if the goiter is retrosternal
° Painful subacute thyroiditis: thyroid gland tenderness
DIAGNOSIS
TABLE 10.2 Conditions of TSH
A. CONDITIONS WITH SUPPRESSED SERUM TSH
Disease
Graves’ disease
T4
↑
T3
↑ (T3 >
T4)
Toxic multinodular
goiter
↑, normal, ↓
↑
24-hr Radioiodine Uptake and
Scan
Other Studies
↑ with
TSI/TRBII positive
homogenous
distribution*
Inappropriately
TSI/TRBII/TPO
in the “normal
negative
range” to ↑
with patchy
distribution
(continues)
48565_ST02_047-110.indd 54
5/1/13 9:34 PM
Diagnosis
55
TABLE 10.2 (continued )
Disease
Toxic adenoma
T4
↑/=/↓
↑
Subacute
thyroiditis
Painless thyroiditis
Iodine-induced
hyperthyroidism
Factitious
hyperthyroidism
Struma ovarii
↑
↑
↑
↑
↑, normal, ↓
↑
24-hr Radioiodine Uptake and
Scan
Other Studies
Inappropriately
TSI/TRBII/TPO
in the “normal
negative
range” to
↑ focal
uptake with
suppression
of the normal
gland
Below normal
TSI/TRBII/TPO
negative
Below normal
TPO positive
Variable
↑ (if T4 is
↑ (if T3 is
Below normal
Low Tg
↓ uptake in the
Whole body iodine
scan: pelvic
uptake
Serum hCG
elevated
and uterine
ultrasound
T3
ingested)
↑
ingested)
↑
neck
Trophoblastic
disease
↑
↑
↑
B. CONDITIONS WITH NORMAL OR ELEVATED TSH
Disease
Pituitary adenoma
T4
T3
↑
↑
Thyroid hormone
resistance
(THRβ)
↑
↑
24-hr Radioiodine
Uptake and Scan
Inappropriately
normal or ↑
Inappropriately
normal or ↑
Other Studies
Pituitary MRI
Sequencing of THRβ
gene
TSH: thyroid stimulating antibodies, T3: triiodothyronine, T4: thyroxine, TSI: thyroid-stimulating immunoglobulin, TRAb: TSH-receptor antibodies, TRBII: Thyroid Receptor Binding Inhibitory Immunoglobulin,
TPO: thyroid peroxidase antibodies; Tg: thyroglobulin; hCG: human chorionic gonadotropin; THRβ: thyroid
hormone receptor beta.
*24-hr radioiodine uptake does not have to be performed for diagnosis if the clinical presentation is typical for Graves’ disease (symptoms of hyperthyroidism for weeks to months, symmetrically enlarged thyroid,
thyroid-associated orbitopathy).
48565_ST02_047-110.indd 55
5/1/13 9:34 PM
56
Thyrotoxicosis and Hyperthyroidism
TABLE 10.3 Laboratory Studies for Diagnosis and Follow-Up
Test
TSH
Description
Highly sensitive direct serum
measurement
T4
Free T4 index: total thyroxine
measurement and estimate of thyroid
binding globulin.
Free T4 by analogue method: indirect
method used in the automated
platform instrument
Free T4 by dialysis: direct measure,
usually sent to reference laboratory
Total T3: direct measure of total
Important in the early disease
serum level
assessment and response
to therapy
Free T3 by analogous methods: indirect
method used in the automated
platform instrument
Free T3 by dialysis: direct measure,
more expensive
Assay for serum immunoglobulin
Support for diagnosis of GD;
interacting with TSH-receptor does
persistent elevation correlates
not distinguish between blocking and
with disease activity; not
stimulating antibodies
necessary for monitoring
Assay measuring cyclic AMP production
after incubation of the patient’s serum
with thyroid follicular cells; specific for
Graves’ disease
Measures antibody to thyroid peroxidase Detected in patients with HT, but
enzyme
can also be positive in GD
T3
TRBII
TSI
TPO
Utility
Required for diagnosis;
standard for monitoring
although will remain
suppressed for up to several
months, even after thyroid
hormone levels are normalized
Effective for monitoring
response to therapy
TRBII: thyroid receptor binding inhibitor immunoglobulin; GD: Graves’ disease; TSI: thyroid-stimulating
immunoglobulin; TPO: thyroid peroxidase antibodies; HT: Hashimoto’s thyroiditis.
• Other diagnostic tests
ultrasound: to assess thyroid enlargement, nodules, and
° Thyroid
thyroid vascularity (generally increased in Graves’ disease)
Iodide Uptake (RAIU) and scan: useful for initial
° Radioactive
diagnosis and to quantify uptake for radioiodine treatment
Electrocardiogram
(ECG): to assess for irregular rhythm and atrial
° fibrillation
48565_ST02_047-110.indd 56
5/1/13 9:34 PM
Management Options 57
°
°
Bone density scan: to assess osteopenia or osteoporosis
CT of the neck: to assess possible tracheal narrowing (in case
of retrosternal goiter or evidence of tracheal deviation or venous
congestion)
MANAGEMENT OPTIONS
• Pharmacological therapy
receptor blocker (short-term adjunctive therapy for
° β-adrenergic
symptom control)
■ Should be given to patients with signs of adrenergic activation
including tremor, tachycardia, and sweating while ATDs are
begun and titrated to normalize circulating thyroid hormone
levels
■ Typical dose is metoprolol 50−200 mg daily, atenolol 25−100 mg
daily, or propanolol 10−40 mg TID; esmolol IV can be used in a
monitored setting for severe thyrotoxicosis or thyroid storm
■ Caution should be taken in patients with asthma, obstructive
lung disease, or CHF
(thionamides: MMI and PTU)
° ATDs
■ Block thyroid hormone synthesis and reduce thyroid hormone
levels
■ Can be used as initial treatment of Graves’ disease,
amiodarone-induced thyrotoxicosis (AIT) type 1, and iodineinduced hyperthyroidism; ATDs are first-line treatment in
children, lactating women, patients with mild hyperthyroidism,
and older patients
■ MMI (10−40 mg daily) is the preferred medication
■ PTU (50−100 mg TID) has a “black box” warning from the FDA
for liver toxicity and should only be considered for use in two
situations, pregnant women who are in the first trimester
(due to the embryopathy associated with MMI use) and in
those with thyroid storm (because PTU also blocks peripheral
T4 to T3 conversion)
■ A complete blood cell count (CBC) and liver profile are recommended before starting treatment for a baseline, although there
is no established interval for prospective monitoring
■ Patient should have thyroid function tests (TFTs) monitored every
4−6 weeks until serum T4 and T3 concentrations are normalized,
then at longer intervals, as appropriate for clinical course
■ ATDs are usually continued for 6−18 months in patients with
Graves’ disease, and tapered or discontinued when a patient has
a persistently normal range (or elevated) serum TSH. Remission,
defined as a normal range serum TSH off of ATDs, is achieved in
about 40% of patients. Most agree that the remission rate does
not increase when treatment is extended longer than 18 months,
48565_ST02_047-110.indd 57
5/1/13 9:34 PM
58
Thyrotoxicosis and Hyperthyroidism
although there is no limit to the duration of medical treatment if
the patient is not experiencing side effects
Major side effects include polyarthritis and agranulocytosis (it
is recommended to discontinue the medication and check the
white blood cell count in case of fever, sore throat, or signs of
infection), hepatitis, cholestasis, urticaria, vasculitis
■ PTU is associated with fulminant hepatic necrosis
■ MMI is associated in pregnancy with rare complications such as
aplasia cutis and embryopathy (choanal and esophageal atresia); some clinicians, therefore, use PTU in the first trimester,
then switch to MMI
Corticosteroids
or dexamethasone)
° ■ Used in severe(prednisone
hyperthyroidism (thyroid storm) or in preparation
for surgery to rapidly reduce T4 to T3 conversion
■ Used in AIT type 2, or subacute thyroiditis with moderate-to
severe symptoms that fails to respond to β-adrenergic blocker
and NSAIDs
potassium iodide (SSKI)
° Supersaturated
■ Acute inhibition of thyroid hormone synthesis and release
(referred to as “Wolff-Chaikoff” effect)
■ In preparation for surgery or in patients with thyroid storm
• Radioactive iodine therapy (131Iodine in capsule or liquid)
be used as first-line therapy or after treatment with ATD
° Can
as preferred treatment in patients with toxic multinodu° Suggested
lar goiter and toxic adenoma
Suffi
cient
radiation
should be given in a single dose to deliver
° 5−7.5 mCI to the gland
based on 24-hour uptake measurement
(e.g., 15 mCI given to a patient with a 50% 24-hour uptake would
deliver 7.5 mCi to the thyroid). More active disease and larger
glands may need higher doses. Although some still attempt to
titrate the radioiodine dose to achieve euthyroidism, most target a
sufficient radioiodine dose to achieve hypothyroidism.
multinodular goiter and toxic adenoma usually require higher
° Toxic
doses of 131I therapy to achieve euthyroidism and have a lower
incidence of posttreatment hypothyroidism
is recommended to discontinue ATD 3−7 days before treatment
° Itand,
if necessary for significant hyperthyroidism, restart 3−7 days
after treatment with a taper over 4−6 weeks as radioiodine has its
full effect
in pregnant and lactating women (pregnancy test
° Contraindicated
should be obtained before treatment) and it is recommended that
conception should not be attempted for at least 6 months after
treatment, to limit any residual radiation effects on the developing
embryo and fetus and to ensure normal thyroid hormone levels
patients with active Graves’ ophthalmophathy (GO), prednisone
° In
(40−80 mg) for 3 months should be considered to prevent the
worsening of GO that can be seen after radioactive iodine (RAI)
■
48565_ST02_047-110.indd 58
5/1/13 9:34 PM
Management Options
59
Smoking significantly worsens GO and patients should be strongly
encouraged to quit. Patients with moderate−severe active GO may
consider ATD or surgery to avoid the worsening seen with RAI
side effects: mild neck tenderness and transient increase of
° Acute
serum thyroid hormone levels, rarely symptomatic
with Graves’ disease achieve hypothyroidism about 80% of
° Patients
the time at 2−6 months and lifelong thyroid hormone replacement
is required; if hyperthyroidism persists at 6 months, retreatment
with 131I should be considered
• Surgery
in case of large goiter with compressive symptoms;
° Recommended
nodule present with abnormal or suspicious cytology; pregnant
patients in the second trimester when rapid control of hyperthyroidism is required; female planning a pregnancy in <6 months;
patients intolerant or refractory to ATD; or relapse after antithyroid
therapy in patients refusing 131I therapy
treatment with SSKI for approximately 1 week is
° Preoperative
recommended; this treatment is used to reduce thyroid vascularity
and reduce the thyroidal release of thyroid hormone
total or total thyroidectomy is the procedure of choice for
° Near
Graves’ disease or toxic multinodular goiter, lobectomy is preferred
for toxic adenoma
surgery for Graves’ disease or toxic multinodular goiter,
° Following
thyroid hormone replacement should be started at a dose appropriate for the patient’s weight (1.6 μg/kg/day) and can be started
when free thyroxine (FT4) levels are in the mid−normal range;
serum T4 levels should fall about 50% every 7−10 days
• Overall approach to hyperthyroid patients
with typical clinical features of Graves’ disease, especially
° Patients
with GO, do not need imaging unless there are abnormalities on
physical exam and are typically started on ATDs
RAI or surgery may be indicated in patients based on the
° Immediate
clinical setting, such as desiring rapid euthyroidism due to desire
for fertility, compressive symptoms, or difficult-to-manage cardiac
disease
RAI uptake and scan are appropriate for patients with suspected
° An
thyroiditis or to plan RAI therapy
can provide additional structural information as well as
° Ultrasound
assess vascularity
Mild
hyperthyroidism
is usually managed with ATDs
° Patients with toxic multinodular
are often treated with RAI
° or surgery, although assessmentgoiter
of nonfunctioning nodules with
fine needle aspiration (FNA) as well as assessment for tracheal
compression should be entertained. Patients with hyperthyroidism
and nodules suspicious for thyroid cancer should be treated
surgically
48565_ST02_047-110.indd 59
5/1/13 9:34 PM
60
Thyrotoxicosis and Hyperthyroidism
THYROID STORM: DIAGNOSIS AND MANAGEMENT
• Thyroid storm is thyrotoxicosis with additional findings, and is associated with a mortality of approximately 10%; appropriate diagnosis and
aggressive treatment are important
• Examples of these additional manifestations include
° Fever
delirium, psychosis, altered consciousness, seizures
° CNS:
CHF, atrial fibrillation
° Cardiac:
Gastrointestinal/hepatic:
nausea, vomiting, diarrhea,
° hyperbilirubinemia
• Fever and CNS manifestations are hallmarks of the thyroid storm,
although the clinical presentation can vary
• There is often a trigger, such as irregular use or discontinuation of
ATDs, infection, surgery, or other stress
• Thyroid storm treatment
TABLE 10.4 Treatment of Thyroid Storm
Drug
β-blockers
Drug/Dose
Propanolol 60−80 mg every
4 hours
Esmolol IV pump 50−100 μg/
kg/min
Antithyroid drugs Propylthiouracil 500−1000-mg
load, 250 mg every 4 hours
MMI 60−80 mg day
Iodine (SSKI)
5 drops (250 mg) every 4 hours
Hydrocortisone
100 mg IV every 8 hours
Comment
At high doses, may reduce
T4-to-T3 conversion
Needs to be administered in a
monitored setting
Blocks T4-to-T3 conversion
Start at least one hour after
antithyroid drug is started
Blocks T4 to T3 conversion;
treats potential adrenal
insufficiency
SUBCLINICAL HYPERTHYROIDISM
• Pattern of suppressed serum TSH and normal range T4 and T3 levels
• Despite the term “subclinical,” it can be associated with symptoms,
bone loss, and cardiac manifestations, such as atrial arrhythmias
• Younger patients with mild TSH suppression (0.1−0.4 mU/L) and
no clinical manifestations can usually be observed with serum TSH
measured at intervals of 6−12 months
• In contrast, older patients and all patients with TSH <0.1 mU/L should
be evaluated with measurement of T4 and T3 and etiology of suppressed TSH (e.g., RAIU, TRBII, TSI), as well as assessments of cardiac
status and bone density
48565_ST02_047-110.indd 60
5/1/13 9:34 PM
References
61
• Persistent TSH suppression is typical of a nodular goiter with areas
of autonomous function, while mild Graves’ disease can resolve
spontaneously
• The decision to treat depends on the magnitude of TSH suppression,
age, and manifestations
TSH <0.1 mU/L, treatment should be considered if
° If■ serum
≥65 years old
■ Hyperthyroid symptoms
■ Evidence of cardiac risk factors or cardiac disease
■ Osteoporosis
■ Postmenopausal woman not being treated with bisphosphonates
■ Treatment can also be considered in patients who are <65 years
old and asymptomatic with no comorbidity
TSH 0.1−0.4 mU/L, treatment should be considered if
° If■ serum
≥65 years old
■ Hyperthyroid symptoms
■ Evidence of cardiac disease
■ Patient <65, asymptomatic with or without osteoporosis, can be
observed with monitor of thyroid function every 6−12 months
REFERENCES
Akamizu T, Satoh T, Isozaki O, et al. Diagnostic criteria, clinical features,
and incidence of thyroid storm based on nationwide surveys. Thyroid,
2012;22(7):661−79.
Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes
of thyrotoxicosis: management guidelines of the American Thyroid
Association and American Association of Clinical Endocrinologists.
Thyroid, 2011;21(6):593−646.
Brent GA. Clinical practice. Graves’ disease. N Engl J Med,
2008;358(24):2594−605.
Cooper DS, Biondi B. Subclinical thyroid disease. Lancet,
2012;379(9821):1142−54.
Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med,
2011;364(6):542−50.
48565_ST02_047-110.indd 61
5/1/13 9:34 PM
48565_ST02_047-110.indd 62
5/1/13 9:34 PM
11 ■ HYPOTHYROIDISM
Jaya Kothapally, MD and Marc J. Laufgraben, MD
BACKGROUND
• Hypothyroidism: insufficient thyroid hormone levels
hypothyroidism
° Primary
■ Usually due to disorders affecting the thyroid gland itself
■ Represents the overwhelming majority (~99%) of hypothyroidism
hypothyroidism
° Central
■ Due to disorders causing insuffi cient TSH
■ Includes both secondary hypothyroidism, where defect is in the
pituitary; and tertiary hypothyroidism, where the defect is in the
hypothalamus
■ Usually seen in conjunction with other aspects of hypopituitarism
• 10x more common in women compared to men
• Increased prevalence with aging
Causes of primary hypothyroidism
• Chronic autoimmune thyroiditis (also known as Hashimoto’s
thyroiditis [HT])
common cause in the developed world
° Most
° Can occur as part of autoimmune polyglandular syndromes
• Other forms of thyroiditis (subacute, silent, postpartum)
• Iodine deficiency
° Very common cause worldwide
• Thyroid surgery, radioiodine therapy, and ATDs
• External radiation (e.g., as part of cancer therapy)
• Medications, e.g., lithium, amiodarone, interferon-α, tyrosine-kinase
inhibitors (TKIs)
• Congenital hypothyroidism including thyroid gland agenesis and
defects in thyroid hormone synthesis
• Miscellaneous: infiltrative or infectious disorders, iodine excess,
thyroid hormone consumption from tumors expressing deiodinase
Causes of central hypothyroidism
• Essentially any disorder disrupting pituitary or hypothalamic function
(see Chapter 2, Hypopituitarism)
• Other causes: congenital abnormalities, defects in TRH or TSH
synthesis, medications (e.g., bexarotene)
48565_ST02_047-110.indd 63
5/1/13 9:34 PM
64 Hypothyroidism
TABLE 11.1 Clinical Presentation* of Hypothyroidism
Symptoms
Signs
Laboratory findings
Fatigue, low energy, weakness, arthralgias, myalgias,
cold intolerance, weight gain, depression, constipation,
sexual dysfunction, menorrhagia, dry skin, coarse brittle
hair and nails, decreased concentration, memory
impairment, slow speech, periorbital puffiness, headaches,
hoarseness
Bradycardia, hypertension, periorbital edema, reflex
delay, ⫹/⫺ goiter, lateral thinning of eyebrows (Queen
Anne’s sign), pericardial effusions, pleural effusion,
ascites
Macrocytic anemia, elevated creatine kinase,
hypercholesterolemia, hyponatremia
*Clinical presentation is highly variable, and individual findings have low sensitivity and low specificity.
DIAGNOSIS
• Testing should be entertained based on the presence of symptoms of
hypothyroidism
of general population is controversial
° Screening
of women who are pregnant or planning pregnancy is
° Screening
controversial
• TSH is best initial screening test (unless there is a suspicion for
central hypothyroidism)
TSH will exclude primary hypothyroidism
° Normal
FT4 in patients with elevated TSH
° Check
■ Low FT4 and elevated TSH is overt hypothyroidism
■ Normal FT4 and elevated TSH is subclinical hypothyroidism
(See Subclinical Hypothyroidism section on page 66)
of TPO antibody can confirm clinical suspicion of chronic
° Testing
autoimmune thyroiditis as the etiology, but is not usually necessary
in clinical practice
■ Exception: may have management implications in patients with
subclinical hypothyroidism
• If central hypothyroidism is suspected, check TSH and FT4
FT4
will be low and TSH will be low or “inappropriately normal”
° Check
pituitary MRI and other tests of pituitary function in patients
° with confi
rmed central hypothyroidism
48565_ST02_047-110.indd 64
5/1/13 9:34 PM
Treatment 65
TREATMENT
• Synthetic LT4 is treatment of choice
therapy with LT4 and T3 not demonstrated to be
° Combination
advantageous in most studies
Dessicated
porcine
thyroid should be avoided as it is not standard° ized and contains excess
T3
generic and branded LT4 formulations are available
° Both
■ Formulations differ in composition and absorption
■ Patients prescribed generic LT4 may receive different formulations each month that may result in fluctuations in thyroid
hormone levels with clinical consequences; for this reason, many
experts recommend use of branded LT4
• To avoid interference with absorption, LT4 should be taken on an empty
stomach (in the morning at least 30 minutes before breakfast or at
bedtime at least 2 hours after the evening meal) and separate from all
medications, vitamins, and supplements
• Can start with full replacement dose of 1.6 mcg/kg/day in young
healthy patients with overt hypothyroidism
should be rechecked 6 weeks after initiation and the dose
° TSH
adjusted if necessary, with further TSH assessment in another
6 weeks
TSH for most patients with primary hypothyroidism is within
° Goal
the normal lab reference range
■ Though controversial, there is no evidence to support that a
TSH goal in the lower part of the reference range improves
patient outcomes
■ TSH goal 0.5−2.5 reasonable in women who may become
pregnant as upper limit of normal range in first trimester
of pregnancy is 2.5 (see Chapter 18, Thyroid Disorders in
Pregnancy)
• In patients >60 years old or with documented heart disease, treatment
should be initiated with 25 mcg daily and increased incrementally
every 2−4 weeks until a normal TSH is achieved
• For patients with central hypothyroidism, treatment goal is a FT4 level
in the upper half of the normal reference range
patient also has central AI, initiate glucocorticoid replacement
° Ifbefore
thyroid replacement (thyroid hormone can accelerate cortisol
metabolism and initiate adrenal crisis)
• Women with hypothyroidism who become pregnant require LT4 dose
adjustment and frequent monitoring, and should be referred to an
endocrinologist or obstetrician with expertise in the management
of thyroid disease in pregnancy (see Chapter 18, Thyroid Disorders
in Pregnancy)
48565_ST02_047-110.indd 65
5/1/13 9:34 PM
66
Hypothyroidism
• AI should be considered in any patient with hypothyroidism who
appears to worsen after initiation of LT4
• If patient’s TFTs do not improve with anticipated doses of LT4, consider
malabsorption (including celiac disease), nonadherence with therapy,
and effect of coadministered medications
weekly therapy may be an option for poorly adherent patients
° Once
who are young and healthy
SUBCLINICAL HYPOTHYROIDISM
• Elevated (usually mildly) TSH with normal FT4 in a patient who is typically asymptomatic or minimally symptomatic
including TPO antibody should be repeated in 3 months to
° Testing
confirm the diagnosis
• Increased risk of progression to overt hypothyroidism in patients with
positive TPO antibodies and/or TSH >10
• Associated with dyslipidemia and other markers of enhanced cardiovascular risk
with LT4 to normalize thyroid parameters improves these
° Treatment
markers, but no evidence for improved patient outcomes
• Consider LT4 treatment in
with positive TPO antibodies
° Patients
with TSH >10
° Patients
Women
who
pregnant or planning a pregnancy
° Patients witharesevere
dyslipidemia
° Patients who are symptomatic
(3−6 month treatment trial; only
° continue if patient reports improvement)
• If patient to be monitored without treatment, check TSH and FT4
annually
MYXEDEMA COMA
• A state of severe decompensated hypothyroidism
seen in elderly women with longstanding hypothyroidism
° Typically
be initiated by illness or exposure to cold
° May
often includes change in mental status (ranging from
° Presentation
confusion to coma), hypothermia, bradycardia, and hypoventilation
which can progress to hypercarbic respiratory failure
may have features of severe hypothyroidism: very dry skin,
° Patients
nonpitting edema, macroglossia, hoarse voice, delayed reflexes,
pericardial effusion, ileus
addition to TFTs consistent with hypothyroidism, labwork may
° In
also show hyponatremia, hypoglycemia, hypercalcemia, macrocytic
anemia, elevated creatinine kinase; arterial blood gas (ABG) may
show hypoxia, hypercarbia, and acidosis
48565_ST02_047-110.indd 66
5/1/13 9:34 PM
References
67
• The diagnosis of myxedema coma is based on typical clinical presentation in a patient with elevated TSH and low FT4
severity of the clinical presentation may be disproportionate
° The
to the TFTs
Treatment
should not be delayed while awaiting TFT results
°
• Management
to intensive care unit (ICU)
° Admission
support if required
° Ventilatory
Fluid
resuscitation
° Passive rewarming and pressors if required
° Correct metabolic disturbances (hyponatremia, hypoglycemia)
° IV HC 100 mg q 8 hours for 24−48 hours
° ■ Rationale
• Cortisol production is low in severe hypothyroidism and
initiation of thyroid replacement can accelerate cortisol
metabolism resulting in a transient AI
• Patients with hypothyroidism may rarely have undiagnosed
primary AI as well
■ Consider definitive testing if signs of AI are evident as HC is
tapered
hormone therapy
° Thyroid
■ If clinical suspicion of myxedema coma is high, treatment should
not be delayed while awaiting TFT results
■ Should be initiated IV due to risk of poor oral absorption from
bowel edema and poor intestinal motility
■ Typical treatment is IV LT4 200−400 mcg daily for 2 days, followed by 50−100 mcg IV daily
• Patient can be changed to typical oral replacement dose as
condition improves
■ Use of IV T3 as an adjunct to IV LT4 in acute management of
myxedema coma is controversial but can be considered (typical
regimen is 10−20 mcg IV q 4 hours for the first 24−48 hours)
Seek
out and treat potential precipitating illness (e.g., infection,
° infarction)
advances in management, mortality from myxedema coma
° Despite
remains 25−50%
REFERENCES
Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am, 2012;96(2):203−21.
Devdhar M, Ousman YH, Burman KD. Hypothyroidism. Endocrinol Metab Clin
North Am, 2007;36(3):595−615.
Jones DD, May KE, Geraci SA. Subclinical thyroid disease. Am J Med,
2010;123(6):502−4.
48565_ST02_047-110.indd 67
5/1/13 9:34 PM
68
Hypothyroidism
McDermott MT. In the clinic. Hypothyroidism. Ann Intern Med,
2009;151(11):ITC6-1–ITC6–16.
Thyroid Disease Manager. Thyroidmanager.org. Accessed July 26, 2012.
Vaidya B, Pearce SH. Management of hypothyroidism in adults. BMJ,
2008;337:a801.
Yamada M, Mori M. Mechanisms related to the pathophysiology and
management of central hypothyroidism. Nat Clin Pract Endocrinol Metab,
2008;4(12):683−94.
48565_ST02_047-110.indd 68
5/1/13 9:34 PM
12 ■ NONTHYROIDAL ILLNESS SYNDROME
Maryam Khan, MD and Marc J. Laufgraben, MD, MBA
BACKGROUND
• Nonthyroidal illness syndrome (NTIS) refers to the complex
alterations in thyroid hormone metabolism occurring in acute and
chronic illness that affect the entire hypothalamic-pituitary-thyroid
(HPT) axis
to considerable difficulty in recognizing preexisting thyroid
° Leads
dysfunction in hospitalized patients
• NTIS is associated with increased mortality
triiodothyronine (T3) is an independent predictor of
° Low
survival
FT4
index
is associated with increased mortality
° Low T3/rT3<3ratio
and high reverse T3 (rT3) on the first day in the
° ICU are also associated
with increased mortality
PATHOPHYSIOLOGY
• Endocrine systems including the HPT axis are affected by inflammation, altered tissue perfusion, and other changes seen in systemic
illness
• Changes at all the levels of the HPT axis including neuroendocrine
regulation, peripheral transport, thyroid hormone metabolism and
receptor binding have been proposed to contribute to altered thyroid
hormone economy in NTIS
such as interleukin-1 (IL-1), IL-6, Interferon-alpha and
° Cytokines
TNF-α are hypothesized as mediators of NTIS
Changes
in
deiodinase activity are felt to be a major component
° ■ Type 1 deiodinase
(D1) catalyses the conversion of T4 to T3
and rT3 to T2; activity of D1 is decreased in patients with NTIS
resulting in reduced T3 levels
■ Type 2 deiodinase (D2) catalyses the conversion of T4 to T3 and
is present in the brain, anterior pituitary, thyroid gland, and
skeletal muscle; D2 is responsible for local T3 production in
these organs
■ Type 3 deiodinase (D3) catalyses the conversion of T4 to rT3 and
T3 to T2, also called inactivating enzyme; activation of D3 is
demonstrated in patients with critical illness
48565_ST02_047-110.indd 69
5/1/13 9:34 PM
70
Nonthyroidal Illness Syndrome
°
Other alterations
■ Reduced TRH gene expression due to elevated rT3 levels in
hypothalamus
■ Reduced levels of binding proteins leading to low total T4 levels
■ Increased monocarboxylate transporter 8 (MCT8) transport
proteins in skeletal muscle, which could increase uptake of T3
even at low tissue levels
■ Reduced uptake of T4 by the liver; inhibitors of thyroid hormone
binding (e.g., bilirubin and nonesterified fatty acids) may reduce
thyroid hormone uptake in the cells
■ Reduced T3 concentrations in tissues of patients with chronic
illness
■ Increased expression of active form of thyroid hormone receptor
to increase sensitivity to T3
• The changes in the HPT axis vary over the time course of the illness
Acute
changes similar to those seen in starvation (low T3,
° normalillness:
to low T4, and low FT3) are felt to represent an adaptive
response to illness with “conservation of resources”
illness: continued reduced activity of HPT axis;
° Chronic
debated as to whether this is adaptive or a form of central
hypothyroidism
improvement in thyroid hormone parameters seen during
° Recovery:
recovery phase of illness are marked by normal T4 and T3 and
slightly increased TSH levels
DIAGNOSTIC EVALUATION
• Measurement of thyroid hormone levels during systemic illness is
confounded by multiple factors: altered binding proteins, presence
of fatty acids that inhibit binding of thyroid hormones to proteins,
effects of concurrent medications (see Table 12.1), altered tissue
perfusion, etc.
• Most hospitalized patients with abnormal TFTs will have normal TFTs
on outpatient follow-up
in hospitalized patients should only be checked if there is a
° TFTs
strong clinical suspicion of underlying thyroid dysfunction
• Evaluation of thyroid status in hospitalized patients should include
measurement of both serum TSH and FT4; if either is abnormal, T3
should be also measured
• T3: low T3 is the most common alteration identified in NTIS
• TSH: TSH levels are highly variable in hospitalized patients
levels of 0.05−20 mIU/L are commonly seen in patients with
° TSH
NTIS
TSH
levels
mIU/L are suggestive of primary hypothyroidism
° TSH levels >20
<0.05 mIU/L are suggestive of thyrotoxicosis (confirmed
° if FT4 is elevated)
48565_ST02_047-110.indd 70
5/1/13 9:34 PM
References
71
TABLE 12.1 Effect of Drugs on Thyroid Hormone Economy
Mechanism
Suppress TSH
Inhibit peripheral conversion
Displace T4 from binding proteins
Increase T4 clearance
Alter thyroid hormone release
Drugs
Glucocorticoids, dopamine, opiates
Glucocorticoids, propranol,
benzodiazepines, amiodarone
Furosemide, salicylates
Barbiturates, antiepileptics
Iodine (IV contrast, dressings)
• FT4: FT4 levels are generally in the normal range during NTIS but may
be low in prolonged severe illness
FT4 generally is measured by analogue methods, which may
° Note:
be affected by binding protein abnormalities
• TT4: low TT4 is also a common finding in ICU patients due to reduced
levels of thyroid hormone binding proteins
• rT3: levels are commonly elevated in NTIS, but measurements of rT3
are not clinically useful as the results are not readily available
MANAGEMENT
• Treatment of NTIS with thyroid hormone replacement has not been
shown to improve outcome and may potentially be harmful
thyroid hormone economy in critical illness might
° beReduced
an adaptive mechanism to conserve energy and reduce
catabolism
• Thyroid hormone replacement should only be considered in situations
in which there is strong clinical suspicion and evidence of preexisting
thyroid dysfunction.
• TRH infusions are currently being investigated as an intervention in
patients with NTIS
REFERENCES
Adler SM, Wartofsky L. The nonthyroidal illness syndrome. Endocrinol Metab
Clin North Am, 2007;36(3):657−72.
Boelen A, Kwakkel J, Fliers E. Beyond low plasma T3: local thyroid
hormone metabolism during inflammation and infection. Endocr Rev,
2011;32(5):670−93.
48565_ST02_047-110.indd 71
5/1/13 9:34 PM
72 Nonthyroidal Illness Syndrome
Farwell, AP. Thyroid hormone therapy is not indicated in majority of
patients with the Sick Euthyroid Syndrome. Endocrine Practice,
2008;14:(9):1180−87
Hassan-Smith Z, Cooper MS. Overview of the endocrine response to critical illness: how to measure it and when to treat. Best Pract Res Clin
Endocrinol Metab, 2011;25(5):705−17.
Mebis L, Van-den Burghe, G. The hypothalamus Pituitary Thyroid axis in
critical illness. Neth J Med, 2009;67(10);331−40.
48565_ST02_047-110.indd 72
5/1/13 9:34 PM
13 ■ DRUGS AFFECTING THYROID FUNCTION
AND THYROID HORMONE REPLACEMENT
Guiseppe Barbesino, MD
GENERAL COMMENTS
• Drugs that affect TH absorption will affect patients relying on a fixed
amount of TH provided by thyroid hormone replacement therapy (THRT)
• Drugs that affect TH metabolism will generally only affect patients
relying on THRT, since most patients with a normally functioning
thyroid axis will be able to increase TH production to compensate for
increased TH metabolism
• Drugs that affect TH production by the thyroid will mostly affect
“normal” patients who rely on typical endogenous production of TH
DRUGS AFFECTING THYROID ABSORPTION
• Normal T4 absorption
of an ingested dose of T4 is absorbed
° 60−80%
is enhanced by gastric acid and occurs in the jejunum
° Absorption
and ileus
• Proton pump inhibitors (PPI) and H2 receptor antagonists
reduction of gastric acidity reduces T4 absorption
° Mechanism:
increased T4 requirement to meet TSH target in patients on
° Effects:
THRT; effect is variable and not confirmed in all studies
increase T4 dose, more frequent TFTs, patient
° Management:
education
• Sevelamer hydrochloride, lanthanum carbonate, and calcium carbonate (phosphate binders)
binding and insolubilization of thyroid hormone
° Mechanism:
marked decreased absorption of T4, increased T4 require° Effect:
ment to meet TSH target in patients on THRT
increase T4 dose, more frequent TFTs, patient
° Management:
education
• Iron and calcium supplements, including those contained in
multivitamins
binding and precipitation of thyroid hormone
° Mechanism:
decreased absorption of T4, increased T4 requirement to
° Effect:
meet TSH target in patients on THRT
interval of 3−4 hours between T4 intake and supple° Management:
ment intake, patient education
48565_ST02_047-110.indd 73
5/1/13 9:34 PM
74
Drugs Affecting Thyroid Function and Thyroid Hormone Replacement
• Bile acid sequestrants: cholestyramine and colsevelam
binding and precipitation of thyroid hormone
° Mechanism:
marked decreased absorption of T4, increased T4 require° Effect:
ment to meet TSH target in patients on THRT
increase T4 dose, more frequent TFTs, and patient
° Management:
education; since these medications are often given in several daily
doses, spacing has uncertain efficacy
cholestyramine has been used to treat endogenous and
° Note:
exogenous thyrotoxicosis
• Sucralfate and aluminum-based antacids
binding and precipitation of thyroid hormone
° Mechanism:
decreased absorption of T4, increased T4 requirement to
° Effect:
meet TSH target in patients on THRT
interval of 3−4 hours between T4 intake and supple° Management:
ment intake, patient education
• Raloxifene
unknown
° Mechanism:
decreased absorption of T4, increased T4 requirement to
° Effect:
meet TSH target in patients on THRT
increase T4 dose, more frequent TFTs, patient
° Management:
education
° Note: only case reports available
DRUGS AFFECTING THYROID HORMONE METABOLISM
• Main pathways regulating thyroid hormone metabolism
see Chapter 9, Thyroid Essentials and Thyroid
° Deiodinases:
Function Tests
Liver
enzymes
for glucuronidation and sulfation leading to biliary
° and urinary excretion
• Rifampicin, barbiturates, phenytoin, carbamazepine
increased liver glucuronidation of TH, other?
° Mechanism:
shorter half-life of absorbed TH
° Effect:
Management:
increase T4 dose (often up to 100%), more frequent
° TFTs, patient education
• Imatinib
unknown, likely increased liver metabolism of TH
° Mechanism:
increased T4 requirement to meet TSH target in patients
° Effect:
on THRT
increase T4 dose (often up to 100%), more frequent
° Management:
TFTs, patient education
48565_ST02_047-110.indd 74
5/1/13 9:34 PM
Drugs Directly Affecting Thyroid Function
75
DRUGS DIRECTLY AFFECTING THYROID FUNCTION
• Amiodarone
° Pharmacology
■ A 300-mg pill of amiodarone contains 111 mg of iodine
■ The rate of iodine release from amiodarone is estimated at 10% per day
■ Lipophilic drug with large distribution volume, half life is
40−60 days
Hypothyroidism
° ■ Early, transient variant
• Mechanism: iodine causing Wolff-Chaikoff effect
• Effect: mild, transient elevation of TSH at the initiation of
amiodarone therapy
• Management: if mild, monitor
■ Late, persistent variant
• Mechanism: precipitation of thyroid autoimmunity in predisposed subjects; cytotoxic effect of amiodarone
• Effect: overt, persistent hypothyroidism
• Management: start LT4, can continue amiodarone
Thyrotoxicosis
° Amiodarone-induced
■ Classifi cation
• Type I AIT
– Unremitting, severe, resistant hyperthyroidism; uncommon
– Mechanism: effect of large iodine load in patient with preexisting thyroid autonomy (mild Graves’ disease or nodular goiter)
• Type II AIT
– Moderate, self-limited thyrotoxicosis; more common than
type I AIT, especially in iodine-replete areas
– Mechanism: cytotoxic effect of drug resulting in destructive
thyroiditis
■ Differential diagnosis
• Type I AIT
– Suggestive: thyroid nodules on ultrasound, increased
thyroidal color flow-doppler
– Definitive: RAIU >3%, positive thyroid-receptor antibody
(TRAb)
• Type II AIT
– Suggestive: normal thyroid appearance on ultrasound, RAIU
<3%, increased serum IL-6 levels
■ Management
• Type I AIT
– MMI 40 to 60 mg daily
– Sodium perchlorate up to 500 mg BID (not available in
the US)
– Thyroidectomy in extreme situations
– Discontinuation of amiodarone should be considered
48565_ST02_047-110.indd 75
5/1/13 9:34 PM
76
Drugs Affecting Thyroid Function and Thyroid Hormone Replacement
• Type II AIT
– Prednisone 40 mg daily, tapered by 10 mg q 2 weeks, upon
favorable response
– Discontinuation of amiodarone may decrease risk of
relapses and speed response, but must be weighed against
benefits of amiodarone
• Note: when the distinction between types I and II cannot be
made with confidence (a frequent scenario), both MMI and
prednisone should be administered
• Lithium
increased intrathyroidal half-life of iodine, leading to
° Mechanisms:
decreased release of thyroid hormone; direct toxic effect on thyroid
follicular cells (both hypothetical)
° Effects
■ Goiter
• Proposed mechanism: increased intrathyroidal half-life of
iodine, leading to decreased release of thyroid hormone
• Incidence is variable across studies; simple, nontoxic, diffuse
goiter is most common
• Management: TSH suppression with LT4 may be considered
in otherwise healthy young subjects, but efficacy not well
documented
■ Hypothyroidism
• Proposed mechanism: increased intrathyroidal half-life of
iodine, leading to decreased release of thyroid hormone
• Incidence is variable across studies; more frequent in TPO
antibody-positive patients
• Management: THRT
■ Painless thyroiditis
• Proposed mechanism: direct toxic effect on thyroid follicular cells
• Clinical presentation: transient-mild to-moderate thyrotoxicosis
with low RAIU; thyroid antibody is negative in >50% of cases
• Management: symptom control with β-blockers if necessary
• Alemtuzumab
unknown; humanized anti-CD-52 used in multiple
° Mechanism:
sclerosis
When
used
in
multiple sclerosis, 20−30% of patients devel° oped Graves’ disease;
smaller number developed autoimmune
hypothyroidism
Management:
usual
Graves’
disease or hypothyroidism treatment
°
• Interferon-α
induction of thyroid autoimmunity
° Mechanism:
are variable
° Effects
■ Development of thyroid antibodies
• Incidence: 10−40%
• Management: monitor TFTs
48565_ST02_047-110.indd 76
5/1/13 9:34 PM
Drugs Causing Central Hypothyroidism
77
Clinical thyroid dysfunction
• Incidence: 5−15%
• Destructive thyroiditis
– Incidence: 50% of thyroid dysfunctions
– Thyroid antibody often negative
– Management: β-blockers in the hyperthyroid phase, prompt
correction of hypothyroidism
• Classical HT with or without hypothyroidism
– Incidence: unknown, but more likely in patients with
preexisting thyroid autoantibody
– Management: treatment of hypothyroidism
• Graves’ disease
– Incidence: uncommon
– Management: usual management of Graves’ disease
• Interleukin-2
Mechanism:
induction of autoimmunity? (Most cases are associated
° with the development
of anti-TPO antibody)
20−40%
° Incidence:
be preceded by transient thyrotoxicosis
° May
° Management: treatment of hypothyroidism
• Sunitinib and sorafenib (TKI)
damage to thyroid microvasculature
° Mechanism:
with hypothyroidism in 30−50% of cases
° Associated
Mild
thyrotoxicosis
seen early on in a minority of cases
° Management: frequent
TSH checks, usual management of
° hypothyroidism
■
DRUGS CAUSING CENTRAL HYPOTHYROIDISM
• Bexarotene
direct suppression of the b-TSH gene transcription
° Mechanism:
in profound symptomatic central hypothyroidism in 70%
° Results
of cases
° Management: FT4 monitoring and THRT
• Glucocorticoid
transient TSH suppression
° Mechanism:
of the transient nature of the phenomenon, this does not
° Because
cause hypothyroid symptoms
• Dopamine
TSH suppression
° Mechanism:
DA is only used short-term, it mostly causes problems in the
° Since
interpretation of TFTs
48565_ST02_047-110.indd 77
5/1/13 9:34 PM
78
Drugs Affecting Thyroid Function and Thyroid Hormone Replacement
REFERENCES
Barbesino G. Drugs affecting thyroid function. Thyroid, 2010;20(7):763−70.
Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate
reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern
Med, 1992;117(12):1010−3.
Eskes SA, Wiersinga WM. Amiodarone and thyroid. Best Pract Res Clin
Endocrinol Metab, 2009;23(6):735−51.
Lazarus JH. Lithium and thyroid. Best Pract Res Clin Endocrinol Metab,
2009;23(6):723−33.
Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine
absorption. Best Pract Res Clin Endocrinol Metab, 2009;23(6):781−92.
Roti E, Minelli R, Giuberti T, et al. Multiple changes in thyroid function in
patients with chronic active HCV hepatitis treated with recombinant
interferon-alpha. Am J Med, 1996;101(5):482−7.
Wong E, Rosen LS, Mulay M, et al. Sunitinib induces hypothyroidism in
advanced cancer patients and may inhibit thyroid peroxidase activity.
Thyroid, 2007;17(4):351−5.
48565_ST02_047-110.indd 78
5/1/13 9:34 PM
14 ■ THYROID NODULE EVALUATION
Ole-Petter R. Hamnvik, MBBCh, BAO and Erik K. Alexander, MD
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
• Palpable nodules are present in 5−10% of women and 1% of men;
prevalence by ultrasound is 19−67%
• Most nodules are benign (85−90%), asymptomatic, and nonfunctional
(i.e., do not produce thyroid hormone)
• Multiple nodules are frequently present; the risk of malignancy in
a given patient is the same whether there is one nodule or multiple
nodules
• Over 50,000 new cases of thyroid cancer are diagnosed annually in
the US
• If cancerous, ~95% are well-differentiated malignancies (papillary
carcinoma or follicular carcinoma) which arise from the thyroid follicular cell; <5% are medullary carcinoma arising from C-cells, and
<1% are anaplastic carcinoma
CLINICAL PRESENTATION
• History
thyroid nodules (90%) are incidental and asymptomatic, often
° Most
detected upon separate imaging (such as CT or MRI) or on physical
examination
present with symptoms, most commonly a sensation of a
° 10%
throat mass; other rare symptoms include voice change (hoarseness), neck pain, or difficulty swallowing
evaluation should focus on identifying factors that impart a
° Initial
higher risk of thyroid cancer. These include a history of childhood
head or neck radiation (before age 16), a family history of thyroid
cancer (or familial syndromes associated with thyroid cancer such
as MEN2, familial adenomatous polyposis, or Cowden’s syndrome),
and high-risk signs or symptoms including hoarseness, dysphagia,
dysphonia, cough, enlarged cervical lymph nodes, large nodules
>4 cm, and rapidly growing nodules
patient should be asked about symptoms of thyrotoxicosis such
° The
as sweating, tremors, heat intolerance, or weight loss, as these may
signal a functional (or “hot”) nodule
48565_ST02_047-110.indd 79
5/1/13 9:34 PM
80
Thyroid Nodule Evaluation
• Physical examination
thyroid isthmus is palpable just below the thyroid and cricoid
° The
cartilage, with a right and left lobe extending laterally and posteriorly along the trachea
examination should always be performed with a glass of water,
° The
with instructions to swallow at the time of examination; observation
and palpation may detect asymmetry, nodules, or tenderness
thyroid gland is best palpated with the patient sitting upright,
° The
head facing straight forward or slightly downward (to relax the
strap muscles)
of the thyroid should assess the size and location of
° Examination
the gland, as well as any nodules
■ Nodules should be assessed for size, texture, tenderness, and
fixation to surrounding structures
■ Tracheal deviation should be assessed
■ Voice quality should also be analyzed for hoarseness.
a nodule that is functional, evidence of thyroid hormone excess
° In
may also be found
DIAGNOSTIC EVALUATION
• Laboratory testing
a nodule is suspected or detected upon examination, a serum TSH
° Ifconcentration
should be measured
• Imaging
the TSH is suppressed, a functional (or “hot” nodule) should be
° Ifruled
out via a thyroid scan
■ If a hot nodule is identifi ed, the risk of malignancy is nearly
zero, and cytologic evaluation is not necessary; hyperthyroidism,
however, must be treated (see Chapter 10, Thyrotoxicosis and
Hyperthyroidism)
Ultrasound
imaging should be performed on all nodules that are not
° hyperfunctioning
(i.e., in patients with normal or elevated TSH, or
patients with “cold” nodules detected on thyroid scan irrespective
of serum TSH)
■ Ultrasound is optimal imaging modality for the thyroid, as it can
obtain high-resolution images of the thyroid gland and confirm
the presence and location of nodules
■ Sonographic features can predict cancer risk; those associated
with increased cancer risk include
• Microcalcifications
• Hypoechogenicity
• Irregular borders
• Presence of lymphadenopathy (especially unilateral)
48565_ST02_047-110.indd 80
5/1/13 9:34 PM
Management 81
■
■
Sonographic features associated with a decreased risk of
cancer include
• >75% cystic fluid
• Spongiform appearance
If two or more high-risk sonographic features are present, the
risk of malignancy is >90%; if one or more low-risk sonographic
features are present, the risk of malignancy is <2%; most
cancers, however, are sonographically unremarkable
MANAGEMENT
• In most circumstances, FNA should be performed on nodules larger
than 1.0−1.5 cm; however, the decision to perform FNA should be
guided by the nodule size as well as other clinical factors (Table 14-1)
° The goal of FNA is to obtain a sample of cells for cytologic examination
• Whenever possible, ultrasound guidance should be used to guide all
FNAs. Under direct visualization, a 24−27 gauge needle is inserted
into the solid component of the nodule. Ultrasound guidance minimizes
nondiagnostic samples and improves sampling accuracy
• Following insertion, the needle is rapidly moved back and forth within
the nodule for about 5 seconds. Cellular material enters the needle tip by
capillary action whether suction is applied or not. Most often 3−4 separate needle samples constitute a complete FNA from a thyroid nodule
• There are few absolute contraindications to thyroid nodule FNA, though
anticoagulation is a relative contraindication because of increased
risk for bleeding
• FNA can also be used to drain >75% cystic nodules, providing symptom relief and decompression
• FNA cytology should be read by an experienced cytopathologist, and
classified using the Bethesda classification system (Table 14-2)
TABLE 14.1 Decision-Making for Thyroid FNA
Clinical/Imaging Features
If high-risk clinical history*
If high-risk features on imaging†
If a solid nodule
If >75% cystic or spongiform nodule
If 100% cystic
If abnormal lymph nodes are detected
Size Threshold to Consider FNA
>0.5 cm
>0.5–1.0 cm
>1.0 cm
>1.5–2.0 cm
No FNA (unless for symptom relief)
>0.5–1.0cm
* High-risk history includes childhood radiation exposure, a family history of thyroid cancer, and known
RET protooncogene mutations.
† High-risk features on imaging include ultrasound findings of microcalcifications, hypoechogenicity,
irregular borders, the presence of lymphadenopathy, or 18FDG avidity on positron emission tomography
(PET) scanning.
48565_ST02_047-110.indd 81
5/1/13 9:34 PM
82
Thyroid Nodule Evaluation
TABLE 14.2 Thyroid Nodule Malignancy Risk by Cytologic Diagnosis
Cytology Category
Nondiagnostic or unsatisfactory
Benign
Atypia of undetermined significance (AUS) or follicular lesion of
undetermined significance (FLUS)
Follicular neoplasm or suspicious for a follicular neoplasm
Suspicious for papillary carcinoma
Malignant
Cancer Risk
1–4%
0–3%
5–15%
20–30%
60–75%
97–99%
• Nondiagnostic samples occur when there is insufficient cellular material for diagnosis (<6 follicular groups, each with 10−15 cells); the
FNA should be repeated to obtain a sufficient sample, as a diagnostic
specimen is subsequently obtained in >50% of cases
• If cytology is malignant (most often papillary thyroid cancer), the
patient should be referred for thyroid surgery
• If cytology is indeterminate (AUS/FLUS, suspicious for a follicular or
Hürthle cell neoplasm, or suspicious for papillary carcinoma)
referral for surgery (hemithyroidectomy or thyroidectomy):
° Consider
this is performed for diagnostic as well as therapeutic purposes;
>50% of indeterminate nodules prove benign upon histopathology
molecular testing of the nodule. Molecular markers such
° Consider
as BRAF, RAS, RET/PTC and PAX8/PPARG have a high positive
predictive value. A separate gene expression classifier test called
Afirma has a high negative predictive value (>95%).
conservative follow-up without intervention if malignancy
° Consider
risk is low or outweighed by the estimated morbidity or risk from
any intervention
• If cytology is benign, a repeat ultrasound in 12−24 months, and then
every 3−5 years thereafter; a repeat FNA should be performed if the
nodule has increased in size by ≥20% in two or more dimensions
• Surgical removal should be considered for benign nodules if they cause
compressive symptoms, or grow >4 cm in diameter
REFERENCES
American Thyroid Association Guidelines Taskforce on Thyroid Nodules
and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, et al.
Revised American Thyroid Association management guidelines for
patients with thyroid nodules and differentiated thyroid cancer. Thyroid,
2009;19(11):1167−214.
48565_ST02_047-110.indd 82
5/1/13 9:34 PM
References
83
Cibas ES, Ali SZ. The Bethesda System for reporting thyroid cytopathology.
Am J Clin Pathol, 2009;132(5):658−65.
Hegedüs L. Clinical practice. The thyroid nodule. N Engl J Med,
2004;351(17):1764−71.
Moon WJ, Jung SL, Lee JH, et al. Benign and malignant thyroid nodules:
US differentiation—multicenter retrospective study. Radiology,
2008;247(3):762−70.
Sherman SI. Thyroid carcinoma. Lancet, 2003;361(9356):501−11.
48565_ST02_047-110.indd 83
5/1/13 9:34 PM
48565_ST02_047-110.indd 84
5/1/13 9:34 PM
15 ■ PAPILLARY AND FOLLICULAR
THYROID CARCINOMA
Hilary Whitlatch, MD
DEFINITION
• Differentiated thyroid cancer (DTC) includes papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) and accounts for
>90% of all thyroid cancer
EPIDEMIOLOGY
• DTC is the most common endocrine malignancy, although it represents
<1% of all human tumors
° 85% PTC, 10% FTC, 3% Hurthle cell (aggressive FTC subtype)
• PTC affects women more often than men (2.5:1), has a higher
incidence among Caucasians than African Americans, and is typically
diagnosed at age 30−50 years
• FTC affects older patients (>40 years of age) and incidence does not
vary substantially by race
• Yearly incidence of DTC has increased from 3.6 per 100,000 in 1973 to
8.7 per 100,000 in 2002 (2.4-fold increase)
the entire change is attributable to an increase in the
° Almost
incidence of PTC
of the rise is attributable to cancers measuring ≤2 cm
° 89%
■ Suggests that earlier diagnosis of small DTC is occurring through
widespread use of neck ultrasonography and FNA cytology
• Despite increasing incidence, the mortality from DTC has declined over
the last 3 decades
if this is due to earlier diagnosis or improved treatment in
° Unclear
disease
RISK FACTORS
• Head and neck external beam radiation therapy (EBRT), particularly
during childhood
used to treat benign childhood conditions (acne, skin
° Previously
lesions)
Treatment
of malignancies
°
• Exposure to a nuclear explosion or fallout
• History of thyroid cancer in a first-degree relative
48565_ST02_047-110.indd 85
5/1/13 9:34 PM
86
Papillary and Follicular Thyroid Carcinoma
• Family history of a syndrome associated with thyroid cancer
complex: developmental delay, pigmented nodular adreno° Carney
cortical disease, myxomas, breast adenomas, PTC and FTC
Werner
syndrome: connective tissue disease, progeria, osteosar° coma, soft
tissue sarcoma, PTC and FTC
syndrome: harmartomas and DTC
° Cowden’s
° Familial polyposis: gastrointestinal adenomatous polyps and PTC
• In areas of iodine deficiency, there is a higher prevalence of follicular
cancer (mechanism unclear)
PATHOGENESIS
• Mutations in the mitogen-activated protein kinase pathway (MAPK)
are often responsible for malignant transformation of thyroid follicular
cells
is a complex sequential phosphorylation cascade pathway
° This
involving serine/thyronine kinases that ultimately acts in the cell
nucleus to promote cell division
occurs when this pathway is constitutively activated
° Tumorigenesis
by mutations in associated genes (RET, TRK, RAS, or BRAF)
■ Activating mutations have been found in up to 70% of DTC
■ Tumors with a BRAF mutation are more aggressive, with higher
rates of extrathyroidal extension, lymph node metastases, and
recurrence
• Inactivating mutations of tumor suppressor genes, such as p53, can
be seen in FTC
• The gene fusion product of thyroid-specific transcription factor (PAX8)
and the nuclear receptor peroxisome proliferator-activated receptor
gamma (PPARγ) results in loss of growth inhibition; associated with
10% of follicular adenomas and 41% of follicular cancers
• VEGF plays a significant role in the process of neovascularization
associated with malignancy; VEGF and its receptors are overexpressed
in thyroid cancer, promoting blood supply and playing an important
role in tumorigenesis and progression
PATHOLOGICAL FEATURES
• PTC is characterized by layers of tumor cells surrounding a fibrovascular core to form papillae
nuclei are oval, large, and overlapping, and may contain
° The
hypodense chromatin, pseudoinclusions, and nuclear grooves
Psamomma
bodies are seen in 50% of PTC; these are round collec° tions of calcium
that form when papillae infarct
PTC is multifocal, either due to intrathyroidal metastasis or
° Often,
due to multiple cancerous clones
48565_ST02_047-110.indd 86
5/1/13 9:34 PM
Prognosis
87
to 80% of patients with PTC have lymph node metastasis at the
° Up
time of diagnosis
■ 1/3 are clinically evident on exam or preoperative ultrasound,
2/3 are microscopic
of patients with PTC have metastases beyond the neck at
° 2−10%
the time of diagnosis
■ Most commonly pulmonary (60%) and skeletal (25%)
• FTC histology ranges from well-differentiated epithelium with clearly
identifiable follicles and colloid to poorly differentiated solid tumors
with marked nuclear atypia and absence of follicles
cell cancer, a variant of FTC, contains eosinophilic oxyphilic
° Hurthle
cells with abundant cytoplasm, closely packed mitochondria, and
round oval nuclei with prominent nucleoli
FTC from a benign follicular adenoma requires
° Distinguishing
identification of vascular invasion or tumor extension through the
tumor capsule
are usually uninodular
° Tumors
node spread is present in 8−13% of cases
° Lymph
° Distant metastases occur in 10−15% of cases
CLINICAL PRESENTATION AND DIAGNOSIS
• DTC is generally detected by palpation or neck ultrasound
• Nodule features on ultrasound associated with malignancy include
hypoechogenicity, microcalcifications, absence of peripheral halo,
irregular borders, solid aspect, increased vascularity, and being taller
than wide
• The gold standard for diagnosis of malignancy is FNA cytology
diagnosis can reliably be made by FNA cytology
° PTC
cytology cannot distinguish benign follicular adenoma/
° FNA
neoplasm from FTC
FTC
can
only be diagnosed by histologic examination of the nodule
° and identifi
cation of vascular or capsular invasion
FNA cytology is suggestive of a follicular neoplasm, surgery is
° Ifrecommended
to determine whether the tumor is FTC (20−30% risk)
PROGNOSIS
• Both PTC and FTC have a generally good prognosis with overall
mortality <10%
• Certain clinical/pathologic features are associated with worse
prognosis
age at diagnosis: involvement of lymph nodes does not affect
° Older
survival of patients <45 years old, but increases risk of death by
46% in those ≥45 years old
48565_ST02_047-110.indd 87
5/1/13 9:34 PM
88
Papillary and Follicular Thyroid Carcinoma
°
°
°
°
°
Larger tumors
Soft tissue invasions increases the risk of death fivefold
Distant metastases
Certain histologic subtypes
■ PTC: tall cell variant, columnar cell variant, diffuse sclerosing
variant
■ FTC: Hurthle cell, insular thyroid cancer
Certain gene mutations, including BRAF mutation
TUMOR NODE METASTASIS (TNM) CLASSIFICATION
• Useful in determining overall risk of mortality from DTC
• Primary tumor (T)
no evidence of primary tumor
° T0:
≤1 cm, limited to thyroid
° T1a:
T1b:
cm but ≤2 cm, limited to thyroid
° T2: >2>1cm
≤4 cm, limited to thyroid
° T3: >4 cm,but
limited to thyroid or minimal extrathyroidal extension
° (sternothyroid
muscle or perithyroid soft tissues)
tumor extends beyond thyroid capsule and invades subcutane° T4a:
ous (SQ) soft tissues, larynx, trachea, esophagus, or recurrent
laryngeal nerve
tumor invades prevertebral fascia or encases carotid artery or
° T4b:
mediastinal vessels
• Regional lymph nodes (N)
no metastatic nodes
° N0:
metastases to level VI (pretracheal, paratracheal, prelaryn° N1a:
geal) lymph nodes
° N1b: metastases to cervical or superior mediastinal nodes
• Distant metastases (M)
no distant metastases
° M0:
° M1: distant metastases
TABLE 15.1 TNM Staging
Stage I
Stage II
Stage III
Stage IVA
Stage IVB
Stage IVC
48565_ST02_047-110.indd 88
<45 years of age
Any T, any N, M0
Any T, any N, M1
≥45 years of age
T1, N0, M0
T2, N0, M0
T3, N0, M0
T1−3, N1a, M0
T4a, N0−1a, M0
Any T, N1b, M0
T4a, N1b, M0
T4b, any N, M0
Any T, any N, M1
5/1/13 9:34 PM
Initial Treatment of DTC
89
INITIAL TREATMENT OF DTC
• Surgery is the primary therapy for DTC
thyroidectomy if >1 cm, extrathyroidal extension, or lymph
° Total
node metastases
Unilateral
and isthmusectomy can be considered if tumor
° <1 cm andlobectomy
confined to one lobe
DTC is incidentally diagnosed on pathology after surgery
° Ifforunifocal
presumed benign thyroid disease, a completion thyroidectomy
should be performed unless tumor <1 cm, intrathyroidal, and of
favorable histologic type (papillary, follicular variant papillary,
minimally invasive follicular)
neck dissection if evidence of nodal involvement on exam
° Regional
or preoperative ultrasound
American Thyroid Association also recommends prophylac° The
tic central neck dissection in patients with advanced papillary
cancer (T3 or T4) even in the absence of clinical evidence of nodal
involvement
• RAI ablation of the thyroid tissue remnant not removed during initial
surgery has several potential benefits
initial staging by identifying previously undiagnosed
° Facilitates
regional or distant metastatic disease on posttreatment whole
body scan
long-term follow-up in enabling early detection of recur° Facilitates
rence based on serum Tg measurement or RAI whole body scan
Serves
as
adjuvant
therapy by destroying persistent thyroid cancer
° cells, thereby reducing
risk for recurrence or DTC-specific mortality
in certain subsets of patients
■ Proven to decrease risk of death and risk of recurrence in patients
≥45 years of age with tumors >4 cm and in those patients with
gross extrathyroidal extension and distant metastases
for those with known distant metastases, gross
° Recommended
extrathyroidal extension, or primary tumor >4 cm
Recommended
select patients with tumor 1−4 cm confined to
° thyroid who havein documented
lymph node metastases or other
high-risk features (vascular invasion, aggressive histologic
subtypes)
RAI ablation (30−100 mCi131I) is performed following LT4 with° drawal
(to achieve a TSH >30) or recombinant-human TSH (rhTSH)
stimulation after 2 weeks of a low-iodine diet to maximize 131I
uptake by remnant thyroid tissue
• LT4 therapy minimizes potential TSH stimulation of tumor growth
TSH suppression <0.1 mU/L is recommended for high-risk
° Initial
and intermediate risk DTC patients
Initial
TSH
° patients suppression 0.1−0.5 mU/L is appropriate for low-risk
48565_ST02_047-110.indd 89
5/1/13 9:34 PM
90
Papillary and Follicular Thyroid Carcinoma
Assessing Risk of Recurrence
• While useful in predicting disease-specific mortality, TNM staging is
less useful in assessing risk of recurrence
patients have a low risk of DTC-related death, but may have
° Young
significant risk of recurrence
• The American Thyroid Association has proposed a system to stage risk
of recurrence based on tumor-related parameters and other clinical
features
TABLE 15.2 Features Indicating Risk of Recurrence of DTC
Low Risk
Intermediate Risk
High Risk
• No local or distant
metastases
• All macroscopic tumor
has been resected
• No invasion of local
tissues
• No aggressive histology
or vascular invasion
• No 131I uptake outside
thyroid bed on
posttreatment whole
body scan
• Microscopic invasion
into perithyroidal soft
tissues
• Cervical lymph node
metastases
• 131I uptake outside
thyroid bed on
posttreatment whole
body scan
• Aggressive histology or
vascular invasion
• Macroscopic tumor
invasion
• Incomplete tumor
resection
• Distant metastasis
• Thyroglobulin levels
higher than would be
expected for 131I uptake
on posttreatment whole
body scan
LONG-TERM MANAGEMENT
• Changes in serum Tg over time are useful in monitoring patients for
recurrence, provided thyroglobulin antibodies (TgAb), which interfere
with Tg assays, are not present
rise in Tg or conversion from negative to positive TgAb status
° Ashould
prompt imaging studies to evaluate for recurrence
• Patients who have undergone total thyroidectomy and RAI remnant
ablation should be assessed for remission 6−12 months after initial
treatment
on thyroid hormone suppression should be undetectable in the
° Tg
absence of TgAb
bed and neck ultrasound to evaluate for abnormal lymph° Thyroid
adenopathy or new/persistent tissue in thyroid bed, which would
warrant biopsy
TgAb negative, measurement of serum Tg after T4 withdrawal or
° IfrhTSH
stimulation
■ A stimulated Tg <1 ng/ml with negative antibodies suggests
disease remission
If TgAb positive, whole-body 123I uptake scans after thyroid hormone
° withdrawal
or rhTSH stimulation
■ Uptake would suggest persistent/recurrent disease
48565_ST02_047-110.indd 90
5/1/13 9:34 PM
Management of Persistent/Recurrent Disease
91
ultrasound is negative for recurrent disease and
° Provided
stimulated Tg <1 ng/ml or stimulated whole-body uptake scan is
negative, low-risk patients can subsequently be followed up with a
yearly clinical exam and Tg/TgAb measurement on thyroid hormone;
neck ultrasounds may also be done periodically
• In patients who have undergone less than a total thyroidectomy
and those who have had a total thyroidectomy but not RAI ablation,
periodic serum Tg/TgAb measurements (every 6−12 months) are
recommended, along with neck ultrasounds
specific Tg cutoff levels during TSH suppression distinguish° While
ing normal residual thyroid tissue from persistent DTC are unknown
in this group of patients, rising Tg value over time is suspicious for
persistent/recurrent disease
• TSH suppression
patients with persistent disease, TSH should be maintained
° In
<0.1 mU/L in the absence of specific contraindications (significant
thyrotoxic symptoms, history of heart disease/cardiac arrhythmias,
osteoporosis)
patients clinically and biochemically free of disease but who
° In
presented with high-risk disease, TSH should be maintained at
0.1−0.5 mU/L for 5−10 years
patients free of disease and at low risk for recurrence, TSH may
° In
be kept in low−normal range (0.3−2.0)
MANAGEMENT OF PERSISTENT/RECURRENT DISEASE
• Detected by clinical examination, rising serum Tg concentration, or
neck ultrasound
neck ultrasound does not reveal disease location, other imaging
° Ifmodalities
include MRI, CT, skeletal X-rays, RAI whole body scans,
and PET (PET is particularly useful if tumor does not concentrate
RAI)
• Surgery is useful to remove clinically significant lymph nodes or
solitary distant metastases
of surgical complications must be weighed against overall
° Risk
disease prognosis
• RAI therapy: rhTSH-stimulated or LT4 withdrawal 131I therapy is useful,
provided there is persistent radioidine uptake
° Tumors may fail to concentrate iodine due to dedifferentiation
• External radiotherapy is useful in patients with aggressive local
disease and bone metastases
• Ethanol injection of cervical nodal metastases
• Radiofrequency ablation of cervical, bone, or pulmonary metastases is
an alternative in poor surgical candidates with RAI-resistant tumors
• Combination cytotoxic chemotherapy has been shown to be minimally
effective in treating progressive thyroid cancer
48565_ST02_047-110.indd 91
5/1/13 9:34 PM
92
Papillary and Follicular Thyroid Carcinoma
• Novel therapies that target the distal steps in the MAPK pathway and
inhibit the action of VEGF are currently under investigation for the
treatment of advanced/resistant DTC
include axitinib, lenvatinib, motesanib, pazopanib, sorafenib,
° TKIs
sunitinib, and vandetanib
REFERENCES
American Thyroid Association (ATA) Guidelines Taskforce on Thyroid
Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM,
et al. Revised American Thyroid Association management guidelines for
patients with thyroid nodules and differentiated thyroid cancer. Thyroid,
2009;19(11):1167−214.
Aschebrook-Kilfoy B, Ward MH, Sabra MM, Devesa SS. Thyroid cancer
incidence patterns in the United States by histologic type, 1992–2006.
Thyroid, 2011;21(2):125−34.
Fagin JA, Mitsiades N. Molecular pathology of thyroid cancer: diagnostic and clinical implications. Best Pract Res Clin Endocrinol Metab,
2008;22(6):955−69.
Jonklaas J, Sarlis NJ, Litofsky D, et al. Outcomes of patients with
differentiated thyroid carcinoma following initial therapy. Thyroid,
2006;16(12):1229−42.
Kojic KL, Kojic SL, Wiseman SM. Differentiated thyroid cancers: a comprehensive review of novel targeted therapies. Expert Rev Anticancer Ther,
2012;12(3):345−57.
Pacini F, Castagna MG. Approach to and treatment of differentiated thyroid
carcinoma. Med Clin North Am, 2012;96(2):369−83.
48565_ST02_047-110.indd 92
5/1/13 9:34 PM
16 ■ MEDULLARY THYROID CANCER
Jennifer Sipos, MD
PATHOPHYSIOLOGY
• Malignancy of calcitonin-secreting parafollicular C cells of the thyroid
gland, derived from the neural crest
start as C-cell hyperplasia (CCH), which progresses to
° May
invasive MTC
may be seen as a secondary condition not associated with MTC
° CCH
inherited disease in ~25%; caused by a
° Autosomal-dominant
germline mutation in the rearranged during transfection (RET )
proto-oncogene; typically multifocal or bilateral
° Sporadic in ~75%, typically unifocal
• The inherited form of medullary thyroid cancer (MTC) may be associated with other endocrine tumors, termed MEN
pheochromocytoma, MTC
° MEN2A-hyperparathyroidism,
mucosal neuromas of the lips and
° MEN2B-pheochromocytoma,
tongue, ganglioneuromatosis of the GI tract, Marfanoid body
habitus, MTC
medullary thyroid cancer (FMTC)-inherited MTC is the only
° Familial
manifestation; at least four family members with no other signs or
symptoms of pheochromocytoma or hyperparathyroidism
TABLE 16.1 Features of Familial Syndromes Associated with Medullary
Thyroid Cancer
Syndrome
MEN2A
MEN2B
FMTC
MTC
Yes
Yes
Yes
Hyperparathyroidism
Yes
No
No
Pheochromocytoma
Yes
Yes
No
Epidemiology
• 3% of all thyroid cancers are MTC
1 in 30,000 people.
° Affects
to 2000 new cases of MTC in US annually
° 1000
Age
at
diagnosis
is older for sporadic cases (51 years) than genetic
° (21 years)
5-year survival for MTC, compared to 94% in patients with
° 83%
PTC; survival is affected by tumor size (stage) at diagnosis, younger
age at diagnosis, and diagnosis by screening (familial form)
48565_ST02_047-110.indd 93
5/1/13 9:34 PM
94
Medullary Thyroid Cancer
CLINICAL PRESENTATION
• Nodule/mass: mass effect from local tumor compression; hoarseness,
dysphagia, lymphadenopathy
• Flushing, diarrhea: unclear etiology, possibly from humoral secretions
by the tumor
• Pheochromocytoma: tumor of the catecholamine-producing chromaffin
cells of the adrenal medulla; presents with refractory hypertension;
may also present with abdominal pain, flushing, and headaches;
poses a risk to health and life if left untreated
• Hyperparathyroidism: may present with kidney stones or fractures
DIAGNOSIS
• Imaging is typical method of initial detection
of the neck reveals thyroid nodule and possibly meta° Ultrasound
static lymph nodes
of the chest may reveal lymph node involvement in mediastinum
° CT
or pulmonary nodules
CT
of
the abdomen may reveal hepatic metastases
°
• FNA under ultrasound guidance into thyroid nodule or suspicious lymph
node
staining for calcitonin
° Immunohistochemical
° Amyloid deposits seen on pathology
• Genetic testing: RET gene testing should be performed in all patients
with MTC; if positive, all first-degree family members should also be
tested
family members who have a RET mutation should have
° Those
a prophylactic thyroidectomy; penetrance of disease in carriers
is very high
• Elevated serum calcitonin
calcitonin >10 pg/ml is elevated
° Basal
■ May be elevated in males and smokers and those with renal
failure, nodular thyroid disease, or Hashimoto’s thyroiditis
calcitonin after pentagastrin infusion (not available in
° Stimulated
US) or calcium injection (not standardized); stimulated values are
more sensitive than basal, but not specific
• Primary hyperparathyroidism (PHPT)
serum parathyroid hormone (PTH)
° Elevated
° Elevated serum calcium
• Pheochromocytoma
plasma metanephrines (MNs) or 24-hour urine
° Fractionated
catecholamines and MNs
If
biochemical
testing is positive, then localizing study with MRI or
° metaiodobenzylguanidine
(MIBG) can be considered
48565_ST02_047-110.indd 94
5/1/13 9:34 PM
Therapy
95
CLINICAL FEATURES
• Locoregional metastases: cervical lymph node metastases occur early
in the disease course and can be seen even with tumors measuring
several millimeters
• Distant metastases: tumors over 1.5 cm are more likely to metastasize
to distant sites (i.e., lung, liver, and bone)
• Cushing’s syndrome: tumor may secrete ACTH
STAGING
• When lymph node metastases are identified or when preoperative calcitonin is >400 pg/mL, CT scanning for distant metastases is advised
with focus on the neck, chest, and liver
• PET scanning is not advised in MTC for initial screening for
metastases
• Testing for parathyroid tumors and pheochromocytoma is advised prior
to thyroidectomy
• Staging is based on the American Joint Committee on Cancer pTNM
staging
I: <2 cm with no evidence of disease outside of the thyroid
° Stage
II: any tumor 2−4 cm with no evidence of extrathyroidal
° Stage
disease
Stage
III:
any tumor >4 cm, central neck nodal metastases, or
° microscopic
extrathyroidal invasion regardless of tumor size
IV: any distant metastases or lymph node involvement
° Stage
outside of the central neck, or gross soft tissue extension
THERAPY
• Surgery: this is the only possible method for curing patients with MTC
thyroidectomy: removal of all thyroid tissue is the preferred
° Total
initial treatment for MTC as many patients with sporadic disease
and nearly all with inherited disease will have bilateral tumors
node dissection: lymph nodes may be present in up to 50%
° Lymph
of patients at initial presentation. Central neck dissection is recommended for most patients with a preoperative diagnosis of MTC
to remove involved nodes. Identification of abnormal nodes in the
lateral neck or mediastinum by ultrasound or CT should prompt a
more extensive neck dissection to remove the disease
disease: removal of all involved nodes or radical neck
° Distant
dissection is not indicated in patients with distant disease as it
does not improve survival; instead, debulking of the tumor and
removing nodes that threaten to extend into vital structures may
be performed
48565_ST02_047-110.indd 95
5/1/13 9:34 PM
96
Medullary Thyroid Cancer
• LT4 replacement: unlike DTCs (papillary and follicular), there are no
TSH receptors on the C cell; TSH suppression therapy is not necessary;
replacement target is to set TSH in the normal range
• EBRT: may be used in nonoperable disease to control the threat of local
extension into vital structures
• Vandetanib TKI: FDA-approved for use in patients with nonoperable
progressive disease
• Cabozantinib TKI: FDA-approved for use in patients with metastatic
disease
• Management in MEN2 (see Chapter 63, Polyglandular Syndrome
(Autoimmune and MEN))
patients with pheochromocytoma require surgical
° Adrenalectomy:
removal of involved glands. There is an increased prevalence of
bilateral tumors. Patients should be administered α blockers prior
to surgery to control hypertension and prevent release of catecholamines intraoperatively
most patients will have multigland involvement;
° Parathyroidectomy:
removal of 3.5 glands with reimplantation into the sternocleidomastoid or forearm is the typical approach
FOLLOW-UP
• Calcitonin: should be measured at the same lab each time; the amount
of time it takes for the calcitonin to double (doubling time) is used to
determine the interval between follow-up visits
• Carcinoembryonic antigen (CEA): a small minority of tumors preferentially secrete this marker rather than calcitonin
• Imaging: CT or ultrasound may be used to follow for progression of
known metastases or for development of new lesions
• Freedom from disease: undetectable basal and stimulated calcitonin
with no evidence of tumor by imaging
rates ~3% if patients are rendered free of disease
° Recurrence
based on above criteria; lifelong follow up is recommended
REFERENCES
American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, et al.
Medullary thyroid cancer: management guidelines of the American Thyroid
Association. Thyroid, 2009;19(6):565−612.
Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet
Med, 2011;13(9):755−64.
Tuttle RM, Ball DW, Byrd D, et al. Medullary carcinoma. J Natl Compr Canc
Netw, 2010;8(5):512−30.
Wu LS, Roman SA, Sosa JA. Medullary thyroid cancer: an update of new
guidelines and recent developments. Curr Opin Oncol, 2011;23(1):22−7.
48565_ST02_047-110.indd 96
5/1/13 9:34 PM
17 ■ ANAPLASTIC THYROID CANCER AND
POORLY DIFFERENTIATED THYROID CANCER
Rebecca Leboeuf, MD
PATHOPHYSIOLOGY
• Anaplastic thyroid cancers (ATCs) are highly aggressive undifferentiated tumors originating from thyroid follicular epithelium
• Accounts for about 1.7% of all thyroid cancers
• There is good evidence suggesting that ATC develops from more
differentiated tumors as a result of dedifferentiation events
of patients with ATC have a history of DTC and ~20−30%
° ~20%
have coexisting DTC
• ATCs have complete loss of expression of thyroid specific proteins
such as Tg, NIS, TSH receptor, and thyroid transcription factor-1
(TTF1)
• Poorly differentiated thyroid cancer (PDTC), an intermediate
between DTC and ATC, can sometime mimic ATC but is usually less
aggressive
CLINICAL PRESENTATION
• A rapidly enlarging neck mass is the most common symptom, occurring
in about 85% of patients
• The vast majority of patients have regional (≥90%) or distant
metastases (up to 50%) at the time of presentation
involvement includes perithyroidal fat and muscle, lymph
° Regional
nodes, tonsils, larynx, trachea, esophagus, and the great vessels of
the neck and mediastinum
metastases often involve the lung, bones and brain, and
° Distant
less frequently, the skin, liver, kidneys, and adrenal glands
• The most frequent symptoms and signs are listed in the following
table
48565_ST02_047-110.indd 97
5/1/13 9:34 PM
98
Anaplastic Thyroid Cancer and Poorly Differentiated Thyroid Cancer
TABLE 17.1 Signs and Symptoms of Anaplastic Thyroid Cancer
Symptoms
Rapidly enlarging neck mass
Neck pain and tenderness
Dyspnea
Dysphagia
Hoarseness
Cough
Hemoptysis
Pains from metastases (bone pain,
headache, confusion, chest pain,
abdominal pain)
Constitutional symptoms, like weight
loss, fatigue, anorexia, fever of unknown
origin
Signs
Thyroid enlargement, often asymetric,
hard, fi xed
Dominant thyroid nodule often present,
often >5 cm
Enlarged cervical lymph nodes
Stridor
Tracheal deviation
Vocal cord paralysis
Venous dilatation, superior vena cava
syndrome
Focal neurological signs if brain
metastases
DIAGNOSTIC EVALUATION
• The diagnosis of ATC is usually established by core biopsy or open
surgical biopsy. In some case, a diagnosis can be made by FNA, though
caution is required with FNA because other disorders may resemble
ATC cytologically (see Table 17.2).
• Cytological or histological examination of ATC tumor will reveal
cells pattern
° Spindle
giant cells pattern
° Pleomorphic
Squamoid
cells pattern
°
TABLE 17.2 Differential Diagnosis of Anaplastic Thyroid Carcinoma on FNAB
Differential Diagnosis of Anaplastic Thyroid Carcinoma on FNAB
Benign cells misinterpreted as ATC
• Fibroblast (granulation tissue, stroma, granuloma)
• Histiocytes
• Atypical follicular cells secondary to 131I therapy
• Degenerating follicular cells
Malignant neoplasms misinterpreted as ATC
• MTC
• Poorly differentiated cancer metastatic to the thyroid
• Lymphoma
48565_ST02_047-110.indd 98
5/1/13 9:34 PM
Diagnostic Evaluation
99
TABLE 17.3 Summary of Differences Between PDTC and ATC
RET/PTC rearrangement
BRAF
RAS
TTF1
PAX8
Thyroglobulin
NIS
p53
B cadherin
Clinical Presentation
Pathology
RAI uptake
PDTC
Mutational status
+
+
+
Immunohistochemical Markers
+
+
+
+ but can be ↓
Rare +
+
Often aggressive
ATC
–
+
+
–
–
–
–
+
–
Fulminant course
• Pleomorphic cells
• Architectural growth
pattern of large,
and nuclei, giant
well-defined solid nests,
multinucleated
mimicking neuroendocrine
cells, spindle cells,
tumor (insular) or
squamoid cells
trabecular growth
• Extensive necrosis
• Tumor cells are uniform • High mitotic activity
• Small foci of necrosis
• Some mitotic activity
May retain some RAI uptake No RAI uptake
• Most patients have normal serum TSH, except for those with tumorinduced thyroiditis
• Imaging studies are useful to define the extent of disease and
plan therapy, but should be scheduled urgently so as not to delay
management
of the neck and mediastinum can accurately identify the extent
° CT
of the tumor and its invasion to local structures
Ultrasonography
can be informative to the extent of extrathyroidal
° extension and nodal
involvement
will demonstrate hypermetabolic lesions where present
° PET/CT
Chest
X-ray
will
often
detect pulmonary metastases
°
• TNM staging definition: all ATC are Stage IV disease
intrathyroidal ATC
° T4a:
° T4b: ATC with gross extrathyroidal extension
48565_ST02_047-110.indd 99
5/1/13 9:34 PM
100 Anaplastic Thyroid Cancer and Poorly Differentiated Thyroid Cancer
TABLE 17.4 TNM Stage Defi nition
Stage
IVA
IVB
IVC
T
T4a
T4b
Any T
N
Any N
Any N
Any N
M
M0
M0
M1
MANAGEMENT
• ATC does not respond to RAI and treatment or scan with RAI should not
be part of management
• Prognostic factors
is almost universally fatal, with median survival ranging from
° ATC
3−7 months and 20% one-year survival
with disease either confined to the thyroid (Stage IVA)
° Patients
or with local and regional metastases (Stage IVB) have a longer
survival than those with distant metastases (Stage IVC)
with tumor <6 cm have a better 2-year survival than those
° Patients
with larger tumors (25% versus 3−15%)
Older
age,
male sex or dyspnea as presenting symptom confers
° worse prognosis
SURGERY
• If the tumor appears to be localized to the thyroid, complete resection
should be attempted with total thyroidectomy and therapeutic lymph
node dissection
• En bloc resection should be considered for patient with extrathyroidal
extension if gross negative margin can be achieved
• Surgery is not indicated when patients present in a more advanced
stage
EXTERNAL RADIATION THERAPY
• Postoperative RT with or without chemotherapy is recommended
for patients with good performance status with complete resection
of gross disease based on uncontrolled data suggesting improved
survival
• Intensity-modulated radiation therapy (IMRT) is preferable for optimal
dose delivery to target tissue while minimizing dose to uninvolved
organs if the planning can be done quickly and not delay primary
therapy
48565_ST02_047-110.indd 100
5/1/13 9:34 PM
External Radiation Therapy 101
• Hyperfractionated RT (multiple small radiation doses allowing >1
radiation treatment per day) of 60 Gy should be considered because
treatment can be accelerated and given over a shorter course of time
than with conventional EBRT
• Adjuvant radiosensitizing chemotherapy may improve ATC outcome and
may be offered to patients with good performance status along with
RT (e.g., taxanes [paclitaxel, docetaxel], anthracyclines [doxorubicin],
or platins [cisplatin, carboplatin])
• If unresectable tumor is present or gross residual disease is present
after surgical attempt, RT with or without chemotherapy should be
offered to patients with good performance status as it may achieve
long-term local control
can be reconsidered after RT as it may render the tumor
° Surgery
resectable
Chemotherapy
• For Stage IVC patients, there are no randomized data suggesting that
systemic therapy may improve survival or improve quality of life, but
transient and occasional more durable tumor regression/control can
be achieved
• Combination or monotherapy including a taxane (paclitaxel, docetaxel)
and/or an anthracycline (doxorubicin) may be considered with the
current data available
• Antimicrotubule disrupting agents (fosbretabulin, combretastatin A4
phosphate, crolibulin) and TKIs (sorafenib, imatinib) are also being
evaluated
• Patients with advanced/metastatic ATC who wish to follow a more
aggressive approach should be offered participation in a clinical trial
when available
TABLE 17.5 Summary of Treatment Options and Suggestions According
to ATC Stage
Stage IVA
Surgery
Stage IVB
En bloc resection if
feasible
IMRT/hyperfractionated RT IMRT/hyperfractionated
RT and reconsider
surgery if now tumor
resectable*
Chemotherapy
Chemotherapy*
Consider clinical trial
Consider clinical trial
Stage IVC
Palliative measures
IMRT/hyperfractionated
RT*
Chemotherapy*
Consider clinical trial
*If good performance status along with the patient’s desire.
48565_ST02_047-110.indd 101
5/1/13 9:34 PM
102 Anaplastic Thyroid Cancer and Poorly Differentiated Thyroid Cancer
REFERENCES
Ain KB, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma
with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative
Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group.
Thyroid, 2000;10(7):587−94.
Brierley JD. Update on external beam radiation therapy in thyroid cancer.
J Clin Endocrinol Metab, 2011;96(8):2289−95.
Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregionally confined anaplastic thyroid carcinoma: a single-institution experience
using aggressive multimodal therapy. Thyroid, 2011;21(1):25−30.
Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A. Anaplastic
thyroid carcinoma. Treatment outcome and prognostic factors. Cancer,
2005;103(7):1330−5.
Ricarte-Filho JC, Ryder M, Chitale DA, et al. Mutational profile of advanced
primary and metastatic radioactive iodine-refractory thyroid cancers
reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer
Res, 2009;69(11):4885−93.
Smallridge RC, Ain KB, Asa SL. American Thyroid Association Guidelines
for Management of Patients with Anaplastic Thyroid Cancer. Thyroid,
2012;22(11):1104−39.
Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer:
molecular pathogenesis and emerging therapies. Endocr Relat Cancer,
2009;16(1):17−44.
48565_ST02_047-110.indd 102
5/1/13 9:34 PM
18 ■ THYROID DISORDERS IN PREGNANCY
Ivana Lukacova-Zib, MD and Geetha Gopalakrishnan, MD
HYPOTHYROIDISM IN PREGNANCY
ETIOLOGY AND PATHOPHYSIOLOGY
• Autoimmune (Hashimoto’s) thyroiditis is the most common etiology;
other causes include pituitary and hypothalamic disorders (see
Chapter 11, Hypothroidism)
• Certain factors in pregnancy exacerbate or precipitate hypothyroidism
in pregnancy. These factors result in higher requirements of thyroid
hormone replacement and iodine intake during pregnancy.
increases production of thyroid binding globulin
° Pregnancy
(TBG) and decreases TBG clearance; as a result both T4 and T3
requirements increase in pregnancy
of iodine increase in pregnancy due to an increase
° Requirements
in maternal T4 production and an increase in renal clearance
of iodine
CLINICAL PRESENTATION
• General signs and symptoms of hypothyroidism are discussed in
Chapter 11. Hypothyroidism
• Pregnancy-related complications of hypothyroidism include premature
birth, miscarriage, placental abruption, gestational hypertension, low
birth weight, fetal death, reduction of infant IQ, motor delay, and a
delay in language and attention
• TPO antibody titers in euthyroid women are associated with fetal loss,
perinatal mortality, and large-for-gestation-age infant
SCREENING FOR HYPOTHYROIDISM IN PREGNANCY
• Universal screening of asymptomatic pregnant women is controversial
• Screening is recommended for high-risk women: family or personal
history of thyroid disease, signs or symptoms suggestive of thyroid
disease, history of head or neck irradiation, presence of other autoimmune condition like type 1 diabetes, infertility, preterm delivery or
miscarriage
48565_ST02_047-110.indd 103
5/1/13 9:34 PM
104 Thyroid Disorders in Pregnancy
LABORATORY EVALUATION
• TRAb
° Screen women with history of Graves’ at 20−24 weeks gestation
• TPO antibody
can be considered in women at high risk for
° Screening
hypothyroidism
• TSH
in high-risk women
° Screening
therapy in primary hypothyroidism
° Monitoring
if >2.5mU/L in the first trimester and >3mU/L in the
° Abnormal
second/third trimester
• FT4
in high-risk women
° Screening
° Monitoring therapy in secondary hypothyroidism
DIAGNOSIS
• See Chapter 11, Hypothyroidism
• Primary hypothyroidism
hypothyroid: elevated TSH and low FT4
° Overt
Subclinical hypothyroid: elevated TSH and normal FT4
°
• Central hypothyroid: low FT4 with low or normal TSH
• Euthyroid with positive antibody: TPO positive and TSH normal
MANAGEMENT
• Primary hypothyroidism
TSH goal in normal range but <2.5 mU/L
° Preconception
pregnant, increase LT4 by 30%
° Once
Monitor
TSH
every
weeks in the first half of pregnancy and at
° least once between4 26
and 32 weeks gestation
TSH within trimester-specific reference ranges (first
° Target
trimester, 0.1–2.5 mIU/L; second trimester, 0.2–3.0 mIU/L; third
trimester, 0.3–3.0 mIU/L)
LT4 should be reduced to prepregnancy levels and TSH
° Postpartum,
measured after 6 weeks
• Central hypothyroidism
replacement preconception and during pregnancy to target
° LT4
mid−upper reference range of FT4
FT4 every 4 weeks for dose titration during the first half of
° Monitor
pregnancy and at least once between 26 and 32 weeks gestation
after target is reached
48565_ST02_047-110.indd 104
5/1/13 9:34 PM
Etiology and Pathophysiology 105
• Euthyroid with positive TPO
cient evidence to support LT4 treatment in this population
° Insuffi
if TSH is abnormal; however, several experts consider starting low
dose LT4 in high-risk women (i.e., those who have had multiple
miscarriages)
these women are at risk for hypothyroidism, monitor TSH
° Since
every 4 weeks during the first half of pregnancy and at least once
between 26 and 32 weeks gestation; if abnormal for pregnancy,
start treatment with LT4
• Iodine supplementation for all pregnant and lactating woman
a minimum of 250 mcg (but not exceeding 500−1100 mcg)
° Ingest
of iodine daily to prevent fetal hypothyroidism
Many
prenatal
vitamins will contain this amount; if not, additional
° potassium iodide
supplements are preferred to kelp or seaweed
which do not contain a consistent quantity of iodine
• Hypothyroid after treatment of Graves’
at 20−24 weeks gestation
° TRAb
elevated (3 times upper limit of normal), perform serial fetal
° Ifultrasound
to evaluate for fetal goiter, growth, heart rate, and
amniotic fluid volume
HYPERTHYROIDISM IN PREGNANCY
ETIOLOGY AND PATHOPHYSIOLOGY
• Graves’ is the most common etiology in reproductive age women
• Other causes include toxic multinodular goiter, toxic adenoma,
factitious hyperthyroidism, hyperthyroid phase of thyroiditis,
struma ovarii, metastatic thyroid cancer, and TSH-secreting
pituitary tumor
• Factors to consider in pregnancy
of HCG (normal pregnancy, multiple gestations,
° Elevation
hydatidiform mole, choriocarcinoma) could stimulate TSH receptor
and cause gestational hyperthyroidism; typically, the normal
physiologic response to HCG is transient and resolves by the
second trimester
elevation in Graves’ disease in third trimester crosses pla° TRAb
centa and can cause fetal goiter or neonatal hypo- or hyperthyroidism (fetal tachycardia, intrauterine growth restriction, accelerated
bone maturation, CHF, and fetal hydrops)
48565_ST02_047-110.indd 105
5/1/13 9:34 PM
106 Thyroid Disorders in Pregnancy
CLINICAL PRESENTATION
• General signs and symptoms of hyperthyroidism and Graves’ disease
(see Chapter 10, Thyrotoxicosis and Hyperthyroidism)
• Pregnancy related: miscarriages, pregnancy-induced hypertension, prematurity, low birth weight, intrauterine growth restriction,
stillbirth, thyroid storm, and maternal CHF
• Gestational hyperthyroidism (i.e., HCG-mediated thyrotoxicosis) is
often associated with hyperemesis gravidarum during the first trimester of pregnancy and resolves by the second trimester; these patients
have a normal thyroid gland on exam
LABORATORY EVALUATION
• TSH
in high-risk women
° Screening
Not used to follow therapy
°
• FT4
in high-risk women
° Screening
° Monitoring therapy with a goal in high−normal range
• TRAb
during second trimester for high-risk women
° Check
■ Graves’ disease (past or current with or without thyroidectomy
or radioiodine ablation)
■ History delivering an infant with hyperthyroidism
elevated (3 times upper limit of normal), perform diagnostic fetal
° Ifultrasound
to evaluate for fetal goiter, amniotic fluid volume, fetal
growth, and heart rate; in high risk cases, cordocentesis can be
considered to evaluate the functional status of the fetal thyroid
DIAGNOSIS
• See Chapter 10, Thyrotoxicosis and Hyperthyroidism
• Gestational hyperthyroid
TSH (⫹/⫺ mild elevations in FT4 and T3) identified in the first
° Low
trimester
° Resolves by 14−18 weeks gestation
• Primary hyperthyroidism
hyperthyroid: low TSH and elevated FT4/T3
° Overt
hyperthyroid: low TSH and normal FT4 (persistent
° Subclinical
abnormality in second and third trimesters)
48565_ST02_047-110.indd 106
5/1/13 9:34 PM
Etiology and Pathophysiology 107
MANAGEMENT
• Gestational hyperthyroidism with or without hyperemesis gravidarum
treatment may be sufficient to prevent dehydration
° Supportive
can be considered if maternal weight loss or fetal growth
° ATDs
retardation
• Thyrotoxicosis related to Graves’ disease, multinodular goiter, thyroid
nodule during pregnancy
iodine is absolutely contraindicated in pregnancy women
° Radioactive
blocking agents
° β-adrenergic
■ Propranolol 20−40 mg every 6−8 hours can be considered to
address symptoms (i.e,. tachycardia and tremors); typically
can be tapered off after symptoms resolve
■ Potential side effects include fetal bradycardia, intrauterine
growth restriction, and neonatal hypoglycemia; monitor and
titrate off medication when appropriate
ATDs:
PTU and MMI can be considered in pregnancy and with
° breastfeeding
■ PTU is recommended for the first trimester of pregnancy
• Starting dose can range from 50−300 mg daily divided
three times per day; monitor FT4 levels every 2−4 weeks
and maintain levels at or slightly above the upper normal
reference range
• Associated with liver toxicity (see Chapter 10, Thyrotoxicosis
and Hyperthyroidism) and therefore, many experts recommend
switching to MMI in the second trimester
■ MMI is recommended second and third trimester
• MMI teratogenicity: choanal and esophageal atresia,
dysmorphic features, and aplasia cutis; avoid in first
trimester
• Starting dose 5−15 mg daily; may decrease the dose or discontinue MMI as the pregnancy progresses; monitor FT4 levels
every 2−4 weeks and maintain levels at or slightly above the
upper normal reference range
■ Warning: fetal goiter and hypothyroidism a complication of
overtreatment with MMI and PTU
° Thyroidectomy
■ Can be consider in the second trimester of pregnancy for noncompliant patients or if antithyroid drugs are contraindicated
THYROID NODULES AND THYROID CANCER
ETIOLOGY AND PATHOPHYSIOLOGY
• Thyroid nodules can increase with pregnancy and parity
• Pregnancy does not affect course or prognosis of DTC
48565_ST02_047-110.indd 107
5/1/13 9:34 PM
108 Thyroid Disorders in Pregnancy
CLINICAL PRESENTATION
• See Chapter 14, Thyroid Nodule Evaluation; Chapter 15, Papillar and
Follicular Thyroid Cancer; Chapter 16, Medullary Thyroid Cancer; and
Chapter 17, Anaplastic and Other Poorly Differentiated Thyroid Cancer
DIAGNOSIS AND MANAGEMENT
• See Figure 18.1
TSH and Ultrasound
Nodule
<1cm
Or
>1cm and
benign US
features
Nodule >1cm
and
US
suspicious for
malignancy
Compressive
symptoms
FNA
Follow
postpartum
Benign
Suspicious
for
malignancy
Malignant
Surgery
Anaplastic
Immediate
surgery
Medullary
Immediate
surgery for
large tumor
Papillary or
follicular
Surgery in
second
trimester or
postpartum
Local or
distant
Yes
No
2nd
trimester
surgery
US and TG
each trimester
LT4 suppressive therapy
TSH goal 0.1–1.5
Nodule growth
or metastasis
Yes
2nd trimester surgery
No
Surgery postpartum
FIGURE 18.1 Thyroid Cancer Diagnosis and Management
Source: Adapted from Stagnaro-Green, Alex et al. Guidelines of the American Thyroid Association ...
Thyroid. 21: 10. 2011. © Mary Ann Liebert, Inc.
48565_ST02_047-110.indd 108
5/1/13 9:34 PM
Diagnostic Evaluation
109
HISTORY OF THYROID CANCER
• LT4 suppressive therapy recommended during pregnancy; monitor TSH,
targets are:
thyroid cancer: TSH goal <0.1 mU/L
° Persistent
high-risk tumor: TSH goal 0.1−0.5
° Disease-free,
Disease-free, low-risk tumor: TSH 0.3−1.5
°
• Thyroid ultrasound
tumor or no evidence of persistence: no need for ultra° Low-risk
sound during pregnancy
levels of Tg or evidence of persistence before pregnancy:
° High
ultrasound every trimester
• Note: RAI administration is contraindicated during pregnancy and at
least 6 months prior to pregnancy
POSTPARTUM THYROIDITIS
ETIOLOGY AND PATHOPHYSIOLOGY
• Autoimmune condition within one year postpartum associated with
elevated TPO and Tg antibody, complement activation, elevated immunoglobulin G (IgG), increased natural killer activity, specific human
leukocyte antigen (HLA) haplotype
• Starts as mild thyroid hormone elevation or isolated hypothyroidism
possibly followed by temporary or permanent hypothyroidism
• Risk increase with multiparty, advanced age, miscarriage, TPO
antibody titer
• Predisposition include: type 1 diabetes, chronic viral hepatitis,
systemic lupus, Graves’ disease, prior episode of postpartum
hyroiditis, HT
CLINICAL PRESENTATION
• Signs and symptoms of hyper- or hypothyroidism can be present
depending on timing of presentation
DIAGNOSTIC EVALUATION
• TSH and FT4
3–6 months postpartum if history positive of type 1
° Screen
diabetes, positive TPO antibody, postpartum depression, prior
postpartum thyroiditis
° Assess in all symptomatic patients
48565_ST02_047-110.indd 109
5/1/13 9:34 PM
110
Thyroid Disorders in Pregnancy
TREATMENT AND MONITORING
• Hyperthyroid phase
° β-blockers: propranolol 10−20 mg four times a day (QID)
• Hypothyroid phase
TSH every 8 weeks for at least 1 year postpartum
° Repeat
can be considered in women who are symptomatic, breastfeed° LT4
ing, or pregnant or attempting pregnancy
can be titrated off after 6−12 months in most women except if
° Dose
■ Breastfeeding
■ Pregnant or attempting pregnancy
■ Permanent hypothyroidism
• 20−40% will eventually develop permanent hypothyroidism
• Yearly TFT recommended for women with history of
postpartum thyroiditis
REFERENCES
Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction
during pregnancy and postpartum: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab, 2007;92(Suppl 8):S1−47.
Committee on Patient Safety and Quality Improvement; Committee on
Professional Liability. ACOG Committee Opinion No. 381: Subclinical
hypothyroidism in pregnancy. Obstet Gynecol, 2007;110(4):959−60.
Stagnaro-Green A. Approach to the patient with postpartum thyroiditis.
J Clin Endocrinol Metab, 2012;97(2):334−32.
Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of
the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid,
2011;21(10):1081−125.
48565_ST02_047-110.indd 110
5/1/13 9:34 PM
SECTION III: ADRENAL
48565_ST03_111-160.indd 111
5/1/13 9:34 PM
48565_ST03_111-160.indd 112
5/1/13 9:34 PM
19 ■ ADRENAL ESSENTIALS
Jane V. Mayrin, MD
ANATOMY
• Pyramidal shape; located above the upper poles of kidneys in
retroperitoneum
• Cortex makes up 90% of adrenal weight, medulla makes up 10%
• Blood supply
superior (from inferior phrenic arteries), middle (from
° Arteries:
aorta), and inferior adrenal arteries (from renal arteries)
Veins:
right
adrenal vein → inferior vena cava; left adrenal vein →
° left renal vein
HISTOLOGY
• Adrenal cortex: divided into three histological and functional zones
(mnemonics: G-F-R or salt-stress-sex)
glomerulosa (outer): secretes aldosterone (mineralocorticoids)
° Zona
■ 15% of cortical volume
■ Lacks 17α-hydroxylase and cannot produce cortisol or
androgens
fasciculata (intermediate): secretes cortisol (glucocorticoids)
° Zona
and androgens
■ 75% of cortex, (cortisol >> androgens)
reticularis (inner): secretes androgens and cortisol
° Zona
■ Androgens > cortisol and estrogens
• Adrenal medulla: neuroendocrine origin, secretes catecholamines
HORMONE SYNTHESIS
• Steroidogenesis (see Figure 19-1)
• Catecholamines synthesis: tyrosine → dehydroxyphenylalanine → DA
(acts primarily as neurotransmitter in CNS) → norepinephrine (NE;
found in adrenal medulla, CNS, and peripheral sympathetic nerves) →
epinephrine (Epi; synthesized only in the adrenal medulla)
48565_ST03_111-160.indd 113
5/1/13 9:34 PM
114
Adrenal Essentials
Cholesterol
17α hydroxylase
17,20–lyase
Pregnenolone
17OH-Pregnenelone
DHEA
Androstenediol
Progesterone
17OH-Progesterone
Androstenedione
Testosterone
11deoxycorticosterone
11-deoxycortisol
3β HSD
11β hydroxylase
Corticosterone
Aldosterone
synthase
21α-hydroxylase
Estrone
Estradiol
18-OH corticosterone
Aldosterone
Cortisol
Zona Glomerulosa
Zona Fasciculata and Zona Reticularis
3β HSD- 3-hydroxysteroid dehydrogenase.
FIGURE 19.1 Adrenal Steroidgenesis
REGULATION OF ADRENAL FUNCTION
• Glucocorticoids
circulates mostly bound to cortisol-binding globulin
° Cortisol
(~75%) and albumin (~15 %); ~10% is free
Hypothalamic-Pituitary-Adrenal
axis (see Figure 19-2).
°
• Mineralocorticoids
controlled by renin-angiotensin-aldosterone system
° Primarily
■ Renin release is stimulated by low Na+ and Cl – load, low renal
perfusion, sympathetic nervous system, K +, angiotensin II, and
atrial natriuretic peptide
Renin release
ACE
■ Angiotensinogen
Angiotensin
Aldosterone release
Angiotensin II
■ System is very sensitive to dietary sodium intake
and high concentrations of ACTH also directly stimu° Hyperkalemia
late aldosterone release
Aldosterone
circulates
bound to albumin and, to a lesser
° extent, cortisol-bindingprimarily
globulin; 30−50% is free
48565_ST03_111-160.indd 114
5/1/13 9:34 PM
Function of Adrenal Hormones 115
Hypothalamus
CRH
Pituitary
ACTH
Cortisol
Adrenal
Cortex
CRH - corticotropin-releasing hormone
ACTH - adrenocorticotropic hormone
FIGURE 19.2 Regulation of Glucocorticoid Synthesis and Release: HypothalamicPituitary-Adrenal Axis (Adopted and modified from Greenspan’s Basic and Clinical
Endocrinology)
FUNCTION OF ADRENAL HORMONES
• Glucocorticoids
to glucocorticoid receptor inside the cytoplasm → steroid-receptor
° Bind
complex enters nucleus → binds to glucocorticoid regulatory elements
→ influences transcription of glucocorticoid-responsive genes
• Normal functions include maintaining vascular tone, permitting lipolysis, increasing plasma glucose during fasting, maintaining emotional
balance, and limiting inflammation
• Adrenal androgens
mostly as precursors for peripheral conversion to the
° Function
active androgens (testosterone and dihydrotestosterone [DHT])
■ In adult males with normal gonadal function, the effect of
adrenal androgen is negligible
■ In females, adrenal androgens contribute ~50% of total
androgens
48565_ST03_111-160.indd 115
5/1/13 9:34 PM
116
Adrenal Essentials
• Mineralocorticoids
functions: regulation of extracellular volume (via Na resorp° Main
tion) and control of K + homeostasis
■ Bind to cytoplasmic mineralocorticoid receptor → steroidreceptor complex enters nucleus → binds to mineralocorticoid
regulatory elements → influences transcription of mineralocorticoid-responsive genes, particularly regulation of Na channels
(Na reabsorption) and the Na+ -K + ATPase pump (Na reabsorption
with K + and H + excretion)
• Catecholamines
through adrenergic receptors (α∙∙ , β, DA)
° Work
vascular and smooth muscle contraction → vasoconstriction
° α-1:
and increased BP
inhibit NE release → decreased BP
° α-2:
positive inotropic and chronotropic effect on heart (responsive
° β-1:
to isoproterenol) → increased heart rate, increased renin secretion
in kidneys
bronchial, vascular, and uterine smooth muscle relaxation →
° β-2:
bronchodilatation, vasodilatation in skeletal muscle; glycogenolysis
β-3:
energy expenditure and lipolysis
° DA-1:regulates
vasodilatation in cerebral, renal, mesenteric, and coronary
° vascular
beds
° DA-2: inhibit release of NE and PRL, and ganglionic transmissions
REFERENCES
Carey RM. Overview of endocrine systems in primary hypertension.
Endocrinol Metab Clin North Am, 2011;40(2):265−77.
Gardner DG, Shoback D. Greenspan’s Basic & Clinical Endocrinology, 8th ed.
New York, NY: McGraw Hill; 2007.
McNicol AM. Lesions of the adrenal cortex. Arch Pathol Lab Med,
2008;132(8):1263−71.
McNicol AM. Update on tumours of the adrenal cortex, phaeochromocytoma
and extra-adrenal paraganglioma. Histopathology, 2011;58(2):155−68.
Miller WL. Disorders of androgen synthesis—from cholesterol to dehydroepiandrosterone. Med Princ Pract, 2005;14(Suppl 1):58−68.
Williams GH. Aldosterone biosynthesis, regulation, and classical mechanism
of action. Heart Fail Rev, 2005;10(1):7−13.
48565_ST03_111-160.indd 116
5/1/13 9:34 PM
20 ■ ADRENAL INSUFFICIENCY
Farah Morgan, MD and Marc J. Laufgraben, MD
CAUSES OF ADRENAL INSUFFICIENCY
• Primary AI
by lack of hormone production at the level of the adrenal
° Caused
gland resulting in both low cortisol and low aldosterone
Etiologies
autoimmune adrenalitis, infection (TB, fungal,
° bacterial),include
inherited disorders (adrenoleukodystrophy, congenital
adrenal hyperplasia [CAH]), drugs (ketoconazole, etomidate),
infiltration, hemorrhage, infarction, metastatic disease
■ Autoimmune adrenalitis is the most common cause in developed
countries, though TB is the most common cause worldwide
■ Autoimmune adrenalitis often seen with other endocrine and nonendocrine autoimmune disorders (see Chapter 63, Autoimmune
Polyglandular Syndroms and Multiple Endocrine Neoplasias)
• Secondary AI
by lack of production of CRH from the hypothalamus and/or
° Caused
ACTH from the pituitary gland, resulting in low cortisol (with normal
aldosterone)
include exogenous glucocorticoids (or megestrol) causing
° Etiologies
suppression of hypothalamic-pituitary-adrenal (HPA) axis, pituitary
disorders (tumor, infiltration, hemorrhage, infarction), traumatic
brain injury, congenital isolated adrenocorticotrophic deficiency,
Prader-Willi Syndrome, POMC deficiency
■ Patients with pituitary disorders resulting in AI will often have other
deficits in pituitary function (see Chapter 2, Hypopituitarism)
TABLE 20.1 Typical Symptoms and Finding in AI
Symptoms
Laboratory Values
Physical Exam Findings
Malaise
Decreased appetite
Weight loss
Dizziness
Nausea/vomiting
Myalgias
Abdominal pain
Hypoglycemia
Hyponatremia*
Hyperkalemia†
Orthostatic hypotension
Low blood pressure
Hyperpigmentation‡
* Hyponatremia due to impaired excretion of free water mimicking SIADH.
† Hyperkalemia in primary AI only due to mineralocorticoid deficiency; in secondary AI, mineralocorticoid
function is intact.
‡ Hyperpigmentation in primary AI only caused by simulation of melanocytes by elevated ACTH levels; in
secondary AI, ACTH not elevated.
48565_ST03_111-160.indd 117
5/1/13 9:34 PM
118
Adrenal Insuffi ciency
DIAGNOSIS OF AI
• Suspect based on laboratory values and symptoms
• Random or 8 AM cortisol >18 mcg/dL rules out AI
• 8 AM cortisol <5 mcg/dL is highly suspicious for AI in patients not
taking exogenous glucocorticoids
• 250-mcg cosyntropin stimulation test (CST) with measurement of
0-minute (baseline), 30-minute, and 60-minute cortisol
cortisol is <18, patient has AI
° If■ stimulated
Check ACTH: high = primary AI, low/normal = secondary AI
cortisol >18 rules out primary or long-term secondary AI
° Stimulated
■ Doesn’t rule out early or partial secondary AI as adrenal atrophy
is not present
■ If CST is normal but partial or early secondary AI is suspected,
perform one of the following
• Overnight metyrapone test: give metyrapone 30 mg/kg (maximum: 3000 mg) at midnight and draw blood for cortisol and
11-deoxycortisol at 8 AM. Normal response is cortisol <5 and
11-deoxycortisol >7. Generally considered safe to perform in
outpatient setting, though very small risk of causing adrenal
crisis. Metyrapone is available directly from HRA Pharma at
www.metopirone.us
• ITT: give regular insulin 0.1 units/kg IV (0.15 units/kg if obese)
and draw blood for cortisol when glucose <40 mg/dL. Normal
response is cortisol >18 mcg/dL. Though often considered the
“gold standard” test for AI, it is infrequently performed as it
requires close medical supervision, is unpleasant for patients,
and is contraindicated in patients >60 yo, patients with
seizure disorder, or patient with CAD.
■ 1-mcg CST has been proposed as a more sensitive investigation
for secondary AI, but concerns about specificity have limited
enthusiasm for its use
• Dexamethasone will not interfere with cortisol assay, but will suppress
ACTH
can be given for emergent treatment of suspected
° Dexamethasone
AI but testing must be performed expediently to avoid altered
results from ACTH suppression
• If primary AI is diagnosed
antiadrenal antibodies
° Check
about other autoimmune diseases in patient or family
° Inquire
Consider
of infections, especially TB, or exposure to
° drugs withpossibility
antiadrenal effects
antibody testing is negative in a young man, measure very−long° Ifchain
fatty acids to exclude adrenoleukodystrophy
If
° antibody testing negative, check adrenal CT scan
48565_ST03_111-160.indd 118
5/1/13 9:34 PM
Chronic Treatment of AI
119
• If secondary AI is diagnosed
about possible exposure to exogenous glucocorticoids (from
° Inquire
any source: oral, IV, intra-articular, topical, inhaled, etc.) or megestrol
If
no
exposure
° ■ Check pituitary MRI
■ Check other tests of pituitary function
CHRONIC TREATMENT OF AI
• Glucocorticoid replacement
HC 20 mg (+/– 5 mg) daily in divided doses
° Typically
■ e.g., 15 mg in the morning and 5 mg in the afternoon; or 10 mg
at breakfast, 5 mg at lunch, and 5 at mg supper
steroids (prednisone 5 mg daily or dexamethasone
° Longer-acting
0.5 mg daily) can be used in patients who cannot or will not take
multiple daily doses of HC
by clinical response to therapy: signs/symptoms of gluco° Monitor
corticoid deficiency or glucocorticoid excess?
■ There are no appropriate lab parameters for monitoring
• Monitoring ACTH leads invariably to overtreatment
• Mineralocorticoid replacement
in primary AI but not secondary AI
° Indicated
■ In secondary AI, the renin-angiotensin-aldosterone system is
intact
start 100 mcg daily, typical dose 50−250 mcg
° Fludrocortisone:
daily
Monitoring
° ■ Plasma potassium should be normal
■ Plasma renin activity (PRA) should be normal
■ Postural hypotension indicates inadequate treatment
■ Edema may indicate overtreatment
• Adrenal androgen replacement
androgens dehydroepiandrosterone (DHEA) and DHEA
° Adrenal
sulfate (DHEA-S) constitute a major source of androgens in women,
less important in men
■ Levels are decreased in AI
data support use of DHEA supplements though long-term
° Some
efficacy and safety data are lacking
Consider
25−50 mg daily in
° ■ FemaleDHEA
AI patients with low libido or other symptoms of androgen
deficiency
■ Male or female AI patients with impaired sense of well-being on
otherwise appropriate therapy
48565_ST03_111-160.indd 119
5/1/13 9:34 PM
120
Adrenal Insuffi ciency
TABLE 20.2 Equivalency Chart for Glucocorticoids (GCs)
Drug Name
Dexamethasone
Methylprednisolone
Prednisone
Hydrocortisone
Equivalent dose (mg)
0.5
4
5
20
GC potency
25−50
5
4
1
½ life (hours)
36−54
18−36
18−36
8−12
ACUTE ADRENAL CRISIS
• Typically a patient with known AI who presents in extremis (volume
depletion and shock) precipitated by infection or other stress, but also
may be initial presentation of AI
• Management
saline for volume resuscitation
° IV
100 mg IV, followed by 50 mg IV q 8 h or 150−200 mg/24 hours
° HC
as a continuous infusion, tapered as patient improves
not required (even in primary AI) unless HC dose
° Fludrocortisone
<50 mg/24 hours
Diagnose
and
treat
precipitating illness
°
CONDITIONS THAT MAY REQUIRE AN ADJUSTMENT IN HC DOSING
Intercurrent illness → double dose
Vomiting → hospital admission for IV HC
Serious medical illness → 50 mg IV HC every 8 hours
Surgery → double dose day of surgery for minor surgery or invasive
diagnostic procedure; IV steroids for major surgery
• Labor and delivery → double dose
• Physical exercise → increase dose by 5 mg, only for strenuous
exercise
•
•
•
•
PATIENT EDUCATION AND “SICK DAY MANAGEMENT”
• All patients with AI should have medical alert identification (bracelet,
necklace)
• Patients should understand the need to increase steroid dose by
2−3 times for illness
• If vomiting, patients should understand the need to go to hospital for
IV treatment
• Consider prescribing HC kit (100 mg to be given IM) for emergent home
use, particularly if patient lives far away from an acute care center
48565_ST03_111-160.indd 120
5/1/13 9:34 PM
References
121
CRITICAL ILLNESS-RELATED CORTICOSTEROID
INSUFFICIENCY (“RELATIVE AI”)
• Remains a highly controversial concept, with debates over its actual
existence, diagnostic criteria, and treatment
• 2012 Surviving Sepsis Guidelines suggest the following
treatment only for patients with septic shock who are
° Corticosteroid
hemodynamically unstable despite adequate fluid resuscitation and
vasopressor therapy
such situations, treat with IV HC 200 mg daily given as a
° In
continuous infusion
■ Continuous infusion reduces glucose fluctuations seen with
bolus steroids
■ Fludrocortisone is not needed
stimulation testing is not necessary
° Cortrosyn
therapy should be tapered when vasopressors are no
° Corticosteroid
longer needed
REFERENCES
Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency.
J Clin Endocrinol Metab, 2009;94(4):1059−67.
Batzofin BM, Sprung CL, Weiss YG. The use of steroids in the treatment of
severe sepsis and septic shock. Best Pract Res Clin Endocrinol Metab,
2011;25(5):735−43.
Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med,
2009;360(22):2328−39.
Chakera AJ, Vaidya B. Addison disease in adults: diagnosis and management. Am J Med, 2010;123(5):409−13.
Dellinger RP, Mitchell ML, Rhodes A, et al. Surviving Sepsis Campaign:
International Guidelines for Management of Severe Sepsis and Septic
Shock: 2012. Crit Care Med, 2013;41(2):580−637.
Neary N, Nieman L. Adrenal insufficiency: etiology, diagnosis and treatment.
Curr Opin Endocrinol Diabetes Obes, 2010;17(3):217−23.
Quinkler M, Hahner S. What is the best long-term management strategy
for patients with primary adrenal insufficiency? Clin Endocrinol (Oxf),
2012;76(1):21−5.
Salvatori R. Adrenal insufficiency. JAMA, 2005;294(19):2481−8.
48565_ST03_111-160.indd 121
5/1/13 9:34 PM
48565_ST03_111-160.indd 122
5/1/13 9:34 PM
21 ■ CUSHING’S SYNDROME
Guari Dhir, MD and Marc J. Laufgraben, MD, MBA
BACKGROUND
• Results from prolonged exposure to excess glucocorticoids
common cause is iatrogenic (exogenous) from use of high° Most
dose glucocorticoids to treat other illnesses
chapter will focus on endogenous Cushing’s syndrome and will
° This
use the term Cushing’s syndrome to refer to endogenous causes
• Cushing’s syndrome is a rare disorder (1−2 per million) with female
preponderance
• Uncontrolled Cushing’s syndrome results in 5× increased mortality
• Clinical features of Cushing’s syndrome
extremely variable as individual features may or may
° Presentation
not present, or may differ depending on age and sex of patient and
severity of hypercortisolism
of Cushing’s syndrome overlap greatly with signs and
° Features
symptoms seen in the general population
Relatively
specific features: facial plethora, wide purple striae,
° proximal muscle
weakness, thin skin/easy bruising, truncal obesity
with thin extremities
■ In children: weight gain with decreased linear growth
that are less specific though common in Cushing’s syn° Features
drome: weight gain or obesity, hypertension, glucose intolerance,
psychiatric symptoms, osteoporosis, menstrual irregularity and
hirsutism in women, hypogonadism in men
• Etiologies of Cushing’s syndrome
divided into ACTH-dependent and ACTH-independent cause
° Typically
■ ACTH-dependent causes make up 80% of Cushing’s syndrome
• Of these, 80% due to an ACTH-secreting pituitary adenoma
(also known as Cushing’s disease)
• The remainder due to ACTH-secreting nonpituitary neoplasms
(especially small-cell lung cancer and bronchial carcinoid
tumors) as well as rare CRH-secreting neoplasms
■ ACTH-independent causes are of adrenal origin and make up
20% of Cushing’s syndrome
• Of these, nearly all are unilateral adrenal neoplasms
■
60% adrenal adenoma, 40% adrenal carcinoma
• Rare adrenal causes include ACTH-independent macronodular
adrenal hyperplasia, primary pigmented nodular adrenal
disease (PPNAD), and McCune-Albright syndrome
48565_ST03_111-160.indd 123
5/1/13 9:34 PM
124
Cushing’s Syndrome
• Cushing’s syndrome must also be distinguished from PsuedoCushing’s syndrome
syndrome: other conditions causing hypercor° Psuedo-Cushing’s
tisolism that may be associated with clinical features similar to
Cushing’s syndrome
■ Examples: psychiatric illnesses (especially depression), alcoholism, pregnancy, morbid obesity, poorly controlled diabetes
DIAGNOSTIC STRATEGY
• Before proceeding with diagnostic studies, exclude (by detailed
history) exposure to exogenous glucocorticoids
• Any testing strategy for Cushing’s syndrome needs to acknowledge
that the available diagnostic tests have limitations in sensitivity,
specificity, and accuracy; therefore use of multiple tests is often
needed to be certain of the diagnosis
• Diagnostic testing is recommended for
with multiple and progressive features of Cushing’s
° Patients
syndrome, particularly those patients with relatively specific
features
with unusual features for their age (e.g., younger people
° Patients
with hypertension or osteoporosis)
Patients
with
incidentaloma
° Children with adrenal
weight gain but decreased linear growth
°
• Diagnostic testing may also be considered for obese patients with
poorly controlled diabetes
° Prevalence of Cushing’s syndrome may be 2−5% in this population
• For initial testing, any of the following tests may be performed
depending on patient characteristics (see Standard Diagnostic Tests for
Cushing’s Syndrome)
mg overnight dexamethasone suppression test (DST)
° 124-hour
urine collection for free cortisol (done two times)
° Late-night
salivary cortisol (done two times)
° 2-day low-dose
DST (0.5 mg q 6 hours × 48 hours)
°
• In patients with a normal test result, further testing may be
performed if there is a very high pretest probability of Cushing’s
syndrome (e.g., a patient with many specific features), if features
progress over 6 months of follow-up, or if cyclic Cushing’s syndrome
is suspected
• Patients with an abnormal test result should be referred to an endocrinologist for further testing
with an abnormal test result should undergo another
° Patients
recommended screening test
Patients
who have positive results on two different tests are likely
° to have Cushing’s
syndrome (assuming Pseudo-Cushing’s syndrome
and use of exogenous glucocorticoids has been considered)
48565_ST03_111-160.indd 124
5/1/13 9:34 PM
Standard Diagnostic Tests for Cushing’s Syndrome
°
°
125
Patients with normal results on two different tests are very unlikely
to have Cushing’s syndrome except in the rare case of cyclic
Cushing’s
Patients with discordant results should be followed and reevaluated
as appropriate, especially if there are progressive features of
Cushing’s syndrome over time
STANDARD DIAGNOSTIC TESTS FOR CUSHING’S SYNDROME
• 1 mg overnight DST
takes 1 mg dexamethasone at 11 PM and reports to lab for
° Patient
cortisol level at 8 AM
■ Using a postdexamethasone cortisol <1.8 mcg/dL as a normal
response is recommended
• A cutoff of 1.8 rather than 5 increases sensitivity, though at
the loss of specificity
positives: use of estrogen-containing compounds including
° False
oral contraceptive pills (OCPs) (increase corticosteroid-binding
globulin [CBG] and cause a 50% false positive rate); use of drugs
that increase dexamethasone metabolism (especially CYP3A4
inducers such as antiepileptics and barbiturates); PseudoCushing’s syndrome
negatives: reduced dexamethasone clearance in renal failure
° False
and hepatic failure; use of drugs that decrease dexamethasone
metabolism (especially CYP3A4 inhibitors such as fluoxetine,
cimetidine, and diltiazem)
• 24-hour urine collection for free cortisol
should receive careful instructions for performing the
° Patients
collection, and creatinine should be measured to ensure a complete
collection
positives: overcollection of urine, fluid intake >5 liters/day,
° False
any stressful condition that increases cortisol production, PseudoCushing’s syndrome
negatives: undercollection of urine, creatinine clearance
° False
<60 ml/min, mild Cushing’s syndrome, collection during an inactive
period in cyclic Cushing’s
cortisol >4 times the upper limit of normal is highly
° Urine-free
specific for Cushing’s syndrome
• Late-night salivary cortisol
loss of the nomal cortisol nadir at midnight is a consistent
° The
finding in Cushing’s syndrome
in saliva is in equilibrium with free cortisol in blood
° Cortisol
■ Patients collect saliva at bedtime by drooling or chewing on
cotton salivette
48565_ST03_111-160.indd 125
5/1/13 9:34 PM
126
Cushing’s Syndrome
°
False positives: conditions that may alter normal circadian rhythms
(shift work, depression, changing time zones, illness), cigarette smoking or use of licorice or chewing tobacco, contamination with blood,
stress before sample is collected, Pseudo-Cushing’s syndrome
False negatives: poor sample collection
°
• 2-day low-dose DST
takes 0.5 mg dexamethasone every 6 hours for 48 hours
° Patient
beginning at 9 AM on day 1 with last dose at 3 AM on day 3; serum
cortisol is drawn 6 hours later at 9 AM on day 3
■ A normal response is considered a postdexamethasone cortisol
<1.8 mcg/dL
Recommended
test for patients who may have Pseudo-Cushing’s
° syndrome
potential for false-postives and false-negatives as 1 mg
° Same
overnight DST
Dexamethasone-CRH
testing (a 2-day low-dose DST followed by
° CRH injection) is occasionally
recommended in equivocal cases and
is reported to have high diagnostic accuracy
DIFFERENTIAL DIAGNOSIS OF CUSHING’S SYNDROME
• Testing to differentiate the cause of Cushing’s syndrome should only
be pursued in patients confirmed to have the disorder based on careful
endocrinologic evaluation
• Check ACTH level to distinguish ACTH-dependent from ACTHindependent causes
<5 pg/ml consistent with ACTH-independent causes
° ACTH
>15 pg/ml consistent with ACTH-dependent causes
° ACTH
5−15 pg/ml is equivocal
° ACTH
■ Perform CRH stimulation test
• Patients with ACTH-independent Cushing’s will not respond
to CRH
• Evaluation of patients with ACTH-independent Cushing’s syndrome
Check
adrenal CT or MRI
° ■ Adrenal
imaging is abnormal in virtually all cases of ACTHindependent Cushing’s syndrome
• Exception: some patients with PPNAD may have normalappearing adrenal glands on CT
• Evaluation of ACTH-dependent Cushing’s syndrome is VERY
CHALLENGING
tests often performed to attempt to distinguish ACTH° Multiple
secreting pituitary adenoma (Cushing’s disease) from ectopic
ACTH-secreting tumors, including
■ High-dose dexamethasone test (HDDST)
• Problems: most (but not all) patients with Cushing’s disease
will suppress, but some patients with carcinoid tumors will
suppress, too
48565_ST03_111-160.indd 126
5/1/13 9:34 PM
Basics of Management of Major Causes of Cushing’s Syndrome
127
CRH testing
• Problems: most (but not all) patients with Cushing’s disease
will stimulate, but some patients with carcinoid tumors will
stimulate, too
■ Pituitary MRI
• Problems: only 50% of patients with Cushing’s disease will
have visible tumor on MRI, while 10% of normal population
has a pituitary incidentaloma
■ If patient has pituitary tumor >6 mm on MRI, and has both CRH
and HDDST consistent with Cushing’s disease, then the diagnosis of Cushing’s is highly likely; otherwise, bilateral inferior
petrosal sinus sampling (IPSS) is necessary
Bilateral IPSS
■ Considered “gold standard” for establishing source of ACTH
secretion, but the procedure is invasive and technically
challenging
■ Test consists of simultaneous sampling of bilateral inferior
petrosal sinuses (venous drainage of pituitary) and peripheral
blood, usually following CRH infusion, to establish whether or
not a gradient exists between petrosal ACTH and peripheral
ACTH
• Petrosal: peripheral ACTH ratio of 2 in basal state, or petrosal:
peripheral ACTH ratio of 3 following CRH, is consistent with
pituitary source of ACTH (Cushing’s disease)
• Patients without an elevated ratio are likely to have ectopic
ACTH production
■
Check CT or MRI of neck/chest
– If negative, image abdomen/pelvis as well
■
Consider other imaging modalities (octreotide scan or PET)
if CT/MRI negative
■
Localization of these tumors can be extremely difficult and
1/3 may remain occult for extended periods of time
■
°
BASICS OF MANAGEMENT OF MAJOR CAUSES OF CUSHING’S SYNDROME
• Adrenal adenoma
° Unilateral adrenalectomy is curative
• Adrenocortical carcinoma
° See Chapter 26, Adrenocortical Carcinoma
• Cushing’s disease (ACTH-secreting pituitary adenoma)
initial treatment is selective neurosurgical resection of the
° Optimal
adenoma
■ If tumor not identifi ed during sellar exploration, total or partial
hypophysectomy may be considered
48565_ST03_111-160.indd 127
5/1/13 9:34 PM
128
Cushing’s Syndrome
Remission is indicated by AM cortisol <2 during the first
postoperative week (assuming glucocorticoids have not been
given)
■ Patients in remission require temporary provision of replacement glucocorticoids until HPA axis recovered from prolonged
suppression
• Occasionally, supraphysiologic doses are needed on a
temporary basis for patients who experience symptoms from
“glucocorticoid withdrawal”
■ Patients in remission require lifelong surveillance for recurrence
patients who have persistent or recurrent disease after initial
° For
neurosurgery, treatment options may include
■ Reoperation
• Can be considered as soon as it is apparent that disease
persists or has recurred after initial surgery
• Accompanied by an increased risk of hypopituitarism
■ Radiotherapy
• Options include fractionated EBRT or SRS
■
Successful control of hypercortisolism in ~1/2 of patients
over 3−5 years
■
Long-term risk of hypopituitarism
■ Bilateral adrenalectomy
• Provides definitive, immediate control of hypercortisolism
• Results in permanent AI
• Risk of development of Nelson’s syndrome (unrestrained
growth of the adenoma)
■ Antiadrenal medical therapy
• Typically used in patients with persistent disease who are
waiting for RT to become effective
■
Occasionally used to prepare very ill patients for surgery
• Antiadrenal agents include ketoconazole (inhibits several
steroidogenic enzymes), metyrapone (inhibits 11β-hydroylase),
and mifepristone (glucocorticoid receptor antagonist)
• Pasireotide: somatostatin analog which directly inhibits ACTH
release from corticotroph tumors
• Ectopic ACTH syndrome
When
possible, surgical resection and cure of the underlying
° neoplasm
effectively resolves the hypercortisolism
■ In the case of metastatic disease or occult tumors, this is not
possible
therapies may be directed at the underlying tumor depending
° Other
on its origin, including chemotherapy, radiotherapy, somatostatin
analogues, etc.
often require antiadrenal medical therapy (see previous
° Patients
section) or bilateral adrenalectomy to control hypercortisolism
■
48565_ST03_111-160.indd 128
5/1/13 9:34 PM
References
129
REFERENCES
Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of
Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab,
2003;88(12):5593−602.
Biller BM, Grossman AB, Stewart PM, et al. Treatment of
adrenocorticotropin-dependent Cushing’s syndrome: a consensus
statement. J Clin Endocrinol Metab, 2008;93(7):2454−62.
Boscaro M, Arnaldi G. Approach to the patient with possible Cushing’s
syndrome. J Clin Endocrinol Metab, 2009;94(9):3121−31.
Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome.
Lancet, 2006;367(9522):1605−17.
Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol
Metab, 2008;93(5):1526−40.
Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A. Cushing’s
syndrome. Endocrinol Metab Clin North Am, 2008;37(1):135−49.
Tritos NA, Biller BM, Swearingen B. Management of Cushing disease. Nat Rev
Endocrinol, 2011;7(5):279−89.
48565_ST03_111-160.indd 129
5/1/13 9:34 PM
48565_ST03_111-160.indd 130
5/1/13 9:34 PM
22 ■ PRIMARY ALDOSTERONISM
Michael Stowasser, MD
TABLE 22.1 Subtypes of Primary Aldosteronism
Unilateral Forms
Bilateral Forms
• Aldosterone-producing adenoma
(+/– associated diffuse or nodular
cortical hyperplasia); 40% of tumors
associated with somatic mutations in
KCNJ5
• Unilateral adrenal hyperplasia
• Aldosterone-producing carcinoma
• Bilateral adrenal hyperplasia, diffuse or
nodular
• Glucocorticoid-remediable
aldosteronism caused by hybrid
CYP11B1/CYP11B2 mutation, leading
to ACTH-regulated aldosterone
overproduction
CLINICAL PRESENTATION
• Hypertension: primary aldosteronism is thought to account for 5−15%
of patients with hypertension
• Hypokalemia: present in <25% of patients with primary aldosteronism, and <50% with aldosterone-producing adenoma; associated
symptoms include nocturia, polyuria, muscle weakness, cramps,
parasthesias, and palpitations
• May be familial
aldosteronism (familial hyperaldosteron° Glucocorticoid-remediable
ism type I) inherited in an autosomal dominant pattern and may be
associated with severe, early-onset hypertension
hyperaldosteronism type II is nonglucocorticoid° Familial
remediable, is not associated with the hybrid gene mutation, and
affected family members may demonstrate either unilateral or
bilateral primary aldosteronism
SCREENING: PLASMA ALDOSTERONE/RENIN RATIO (ARR) TESTING
• Prior to testing
hypokalemia
° Correct
patient to liberalize sodium intake
° Encourage
Where
possible,
withdraw medications that significantly affect
° the ratio
■ At least 4 weeks for diuretics including spironolactone, eplerenone, and amiloride
48565_ST03_111-160.indd 131
5/1/13 9:34 PM
132
Primary Aldosteronism
■
At least 2 weeks before testing for β-blockers, clonidine,
methyldopa, NSAIDs, angiotensin-converting enzyme inhibitors
(ACEIs), angiotensin II receptor blockers (ARBs), dihydropyridine
calcium blockers
TABLE 22.2 Effect of Medication on Ratio
Medications That Lower the Ratio
(Could Cause False Negatives)
Diuretics (including spironolactone,
eplerenone, and amiloride)
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Dihydropyridine calcium blockers
Medications That Raise the Ratio
(Could Cause False Positives)
β-blockers
Clonidine
Methyldopa
Nonsteroidal anti-inflammatory drugs
°
Substitute other antihypertensives that have lesser effects on
the ratio (verapamil slow-release ± hydralazine, and prazosin or
doxazosin)
estrogen-containing oral contraceptives may lower direct renin
° FYI:
concentration and cause false positive ratios; testing for PRA is
recommended
• Collect blood midmorning, when the patient has been ambulatory for
at least 2 h, seated for 5−15 min
• Ratio of >20 (plasma aldosterone in ng/dL, PRA in ng/mL/h) or >70
(plasma aldosterone in pmol/L, plasma active renin concentration in
mU/L) suggestive of primary aldosteronism; repeat before considering
confirmatory testing
• When the absolute plasma aldosterone level is <166 pmol/L (<6 ng/dL),
primary aldosteronism is unlikely, even in the presence of an elevated
ARR
CONFIRMATORY TESTING OPTIONS
• Oral salt loading: 24-hour urinary aldosterone level of >12 μg/day on
the third day of oral salt loading (sufficient to achieve a urine sodium
excretion of >200 mmol/day [which requires a dietary intake of at
least 12 g per day] with enough KCl supplementation to maintain
normokalaemia) is regarded as diagnostic
• IV saline infusion testing: at the conclusion of an IV infusion of 0.9%
saline (2 L over 4 hours), diagnosis is unlikely if plasma aldosterone
level <5 ng/dL (<140 pmol/L), probable if >10 ng/dL (>280 pmol/L),
and indeterminate if 5−10 ng/dL (140–280 pmol/L)
48565_ST03_111-160.indd 132
5/1/13 9:34 PM
Subtype Differentiation 133
• Fludrocortisone suppression testing: positive if plasma aldosterone
>6 ng/dL (>165 pmol/L) after 4 days of fludrocortisone (0.1 mg every
6 hours), slow release NaCl (30 mmol three times daily with meals) and
sufficient dietary salt to maintain urinary excretion rate of ≥3 mmol
sodium/kg/day, provided that on day 4:
renin is suppressed (<1 ng/mL/h or <8 mU/L)
° Upright
cortisol levels are lower at 1000 h than at 0700 h (excludes
° Plasma
an acute ACTH rise)
potassium is in the normal range, achieved by giving
° Plasma
sufficient slow-release KCl 6 times hourly
SUBTYPE DIFFERENTIATION
• Differentiating unilateral from bilateral primary aldosteronism
CT detects all aldosterone-producing carcinomas but
° Adrenal
only 50% of aldosterone-producing adenomas and can be frankly
misleading as detected nodules may be nonfunctioning
venous sampling is the only way to reliably distinguish
° Adrenal
unilateral from bilateral primary aldosteronism
■ Requires admission to a center with high expertise
■ Patient kept recumbent overnight and throughout procedure
■ Samples (at least 2) collected from each adrenal vein in turn and
simultaneously from a peripheral vein
■ Adrenal/peripheral venous cortisol ratios of ≥3 indicate successful sampling
■ If the aldosterone/cortisol ratio on one side is >2 times higher
than simultaneous peripheral ratios, and if the aldosterone/
cortisol ratio on the other side is no higher than peripheral, the
study shows lateralization
• Glucocorticoid-remediable aldosteronism (GRA)
Consider
especially in patients with early-onset hypertension, a
° family history
of hypertension, or a personal or family history of
stroke
gene mutation detected by genetic blood testing
° Hybrid
genetic testing not available, perform DST (0.5 mg q 6 h: plasma
° Ifaldosterone
falls to <4 ng/dL [110 pmol/L] within 1−2 days and
remains suppressed up to day 4)
24-hour urinary levels of “hybrid steroids” (18-hydroxy° Elevated
and 18-oxo-cortisol) occur in patients with GRA, but also in some
patients with aldosterone-producing adenoma
48565_ST03_111-160.indd 133
5/1/13 9:34 PM
134
Primary Aldosteronism
MANAGEMENT
• Unilateral primary aldosteronism
unilateral adrenalectomy results in cure of hyperten° Laparoscopic
sion in 60−80% and improvement in remaining patients
If
surgery
declined
° aldosteronism or contraindicated, treat as for bilateral primary
• Bilateral primary aldosteronism
(12.5–50 mg daily): side effects (e.g., gynecomastia
° Spironolactone
or menstrual irregularities) are dose-dependent
(2.5–20 mg daily) or, where available, eplerenone
° Amiloride
(25–100 mg daily) are useful alternatives (these drugs avoid the
side effects associated with spironolactone)
caution with potassium supplements; carefully monitor renal
° Use
function and electrolytes especially if renal function impaired or on
other agents that retain K + (e.g., nonsteroidal anti-inflammatory
drugs, drugs blocking the renin-angiotensin system)
• Glucocorticoid-remediable aldosteronism
(0.25–0.5 mg daily) or prednisolone (2.5–5 mg
° Dexamethasone
daily)
Alternatively,
treat
as for bilateral primary aldosteronism
°
REFERENCES
Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical
practice guideline. J Clin Endocrinol Metab, 2008;93(9):3266–81.
Gordon RD. Primary aldosteronism. J Endocrinol Invest, 1995;18(7):495–511.
Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary
aldosteronism, including surgically correctable forms, in centers from five
continents. J Clin Endocrinol Metab, 2004;89(3):1045–50.
Stowasser M, Gordon RD. The aldosterone-renin ratio for screening for
primary aldosteronism. Endocrinologist, 2004;14:267–76.
Stowasser M, Gordon RD, Rutherford JC, Nikwan NZ, Daunt N, Slater GJ.
Diagnosis and management of primary aldosteronism. J Renin Angiotensin
Aldosterone Syst, 2001;2(3):156–69.
Young WF, Stanson AW. What are the keys to successful adrenal venous
sampling (AVS) in patients with primary aldosteronism? Clin Endocrinol
(Oxf), 2009;70(1):14–7.
48565_ST03_111-160.indd 134
5/1/13 9:34 PM
23 ■ PHEOCHROMOCYTOMA
Urvi Shah, MD and Karel Pacak, MD, PhD, DSc
PATHOPHYSIOLOGY
• Prevalence: 0.05–0.6% of all hypertensive patients
• Catecholamine-producing tumors of chromaffin cells
adrenal origin (also known as pheochromocytoma)
° 80%
extra adrenal origin (also known as paraganglioma)
° 20%
■ Sympathetic: paravertebral and paraaortic (neck to pelvis)
■ Parasympathetic: head and neck (glomus, carotid body)
• May be sporadic or hereditary
about 35% of patients, younger age group
° Hereditary/genetic:
usually <40 years
■ Major susceptibility genes (85–90% of hereditary tumors)
• RET → MEN-2
• VHL → Von Hippel-Lindau syndrome (VHL)
• SDHB/D (Succinate Dehydrogenase subunits B and
D) → familial paraganglioma syndrome
• NF1 → neurofibromatosis type 1
■ Minor susceptibility genes (10–15% of hereditary tumors)
• Include SDHA/C, SDHAF2, MAX, TMEM127, HIF2α
° Sporadic: about 60% of patients, older age group >40–50 years
• Most produce Epi and/or NE
produce DA
° Some
15–20% are biochemically silent (do not release catecholamines)
°
• Effects mediated via catecholamine receptors
of α1 receptors: vasoconstriction and hypertension
° Stimulation
of α2 receptors: vasodilatation (except coronary
° Stimulation
vasoconstriction)
■ α1 effect causing vasoconstriction predominates
of β1 receptors: positive ionotropic and chronotropic
° Stimulation
effects (palpitations)
β2 receptors: vasodilatation and hypotension
° Stimulation
Epi stimulates α1, α2, β1, and β2 but NE stimulates only α1, α2,
° and
β1, not β2
■ Predominantly NE-producing tumors present with hypertension
■ Predominantly Epi-producing tumors may present with palpitations and normotension (or even hypotension)
48565_ST03_111-160.indd 135
5/1/13 9:34 PM
136 Pheochromocytoma
CLINICAL PRESENTATION
• Classic triad: episodic headache + diaphoresis + palpitations
of pheochromocytoma patients will have at least one symptom
° 90%
of the classic triad
Full
triad
present in 20–30% of pheochromocytoma patients
°
• General presentation: history of paroxysmal spells lasting several
minutes to an hour
symptoms: palpitations, anxiety/panic attacks,
° Predominant
pallor
potential symptoms: dyspnea, headaches, blurry vision,
° Other
tremors, constipation, polyuria, nausea, vomiting, sweating,
weakness, polydipsia, flushing, pallor
• Family history of similar symptoms, associated genetic disorders, or
Pheo?
• Look for clinical manifestations of
MTC, hyperparathyroidism
° MEN2A:
MTC, marfanoid habitus, mucosal ganglioneuromas
° MEN2B:
retinal angiomas, CNS hemangioblastomas, renal cysts
° VHL:
skin and mucosal neurofibromas, café-au lait-spots
° NF1:
HIF2α: polycythemia, multiple duodenal somatostatinomas (Pacak° Zhuang
syndrome)
renal cell carcinoma, pulmonary chondroma, gastro° SDHB/D/C:
intestinal stromal tumor (Carney-Stratakis syndrome), pituitary
adenoma
• Assess for exposure to foods/medications/substances that can cause
symptoms that mimic pheochromocytoma: tricyclic antidepressants,
metoclopramide, glucagon, tyramine-containing foods, amphetamines,
nicotine, and caffeine
• DA-producing tumor may present with symptoms of tumor mass effect
without other typical symptoms
• Physical examination/signs
° BP
■ Paroxysmal hypertension: 50%
■ Sustained hypertension: 35−45%
■ Normotensive: 5−15%
■ Hypotension: in predominantly DA- or Epi-producing tumors
■ Orthostatic hypotension: due to chronic vasoconstriction and
volume contraction
° Tachycardia
Other
signs: fever, cervical/abdominal lymphadenopathy,
° edemapotential
(especially if cardiomyopathy), arrhythmias, palpable tumor
in neck or abdomen, tremors
• Adrenal incidentaloma: ~5% of adrenal incidentaloma are pheochromocytomas; all patients with adrenal incidentaloma should be
screened for Pheo even if asymptomatic; ~25% of pheos are diagnosed
based on evaluation of incidentaloma
48565_ST03_111-160.indd 136
5/1/13 9:34 PM
Diagnostic Evaluation
137
DIAGNOSTIC EVALUATION
• Screening test strategy
with plasma-free MNs or 24-hour urinary fractionated MNs
° Begin
■ MNs (metabolites of Epi and NE) are secreted in a constant
fashion from Pheo
■ Both tests are highly sensitive
■ Plasma-free MNs usually favored over urinary fractionated MNs
since easier to obtain and greater specificity
• Draw blood after patient resting supine for at least
15−20 minutes prior to a blood draw
of MN testing
° Interpretation
■ > 4 times the upper limit of normal: almost 100% probability
of Pheo (exceptions may be in patients taking certain
antidepressants)
■ Normal result: high negative predictive value, pheochromocytoma is very unlikely
■ 1−4 times the upper limit of normal: pheochromocytoma
possible
• Rule out false positives from drugs and food
■
Common culprits: antidepressants, cold medication,
chocolate, wine, stress
• Consider clonidine suppression test
■
Measure plasma catecholamines and MNs before and
3 hours after a 0.3 mg/70 kg−oral dose of clonidine
■
Suppression of plasma normetanephrine to <40% of
baseline (or into the normal range) has a high negative
predictive value (i.e. pheochromocytoma is unlikely)
Other
biochemical
° ■ Plasma or urine tests
catecholamines (NE, Epi, DA)
• Not recommended for initial diagnosis, but biochemical profile
may give guidance for anatomic localization and genetic
testing
■ Plasma methoxytyramine (DA metabolite)
• Useful to assess for metastases in patients with familial
paraganglioma
■ Plasma chromogranin A
• Nonspecific marker of neuroendocrine tumors
• Elevation supports diagnosis of pheochromocytoma
• Can be monitored for follow-up after initial treatment
48565_ST03_111-160.indd 137
5/1/13 9:34 PM
138 Pheochromocytoma
• Anatomical imaging: CT or MRI for initial tumor localization
and MRI are sensitive but not specific
° CT
CT scan used for adrenal and abdominal extraadrenal
° Abdominal
tumors
■ No adrenergic blockade required
MRI (T2-weighted with gadolinium enhancement)
° Abdominal
preferred for pregnant women, children, extraadrenal tumors, or
allergies to contrast
■ No adrenergic blockade required
■ Pheochromocytomas appear hyperintense and other adrenal
tumors appear isointense as compared to liver
• Functional imaging
123
I-labeled
MIBG scintigraphy
° ■ More specifi
c than CT or MRI
■ Used for patients with extraadrenal or large (>5 cm)
adrenal tumors with increased risk of malignant disease or
patients with high suspicion of the presence of multifocal
disease
■ Also used in patients with a high suspicion of pheochromocytoma due to clinical and biochemical evidence but who have had
a negative CT/MRI
scanning: for use in specialized situations usually involving
° PET
metastatic disease
• Genetic testing (see Figure 23-1)
indicated in patients <50 years, patients with multiple
° Usually
tumors or extraadrenal tumors, a family history of pheochromocytoma or associated disorders, metastatic tumors, or increased DA
secretion
for sequence in which to test for mutations is based
° Decision
on clinical presentation, family history, biochemistry, and
imaging
general guidance
° Some
■ NF1 gene too large to be tested and diagnosis always made
clinically
■ If elevated MN and no clinical features of neurofibromatosis,
start with RET
■ In patients with metastatic disease but no family history of
pheochromocytoma, start with SDHB
■ If adrenal tumor secretes normetanephrine/NE but not MN/Epi,
start with VHL
■ If head or neck paraganglioma, or multiple abdominal paraganglioma, start with SDHD
48565_ST03_111-160.indd 138
5/1/13 9:34 PM
FIGURE 23.1 Clinical Algorithm for Sequential Gene Testing for Functional Pheo/PGL Based on
Clinical and Biochemical Predictors. Courtesy of Karel Pacak and the NIH.
Diagnostic Evaluation
48565_ST03_111-160.indd 139
139
5/1/13 9:34 PM
140 Pheochromocytoma
MANAGEMENT
Preoperative management
• α blockade
with an α-blocker beginning about 10−14 days prior
° Pretreatment
to surgery
noncompetitive α blockers
° Phenoxybenzamine:
■ Advantage: cannot be displaced from receptors by an overwhelming surge of catecholamines during surgery
■ Disadvantage: risk of postoperative hypotension
■ Side effects: orthostasis, nasal stuffiness, marked fatigue
■ Dose: 10 mg twice a day; can be increased by 10−20 mg every
2−3 days; max dose 1 mg/kg/day
or other competitive α-blockers can be used instead
° Doxazosin
■ Advantage: less risk of postoperative hypotension
• β blockade
patients with tachyarrhythmia, β-blockers (propranolol 40 mg
° In
three times daily, atenolol 25−50 mg once daily) can be added
several days after initiation of α blockade
blockade should always precede β blockade to avoid unopposed
° αα-mediated
vasoconstriction resulting in hypertensive crisis
• In phenoxybenzemine-intolerant patients, labetalol or nicardipine can
be used
• Metyrosine (inhibitor of catecholamine synthesis) is sometimes used preoperatively and is an excellent option for patients with metastatic disease
• Liberal salt and fluid intake are encouraged to promote intravascular
expansion
• Adequate preoperative preparation indicated by
<160/90 for at least 24 hours
° BP
of orthostatic hypotension (though BP in upright position
° Presence
should not fall below 80/45 mm Hg)
ventricular extrasystole every 5 min
° <1
° No new ST-segment changes or T-wave inversions on ECG
Operative management
• Elective surgery preferred as adequate preoperative preparation
improves survival
• Laparoscopic removal preferred as reduces postoperative morbidity,
hospital stay, and expense compared to conventional laparotomy
is preferred for patients with recurrent disease or
° Laparotomy
tumors >10 cm
• In patients with bilateral disease adrenal cortical−sparing surgery
(partial adrenalectomy) is preferred, as this would avoid morbidity
associated with medical adrenal replacement
• Intraoperative hypertensive crisis
by manipulation of the tumor during surgery leading to
° Caused
release of catecholamines
48565_ST03_111-160.indd 140
5/1/13 9:34 PM
Acknowledgments
141
°
Treatment
■ IV infusion of sodium nitroprusside 0.5−5 μg/kg/min
■ Other drugs used: phentolamine, nicardipine
Postoperative management
• Close BP monitoring required
due to acute withdrawal of catecholamines
° Hypotension:
■ Volume replacement is the treatment of choice
■ Volume of fluid required is often large, can be 0.5−1.5 times the
patient’s total blood volume during the first 24−48 hours after
surgery
Hypertension:
related to pain, volume overload, autonomic instabil° ity, essential hypertension,
or residual tumor
• Risk of hypoglycemia
MALIGNANT PHEOCHROMOCYTOMAS
• If disease is limited at the time of diagnosis, surgery may be
curative
• Debulking surgery may facilitate subsequent chemotherapy and
131
I-MIBG in patients with more widespread disease
• 131I-MIBG therapy: option for patients who are 123I-MIBG scintigraphy
positive
° More effective for soft tissue than bony metastasis
• Chemotherapy: cyclophosphamide, vincristine and dacarbazine
indicated in patients with negative 123I-MIBG scintigraphy or with
rapidly growing tumors
• EBRT can be used for solitary bone lesions
FOLLOW-UP
• Patients with sporadic tumors: to check for recurrence of tumor,
biochemical testing is done yearly for at least 10 years after
surgery
• Patients with familial or extraadrenal tumors: annual biochemical
testing is done indefinitely
• Patients with malignant pheochromocytoma: the 10-year survival
is ~40%
ACKNOWLEDGMENTS
This work was supported by the Intramural Research Program of the Eunice
Kennedy Shriver National Institute of Child Health and Human Development,
National Institutes of Health (NIH), Bethesda, Maryland.
48565_ST03_111-160.indd 141
5/1/13 9:34 PM
142 Pheochromocytoma
REFERENCES
Chen H, Sippel RS, O’Dorisio MS, et al. The North American Neuroendocrine
Tumor Society consensus guideline for the diagnosis and management of
neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas, 2010;39(6):775−83.
Kantorovich V, Pacak K. Pheochromocytoma and paraganglioma. Prog Brain
Res, 2010;182:343−73.
K. Pacak. Phaeochromocytoma: a catecholamine and oxidative stress
disorder. Endo Reg, 2011;45(2):23:65−90.
Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet,
2005;366(9486):665−75.
Mittendorf EA, Evans DB, Lee JE, Perrier ND. Pheochromocytoma: advances
in genetics, diagnosis, localization, and treatment. Hematol Oncol Clin
North Am, 2007;21(3):509−25.
Zhuang Z, Chunzhang Y, Felipe L, et al. Somatic HIF2A Gain-of-Function
Mutations in Paraganglioma with Polycythemia. N Engl J M, 2012;367(10):
922–30.
48565_ST03_111-160.indd 142
5/1/13 9:34 PM
48565_ST03_111-160.indd 143
17α
17α
Cortisol
11β
Deoxycortisol
21
17-hydroxypregesterone
3β
17-hydroxypregnenolone
FIGURE 24.1 Steroid Biosynthesis Pathway
Aldosterone
Coritcosterone
11β
Deoxycorticosterone
21
Progesterone
3β
Pregnenolone
Cholesterol
17,20
17,20
Dihydrostestosterone
Testosterone
Androstenedione
DHEA
3β
Estradiol
Estrone
24 ■ CONGENITAL ADRENAL HYPERPLASIA
Richard Auchus, MD, PhD
• Autosomal recessive disorders
• Deficiencies in various adrenal enzymes result in hormone deficiencies
below block (see Figure 24-1)
PATHOPHYSIOLOGY
5/1/13 9:34 PM
144
Congenital Adrenal Hyperplasia
• Block in cortisol production increases ACTH and production of
precursors above blocks
• Hormone excess from precursors above enzyme block are shunted to
other pathways
• Fetal exposure to high or low androgens causes disorders of sex development (DSD) and results in hyperplasia of the adrenal cortex
TYPES OF CAH
• 21-hydroxylase deficiency (21OHD): most common >95% including
nonclassical
presents at birth
° Classical:
■ Block in cortisol and aldosterone production, androgen excess
• “Salt-wasting” (no enzyme activity)
• “Simple virilizing (trace enzyme activity)
Nonclassical:
normal at birth
° ■ Androgen excess
but no cortisol or aldosterone deficiency
• 11-hydroxylase deficiency (11OHD)
Block
in
cortisol
production;
mineralocorticoid and androgen excess
°
• Lipoid CAH (LCAH)
in cholesterol transport resulting in adrenal hormone
° Defect
deficiencies
Classical
form: no steroids formed (often lethal)
° Nonclassical
form: manifests primarily cortisol deficiency
°
• 17-hydroxylase/17,20-lyase deficiency (17OHD)
in cortisol and androgen production, mineralocorticoid
° Block
excess
Isolated
° only 17,20-lyase deficiency is not CAH, androgen deficiency
• 3β-hydroxysteroid dehydrogenase deficiency (3βHSDD)
in all steroid hormones, moderate androgen excess in
° Block
females
• P450-oxidoreductase deficiency (PORD)
in all steroids past progesterone (similar presentation to
° Block
21OHD)
Paradoxical
virilization of girls and mother
°
CLINICAL PRESENTATION
• History
maternal virilization, DSD (genital ambiguity), hypotension,
° Birth:
poor feeding
Childhood:
timing of pubic hair and puberty, growth rate
° Adult: menses,
muscle weakness, fatigue, androgenization
°
48565_ST03_111-160.indd 144
5/1/13 9:34 PM
Management 145
• Physical exam
labioscrotal fusion and phallic length, contra—or
° Genitalia:
isosexual
BP,
orthostatics,
body proportions
° Skin pigmentation,weight,
thinning (on treatment)
° Males: testis size, consistency,
masses
° Females: hirsutism, acne, virilization
°
DIAGNOSTIC EVALUATION
• Laboratory testing: precursor/product ratio after cosyntropin high
across block
TABLE 24.1 Laboratory Testing and Diagnostic Evaluation
21OHD
11OHD
LCAH
17OHD
Gene(s)
CYP21A2
CYP11B1
STAR*
CYP17A1
3␤HSDD PORD
HSD3B2
POR
High
17OHP, C19
DOC, S
None
DOC, B
17Preg
Prog
Low
F, Aldo
F
All
F, C19
Δ4
Varies
Nonclassic
Common
Rare
Yes
No
Rare
No†
* Rarely CYP11A1.
† All cases are partial but highly variable phenotypes.
17OHP = 17-hydroxyprogesterone, C19 = 19-carbon steroids, DOC = 11-deoxycorticosterone,
S = 11-deoxycortisol, B = corticosterone, 17Preg = 17-hydroxypregnenolone, Prog = progesterone,
F = cortisol, Aldo = aldosterone, Δ 4 = all Δ 4-steroids.
• Imaging
CT or MRI: hyperplasia, usually not necessary
° Adrenal
myelolipomas: low-density CT and loss of signal MRI
° Massive
out-of-phase
Testis
ultrasound:
° Ovarian ultrasoundhypoechoic testicular adrenal rest tissue (TART)
° ■ Polycystic if androgen excess
■ Hypoplasia if androgen block
films: bone age in childhood (see Management section,
° Plain
following)
MANAGEMENT
• 21OHD
of treatment
° Principles
■ Maintain euvolemia and BP
■ Treat AI plus stress dosing
■ Normalize androgens not precursors
48565_ST03_111-160.indd 145
5/1/13 9:34 PM
146
Congenital Adrenal Hyperplasia
Minimal glucocorticoids dose to minimize androgen excess
consequences
• Hydrocortisone (HC) best if given in 3 divided doses
• Consider longer acting dexamethasone, prednisone,
prednisolone
• Combination therapies: HC during day, prednisolone at night
Newborn (classical): HC + fludrocortisone acetate (FA) + salt
■ Higher dose HC (20−30 mg/m2 /day) initially until controlled
■ Maintenance HC <17 mg/m2 /day in 3 divided doses
■ Consider genital reconstruction surgery in females
■ Monitor electrolytes, PRA, 17-hydroxyprogesterone (17-OHP)
■ Nearly all identifi ed via newborn screening in the US
Child/adolescent
■ Classic: similar to newborn
■ Also monitor growth rate, bone age
■ If true precocious puberty occurs, suppress with GnRH agonist
■ Nonclassic: Rx indications—advancing bone age, hirsutism,
irregular menses
• Replacement HC an option
• Dexamethasone minimal dose (0.25 mg 3 times a week)
• Monitor testosterone, menses, growth and bone age,
hirsutism
Adult
■ Male: replacement HC + FA normally suffi cient if compliant
• Screen for TART with physical exam, sonography
• LH, FSH, androstenedione to determine source of testosterone
• Semen analysis if fertility desired
• TART
■
Dexamethasone 1−2 mg at night
■
Dexamethasone 0.1−0.25 mg at night + HC in AM
■ Female: replacement HC + FA if compliant
• Prednisone sometimes controls with 5−7.5 mg/AM
• Prednisolone: active drug, more reliable 5 mg/AM
• Combo Rx
■
Daytime HC + prednisolone 1−2 mg
■
Daytime HC + dexamethasone 0.1−0.2 mg night
■ Nonclassic males rarely ascertained or require Rx unless severe
■ Nonclassic females glucocorticoids sparingly if symptoms,
infertility
• Other treatments (spironolactone, OCP, mechanical) for
hirsutism
• Genetic counseling: ~70% carriers of classic 21OHD allele
■ Pregnancy
• Continue HC in pregnancy
• Dexamethasone to prevent DSD in female fetus of carrier
parents is not recommended at this time and is considered
experimental
■
°
°
°
48565_ST03_111-160.indd 146
5/1/13 9:34 PM
Management
147
Monitor androstenedione, testosterone, 17-OHP, DHEA-S with
goal of lowering serum concentrations to slightly above upper
normal range
11OHD
Glucocorticoid
replacement similar to 21OHD
° Mineralocorticoid
antagonist (spironolactone or eplerenone)
° for BP, K
■ Spironolactone also treats androgen excess, ideal in females
■ Goal: normalize PRA, K, BP
■ Alternatives to mineralocorticoid antagonist: triamterene,
amiloride
LCAH
Classical:
raise as females, provide complete steroid hormone
° replacement
glucocorticoid replacement only although variable
° Nonclassical:
Monitor for replacement only
°17OHD
raised as females
° All
AI due to high corticosterone, mineralocorticoid excess
° No
Control
and potassium (K) with spironolactone or eplerenone
° Monitor BP
BP, PRA (want PRA detectable, low−normal)
° ConsiderK,10−20
° hyperplasia mg/day HC if difficult to control or adrenal
11-deoxycorticosterone with goal slightly above upper
° Monitor
normal range
Estrogen replacement at puberty and adult, add progestin if 46,XX
°3βHSDD
glucocorticoids and sometimes mineralocorticoid
° Require
replacement
generally infertile, require testosterone replacement
° Males
often mild androgen excess controlled with HC
° Females
Nonclassic
form very rare
° Males and females
have DSD and some require reconstruction
° surgery
PORD
variable phenotypes
° Highly
glucocorticoids and mineralocorticoid replacement
° Requires
precursors poorly metabolized to active steroids
° Accumulating
gonadal steroid replacement: estrogen for girls, testos° Requires
terone for boys
and females have mild DSD, some require reconstruction
° Males
surgery
■
•
•
•
•
•
48565_ST03_111-160.indd 147
5/1/13 9:34 PM
148
Congenital Adrenal Hyperplasia
REFERENCES
Arlt W, Willis DS, Wild SH, et al. Health status of adults with congenital
adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol
Metab, 2010;95(11):5110−21.
Auchus RJ. Congenital adrenal hyperplasia in adults. Curr Opin Endocrinol
Diabetes Obes, 2010;17(3):210−6.
Casteràs A, De Silva P, Rumsby G, Conway GS. Reassessing fecundity
in women with classical congenital adrenal hyperplasia (CAH):
normal pregnancy rate but reduced fertility rate. Clin Endocrinol (Oxf),
2009;70(6):833−7.
Claahsen-van der Grinten HL, Otten BJ, Hermus AR, Sweep FC, Hulsbergenvan de Kaa CA. Testicular adrenal rest tumors in patients with congenital
adrenal hyperplasia can cause severe testicular damage. Fertil Steril,
2008;89(3):597−601.
Merke DP. Approach to the adult with congenital adrenal hyperplasia due to
21-hydroxylase deficiency. J Clin Endocrinol Metab, 2008;93(3):653−60.
Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of
human steroidogenesis and its disorders. Endocr Rev, 2011;32(1):81−151.
Reisch N, Flade L, Scherr M, et al. High prevalence of reduced fecundity
in men with congenital adrenal hyperplasia. J Clin Endocrinol Metab,
2009;94(5):1665−70.
Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to
steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice
guideline. J Clin Endocrinol Metab, 2010;95(9):4133−60.
48565_ST03_111-160.indd 148
5/1/13 9:34 PM
25 ■ ADRENAL INCIDENTALOMA
Kevin M. Pantalone, MD and Amir H. Hamrahian, MD
INTRODUCTION
• The development and widespread use of modern imaging techniques
has led to the detection of adrenal masses in patients with increasing
frequency
• Adrenal masses incidentally discovered by these techniques in the
absence of clinical signs and symptoms of adrenal disease have been
termed adrenal incidentalomas (this definition excludes patients who
are undergoing evaluation for a known malignancy)
• Adrenal masses are found in approximately 4% of patients undergoing
high-resolution imaging studies, and their prevalence increases
with age
• When an adrenal mass is discovered, one must determine whether the
mass is functional and/or malignant, both of which usually necessitate
surgical resection of the mass
ASSESSMENT FOR HORMONE HYPERSECRETION
• All patients with an adrenal incidentaloma should be evaluated
for autonomous cortisol secretion referred to as subclinical
Cushing’s syndrome (SCS), pheochromocytoma, and if hypertensive,
hyperaldosteronism
• Additional hormonal evaluation may be considered based on a detailed
history and physical exam
PHEOCHROMOCYTOMA
• An increasing number of pheochromocytomas are diagnosed as
adrenal incidentalomas, and up to 1/2 of such patients are without
hypertension at the time of diagnosis
• Both fractionated plasma MNs and 24-hour urinary MNs are reasonable initial screening tests; however, measurement of plasma MNs
is more convenient for the patient and a normal result makes the
diagnosis of a pheochromocytoma extremely unlikely
• Using the reference range currently utilized by most commercial
laboratories, the measurement of plasma MNs is associated with a
false-positive result in 15−20% of patients
48565_ST03_111-160.indd 149
5/1/13 9:34 PM
150
Adrenal Incidentaloma
• An elevation of plasma MNs > four times the upper limit of normal is
usually diagnostic for a pheochromocytoma, and further evaluation
may include additional imaging
• Most patients with elevated plasma MNs < three to four times the
upper limit of normal do not have a pheochromocytoma; such patients
need to proceed with measurement of 24-hour urine MNs, and in
selected cases, undergo further confirmatory tests such as a clonidine
suppression test before proceeding with imaging studies
SUBCLINICAL CUSHING’S SYNDROME
• Subtle elevations in serum cortisol insufficient to result in the typical
clinical manifestations of overt Cushing’s syndrome, but enough to
suppress ACTH secretion from the anterior pituitary is commonly
referred to as SCS
• Identification of patients with SCS is important because associated
comorbidities such as hypertension and/or diabetes may abate or even
disappear with surgical resection of the tumor
• The 1-mg overnight DST is the best test to evaluate for SCS
• Although a variety of different cut-off values for cortisol during
the 1-mg DST have been proposed, in the setting of an adrenal
incidentaloma, a serum cortisol >5 μg/dL is used for the diagnosis
of SCS in the presence of an early-morning low or undetectable
ACTH level
PRIMARY ALDOSTERONISM
• An adrenal incidentaloma in a hypertensive patient requires investigation for primary aldosteronism, with a prevalence <2%
• Most patients with an aldosterone-producing adenoma are normokalemic and therefore lack of hypokalemia should not preclude further
evaluation
• Measurement of plasma aldosterone and PRA to calculate the ARR is
the best initial test for evaluation of primary aldosteronism
>20 with a serum aldosterone level >9 ng/dL is suggestive
° Aofratio
primary aldosteronism; in such patients the PRA is usually suppressed (<1 ng/mL/hour).
• Aldosterone antagonists (spironolactone or eplerenone) should be
discontinued for at least 4 weeks prior to screening
• Patients with an elevated ARR should proceed with a confirmatory test
such as the salt loading test or saline suppression test
48565_ST03_111-160.indd 150
5/1/13 9:34 PM
Differentiating Benign and Malignant Adrenal Masses
151
DIFFERENTIATING BENIGN AND MALIGNANT ADRENAL MASSES
• The preferred imaging modality for the evaluation of an adrenal mass
is CT
• A variety of techniques have been used to estimate the probability
of malignancy in an adrenal mass, including the size of the mass,
the imaging characteristics such as noncontrast CT Hounsfi eld
units [HU] and washout percentage, and the growth rate on
serial imaging
• The lack of a primary cancer site in a patient with a true adrenal
incidentaloma would make the diagnosis of a metastatic lesion
unlikely
• All adrenal incidentalomas >4 cm that lack characteristic benign
radiological features should be surgically removed, regardless of
whether or not they are functional
• The noncontrast CT HU is a measure of density; a HU ≤10 is observed
in lipid-rich adrenal adenomas and is always consistent with a benign
pathology
• A HU >10 can be observed in both lipid-poor adrenal adenomas
(benign) as well as in nonadenomas (pheochromocytoma, metastases,
or primary adrenal malignancy such as lymphoma or adrenal cortical
carcinoma)
• Adrenal tumors ≥4 cm in size with a HU >10 are concerning for
malignancy and should be referred for surgery
• If the adrenal mass is <4 cm and has a HU >10, one can obtain the
absolute washout percentage 15 minutes after the administration of
IV contrast to further assist in characterizing the mass; an absolute
washout percentage of more than 60% supports the diagnosis of a
benign adenoma
• Lipid-poor adrenal tumors with lower washout percentages should be
surgically removed
• A pheochromocytoma may occasionally manifest with washout characteristics similar to that of an adrenal adenoma
• Adrenal mass growth has also been shown to be a modest predictor
of malignancy; an absolute growth of ≥0.8 cm within 3−12 months is
suggestive of malignancy, and surgical resection in the appropriate
clinical and radiological setting may be considered
• Figure 25-1 illustrates the algorithm for approach to patients with
adrenal incidentaloma
• The role of FNA in the evaluation and management of an adrenal
incidentaloma is limited and is not generally recommended
• FNA of an adrenal mass may be warranted in patients with a known
malignancy without any other evidence of metastasis
• A pheochromocytoma should always be excluded prior to FNA to avoid
a potential hypertensive crisis
48565_ST03_111-160.indd 151
5/1/13 9:34 PM
152
Adrenal Incidentaloma
Incidentally Discovered
Adrenal Mass
Surgically
remove
Functional
Noncontrast CT attenuation
value > 10 HU
Noncontrast CT attenuation
value ≤ 10 HU
≥ 4 cm
< 4 cm
Yearly hormonal
evaluation for up
to 5 years and then
intermittently as
clinically indicated
Calculate the absolute
washout percentage
at 15 min
≥ 60%
No change in size
in 3–12 months
Follow up CT
image for up to
two years
< 60%
Surgically
remove
≥ 0.8 cm increase in
size in 3–12 months
Concerning
radiological
features
FIGURE 25.1 Evaluation and Management of Patients with Adrenal Incidentaloma
Adapted from J Clin Endocrinol Metab. 2011 Jul;96(7):2004–15. 2011 Jun 1
48565_ST03_111-160.indd 152
5/1/13 9:34 PM
References
153
NATURAL HISTORY AND FOLLOW-UP OF PATIENTS
WITH ADRENAL INCIDENTALOMAS
• Excess hormone secretion may develop in up to 20% of patients with
previously nonfunctional adrenal tumors during follow-up
• Annual biochemical evaluation for hormone hypersecretion for up to
5 years is recommended for adrenal incidentalomas that do not
undergo resection, especially if the tumor size is >3 cm
• A routine follow-up imaging study for adrenal incidentalomas with a
noncontrast CT attenuation value ≤10 HU is not required, although a
one-time follow-up scan in 6−12 months may be reassuring
• Patients with adrenal masses <4 cm in size and a noncontrast attenuation value >10 HU should have a repeat CT study in 3−6 months
and then yearly for two years; there is no good evidence supporting
continued radiological surveillance in such patients
REFERENCES
Boland GW, Blake MA, Hahn PF, Mayo-Smith WW. Incidental adrenal lesions:
principles, techniques, and algorithms for imaging characterization.
Radiology, 2008;249(3):756−75.
Bovio S, Cataldi A, Reimondo G, et al. Prevalence of adrenal incidentaloma
in a contemporary computerized tomography series. J Endocrinol Invest,
2006;29(4):298−302.
Hamrahian AH, Ioachimescu AG, Remer EM, et al. Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland
Clinic experience. J Clin Endocrinol Metab, 2005;90(2):871−7.
Motta-Ramirez GA, Remer EM, Herts BR, Gill IS, Hamrahian AH. Comparison
of CT findings in symptomatic and incidentally discovered pheochromocytomas. AJR Am J Roentgenol, 2005;185(3):684−8.
Nunes ML, Vattaut S, Corcuff JB, et al. Late-night salivary cortisol
for diagnosis of overt and subclinical Cushing’s syndrome in
hospitalized and ambulatory patients. J Clin Endocrinol Metab,
2009;94(2):456−62.
Pantalone KM, Gopan T, Remer EM, et al. Change in adrenal mass size as a
predictor of a malignant tumor. Endocr Pract, 2010;16(4):577−87.
Sawka AM, Jaeschke R, Singh RJ, Young WF Jr. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated
plasma metanephrines compared with the combination of 24-hour
urinary metanephrines and catecholamines. J Clin Endocrinol Metab,
2003;88(2):553−8.
48565_ST03_111-160.indd 153
5/1/13 9:34 PM
154
Adrenal Incidentaloma
Vanderveen KA, Thompson SM, Callstrom MR, et al. Biopsy of pheochromocytomas and paragangliomas: potential for disaster. Surgery,
2009;146(6):1158−66.
Zeiger MA, Siegelman SS, Hamrahian AH. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol Metab,
2011;96(7):2004−15.
Zeiger MA, Thompson GB, Duh QY, et al. American Association of
Clinical Endocrinologists and American Association of Endocrine
Surgeons Medical Guidelines for the Management of Adrenal
Incidentalomas: executive summary of recommendations. Endocr Pract,
2009;15(5):450−3.
48565_ST03_111-160.indd 154
5/1/13 9:34 PM
26 ■ ADRENOCORTICAL CARCINOMA
André Lacroix, MD
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
• Rare disease: incidence is about 2 people out of every 1 million in the
population, mostly sporadic
• Bimodal age distribution, with peaks before five years and between
fourth to fifth decades
• Women are more often affected than men (1.5:1)
• Adrenocortical carcinoma (ACC) in adrenal incidentaloma: 2% if
<4 cm, 6% if 4.1–6 cm, 25% if >6 cm
• Incidence is 10-fold higher in children in southern Brazil where specific
TP53 germline mutation (R337H) occurs
• Many genetic alterations in sporadic ACC with loss of heterozygosity
(LOH) or allelic imbalance at chromosomes 11q13 (≥90%), 17p13
(≥85%) and 2p16 (92%) and overexpression of IGF-2
• Hereditary forms: Li-Fraumeni syndrome (TP53 mutations),
Beckwith-Wiedemann syndrome (IGF-2 overexpression), rarely
MEN-1
CLINICAL PRESENTATION
• Hormone-secreting ACC (~60%): Cushing’s syndrome (45%);
Cushing’s syndrome with hyperandrogenemia/virilization (25%);
hyperandrogenemia/virilization alone (10%); estrogen excess (gynecomastia in men, uterine bleeding in women) or mineralocorticoid excess
(hypertension, edema) in <10%
• Nonsecreting tumors (~40%): abdominal pain or incidental
adrenal mass
• Fever and leucocytosis may occur from tumor necrosis
48565_ST03_111-160.indd 155
5/1/13 9:34 PM
156 Adrenocortical Carcinoma
TABLE 26.1 Hormonal Evaluation
Cortisol excess
(minimum 3 out of 4 tests)
–
–
–
–
DST (1 mg, 23:00 h)
Urinary free cortisol (24-hour urine)
Basal cortisol (serum)
Basal ACTH (plasma)
Sexual steroids and steroid
precursors
–
–
–
–
–
DHEA-S (serum)
Androstenedione (serum)
Testosterone (serum)
17-OH-progesterone (serum)
17β-estradiol (serum, in men and
postmenopausal women)
Mineralocorticoid excess
– Potassium (serum)
– ARR (only in patients with arterial hypertension
and/or hypokalemia)
Exclusion of pheochromocytoma
(minimum 1 out of 3 tests)
– Catecholamine excretion (24-hour urine)
– MN excretion (24-hour urine)
– Meta- and normetanephrines (plasma)
Based on recommendations of the European Network for the Study of Adrenal Tumors (ENS@T) www.ensat.
org/acc.htm in 2005.
Imaging investigation
• Unenhanced CT scan attenuation >10 HU: review with radiologist for
features suggesting ACC: size >6 cm, irregular borders, heterogeneous
density, calcifications, local invasion, adjacent adenopathies
TABLE 26.2 Staging for Adult ACC
Stage
UICC/WHO 2004
TNM
5-year DiseaseFree Survival
ENSAT 2008
TNM
5-year DiseaseFree Survival
I
T1, N0, M0
82%
T1, N0, M0
II
T2, N0, M0
58%
T2, N0, M0
82%
61%
III
T1–2, N1, M0
T3, N0, M0
55%
T1-2, N1, M0
T3–4, N0–1, M0
50%
IV
T1–4, N0–1, M1
T3, N1, M0 T4,
N0–1, M0
18%
T1–4, N0–1, M1
13%
ENSAT: also venous tumor thrombus in vena cava/renal vein; T1 tumor = <5 cm, T2 tumor = >5 cm, T3
tumor= infiltration in surrounding tissue, T4 tumor = invasion in adjacent organs, N0 = no positive lymph
nodes, N1= positive lymph node(s), M0 = no distant metastases, M1 = presence of distant metastasis
48565_ST03_111-160.indd 156
5/1/13 9:34 PM
Adjuvant Mitotane or Radiotherapy and Follow-Up
157
• MRI may better identify vascular invasion
• FDG-PET to better characterize suspicious lesions on CT scan or MRI
with Standard Uptake Value (SUV) > 1.45
• When ACC is likely, look for extent of disease with chest CT and
FDG-PET; bone imaging or brain MRI if symptoms of metastasis at
these sites
INITIAL THERAPY AND SURGICAL APPROACH
• Patient should be followed by multidisciplinary team including endocrinologist, expert surgeon, medical oncologist, systematic follow-up
nurse, psychologist, palliative care team
• Noninvading incidentaloma up to 10 cm: laparoscopic or open surgery
according to expert surgeon evaluation; incidentaloma >10 cm, local
invasion or high suspicion of ACC: open radical surgery avoiding tumor
spillage
• Recent limited studies indicate that lymphadenectomy may improve
outcome, but this will require larger studies
• Distant disease: remove primary lesion only if this allows removal of
high proportion of tumor burden and improves excess steroid secretion
PATHOLOGICAL EVALUATION
• Review slides of tumor or biopsy material with expert pathologist and
assess Weiss score
• Five criteria are used in the updated Weiss score: >6 mitoses/50 high
power fields, ≤25% clear tumor cells, abnormal mitoses, necrosis, and
capsular invasion
is scored 0 when absent, or 2 for the first two criteria and
° Each
1 for the last three when present; malignancy is a total score ≥3
• Evaluate Ki-67 index, IGF-2, P-53, and SF1 by immunohistochemistry
• Tumor genetic markers of malignancy and prognosis under
development
ADJUVANT MITOTANE OR RADIOTHERAPY AND FOLLOW-UP
• Recommend adjuvant mitotane for tumors with revised Weiss criteria ≥3
• Use 2 g/day initially for Stage I and II tumors during a minimum period
of 2 years
• Increase to 6 g/day rapidly if tolerated for Stage III tumors or Stage I or
II tumors with Ki-67 >10% (5 years duration)
• Monitor serum mitotane levels and adjust dose to reach levels between
14–20 mcg/ml
• Initiate replacement with HC (see section Mitotane Effect on Endocrine
Function)
48565_ST03_111-160.indd 157
5/1/13 9:34 PM
158 Adrenocortical Carcinoma
• Mitotane is a potent inducer of CYP3A4 with potential interactions
with many drugs
• Monitor liver function and cholesterol; treat with statins (pravastatin
or rovustatin as non-CYP3A4 substrates) if needed
• Use effective contraception in female patients during reproductive
age (oral contraceptives not utilized by some experts as mitotane
increases its metabolism and reduces its efficiency)
• Follow with chest CT and abdominal CT/MRI every 3 months for
2 years, every 6 months until 5 years, and yearly x 10 years; FDG-PET
can also be utilized in early follow-up
• Monitor urinary cortisol, ACTH, renin, and marker steroid levels
• Consider adjuvant radiotherapy in patients with Stage III disease, R1
incomplete resection, complete resection with initial tumor >8 cm,
blood vessel invasion, and Ki-67 >10%
ADVANCED DISEASE
• Surgically remove resectable residual tumor or isolated metastatic
lesions if complete resection is possible
• Initiate mitotane as rapidly as possible to 6 g/day split during 3 meals
to reach serum levels of 14–20 mcg/ml; monitor every 2–3 weeks
initially to adjust dose
• Use antinausea drugs as needed (prochloperazine, metoclopramide,
serotonin 5-HT3 receptor antagonist)
• Control steroid excess with mitotane and steroid enzyme inhibitors
such as metyrapone or ketoconazole
• Correct hypokalemia with potassium supplements, spironolactone,
eplerenone, or amiloride
• Frequent monitoring of electrolytes, creatinine, urinary cortisol to
avoid acute hyperkalemia when cortisol excess is controlled
• Treat diabetes and high BP
MITOTANE EFFECT ON ENDOCRINE FUNCTION
• After ACC-induced hypercortisolism (if present) is resolved, begin HC
30 mg/day in three divided doses
progressively increases HC requirements by 2–3 times
° Mitotane
■ Adjust doses based on symptoms and levels of plasma ACTH and
urinary-free cortisol
■ Serum cortisol levels are not reliable because mitotane increases
CBG levels
• Add fludrocortisone replacement when renin levels increase; requirements may be increased two-to threefold by mitotane and are adjusted
based on BP and renin levels
• Monitor TSH, FT4, and testosterone, which can be effected by mitotane
48565_ST03_111-160.indd 158
5/1/13 9:34 PM
References
159
Systemic Chemotherapy
• In advanced metastatic disease, administer combination of etoposide,
doxorubicin, and cisplatin (EDP) with mitotane as first choice
• Second-line therapy may be steptozotocin and mitotane or other
combination therapies preferably in the context of multicenter
collaborative research protocols
• Consider salvage therapy with new drugs such as IGF-1 receptor
antagonists or TKI within multicenter research protocols
REFERENCES
Berruti A, Fassnacht M, Baudin E, et al. Adjuvant therapy in patients with
adrenocortical carcinoma: A position of an international panel. J Clin
Oncol, 2010;28:e401–e402.
Fassnacht M, Johanssen S, Quinkler M, et al. Limited prognostic value of
the 2004 International Union Against Cancer staging classification for
adrenocortical carcinoma: proposal for a Revised TNM Classification.
Cancer, 2009;115(2):243–50.
Fassnacht M, Libé R, Kroiss M, Allolio B. Adrenocortical carcinoma: a
clinician’s update. Nat Rev Endocrinol, 2011;7(6):32–35.
Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in
advanced adrenocortical carcinoma. N Engl J Med, 2012;366(23):2189–97.
Kroiss M, Quinkler M, Lutz WK, Allolio B, Fassnacht M. Drug interactions with
mitotane by induction of CYP3A4 metabolism in the clinical management
of adrenocortical carcinoma. Clin Endocrinol (Oxf), 2011;75(5):585–91.
Lacroix A. Approach to the patient with adrenocortical carcinoma. J Clin
Endocrinol Metab, 2010;95(11):4812–22.
Polat B, Fassnacht M, Pfreundner L, et al. Radiotherapy in adrenocortical
carcinoma. Cancer, 2009;115(13):2816–23.
Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with
adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer, 2005;12(3):667–80.
Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations
and the use of mitotane as a chemotherapeutic agent for adrenocortical
carcinoma. J Clin Oncol, 2009;27(27):4619–29.
Zini L, Porpiglia F, Fassnacht M. Contemporary management of adrenocortical
carcinoma. Eur Urol, 2011;60(5):1055–65.
48565_ST03_111-160.indd 159
5/1/13 9:34 PM
48565_ST03_111-160.indd 160
5/1/13 9:34 PM
SECTION IV: CALCIUM AND BONE
48565_ST04_161-198.indd 161
5/1/13 9:33 PM
48565_ST04_161-198.indd 162
5/1/13 9:33 PM
27 ■ CALCIUM METABOLISM ESSENTIALS
Chad D. Sagnella, MD and Pam Taxel, MD
MAINTENANCE OF OVERALL CALCIUM BALANCE
• Calcium is an essential dietary element with critical roles in normal
physiology
calcium functions in bone mineralization, blood
° Extracellular
coagulation, membrane excitability, enzyme kinetics
Intracellular
calcium
in neuronal activation, muscle
° contraction, hormonefunctions
secretion
• Human body contains about 1000 g of calcium, the majority of which
(99%) resides in bone and teeth as calcium hydroxyapatite
• Dietary intake of calcium
lost in feces
° 75%
absorbed in the proximal small intestine
° 25%
■ By passive diffusion
■ By hormonally regulated active transport (stimulated by vitamin D)
• Renal excretion normally results in 100–250 mg of calcium loss per
day (with adequate intake)
• Plasma calcium divided into three fractions
ionized calcium
° 50%
protein-bound calcium (albumin, globulins)
° 40%
complexed to anions (including citrate, phosphate, sulfate,
° 10%
bicarbonate)
• Calcium-sensing receptor (CaSR)
in the parathyroid glands and kidney
° Located
■ Regulates PTH secretion
■ Regulates renal excretion of calcium
to fluctuations in ionized calcium on minute-to-minute
° Responds
basis
• Approximately 1 g of calcium is recommended per day (Table 27.1)
sources of calcium (1 dairy serving size = 250–300 mg
° Dietary
calcium)
■ Dairy products including milk, cheeses, yogurts, calciumfortified soy milk, and calcium-fortified tofu
■ Canned salmon with bones
■ Green vegetables such as turnips, collard greens, kale, and
broccoli
calcium intake (i.e., multivitamin and calcium
° Supplemental
supplements)
48565_ST04_161-198.indd 163
5/1/13 9:33 PM
164 Calcium Metabolism Essentials
TABLE 27.1 Recommended Intakes for Calcium
9–18 years old
19–50 years old
51–70-year-old
males
51–70-year-old
females
>70 years old
Estimated Average
Requirement
(mg/day)
1100
800
800
Recommended
Upper Level
Dietary Allowance*
Intake
(mg/day)
(mg/day)
1300
3000
1000
2500
1000
2000
1000
1200
2000
1000
1200
2000
*RDA includes total dietary + supplemental calcium intake.
PTH
• Parathyroid gland anatomy
small ovoid glands located on the dorsal aspect of left and right
° 4lobes
of the thyroid
■ Inferior parathyroid glands derived from third branchial pouches
■ Superior parathyroid glands derived from fourth branchial pouches
■ Approximately 10–20% of humans have fi fth parathyroid gland,
often located in mediastinum
2
types
° ■ cell
Chief (or principal) cells: predominant epithelial cell type with
clear cytoplasm
■ Oxyphil cells: larger, mitochondria-rich cell type with granular
eosinophilic cytoplasm
• Structure and synthesis of PTH
acid polypeptide synthesized as a pre-prohormone by the
° 84-amino
chief cells of the parathyroid
PTH
proteolytically
° ing PTH <5 minutes)cleaved by liver and kidney (half-life of circulat° Normal range for serum intact PTH is approximately 10–65 pg/mL
• Secretion of PTH
by serum ionized calcium (iCa2+)
° Regulated
■ ↑ iCa2+ can activate CaSR and suppress PTH secretion
2+
■ ↓ iCa
stimulates PTH secretion
by serum magnesium Mg2+
° Regulated
■ ↓ Mg 2+ can inhibit PTH secretion and action
■ ↑ Mg 2+ can activate CaSR and thus suppress PTH secretion
• PTH 1-receptor (PTH-1R)
G-protein−coupled receptor (Gs/Gq) expressed
° 7-transmembrane
on osteoblasts and proximal and distal tubules of the kidney
PTH-1R
binds
PTH
and
PTH-related protein (PTHrP) with equal affinity
°
48565_ST04_161-198.indd 164
5/1/13 9:33 PM
Vitamin D 165
• Actions of PTH
° Bone
■ ↑ bone resorption of calcium by directly stimulating osteoblasts
and indirectly stimulating osteoclasts via Macrophage-Colony
Stinulatin Factor (M-CSF), receptor activator of nuclear factor
kappa-B ligand (RANKL), Osteoprotegrin (OPG) (decoy receptor
for RANKL)
Kidney
° ■ ↑ renal reabsorption of calcium by ↑ insertion of apical Ca2+
channels in the distal tubule
■ ↑ renal 1α-hydroxylase activity to ↑ 1,25-(OH) vitamin D
2
production in the proximal tubule, to increase both calcium and
phosphate absorption in gut
VITAMIN D
• Structure and synthesis of vitamin D
prohormones
° Inactive
■ Vitamin D : ergocalciferol
2
• Produced by photolysis (UVB) from ergosterol (in plants)
■ Vitamin D : cholecalciferol
3
• Produced by UVB from 7-dehydrocholesterol
• Formed in the skin, mainly in the deepest layers of the
epidermis
■ 25-hydroxyvitamin D: calcidiol (or calcifediol)
• Vitamin D2 /D3 rapidly converted in the liver to
25-hydroxyvitamin D by hepatic 25-hydroxylase (constitutively
active)
• >85% of vitamin D metabolites carried in the blood bound to
vitamin D–binding protein (VDBP)
of vitamin D
° Regulation
■ Activation to 1,25-(OH) vitamin D (calcitriol) occurs via
2
3
1α-hydroxylase cytochrome P-450 1-alpha (CYP1α) in the
mitochondria of renal proximal tubule
• ↓ [iCa2+] stimulates 1,25-(OH)2 vitamin D via CaSR to ↑
1α-hydroxylase production
• ↑ PTH stimulates 1,25-(OH)2 vitamin D via PTH-1R to ↑
1α-hydroxylase production
• ↑ 1,25-(OH)2 vitamin D causes ↓ 1α-hydroxylase activity
(feedback inhibition)
• ↓ [phosphate] stimulates 1,25-(OH)2 vitamin D generation
48565_ST04_161-198.indd 165
5/1/13 9:33 PM
166 Calcium Metabolism Essentials
Inactivation to 24,25-(OH)2 or 1,24,25-(OH)2 occurs alternatively
via renal 24-hydroxylase (CYP24) in the proximal tubule
• Vitamin D receptor (VDR)
nuclear hormone receptor that acts as a transcription fac° 50-kDa
tor by binding to vitamin D-responsive elements in deoxyribonucleic
acid (DNA)
gene expression in target tissues of the small intestine,
° Regulates
bone, parathyroid gland, and kidney
• Actions of 1,25 (OH)2 D3
intestinal Ca2+ absorption via the active-transport transcellular
° ↑route
■ ↑ enterocyte expression of luminal epithelial calcium channels
known as transient receptor potential channels –villanoid 5 and
6 (TrpV5 and TrpV6)
■ ↑ intracellular calcium-binding protein, calbindin-D9K, facilitator of enterocyte Ca2+ diffusion, and apical-to-basolateral
transport
■ ↑ expression of plasma membrane calcium adenosine triphosphate
(ATPase) (PMCA), basolateral Ca2+ transporter out of enterocyte
↑
resorption of Ca2+
° ■ bone
↑ osteoblast differentiation, indirectly ↑ osteoclast activity,
sensitizes osteoblasts to PTH
■ facilitates osteoid production and proper bone calcifi cation
↑
renal
Ca2+ reabsorption
° ↓ parathyroid
gland PTH secretion
° ■ ↓ PTH polypeptide
gene expression
■ ↑ CaSR gene expression
• Recommended vitamin D
source: dairy, fish (e.g., salmon, trout, and tuna), liver,
° Dietary
egg
to UVB: direct sunlight to the skin for 10−15 minutes
° Exposure
a day
■
TABLE 27.2 Recommended Intakes for Vitamin D
9–18 years old
19–70 years old
>70 years old
48565_ST04_161-198.indd 166
Estimated Average
Requirement
(IU/day)
400
400
400
Recommended
Dietary Allowance
(IU/day)
600
600
800
Upper Level
Intake
(IU/day)
4000
4000
4000
5/1/13 9:33 PM
References
167
CALCITONIN
• Structure and synthesis of calcitonin
acid polypeptide hormone synthesized by the para° 32-amino
follicular C cells of the thyroid
Normal
serum
calcitonin levels <19 pg/mL with a half-life <1 hour
°
• Secretion of calcitonin
↑ serum ionized Ca2+ levels stimulate calcitonin secretion, release
° inhibited
by hypocalcemia
under control of serum ionized calcium using the same
° Secretion
CaSR that regulates PTH secretion in the parathyroid gland
physiologic role in human calcium handling or bone
° Nonessential
metabolism; decrease in serum levels of calcium (and phosphate)
requires supraphysiologic calcitonin levels
natriuresis as well as calcium and phosphate excretion in
° Causes
renal tubules
• Calcitonin receptor (CTR)
expressed on osteoclasts in addition to the proximal tubules
° Gs/Gq
of the kidney
• Actions of calcitonin
° Bone
■ ↓ bone resorption of calcium by rapidly deactivating osteoclasts,
causing shrinkage in size of osteoclasts and retraction of their
ruffled border
Kidney
° ■ ↓ renal reabsorption of phosphorous and ↑ excretion of renal
Ca2+
REFERENCES
Costanzo LS. Chapter 9. Endocrine Physiology. In: Costanzo LS, ed. Physiology.
4th ed. Philadelphia, PA: Saunders-Elsevier; 2010.
Gardner DG, Shoback D. Greenspan’s Basic & Clinical Endocrinology. 9th ed.
New York, NY: McGraw-Hill; 2011.
Institute of Medicine of the National Academies. Dietary reference intakes
for calcium and vitamin D. Available at: www.iom.edu/Reports/2010/
Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed
Nov, 2010.
48565_ST04_161-198.indd 167
5/1/13 9:33 PM
168 Calcium Metabolism Essentials
Melmed S, Polonsky KS, Larson PR, Kronenberg, HM. Williams Textbook of
Endocrinology. 12th ed. Philadelphia, PA: Saunders Elsevier; 2011.
Molina P. Endocrine Physiology. 3rd ed. New York, NY: McGraw-Hill; 2010.
Porterfield SP, White B. Endocrine Physiology. 3rd ed. St. Louis, MO. MosbyElsevier; 2007.
Rose DB, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders.
5th ed. New York, NY: McGraw-Hill; 2001.
Whitehead SA, Nussey SS. Endocrinology: An Integrated Approach. Osford, UK:
BIOS Scientific Publishers; 2001.
48565_ST04_161-198.indd 168
5/1/13 9:33 PM
28 ■ HYPERCALCEMIA
Azeez Farooki, MD
INCIDENCE
• Primary Hyperparathyroidism (PHPT) and malignancy account for 90%
of hypercalcemia cases
PATHOPHYSIOLOGY
• Increase bone resorption
° PHPT
■ Autonomous production of PTH via: an adenoma (85%), 4-gland
hyperplasia (15−20%) or carcinoma (<1%) causes ↑ in bone
resorption, renal calcium reabsorption, and GI calcium absorption
° Malignancy
■ Local osteolysis via osteoclast stimulation (due to release of
cytokines by tumor cells in the bone microenvironment)
• Bone metastases due to breast, prostate, lung, thyroid, and
others
• Multiple myeloma
• Rarely lymphoma and leukemia
■ Without advanced cancer in the bone
• PTHrP production by primary tumor: “humoral hypercalcemia of malignancy”; causes increased bone resorption and
decreased renal calcium clearance
■ Solid tumors: head and neck or lung squamous cell carcinomas, renal, bladder, breast, or ovarian carcinomas
■ Other tumors: non-Hodgkins lymphoma, blast phase of chronic
myeloid leukemia, and adult T-cell leukemia-lymphoma
• Ectopic PTH production by primary tumor (rare)
causes
° Other
■ Immobilization
■ Hypervitaminosis A
■ Thyrotoxicosis
■ Teriparatide therapy
• Increased calcium intake, absorption, and/or decreased renal calcium
excretion
calcium intake in the setting of renal insufficiency
° High
renal disease
° Chronic
Milk-alkali
syndrome
° Vitamin D intoxication
° Thiazide diuretics (decreased renal excretion)
°
48565_ST04_161-198.indd 169
5/1/13 9:33 PM
170
Hypercalcemia
°
Extrarenal production of 1,25 dihydroxyvitamin D: accelerated GI
absorption plus increased resorption exceeds renal threshold for
excretion
■ Granulomatous diseases
■ Lymphoma
• Miscellaneous
therapy
° Lithium
crisis
° Addisonian
Familial
hypocalciuric hypercalcemia
° Theophylline
toxicity
° Pheochromocytoma
° Acute renal failure (usually with rhabdomyolysis)
°
CLINICAL PRESENTATION
• History: symptoms depend on the severity and rapidity of
hypercalcemia
increase to >12 mg/dL: polyuria, polydipsia, volume deple° Acute
tion, anorexia, nausea, weakness, and change in mental status
Chronic
°
TABLE 28.1 Symptoms of Chronic Hypercalcemia
Mild: upper limit of
normal to 12 mg/dL
Chronic
Asymptomatic
elevation
or nonspecific
symptoms symptoms like
malaise, depression,
constipation,
musculoskeletal pain
Moderate: 12−14
mg/dL
Severe: >14 mg/dL
Asymptomatic
Nausea, weakness,
or nonspecific
mental status
symptoms like
change, progressive
malaise, depression, volume depletion,
constipation,
renal failure
musculoskeletal pain
°
Clinical manifestations may include
■ Nephrolithiasis, nephrocalcinosis
■ Cognitive dysfunction
■ Constipation, anorexia, nausea
■ Mild weakness
• Physical exam: findings related to underlying disease
DIAGNOSTIC EVALUATION
• Laboratory testing and imaging
calcium with albumin and ionized calcium
° Check
■ Calculate corrected calcium
• Corrected calcium [Ca] = Measured total [Ca] + (0.8 ×
(4.0 - [albumin]))
48565_ST04_161-198.indd 170
5/1/13 9:33 PM
Diagnostic Evaluation
171
If normal ionized calcium in setting of myeloma, then suspect
paraprotein binding calcium and spuriously elevating total
calcium (pseudohypercalcemia)
Check PTH
■ Inappropriately high (>20 pg/mL) = parathyroid autonomy
versus familial hypercalciuric hypercalcemia (FHH) versus
lithium use
• Ask medical history (i.e., lithium use or hypercalcemia
duration)
• Ask family history
■ Autosomal dominant family history of hypercalcemia →
suspect FHH
■ Positive family or personal history of endocrine tumors →
suspect MEN syndrome
• Check 24-hour urine calcium (Ca) and creatinine (Cr)
• Calculate Ca/Cr clearance ratio
■ Ca/Cr clearance ratio = [24-hour urine Ca ⫻ serum Cr] ⫼
[serum Ca ⫻ 24-hour urine Cr]
■ If ratio < 0.01, consistent with FHH
■ If ratio > 0.02, consistent with PHPT (see Chapter 29,
Hyperarathyroidism
• Determine if surgical indications (Figure 28-2)
• Parathyroid imaging only required if patient meets surgical
indications
■ Appropriately suppressed (<20) = malignancy versus other
conditions
• Ask medical history
■ Intake of large doses of calcium-based antacids (milkalkali syndrome)
■ Vitamin D intoxication (high 25-hydroxyvitamin D (25OHD)
>125 ng/mL)
■ Vitamin A (including analogues used to treat acne)
■ Hydrochlorothiazide (HCTZ), theophylline ,and teriparatide
use
■ Immobilization
• Pursue malignancy and granulomatous disease work up
• Rule out myeloma (Serum and Urine protein electrophoresis)
• Check PTHrP (high PTHrP → scan to locate primary
malignancy)
• Check 1,25 D and 25OHD
■ High 1,25OHD: granulomatous disease versus lymphoma
■ PPD, chest X-ray, other imaging as needed
■ Check TSH and cortisol
• TSH <0.1: likely hyperthyroidism (see Chapter 10,
Thyrotoxicosis and Hyperthyroidism)
• If AM cortisol low and symptoms of AI, ACTH stimulation test
(see Chapter 20, Adrenal Insufficiency)
■
°
48565_ST04_161-198.indd 171
5/1/13 9:33 PM
172
Hypercalcemia
TABLE 28.2 Indications for Parathyroidectomy in Asymptomatic Primary
Hyperparathyroidism
Serum calcium concentration ≥1.0 mg/dL above the upper limit of normal
Creatinine clearance <60 mL/min
History of fragility fracture or osteoporotic bone density (T score at lumbar spine, hip,
or distal radius <-2.5)
Age <50 years
MANAGEMENT
• Acute treatment
>12 mg/dL with severe symptoms (change in mental
° Calcium
status)
■ Reverse intravascular volume depletion
• IV NS at 200−300 cc/hour (lower rate if heart failure or renal
disease)
• Once volume replete, loop diuretics prn to prevent volume
overload
• If NS not feasible, hemodialysis
■ IV bisphosphonate (zoledronic acid or pamidronate)
• Maximum effect seen in 2−4 days
■ SQ salmon calcitonin at 4 IU/kg every 8 hours
• Consider if calcium >14 mg/dL
• Maximum effect in 4−6 hours
• Efficacy limited by tachyphylaxis in 48−72 hours
• Chronic treatment: directed to underlying cause
patients should maintain adequate hydration since hypercalce° All
mia predisposes to dehydration
■ PHPT (see Chapter 29, Hyperparathyroidism)
• If poor surgical candidate and calcium ≥1.0 mg/dL above
normal: consider Rx cinacalcet to lower calcium level
• Without a surgical indication → observation
■ Malignancy with bone metastases or myeloma
• Monthly IV bisphosphonates or denosumab to prevent skeletal
events
■ Granulomatous disease or lymphoma
• Prednisone 20−40 mg/day to reduce 1,25 D production
• Do not aggressively replace vitamin D (goal 25OHD:
20−30 ng/mL)
■ Immobilization
• If mobilization not possible, IV or oral bisphosphonate
48565_ST04_161-198.indd 172
5/1/13 9:33 PM
References
173
REFERENCES
Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third
international workshop. J Clin Endocrinol Metab, 2009;94(2):335−9.
Deftos LJ. Hypercalcemia in malignant and inflammatory diseases.
Endocrinol Metab Clin North Am, 2002;31(1):141−58.
Kacprowicz RF, Lloyd JD. Electrolyte complications of malignancy. Hematol
Oncol Clin North Am, 2010;24(3):553−65.
Lafferty FW. Differential diagnosis of hypercalcemia. J Bone Miner Res,
1991;6(Suppl 2):S51−9.
Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J
Med, 2005;352(4):373−9.
48565_ST04_161-198.indd 173
5/1/13 9:33 PM
48565_ST04_161-198.indd 174
5/1/13 9:33 PM
29 ■ HYPERPARATHYROIDISM
Zohair Rahman, MD and Amina Khan, MD, FRCPC, FACP, FACE
PATHOPHYSIOLOGY
• PHPT
90% of cases are caused by sporadic PTH-secreting
° Approximately
solitary adenoma of parathyroid chief cells, multiglandular hyperplasia approximately 5%, parathyroid carcinoma <1%
be associated with hereditary syndromes such as
° May
■ Multiple endocrine neoplasia type 1
■ Multiple endocrine neoplasia type 2a
■ Familial hyperparathyroidism jaw tumor syndrome
■ Neonatal severe hyperparathyroidism
■ Familial-isolated hyperparathyroidism
can be mimicked by FHH
° PHPT
■ FHH is a benign cause of hypercalcemia
■ Inherited as an autosomal dominant condition
■ Caused by an inactivating mutation of the CaSR gene
• FHH: calcium to creatinine clearance ratio usually <0.01
• PHPT: calcium to creatinine clearance ratio >0.01 in ~80%
of cases
PHTP
° lithiumcan also be mimicked by drugs such as thiazide diuretics or
■ Thiazide diuretics ↓ urinary calcium excretion
■ Lithium shifts the set point of calcium PTH curve to the right
radiation exposure to head and neck or RAI may also contrib° Prior
ute to development of PHPT
• Secondary hyperparathyroidism
seen in hypocalcemia, vitamin D insufficiency, or chronic
° Commonly
kidney disease
■ Hypocalcemia simulates PTH
■ Vitamin D insufficiency ↓ intestinal calcium absorption and ↑ PTH
when 25-hydroxyvitamin D levels are <20 ng/mL (50 nmol/L)
■ Chronic kidney disease causes ↑ PTH by ↓ serum calcium,
↑ phosphate, ↓ 1,25 hydroxyvitamin D; PTH ↑ when glomerular
filtration rate (GFR) <60 mls/min
• Tertiary hyperparathyroidism
in chronic kidney disease
° Seen
stimulation of parathyroid glands by high phosphate levels
° Chronic
results in nodular hyperplasia of the parathyroid glands and high
PTH levels in the presence of hypercalcemia
48565_ST04_161-198.indd 175
5/1/13 9:33 PM
176 Hyperparathyroidism
CLINICAL PRESENTATION
• PHPT
PHPT
° Symptomatic
■ Only 15% of patients present at this stage in developed countries,
but symptomatic presentation still common in developing countries
■ Clinical features may include
• Bone pain, fragility fractures or osteitis fibrosa cystica
(parathyroid bone disease)
• Nephrolithiasis, nephrocalcinosis, and renal insufficiency
• Polyuria, polydipsia (↑ calcium decreases renal concentrating
ability)
• Nausea, vomiting, peptic ulcer disease, constipation,
pancreatitis
• Depression, lethargy, cognitive impairment
• Psychosis, coma
• Gout, pseudogout may be associated with PHPT
• Hypercalcemic crisis usually precipitated by intercurrent
illness or volume contraction
PHPT
° Asymptomatic
■ 85% of patients currently present at this stage in developed
countries
■ May have fatigue or mild depression
■ May have low bone density with preferential bone loss at cortical
skeletal sites
hyperparathyroidism
° Normocalcemic
■ Normal serum calcium and persistently elevated PTH levels with
normal vitamin D levels and normal renal function
■ May progress to symptomatic PHPT
■ No physical findings on examination
■ Typically identifi ed on workup for osteoporosis
• Secondary hyperparathyroidism
Osteoporosis,
pain, fractures
° Bowing of the bone
tibiae and femora may be seen in children
° Proximal muscle
weakness may occur with vitamin D deficiency
° Myopathy
°
• Tertiary hyperparathyroidism
° Fragility fractures, muscle weakness
DIAGNOSTIC EVALUATION
• History: evaluate for evidence of skeletal fragility or prior renal stones;
exclude other causes of hypercalcemia including thyroid disease, AI,
granulomatous disease, immobility, presence of malignancy; evaluate
medications particularly use of thiazide diuretics, vitamin D, vitamin A,
antacids, or lithium (see Chapter 28, Hypercalcemia)
48565_ST04_161-198.indd 176
5/1/13 9:33 PM
Diagnostic Evaluation
177
• On examination check
pulse, volume status
° BP,
masses
° Neck
Dorsal
kyphosis, height loss
°
• Biochemical evaluation
PTH
° Intact
■ PTH ↑ in parathyroid related causes of hypercalcemia
■ PTH ↓ or undetectable in association with other causes of hypercalcemia like malignancy related or granulomatous disease
(see Chapter 28, Hypercalcemia)
° Calcium
■ Correct total serum calcium for albumin
■ Measure ionized calcium
phosphorous
° Serum
■ ↓ or low normal in PHPT
■ ↑ in secondary PHPT due to CKD and tertiary PHPT
hydroxyvitamin D
° 25
■ In PHPT, 25-hydroxyvitamin D is usually low-normal since it is
converted to 1,25-dihydroxyvitamin D. Typically, 1,25-dihydroxy
vitamin D is normal or elevated in PHPT
■ Vitamin D defi ciency (low 25-hydroxy vitamin D) can result in
secondary HPT. Treatment with vitamin D can normalize PTH
levels (see Chapter 31, Vitamin D Deficiency)
calcium to creatinine clearance ratio (see Chapter 28,
° Urinary
Hypercalcemia)
■ <0.01 in FHH and >0.01 in PHT in 80% of cases
■ DNA analysis of the CaSR gene if de novo case of FHH
suspected
Check
creatinine and estimate GFR
° Consider
ultrasound of kidneys to exclude occult renal stones
° Bone density
spine, hip, and 1/3 radial site to assess
° skeletal effectatoflumbar
PHPT
Parathyroid
imaging
of
value
to determine if a
° minimally invasive unilateral preoperatively
surgical approach is possible; imaging
does not confirm diagnosis or exclude PHPT
■ Sestamibi scanning: sensitivity 78% and positive predictive
value 90% (varies from center to center)
■ Ultrasound: can be considered in patients who are not candidates for sestamibi scanning
■ CT scanning (4 Dimensional CT) can be considered in some
patients for localizing adenomas especially individuals with
prior neck surgery
in young adults or children consider familial hyperparathy° PHPT
roid syndrome and consider DNA analysis to exclude MEN, FHHH,
Hyperparathyroid Jaw tumor syndrome and familial isolated
hyperparathyroidism
48565_ST04_161-198.indd 177
5/1/13 9:33 PM
178 Hyperparathyroidism
°
If family history of hyperparathyroidism; multiple endocrine tumors
present; or presence of coexisting hypertension, peptic ulcer disease, symptoms of pheochromocytoma, exclude MEN and consider
DNA analysis of the MEN1 and/or RET gene
MANAGEMENT
• Stop precipitating medications if possible (e.g., HCTZ and lithium)
• Calcium supplements can be discontinued if serum calcium is
elevated
• If hypercalcemic crisis (see Chapter 28, Hypercalcemia)
saline infusion to correct volume contraction
° Begin
increases GFR and filtered calcium load
° Saline
(i.e., furosemide) following volume replacement esp. in
° Diuretics
patients at risk for heart failure
IV
bisphosphonates
and calcitonin can be considered for severe or
° symptomatic hypercalcemia
• Treatment in primary HPT
for symptomatic PHPT and tertiary
° Parathyroidectomy
hyperparathyroid
recommended if any of the following:
° Parathyroidectomy
■ Symptoms including renal stones
■ Serum calcium >1 ng/dL (0.25 mmol/l) above upper limit of
normal
■ Calculated creatinine clearance <60 mls/min
■ BMD T-score ≤ ⫺2.5 at any site or previous fragility fracture
■ Age <50
management recommended for asymptomatic PHPT and
° Medical
patients not meeting the guidelines for surgery or unable/unwilling
to have surgery
■ Skeletal protection
• Aminobisphosphonates (antiresorptive agent)
■ BMD increases
■ No change in serum calcium or PTH
• Estrogen (antiresorptive agent)
■ BMD increases
■ No change in serum calcium or PTH
■ For lowering calcium levels in patients who are not candidates
for parathyroid surgery as well as in patients with secondary HPT
due to chronic renal failure
• Cinacalcet (calcimimetic agent)
■ ↓ serum calcium and PTH
48565_ST04_161-198.indd 178
5/1/13 9:33 PM
References
179
REFERENCES
Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the Management of
Asymptomatic Primary Hyperparathyroidism: Summary Statement
from the Third International Workshop. J. Clin Endocrinol Metab,
2009;94(2):335–39.
Khan A, Bilezikian JP, Potts JT Jr. The Diagnosis and Management of
Asymptomatic Primary Hyperparathyroidism Revisited. J. Clin. Endocrinol
Metab, 2009;94(2):333–334.
Pallan S, Rahman O, Khan A. Hyperparathyroidism Diagnosis and
Management A Clinical Review BMJ, 2012;344:e1012.
Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Rubin MR. Presentation
of asymptomatic primary hyperparathyroidism: proceedings of the Third
International Workshop. J Clin Endocrinol Metab, 2009;94(2):351–65.
48565_ST04_161-198.indd 179
5/1/13 9:33 PM
48565_ST04_161-198.indd 180
5/1/13 9:33 PM
30 ■ HYPOCALCEMIA
Mark Cooper, MD and Neil Gittoes, MD
PATHOPHYSIOLOGY
• Common and potentially life threatening condition caused by
imbalance in the absorption of calcium from the GI tract and its
° An
urinary excretion
excessive amount of calcium leaving the circulation to be
° An
incorporated into bone matrix
SPECIFIC CAUSES
• Vitamin D deficiency/resistance
exposure to UV light
° Low
nutritional intake
° Low
Malabsorption
° Drugs that accelerate vitamin D metabolism (e.g., anticonvulsants)
° VDR mutations (very rare)
°
• Reduced vitamin D activation
(post–neck surgery or autoimmune)
° Hypoparathyroidism
(functional hypoparathyroidism)
° Hypomagnesemia
disease
° Kidney
° PTH resistance
• Other etiology
dominant hypocalcemia (calcium-sensing mutation,
° Autosomal
usually asymptomatic)
metastases (movement of circulating calcium into
° Sclerotic
bone)
Hungry
bone
syndrome (massive skeletal uptake of calcium and
° magnesium after
successful surgery for PHPT)
blood transfusion (due to calcium chelators in blood
° Massive
products)
rst dose of IV bisphosphonates (usually only if vitamin D
° Post–fi
deficient)
° Pancreatitis
48565_ST04_161-198.indd 181
5/1/13 9:33 PM
182
Hypocalcemia
CLINICAL PRESENTATION
•
•
•
•
Depends on degree of hypocalcemia and its rate of onset
Risks of symptoms much higher if rapid fall in calcium level
Acute symptoms due to abnormal neuromuscular function
Symptoms
(tingling in hands or perioral)
° Paraesthesia
twitches or spasms
° Muscle
Diffi
culty
breathing
(suggests laryngeal spasm)
° Seizures
° Palpitations (rare)
° Psychiatric manifestations (e.g., depression, psychosis)
° Visual symptoms (secondary to optic atrophy; rare)
°
• Features suggesting underlying diagnosis: frequency of sun exposure,
dietary intake of foods containing vitamin D, previous neck surgery,
symptoms suggesting malabsorption, family history of hypocalcemia
or neck operations
• Drug history with focus on medications that could cause vitamin D
deficiency (e.g., anticonvulsants) or hypomagnesemia (diuretics, PPIs)
• Physical examination
for overt signs of neuromuscular excitability (e.g., muscle
° Examine
twitches, spasms)
sign: muscle twitching of facial muscles following
° Chvostek’s
pressure over facial nerve in the parotid region (positive in ~70%
of patients with hypocalcemia and in ~10% of nonhypocalcemic
individuals)
sign: carpal spasm induced by mild tissue hypoxia
° Trousseau’s
induced by inflation of BP cuff for up to 3 minutes (positive in
>90% of patients with hypocalcemia and in ~1% of nonhypocalcemic individuals)
myopathy (would support vitamin D deficiency)
° Proximal
of skeletal dysplasia (Albright’s hereditary
° Evidence
osteodystrophy) – short third and fourth metacarpals
LABORATORY TESTING
• Serum calcium exists either in an ionized form (~50%) or is bound to
albumin or other ions
only ionized calcium is biologically important, typical lab
° While
measurement of serum calcium measures “total” (bound and
unbound) calcium and therefore needs to be adjusted for serum
albumin, using the following formula
■ Corrected calcium (mg/dL) = serum calcium + [0.8 × (4-serum
albumin in g/dL)]
■ This is only an approximation
■ Ionized calcium can also be measured directly
48565_ST04_161-198.indd 182
5/1/13 9:33 PM
Management 183
Hypocalcemia (adjusted
for albumin)
LOW OR
NORMAL
Serum PTH
HIGH
LOW
Magnesium
deficiency
HIGH
Magnesium
Urea, Creat
Hypoparathyroidism
Calcium sensing defect
(rare)
25-hydroxy
vitamin D
LOW
Vitamin D
deficiency
Renal failure
NORMAL
Pseudohypoparathyroidism
Calcium deficiency
(rare)
FIGURE 30.1 Diagnostic Evaluation Scheme for Hypocalcemia
Source: BMJ June 7, 2008 Volume 336 page 1301
• Diagnoses can be made quickly on basis of limited number of tests:
serum PTH, creatinine, alkaline phosphatase, magnesium, phosphorus
and 25-hydroxyvitamin D (Figure 30-1)
• Other tests that might be needed
calcium to creatinine excretion ratio (high in autosomal
° Urinary
dominant hypocalcemia)
normally not needed
° Imaging
■ Hand X-rays indicated if pseudohypoparathyroidism suspected
■ Skull X-rays or head CT might show basal ganglia calcifi cation
if hypocalcemia long standing
MANAGEMENT
• See Figure 30-2
• In hypomagnesemia, hypocalcemia is unlikely to correct without
replacement of magnesium
• Calcium infusion: 10 ampoules of 10 mL of 10% calcium gluconate
in 1L of 5% dextrose or 0.9% saline; initial infusion rate 50 mL/
hour aiming to maintain serum calcium at lower end of reference
range; infusion of 10 mL/kg of this solution over 4–6 hours is likely to
increase serum calcium ~1.2–2.0 mg/dL
48565_ST04_161-198.indd 183
5/1/13 9:33 PM
184
Hypocalcemia
Symptomatic hypocalcemia or calcium
<7.6mg/dL with unknown cause
For control over
minutes to hours
IV calcium gluconate
10 mls of 10%
solution over 10 min
If hypocalcemia
persistent or recurrent,
then start calcium
gluconate infusion
(see text) and adjust
rate every 4 hours as
required
For control over days
to weeks if indicated
Vitamin D treatment
PTH deficient
PTH intact
Vitamin D analogue
(calcitriol or α-calcidol)
Colecalciferol or
ergocalciferol
Start dose 0.5-1 μg/day
Typical dose 50,000
IU per week orally
for 8 weeks
Can be increased
every 4-7 days
FIGURE 30.2 Management Scheme for Hypocalcemia
Source: BMJ, 2008;336:1301
REFERENCES
Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ,
2008;336(7656):1298–302.
Pearce SH, Cheetham TD. Diagnosis and management of vitamin D
deficiency. BMJ, 2010;340:b5664.
Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med,
2008;359(4):391–403.
48565_ST04_161-198.indd 184
5/1/13 9:33 PM
31 ■ VITAMIN D DEFICIENCY
Vin Tangpricha, MD, PhD
PATHOPHYSIOLOGY
• Vitamin D is a steroid hormone important in the maintenance of
calcium homeostasis and optimal skeletal health; vitamin D may have
other effects outside its classic role in calcium and bone
• Metabolism of vitamin D
D is made in skin (vitamin D3) or absorbed in the intestines
° Vitamin
(vitamin D2 and vitamin D3)
D enters the circulation and is hydroxylated in the liver to
° Vitamin
form 25-hydroxyvitamin D (25(OH)D), which is the best marker for
vitamin D status
hydroxylation step occurs in the kidney and other tissues
° Atosecond
form 1,25-dihydroxyvitamin D (1,25(OH)2D), which is the hormonally active form of vitamin D
2D binds to the VDR and then DNA in cells to regulate over
° 1,25(OH)
900 genes
PREVALENCE OF VITAMIN D DEFICIENCY
• Vitamin D insufficiency (25-D <30 ng/mL)
of the United States population
° 75%
of non-Hispanic blacks
° 95%
60%
of Hispanic whites
°
• Vitamin D deficiency (25-D <20 ng/ml)
of the United States population
° 30%
of non-Hispanic blacks
° 70%
22%
of Hispanic whites
°
RISK FACTORS FOR VITAMIN D DEFICIENCY
•
•
•
•
•
•
Increased age
Increased adiposity
Indoor lifestyle
Malabsorption
Decreased or little intake of vitamin D−containing foods
Darker skin tone
48565_ST04_161-198.indd 185
5/8/13 1:34 PM
186
Vitamin D Defi ciency
CLINICAL PRESENTATION
• Medical history
patients with vitamin D deficiency are asymptomatic
° Most
moderate-to-severe deficiency may result in muscle and bone
° More
pain
vitamin D deficiency can result in symptoms of hypocalcemia
° Severe
vitamin D deficiency can result in rickets in children and
° Prolonged
osteomalacia/osteoporosis in adults
• Physical exam
bowing of the legs, enlargement of the costochondral
° Rickets:
junction, frontal bossing, widening of wrist, craniotabes (soft skull
bones)
° Osteomalacia: sternal or periostial tenderness
DIAGNOSIS
• Serum 25-hydroxyvitamin D
D insufficiency: <30 ng/mL
° Vitamin
° Vitamin D deficiency: <20 ng/mL
• Vitamin D insufficiency/deficiency can be accompanied by
serum PTH concentrations (secondary
° Elevated
hyperparathyroidism)
Hypocalcemia
and/or hypophosphatemia can be seen in severe
° vitamin D deficiency
• 1,25-dihydroxyvitamin D should not be routinely measured to assess
vitamin D status since its concentrations are much lower than 25(OH)
D and it is much more tightly regulated by PTH in response to serum
calcium concentrations; as a result, it could be high, normal, or low
• Evaluation of malabsorption syndromes (e.g., celiac disease) should be
considered in patients with persistently low 25-hydoxvitamin D levels
despite replacement
MANAGEMENT
• Vitamin D 400−800 IU recommended per day (see Chapter 27, Calcium
Metabolism Essentials)
sources of vitamin D include milk, fish (e.g., salmon, tuna),
° Dietary
beef liver
Exposure
to UVB: direct sunlight to the skin for 10−15 minutes a
° day (the amount
may vary according to time of day, season, age,
adiposity, skin tone)
• Vitamin D insufficiency/deficiency requires additional supplementation; cholecalciferol (D3) appears to be superior to ergocalciferol (D2) in
terms of bioavailability and circulating half-life of 25(OH)D
48565_ST04_161-198.indd 186
5/1/13 9:33 PM
References
187
• For patients with vitamin D insufficiency, increasing the daily intake
with a daily vitamin D supplement is one approach; the rule of thumb
is for every 1 ng/mL of 25(OH)D that is desired, you need an additional
100 IU of vitamin D daily
• For patients with vitamin D deficiency, additional daily vitamin D as
above or a short course of weekly bolus vitamin D can be implemented;
an example is cholecalciferol 50,000 IU weekly for 8−12 weeks followed by a maintenance amount of vitamin D 1500 – 2000 IU daily in
children and adults >1 year of age
REFERENCES
Ganji V, Zhang X, Tangpricha V. Serum 25-hydroxyvitamin D concentrations
and prevalence estimates of hypovitaminosis D in the U.S. population
based on assay-adjusted data. J Nutr, 2012;142(3):498−507.
Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and
prevention of vitamin D deficiency: an Endocrine Society clinical practice
guideline. J Clin Endocrinol Metab, 2011;96(7):1911−30.
Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference
intakes for calcium and vitamin D from the Institute of Medicine: what
clinicians need to know. J Clin Endocrinol Metab, 2011;96(1):53−8.
48565_ST04_161-198.indd 187
5/1/13 9:33 PM
48565_ST04_161-198.indd 188
5/1/13 9:33 PM
32 ■ OSTEOPOROSIS
Ben O’Donnell, MD and Geetha Gopalakrishnan, MD
EPIDEMIOLOGY
• In the US, it is estimated that there are 10 million people with osteoporosis and another 33 million at risk for osteoporosis (i.e., osteopenia)
• Osteoporotic fractures are estimated to occur in
in 2 postmenopausal Caucasian women
° 11 in
5 men >50 years
°
• Osteoporotic fractures typically involve the spine, hip, and forearm
(spine) fractures are usually asymptomatic but can lead
° Vertebral
to kyphosis and restrictive lung disease
Hip
fractures
° mortality are associated with an increase in morbidity and
■ Mortality rates can be as high as 10−20% after a hip fracture
■ Only 40% return to a prefracture level of independence and 25%
require long-term nursing home care
DEFINITION
• Osteoporosis is diagnosed based on BMD measurements at spine, hip,
or forearm
sites, typically spine and hip, are measured with a dual-energy
° Two
X-ray absorptiometry (DEXA)
• The World Health Organization (WHO) has set criteria for diagnosis
based on the T-score, which represents a standard deviation of
the calculated BMD when compared with healthy 20−30 year-old
controls
TABLE 32.1 BMD by DEXA
WHO Classifi cation
Normal
Osteopenia
Osteoporosis
Severe Osteoporosis
48565_ST04_161-198.indd 189
T-Score
≥-1
-2.5 to -1
≤-2.5
≤-2.5 with ≥1 fragility fracture
5/1/13 9:33 PM
190 Osteoporosis
• The diagnostic criteria can only be applied to postmenopausal women
and men >age 50
• In premenopausal women and men <age 50, the diagnosis of osteoporosis should not be made on the basis of BMD criteria alone
and race-matched Z-scores define individuals as “below
° Ageexpected range for age” if Z-score is <-2.0
• Osteoporosis can also be diagnosed based on presence of a fragility
fracture when the T-score is low, but not in the osteoporotic range;
fragility fractures occur as a result of low trauma (i.e., fall from standing height, fall from one step or less, spontaneous vertebral fracture)
and typically involve the spine, hip and forearm
BONE METABOLISM
• Bone remodeling exists in a state of balance between bone formation
and bone resorption
are responsible for new bone formation
° Osteoblasts
° Osteoclasts are responsible for bone resorption
• Prior to age 25−30, this balance favors bone formation. As a person
ages, the balance shifts towards bone resorption. Reductions in sex
hormones, testosterone and estrogen, accelerate the bone loss.
• A person’s peak bone mass will determine the density of bone present
prior to the expected bone loss seen with aging, and is influenced by
a number of factors, including genetics, lifetime calcium and vitamin
D intake, level of physical activity, and exposure to a number of
secondary causes
TABLE 32.2 Secondary Causes of Osteoporosis (Selected)
Hypogonadism or premature menopause (<45 years)
Chronic malnutrition, or malabsorption and chronic liver disease
Rheumatoid arthritis, systemic lupus erythematosus (SLE), or ankylosing spondylitis
Malignancy such as multiple myeloma
Untreated long-standing hyperthyroidism
Type 1 (insulin dependent) diabetes mellitus
Osteogenesis imperfecta in adults
Immobility
Medications (antiepileptics, chemotherapy, glucocorticoids)
Source: FRAX Who Calculation Tool/NOF Clinical Guidelines
48565_ST04_161-198.indd 190
5/1/13 9:33 PM
Treatment 191
RISK FACTORS
• Major risk factors associated with fractures in Caucasian women
TABLE 32.3 Risk Factors for Osteoporosis and Fracture
Major Risk Factors
Personal history of fracture as an adult
History of hip fracture in first-degree relative
Low body weight
Current smoking
Use of oral glucocorticoid (equivalent of ≥5 mg of
prednisone for ≥ 3 months)
Additional Risk Factors
Impaired vision
Early menopause (<age 45)
Dementia
Poor health or frailty
Recent falls
Low lifelong calcium intake
Low level of physical activity
>2 alcoholic drinks per day
SCREENING
• Multiple guidelines exist for screening (Table 32-4)
• In general, all women > age 65 should be screened
• Little consensus exists in terms of interval between screening
TABLE 32.4 Screening Guidelines (Men and Women)
US Preventive Services Task Force
(2011)
Women >65 years old; postmenopausal Women;
<65 with FRAX score >9.3%; Men: no evidence
to screen (www.shef.ac.uk/FRAX/tool.jsp)
Women >65 y/o, men >70 y/o; Postmenopausal
National Osteoporosis Foundation
women <65 and men >50 with risk factor(s)
(2010)
American Congress of Obstetricians Women >65 years old; postmenopausal women
and Gynecologists (2008)
<65 with risk factor(s)
American College of Physicians
Periodically screen men for risk and obtain DEXA
(2008)
in those with risk and who are candidates
for therapy
TREATMENT
• For a diagnosis of osteopenia or osteoporosis both calcium (1000−
1200 mg daily) and Vitamin D (800−1000 units daily) are recommended;
dietary sources of calcium are preferred (see Chapter 27, Calcium
Metabolism Essentials)
• Weight-bearing and balance exercises can also help to prevent fractures
48565_ST04_161-198.indd 191
5/1/13 9:33 PM
192 Osteoporosis
• Pharmacological therapy is recommended for individuals with a
or hip fragility fracture
° Vertebral
diagnosis of osteoporosis (T-score ≤-2.5)
° BMD
Other
high-risk
° ■ A risk profile individuals
can be determined by using Fracture Risk
Assessment (FRAX) WHO Calculation Tool (http://www.shef.
ac.uk/FRAX/tool.jsp)
■ Pharmacological therapy is recommended in patients with
osteopenia (T-score between -1 and -2.5) if the FRAX tool
calculates the
• 10-year probability of a hip fracture to be >3%
• 10-year probability of other major osteoporotic fractures to
be >20%
• Several pharmalogical agents have been approved for the treatment
and prevention of osteoporosis (Table 32-3). Recommendations for
choosing drugs to treat osteoporosis
agents: alendronate, risedronate, zoledronic acid, denosumab
° First-line
agent: ibandronate, raloxifene
° Second-line
agent: calcitonin
° Third-line
Treatment
for
with very high fracture risk (i.e., T-score < -3.5
° and/or multiplepatients
fragility fractures) or in whom bisphosphonate therapy
has failed: teriparatide
• Although no consensus exists on the frequency of retesting, DEXA
should not be repeated more frequently than every 2 years in postmenopausal osteoporosis
TABLE 32.5 Medical Therapy for Use in Osteoporosis
Name
Action
Alendronate (Fosamax) Inhibits osteoclasts
Risedronate (Actonel) Inhibits osteoclasts
Form
PO
PO
Ibandronate (Boniva)
Inhibits osteoclasts
PO/IV
Zoledronic acid
(Reclast, Zometa)
Teriperatide (Forteo)
Inhibits osteoclasts
IV
Dose
70 mg/week
35 mg/week or
150 mg/month
150 mg po/mo or
3 mg IV q 3 mo
5 mg/year
PTH analog, stimulates
bone formation
Monoclonal antibodies
to RANKL, inhibits
osteoclast
Inhibits osteoclasts
Stimulates estrogen
receptors in bone
Stimulates estrogen
receptors in bone
Subcutaneous
20 mcg/day
Subcutaneous
60 mg q6mo
Denosumab (Prolia)
Calcitonin
SERM-Raloxifene
(Evista)
Estrogen HRT
48565_ST04_161-198.indd 192
Intranasal/SQ/IM 1 spray/day
PO
60 mg/day
PO
Variable
5/1/13 9:33 PM
References
193
REFERENCES
ACOG Committee Opinion No. 407: low bone mass (osteopenia) and fracture
risk. Obstet Gynecol, 2008;111(5):1259−61.
Cummings, SR, MD et al, Risk Factors for Hip Fracture in White Women, The
Study of Osteoporotic Fractures Group, N Engl J Med, 1995;332:767–73.
Khosla, Sundeep MD and Melton, Joseph, MD, MPH. Osteopenia. N Engl J Med,
2007;356:2293–300.
Low bone mass (osteopenia) and fracture risk. ACOG Committee Opionion
No. 407. American College of Obstetricians and Gynecologists. Obstet
Gynecol, 2008;111:1259–61.
National Osteoporosis Foundation. Clinician’s Guide to Prevention and
Treatment of Osteoporosis. Washington, DC: National Osteoporosis
Foundation; 2010.
Qaseem, Amir MD et al; Screening for Osteoporosis in Men: A Clinical Practice
Guideline from the American College of Physicians. Annals of Internal
Medicine. 2008 May;148(9):680–684.
Screening for Osteoporosis: U.S. Preventive Services Task Force
Recommendation Statement. Annals of Internal Medicine. 2011
Mar;154(5):356–364.
48565_ST04_161-198.indd 193
5/1/13 9:33 PM
48565_ST04_161-198.indd 194
5/1/13 9:33 PM
33 ■ PAGET’S DISEASE OF BONE
(OSTEITIS DEFORMANS)
Joseph Tucci, MD
ETIOLOGY
• Genetic: data consistent with important genetic component with
documented mutations in sporadic and familial Paget’s disease
• Viral: possibility of an underlying paramyxoviral infection based
on findings of viral-like inclusions in pagetic osteoclasts and other
extensive but somewhat conflicting laboratory data
PATHOPHYSIOLOGY
• Focal disorder of one or more bones (frequent sites include pelvis,
skull, spine, femur, tibia) characterized by accelerated remodeling,
high bone turnover
• Initially, bone changes characterized by an increase in number and bone
resorbing activity of enlarged osteoclasts with up to 100 nuclei per cell
• Subsequently, there is an associated increase in abnormal activity
of marrow stromal cells and an increase in number and activity of
osteoblasts with abnormal bone formation
• As a result, bone mass tends to increase and normal lamellar bone is
replaced by a chaotic mosaic pattern of woven and lamellar bone that
is structurally inferior to normal bone
• Increased vascularity of pagetic bone and marrow, replacement of
bone marrow by fibrous connective tissue
• A later phase is characterized by diminished bone turnover and sclerotic bone consistent with so-called “burned out” Paget’s disease
CLINICAL PRESENTATION
• Frequently, an asymptomatic patient with an incidental radiologic finding
and/or an increase in serum alkaline phosphatase on blood chemistry profile
• Bone pain related to increased vascularity, advancing lytic lesions in
long bones, deformation, fissure and chalkstick fractures, nonunion of
fractures in up to 10% of cases
• Joint pain due to degeneration of hip and/or knee joints (secondary
osteoarthritis) adjacent to pagetic bone
• Abnormal posture with abnormal tilt of trunk due to enlarged vertebral,
pelvic, and/or long bone deformities
• Bone deformity, long-bone bowing, skull enlargement with and without
frontal bossing, facial bone deformities
48565_ST04_161-198.indd 195
5/1/13 9:33 PM
196
Paget’s Disease of Bone (Osteitis Deformans)
• Neurologic symptoms: pagetic changes in skull with headaches,
cranial nerve deficits related to narrowed foramina especially hearing
loss, platybasia, brain stem compression, obstructive hydrocephalus,
myelopathy, spinal cord compression, spinal vascular steal syndrome,
spinal stenosis
• Cardiovascular complications: especially with extensive disease, highoutput CHF, endocardial and aortic valve calcifications, generalized
atherosclerosis
• Neoplastic: osteosarcoma (in <1% of patients), benign giant cell tumors
• Metabolic: hypercalcemia and/or hypercalciuria with immobilization of
patients with extensive disease, secondary hyperparathyroidism in up
to 20% of patients, coincidental PHPT
PHYSICAL EXAMINATION
• Angioid streaks on retinal exam
• Skull enlargement with or without frontal bossing or supraorbital
deformities, corrugation of skull surface, hearing deficits, deformation
of long bones with bowing, facial and clavicular deformities
• Increased warmth over pagetic bone
• Postural changes and gait abnormalities related to severe deformities
of spine, pelvis, and/or long bones
DIAGNOSTIC EVALUATION
• Biochemical
in serum alkaline phosphatase and/or bone-specific
° Increase
alkaline phosphatase, increase in bone resorption markers such as
urine N-telopeptide of collagen cross-links (NTx)/creatinine ratio or
plasma C-telopeptide of collagen cross-links (CTx)
of biochemical abnormalities related to extent of disease
° Degree
and skull involvement
• Imaging
bone scan most sensitive in delineating pagetic sites
° Technetium
of involvement
X-rays provide a definitive assessment of positive sites
° Skeletal
on scan
• Radiologic findings: bone enlargement, bowing of long bones, osteolytic wedge or “blade of grass” appearance in long bones, lytic and
sclerotic bone changes, cortical and trabecular thickening, skull with
osteoporosis circumscripta, external and/or internal cranial thickening,
“picture frame” vertebrae, pelvic changes with sclerosis, and lytic
lesions with or without protrusion acetabuli
• Histologic: bone biopsy through pagetic bone occasionally performed
to distinguish Paget’s disease from metastatic cancer (e.g., prostate
cancer) or osteosarcoma
48565_ST04_161-198.indd 196
5/1/13 9:33 PM
Management 197
MANAGEMENT
• Rationale: to decrease bone turnover through inhibition of osteoclastic
bone resorption with bisphosphonates or calcitonin
• Objectives: to alleviate pagetic-related symptoms, effect sustained
biochemical and clinical remissions, prevent progression of pagetic
disease
• Comments
the greater the activity and extent of disease, the higher
° Generally,
the serum alkaline phosphatase level and the greater likelihood of a
diminished response to therapy
therapy, critically important to optimize calcium and vitamin D
° Before
intake to avoid hypocalcemia with bisphosphonate therapy
• Indications for therapy
disease
° Extensive
pain
° Pagetic
Pagetic
fracture
° Pagetic deformity
° Neurologic complications
° Area(s) of critical involvement
° High-output CHF
° Preparation for surgery on pagetic bone to prevent excess bleeding
° Sarcoma
°
• Pharmacotherapy
° Aminobisphosphonates
■ Pamidronate (Aredia): 30 mg each day for 3 days given IV (over
4 hours in normal saline or 5% dextrose in water), 60 mg weekly
for 3 weeks, or up to 90 mg weekly for 4 weeks
• Normalization of serum alkaline phosphatase in majority of
patients
• Adverse effects: transient bone pain, acute phase reaction
or flulike syndrome occurring within several days following
the first infusion lasting up to two days or so (alleviated by
acetaminophen therapy), rare cases of uveitis
■ Zoledronic acid (Reclast): a single infusion of 5 mg over a 15-to30−minute period
• Efficacy: single most potent therapy with rapid normalization
of serum alkaline phosphatase and more sustained remissions
in 90% of patients
• Adverse effects: similar to therapy with pamidronate
■ Alendronate (Fosamax): 40 mg per day given orally for 6 months
in the fasting state with 8 oz of water and no food for
30−60 minutes, then remain sitting or standing for 30 minutes
• Efficacy: normalization of serum alkaline phosphatase in
60−70% of patients
• Adverse effects: chest and/or abdominal pain, reflux
symptoms, esophagitis
48565_ST04_161-198.indd 197
5/1/13 9:33 PM
198
Paget’s Disease of Bone (Osteitis Deformans)
Risedronate (Actonel): 30 mg per day given orally for 2 months in
fasting state with 8 oz of water and no food for 30−60 minutes,
then remain sitting or standing for 30 minutes
• Efficacy: normalization of serum alkaline phosphatase in
>70% of patients
• Adverse effects: chest and/or abdominal pain, reflux symptoms, esophagitis
Salmon calcitonin (Miacalcin) second-line therapy: 50−100 units
injected SQ, 3 or 4 times weekly to daily
■ Particularly useful in patients intolerant to bisphosphonates and
in those with renal insufficiency
■ Therapeutic effect
• Generally 50% reduction in serum alkaline phosphatase with
no further reduction despite continued therapy (so-called
plateau response)
• Therefore, probable biochemical normalization in those with
serum alkaline phosphatase levels no higher than 2−3 times
upper limit of normal
• There may be an analgesic effect
■ Adverse effects: nausea, flushing of ears, possible development
of resistance especially with prolonged therapy
■
°
ASSESSMENT OF THERAPEUTIC RESPONSE
• Serum alkaline phosphatase and/or urine NTx creatinine ratio or
plasma CTx 1−2 months following initiation of therapy and then at
3-, 4-, or 6-monthly intervals
• Retreatment: 6 months or longer after initial therapy if remission not
effected or evidence of reactivation evidenced by an increase in serum
alkaline phosphatase of 25% above therapeutic peak response
• Other effects of therapy: alleviation of pagetic pain, replacement of
pagetic bone by more normal bone as evidenced by technetium scanning, X-rays, or bone biopsy
REFERENCES
Ralston SH, Langston AL, Reid IR. Pathogenesis and management of Paget’s
disease of bone. Lancet, 2008;372(9633):155–63.
Reid IR, Lyles K, Su G, et al. A single infusion of zoledronic acid produces
sustained remissions in Paget disease: data to 6.5 years. J Bone Miner
Res, 2011;26(9):2261–70.
Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of
zoledronic acid with risedronate for Paget’s disease. N Engl J Med,
2005;353(9):898–908.
Shankar S, Hosking DJ. Biochemical assessment of Paget’s disease of bone.
J Bone Miner Res, 2006;21(Suppl 2):22–7.
48565_ST04_161-198.indd 198
5/1/13 9:33 PM
SECTION V: REPRODUCTION
48565_ST05_199-250.indd 199
5/1/13 9:32 PM
48565_ST05_199-250.indd 200
5/1/13 9:32 PM
34 ■ MALE REPRODUCTION ESSENTIALS
Bruce Redmon, MD
TESTES
• Paired organs, each 15–30 ml volume (3.5–5.5 cm length, 2–3 cm
width)
• Endocrine and exocrine functions
function: synthesis and secretion of androgenic and
° Endocrine
estrogenic hormones (primarily testosterone) and other hormones
involved in sexual differentiation and spermatogenesis (antimullerian hormone [AMH], inhibin, androgen-binding protein, insulin-like
factor 3 [INSL3])
° Exocrine function: spermatogenesis
• Two compartment model
tubules (exocrine compartment): 600–1200 per testis
° Seminiferous
■ Differentiating germ cells (germ cell → spermatogonia →
spermatocytes → spermatid → spermatozoa)
• 40–70 day time span for sperm differentiation/maturation
• ~120 million sperm produced per day
• Key genes regulating spermatogenesis localized to the
azoospermic factor (AZF) region of the long arm of the Y
chromosome (Yq)
■ Three regions (AZFa, AZFb, AZFc) identifi ed
■ Microdeletions of genes in these regions associated with
azoospermia or severe oligospermia
■ Sertoli cells
• “Nurse cells” surrounding differentiating germ cells
• Tight junctions form blood-testis barrier
■ Maintain specialized, immunologically restricted
environment for spermatogenesis
• Receptors for FSH and androgens
• Secretory function: proteins (e.g., androgen-binding protein,
inhibin, AMH) and extracellular matrix constituents
Interstitial
compartment
° ■ Leydig cells
• Production and secretion of testosterone and other steroids in
response to LH
■ Three peaks in testosterone production: 12–18 weeks
gestation, 1–2 months of age, second to third decade
• Production of INSL3 (regulator of early testicular descent)
■ Supporting cells: myoid cells, fibroblasts, macrophages,
neurovascular cells
48565_ST05_199-250.indd 201
5/1/13 9:32 PM
202
Male Reproduction Essentials
REPRODUCTIVE OUTFLOW TRACT
• Epididymis
tubule 3–6 m in length connecting testes to vas deferens
° Coiled
of sperm storage (estimated 155–200 million sperm stored in
° Site
each epididymis) and maturation; estimated transit time 2–12 days;
transit associated with acquisition of motility and ability to fertilize egg
° Androgen-dependent (primarily DHT)
• Seminal vesicle/ejaculatory duct
vesicle: collagenous tubular structure with outer muscular
° Seminal
layer, secretes up to 80% of seminal plasma (alkaline fluid containing
fructose, prostaglandins, coagulants)
duct: tubular continuation of seminal vesicle, extending
° Ejaculatory
from junction of vas deferens and seminal vesicle to prostatic urethra
• Prostate/bulbourethral glands
secretes thin, acidic fluid (~20% of semen volume)
° Prostate:
containing citric acid, acid phosphatase, proteolytic enzymes
■ Contributes to seminal plasma for sperm transport, nourishment,
and function
Bulbourethral
glands: secrete initial part of the ejaculate, a clear
° alkaline fluid containing
glycoproteins that provides mechanical
lubrication and neutralizes the acidic mileu in the male urethral
and female vaginal tract
SEXUAL DIFFERENTIATION
• Four to six weeks gestation: migration of primordial germ cells from yolk
sac to genital ridge (primitive bipotential gonad) and development of
mesonephric (Wollfian) and paramesonephric (Mullerian) duct systems
• Testicular differentiation occurs in the presence of a Y chromosome via
activation of the transcription factor SRY (sex-determining region of
the Y chromosome) leading to
differentiation (week 7)
° Sertoli
production with Mullerian duct regression (weeks 7–12)
° AMH
Leydig
cell
° (weeks 8–9)differentiation with androgen and INSL3 production
• Wollfian duct differentiation to form epididymis, vas deferens, seminal
vesicles in response to fetal testosterone (weeks 8–15)
• Development of external genitalia (scrotal fusion, development of
penis, prostate) in response to fetal DHT (weeks 8–15)
• Testicular descent
weeks 10–23, regulated by testosterone and INSL3
° Transabdominal:
° Inguinal-scrotal: weeks 26–birth, regulated by testosterone
• Early postnatal period: transient activation of hypothalamic-pituitarytesticular axis at 1–6 months with increased LH, FSH, testosterone
production, Sertoli cell proliferation, formation of early spermatogonia
48565_ST05_199-250.indd 202
5/1/13 9:32 PM
Neuroendocrine Regulation 203
• Puberty: sustained reactivation of hypothalamic-pituitary-testicular axis
with increased gonadotropins, testosterone production, development of
secondary sexual characteristics, Sertoli cell stimulation of spermatogenesis with seminiferous tubule growth and increased testicular size
NEUROENDOCRINE REGULATION
• Pulsatile hypothalamic GnRH release drives pulsatile LH (12–16 pulses/
day) and FSH release (less pulsatility)
activation of gonadotropins gene expression in
° Differential
response to pulse frequency
• Regulation of GnRH via central neurotransmitters (stimulatory:
kisspeptin, neurokinin; inhibitory: dynorphin, PRL, opiates, CRH/
glucocorticoids) and peripheral metabolic signals (stimulatory: leptin)
Opiates
Prolactin
Glucocorticoids
-+
Hypothalmus
+/-Hypothalamic
KNDy neurons
GnRH
+
Leptin
--
Pituitary
Estrogen
-LH
Peripheral
fat stores
FSH
Inhibin
+
Testosterone
DHT
Testes
Note: Steroid hormone feedback regulation at the level of the hypothalamus is felt
to be indirect and mediated via hypothalamic KNDy neurons containing kisspeptin
(K), neurokinin (N) and dynorphin (Dy). Kisspeptin and neurokinin promote GnRH
release while dynorpnin is inhibitory.
FIGURE 34.1 Hypothalamic-Pituitary-Testes Axis
48565_ST05_199-250.indd 203
5/8/13 8:14 PM
204
Male Reproduction Essentials
• Negative feedback by sex steroids at level of hypothalamus (testicularderived testosterone, progesterone, and estradiol derived via aromatization of testosterone by aromatase found in multiple tisses, including
testis, fat, brain, and liver) and pituitary (estradiol primarily), and
Sertoli cell-derived inhibin B (suppression of FSH)
steroid regulation at the hypothalamus likely indirect, possibly
° Sex
via neurons co-staining for kisspeptin/neurokinin/dynorphin
• Autocrine/paracrine regulation of FSH secretion via gonadotrope-derived
peptides: activins (stimulatory), inhibin (structurally related to activins
but inhibitory) and follistatin (inhibitory activin-binding protein)
REFERENCES
Bronson R. Biology of the male reproductive tract: its cellular and morphological considerations. Am J Reprod Immunol, 2011;65(3):212–9.
Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin
B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the
control of gonadotropin-releasing hormone secretion. Endocrinology,
2010;151(8):3479–89.
Matsumoto AM, Bremner WJ. Testicular disorders. In: Melmed S, Polonsky KS,
Larsen PR, Kronenberg HM. Williams Textbook of Endocrinology. 12th ed.
Philadelphia, PA: Saunders Elsevier; 2011:688–777.
Sam S, Frohman LA. Normal physiology of hypothalamic pituitary regulation.
Endocrinol Metab Clin North Am, 2008;37(1):1–22.
Turek P. Male reproductive physiology. In: Wein A, Kavoussi W, Novick A,
Partin A, Peters C. Urology. 10th ed. Boston, MA: Saunders Elsevier; 2011:
591 Chapter 20:591–625.
48565_ST05_199-250.indd 204
5/1/13 9:32 PM
35 ■ GYNECOMASTIA
Harmeet Narula, MD and Harold Carlson
• Gynecomastia definition
° Benign enlargement of male breast
• Pseudogynecomastia (lipomastia)
breasts, common in obese men, no true glandular breast
° Fatty
tissue palpable
• Pathophysiology
androgen (A) to estrogen (E) ratio
° Altered
■ ↓ level or action of androgens, and/or
■ ↑ level or action of estrogens
TABLE 35.1 Pathogenesis of Gynecomastia
Decreased Androgens
(↓Total or Bioavailable Testosterone)
Primary hypogonadism
Secondary hypogonadism
(↑ LH/FSH)
(normal or ↓ LH/FSH )
Klinefelter’s syndrome: only cause of
Kallman syndrome and all other causes of
gynecomastia with increased breast
secondary hypogonadism
cancer risk
Mumps orchitis and any cause of
Elevated prolactin from any cause including
primary hypogonadism
drugs (antipsychotics, metoclopramide)
Drugs: cytotoxic chemotherapy,
Drugs: GnRH agonists/antagonists, opiates
ketoconazole, spironolactone in high doses in high doses
Increased Estrogens
Exogenous estrogens
Endogenous estrogens
Oral, injectable, or percutaneous
Testicular
exposure
Sertoli or Leydig cell tumors;
stimulation of normal testes by LH/hCG
Anabolic steroids (if aromatized to
Adrenal
estrogens)
Feminizing adrenocortical tumors
Increased aromatization of androgens
to estrogens: aging, obesity, cirrhosis,
hyperthyroidism, aromatase excess syndrome
Decreased androgen action
Altered A to E ratio
Defective androgen receptors (AR)
Puberty, aging (physiologic)
AR blockade: marijuana, spironolactone, “Refeeding” gynecomastia: dialysis,
cimetidine, bicalutamide, flutamide
cirrhosis, CHF, hyperthyroidism
Drugs (e.g., finasteride)
Kennedy disease (↑ CAG repeats in
AR gene)
48565_ST05_199-250.indd 205
5/1/13 9:32 PM
206 Gynecomastia
CLINICAL PRESENTATION
• Often asymptomatic, incidentally found on routine exam, especially at
extremes of age (puberty and aging)
• Breast pain, sensitivity: in men with recent-onset enlargement
• Breast enlargement: usually symmetrical, bilateral
TABLE 35.2 History and Physical Examination in Gynecomastia
History
Duration of gynecomastia
Breast pain or tenderness
Underlying systemic disease
Physical Exam
General: thyroid, stigmata of liver disease
Degree of virilization: voice, facial and
body hair, skeletal muscle mass
Genitalia: penile size and development,
testicular size and/or masses
Fertility and sexual function
Use of medications, recreational drugs,
and supplements (specifically anabolic
steroids, marijuana, opiates)
Any exposure to estrogenic chemicals
including phytoestrogens
Family history of gynecomastia: suggests
androgen insensitivity or aromatase
excess syndromes
Breast exam: rule out fatty breasts
(lipomastia) and malignancy, unilateral
or bilateral, symmetric or asymmetric
enlargement
Worrisome findings suggestive of breast
cancer: asymmetry, eccentric location (not
centered beneath the areola), fixation to
the skin or chest wall, nipple retraction,
bleeding or nipple discharge, ulceration, or
associated lymphadenopathy (if present,
refer to expert breast surgeon for excision
and/or biopsy)
DIAGNOSTIC EVALUATION
• Laboratory testing: serum testosterone (total and/or bioavailable),
estradiol, LH, FSH, PRL, β-hCG, TSH, BUN/creatinine, LFTs
• Imaging: NO need for routine mammograms, ultrasounds, or any other
imaging study in men with gynecomastia unless there are any worrisome signs of malignancy or the breast enlargement is asymmetric,
unilateral, or recent onset
48565_ST05_199-250.indd 206
5/1/13 9:32 PM
References
207
MANAGEMENT
• Observation: in healthy men with longstanding stable gynecomastia,
puberty, aging
• Withdrawal of offending agent (if reversible cause of gynecomastia
found on workup)
to 50% of gynecomastia may be due to drugs; stopping offend° Up
ing drug may lead to spontaneous resolution of gynecomastia in
6−12 months
• Medical Rx
symptomatic men, especially if gynecomastia of recent onset
° In
(<2 years)
Testosterone
in men with hypogonadism
° ■ May worsenRx:gynecomastia
(testosterone aromatized to estradiol)
(antiestrogen): drug of choice (off-label); 10−20 mg/day
° Tamoxifen
for 3−9 months; raloxifene 60 mg/day may be equally effective
(aromatase inhibitor): in men with aromatase excess
° Anastrazole
syndrome or who develop gynecomastia on testosterone therapy
• Breast irradiation: in men with prostate cancer planning androgen
ablation therapy, breast irradiation may prevent gynecomastia
• Surgery
medical therapy ineffective or declined, for longstanding gyneco° Ifmastia,
or for cosmesis
Rule
out underlying endocrine disorder BEFORE surgery (to prevent
° regrowth
of breast tissue after surgery)
REFERENCES
Braunstein GD. Clinical practice. Gynecomastia. N Engl J Med, 2007;357(12):
1229−37.
Carlson HE. Approach to the patient with gynecomastia. J Clin Endocrinol
Metab, 2011;96(1):15−21.
Narula HS, Carlson HE. Gynecomastia. Endocrinol Metab Clin North Am,
2007;36(2):497−519.
48565_ST05_199-250.indd 207
5/1/13 9:32 PM
48565_ST05_199-250.indd 208
5/1/13 9:32 PM
36 ■ TESTOSTERONE DEFICIENCY IN MEN
Diana R. Engineer, MD and Glenn R. Cunningham, MD
PREVALENCE
• Symptomatic androgen deficiency prevalence increases with age:
<70 yrs age 3.1−7%; >70 yrs age 18.4%
• Diagnosis requires presence of signs/symptoms + low testosterone
level
PATHOPHYSIOLOGY
FIGURE 36.1 Hypothalamic-pituitary-testicular axis in a normal male.
• Hypothalamic-pituitary-testicular axis in a normal male. GnRH =
gonadotropin-releasing hormone, LH = luteinizing hormone, FSH =
follicular stimulating hormone, DHT = 5α-dihydrotestosterone
48565_ST05_199-250.indd 209
5/8/13 8:14 PM
210 Testosterone Defi ciency in Men
ETIOLOGY
TABLE 36.1 Etiology of Testosterone Defi ciency in Men
Secondary (hypothalamic- Primary (testicupituitary dysfunction)
lar dysfunction)
Congenital
Idiopathic GnRH deficiency, Chromosomal
Kallman syndrome, Prader- abnormalities
Willi syndrome, Laurence(Klinefelter’s,
Moon-Biedl syndrome,
XX male gonadal
panhypopituitarism,
dysgenesis),
pituitary hypoplasia
defects in
androgen
biosynthesis,
myotonia
dystrophica,
cryptorchidism,
varicocele
Inflammatory
Orchitis (mumps,
human
immunodeficiency
virus [HIV], viral,
leprosy)
Trauma
Postsurgical blunt head
Orchiectomy
trauma
Tumor
Pituitary adenoma,
craniopharyngioma
Vascular
Pituitary infarct/apoplexy,
Testicular torsion
insult
carotid aneurysm
Drugs
Sex steroids, drug-induced Cytotoxic drugs,
hyperprolactinemia,
ketoconazole,
opioids
cimetidine,
spironolactone
Systemic
Anorexia nervosa
Illness
Autoimmune
Infiltrative
Toxins
Other
48565_ST05_199-250.indd 210
Mixed
Chronic infection
(HIV, tuberculosis,
fungal infection)
Irradiation
Corticosteroids
Malnutrition,
chronic renal
failure, liver
failure, chronic
inflammatory
disease
Autoimmune hypophysitis
Sarcoidosis,
histiocytosis,
hemochromatosis
Alcohol,
fungicides,
insecticides,
heavy metals
Obesity, aging
5/1/13 9:33 PM
Chronic Conditions with High Prevalence of Hypogonadism
211
HISTORY
• Depressed mood, quality of life, confidence
• Developmental history (testicular descent, onset of puberty, body/
facial hair development, age achieved maximal height)
• Detailed medical history (systemic illness, sexually transmitted diseases
[STDs], orchitis, orchiectomy, irradiation, prostate surgery, drugs)
• Detailed sexual history (libido, erectile and ejaculatory function,
coitus, fertility)
• Frequency of shaving, body hair patterns
• Height loss, decreased bone density, fragility fractures
• Hot flashes or sweats
• Mild anemia (normochromic, normocytic)
• Sleep disturbance, increased sleepiness, sleep apnea
PHYSICAL EXAM
• Breast tenderness or gynecomastia
• Eunuchoid proportions (arm span ≥2 inches greater than height; lower
segment [floor to pubis] ≥2 inches greater than upper body segment
[pubis to crown])
• Hair patterns: decreased facial/axillary/chest/pubic hair, female
(triangular) escutcheon
• Increased body and visceral fat
• Acne
• GU exam: penis length, urethra for hypospadia, prostate exam for
small/atrophied prostate (can be obscured by benign prostatic
hyperplasia [BPH])
• Scrotal exam for testicular descent, consistency, and size (<4 × 2 cm
or <20 mL), varicocele
• Musculoskeletal development, strength, muscle atrophy, bone
deformity/fractures
CHRONIC CONDITIONS WITH HIGH PREVALENCE OF HYPOGONADISM
• Consider screening for testosterone deficiency
liver disease
° Chronic
obstructive pulmonary disease (COPD), moderate−severe
° Chronic
End-stage
renal disease (ESRD) and hemodialysis
° Glucocorticoid
or opiod use
° Human immunodefi
ciency virus (HIV)-associated weight loss
° Hypertension
° Hyperlipidemia
° Infertility
° Obesity
°
48565_ST05_199-250.indd 211
5/1/13 9:33 PM
212 Testosterone Defi ciency in Men
°
°
°
°
°
Obstructive sleep apnea
Osteoporosis or fragility fracture
Rheumatoid arthritis
Sellar mass, radiation to sella
Type 2 diabetes
ASSAYS/TESTS
• Total testosterone: liquid chromatography with tandem mass spectrometry (preferred), radioimmunoassay (RIA), platform immunoassays
(more variable)
• Direct analogue free testosterone: not valid
• Total testosterone/sex hormone–binding globulin (SHBG) ratio: not
very reliable
• Free testosterone: equilibrium dialysis (gold standard); calculated free
T (need total + SHBG)
• Bioavailable testosterone: NH4SO4 precipitation of T-SHBG; calculated
bioavailable T (need total T, SHBG, albumin)
• SHBG: varies in different conditions; 40−50% of testosterone is bound
to SHBG; changes in SHBG will affect the total testosterone level, but
will not affect the free or bioavailable testosterone level
TABLE 36.2 Variations in SHBG
Increased SHBG
Aging
Anticonvulsant use
Cirrhosis
Estrogen use
Hyperthyroidism
HIV infection
Malnutrition, malabsorption
Decreased SHBG
Glucocorticoid, progestin, anabolic
steroid use
Hypothyroidism
Nephrotic syndrome
Obesity, metabolic syndrome
Type 2 diabetes
DIAGNOSIS
• Requires signs/symptoms + low total testosterone level
and low testosterone levels should be defined for each
° Normal
assay. There is an ongoing effort by the US Centers for Disease
Control and Prevention (CDC) to harmonize testosterone assays to
the same standard, which should help to harmonize normal ranges.
The International Society of Andrology defines low testosterone
as levels <231 ng/dL and borderline levels 231–346 ng/dL. The
Endocrine Society uses <300 ng/dL
48565_ST05_199-250.indd 212
5/1/13 9:33 PM
Potential Risks of Androgen Replacement
213
TABLE 36.3 Etiology of Testosterone Defi ciency in Men
Hypogonadism Etiology
Hypogonadotropic
hypogonadism (central)
Testicular insufficiency
(primary)
Further Work-Up
Treatment
Prolactin, iron saturation, HCG or T to virilize,
pituitary function testing, gonadotropins or
MRI sella turcica*
pulsatile GnRH for fertility
+ virilization
Karyotype
T to virilize
T = serum testosterone
*MRI pituitary in secondary/central hypogonadism if tumor suspected clinically or if total testosterone
<150 ng/dL.
• Initial labs: fasting 7−10 AM serum total testosterone; if low total
testosterone, repeat and include LH, FSH, PRL
• Measure free or bioavailable testosterone level in men with borderline
low total testosterone or in whom alterations in SHBG are suspected
• Evaluation of androgen deficiency should not be done during any acute
or subacute illness
• DEXA scan recommended for all men with severe testosterone
deficiency or fragility fracture
Avoid Testosterone Therapy if:
• Breast or untreated prostate cancer
• Hematocrit >50%
• Untreated, severe obstructive sleep apnea
• Severe lower urinary tract symptoms (American Urological Associaton
(AUA) International Prostate Sympton Score (IPSS) >19)
• Uncontrolled CHF (New York Heart Association (NYHA) Class III or IV)
• Desire for fertility
POTENTIAL RISKS OF ANDROGEN REPLACEMENT
•
•
•
•
•
•
•
•
•
•
Acne/oily skin
Decreased high-density lipoprotein (HDL) cholesterol
Erythrocytosis (excessive increase in red blood cell count [RBC])
Growth of metastatic prostate cancer, breast cancer
Gynecomastia (via aromatization)
Increased male pattern balding
Induce or worsen sleep apnea
Possible increase in cardiovascular disease (CVD) risk
Reduced sperm production and fertility
Worsening of benign prostatic hypertrophy or lower urinary tract
symptoms
48565_ST05_199-250.indd 213
5/1/13 9:33 PM
214 Testosterone Defi ciency in Men
TABLE 36.4 Androgen Replacement
Preparations
Injectable/
Intramuscular
Transdermal
Buccal
48565_ST05_199-250.indd 214
Dosage
• Testosterone
enanthate
• Testosterone
cypionate
• Start 50–100
mg/week or
100–200 mg
q2weeks
• Testosterone
undecanoate*
• Gel (Androgel 1%
or 1.6%, Testim
1%)
• Start 5–10 g
of 1% gel/day
(provides 50–100
mg T daily)
• Lotion (Axiron):
60 mg once daily
applied to axilla
(30–120 mg/d)
• Fortesta 2% gel
60 mg/d
• Patch (Andoderm)
• Start 4–8 mg
daily
• Tablets: 30 mg
applied twice
daily
Pros
• Inexpensive
• Certainty of
compliance
• Testosterone
undecanoate
requires less
frequent dosing
Cons/Risks
• Nonphysiologic
troughs/peaks
• Pain at injection
site
• Check serum T
mid-way between
injections (goal
400–700 ng/dL)
Relatively steady
serum
concentrations
Ease of application
• Transfer by
intimate contact
(gel)
• Skin irritation
(patch)
• Check level
4–8 hours after
application
• Ease of
administration
• Variable
absorption
• 2x/day dosing
• Alteration in
taste
• Gum irritation
• Check serum
T immediately
before or after
application
(continues)
5/1/13 9:33 PM
Potential Risks of Androgen Replacement
215
TABLE 36.4 (continued )
Preparations
Implants
Dosage
• Pellets: 100–200
mg, 3–6
pellets inserted
subcutaneously
every 4–6
months
Pros
• Steady serum
concentrations
• Less frequent
dosing
• Compliance
Oral
• Testosterone
undecanoate*
• Ease of
administration
Cons/Risks
• Surgical
insertion
• Infection
• Expulsion of
pellet
• Check T level
1–2 months after
implantation
• Variable
absorption*
*Only available in Europe.
TABLE 36.5 Monitoring
Parameter
Symptom
Response
Adverse
Events
Testosterone
Level
Hematocrit*
PSA†
DRE†
BMD‡
Baseline
2−3 Months
√
6 Months
√
12 Months
√
Every 6−12
Months
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
DRE = digital rectal exam
* If Hct >54%, stop therapy until Hct decreases to safe levels, evaluate for hypoxia and OSA, and restart
testosterone therapy with reduced dose.
† After 3 months, continue to follow PSA and DRE per age and race-appropriate guidelines.
‡ For patients with osteoporosis or fragility fracture; recheck at 12−24 months.
• Stop therapy and refer to urology if
increases >1.4 ng/mL within 12 months
° PSA
ng/mL
° PSA>4
PSA
>0.4 ng/mL per year over >6 months (must have PSA
° levelsvelocity
≥2 years)
Digital Rectal Exam (DRE)
° Abnormal
° AUA/IPSS >19
48565_ST05_199-250.indd 215
5/1/13 9:33 PM
216 Testosterone Defi ciency in Men
REFERENCES
Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen
deficiency in men. J Clin Endocrinol Metab, 2007;92(11):4241–7.
Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone Therapy in Men
with Androgen Deficiency Syndromes: Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab, 2010;95:2536–59.
Guay AT, Spark RF, Bansal S, et al. American Association of Clinical
Endocrinologists medical guidelines for clinical practice for the evaluation
and treatment of male sexual dysfunction: a couple’s problem—2003
update. Endocr Pract, 2003;9(1):77–95.
Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and
ASA recommendations. Eur J Endocrinol, 2008;159(5):507–14.
Wu FCW, Tajar A, Beynon JM. Identification of Late-Onset Hypogonadism in
Middle-Aged and Elderly Men. N Engl J Med, 2010;363:123–35.
48565_ST05_199-250.indd 216
5/1/13 9:33 PM
37 ■ MALE INFERTILITY
Bradley Anawalt, MD
DEFINITION OF INFERTILITY
• Failure to conceive after 1 year of frequent intercourse without
contraception
PATHOPHYSIOLOGY OF MALE INFERTILITY
• Broad categories (prevalence %)
testicular defect in sperm production (70−80%)
° Primary
■ Idiopathic
■ Chemotherapy
■ Pelvic irradiation
■ Orchidectomy (even unilateral)
■ Trauma
■ Klinefelter’s syndrome
■ Testicular cancer
■ Large varicoceles
■ Autoimmune
of sperm defect (5−10%)
° Transport
■ Obstruction
• Congenital absence of the vas deferens (usually due to cystic
fibrosis)
■ Ejaculatory dysfunction
• Anejaculation (e.g., spinal cord lesions)
• Retrograde ejaculation
Endocrinopathies
(5%)
° ■ Hypothalamopituitary
disease (masses, infiltrative disorders)
■ Hyperprolactinemia
■ Thyroid dysfunction
• Untreated hyperthyroidism
• Untreated hypothyroidism
■ Obesity
■ Cushing’s syndrome
disorders (5%)
° Sexual
■ Erectile dysfunction
■ Failure to have intercourse
• Lack of libido
• Relationship dysfunction
■ Anorgasmia (sometimes associated with anejaculation) due
to selective serotonergic reuptake inhibitors
48565_ST05_199-250.indd 217
5/1/13 9:33 PM
218 Male Infertility
CLINICAL PRESENTATION
• History
history
° Sexual
■ Normal libido? Normal erections? Cloudy postcoital urine
(suggesting retrograde ejaculation)? Frequency of vaginal
intercourse (at least 2−3 times weekly)? Ever fathered a child?
Medical
° ■ Historyhistory
of testicular trauma, surgery, pelvic irradiation?
■ Systemic illness (any severe systemic illness can suppress
sperm production)
■ History of chemotherapy
■ Drugs and toxins such as tetrahydracannabinol, opiates, nicotine
• Physical examination
weight, body mass index (BMI)
° Height,
examination for evidence of corticosteroid excess (broad
° Skin
purple striae, ecchymoses)
exam for goiter
° Thyroid
exam for gynecomastia, galactorrhea
° Breast
Genitourinary
exam for evidence of hypospadias, penile fibroses,
° large varicocele,
small testes (<15 cc or <3.5 cm in longest axis),
testicular mass, palpable vas deferens (if not palpable, consider
forme fruste of cystic fibrosis)
examination for signs of autonomic neuropathy, saddle
° Neurologic
anesthesia
DIAGNOSTIC EVALUATION
• Blood tests
total and calculated free testosterone, LH, and FSH from a
° Serum
fasting early morning blood sample
If
testosterone
low and LH and FSH are both high (FSH >
° LH), then patientis has
primary testicular dysfunction (primary
hypogonadism)
If
testosterone
is
low
and
LH and FSH are both normal or low,
° then patient has hypothalamopituitary
disease (secondary
hypogonadism)
testosterone and LH are both normal but FSH is high, then patient
° Iflikely
has an isolated defect in testicular sperm production
Serum
if clinical evidence of thyroid dysfunction
° Serum TSH
and iron saturation if testosterone is low and LH and
° FSH arePRL
both normal or low
karyotyping if patient has small testes and primary
° Serum
hypogonadism
autoantibodies: consider if history of trauma, torsion, or uni° Sperm
lateral orchidectomy, or if clumps of sperm on seminal fluid analysis
48565_ST05_199-250.indd 218
5/1/13 9:33 PM
Treatment of Male Infertility
219
mutation testing for cystic fibrosis if patient does not have
° Gene
palpable vas deferens and seminal fluid suggestive of obstruction
for Y chromosome microdeletion if patient has normal serum
° Testing
testosterone and LH, but sperm concentration 0−10 million/ml
• Seminal fluid analysis
least two seminal fluid analyses obtained after abstention from
° At
ejaculation for at least 48 hours
Seminal
volume should exceed 1.5 ml
° ■ If ≤1.5fluid
cc (many experts use ≤2.0 ml), then it is either an incomplete collection (spilled) or a sign of obstruction
■ Other signs of obstruction: pH <7.2, absence of fructose
Sperm
concentration should exceed 15 million/ml
° There should
be few white blood cells (<1 million/ml) in seminal fluid
°
DIAGNOSTIC IMAGING
• Scrotal ultrasound if scrotal or testicular mass or large varicocele
• Transrectal ultrasound if seminal fluid analysis suggests obstruction
or if significant number of white blood cells repeatedly in seminal fluid
• Sellar imaging if patient has biochemical evidence of secondary
hypogonadism
TREATMENT OF MALE INFERTILITY
• Adoption may be considered as an option for any couple
• Therapies for primary testicular failure
referral to specialist for assisted reproductive technology
° Consider
■ Sperm retrieval by microsurgery followed by intracytoplasmic
sperm injection (ICSI) into recipient egg
• Expensive
Consider
varicocelectomy for a large varicocele
°
• Therapies for transport of sperm defects
° Obstruction
■ Referral to specialist for possible surgery or sperm retrieval by
microsurgery
dysfunction
° Ejaculatory
■ α agonist for retrograde ejaculation
■ Referral for electrostimulation for anejaculation (e.g., patient
with spinal cord injury)
• Therapies for endocrinopathies
disease
° Hypothalamopituitary
■ Gonadotropin therapy with hCG +/– rhFSH generally
recommended
48565_ST05_199-250.indd 219
5/1/13 9:33 PM
220 Male Infertility
°
Hyperprolactinemia
■ DA agonists
■ Gonadotropin therapy
Thyroid
dysfunction
° ■ See Section
II, Thyroid
° Obesity
■ Weight loss via lifestyle or bariatric surgery
■ Consider gonadotropin therapy
■ Consider an aromatase inhibitor (for <12−18 months)
syndrome
° Cushing’s
■ See Chapter 12, Cushing’s Syndrome
• Therapies for sexual disorders
dysfunction
° Erectile
■ Oral phosphodiesterase therapy and/or alprostadil administered
via urethral capsule or intracavernosal injection
to have intercourse
° Failure
■ Counseling
due to selective serotonergic reuptake inhibitors
° Anorgasmia
■ Consider adding or switching to bupropion
REFERENCES
Bhasin S. Approach to the infertile man. J Clin Endocrinol Metab,
2007;92(6):1995−2004.
Jungwirth A, Giwercman A, Tournaye H, et al. European Association
of Urology guidelines on Male Infertility: the 2012 update. Eur Urol,
2012;62(2):324−32.
McLachlan RI, O’Bryan MK. Clinical Review: state of the art for genetic testing of infertile men. J Clin Endocrinol Metab, 2010;95(3):1013−24.
Patel ZP, Niederberger CS. Male factor assessment in infertility. Med Clin
North Am, 2011;95(1):223−34.
48565_ST05_199-250.indd 220
5/1/13 9:33 PM
38 ■ FEMALE REPRODUCTION ESSENTIALS
Natali Franzblau, MD
DEVELOPMENT OF THE FEMALE REPRODUCTIVE TRACT IN THE EMBRYO
• During the sixth week of gestation the undifferentiated gonad begins to
develop into an ovary. This development process continues with mitosis
to increase the number of oogonia and then at approximately 12 weeks,
some of the oogonia begin to undergo meiosis becoming primary oocytes.
Meiosis arrests in prophase I until ovulation begins in the teen years.
• The uterus, cervix, and fallopian tubes develop from the parmesonephric ducts (mullerian ducts). These two ducts remain separate to
form the fallopian tubes and fuse more caudally to form one uterus
and cervix. Abnormalities in this process result in anatomic anomalies
of the uterus and cervix
• The vagina develops from the urogenital sinus in conjunction with
the fused mullerian ducts. The primordial vagina starts out as a solid
structure that then canalizes. Abnormalities in this development will
lead to congenital anomalies of the vagina, primarily horizontal or
transverse vaginal septums
PUBERTY
• Menarche: age of first menses; usually occurs at age 11−15
° It may take up to two years for an adolescent to have regular menses
• Preceded by
start of breast development, occurs at age 8−13
° Thelarche:
start of axillary and pubic hair growth and
° Pubarche/adrenarche:
sweat gland maturation, begins between the ages of 8 and 10
Growth
spurt
begins
between
10 and 14 years of age
°
HORMONES OF THE MENSTRUAL CYCLE
• GnRH
released from the arcuate nucleus of the hypothalamus
° Deca-peptide
in a pulsatile fashion
Secreted
into
° pituitary glandthe portal circulation, which goes directly to the
changes in the amplitude and frequency of the pulsatile
° The
secretion contributes to the hormonal changes in the menstrual
cycle. Estrogen increases the frequency of pulses and progesterone
and testosterone decrease the frequency of pulses. Catecholamine
neurotransmitters also increase the frequency of the pulses
48565_ST05_199-250.indd 221
5/1/13 9:33 PM
222
Female Reproduction Essentials
• FSH
secreted from anterior pituitary in pulsatile fashion
° Glycoprotein
vary by age and time in cycle
° Levels
Secreted
in
greater
amounts when estrogen levels are lower in the
° follicular phase of cycle
granulosa cells of the ovary to produce estradiol
° Stimulates
the development of ovarian follicles
° Stimulates
As
estradiol
levels rise, there is negative feedback on the anterior
° pituitary to inhibit
secretion of FSH
elevated FSH in particular clinical settings is highly suggestive
° An
of menopause
• LH
secreted from anterior pituitary in pulsatile fashion
° Glycoprotein
estradiol reaches the appropriate level, there is a positive
° When
feedback loop that stimulates LH secretion
LH surge triggers oocyte maturation and ovulation
° This
ovulation, LH promotes the development and maintenance
° After
of the corpus luteum
• Estradiol
primarily by the ovary and by the corpus luteum
° Produced
free in blood with 40% bound to SHBG; remaining is bound
° 1−3%
to albumin
■ Estrogens have a negative feedback effect on the secretion of
FSH. Estrogen can have either positive or negative feedback
effects on LH at different times and in different hormonal milieus
can be checked to monitor follicular development in women
° Levels
undergoing infertility evaluation and treatment
Signifi
cant
in estradiol levels in women of different stages
° of menstrualoverlap
cycle; perimenopause and early menopause make it
less reliable for determining if a woman is in menopause
• Progesterone
by the corpus luteum (formed from the follicle after
° Produced
ovulation)
the uterine lining for implantation of an embryo if concep° Prepares
tion occurs
Levels
can
to assess if ovulation has occurred
° 80% boundbetoused
albumin, 2% free; remainder bound to SHBG and
° other binding globulins
can vary greatly in the luteal phase because it is secreted in
° Levels
a pulsatile fashion
Progesterone
is crucial to the maintenance of a pregnancy. If
° conception occurs,
hCG (produced by the placenta starting 10 days
postovulation) maintains the integrity of the corpus luteum’s hormone
production in early pregnancy. Later, the placenta itself produces
progesterone
48565_ST05_199-250.indd 222
5/1/13 9:33 PM
Hormones of the Menstrual Cycle
223
• Androgens
(androstenedione, DHEA and testosterone) are produced
° Androgens
in varying amounts by the ovary in response to LH and FSH by the
theca cells
granulosa cells of the ovary aromatize androgens to produce
° The
estradiol
° Androgens are also produced by the adrenal gland
TABLE 38.1 The Menstrual Cycle
Pituitary Hormones
Ovarian
Hormones
Ovary
Menses/Follicular
Phase
Ovulation
FSH stimulates
LH surge at day
follicular
14 in response
development
to increasing
and estrogen
estrogen levels
production;
positive feedback
of estrogen
stimulates LH
production
Estrogen slowly
Estrogen is at
increases and
its peak and
progesterone
progesterone
remains low during begins to rise
the follicular
phase
Luteal Phase
Low levels of FSH
and LH due to
suppression by
progesterone
Progesterone
starts to peak
4 days after
ovulation; if there
is no fertilization,
progesterone
levels begin to
recede, resulting
in beginning of
the next cycle;
estrogen levels
slowly return to
baseline
Follicle development Mature oocyte is
Follicle converts
begins with a rise
released from
to corpus luteum
in FSH. By the
follicle in response and produces
fourth day of cycle, to the LH surge
progesterone
estrogen levels
increase. Follicles
continue to mature
until one is singled
out to be the
dominant follicle
and others become
atretic.
(continues)
48565_ST05_199-250.indd 223
5/1/13 9:33 PM
224
Female Reproduction Essentials
TABLE 38.1 (continued )
Endometrium
Menses/Follicular
Phase
Menses start and
the endometrium
sloughs down to
its base levels
within 4−6 days.
Then it begins to
regenerate again
in response to
rising estrogen
levels. In this
proliferative
phase,
endometrial
glands elongate
and stroma
thickens.
Ovulation
Luteal Phase
Endometrium
Progesterone
reaches a maximal stimulates
thickness by
the stroma to
ovulation
become loose
and edematous;
the blood vessels
thicken and the
glands become
tortuous
NORMAL MENSTRUAL CYCLE
•
•
•
•
•
Cycle length: 21−35 days
Period length: 2−7 days
Amount of blood loss: average is 30 ml, >80 ml is abnormal
Pattern: no bleeding between the periods
Conventional terminology: first day of cycle is the day the menstrual
bleeding starts
MENOPAUSE
• Menopause: average age of occurrence is 51; defined as 1 year without
menses
• Perimenopause usually begins sometime between ages 39 and 51, a
time during which menstrual cycles may be less predictable
this time, gynecological evaluation is recommended if
° During
periods last >7 days in length, if periods are more frequent than
every 21 days, if there is bleeding between periods, or if the
bleeding becomes significantly heavier
48565_ST05_199-250.indd 224
5/1/13 9:33 PM
Menopause
FIGURE 38.1 Menstrual Cycle diagram
48565_ST05_199-250.indd 225
225
(continues)
5/1/13 9:33 PM
226
Female Reproduction Essentials
(continued )
Source: © Grei/ShutterStock, Inc.
REFERENCES
American College of Obstetricians & Gynecologists, Precis. Precis: An Update in
Obstetrics and Gynecology: Reproductive Endocrinology. 3rd ed. Washington,
DC: American College of Obstetricians; 2007.
Droegmueller W; Herbst A; Mishell D; Stenchever M., Comprehensive
Gynecology, 1st edition. Philadelphia, PA: Mosby; 1987: 3–242.
Emans SJ, Goldstein D, Laufer M. Pediatric and Adolescent Gynecology. 5th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2005: 120–155.
Fritz MA, Speroff L. Clinical Gynecology Endocrinology and Infertility. 8th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2011:105–120;199–242.
48565_ST05_199-250.indd 226
5/1/13 9:33 PM
39 ■ POLYCYSTIC OVARY SYNDROME (PCOS)
Thozhukat Sathyapalan, MD, FRCP and Stephen L. Atkin, FRCP, PhD
BACKGROUND
• Heterogeneous syndrome involving ovarian abnormality, disturbance
to the menstrual cycle, infrequent or absent ovulation, hyperandrogenism, and metabolic disturbances
• Most common endocrine disorder of women in reproductive age group
• Affects 6−8% of Caucasian women; more prevalent in Asian
population
DEFINITIONS
• There are two different but overlapping criteria for PCOS (the NIH and
the Rotterdam criteria) in wide use
• NIH criteria
irregularity due to oligo- or anovulation
° Menstrual
of hyperandrogenism, whether clinical (hirsutism, acne,
° Evidence
or male-pattern balding) or biochemical (high-serum androgen
concentrations)
of other causes of hyperandrogenism and menstrual
° Exclusion
irregularity, such as CAH, androgen-secreting tumors, and
hyperprolactinemia
• Revised Rotterdam 2003 criteria
of the following three criteria must be fulfilled for a diagnosis
° Two
of PCOS
■ A clinical diagnosis of oligomenorrhoea or amenorrhoea:
menstrual cycles >35 days or <10 periods a year
■ Clinical (hirsutism, acne, or androgen alopecia) or biochemical
(raised free-androgen index) evidence of hyperandrogenism
■ Polycystic ovaries on ultrasound examination
Late-onset
CAH, androgen-secreting tumors, and Cushing’s
° syndrome must
be excluded in women with raised androgens;
thyroid disorders and raised PRL should be excluded in women with
menstrual disturbances
SYMPTOMS
• Age of onset usually around the time of menarche
• Variable progression: many will later have normal ovulatory cycle,
whereas others will develop menstrual cycle irregularities and hyperandrogenism in adulthood
48565_ST05_199-250.indd 227
5/1/13 9:33 PM
228
Polycystic Ovary Syndrome (PCOS)
• Hyperandrogenism
° Acne, oily skin, hirsutism, male pattern alopecia
• Menstrual abnormalities
scant, or infrequent periods, often starting at menarche
° Irregular,
° Amenorrhea
to 25% of patients with PCOS (by Rotterdam criteria) have
° Up
regular periods
• Infertility or subfertility
• Obesity is common, but many women with PCOS are of normal weight
SIGNS
•
•
•
•
Hirsutism: if present assess pattern and severity of hair growth
Acne or oily skin
Male pattern alopecia
Acanthosis nigricans (brown pigmentation on neck, axillae, submammary area, subpanniculus, perineum)
• Signs of virilization (e.g., deep voice, reduced breast size, increased
muscle bulk, clitoral hypertrophy) rarely seen in PCOS; if present,
exclude androgen-producing ovarian or adrenal tumor
INVESTIGATIONS
• Samples should be taken between days 1 and 5 of the menstrual cycle
if woman has a regular cycle; with amenorrhoea, testing will need to
be random
• Recommended for all patients
test
° Pregnancy
of testosterone status
° Assessment
■ Total testosterone
■ Free testosterone, if available
■ If free testosterone not available, measure SHBG (inversely proportional to insulin resistance) and calculate free androgen index
(FAI; calculated as total testosterone/SHBG x 100; this correlates
with free testosterone and may be raised in PCOS)
and FSH: high levels indicate premature ovarian failure
° LH
■ N.B. LH/FSH ratio not within the diagnostic criteria for PCOS
Thyroid
° Prolactinfunction tests
°
• If there is clinical evidence of virilization and total testosterone
≥150 ng/dL (≥5 nmol/L)
to exclude CAH (especially if a high index of suspicion in
° 17-OHP
specific groups such as Ashkenazi Jews)
may be normal or slightly elevated in PCOS; values
° DHEA-S:
≥800 μg/dL (≥21.7 μmol/L) warrant consideration of an adrenal tumor
Exclude
androgen-secreting
tumors
°
48565_ST05_199-250.indd 228
5/1/13 9:33 PM
General Management of PCOS
229
• If there is clinical suspicion of Cushing’s syndrome: 24-hour urine free
cortisol or 1-mg overnight DST
• For women with confirmed PCOS
fasting lipid profile
° BP,
testing
° Glycemic
■ Fasting glucose tests in all women with PCOS
■ Performing an OGTT in women who have a BMI >30 kg/m2, a
strong family history of type 2 diabetes, or a fasting glucose
level of 100 mg/dL (5.6 mmol/L) or greater
■ A1c testing for glycemic screening has not been validated in
women with PCOS
■ In women who have impaired glucose tolerance, offer an OGTT
annually to evaluate for progression to diabetes
■ Offer early screening for gestational diabetes mellitus (GDM) if
patient with PCOS becomes pregnant
obstructive sleep apnea
° Consider
■ PCOS is associated with sleep apnea
■ Inquire about snoring, daytime fatigue, and/or somnolence
■ Investigate and treat as appropriate
IMAGING
• Ovarian ultrasound not necessary to diagnose PCOS by NIH criteria
• Transvaginal ultrasound of ovaries preferred imaging modality
(when using Rotterdam criteria)
• Characteristics of polycystic ovaries
ovary has at least one of the following:
° A■ polycystic
12 or more follicles in each ovary, each follicle measuring
2−9 mm in diameter
■ Ovarian volume >10 ml
polycystic ovary is sufficient for the diagnosis
° One
of PCOS
GENERAL MANAGEMENT OF PCOS
• Education
the possible long-term risks of the condition, particularly
° About
type 2 diabetes and cardiovascular disease
• Offer psychological support and counseling
• Weight loss
to keep weight in the normal range and to exercise
° Advise
regularly
48565_ST05_199-250.indd 229
5/1/13 9:33 PM
230
Polycystic Ovary Syndrome (PCOS)
°
°
°
°
°
Regular exercise and weight loss are reported to
■ Normalize glucose metabolism and decrease risk of developing
type 2 diabetes
■ Lower androgen levels and raise levels of SHBG hormone, which
binds with excess testosterone levels
■ Resume ovulation and improve fertility
Aim for 30 minutes moderate−intensity exercise daily
■ Nutrition counseling
Consider Orlistat
Consider metformin if concomitant diabetes or prediabetes
Consider bariatric surgery in morbidly obese women with PCOS
APPROACH TO HIRSUTISM IN PCOS
• Laser and photoepilation treatments may lead to temporary short-term
hair removal
• Combined oral contraceptives
as androgen suppressors and are usually the first-line of treat° Act
ment for PCOS
Increase
production of SHBG, which reduces levels of free
° testosterone
° Improves acne and hirsutism (in addition to restoring regular menses)
• Metformin
as an insulin sensitizer
° Acts
hyperandrogenemia
° Improves
° Modest beneficial effects on hirsutism
• Antiandrogens (may not be available in some countries)
used in addition to the combined OCP; can also be used alone
° Often
adding an antiandrogen if combined OCPs do not improve
° Consider
acne or hirsutism sufficiently
Whenever
are used, it is essential to consider the
° adequacy ofantiandrogens
contraception
options
° Antiandrogen
■ Spironolactone
■ Cyproterone acetate (a synthetic progestin with antiandrogenic
activity) plus ethinylestradiol can be used for the treatment
of hirsutism; contraindicated in those with high risk of venous
thromboembolism (VTE) (not available in the US)
■ Drospirenone (a spironolactone-like drug) may be considered
if cyproterone acetate−ethinylestradiol or second-generation
combined oral contraceptives are not tolerated (not available
in the US)
■ Flutamide: not recommended for PCOS as it is associated with
fatal liver toxicity
■ Finasteride
• Other options: topical eflornithine cream
48565_ST05_199-250.indd 230
5/1/13 9:33 PM
References
231
APPROACH TO MENSTRUAL IRREGULARITY IN PCOS
• Induction of regular withdrawal bleeding reduces the risk of endometrial hyperplasia and possibly endometrial cancer in women with
infrequent periods (interval between periods of 3 months or longer)
oral contraceptives restore menstrual regularity
° Combined
progestin such as medroxyprogesterone 10 mg for
° Intermittent
10−12 days every 2−3 months may be used
• Metformin improves menstrual irregularity and may be appropriate for
women who don’t want to take OCP
APPROACH TO INFERTILITY IN PCOS
• Carry out an assessment to identify possible causes of infertility,
which might not be due to PCOS
• Strongly advise the woman to lose weight, if appropriate
• Women with PCOS may be offered clomiphene citrate as first-line
treatment for up to 12 months to induce ovulation; should be used in
women with a BMI of 35 or less
• Women with PCOS who have not responded to clomiphene citrate may
be offered treatment with gonadotrophins or laparoscopic ovarian
drilling
• The role of metformin in fertility treatment is controversial, though it
may still have some merit in obese women with PCOS
REFERENCES
Ledger WL, Atkin SL, Cho LW. Long term consequences of polycystic ovary
syndrome. RCOG, 2007;33:11
Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of
hirsutism in premenopausal women: an endocrine society clinical practice
guideline. J Clin Endocrinol Metab, 2008;93(4):1105−20.
Mason H, Colao A, Blume-Peytavi U, et al. Polycystic ovary syndrome
(PCOS) trilogy: a translational and clinical review. Clin Endocrinol (Oxf),
2008;69(6):831−44.
Morin-Papunen L, Rantala AS, Unkila-Kallio L, et al. Metformin improves
pregnancy and live-birth rates in women with polycystic ovary syndrome
(PCOS): a multicenter, double-blind, placebo-controlled randomized trial.
J Clin Endocrinol Metab, 2012;97(5):1492−500.
Sathyapalan T, Atkin SL. Recent advances in cardiovascular aspects of
polycystic ovary syndrome. Eur J Endocrinol, 2012;166(4):575−83.
48565_ST05_199-250.indd 231
5/1/13 9:33 PM
48565_ST05_199-250.indd 232
5/1/13 9:33 PM
40 ■ HIRSUTISM
Nupur Bahl, MD and Geetha Gopalakrishnan, MD
PATHOPHYSIOLOGY
• Hirsutism: excessive terminal hair in a male-pattern distribution.
• Differential diagnosis for excess androgen production
(See Chapter 24, Congenital Adrenal Hyperplasia)
° CAH
congenital adrenal hyperplasia (NCCAH)
° Nonclassic
■ Present in <5% of hyperandrogenic women
■ Patients present after puberty with menstrual dysfunction,
infertility, and oligoanovulation
tumors (0.2% of hyperandrogenic women)
° Androgen-secreting
■ >50% are malignant
Hyperprolactinemia,
Cushing’s syndrome, acromegaly, and thyroid
° dysfunction can be associated
with hirsutism, though hirsutism is
usually not the presenting problem in these disorders
Androgen
or
androgenic
medications
(i.e., anabolic steroids,
° danazol, valproic acid)
(See Chapter 39, Polycystic Ovary Syndrome [PCOS])
° PCOS
■ Most common etiology of hirsutism
Idiopathic
hirsutism
° ■ Hirsutism
associated with normal ovulation and androgen levels
■ Accounts for 4−7% of all hirsutism cases
hyperandrogenemia
° Idiopathic
■ Presents as hirsutism with normal menses, normal ovaries on
ultrasound, but elevated androgen levels
■ Accounts for <20% of cases
CLINICAL PRESENTATION
• Hirsutism is a clinical diagnosis
• Physical exam
must be differentiated from hypertrichosis
° Hirsutism
■ Hypertrichosis is not due to excess androgen; it is characterized
by generalized excessive hair growth in a nonsexual pattern that
may be hereditary, due to a metabolic condition (such as thyroid
dysfunction, anorexia, or porphyria), or a side effect from certain
medications
women with twofold or greater elevation in androgen levels
° Most
will have some degree of hirsutism or another pilosebaceous
response such as acne vulgaris, seborrhea, or male-pattern
alopecia
48565_ST05_199-250.indd 233
5/1/13 9:33 PM
234
Hirsutism
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
FIGURE 40.1 Ferriman Gallwey Hirsutism Scoring System
48565_ST05_199-250.indd 234
5/1/13 9:33 PM
Diagnostic Evaluation
°
235
Gold standard is the modified Ferriman-Gallwey hirsutism scoring
system (excludes forearm and leg from original 11-area scoring
system)
■ Score of 0−4 given in the following body areas: upper lip, chin/
neck, chest, upper abdomen, lower abdomen, upper back, lower
back, upper arms, thighs
■ Score 8−16 is mild hirsutism, 16−25 is moderate, >25 is severe
DIAGNOSTIC EVALUATION
• Laboratory testing for elevated androgens in the following patients
or severe hirsutism
° Moderate
level of hirsutism associated with
° Any
■ Menstrual irregularity or infertility
■ Rapid progression
■ Clitoromegaly
■ Male-pattern balding
■ deepening of voice
■ Acne
■ Central obesity (Cushingoid habitus)
• Basic initial evaluation may include
test for patients with amenorrhea
° Pregnancy
testosterone and DHEA-sulfate
° Total
■ Mildly elevated in PCOS
■ Androgen-producing tumors should be considered if levels are
2−3 times the upper limit of normal
• Pelvic ultrasound to detect ovarian neoplasm; morning
testosterone level often >200 ng/dL (6.94 nmol/L)
• Adrenal ultrasound to detect adrenal tumors; DHEA-s level
usually >700 mcg/dL (13.6 μmol/L)
of Cushing’s syndrome, thyroid dysfunction, hyper° Assessment
prolactinemia, or acromegaly if other features of these conditions
are present
patients at high risk for CAH (i.e., Ashkenazi Jews, Hispanic and
° In
Slavic people), check an early morning follicular phase level of
17-OHP. Levels >200 ng/dL suggest the diagnosis and patient need
to undergo follow-up testing with ACTH stimulation. (See Chapter 24,
Congenital Adrenal Hyperplasia)
this evaluation is negative, consider PCOS if there is an elevated
° Iftestosterone
level, menstrual irregularity, or polycystic ovaries
48565_ST05_199-250.indd 235
5/1/13 9:33 PM
236
Hirsutism
MANAGEMENT
• Weight reduction
increases serum androgen levels in women and therefore over° Obesity
weight or obese patients should be strongly encouraged to lose weight
• Pharmacological therapy (recommend 6-month trial so hair follicles can
go through 1 average life cycle prior to changing dose or medication, or
adding medication)
contraceptives: contain synthetic estrogen in the form of
° Oral
ethinyl estradiol combined with progestin
■ OCPs reduce hyperandrogenism in several ways
• Suppression of LH secretion leading to decreased ovarian
androgen secretion
• Stimulation of hepatic SHBG production to increase androgen
binding and thus decrease free androgen concentrations
• Reduced secretion of adrenal androgens
• Blockage in the binding of androgens to their receptor
■ Progestins derived from testosterone show mild androgenicity on
laboratory markers. However, progestins not structurally related
to testosterone (i.e., cyproterone acetate [not available in the US]
and drospirenone) function as androgen receptor (AR) antagonists. These agents are preferred in the treatment of hirsutism.
° Antiandrogens
■ Can be added if suboptimal response after 6 months of OCP
therapy
■ These agents have teratogenic potential (i.e., fetal male pseudohermaphroditism) and therefore, contraceptive agents are also
prescribed with these agents
■ Spironolactone
• Androgen receptor (AR) antagonist (in addition to aldosterone
receptor antagonism)
■ Competes with DHT for binding to the AR
■ Inhibits enzymes involved in androgen biosynthesis
• Starting dose is 50 mg BID and titrated to 100 mg BID
• May have side effects of hyperkalemia, postural hypotension,
and dizziness
■ Cyproterone acetate (CPA)
• Progestogenic compound with antiandrogen effects
■ Competes with DHT for binding to the AR
■ Reduces serum LH and ovarian androgen concentrations
• Potential risk of hepatotoxicity limits use of this agent
■ OCPs with low dose CPA (2 mg) and monotherapy in higher dose
(12.5−100 mg) are available in Europe but not in the US
48565_ST05_199-250.indd 236
5/1/13 9:33 PM
Management
237
Drospirenone acts as a weak antiandrogen and is used in some
OCPs; dose used in OCPs is 3 mg, which is equivalent to 25 mg
of spironolactone
■ Finasteride inhibits type 2 5α-reductase activity, but does not
inhibit type 1 so only a partial effect is noted. Potential harm with
pregnancy (i.e., teratogenic effect on male fetus), so contraception
recommended with treatment
■ Flutamide is a nonsteroidal AR blocker; limited use as a result
of hepatotoxicity that can lead to liver failure and death even at
very low doses
■ Data equivocal regarding topical antiandrogens (such as
canrenone and finasteride)
medications for patients with PCOS and metabolic
° Insulin-lowering
abnormalities
■ Metformin (a biguanide)
• Inhibits hepatic glucose output, leading to lower insulin
concentrations, and thus reducing theca cell production
of androgens
• May also have a small direct effect on ovarian steroidogenesis
Glucocorticoids
be used long-term to suppress adrenal andro° gens in patientscan
with CAH and NCCAH due to 210HD (CYP21A2)
(see Chapter 24, Congenital Adrenal Hyperplasia)
agonists
° GnRH
■ Inhibit LH and FSH leading to decreased ovarian androgen
production
■ Limitations
• Less effective for hirsutism than OCPs and antiandrogens
• Leads to severe estrogen deficiency with menopausal symptoms of bone loss and hot flashes
• Requires injections
• Relatively more expensive than other therapies
■ Can be considered in women with severe forms of hyperandrogenemia (i.e., ovarian hyperthecosis) who have suboptimal
response to OCPs and antiandrogens
• Other pharmacologic treatments
Efl
ornithine
cream
° ■ Inhibits ornithine
decarboxylase, an enzyme necessary for
hair growth
■ Applied topically to affected area
■ May take several months for results, but should be stopped if no
improvement after 4 months
■ Hair regrows if discontinued
■ Can be considered in mild or localized hirsutism
■
48565_ST05_199-250.indd 237
5/1/13 9:33 PM
238
Hirsutism
• Cosmetic therapies
usually contains hydrogen peroxide and sulfates; side
° Bleach:
effects include irritation, pruritus, and possible skin discoloration
Direct
hair
removal techniques
° ■ Depilation:
removes hair shaft from skin surface
• Shaving does not affect hair regrowth or diameter, but blunt
tip may cause hair to appear thicker
• Chemical depilation: most contain sulfur and thioglycolates to
disrupt disulfide bonds; may cause irritant dermatitis
■ Epilation: extracts hair to above the bulb
• Plucking/waxing
• Electrolysis: electrical current destroys hair follicle with a
heat or chemical
• Laser/photoepilation: hair is damaged by wavelengths of light
REFERENCES
Azziz R, Sanchez LA, Knochenhauer ES, et al. Androgen excess in women:
experience with over 1000 consecutive patients. J Clin Endocrinol Metab,
2004;89(2):453−62.
Bode D, Seehusen DA, Baird D. Hirsutism in women. Am Fam Physician,
2012;85(4):373−80.
Escobar-Morreale HF, Carmina E, Dewailly D, et al. Epidemiology, diagnosis
and management of hirsutism: a consensus statement by the Androgen
Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update,
2012;18(2):146−70.
Franks S. The investigation and management of hirsutism. J Fam Plann
Reprod Health Care, 2012;38(3):182−6.
Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of
hirsutism in premenopausal women: an endocrine society clinical practice
guideline. J Clin Endocrinol Metab, 2008;93(4):1105−20.
Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med, 2005;353(24):
2578−88.
Unluhizarci K, Kaltsas G, Kelestimur F. Non polycystic ovary syndromerelated endocrine disorders associated with hirsutism. Eur J Clin Invest,
2012;42(1):86−94.
48565_ST05_199-250.indd 238
5/1/13 9:33 PM
41 ■ ADULT-ONSET PRIMARY OVARIAN
INSUFFICIENCY (POI)
Lawrence M. Nelson, MD
DEFINITION
• Overt POI: FSH levels in the menopausal range on two occasions, at
least one month apart, and in association with 4 months of disordered
menses in a woman under the age of 40
• In fact, this condition is a continuum of impaired ovarian function to
include occult POI. This category includes women who have regular
menses but evidence of impaired ovarian function as determined by:
(1) low response to gonadotropin stimulation as part of infertility
therapy; or (2) elevated menstrual cycle day 3 serum FSH levels
PATHOPHYSIOLOGY
• May be a result of chemotherapy or radiation
• May be due to follicle depletion or follicle dysfunction
• 90% of spontaneous cases are idiopathic
due to steroidogenic cell autoimmunity
° ~4%
due to a premutation in the FMR1 gene
° ~6%
2% are due to an X-chromosomal abnormality
° ~Rarely
due to a single gene defect such as FSH-receptor mutation,
° LH-receptor
mutation, G-protein mutation
Rarely
may
be part of a syndrome such as autoimmune polyendocrine
° syndrome, type
1 (APS-1); CAH due to 17-α-hydroxylase deficiency;
galactosemia; aromatase deficiency; Fanconi anemia; and others
Rarely
due
to
industrial
exposure such as to 2-bromopropane
°
• In spontaneous cases 75% of women have ovarian follicles remaining
in the ovary
• Characteristically, spontaneous cases exhibit intermittent and unpredictable ovarian function that may persist for decades
CLINICAL PRESENTATION
• History
factors might have induced secondary amenorrhea? Is the
° What
patient pregnant? Has there been a decline in general health as a
result of chronic illness? Is there excessive exercise, inadequate
caloric intake, or emotional stress? Has there been prior radiation
or chemotherapy?
■ It is inappropriate to attribute oligo-/amenorrhea to stress
without more in depth evaluation
48565_ST05_199-250.indd 239
5/1/13 9:33 PM
240
Adult-Onset Primary Ovarian Insuffi ciency (POI)
°
The four most common causes of secondary amenorrhea (aside
from pregnancy) are PCOS, hypothalamic amenorrhea, hyperprolactinemia, and POI
° In■ POI
Menses may stop abruptly or fail to resume after a normal
pregnancy or after stopping oral contraceptives; however,
most commonly there is a prodrome of oligomenorrhea,
polymenorrhea, or dysfunctional uterine bleeding
■ Symptoms of estrogen defi ciency such as vasomotor instability
and vaginal dryness are not always present due to residual
ovarian function in many women
■ There is a positive family history in 10−15%
■ Query regarding other autoimmune disorders such as hypothyroidism and AI
■ Query regarding family history of fragile X syndrome, intellectual
disability, and tremor ataxia syndrome (related to the FMR1
premutation)
• Physical exam
or signs of androgen excess?
° Galactorrhea
exam may suggest normal estrogenization because not all
° Vaginal
patients have profound estrogen deficiency
for vitiligo or hyperpigmentation (related to AI)
° Look
for thyroid enlargement
° Look
Look
stigmata of Turner syndrome such as short stature, webbed
° neck,for
and high, arched palate
DIAGNOSTIC EVALUATION
• Laboratory testing
out pregnancy
° Rule
the evaluation of secondary amenorrhea, measure serum PRL,
° In
FSH, and TSH levels
cases of amenorrhea caused by stress (i.e., hypothalamic amen° In
orrhea), the serum FSH is in the low or normal range
If
the
FSH is in the menopausal range, as defined by the reporting
° laboratory,
the test should be repeated in 1 month along with a
serum estradiol measurement
of the progestin challenge test is not recommended: nearly
° Use
50% of women with POI have withdrawal bleeding in response to
the test despite the presence of menopausal-level gonadotropins;
relying on this method delays diagnosis
serum FSH levels in the menopausal range (at least one month
° Two
apart) associated with four months of disordered menses confirm
the diagnosis of POI
48565_ST05_199-250.indd 240
5/1/13 9:33 PM
Management 241
the diagnosis is confirmed, further tests to define the mecha° Once
nism and identify associated disorders
■ Ovarian antibodies lack specifi city, so testing for them is not
warranted
■ Karyotype analysis to detect Turner syndrome
■ Test for an FMR1 premutation to detect fragile X-associated
primary ovarian insufficiency (FXPOI)
■ Test for adrenal antibodies using indirect immunofluorescence
and 21-hydroxlase (CYP21) immunoprecipitation. Positive tests
indicate women with steroidogenic cell autoimmune primary
ovarian insufficiency (SCA-POI). These women are at risk of
developing autoimmune AI, and cosyntropin stimulation testing
should be performed annually
■ Check serum TSH and TPO antibodies
• Imaging
ultrasound is indicated at the time of diagnosis in all women
° Pelvic
with overt POI to identify cases involving enlarged, multifollicular
ovaries
■ These may be seen in isolated 17,20-lyase defi ciency or autoimmune lymphocytic oophoritis
■ In these cases the ovarian enlargement is not neoplastic and
surgery is not indicated except in the case of torsion
BMD at the time of diagnosis in all women with overt POI
° Measure
as hypogonadism is a risk factor for bone loss
MANAGEMENT
• The diagnosis of POI has profound effects on a woman’s sense of
well-being: there are emotional and physical sequelae, and both must
be addressed with vigor
• Many women report severe emotional distress upon hearing the
diagnosis: inform with sensitivity in person, face to face, and in an
unhurried comfortable setting; informing by telephone, voice mail, or
email is inappropriate
• Associated conditions may develop such as generalized anxiety disorder, major depression, and posttraumatic stress disorder. Shyness,
social anxiety, impaired self esteem, and perceived low level of social
support are more common than in controls
• Help patients identify sources of emotional support and refer them for
guidance on how to cope with the emotional sequelae
48565_ST05_199-250.indd 241
5/1/13 9:33 PM
242
Adult-Onset Primary Ovarian Insuffi ciency (POI)
• Treat the estradiol deficiency with a full replacement dose of
transdermal or transvaginal estradiol (100 micrograms per day) until
the normal age of menopause (age 50). Avoid use of oral estrogens,
which increase risk of VTE due to the first pass effect on the liver.
To avoid endometrial hyperplasia and reduce the risk of endometrial
cancer, prescribe 10 mg of medroxyprogesterone acetate for the first
12 calendar days of each month to induce regular menses
• OCPs contain more hormone than is needed for physiologic replacement and should not be prescribed for this purpose. Furthermore,
they have not been shown to be safe and effective as a contraceptive
in this group and cannot be relied upon for this purpose. Patients
who desire to avoid pregnancy should use a barrier method or an
intrauterine device
• Have patients keep a menstrual calendar. If expected menses fails to
occur, get a pregnancy test and have them stop the hormone replacement therapy. Approximately 5−10% of women with POI conceive
without medical intervention. The hormone replacement regimen noted
previously does not inhibit ovulation in these women, and there are
theoretical reasons and evidence to suspect it may in fact increase the
chance of ovulation
• If patients are interested in conceiving, prescribe intercourse 2 or
3 times a week to assure there are always sperm waiting for that
intermittent and unpredictable ovulation that may occur. Sperm live in
the female genital track for 3−5 days. Efforts to time intercourse are
stress-inducing, ineffective, and not indicated
• Other associated endocrine deficiencies may develop
women with documented adrenal autoimmunity, there is a 50%
° In
risk of developing AI, a potentially fatal disorder. Patients with
evidence of adrenal autoimmunity need annual corticotropin stimulation tests indefinitely. All patients with POI should be educated
regarding the symptoms of AI
20% develop thyroid autoimmunity, most commonly
° Approximately
Hashimoto’s thyroiditis and associated hypothyroidism. If TPO
antibodies are positive, check TFTs yearly. If TPO antibodies are
negative, check TFTs every 4−5 years, or sooner if symptoms of
hypothyroidism develop
• Approximately 20% develop dry eye syndrome; refer those with
symptoms to an ophthalmologist
• Maintain BMD
milligrams of elemental calcium per day
° 1200
units of vitamin D3 per day
° 1000
minutes of weight bearing exercise per day
° 30
are not advised
° Bisphosphonates
■ Unexpected pregnancies occur
■ Long serum half-life
■ Fetal effects uncertain
48565_ST05_199-250.indd 242
5/1/13 9:33 PM
Acknowledgments
243
• Maintain cardiovascular health
exercise
° Regular
diet to avoid obesity
° Healthy
Attend
to
metabolic risk factors
°
• Family planning
° Contraception
■ Use a barrier method or perhaps an IUD
■ Oral contraceptives not proven effective in this population
a family
° Creating
■ No proven markers to define increased rate of remission
■ No proven therapies to restore ovarian function
■ Attempts at egg retrieval for in vitro fertilization are not
indicated
■ Spontaneous remission resulting in pregnancy occurs in 5−10%
of cases; generally remissions are temporary, but rarely may
last for years
■ Couples need time to adjust to the diagnosis emotionally and to
consider their options. Many couples are relieved to have the clinician remove urgency from the situation by suggesting a plan to
attempt conception as detailed previously for three years while
they make other plans if this does not result in a pregnancy.
■ Some couples will decide to nurture other dreams rather
than adopt, foster a child, or employ advanced reproductive
technologies
■ There is no medical urgency to proceed to egg donation; the
pregnancy rates depend on the egg donor’s age rather than
the recipient
■ Women who become pregnant by egg donation may have an
increased risk of delivering infants who are small for gestational
age and of having pregnancy-induced hypertension and postpartum hemorrhage, although these findings are controversial
ACKNOWLEDGMENTS
This work was supported by the Intramural Research Program on
Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National
Institute of Child Health and Human Development, NIH, Bethesda, MD
48565_ST05_199-250.indd 243
5/1/13 9:33 PM
244
Adult-Onset Primary Ovarian Insuffi ciency (POI)
REFERENCES
Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med,
2009;360(6):606−14.
Sterling EW, Nelson LM. From victim to survivor to thriver: helping women
with primary ovarian insufficiency integrate recovery, self-management,
and wellness. Semin Reprod Med, 2011;29(4):353−61.
Wittenberger MD, Hagerman RJ, Sherman SL, et al. The FMR1 premutation
and reproduction. Fertil Steril, 2007;87(3):456−65.
48565_ST05_199-250.indd 244
5/1/13 9:33 PM
42 ■ FEMALE INFERTILITY
Wendy Vitek, MD
PATHOPHYSIOLOGY
• Infertility is defined as the failure to conceive after ≥1 year of regular,
unprotected intercourse (10−15% of healthy young couples will
experience infertility)
• Causes of infertility
dysfunction (20−40%)
° Ovulatory
■ Oligomenorrhea (>35-day intervals between periods) or amenorrhea (>6 months without a period)
• PCOS, thyroid dysfunction, hyperprolactinemia, hypothalamic
amenorrhea (obesity, eating disorder, stress, exercise),
premature ovarian insufficiency
uterine, cervical and peritoneal factors (30−40%)
° Tubal,
■ Tubal factors
• Pelvic infection, ruptured appendix, surgical trauma,
endometriosis
■ Uterine factors
• Fibroids, polyps, intrauterine adhesions, mullerian anomalies
■ Cervical factors
• Cervical stenosis, surgical trauma
■ Peritoneal factor
• Endometriosis
factors (30−40%)
° Male
■ Genital anomalies, trauma, surgical trauma, sexual dysfunction,
genetic abnormalities, endocrine disorders
infertility (10%)
° Unexplained
■ Couples with patent fallopian tubes, without cervical or uterine
factors, adequate sperm production, regular ovulation
• Female fertility declines with age due to a decline in follicular pool and
an increase in aneuploid oocytes with chromosomal abnormalities,
young women with infertility may exhibit advanced ovarian aging or
diminished ovarian reserve (DOR)
may be elevated on cycle day 2 or 3 due to less feedback inhibi° FSH
tion from a declining follicular pool
Inhibin
B and AMH are derived from granulosa cells of small
° antral follicles
and decrease with a declining follicular pool;
likewise, antral follicle counts (AFC) decrease with a declining
follicular pool
48565_ST05_199-250.indd 245
5/1/13 9:33 PM
246 Female Infertility
CLINICAL PRESENTATION
• Evaluation can be initiated after the definition for infertility has
been met
• Earlier evaluation is warranted for
>35 years old who have not conceived after 6 months of
° Women
regular unprotected intercourse
Women
with
or amenorrhea
° Women with oligomenorrhea
history of pelvic infection or endometriosis
° Men with known
or suspected subfertility
°
DIAGNOSTIC EVALUATION
• General health should be optimized prior to conception. Assess for
conditions
° Medical
medications
° Teratogenic
tobacco, alcohol, illicit drug use
° Caffeine,
history of birth defects or mental retardation
° Family
2
° Obesity (BMI ≥30 kg/m )
• Infertility evaluation
dysfunction
° Ovulatory
■ Assess for signs and symptoms of thyroid disease, hyperprolactinemia, androgen excess, or menopause
• TSH, PRL, total testosterone, day 2 or 3 FSH and estradiol
uterine, cervical, peritoneal factors
° Tubal,
■ Tubal factors
• Evaluate tubal patency by hysterosalpingogram (HSG)
■ Antibiotic prophylaxis (doxycycline 100 mg po BID × 5 days)
is indicated if history of pelvic inflammatory disease or
dilated fallopian tubes noted on HSG
■ Uterine factors
• Assess for menorrhagia (fibroids), metrorrhagia (polyps), and
hypomenorrhea (intrauterine adhesions)
• Bimanual exam may reveal fibroids
• Fibroids can be characterized by transvaginal ultrasound
(TVUS) or MRI
• Submucosal myomas, polyps and intrauterine adhesions can
be detected by HSG or saline sonohysterogram (SHG)
• Mullerian anomalies can be diagnosed by MRI or HSG and TVUS
■ Cervical factors
• Assess for history of abnormal pap smears and treatment
48565_ST05_199-250.indd 246
5/1/13 9:33 PM
Management
247
Peritoneal factor
• Assess for dysmenorrhea, dyspareunia, and dyschezia
• Bimanual exam may reveal adnexal mass (endometrioma),
tenderness, or nodularity (endometriotic implant) in
cul-de-sac
• Laparoscopy may be performed to diagnose and treat
enometriosis
Male factors
■ Semen analysis × 2
• Azospermia: absence of sperm
• Oligospermia: sperm concentration <15 million/ml or total
sperm number <39 million/ejaculate
• Asthenozoospermia: progressive motility <32%
• Teratospermia: normal morphologic forms <4%
■ The likelihood of male infertility increases with the number of
abnormal parameters and should prompt referral to a urologist
for evaluation
Unexplained infertility
■ Infertility despite evidence of ovulation, patent fallopian tubes,
normal uterine cavity, and adequate sperm production
■ DOR can be diagnosed by any of the following ovarian reserve tests
• Day 2 or 3 FSH >10 mIU/ml and/or estradiol >80 pg/ml
• AFC (number of follicles measuring 2−10 mm in diameter by
TVUS) is abnormal if <5−10 antral follicles/ovary are noted
■ Other tests that can be considered
• AMH <0.02−0.07 ng/ml (cycle day independent)
• Day 2 or 3 inhibin B <40−45 pg/ml
• Clomid challenge test (clomiphene 100 mg/day days 5−9) is
abnormal if FSH is elevated on day 3 or 10
■
°
°
MANAGEMENT
• Preconception counseling
the management of medical disorders
° Optimize
to medications that are safe in pregnancy
° Transition
Limit
caffeine
intake (~two 8-ounce cups of coffee) and discontinue
° tobacco, alcohol,
and illicit drug use
counseling if family history of birth defects or mental
° Genetic
retardation
2
° Weight loss to achieve BMI between 20 and 25 kg/m
48565_ST05_199-250.indd 247
5/1/13 9:33 PM
248 Female Infertility
• Treatment of infertility
dysfunction
° Ovulatory
■ Treat thyroid dysfunction and hyperprolactinemia
■ Counseling and weight management for hypothalamic amenorrhea
■ Weight loss of 5−10% may restore ovulation in women with
PCOS
■ Ovulation induction
• Clomiphene citrate
■ 80% will ovulate, cycle fecundity (i.e., probability of
achieving a live birth in a single cycle) is ~15%
■ Risks: multiple gestations (8%)
■ Side effects: hot flushes, mood swing, discontinue therapy
if visual disturbance develops
■ Protocol
– If negative pregnancy test, initiate progestin-induced
withdrawal bleed with medroxyprogesterone 10 mg
po × 5−10 days
– Start with clomiphene citrate 50 mg/day cycle days
5−9 with timed intercourse
– Monitor for ovulation with urinary LH kit, luteal progesterone (>3 ng/ml) or serial ultrasounds
- If ovulatory and no conception, repeat cycle and limit
lifetime clomiphene exposure to 12 cycles
- If anovulatory, increase clomiphene to 100 mg/day on
days 5−9 and monitor for ovulation; if no ovulation,
increase clomiphene to 150 mg/day days 5−9 and
monitor for ovulation
• Resistance to clomiphene (i.e., no ovulation in response
to clomiphene) in women with PCOS can be managed with
clomiphene plus metformin (1000−2000 mg/day in divided
dose), letrozole, ovarian drilling, or gonadotropins
■ Ovulation induction in patients with hypothalamic amenorrhea can be achieved with gonadotropins
uterine, or peritoneal factors
° Tubal,
■ Tubal factors
• Tubal cannulation can treat isolated proximal tubal blockage
• Laparoscopic fimbroplasty or neosalpingostomy can treat mild
hydrosalpinges
• Microsurgical tubal reanastomosis can be performed for tubal
ligation reversal in appropriate candidates
• Large hydosalpinges can be removed or proximally occluded to
improve in vitro fertilization (IVF) pregnancy rates
48565_ST05_199-250.indd 248
5/1/13 9:33 PM
References
249
Uterine
• Myomectomy for submucosal fibroids and large intramural
fibroids may improve pregnancy rates
• Hysteroscopic polypectomy for polyps may improve pregnancy
rates
• Hysteroscopic lysis of adhesions may improve pregnancy rates
with intrauterine adhesions
• Treatment of mullerian anomalies should be individualized
■ Cervical factors
• Cervical dilation or intrauterine insemination (IUI) may be
indicated for cervical stenosis after treatment for dysplasia
■ Peritoneal factor
• Laparoscopic excision or ablation of endometriotic implants
may improve pregnancy rates
• Superovulation/IUI or IVF may be indicated based on severity
of endometriosis and additional prognostic factors
Male factors
■ Medical treatment, surgical correction, and/or genetic counseling as recommended by a urologist
■ IUI may improve pregnancy rates with oligospermia
■ IVF/ICSI is indicated for severe oligospermia and testicular
extraction sperm aspiration (TESA) specimens
■ Donor sperm is an option for severe male factor
Unexplained infertility
■ Superovulation (i.e., ovulating multiple oocytes in a single cycle)
/IUI with clomiphene may improve the pregnancy rate in couples
with unexplained infertility, but clomiphene alone or natural
cycle IUI do not improve pregnancy rates
■ Gonadotropin/IUI may improve pregnancy rates when there is a
failure to achieve multifollicular development with clomiphene;
otherwise the cycle fecundity is similar to clomiphene/IUI
■ IVF is the most effective treatment for couples with unexplained
infertility
■ Women with DOR may have lower pregnancy rates with superovulation/IUI and IVF; donor oocyte IVF is an option
■
°
°
REFERENCES
Committee on Gynecologic Practice of American College of Obstetricians and
Gynecologists; Practice Committee of American Society for Reproductive
Medicine. Age-related fertility decline: a committee opinion. Fertil Steril,
2008;90(Suppl 5):S154−5.
Cooper TG, Noonan E, von Eckardstein S, et al. World Health Organization
reference values for human semen characteristics. Hum Reprod Update,
2010;16(3):231−45.
48565_ST05_199-250.indd 249
5/1/13 9:33 PM
250 Female Infertility
Practice Committee of the American Society for Reproductive Medicine.
Committee opinion: role of tubal surgery in the era of assisted reproductive technology. Fertil Steril, 2012;97(3):539−45.
Practice Committee of the American Society for Reproductive Medicine.
Optimal evaluation of the infertile female. Fertil Steril, 2006;86(5 Suppl 1):
S264−7.
Practice Committee of the American Society for Reproductive Medicine. Use
of clomiphene citrate in women. Fertil Steril, 2006;86(5 Suppl 1):S187−93.
Practice Committee of American Society for Reproductive Medicine. Use
of exogenous gonadotropins in anovulatory women: a technical bulletin.
Fertil Steril, 2008;90(Suppl 5):S7−12.
48565_ST05_199-250.indd 250
5/1/13 9:33 PM
SECTION VI: DIABETES, METABOLISM,
AND OBESITY
48565_ST06_251-352.indd 251
5/1/13 9:32 PM
48565_ST06_251-352.indd 252
5/1/13 9:32 PM
43 ■ ENDOCRINE PANCREAS AND FUEL
METABOLISM ESSENTIALS
Robert J. Smith, MD
• Normal growth and metabolic homeostasis require precise regulation of
assimilation of macronutrients absorbed from the diet
° The
(e.g., glucose, amino acids, and free fatty acids [FFA])
appropriate storage or synthesis of these body fuels
° The
° The exchange of body fuels between organs and tissues
• The pancreatic islets (islets of Langerhans) have a central role in
regulating body fuel metabolism
are vascularized, innervated organelles containing multiple
° Islets
secretory endocrine cell types
The
islets
are scattered throughout the pancreas, accounting for
° approximately
2% of pancreatic mass
• The most common islet cell type, the β cell, synthesizes and stores the
peptide hormone insulin
is comprised of A and B chains that are cleaved from the
° Insulin
precursor peptide, proinsulin, and linked together by disulfide bonds
Connecting peptide (C-peptide) is also cleaved from proinsulin, in
° amounts
equal to insulin, when insulin is formed
C-peptide
uncertain functions, but can be measured in the
° plasma as has
an index of insulin synthesis
■ Low plasma C-peptide (consult individual lab reference range)
indicates β-cell deficiency and can be useful in distinguishing
type 1 from type 2 diabetes
■ Simultaneous insulin and C-peptide measurements can be useful in identifying causes of hypoglycemia
• Hypoglycemia from injected insulin occurs with high plasma
insulin and low C-peptide levels (pharmacological insulin
contains no C-peptide)
• Hypoglycemia from endogenous insulin overproduction (e.g., with
an insulinoma) has high levels of C-peptide as well as insulin
is secreted from β cells primarily in response to glucose
° Insulin
and also in response to ketone bodies and certain amino acids. The
actions of insulin include
■ In skeletal muscle: stimulation of glucose uptake, glycogen
synthesis, and glucose metabolism for energy
■ In liver: stimulation of glycogen synthesis and glucose
metabolism for energy; suppression of glycogen breakdown and
gluconeogenesis
■ In adipose tissue: stimulation of glucose uptake and fat
(triglyceride) synthesis; suppression of triglyceride breakdown
and FFA release
48565_ST06_251-352.indd 253
5/1/13 9:32 PM
254
Endocrine Pancreas and Fuel Metabolism Essentials
• The second most common islet cell type, the α cell, secretes the peptide hormone glucagon.; insulin and glucagon have generally opposing
actions in the regulation of body fuel metabolism
secretion from a cell is suppressed by glucose. Glucagon
° Glucagon
actions occur mostly in the liver and include
■ Breakdown of glycogen and release of glucose from the liver to
the blood stream
■ Synthesis of glucose from lactate, pyruvate, and amino acids
(gluconeogenesis) with resulting glucose release from the liver
to the blood stream
■ Stimulation of ketone body formation from FFAs in the liver
• Changes in insulin and glucagon levels are important for metabolic
adjustments during transitions between fed and fasted states
fasting, a low insulin/glucagon ratio contributes to
° During
■ Diminished uptake of glucose from the circulation
■ Release of glucose from the liver to the circulation (from glycogenolysis and gluconeogenesis)
■ Breakdown of adipose tissue triglyceride stores and release of
FFAs to the circulation
■ Increased use of FFAs as metabolic fuels (instead of glucose)
■ Formation of ketone bodies in the liver (an important alternative
to glucose as a metabolic fuel in the brain and other tissues)
fed state, a high insulin/glucagon ratio contributes to
° In■ the
Removal of absorbed glucose from the circulation, with its
metabolism for energy and storage as glycogen
■ Suppression of hepatic glucose production from glycogenolysis
and gluconeogenesis
■ Conversion of glucose and absorbed FFAs to triglyceride stores
■ Suppression of fat breakdown (lipolysis)
■ Suppression of ketone body formation (ketogenesis)
• Incretins are peptide hormones secreted into the blood stream from
the intestine in response to glucose and nutrient ingestion with
important effects on body fuel metabolism
account for a greater insulin secretory response to oral
° Incretins
than IV glucose (designated the “incretin effect”)
The
two
major
incretins are glucagon-like peptide 1 (GLP-1) and
° gastric inhibitory
peptide (GIP)
actions include
° Incretin
■ Stimulation of β-cell glucose-dependent insulin secretion and
insulin biosynthesis
■ Inhibition of α-cell glucagon secretion
■ Delay of gastric emptying
■ Decreased appetite and weight loss
■ Additional potential (unproven) actions
• Increased β-cell number
• Increased peripheral insulin sensitivity
48565_ST06_251-352.indd 254
5/1/13 9:32 PM
Endocrine Pancreas and Fuel Metabolism Essentials
255
type 2 diabetes, there is loss of effectiveness of GIP, but retained
° In
responsiveness to GLP-1. This forms the mechanistic basis for two
classes of oral hypoglycemic agents
■ GLP-1 analogues (forms of GLP-1 stable to degradation)
■ Dipeptidyl dipeptidase inhibitors (delay endogenous GLP-1
degradation)
• Other hormones with important roles in body fuel homeostasis include
glucocorticoids, catecholamines, and GH
of these hormones has individualized actions with distinct
° Each
pathological consequences when deficient or present in excess
a group, together with glucagon, they are designated “insulin
° As
counter-regulatory hormones,” since a part of their actions directly
or indirectly inhibits the actions of insulin
some patients, excess of one or more of these counter-regulatory
° In
hormones (e.g., as part of a stress response with severe illness,
or as a result of a hormone-secreting tumor) can result in a state
of “relative insulin deficiency” and lead to the development of
diabetes mellitus. In uncontrolled diabetes mellitus, it therefore is
important to identify clinical conditions that may be contributing by
increasing counter-regulatory hormone levels. These include
■ Sources of infection or stress (e.g., silent myocardial infarction [MI]) that result in elevated levels of counter-regulatory
hormones
■ Conditions with primary hypersecretion of counter-regulatory
hormones (e.g., Cushing’s syndrome or acromegaly)
■ Pharmacologic administration of glucocorticoids for treatment
of another disorder
• Counterposed to the role of insulin in regulating body fuel homeostasis, excess nutrient intake is of major clinical importance in causing
insulin deficiency and diabetes
is thought to result from both insulin resistance secondary to
° This
obesity, and a loss of insulin-secreting pancreatic β cells possibly
caused by the demand for excess insulin secretion or a pancreatic
islet inflammatory process precipitated by obesity
role of obesity is most evident in type 2 diabetes, with obesity
° The
present in more than 80% of patients prior to the development of
diabetes
can also accelerate the time of presentation of incipient
° Obesity
type 1 diabetes, or result in the development of combined types
1 and 2 diabetes in some individuals
the amount of insulin required for metabolic control relates
° Since
to the quantity of ingested glucose and other nutrients in addition
to the overall sensitivity to insulin, reducing calorie intake can have
benefit in the correction of hyperglycemia in obese individuals even
before there has been significant change in the degree of obesity
48565_ST06_251-352.indd 255
5/1/13 9:32 PM
256
Endocrine Pancreas and Fuel Metabolism Essentials
REFERENCES
American Diabetes Association. Standards of medical care in diabetes—
2012. Diabetes Care, 2012;35(Suppl 1):S11−63.
Ferrannini E. Physiology of glucose homeostasis and insulin therapy in type 1
and type 2 diabetes. Endocrinol Metab Clin North Am, 2012;41(1):25−39.
Phillips LK, Prins JB. Update on incretin hormones. Ann NY Acad Sci,
2011;1243:E55−74.
48565_ST06_251-352.indd 256
5/1/13 9:32 PM
44 ■ DIABETES MELLITUS
Lillian Lien, MD and Mark Feinglos, MD
BACKGROUND
• Diabetes mellitus (DM) is a complex multiorgan system process, with
defects in pancreatic insulin secretion, central and peripheral insulin
action, and glucose utilization and production
ammation has now been recognized as an underlying patho° Infl
physiologic process
Chronic
hyperglycemia is associated with damage to various end
° organs, including
the eyes, kidneys, nerves, blood vessels, and heart
• Diagnosing type 1 versus type 2 versus other forms of DM is important
for optimal care
° However, this distinction is not always possible
PATHOPHYSIOLOGY OF TYPE 1 DM
• Fundamentally an immune-mediated process: T-cell mediated autoimmune
destruction of pancreatic β cells leads to an absolute insulin deficiency
• Patients must receive exogenous insulin therapy
• Accounts for only 5−10% of those with DM
• Autoantibodies can be detected in as many as 85−90% of these
patients
cell autoantibodies, autoantibodies to insulin, autoantibodies
° Islet
to GAD (GAD65), and autoantibodies to the tyrosine phosphatases
IA-2 and IA-2β
• Patients may have additional autoimmune disorders
CLINICAL PRESENTATION OF TYPE 1 DM
• Typically <40 years of age, although not exclusively a disease of childhood
• Nonspecific symptoms often associated with type 1 DM: polyuria, polydipsia, weight loss, fatigue, blurred vision, susceptibility to infection
• Diabetic ketoacidosis (DKA; see Chapter 46, Hyperglycemic Emergencies)
may be the initial presentation of type 1 diabetes
PATHOPHYSIOLOGY OF TYPE 2 DM
• Multifactorial, including both defects in insulin action and insulin
secretion
to insulin action is generally present, but failure of the
° Resistance
β cell to compensate causes hyperglycemia
48565_ST06_251-352.indd 257
5/1/13 9:32 PM
258
Diabetes Mellitus
• Accounts for approximately 90% of those with DM
• Often associated with caloric excess and obesity
conditions lead directly to visceral adiposity and insulin
° These
resistance
• Due to insulin resistance, insulin levels may be normal or elevated at
diagnosis
• Complex genetics with strong familial predisposition
CLINICAL PRESENTATION OF TYPE 2 DM
• Often associated with weight gain, being overweight, or obesity; or in
women with a history of GDM
• Similar nonspecific symptoms as in type 1, but may be undiagnosed
for many years
• May present with hyperosmolar hyperglycemic syndrome (HHS; see
Chapter 46, Hyperglycemic Emergencies); DKA can also occur, usually
in association with a specific stressor such as infection
PATHOPHYSIOLOGY AND CLINICAL PRESENTATION
OF OTHER FORMS OF DM
• Maturity-onset diabetes of the young (MODY) (see Chapter 45)
Monogenic Diabetes)
dominant monogenic diabetes with defects in insulin
° Autosomal
secretion
Age
of
presentation
is usually <25 years old
° Often managed effectively
with diet alone or sulfonylurea drugs
°
• Latent autoimmune diabetes of the adult (LADA)
diagnosed in patients 25 years of age or older
° Usually
presentation may mimic type 2 DM, but patients are not
° Initial
obese and often progress rapidly to insulin requirement
° Autoimmune pathophysiology
• Nonimmune causes of pancreatic destruction
variety of causes such as pancreatectomy, pancreatitis,
° Wide
hemochromatosis, and cystic fibrosis (cystic fibrosis-related
diabetes [CFRD])
often require treatment with insulin depending on extent
° Patients
of β-cell loss
Loss
of
glucagon-producing
° ties in glycemic control α cells may lead to additional difficul• Drug-induced DM: many potential causative agents including corticosteroids, immunosuppressive agents, protease inhibitors, atypical
antipsychotics, antineoplastics, anticonvulsants, pentamidine, niacin,
thiazide diuretics, β-adrenergic blockers
48565_ST06_251-352.indd 258
5/1/13 9:32 PM
ADA Criteria for the Diagnosis of DM
259
• Gestational DM
intolerance first recognized in pregnancy
° Glucose
of gestational DM is made from an OGTT performed at 24−28
° Diagnosis
weeks gestation in women not previously diagnosed with overt DM
■ High-risk women found to have DM at the initial prenatal visit
are considered to have “overt,” not gestational, DM
AMERICAN DIABETES ASSOCIATION (ADA) CRITERIA
FOR DM SCREENING IN ADULTS
• Adults with BMI ≥25 kg/m2 and one or more additional risk factor
inactivity
° Physical
relative with DM
° First-degree
race/ethnicity (e.g., African American, Latino, Native
° High-risk
American, Asian American, Pacific Islander)
who delivered a baby weighing >9 lbs or who were diag° Women
nosed with gestational DM
(BP ≥140/90 mm Hg or on therapy for hypertension)
° Hypertension
cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglycer° HDL
ide level >250 mg/dL (2.82 mmol/L)
with PCOS
° Women
>5.7%, impaired glucose tolerance (IGT), or impaired fasting
° A1c
glucose (IFG)
conditions associated with insulin resistance (e.g., severe
° Clinical
obesity, acanthosis nigricans)
° History of CVD
• In the absence of the above, testing for DM should begin at age 45
• If results are normal, testing should be repeated at least at 3-year intervals
ADA CRITERIA FOR THE DIAGNOSIS OF DM
1. A1C ≥ 6.5%*
test should be performed in a laboratory using a method that is
° The
National Glycohemoglobin Standardization Program (NGSP)–certified
and standardized to the Diabetes Control and Complications Trial assay
2. Fasting plasma glucose (PG) (at least 8 hours fasting)*
<100 mg/dL
° Normal
(IFG)” 100–125 mg/dL
° “Prediabetes
DM
≥126
mg/dL (7.0 mmol/l)*
°
3. OGTT: 2-hour PG after a 75-gram glucose load*
<140 mg/dL
° Normal
(IGT)” 140–199 mg/dL
° “Prediabetes
DM
≥200
mg/dL (11.1 mmol/L)*
°
4. Random PG ≥200 mg/dL (11.1 mmol/L), with symptoms of
hyperglycemia/crisis
*In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing.
48565_ST06_251-352.indd 259
5/1/13 9:32 PM
260
Diabetes Mellitus
ADDITIONAL LABORATORY TESTING FOR THE DIAGNOSIS
AND MANAGEMENT OF GLYCEMIA IN DM
• PG: obtained by venipuncture; to avoid false lows, must process
promptly; serum glucose is more stable
• Point-of-care testing (POCT) glucose: POCT glucose, or capillary
glucose, measures whole blood glucose by a portable glucose meter;
usually obtained by fingerstick
glucose can differ by 10–15% from plasma glucose
° POCT
reliable at extremes: <60 mg/dL (3.3 mmol/L) or >500 mg/dL
° Less
(27.7 mmol/L)
• Hemoglobin A1c: a measure of glycosylation of the hemoglobin
molecule; with increased ambient blood glucose levels, glycosylation
rates rise
ects average glucose over lifetime of a red blood cell ~120 days
° Refl
levels of 5.7–6.5% are considered “at risk” for progression
° A1c
to DM
ADA
targets A1c levels <7% as the goal for most patients with DM
° Causes
of inaccurate A1cs: abnormal hemoglobin, blood transfu° sion, anemia,
early pregnancy, splenectomy
• C-peptide
Proinsulin,
the
molecule to insulin, consists of the future
° insulin moleculeprecursor
and a 31-amino acid polypeptide known as C-peptide
C-peptide reflects endogenous insulin production
° Thus,
be measured either 1 hour after a 75-gm carbohydrate load
° Should
or when glucose is at least 150 mg/dL
patients with type 2 DM, it may be useful to see whether detect° In
able C-peptide levels are present to evaluate whether there is a role
for oral agent therapy
measurement may be required by an insurance company
° C-peptide
for coverage of insulin pump therapy initiation
• Antibody testing
antibodies associated with autoimmune forms of diabetes:
° Various
islet cell autoantibodies, autoantibodies to insulin, autoantibodies
to GAD (GAD65), and autoantibodies to the tyrosine phosphatases
IA-2 and IA-2β
always present in type 1 diabetes and no data to support rou° Not
tine use, though elevated levels are consistent with an autoimmune
etiology (type 1 DM or LADA)
states that testing for islet cell autoantibodies may be
° ADA
appropriate in high-risk cases: those with transient hyperglycemia,
relatives with type 1 DM, or enrolled in clinical research studies
48565_ST06_251-352.indd 260
5/1/13 9:32 PM
Pharmaceutical Options for Diabetes Management
261
PHARMACEUTICAL OPTIONS FOR DIABETES MANAGEMENT
TABLE 44.1 Insulin Formulations
Type
Rapid-Acting
Short-Acting
Intermediate-Acting
Long-Acting (Basal)
Premixed
Product
Lispro
Aspart
Glulisine
Regular
NPH
Brand
Humalog
Novolog
Apidra
“R” Humulin, Novolin, ReliOn
“N” Humulin, Novolin, ReliOn
Glargine
Detemir
70/30 regular
75/25 lispro
70/30 aspart
50/50 lispro
Lantus
Levemir
Humulin 70/30, Novolin 70/30
Humalog Mix 75/25
Novolog Mix 70/30
Humalog Mix 50/50
Insulin Type
Onset
Time to Peak
Lispro (Humalog),
Aspart (Novolog),
Glulisine (Apidra) Regular NPH
15–30 min
30 min
1–2 hours
1–2 hours
2–4 hours 4–10 hours
Duration
3–5 hours
Administration
≤15 min before,
or right after
meals
48565_ST06_251-352.indd 261
Glargine
(Lantus)
1–2 hours
No peak
Detemir
(Levemir)
~1 hour
No/little
peak
4–8 hours 12–20 hours ~24 hours Up to
24 hours
Without
30–60 min 30–60 min Without
regard to
regard
before
before
to meals meals
meals or
meals
at bedtime
5/1/13 9:32 PM
48565_ST06_251-352.indd 262
Thiazolidinedione Oral
Meglitinide
Alphaglucosidase
inhibitor
DPP-4 inhibitor
GLP-1 mimetic
Pioglitazone (Actos*),
rosiglitazone (Avandia†)
Repaglinide (Prandin),
nateglinide (Starlix)
Acarbose (Precose),
miglitol (Glyset)
Sitagliptin (Januvia),
saxagliptin (Onglyza),
linagliptin (Tradjenta)
Liraglutide (Victoza)
SQ
Oral
Oral
Oral
Oral
Biguanide
Metformin (Glucophage,
Glucophage XR)
Oral
Route
Sulfonylurea
Drug Class
Glipizide (Glucotrol),
glimepiride (Amaryl),
glyburide (Diaβeta, Glynase
PresTabs, Micronase)
Noninsulin Antidiabetic
Medication
TABLE 44.2 Noninsulin Antidiabetic Medications
Type 1 diabetes, DKA
Contraindications
GI pancreatitis (rare)
Hypersensitivity
GI (flatulence, diarrhea,
abdominal discomfort)
Hypoglycemia
Edema, weight gain, bone
fractures
Type 1 diabetes, DKA, personal or
family history of MTC or MEN2,
pancreatitis
Type 1 diabetes, DKA, pancreatitis,
hypersensitivity
Type 1 diabetes, DKA, hepatic cirrhosis,
chronic intestinal diseases
Type 1 diabetes, DKA
Type 1 diabetes, DKA, symptomatic CHF
GI (N/V, diarrhea, abdominal Type 1 diabetes, DKA, Cr >1.5 in men,
pain), Vitamin B12
Cr >1.4 in women, acute or chronic
deficiency
metabolic acidosis
Hypoglycemia
Common Adverse Effects
1–2%
0.5–1%
0.5–1%
0.5–1%
1.5%
1.5–2%
1–2%
% A1c
lowering
262
Diabetes Mellitus
5/1/13 9:32 PM
Amylin mimetic
Dopamine
Oral
receptor agonist
Bile acid
sequestrant
Pramlintide (Symlin)
48565_ST06_251-352.indd 263
Bromocriptine mesylate
(Cycloset)
Colesevelam (Welchol)
DPP-4 = Dipeptidyl peptidase-4
* Pioglitazone (Actos): possible association with bladder cancer.
† Rosiglitazone (Avandia): use highly restricted, as may increase risk of MI.
Oral
SQ
SQ
Long-acting
GLP-1 mimetic
(once weekly)
Exenatide extended-release
(Bydureon)
SQ
GLP-1 mimetic
Exenatide (Byetta)
Constipation,
hypertriglyceridemia,
absorption of medicines
GI, orthostatic hypotension,
somnolence, psychosis,
dizziness
GI, headache
GI pancreatitis (rare)
GI pancreatitis (rare)
Type 1 diabetes, DKA, history of bowel
obstruction, hypertriglyceridemia,
pancreatitis
Type 1 diabetes, DKA, syncopal
migraines, lactating women
Confirmed gastroparesis, hypoglycemic
unawareness
Type 1 diabetes, DKA, personal or
family history of MTC or MEN2,
pancreatitis
Type 1 diabetes, DKA, pancreatitis
0.5%
0.5%
0.5–1%
1–2%
1–2%
Pharmaceutical Options for Diabetes Management
263
5/1/13 9:32 PM
264
Diabetes Mellitus
GLYCEMIC MANAGEMENT IN TYPE 1 DIABETES:
INITIATING OUTPATIENT REGIMENS
• DCCT showed intensive insulin therapy to be associated with better
microvascular outcomes
• Intensive insulin therapy requires the use of multiple-dose insulin
injections daily or insulin pump therapy
• Multiple-dose insulin therapy
ADA recommends the use of insulin analogues in order to
° The
reduce the risk of hypoglycemia
■ However, if financial issues preclude the above, a 4-shot regimen
using regular insulin TID with meals and NPH Insulin at bedtime
can still be considered
daily dose (TDD): in type 1, the TDD can be estimated at
° Total
0.3–0.5 units/kg/day
■ Type 1 DM patients are often insulin sensitive; it is reasonable to
start on the low end
analogue insulins, the TDD is divided into 4 daily injections
° Using
as follows
■ 50% of the TDD is given as one basal (long-acting, peakless,
analogue) insulin injection every 24 hours
■ The remaining 50% of the TDD is divided into three mealtime
injections of prandial (rapid-acting analogue) insulin (i.e.,
~17% of TDD is administered at each meal)
• Alternatively, the dose for each mealtime injection can be
matched to carbohydrate intake using insulin to carbohydrate
ratios (the ratio reflects the amount of insulin needed to cover
a specific amount of carbohydrate, i.e., 1:15 ratio, representing 1 unit of insulin per 15 g carbohydrate intake)
always give basal insulin, even if the patient is NPO, to pre° Inventtypethe1,development
of DKA; IV calories may be needed in association
In
some
patients,
a single injection of basal insulin may not last a full
° 24 hours; in this case,
it is reasonable to divide the basal into 2 separate injections given 12 hours apart (of note, this then is a 5-injection
daily regimen: 2 basal and 3 prandial injections daily)
• Continuous SQ insulin therapy (i.e., insulin pump)
insulin pump is a small mechanical device that delivers a continu° An
ous infusion of SQ insulin to the patient through a flexible catheter.
a thorough understanding of the hardware and a proven
° Requires
ability to perform self-care
48565_ST06_251-352.indd 264
5/1/13 9:32 PM
Glycemic Management in Type 2 Diabetes: ADA Guidelines
°
265
In most cases, a rapid-acting analogue insulin is used in the pump.
Even though only one type of insulin is used, the pump can deliver
both basal and bolus (prandial) components
■ Basal insulin is infused at programmed hourly rates; usually
multiple different basal rates throughout the day
■ Bolus insulin is infused at discrete (meal) times; calculation of
the dose is based on factors including: the insulin-to-carbohydrate ratio, target blood glucose range, active insulin time, and
insulin sensitivity factor
GLYCEMIC MANAGEMENT IN TYPE 2 DIABETES: ADA GUIDELINES
• Choice of regimen must account for multiple patient factors: patient
attitude and expected treatment effects, risk of hypoglycemia, disease
duration, comorbidities, life expectancy, established complications,
and resources
• The ADA recommends lifestyle intervention and metformin therapy
both be initiated at the time of initial type 2 DM diagnosis; as long as
metformin is not contraindicated, it is first-line therapy
• If metformin monotherapy does not achieve control over 3 months,
the ADA recommends adding a second oral agent, a GLP-1 receptor
agonist, or basal insulin
are few data regarding comparative long-term effectiveness
° There
of different drugs combined with metformin. Thus, no standard
recommendations regarding combinations are available. The ADA
suggests that the advantages and disadvantages of specific drugs
for each patient should be considered in order to improve glycemic
control while minimizing side effects (see Table 44-2 for choices).
• Adding a third noninsulin agent to a two-drug regimen that has not
achieved control can be considered, but ADA states a more robust
response may be achieved by adding insulin
• The higher the hemoglobin A1c (i.e., A1c ≥9%), the more likely insulin
will be needed
moving to more complex regimens, ADA suggests first using
° Before
basal insulin, added onto noninsulin therapies; the noninsulin
therapies are necessary to cover prandial needs, which cannot be
safely covered by basal insulin
insulin is usually added at a low dose (estimated
° Basal
0.1−0.2 units/kg/day)
• If the patient is still having significant postprandial hyperglycemia
despite the previous recommendation, intensification may be needed
in patients willing to take more than 1 injection
2-injection regimen can be achieved with the use of twice-daily
° Apremixed
insulins
48565_ST06_251-352.indd 265
5/1/13 9:32 PM
266
Diabetes Mellitus
°
Alternatively, a 2-injection regimen could consist of basal insulin
plus a single prandial insulin injection at the largest meal
■ If still insuffi cient, another prandial injection could be added at
another meal (i.e., 3 injections daily: 1 basal plus 2 prandial)
■ If still insufficient, intensification up to a full 4-shot basal-bolus regimen may be needed (see dosing instructions in the section Glycemic
Management in Type 1 Diabetes: Initiating Outpatient Regimens)
• Individualization of therapy is essential, accounting for the degree of
hyperglycemia versus overall patient capabilities
REFERENCES
American Diabetes Association. Diagnosis and classification of diabetes
mellitus. Diabetes Care, 2012;35:Suppl:1:S64−71.
American Diabetes Association. Standards of medical care in diabetes—2012.
Diabetes Care, 2012;35(Suppl 1):S11−63.
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in
type 2 diabetes: a patient-centered approach: position statement of the
American Diabetes Association (ADA) and the European Association for
the Study of Diabetes (EASD). Diabetes Care, 2012;35(6):1364−79.
Pearce SH, Merriman TR. Genetics of type 1 diabetes and autoimmune
thyroid disease. Endocrinol Metab Clin North Am, 2009;38(2):289−301.
48565_ST06_251-352.indd 266
5/1/13 9:32 PM
45 ■ MATURITY ONSET DIABETES
OF THE YOUNG
Rebecca McEachern, MD
PATHOPHYSIOLOGY
• Heterogeneous group of disorders causing diabetes due to single gene
defects in pancreatic β cell causing insulin secretory deficits
• Now subtyped according to gene involved but old nomenclature persists
• Autosomal dominant genetic transmission with variable penetrance
and expression
• Represents 2−5% of all cases of diabetes although exact prevalence
unknown and may be misdiagnosed as type 2 diabetes or antibodynegative type 1 diabetes
CLINICAL PRESENTATION
• Young age of onset (<25 years of age)
nonobese individuals without signs of insulin resistance
° Usually
(e.g., no acanthosis nigricans)
disease progression
° Slow
° Low insulin requirements
• Family history of diabetes over 2 generations consistent with autosomal dominant inheritance is mandatory for diagnosis
• Subtype determines presentation
2 (GCK subtype)
° MODY
■ Lifelong mild hyperglycemia
■ Often presents with incidentally detected hyperglycemia
■ Typical symptoms of diabetes are rare
Other
forms of MODY
° ■ Normoglycemia
early in childhood and adolescence
■ Overt diabetes symptoms of polyuria and polydipsia
■ Progressive hyperglycemia
DIAGNOSTIC EVALUATION
• Patients who do not fulfill classic criteria for either type 1 or type 2
diabetes should be screened (see previous section)
• Serum glucose +/− A1C levels in the diabetic range (although glucokinase [GCK] mutations may only have impaired glucose levels)
• Some have disproportionate glycosuria (MODY 1 or hepatocyte nuclear
factor 1α [HNF-1α] subtype)
• Genetic testing is commercially available for the most common subtypes
48565_ST06_251-352.indd 267
5/1/13 9:32 PM
268
Maturity Onset Diabetes of the Young
MANAGEMENT
• Correctly diagnosing MODY (rather than type 1 or type 2 diabetes) has
a significant impact on treatment options and monitoring
• Treatment is geared towards improving hyperglycemia
1 and 3
° MODY
■ Sulfonylurea can be considered in MODY 1 and 3
■ Insulin is required with progression in MODY 1 and 3
° Insulin is recommended for all other forms of MODY
TABLE 45.1 Pathophysiology of MODY Subtypes
Original
Name
Gene
Pathogenesis
Affected Sites
Additional
Features
MODY 1
HNF-4α
(rare)
Defect in
Pancreas, liver
transcription
factor
regulating β cell
development and
differentiation
⇒ severe insulin
secretory defect
Lipid
abnormalities,
gain of function
mutations
cause neontatal
hypoglycemia
and macrosomia
MODY 2
GCK (15−32%
of MODY
subtypes)
Decreased
Pancreas, liver
sensitivity of β
cell to glucose
⇒ change in
glucose threshold
for normal insulin
secretion
Low birth
weight, hepatic
glycogen
storage defects,
neonatal
diabetes in
homozygotes
MODY 3
HNF-1α
(52−65%
of all MODY
subtypes)
Defect in
Pancreas,
transcription
kidneys
factor regulating β
cell development
and differentiation
⇒ severe insulin
secretory defect
Glycosuria,
impaired
glucagon
secretion,
pancreatic
exocrine
dysfunction
MODY 4
Insulin promoter Defect in
Pancreas
factor-1 (IPF-1) transcription
(rare)
factor
regulating β cell
development and
differentiation
⇒ insulin
secretory defect
Pancreatic
agenesis in
homozygotes
(continues)
48565_ST06_251-352.indd 268
5/1/13 9:32 PM
Management
269
TABLE 45.1 (continued )
Original
Name
Gene
Additional
Features
Pathogenesis
Affected Sites
Defect in
transcription
factor
regulating β cell
development and
differentiation
⇒ severe insulin
secretory defect
Pancreas,
liver, kidney,
genitalia
Polycystic
kidney disease,
urogenital tract
anomalies,
hepatic
dysfuntion,
hyperuricemia
Pancreas
CNS defects in
homozygotes
MODY 5
HNF-1β (rare)
MODY 6
Neurogenic
Defect in
differentiation transcription
factor 1
factor
(NeuroD1)
regulating β cell
(rare)
development and
differentiation
⇒ severe insulin
secretory defect
None
Preproinsulin
gene (INS)
(unknown
frequency)
Defect in insulin
Pancreas
precursor folding
and processing
Unknown
Other
CEL, PAX4,
KLF11, BLK
Pancreatic β
nuclear factor
defects
Pancreas
Unknown
Treatment
Long-Term
Complications
TABLE 45.2 Clinical Features of MODY
Presentation
Age of Onset
Overt diabetes
Adolescence− Responsive to
Screening for
HNF-1α
with progression early
sulfonylurea but diabetes
subtype
adulthood
1/3 eventually
complications is
(MODY 1) in some
individuals
require insulin
required
Mild fasting
Very young
GCK
hyperglycemia
subtype
(MODY 2) (due to glycogen
abnormalities)
and impaired
glucose
tolerance, GDM in
50% carriers
Often no
pharmacologic
intervention
required
Very low risk
(continues)
48565_ST06_251-352.indd 269
5/1/13 9:32 PM
270
Maturity Onset Diabetes of the Young
TABLE 45.2 (continued )
Presentation
Age of Onset
Treatment
Long-Term
Complications
Overt diabetes
Adolescence− Responsive to
Screening for
HNF-1α
with progression early
sulfonylurea but diabetes
subtype
adulthood
1/3 eventually
complications
(MODY 3)
require insulin
is required
IPF-1
Ranges from
subtype
impaired
(MODY 4) glucose
tolerance to
overt diabetes
Early adulthood Insulin therapy
Unknown and
thus screening
for diabetes
complications
suggested
Progressive
HNF-1β
hyperglycemia,
subtype
(MODY 5) renal cysts
(which may
precede
diagnosis of
diabetes)
Early adulthood Insulin therapy
Unknown and
thus screening
for diabetes
complications
suggested
NeuroD1
Progressive
subtype
hyperglycemia
(MODY 6)
Variable age
of onset
Unknown and
thus screening
for diabetes
complications
suggested
Insulin therapy
REFERENCES
Giuffrida FM, Reis AF. Genetic and clinical characteristics of maturity-onset
diabetes of the young. Diabetes Obes Metab, 2005;7(4):318−26.
Nyunt O, Wu JY, McGown IN, et al. Investigating maturity onset diabetes of
the young. Clin Biochem Rev, 2009;30(2):67−74.
Rubio-Cabezas O, Edghill EL, Argente J, Hattersley AT. Testing for monogenic
diabetes among children and adolescents with antibody-negative clinically defined Type 1 diabetes. Diabet Med, 2009;26(10):1070−4.
Steck AK, Winter WE. Review on monogenic diabetes. Curr Opin Endocrinol
Diabetes Obes, 2011;18(4):252−8.
Vaxillaire M, Bonnefond A, Froguel P. The lessons of early-onset monogenic
diabetes for the understanding of diabetes pathogenesis. Best Pract Res
Clin Endocrinol Metab, 2012;26(2):171−87.
Vaxillaire M, Froguel P. Monogenic diabetes in the young, pharmacogenetics
and relevance to multifactorial forms of type 2 diabetes. Endocr Rev,
2008;29(3):254−64.
48565_ST06_251-352.indd 270
5/1/13 9:32 PM
46 ■ HYPERGLYCEMIC EMERGENCIES:
DIABETIC KETOACIDOSIS (DKA) AND THE
HYPEROSMOLAR HYPERGLYCEMIC STATE (HHS)
Steven Kaufman, MD
PATHOPHYSIOLOGY
• Results from decreased ratio of insulin to counterregulatory hormones
(most importantly glucagon)
result from decreased insulin, increased counterregulatory
° Can
hormones, or both
• Development of hyperglycemia
glucose uptake by peripheral tissues, increased glycoge° Decreased
nolysis, and gluconeogenesis
° Volume depletion leads to impaired glucose excretion
• Development of ketoacidosis
lipolysis → increased FFA delivered to liver → ketogen° Increased
esis (in setting of significant insulinopenia)
■ β hydroxybutyrate: predominant ketoacid in DKA, can be measured quantitatively but not by standard ketone assay
■ Acetoacetate: usually minor portion of acid load in DKA,
assessed by ketone assay
■ Acetone: not a weak acid, most notable for causing “fruity” odor
on breath of patients with DKA
hydroxybutyrate and acetoacetate are weak acids → decrease
° βserum
alkali reserve (decrease bicarbonate) → metabolic acidosis
is typical presentation of hyperglycemic emergency
° Ketoacidosis
in type 1 diabetes; can also occur in type 2 diabetes but there is
usually sufficient insulin to suppress ketogenesis
• Development of hyperosmolarity
results in osmotic diuresis, leading to water loss →
° Hyperglycemia
solute loss → hyperosmolarity
Hyperosmolarity
typical presentation of hyperglycemic emergency
° in type 2 diabetes;is can
also occur in type 1 diabetes but patients
typically present with DKA before significant water loss occurs
48565_ST06_251-352.indd 271
5/1/13 9:32 PM
272 Diabetic Ketoacidosis (DKA) and the Hyperosmolar Hyperglycemic State (HHS)
TABLE 46.1 Diagnosis
Glucose
pH
CO2
Serum osmolality
Anion gap
Serum ketones
Mental status
DKA
>250 mg/dl
<7.30
<18 mmol/L
Normal
Elevated
Elevated
Alert to stuporous/coma
HHS
>600 mg/dl
>7.3
>15 mmol/L
>320 mOsm/kg
Normal
Normal
Stuporous/coma
TYPICAL PRECIPITATING FACTORS
• Inadequate insulin: new-onset diabetes, omission of insulin, insulin
pump failure
• Infections: especially pneumonia or urinary tract infection (UTI)
• Other acute medical conditions: especially MI, pancreatitis, cerebrovascular accident (CVA)
• Drugs: especially corticosteroids, thiazide diuretics, atypical
antipsychotics
• Other: including parenteral nutrition, substance abuse, and various
endocrine conditions
EVALUATION
• Initial laboratory studies: glucose, electrolytes, phosphorus, BUN,
creatinine, urinalysis, CBC with differential, ECG, urine for ketones or
serum for β hydroxybutyrate
• Assessment for precipitating factors, especially infection or MI
TABLE 46.2 Common Calculations
Calculations
Formula
Na+− (Cl−+ HCO3−)
2 × [measured Na+] + [glucose (mg/dl)/18] +
[BUN (mg/dl)/2.8]
“Corrected” serum sodium Corrected Na+ = [(serum glucose − 100) × 1.6] +
measured Na+
Anion gap
Serum osmolality
48565_ST06_251-352.indd 272
5/1/13 9:32 PM
Management
273
COMMONLY SEEN LABORATORY ABNORMALITIES
• Anion gap: elevated in DKA, normal in HHS
• Bicarbonate: can be very low in DKA, usually normal in HHS
unless there is another supervening condition such as lactic
acidosis
• Potassium: serum levels may vary from frankly low to frankly elevated,
but all patients have had loss of total body potassium
• Phosphate: levels may initially be normal to elevated, but usually
decline with treatment
• Sodium: measurement is “diluted” by water drawn into circulation by
excess glucose
serum sodium used to estimate what serum sodium
° “Corrected”
will be when glucose is removed
implication: patient with normal serum sodium and
° Clinical
very high glucose will likely be hypernatremic when glucose
levels fall
• Amylase: increased in up to 90% of patients with DKA
• Lipase may also be elevated in DKA
• Leukocytosis of 10,000−15,000 mm is common
>25,000 mm or greater than 10% band neutrophils should
° WBC
increase the clinical suspicion for an active infection
• Mild increases in creatinine kinase and troponin may occur in the
absence of myocardial damage
MANAGEMENT
• Goals
of management of DKA is correction of the acidosis
° Goal
of management of HHS is correction of the hyperosmolar state
° Goal
and electrolyte imbalances
of DKA or HHS with appropriate fluid, insulin, and
° Management
electrolyte replacement will improve the hyperglycemia as well
• IV fluids
can be started while initial laboratory assessment is
° Fluids
pending
Start
normal
saline at 15−20 ml/kg body weight/hour (maximum of
° 1 liter per hour)
infusion rate to 250–500 cc per hour once BP stabilizes
° Reduce
the sodium corrects to the eu- or hypernatremic level, change
° Once
the IV fluid to ½ normal saline
fluid rates based on the response to treatment and volume
° Titrate
status
Use
caution
aggressive fluid replacement in patients with CHF,
° an acute MI,with
evidence of volume overload, or anuria
48565_ST06_251-352.indd 273
5/1/13 9:32 PM
274 Diabetic Ketoacidosis (DKA) and the Hyperosmolar Hyperglycemic State (HHS)
°
Add dextrose to the IV fluids once the glucose drops to below
250 mg/dL to avoid hypoglycemia while allowing the insulin infusion
to continue until the acidosis or hyperosmolarity has resolved
edema occurs primarily in children, but has been
° Cerebral
described in adults
• Insulin
not start IV insulin until serum potassium measured
° Do
insulin IV bolus at 0.1−0.15 units/kg body weight
° Regular
Start
insulin infusion at 0.1 units/kg body weight/hour
° InitiallyIV the
glucose level may fall precipitously due to volume
° expansion; thereafter,
glucose levels should make a steady decline
of 50−75 mg/dL each hour
Adjust
the
rate
of
insulin
infusion to allow the glucose to trend
° downward at an appropriate
rate
• Bicarbonate
Bicarbonate
is
largely
regenerated
as insulin reverses ketone
° formation
bicarbonate replacement is not recommended (and may be
° Routine
detrimental), but can be considered if pH <6.9
TABLE 46.3 Potassium
Potassium Level
<3.3 mmol/L
3.3−5.0 mmol/L
>5.0 mmol/L
Potassium Replacement
Hold insulin, give 20–30 mmol of K + /hr until K +
>3.3 mmol/L, then start insulin
20–30 mmol of K + /L
Hold potassium repletion, repeat K + in 2 hours
• Phosphate
use of phosphate replacement not recommended
° Routine
replacement suggested in patients with phosphate levels
° Selective
<1.0 mg/dL, anemia, respiratory failure, or CHF
COMPLICATIONS OF MANAGEMENT
• Hypoglycemia
risk by adding dextrose to IV fluids as glucose falls below
° Reduce
250 mg/dL
• Hypokalemia
risk by frequent assessment of potassium level and atten° Reduce
tion to potassium repletion
48565_ST06_251-352.indd 274
5/1/13 9:32 PM
Transition from IV Insulin Infusion 275
• Hyperchloremic acidosis
(Cl−) in saline solution replaces the lost negative charge of
° Chloride
bicarbonate (HCO3−) to help maintain electroneutrality
gap has improved, but bicarbonate levels remain low
° Anion
benign process resolves gradually in the hours to days after
° This
the saline infusion is reduced or stopped
• Cerebral edema
edema occurs primarily in children, but has been
° Cerebral
described in adults
is unclear, but cerebral edema is not related to the degree
° Etiology
of hyperosmolality
Avoid
rapid
changes in glucose and osmolarity
°
RESOLUTION OF THE HYPERGLYCEMIC CRISIS
• Resolution of DKA: normalization of the anion gap and/or drop in the
β hydroxybutyrate level to less than 3 mmol/L
• Resolution of HHS: correction of the fluid and electrolyte
abnormalities
TRANSITION FROM IV INSULIN INFUSION
• Transition to SQ insulin regiment once the acute abnormalities (acidbase, osmolar, and electrolyte) have resolved and the glucose level
has improved
• Do not stop IV insulin until adequate time for absorption of SQ insulin
least 30 minutes for short-acting insulin or 2 hours for longer° At
acting insulin
• Start a physiologic insulin regimen consisting of
insulin (NPH, glargine, or detemir)
° Basal
° Mealtime, or “nutritional,” insulin (regular, lispro, apidra, or aspart)
• Use of corrective (“sliding scale”) insulin as the sole SQ insulin strategy is never appropriate in a patient recovering from a hyperglycemic
emergency
• Calculate TDD of insulin requirements
= stable IV insulin infusion rate (over last 4−6 hours) ⫻ 20
° TDD
of TDD as basal insulin given once daily as either (1) glargine
° ½
daily or (2) detemir or NPH twice daily in divided doses
of TDD as mealtime insulin given in three equal doses at break° ½
fast, lunch, and dinner
Supplemental
insulin doses can be administered to correct unan° ticipated hyperglycemia
48565_ST06_251-352.indd 275
5/1/13 9:32 PM
276 Diabetic Ketoacidosis (DKA) and the Hyperosmolar Hyperglycemic State (HHS)
REFERENCES
DeSantis AJ, Schmeltz LR, Schmidt K, et al. Inpatient management
of hyperglycemia: the Northwestern experience. Endocr Pract,
2006;12(5):491−505.
Kitabchi AE, Umpierrez GE, Fisher JN, Murphy MB, Stentz FB. Thirty years
of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state. J Clin Endocrinol Metab,
2008;93(5):1541−52.
Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult
patients with diabetes. Diabetes Care, 2009;32(7):1335−43.
O’Malley CW, Emanuele M, Halasyamani L, Amin AN; Society of Hospital
Medicine Glycemic Control Task Force. Bridge over troubled waters: safe
and effective transitions of the inpatient with hyperglycemia. J Hosp Med,
2008;3(Suppl 5):55−65.
Trachtenbarg DE. Diabetic ketoacidosis. Am Fam Physician, 2005;71(9):
1705−14.
Wilson JF, Laine C, Turner BJ, et al. Diabetic ketoacidosis. Ann Int Med, 2010;
152(1):ITC1-16.
48565_ST06_251-352.indd 276
5/1/13 9:32 PM
47 ■ HYPOGLYCEMIA IN PATIENTS
WITH DIABETES
Hilary Whitlatch, MD and Geetha Gopalakrishnan, MD
DEFINITION
• PG concentration ≤70 mg/dL with or without symptoms
SYMPTOMS OF HYPOGLYCEMIA
• Increased Epi secretion: tremor, palpitations, diaphoresis
• Neuroglycopenic symptoms: confusion, behavior change, seizure, coma
CLASSIFICATION OF HYPOGLYCEMIA IN PATIENTS WITH DIABETES
• Severe: requires assistance of another person
• Documented symptomatic: typical symptoms and measured
PG ≤70 mg/dL
• Asymptomatic: measured PG ≤70 mg/dL without symptoms
• Probable symptomatic: typical symptoms but PG not measured
• Relative: typical symptoms but measured PG >70 mg/dL
with chronic hyperglycemia may experience hypoglycemic
° People
symptoms when blood sugars decline to the physiologic range
uncomfortable, likely poses no direct harm, as there is
° Although
adequate glucose supply to vital organs
ETIOLOGIES OF HYPOGLYCEMIA IN DIABETES
• Insulin excess
exogenous insulin or medications that stimulate
° Excess/mistimed
release of endogenous insulin from the pancreas independently of
blood glucose (sulfonylureas and meglitinides)
of increased insulin sensitivity or glucose utilization
° Situations
(exercise, weight loss)
° Decreased insulin clearance (renal failure)
• Decreased glucose availability
exogenous glucose intake (overnight fast, missed meal)
° Decreased
endogenous glucose production (liver failure, alcohol
° Decreased
consumption)
• Abnormal counterregulatory response to hypoglycemia
insulin is not subject to normal physiologic feedback
° Exogenous
regulation in response to hypoglycemia
48565_ST06_251-352.indd 277
5/1/13 9:32 PM
278
Hypoglycemia in Patients with Diabetes
°
°
Lack of hypoglycemia-induced glucagon secretion from pancreatic
α cells results in failure to stimulate liver glycogenolysis and
gluconeogenesis.
■ Develops within 5 years of type 1 diabetes onset and more
slowly in type 2 diabetes (>10 years), mirroring β-cell
failure
■ The pathogenesis is unknown; hypotheses include inhibition
of glucagon secretion by exogenous insulin or by intraislet
sympathetic neuropathy
Lack of hypoglycemia-induced Epi secretion occurs as a result
of alteration in the function of glucose-sensing receptors on
autonomic neurons
■ Results in a failure to appropriately stimulate liver glycogenolysis and gluconeogenesis
■ Reduces autonomic symptoms of hypoglycemia (tremor, diaphoresis, palpitations), causing hypoglycemic unawareness and
delayed recognition and treatment of hypoglycemia
HYPOGLYCEMIA-ASSOCIATED AUTONOMIC FAILURE (HAAF)
• Occurs when the glycemic threshold for sympathetic autonomic activation is shifted to a lower PG concentration by a prior hypoglycemic
event, prior exercise, or sleep
is not clearly defined, but is thought to reside in the
° Mechanism
brain, possibly the ventromedial hypothalamus
• Results in reduced sympathetic neural response to hypoglycemia,
reducing symptoms and leading to hypoglycemic unawareness
• Results in a cycle of recurrent hypoglycemia and is associated with a
sixfold increased risk for severe hypoglycemia
• Risk factors for HAAF include absolute endogenous insulin deficiency
(type 1 diabetes, postpancreatectomy, long-standing type 2 diabetes),
history of severe hypoglycemia, recent antecedent hypoglycemia, prior
exercise or sleep, and aggressive glycemic therapy to achieve lower
glycemic goals
• 2−3 weeks of strict avoidance of treatment-induced hypoglycemia
can reverse HAAF and restore the Epi counterregulatory
response
48565_ST06_251-352.indd 278
5/1/13 9:32 PM
Prevention of Hypoglycemia in Diabetes
279
ACUTE TREATMENT OF HYPOGLYCEMIA IN DIABETES
• In general, all hypoglycemic episodes, with the exception of relative
hypoglycemia, should be treated
° HAAF can lead to a cycle of recurrent hypoglycemia
• If conscious, treat with 15−20 g of oral glucose (4 ounces of juice,
3 glucose tablets, 1 tube of glucose gel)
improvement usually occurs within 15 minutes; a finger° Clinical
stick can confirm resolution (FS > 70 mg/dL)
Given
risk
of recurrent hypoglycemia, a subsequent snack or meal
° may be required
• If unconscious or unable to take glucose by mouth at home, a trained
family member/associate can administer 1 mg of glucagon SQ or IM
• If unconscious and IV access available, 12.5−25 g IV 50% dextrose
can be administered by medical personnel.
PREVENTION OF HYPOGLYCEMIA IN DIABETES
• Individualize glycemic goals
the risk of complications from hypoglycemia and the risk of
° Balance
long-term complications of hyperglycemia
higher glycemic treatment target, such as a A1C of 7−8% is
° Aappropriate
in the elderly, those at high risk of hypoglycemia, and
those with hypoglycemic unawareness
• Individualize therapy
the sulfonylureas, hypoglycemia is less frequent with
° Among
glimepiride and glipizide than with glyburide
Use
of
a
long-acting insulin analogue (glargine or detemir) results
° in less hypoglycemia
than use of NPH insulin
of a rapid-acting insulin analogue (aspart, lispro, glulisine) for
° Use
mealtime insulin coverage is associated with less hypoglycemia
than use of regular insulin
• Patient and family education
self-monitoring of blood glucose
° Frequent
of early symptoms of hypoglycemia
° Recognition
Recognition
of situations in which dose or timing of medication
° should be altered
(exercise, illness, fasting)
of situations in which a preemptive snack or glucose
° Recognition
load is appropriate (exercise, alcohol consumption)
availability of treatment (glucose tablets, gel)
° Ready
of family members on glucagon administration
° Instruction
medical alert identification, particularly in those with a
° Consider
prior history of severe hypoglycemia or hypoglycemic unawareness
48565_ST06_251-352.indd 279
5/1/13 9:32 PM
280
Hypoglycemia in Patients with Diabetes
REFERENCES
Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in type 2 diabetes.
Diabet Med, 2008;25(3):245−54.
Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of
adult hypoglycemic disorders: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab, 2009;94(3):709−28.
McCrimmon RJ, Sherwin RS. Hypoglycemia in type 1 diabetes. Diabetes,
2010;59(10):2333−9.
Workgroup on Hypoglycemia, American Diabetes Association. Defining
and reporting hypoglycemia in diabetes: a report from the American
Diabetes Association Workgroup on Hypoglycemia. Diabetes Care,
2005;28(5):1245−9.
48565_ST06_251-352.indd 280
5/1/13 9:32 PM
48 ■ DIABETIC RETINOPATHY
Harikrashna Bhatt, MD and Geetha Gopalakrishnan, MD
PATHOPHYSIOLOGY
• Diabetic retinopathy is the leading cause of adult blindness in the
United States
• 95% of type 1 diabetics and 60% of type 2 diabetics will develop
diabetic retinopathy after 20 years of diabetes
hyperglycemia causes diabetic retinopathy
° Long-term
of diabetic retinopathy can be delayed by improving
° Progression
glycemic control and by reducing A1C; target goal for A1C is <7%
• Diabetic retinopathy can occur in those with impaired glucose
tolerance
• Damage to the retinal vasculature by chronic hyperglycemia is the
underlying cause of diabetic retinopathy
mechanisms: sorbitol accumulation, advanced glycation
° Proposed
end products (AGEs), reactive oxygen species
Retinal
microthrombosis
and certain growth factors such as VEGF
° may play role
• Two types of retinopathy: nonproliferative and proliferative
progression from mild nonproliferative diabetic retinopathy
° General
to proliferative diabetic retinopathy
CLINICAL PRESENTATION
• Patients may have no symptoms in the early stages of retinopathy
• With progression, patients may experience poor visual acuity and
blindness
DIAGNOSTIC EVALUATION
• Diabetic retinopathy progresses with hyperglycemia; monitor A1C and
target levels <7%
• Comprehensive dilated eye exam necessary
diabetic retinopathy ophthalmoscopic features:
° Nonproliferative
retinal hemorrhages, macular edema, hard exudates, microaneurysms, venous beading, and cotton wool spots
diabetic retinopathy ophthalmoscopic features:
° Proliferative
preretinal hemorrhages, macular edema, fibrovascular proliferation,
and neovascularization
48565_ST06_251-352.indd 281
5/1/13 9:32 PM
282
Diabetic Retinopathy
TABLE 48.1 Retinal Findings
Retinal Findings
Retinal hemorrhages
Microaneurysms
Hard exudates
Venous beading
Cotton wool spots
Preretinal hemorrhages
Macular edema
Etiology
Bleeding from retinal
vessels
Leakage of serum from
retinal capillaries
Lipid deposits within
retina
Retinal hypoxia
Retinal ischemia
Descriptions
Appear as red dots
Small dots along retinal
capillaries
Appear yellow with clear
edges
Dilated retinal veins
White/soft-edged spots
(transient)
Vitreous blood
Red areas
Fluid within the intraretinal Loss of central vision
portion of macula
MANAGEMENT
• BP and blood glucose control is essential for the prevention and
progression of diabetic retinopathy
• Start ophthalmologic evaluation
time of diagnosis for patient with type 2 diabetes
° At
3−5 yrs after diagnosis of type 1 diabetes
°
• Follow up interval is based on severity of retinopathy, ranging from 3 to
12 months
• Pregnant women can get worsening of retinopathy as pregnancy
progresses
postulated include lower retinal blood flow (due to physi° Reasons
ologic systemic lowering of BP in pregnancy) worsening retinal
ischemia/hypoxia
women with type 1 or 2 diabetes should get an eye exam
° Pregnant
prior to conception or in the early first trimester
° Follow-up ophthalmologic evaluation every trimester may be necessary
• Treatment
and moderate nonproliferative diabetic retinopathy is generally
° Mild
not treated; focal laser photocoagulation can be considered if
macular edema present
photocoagulation can be used in the treatment of severe
° Panretinal
nonproliferative diabetic retinopathy; potential side effects include
poor adaptation to dark and reduced peripheral vision/central vision
photocoagulation can be performed during pregnancy
° Laser
detachment or vitreous hemorrhage may require surgical
° Retinal
intervention
therapeutic directions: antiplatelet agents, protein kinase
° Future
C inhibitors, anti-VEGF agents (anti-VEGF agents have shown the
most promise)
48565_ST06_251-352.indd 282
5/1/13 9:32 PM
References
283
REFERENCES
Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med,
2012;366(13):1227−39.
Bhavsar AR. Diabetic retinopathy: the latest in current management. Retina,
2006;26(Suppl 6):S71−9.
Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy:
a systematic review. JAMA, 2007;298(8):902−16.
48565_ST06_251-352.indd 283
5/1/13 9:32 PM
48565_ST06_251-352.indd 284
5/1/13 9:32 PM
49 ■ DIABETIC NEPHROPATHY
M. Luiza Caramori, MD, MSc, PhD
EPIDEMIOLOGY
• Diabetic nephropathy develops in 25–35% of patients with a peak in
incidence around 20 years of diabetes duration
• Rates of diabetic nephropathy are similar in type 1 and type 2 diabetes
• Diabetic nephropathy is the most common cause of ESRD in adults
• Patients with diabetic nephropathy have increased mortality, mainly
due to cardiovascular disease
RISK FACTORS
• Glycemic control, systemic BP, and genetic factors are very important
determinants of diabetic nephropathy risk
• Other factors (smoking, obesity, lipid levels) may modulate this risk
• There is a high concordance in diabetic nephropathy risk among
siblings with diabetes
• Diabetic nephropathy risk is greater in patients with family history of
hypertension and CVD
PATHOPHYSIOLOGY
• Renal lesions in diabetes are mainly related to extracellular matrix
accumulation in the glomerular and tubular basement membranes,
mesangium, and interstitium
• Expansion of the mesangium reduces the glomerular capillary luminal
space, decreasing glomerular filtration surface and GFR
• There is a strong relationship between renal structure and function in
patients with type 1 diabetes
• Progressive tubular atrophy, interstitial fibrosis, renal glomerular
arteriolar hyalinosis, arteriosclerosis, and glomerulosclerosis are also
important components of diabetic nephropathy that may contribute to
the reduction in GFR
• Larger vessel atherosclerosis, especially in type 2 diabetes, may lead
to ischemic renal tissue damage
• Hyperglycemia, AGEs, and increased oxidative stress have all been
associated with diabetic nephropathy
48565_ST06_251-352.indd 285
5/1/13 9:32 PM
286
Diabetic Nephropathy
CLINICAL PRESENTATION
• Didactically, the course of diabetic nephropathy in type 1 diabetes can
be divided in 5 stages (Table 49.1)
• Patients with type 2 diabetes can have microalbuminuria or proteinuria
at diagnosis, generally attributed to a prior period of undiagnosed
diabetes; GFR decline is also more variable, reflecting the heterogeneity of renal lesions in these patients
TABLE 49.1 Stages of Diabetic Nephropathy
Diabetes Duration
0 to 3−5 years
3−5 to 7 years
7 to 15−20 years
15−20 to 25 years
After 25 years
Stage Manifestations
I
• Renal hypertrophy
• Increased-to-normal GFR
II
• Normal urinary albumin
excretion
• Basement membrane
thickening
• Mesangial expansion
III
• Microalbuminuria
• Increases in blood
pressure levels
• Normal-to-declining GFR
IV
• Proteinuria
• Hypertension
• Decreased GFR
• Dyslipidemia
V
Characteristics
• Present at diagnosis
• Common in all
patients with
diabetes
• 20−45% progression
to Stage IV in 10 years
• Increased
cardiovascular
mortality
• Progression to ESRD
in 5−15 years
• Associated with other
chronic complications
of diabetes
• ESRD
Adapted from: Caramori ML, Maver M. Pathogenesis and pathophysiology of diabetic nephropathy. In:
Greenberg A, ed. Primer on Kidney Diseases, 5th ed. Philadelphia, PA: Saunders Elsevier; 2009:214–223.
GFR = glomerular filtration rate; ESRD = end-stage renal disease
DIAGNOSTIC EVALUATION
• Diagnosis is based on the presence of increased urinary albumin
excretion (UAE) (Table 49.2) and/or reduced GFR
• Renal biopsies may be necessary for diagnosis in patients with an
atypical clinical course, since, although not common, other nephropathies can be present
48565_ST06_251-352.indd 286
5/1/13 9:32 PM
Management 287
TABLE 49.2 Categories of Urinary Albumin Excretion
Category/Urine
Collection
Normoalbuminuria
Microalbuminuria
Macroalbuminuria/
Proteinuria
Spot Collection
24-h Collection
(μg/mg creatinine) (mg/24h)
<30
30−300
>300
<30
30−300
>300
Timed Collection
(μg/min)
<20
20−200
>200
Adapted from: Caramori ML, Maver M. Pathogenesis and pathophysiology of diabetic nephropathy. In:
Greenberg A, ed. Primer on Kidney Diseases, 5th ed. Philadelphia, PA: Saunders Elsevier; 2009:214–223.
MANAGEMENT
• Blood glucose control: primary prevention of diabetic nephropathy is
mainly achieved by intensive blood glucose control (A1c around 7%)
• All patients with overt diabetic nephropathy (proteinuria and/or
reduced GFR) should be treated with ACEIs or ARBs
• BP control: in patients with hypertension, BP control is key
most patients, a BP goal of <130/80 is acceptable; however, the
° For
BP target may vary depending on the presence of comorbidities
patients need multiple antihypertensive agents to reach BP
° Most
goals
Thiazide
calcium channel blockers, and/or β blockers are
° frequentlydiuretics,
used in combination with an ACEI or ARB
the combination of an ACEI and ARB may further reduce
° Although
proteinuria, mortality is increased and, in most instances, these
agents should not be used together
may have other clinical conditions for which a specific
° Patients
class of antihypertensive agent is indicated (e.g., ACEIs or ARBs if
proteinuria or elevated creatinine, β blockers following MI)
• Lipid control: control of lipid levels (low-density lipoprotein [LDL]
<100 mg/dL), in association with other measures, is associated with
slower rates of diabetic nephropathy development and progression
• Smoking cessation
• Patients with progressive nephropathy, especially when estimated GFR
is <60 ml/min/1.73m2, should be referred to a nephrologist if there is
concern for the presence of non-diabetic kidney disease
• All patients with estimated GFR <30 ml/min/1.73m2 should be
referred to a nephrologist
48565_ST06_251-352.indd 287
5/1/13 9:32 PM
288
Diabetic Nephropathy
REFERENCES
American Diabetes Association. Standards of medical care in
diabetes—2013. Diabetes Care, 2013;36(Suppl 1):S11−63.
KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations
for Diabetes and Chronic Kidney Disease. Am J Kidney Dis, 2007;49
(2 Suppl 2):S12−154.
US Renal Data System. USRDS 2010 Annual Data Report: Atlas of Chronic
Kidney Disease and End-Stage Renal Disease in the United States.
Bethesda, MD: National Institutes of Health, National Institute of Diabetes
and Digestive and Kidney Diseases; 2010. Available at: hwww.usrds.org/
atlas10.aspx.
48565_ST06_251-352.indd 288
5/1/13 9:32 PM
50 ■ DISTAL SYMMETRIC POLYNEUROPATHY
Elias S. Siraj, MD
PATHOPHYSIOLOGY
• Hyperglycemia is clearly associated with the development of diabetic
neuropathy
• Proposed mechanisms include
of AGEs; increased sorbitol production via the aldose
° Formation
reductase pathway
Activation
of protein kinase C
° Increased activation
of the hexosamine pathway
° Increased oxidative stress
°
• Other mechanisms may include: vascular factors such as ischemia and
hypertension, autoimmunity, and defects in nerve fiber repair mechanisms
CLINICAL PRESENTATION
• Presentation tends to be “glove and stocking” distribution with
feet much more frequently affected than hands; symptoms include
numbness, pain (usually burning and sometimes pronounced at night),
altered sensation, and paresthesias
• Impairment of pain, light touch, and temperature is secondary to
loss of small fibers and tends to appear early even though it may be
asymptomatic and undetected
• Loss of vibratory sensation and altered proprioception reflect largefiber loss
• Decreased or absent ankle reflexes may be noted
• In severe cases, muscle weakness may be seen
SCREENING AND MONITORING OF DISTAL SYMMETRIC
POLYNEUROPATHY (DSPN)
• DSPN is usually diagnosed clinically based on symptoms and physical
exam findings
• All patients with type 2 diabetes should be screened for DSPN at the
time of diagnosis and those with type 1 diabetes should be screened
five years after diagnosis
• After initial screening, all patients should be followed at least annually by
examining sensory function in the feet and checking ankle reflexes. One or
more of the following tests can be used to assess sensory function:
° Pinprick
° Temperature
48565_ST06_251-352.indd 289
5/1/13 9:32 PM
290
Distal Symmetric Polyneuropathy
°
°
Vibration perception (using a 128-Hz tuning fork)
Pressure sensation (using a 10-g monofilament pressure sensation
at the distal halluces)
• Nerve conduction studies are occasionally useful to exclude other
types of neuropathy
MANAGEMENT OF DSPN
• All patients with DSPN require comprehensive foot care
• Glycemic control reduces the onset and progression of DSPN
improvement of glycemic control may lead to a transient
° Rapid
worsening of neuropathic symptoms
• Pain management
used as first-line agents in most cases
° Antidepressants:
■ Tricyclics
• Amitriptyline 25−100 mg /day
■ Dual serotonin and NE reuptake inhibitors
• Duloxetine 60−120 mg/day
• Venlafaxine 75−225 mg/day
Anticonvulsant
therapy: can be used as monotherapy or combina° tion with antidepressants
■ Pregabalin 300−600 mg/day
■ Gabapentin 900−3600 mg/day
■ Sodium valproate 500−1200 mg/day
° Others
■ Capsaicin cream 0.075%: a naturally occurring component of
some types of hot peppers that causes analgesia by depleting
substance P
• Can be added if refractory to antidepressants or
anticonvulsants
• Applied up to 4 × daily
■ Opiods: oxycodone, morphine sulphate
■ Topical lidocaine
■ Others: dextromethorphan, tramadol
REFERENCES
Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment
of painful diabetic neuropathy—report of the American Association of
Neuromuscular and Electrodiagnostic Medicine, the American Academy
of Neurology, and the American Academy of Physical Medicine &
Rehabilitation. Muscle Nerve, 2011;43(6):910–7.
Consensus statement: Report and recommendations of the San Antonio conference on diabetic neuropathy. American Diabetes, Association American
Academy of Neurology. Diabetes Care, 1988;11(7):592–7.
48565_ST06_251-352.indd 290
5/1/13 9:32 PM
References
291
England JD, Gronseth GS, Franklin G, et al. Distal symmetric polyneuropathy:
a definition for clinical research: report of the American Academy of
Neurology, the American Association of Electrodiagnostic Medicine, and
the American Academy of Physical Medicine and Rehabilitation. Neurology,
2005;64(2):199–207.
Hartemann A, Attal N, Bouhassira D, et al. Painful diabetic neuropathy:
diagnosis and management. Diabetes Metab, 2011;37(5):377–88.
Said G. Diabetic neuropathy—a review. Nat Clin Pract Neurol,
2007;3(6):331–40.
48565_ST06_251-352.indd 291
5/1/13 9:32 PM
48565_ST06_251-352.indd 292
5/1/13 9:32 PM
51 ■ CARDIOVASCULAR DISEASE
IN TYPE 2 DIABETES
Tessey Jose, MD, Raymond R. Russell, MD, and Silvio E. Inzucchi, MD
DIABETES AND CARDIOVASCULAR RISK: OVERVIEW
• CVD is the leading cause of mortality in diabetes (responsible for nearly
70% in individuals >65 years old)
• Diabetes imparts a ~2- to 4-fold risk of CVD: MI, stroke, peripheral
arterial disease (PAD), and CHF
• Outcomes after CVD events, including mortality, are more adverse in
the diabetic population
• In general, atherosclerosis is more diffuse and advanced in the presence of diabetes
PATHOPHYSIOLOGY
FIGURE 51.1 Pathophysiology of Insulin Resistance and its Association with
Cardiovascular Disease
48565_ST06_251-352.indd 293
5/1/13 9:32 PM
294
Cardiovascular Disease in Type 2 Diabetes
• Type 2 diabetes and atherosclerosis (attributed to the following risk factors and intermediaries, each exhibiting complex interrelationships)
resistance/metabolic syndrome
° Insulin
° Obesity
Hyperglycemia
° Dyslipidemia (and AGEs)
° Hypertension
° Proinflammatory state
° Hypercoagulability (prothrombotic state)
° Microvascular/endothelial dysfunction
° Oxidative stress
°
• Diabetic cardiomyopathy
(sometimes silent) → regional and global ventricular
° MI
dysfunction
disease
° Microvascular
autonomic neuropathy
° Cardiac
Elevated
glucose
and fatty acids → glucolipotoxicity
°
GLYCEMIC CONTROL
• Glycemic control and CVD outcomes: implications of major trials
in newly diagnosed patients with type 2 DM, sulfonylureas
° UKPDS:
or insulin therapy showed neutral effect on MI risk as compared to
standard diet therapy; in contrast, metformin reduced MI risk in
overweight patients
10-year follow-up study: group previously treated more
° UKPDS
intensively with sulfonylureas/insulin (A1c ~7%) demonstrated
modestly reduced cardiovascular risk, as compared to standard diet
therapy group (A1c ~8%); metformin’s cardiovascular advantage
persisted as well
ADVANCE, VADT: in patients with longstanding type 2 DM
° ACCORD,
and higher cardiovascular risk, there is no apparent cardiovascular
advantage to A1c targets more intensive than ~7% (or slightly
higher); the risks of intensive glycemic control may outweigh
benefits in some patients: advanced age (>70–75 years), long
disease duration (>20 years), established CVD, increased risk of
hypoglycemia
48565_ST06_251-352.indd 294
5/1/13 9:32 PM
Glycemic Control 295
TABLE 51.1 CV Considerations of the Most Commonly Used
Antihyperglycemic Medications
Drug Class
Biguanides
Sulfonylureas
Mechanism
of Action
Decreases
hepatic
glucose
production
HbA1c
Efficacy
–1 to 2%
Binds to
–1 to 2%
sulfonylurea
receptors on
pancreatic
β cells,
stimulating
insulin
release
Thiazolidinediones Activates,
PPARγ,
increasing
peripheral
insulin
sensitivity
–1 to 1.5%
CV Considerations
Potential
Benefi ts
Concerns
• Contraindicated
• Insulinsensitizing
in unstable/
properties
severe CHF
• Improved CVD • Possible
outcomes in
lactic acidosis
UKPDS
in patients
• Retrospective
with renal
studies
dysfunction
show ↓
receiving
cardiovascular contrast
mortality
–
• Hypoglycemia
risk
• Weight gain
• ? Impairs
ischemic
preconditioning
• Retrospective
studies show ↑
cardiovascular
mortality
• Edema/heart
• Insulinsensitizing
failure
properties
• Weight gain
• Question of
• Beneficial
effects on
↑ MIs with
multiple
rosiglitazone
intermediate
CVD markers/
surrogates
• ↓ TGs ,
↑ HDL-C
• ↓ MACE* in
PROactive
(pioglitazone)
(continues)
48565_ST06_251-352.indd 295
5/1/13 9:32 PM
296
Cardiovascular Disease in Type 2 Diabetes
TABLE 51.1 (continued )
Drug Class
GLP-1 Receptor
Agonists
DPP-4 Inhibitors
Insulin
Mechanism
of Action
Activates
GLP-1
receptors,
stimulating
insulin
release
(glucosedependent),
suppressing
glucagon,
slowing
gastric
emptying,
and
enhancing
satiety
Inhibits
enzyme that
deactivates
endogenous
incretins,
GLP-1
and GIP,
augmenting
their activity
Activates
insulin
receptors,
increasing
peripheral
glucose
uptake and
decreasing
hepatic
glucose
production
HbA1c
Efficacy
–1 to 1.5%
CV Considerations
Potential
Benefi ts
Concerns
• Weight loss • Slight ↑ heart
• Beneficial
rate
effects on
several
intermediate
CVD markers/
surrogates
• ? benefits
from
activating
cardiac GLP-1
receptors
–
–0.6 to 0.8% • ? benefits
from inhibiting
degradation
of SDF-1α,
increasing
circulating
endothelial
progenitor
cells
• ? benefits
from
activating
cardiac GLP-1
receptors
Theoretically • Anti• Hypoglycemia
limitless
inflammatory
risk
action
• Weight gain
• Retrospective
• ↓ AMI
mortality in
studies show ↑
DIGAMI
cardiovascular
mortality in
heart failure
*Major adverse cardiovascular events
48565_ST06_251-352.indd 296
5/1/13 9:32 PM
Hypertension Management
297
HYPERTENSION MANAGEMENT
• Major risk factor for both CVD and microvascular complications
• Lowering BP with various antihypertensive regimens has been shown
to be effective in reducing cardiovascular events (UKPDS, HOT)
• No benefit in reduction of cardiovascular events with intense BP
control (systolic blood pressure [SBP] <120 mm Hg) compared to SBP
of 130−140 mm Hg in type 2 DM patients at high CVD risk (ACCORD)
• Goals: ADA and 7th Report of the Joint National Committee (JNC)
on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC-7) – in patients with diabetes
BP <130 mm Hg (JNC), <140* (ADA)
° Systolic
BP <80 mm Hg
° Diastolic
During
pregnancy
110–129/65–79 mm Hg
° Screening and diagnosis
° ■ BP should be measured at every office visit
■ Elevated levels should be confirmed on a separate day
° Treatment
■ Patients with SBP of 130–139 mm Hg or diastolic blood pressure
(DBP) of 80–89 may be given a 3-month period of lifestyle
modification
■ Lifestyle therapy for hypertension includes weight loss, diet rich
in fruits and vegetables, increased physical activity, reduced
sodium intake (<1500 mg/day), increased potassium intake, and
moderation of alcohol consumption
■ Patients with higher BP (SBP ≥140 or DBP ≥90) should be
treated with pharmacological therapy
■ Most patients will need combination therapy with at least
3 agents for optimal control
■ First-line therapy is with an ACEI (or an ARB if an ACEI is not
tolerated)
• During pregnancy, ACEIs and ARBs are contraindicated
• In patients with microalbuminuria or established nephropathy,
either ACEIs or ARBs are considered first-line therapy
■ Second-line agent after ACEI/ARB: usually a thiazide diuretic
■ Third-line agents: Ca + channel blockers and β-blockers
*Lower systolic targets, such as <130 mmHg, may be appropriate for certain individuals, such as younger
patients, if achieved without undue treatment burden.
48565_ST06_251-352.indd 297
5/1/13 9:32 PM
298
Cardiovascular Disease in Type 2 Diabetes
DYSLIPIDEMIA
• Type 2 DM patients have an increased prevalence of lipid abnormalities, contributing to their higher CVD risk
• Major abnormalities include increased triglycerides (TG), low HDL
cholesterol (HDL-C), and more atherogenic LDL particles
• Major reductions in CVD event rates from statin therapy has been
reported in multiple trials focused on or including large numbers of
diabetic patients (CARDS, Heart Protection Study, TNT, PROVE IT)
• Fasting lipid profile should be measured annually
LIPID GUIDELINES
• ADA Standards of Medical Care in Diabetes (2013)
of CVD events with statins correlates well with lowering
° Reduction
of LDL cholesterol (LDL-C), so targeting LDL remains the preferred
strategy. Secondary goals include
■ TG <150 mg/dL
■ HDL >40 mg/dL in men; >50 mg/dL in women
Statin
therapy should be added to lifestyle therapy for DM patients
° with overt
CAD and those without CVD who are > age 40 who have
≥1 CVD risk factors (family history of CVD, hypertension, smoking,
dyslipidemia, or albuminuria)
individual without overt CVD, primary LDL goal is <100 mg/dL
° In
very high-risk individuals (e.g., with overt CVD), lower LDL goal of
° In
<70 mg/dL is recommended
patients do not reach the above goals, then a reduction in LDL of
° If30−40%
from baseline is an acceptable goal
Additional
pharmacological agents (fibrates, niacin, ezetimibe, bile
° acid sequestrants)
may improve lipid parameters but no evidence
that such therapy will reduce event rates or that combinations of
these agents with statins is beneficial
TABLE 51.2 ADA Lipid Management Recommendations
Assessment
LDL-C
• With CVD
• No CVD
TG
HDL-C
Frequency
Goal
Drug Rx Initiation*
Yearly
Yearly
Yearly
Yearly
<70 mg/dL
<100 mg/dL
<150 mg/dL
>40 mg/dL (men)
>50 mg/dL (women)
≥70 mg/dL
≥100 mg/dL
>400 mg/dL
Uncertain
* Irrespective of baseline lipid profile, statin therapy should be added to lifestyle therapy for DM patients
with overt CAD and those without CVD who are > age 40 who have ≥1 CVD risk factor (family history of
CVD, hypertension, smoking, dyslipidemia, or albuminuria).
48565_ST06_251-352.indd 298
5/1/13 9:32 PM
Antiplatelet Therapy
299
TABLE 51.3 Natioxnal Cholesterol Education Program (NCEP)—Adult
Treatment Panel III
LDL-C level to initiate lifestyle change ≥100 mg/dL
LDL-C level to initiate a statin
≥100mg/dL
TG Goal < 150 mg/dL (initiate once LDL-C treated)
(or non–HDL-C goal <130 mg/dL)
TG 150−199 mg/dL
1° aim: LDL-C goal
2° aim: Lifestyle modification (diet,
weight loss)
TG 200−499 mg/dL
1° aim: LDL-C goal
2° aim: Non−HDL-C goal by adding fibrate,
nicotinic acid or increasing dose of
LDL-C drug
TG ≥500 mg/dL
1° aim: Reduce risk of pancreatitis by
starting low-fat diet, weight loss, and
fibrate or nicotinic acid
2° aim: LDL-C goal
Consider adding fibrate or nicotinic acid if
LDL-C and non−HDL-C goals are met
Low HDL-C (men <40 mg/dL,
women <50 mg/dL)
ANTIPLATELET THERAPY
• 2010 Position Statement of the ADA, American Heart Association
(AHA), and American College of Cardiology (ACC). Aspirin therapy
(75−162 mg/day) as primary prevention in patients with types
1 or 2 diabetes at increased CV risk (10-year risk >10%: most men
>50 and women >60 who have at least 1 of the following additional
major risk factors: smoking, hypertension, dyslipidemia, family history
of premature CVD, albuminuria)
• Aspirin not recommended for CVD prevention for adults at low CVD risk
(10-year risk <5%: most men <50 and women <60 who have no other
major CVD risk factor)
• Clinical judgment required for patients in these age groups at intermediate risk with a 10-year risk of 5−10%
• Aspirin therapy recommended as secondary prevention in those with
diabetes and a history of CVD
• For those with an aspirin allergy, clopidogrel 75 mg/day should
be used
• Combination therapy with aspirin and clopidogrel may be used for up
to 1 year following an acute coronary syndrome
• Aspirin for patients <21 is contraindicated due to the associated risk
of Reye’s syndrome
48565_ST06_251-352.indd 299
5/1/13 9:32 PM
300
Cardiovascular Disease in Type 2 Diabetes
CORONARY HEART DISEASE (CHD) SCREENING
• Standards of Medical Care in Diabetes—2013
asymptomatic patients, routine screening for CAD is not recom° In
mended, since it does not improve CVD outcomes as long as risk
factors are treated (DIAD study)
with typical or atypical cardiac symptoms or an abnormal
° Patients
resting ECG should be tested
In
patients
with diabetes, CVD risk factors, including dyslipidemia,
° hypertension,
smoking, family history of premature CAD, and the
presence of albuminuria, should be assessed at least annually
MANAGEMENT OF DM IN ACUTE CORONARY SYNDROME
• Unstable angina (UA)/non-ST elevation myocardial infarction
(NSTEMI): 2011 ACCF/AHA Guidelines
of hyperglycemia is associated with improved outcomes
° Treatment
■ However, it is unclear whether hyperglycemia is a marker
of underlying health status or whether it is a mediator of
complications
Since
is a paucity of well-designed trials of target-driven
° glucosethere
control in UA/NSTEMI patients, goals are in accordance
with the current standard of care as per the ADA guidelines for
critically ill patients
■ Insulin therapy should be initiated for hyperglycemia at a threshold no greater than 180 mg/dL
■ Target glucose level of 140−180 mg/dL
■ Stringent goals, such as 110−140 mg/dL, may be appropriate
for selected patients as long as targets are achieved without
hypoglycemia
■ An IV insulin protocol has shown to demonstrate effi cacy
and safety in achieving glycemic targets without significant
hypoglycemia
■ Consider obtaining an A1c on patients with diabetes if testing
within the last 2−3 months is not available
• UA/ST elevation myocardial infarction (STEMI): 2009 ACC/AHA Focused
Update: STEMI and PCI Guidelines
to the lack of randomized trials with target-driven glucose
° Due
control in STEMI patients, it is reasonable to use an insulin-based
regimen to achieve and maintain blood sugars <180 mg/dL while
avoiding hypoglycemia
48565_ST06_251-352.indd 300
5/1/13 9:32 PM
References
301
REFERENCES
ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med,
2010;362(17):1563−74.
ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood
glucose control and vascular outcomes in patients with type 2 diabetes.
N Engl J Med, 2008;358(24):2560−72.
American Diabetes Association. Standards of medical care in diabetes—2013.
Diabetes Care, 2013;36(Suppl 1):S11−63.
Anderson JL, Adams CD, Antman EM, et al. 2011 ACC/AHA Focused Update
Incorporated Into the ACC/AHA 2007 Guidelines for the Management of
Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction:
a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. Circulation,
2011;123(18):e426−579.
Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure. Hypertension, 2003;42(6):1206−52.
Deedwania P, Kosiborod M, Barrett E, et al. Hyperglycemia and acute
coronary syndrome: a scientific statement from the American Heart
Association Diabetes Committee of the Council on Nutrition, Physical
Activity, and Metabolism. Circulation, 2008;117(12):1610−9.
Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med,
2009;360(2):129−39.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year followup of intensive glucose control in type 2 diabetes. N Engl J Med,
2008;359(15):1577−89.
Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/
AHA Guidelines for the Management of Patients With ST-Elevation
Myocardial Infarction (updating the 2004 Guideline and 2007 Focused
Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary
Intervention (updating the 2005 Guideline and 2007 Focused Update):
a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. Circulation,
2009;120(22):2271−306.
National Heart Lung and Blood Institute. Third Report of the Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III ) . Available at. www.nhlbi.nih.gov/guidelines/
cholesterol.
48565_ST06_251-352.indd 301
5/1/13 9:32 PM
302
Cardiovascular Disease in Type 2 Diabetes
Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of
cardiovascular events in people with diabetes: a position statement of the
American Diabetes Association, a scientific statement of the American
Heart Association, and an expert consensus document of the American
College of Cardiology Foundation. Circulation, 2010;121(24):2694−701.
Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and
the prevention of cardiovascular events: implications of the ACCORD,
ADVANCE, and VA diabetes trials: a position statement of the American
Diabetes Association and a scientific statement of the American College
of Cardiology Foundation and the American Heart Association. Circulation,
2009;119(2):351−7.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive bloodglucose control with metformin on complications in overweight patients
with type 2 diabetes (UKPDS 34). Lancet, 1998;352(9131):854−65.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment
and risk of complications in patients with type 2 diabetes (UKPDS 33).
Lancet, 1998;352(9131):837−53.
48565_ST06_251-352.indd 302
5/1/13 9:32 PM
52 ■ DIABETES IN PREGNANCY
Kenneth Chen, MD and Geetha Gopalakrishnan, MD
CLASSIFICATION
• Preexisting type 1 (7.5%) or type 2 diabetes (5%)
• Gestational Diabetes (GDM) (87.5%)
production of human placental lactogen increases
° Placental
maternal tissue resistance and leads to the development of glucose
intolerance in pregnancy
after the delivery of baby
° Resolves
diabetes will develop in 20−30% of women who experience
° Overt
GDM within 5 years
RISK FACTORS FOR GDM
BMI >30kg/m2
Previous macrosomic baby weighing 9 lbs (4.1 kg) or above
Previous GDM
Family history of type 2 diabetes in first-degree relatives
Ethnic origin with a high prevalence of type 2 diabetes (African American,
Asian American, Hispanic, Native American, or Pacific Islander)
• PCOS
• Presence of glycosuria in routine urinalysis testing
• Previous unexplained perinatal death or severe polyhydramnios
•
•
•
•
•
DIAGNOSIS OF GDM
• No universally accepted criteria as yet but International Association of
Diabetes in Pregnancy Study Groups (IADPSG) has been convened to
resolve this issue
• The following criteria has been proposed by the IADPSG and is currently endorsed by the ADA but not yet by the American College of
Obstetrics & Gynecology (ACOG)
75 g OGTT between 24 and 28 weeks gestation
° 2-hour
has GDM if any one of these are met
° Woman
■ Fasting ≥92 mg/dL (5.1 mmol/l)
■ 1-hour post 75 g OGTT ≥180 mg/dL (10.0 mmol/l)
■ 2-hour post 75 g OGTT ≥153 mg/dL (8.5 mmol/l)
• Diagnostic algorithm as currently endorsed by ACOG
50-g glucose challenge test (nonfasting)
° 1-hour
■ If blood glucose level ≥140 mg/dL or 7.8 mmol/l on 50-g challenge,
then proceed to 3-hour 100-g OGTT
48565_ST06_251-352.indd 303
5/1/13 9:32 PM
304
Diabetes in Pregnancy
°
Woman has GDM if two or more of these are met on 100-g OGTT
■ Fasting ≥95 mg/dL (5.3 mmol/l)
■ 1-hour post 100-g OGTT ≥180 mg/dL (10.0 mmol/l)
■ 2-hour post 100-g OGTT ≥155 mg/dL (8.6 mmol/l)
■ 3-hour post 100-g OGTT ≥140 mg/dL (7.8 mmol/l)
• All pregnant women with risk factors should be screened with an OGTT
and A1C for preexisting diabetes at first prenatal visit using standard
diagnostic criteria for DM (2 fasting PG levels ≥126 mg/dL confirmed on
separate days, any random PG level ≥200 mg/dL or A1C >6.5%). Patients
with normal results should then have screening for GDM at 24–28 weeks
• All women with previous GDM should be offered early self-monitoring
of blood glucose levels or an OGTT at 16−18 weeks followed by a
repeat OGTT at 28 weeks if the results are normal
PRECONCEPTION CARE OF WOMEN WITH PREEXISTING DIABETES
• Women with diabetes who are planning to become pregnant should
have baseline BMI ≤27 kg/m2
° Ideally
folic acid supplements 5 mg/day until 12 weeks gestation to
° Take
reduce incidence of neural tube defects
self-monitoring blood glucose levels on a regular basis
° Be
baseline A1C as close to 6.0% as possible
° Have
Use
contraception until glycemic control is optimized as risk of
° miscarriages
and congenital anomalies are significantly increased
in women whose preconception A1C is >7%
preconception complications screening with regards to reti° Have
nopathy and nephropathy as presence of these can worsen during
the course of pregnancy
screened for concurrent disorders such as thyroid disease or
° Be
celiac disease
Women
on oral hypoglycemic agents should be switched over to
° insulin therapy
preconception
■ There is evidence that both metformin and glyburide cross the
placenta (cord blood studies)
■ There is no data to confirm that either of these agents is harmful
to the fetus in the long run
■ Therefore, some experts consider the use of these agents in patients
who are unwilling or unable to take insulin during pregnancy
and angiotensin-II receptor antagonists should be discontin° ACEIs
ued before conception and switched to alternative antihypertensive
agents such as labetalol, methyldopa, or nifedipine; statins should
also be discontinued before conception
MANAGEMENT OF DIABETES IN PREGNANCY
• Monitor blood glucose levels regularly
levels should be <95 mg/dL
° Fasting
° 1−2-hour postprandial levels should be <120 mg/dL consistently
48565_ST06_251-352.indd 304
5/1/13 9:32 PM
Postnatal Care
305
• A1C can be monitored monthly to achieve target goals of <6.0%
throughout pregnancy
• If target glycemic goals are not met
counseling to address diet and exercise regimen
° Recommend
therapy (Gold standard)
° Insulin
■ Approximately 15% of women with GDM will require insulin
■ Insulin approved for use in pregnancy
• Rapid-acting insulin analogues (aspart and lispro)
• Regular insulin
• NPH insulin
• Insulin detemir
• Insufficient evidence supporting the use of glargine in pregnancy but increasing data suggests that it does not cause any
issues for the fetus
■ Metformin or glyburide can be considered in GDM and type 2 DM
if patient unable or unwilling to take insulin; there is insufficient
data to support the use of any other oral agents in pregnancy
• Suboptimally controlled blood glucose level will lead to an increased
risk of a large-for-gestational-age baby (increasing the risk of shoulder dystocia, induction of labor, and Cesarean section), polyhydramnios, preeclampsia, neonatal hypoglycemia, perinatal complications
such as respiratory tract infections or neonatal jaundice, and an
increased risk of the baby developing obesity and/or diabetes in later
life (fetal programming effect, Barker’s hypothesis)
SPECIAL PRENATAL CONSIDERATIONS FOR DIABETIC PATIENTS
• Routine high resolution level 2 ultrasound at 18−20 weeks looking at
4-chamber view of fetal heart and outflow tracts
• Regular ultrasounds every 4 weeks from 28 to 36 weeks to assess fetal
growth and amniotic fluid volumes
• Women on insulin therapy or whose blood glucose levels are not well
controlled on dietary therapy may require twice weekly nonstress tests
from 32 weeks to assess fetal well-being
• Delivery is usually recommended at 39 weeks; provided that baby is
normal size, Cesarean section does not confer any advantages over
vaginal delivery and hence the latter is preferred mode of delivery
POSTNATAL CARE
• Women with GDM can discontinue all hypoglycemic treatments
immediately after birth but keep monitoring their blood glucose levels
for 48 hours on a normal diet
who required insulin or oral medications during pregnancy
° Women
should be offered an OGTT 6−12 weeks postpartum to ensure that
their glucose tolerance has returned to normal. If 6−12 week OGTT
is normal, they should be offered OGTT every 1−3 years thereafter.
48565_ST06_251-352.indd 305
5/1/13 9:32 PM
306
Diabetes in Pregnancy
°
Women who did not require insulin or oral medications during
pregnancy should be offered OGTT at 1-year postpartum and every
1–3 years thereafter
OGTT results are abnormal postpartum, prediabetes and diabetes
° Ifshould
be treated appropriately with lifestyle intervention and
medical management
• Women with preexisting diabetes (on insulin therapy) should have
their insulin doses reduced back to prepregnancy levels; some oral
agents can be restarted postpartum in type 2 diabetes based on the
breastfeeding status
• Breastfeeding
utilizes an additional 500 Kcal per day; women who
° Breastfeeding
breastfeed will usually require lower-than-baseline insulin dose
Metformin
(preferred)
glyburide are generally safe with
° breastfeeding and canand
be considered for the management of type 2
DM postpartum.
• Women with preexisting DM or GDM can use any form of contraception
postpartum
REFERENCES
American Diabetes Association. Detection and diagnosis of gestational
diabetes mellitus (GDM). Diabetes Care, 2012;35(Suppl 1):S15–S16.
Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med,
2005;352(24):2477–86.
HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, et al.
Hyperglycemia and adverse pregnancy outcomes. N Engl J Med,
2008;358(19):1991–2002.
International Association of Diabetes and Pregnancy Study Groups
Consensus Panel, Metzger BE, Gabbe SG, et al. International association
of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care,
2010;33(3):676–82.
Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med, 2009;361(14):1339–48.
Löbner K, Knopff A, Baumgarten A, et al. Predictors of postpartum diabetes
in women with gestational diabetes mellitus. Diabetes, 2006;55(3):792–7.
Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators.
Metformin versus insulin for the treatment of gestational diabetes. N Engl
J Med, 2008;358(19):2003–15.
48565_ST06_251-352.indd 306
5/1/13 9:32 PM
53 ■ GLYCEMIC ISSUES IN HOSPITALIZED
PATIENTS
Steven Kaufman, MD and Marc Laufgraben, MD, MBA
FOR HOSPITALIZED PATIENTS OUTSIDE THE ICU
• Glucose goals
or premeal glucose less than 100–140 mg/dL
° Fasting
glucose less than 180 mg/dL
° Random
glucose goals should be individualized; higher goals are
° Blood
reasonable for patients with limited life expectancy or who have
recurrent hypoglycemia
• POCT glucose is recommended for patients under the following
circumstances: history of diabetes, PG >140 mg/dL on lab testing,
risk factors for diabetes, tube feeds or parenteral nutrition, or starting
glucocorticoids
can be reduced or discontinued if patient not started on
° Testing
insulin regimen and glucoses remain <140 mg/dL after 48 hours
• Frequency of POCT
eating: test premeal and at bedtime
° IfIf NPO
or on continuous nutrition: test q 4−6 h
°
• Check an A1C (if not performed in past 3 months) for patients with
diabetes or glucose >140 mg/dL
patients with prior history of diabetes, helps to determine
° For
efficacy of outpatient diabetes regimen
hyperglycemic patients without a history of diabetes, an
° For
elevated A1C is consistent with undiagnosed diabetes preceding
the hospitalization
A1C unreliable in patients with anemia, hemogolobin° Hemoglobin
opathies, or who have received transfusions
• Discontinue oral antidiabetic agents and noninsulin injectable
medications in most patient
is the patient with good outpatient glycemic control,
° Exception
glucose levels <140 mg/dL during hospitalization, no contraindication to the use of their outpatient medications, ability to tolerate
orals, and not expected to be NPO
Switch to insulin therapy if clinical condition changes
°
• Start insulin for glucose levels above goal
48565_ST06_251-352.indd 307
5/1/13 9:32 PM
308
Glycemic Issues in Hospitalized Patients
TABLE 53.1 Currently Available Preparations of Insulin
INJECTABLE INSULINS*
Onset (h)
<0.2
Rapid/short- Insulin aspart (NovoLog)
acting
Insulin glulisine (Apidra)
0.30–0.4
0.25–0.5
Insulin lispro (Humalog)
Regular (Novolin R, Humulin R)
0.5–1
2–4
Intermediate/ NPH (Novolin N, Humulin N)
long-acting Insulin detemir (Levemir)
n.a.
Mixtures
Insulin glargine (Lantus)
Insulin aspart protamine
susp/aspart (NovoLog
Mix 70/30)
Insulin lispro protamine
susp/insulin lispro
(HumaLog Mix 75/25,
HumaLog Mix 50/50)
NPH/Reg (Humulin 70/30,
Novolin 70/30)
2–4
0.25
Peak (h) Duration (h)
1–3
3–5
1
4–5
0.5–2.5
≤5
2–3
3–6
4–10
10–16
up to 23†
flat action
profile
peakless
24
up to 24
1–4
(biphasic)
<0.25
1–3
(biphasic)
10–20
0.5–1
2–10
(biphasic)
10–20
*These are general guidelines, as onset, peak, and duration of activity are affected by the site of injection,
physical activity, body temperature, and blood supply.
†Dose dependent duration of action, range from 6 to 23 h.
n.a., not available.
• Protocol for initiating insulin if the patient has glucose levels above
goal or a history of diabetes
resuming home basal-bolus regimen if the patient reports
° Consider
good glucose control
insulin regimen
° Weight-based
■ Calculate TDD of insulin
• Standard: 0.4 units/kg body weight (BMI 25−30)
• Insulin-sensitive (BMI <25, decreased GFR [CrCl <30]),
hepatic insufficiency): 0.3 units/kg body weight
• Insulin-resistant (BMI >30): 0.5 units/kg body weight
■ Divide insulin into basal and nutritional components
• ½ TDD as basal insulin: glargine daily, detemir divided BID, or
NPH divided BID
• ½ TDD divided into 3 equal mealtime doses (regular, lispro,
aspart, or glulisine)
■ Use correction-dose insulin (“sliding scale”) as supplement to
basal-bolus regimen
• Do not use correction-dose insulin as the sole insulin strategy
in hospitalized patients
48565_ST06_251-352.indd 308
5/1/13 9:32 PM
For Patients in ICU S
309
• Correctional insulin doses should be proportional to the basal and
mealtime insulin doses (i.e., an insulin-resistant patient requires
higher supplemental doses than a patient who is insulin sensitive)
■ Glycemic data should be reviewed daily with insulin dose
adjusted for occurrence of hypoglycemia or hyperglycemia, or use
of correctional-dose insulin
• Special considerations: parenteral nutrition, enteral nutrition, and
glucocorticoids
and parenteral feedings
° Enteral
■ Enteral and parenteral feeding preparations are associated with
an increase in glucose
■ SQ regimens: glargine daily, detemir every 12−24 hours, or NPH
every 8−12 hours
■ The initial dose of insulin is calculated at ½ the TDD
• Standard: 0.2 units/kg body weight (BMI 25−30)
• Insulin-sensitive (BMI <25, decreased GFR [CrCl < 30]),
hepatic insufficiency): 0.15 units/kg body weight
• Insulin-resistant (BMI >30): 0.25 units/kg body weight
■ The shorter half-life of NPH allows for more frequent titration of
the insulin doses in response to changes in nutrition
■ Regular insulin may be added directly to the parenteral nutrition
bag at an initial dose of 1 unit for each 15 grams of dextrose
■ When nutrition is held or discontinued, reduce the insulin dose
and/or provide dextrose-containing IV fluid
° Glucocorticoids
■ Glucocorticoids cause hyperglycemia by increasing insulin
resistance and promoting gluconeogenesis
■ SQ insulin therapy may be started for glucocorticoid-induced hyperglycemia with an initial TDD of 0.3−0.5 units per kg body weight
■ IV insulin infusion is appropriate for moderate−severe
hyperglycemia
■ Insulin doses will need to be titrated for changes in steroid dose
• Insulin doses should be lowered to decrease the risk of hypoglycemia as the dose of the glucocorticoid decreases
FOR PATIENTS IN ICU S
• Background and goals
is associated with increased morbidity and mortality
° Hyperglycemia
in critically ill patients
despite initial enthusiasm, intensive insulin therapy
° However,
aimed at normalizing blood glucose in ICU patients has not been
demonstrated to improve outcomes, and hypoglycemia from insulin
therapy is associated with increased mortality
recommendations are to start an IV insulin infusion for
° Current
glucose >180 mg/dL with a goal of 140−180 mg/dL
48565_ST06_251-352.indd 309
5/1/13 9:32 PM
310
Glycemic Issues in Hospitalized Patients
• IV insulin protocols
standardized insulin protocol should be employed in order to
° Amaintain
goal glucose levels and reduce hypoglycemia
The
insulin protocol should allow for titration of IV insulin as
° glucose
levels change
published protocols are available
° Multiple
■ The protocol should be adapted to fi t the needs of the local
institution
• Transitioning from IV insulin to SQ insulin is appropriate as critical
illness resolves
° See section Transition from IV Insulin Infusion in Chapter 46
REFERENCES
Donaldson S, Villanuueva G, Rondinelli L, Baldwin D. Rush University guidelines and protocols for the management of hyperglycemia in hospitalized
patients: elimination of the sliding scale and improvement of glycemic
control throughout the hospital. Diabetes Educ, 2006;32(6):954−62.
Jakoby MG 4th, Nannapaneni N. An Insulin Protocol for Management of
Hyperglycemia in Patients Receiving Parenteral Nutrition Is Superior to Ad
Hoc Management. J Parenter Enteral Nutr. 2011 Aug 8. PMID: 21825091.
Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association
of Clinical Endocrinologists and American Diabetes Association
consensus statement on inpatient glycemic control. Endocr Pract,
2009;15(4):353−69.
NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive
versus conventional glucose control in critically ill patients. N Engl J Med,
2009;360(13):1283−97.
Umpierrez GE, Hellman R, Korytkowski MT, et al. Management of
hyperglycemia in hospitalized patients in non-critical care setting: an
endocrine society clinical practice guideline. J Clin Endocrinol Metab,
2012;97(1):16−38.
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in
critically ill patients.
48565_ST06_251-352.indd 310
5/1/13 9:32 PM
54 ■ PREDIABETES AND DIABETES
PREVENTION
Jennifer M. Argumedo, MD
PATHOPHYSIOLOGY
• Increased insulin resistance
Fasting Glucose (IFG): higher hepatic insulin resistance
° Impaired
Impaired Glucose Tolerance (IGT): higher muscle insulin resistance
°
• Decreased insulin secretion
to β-cell failure
° Secondary
and IGT both with impaired first-phase insulin secretion
° IFG
° IGT has impaired second-phase insulin secretion
• Environmental factors that aggravate genetic components
gain
° Weight
inactivity
° Physical
° Aging
CLINICAL PRESENTATION
• Those with prediabetes are typically asymptomatic
• Screening for prediabetes is based on screening criteria for diabetes in
asymptomatic patients
TABLE 54.1 Diagnostic Evaluation
Test
IFG
IGT*
HbA1c
Results
100−125 mg/dL (5.6−6.9 mmol/L)
140−199 mg/dL (7.8−11.0 mmol/L)
5.7−6.4% (6−6.4% considered high-risk for diabetes)
*2-h value in the 75-g OGTT.
ASSOCIATED CONDITIONS
• Obesity
• CVD
strong predictor of CVD
° IGT:
incidence of both microvascular (microalbuminuria,
° Higher
retinopathy, and neuropathy) and macrovascular complications as
compared to those with normoglycemia
• Dyslipidemia with high TG levels ± low HDL-C
• Hypertension
48565_ST06_251-352.indd 311
5/1/13 9:32 PM
312
Prediabetes and Diabetes Prevention
RECOMMENDATIONS FOR DELAY OF DM TYPE 2
• Lifestyle modifications with goal of 7% weight loss and moderate
physical activity of at least 150 minutes per week
• Medical nutrition therapy (MNT)
caloric intake
° Reduced
dietary fat intake
° Reduced
to achieved US Department of Agriculture’s (USDA) recommen° Aim
dation for dietary fiber (14 g fiber/1000 kcal) and foods containing
whole grains
Limited intake of sugar-sweetened beverages
°
• Follow-up counseling
• Consider initiation of metformin
does not advocate use of other drug therapies such as
° ADA
thiazolidinediones, sulfonylureas, α-glucosidase inhibitors, GLP-1
analogues at this time
• At least annual monitoring for the development of diabetes
TABLE 54.2 High-Risk Patients Who May
Benefi t from Metformin
BMI >35 kg/m2
Age <60 years old
Women with history of GDM
Those with more severe or progressive hyperglycemia
MANAGEMENT OF CVD IN PREDIABETES
• High risk of adverse cardiac events in prediabetic state similar to that
seen in type 2 diabetes
• Try to achieve same lipid-lowering goals as in diabetic patients
lowering to <100 mg/dL with statins
° LDL-C
fibrates if low HDL-C or high TG
° Consider
° At least annual monitoring of fasting lipid concentrations
• Monitor for hypertension at least annually
BP goals as in diabetic patients, ≤130/80
° Same
agents include
° First-line
■ ACEIs
■ ARBs
thiazides and β blockers: may increase risk of developing
° Avoid
diabetes in prediabetics
• At least annual monitoring for microalbuminuria
TREATMENT GOALS WITH PHARMACOLOGIC THERAPY
• Normalize glucose levels
• Prevent progression to diabetes
• Prevent microvascular and macrovascular complications
48565_ST06_251-352.indd 312
5/1/13 9:32 PM
References
313
REFERENCES
American Diabetes Association. Standards of medical care in diabetes—2012.
Diabetes Care, 2012;35(Suppl 1):S11−63.
DeFronzo RA, Abdul-Ghani MA. Preservation of β-cell function: the key to
diabetes prevention. J Clin Endocrinol Metab, 2011;96(8):2354−66.
Grundy SM. Prediabetes, metabolic syndrome, and cardiovascular risk. J Am
Coll Cardiol 2012; 59:635–43.
Moutzouri E, Tsimihodimos V, Rizos E, Elisaf M. Prediabetes: to treat or not to
treat? Eur J Pharmacol, 2011;672(1-3):9−19.
Rhee SY, Woo JT. The prediabetic period: review of clinical aspects. Diabetes
Metab J, 2011;35(2):107−16.
48565_ST06_251-352.indd 313
5/1/13 9:32 PM
48565_ST06_251-352.indd 314
5/1/13 9:32 PM
55 ■ DIABETIC FOOT DISEASE
William Jeffcoate, MRCP
DIABETIC FOOT ULCERATION AND INFECTION
• Background
ulcer is a break in the epidermis that does not promptly heal
° An
2.5 and 5.0% of the population with diabetes have an
° Between
ulcer at any one time
Incidence
~20 per 1000 person-years
° It is a major,
and sometimes neglected, source of suffering and cost
°
• Pathophysiology: predisposing factors
° PAD
■ Leading to skin and SQ tissue that is thinned and dysmorphic
■ PAD is both macrovascular (atheromatous occlusion of large and
medium arteries) and microvascular (both structural [basement
membrane thickening] and functional [abnormal vasomotor
regulation caused by neuropathy])
Distal
symmetrical neuropathy
° ■ Sensory:
making the person unaware of incipient skin damage
(e.g., from ill-fitting shoes, unnoticed sharp objects, burns from
walking barefoot in very hot weather)
■ Motor: altered balance of long fl exor and extensor muscles,
combined with small muscle atrophy and shortening of connective tissue caused by glycation leads to clawing of the
foot, dislocation of metatarsophalangeal joints and abnormal
distribution of plantar forces during walking; build of callus at
pressure points increases the forces and can lead to ulceration
through pressure necrosis
■ Vasomotor: abnormal regulation of the microvasculature
■ Autonomic: loss of skin integrity through reduced sweating
complications or comorbidities of diabetes including impaired
° Other
vision and immobilization through ill health
■ Pressure sores on the heel are a common complication of hospital
admission; the median time to healing of a heel ulcer is 200 days
• Pathophysiology: precipitating factors
° Trauma/pressure
pedis: causing breaks in the skin that can lead to secondary
° Tinea
bacterial infection
cracks in the heel that can complicate distal
° Spontaneous
neuropathy
• Pathophysiology: failure to heal
(see next section)
° Infection
° PAD: leading to delayed healing
48565_ST06_251-352.indd 315
5/1/13 9:32 PM
316
Diabetic Foot Disease
°
Continued trauma to the wound bed from
■ Failure to provide adequate off-loading (protection)
■ Inability of the patient to reduce weight-bearing
■ Distal sensory neuropathy: reduced sensation makes the patient
less aware of the need to reduce weight-bearing
■ Acquisition of the biology of the chronic wound, which is an illdefined change resulting in the process of healing being arrested
in a phase of chronic inflammation
• Pathophysiology: infection
is a complication of foot ulceration and not a cause
° Infection
it occurs, infection can seriously worsen the condition of the
° Once
wound, as well as worsen the prognosis for healing
broad categories of infection
° Two
■ Soft tissue infection
■ Osteomyelitis
of infection is clinical
° Diagnosis
■ Microbiologic studies should only be used to determine the
pathogen
• Management of diabetic foot ulcers
Provision
adequate off-loading to prevent the ulcer site being
° exposed toofcontinuing
trauma
of the wound edge and removal of necrotic material
° Debridement
of the wound with simple dressing products
° Dressing
■ There is no robust scientifi c evidence to justify the use of any
dressing product, application, or other advanced wound care
procedure on a routine basis (even though these are frequently
selected by experts)
■ Negative pressure therapy may improve healing of postoperative
wounds
of appropriate antibiotic therapy or other modalities to elimi° Use
nate infection (see section on soft tissue infection)
Consider
revascularization for significant PAD
° Organization
of frequent review of the status of the wound
°
• Soft tissue infection (STI)
newly occurring STI, the infecting organisms are usually aerobic
° In
Gram-positive cocci and empiric treatment can be based on narrow
spectrum antibiotics such as flucloxacillin (dicloxacillin in the US)
or erythromycin, but must be governed by local prescribing policy
the patient has already been exposed to antibiotic treatment
° When
and/or the wound is deeper or necrotic, the responsible pathogens
may be Gram-positive, Gram-negative, aerobic or anaerobic, and
therefore empiric antibiotic choice must broad spectrum, such as
ampicillin/sulbactam or clindamycin plus quinolone, but must be
guided by local prescribing policy
Treatment should ideally be based on microbiologic examination of
° specimen
of deep soft tissue
■ Swabs (either superfi cial or deep) are not useful
48565_ST06_251-352.indd 316
5/1/13 9:32 PM
Charcot Neuroosteoarthropathy (CN; The Charcot Foot)
317
therapy can be administered orally for mild infections,
° Antibiotic
but IV treatment is preferred for severe as well as for some moderate infections
■ Initial therapy should not be continued for more than 1−2 weeks
without expert review
• Osteomyelitis
frequently complicates neuropathic ulcers (pedal
° Osteomyelitis
pulses palpable) on the forefoot and can complicate ulcers of the
heel
rests on clinical features reinforced by imaging
° Diagnosis
clinical features are of local inflammation, usually of the
° The
forefoot (typically the “sausage-shaped toe”)
■ Systemic symptoms and signs are uncommon
X-rays may be normal for several weeks following the onset
° Plain
of the disease
If
plain
are normal, the diagnosis may established by MRI
° The mostX-rays
infecting organism is S. aureus but other patho° gens may common
be involved
experts have emphasized the need for surgical exci° Traditionally,
sion of infected bone, but in recent years, an increasing percentage
attempt eradication with prolonged (two months or more) courses
of systemic antibiotics either alone or in combination with limited
surgery
■ Ideally, prolonged antibiotic therapy should be targeted at
organisms isolated from bone biopsy, as soft tissue sampling is
of limited value
• Long-term care
When
the wound is healed, there is a 40% chance of recurrence in
° the succeeding
12 months and the patient should ideally remain
under expert care
risk factor reduction is crucial because of reduced
° Cardiovascular
life expectancy in this group.
The
overall
survival
° only ~50% at 5 yearsof people presenting with a new foot ulcer is
patient should be instructed to seek care immediately if a new
° The
ulcer occurs
■ The rate of healing correlates with ulcer area and duration at the
time of first expert assessment
CHARCOT NEUROOSTEOARTHROPATHY (CN; THE CHARCOT FOOT)
• Background
is frequently delayed in routine practice, often for weeks
° Diagnosis
or months, with the inflammation being variously attributed to
infection, sprain, gout, or thrombosis
48565_ST06_251-352.indd 317
5/1/13 9:32 PM
318
Diabetic Foot Disease
°
People with diabetes complicated by neuropathy should be
instructed to seek medical evaluation to rule out CN should they
develop inflammation of the foot that is not explained by obvious
trauma
relies on the demonstration of characteristic fracture and
° Diagnosis
dislocation of the bones of the foot; or if the skeletal architecture
appears normal on X-ray by demonstrating edema of bone marrow
on MRI and/or microfractures of pedal bones on CT
CN is suspected, the patient should be referred for urgent
° When
expert assessment and urged not to bear weight in order to limit
damage to the foot
• Pathophysiology
is a complication of neuropathy
° CN
■ Diabetes is the most common cause, but essentially any cause of
neuropathy (e.g., alcohol abuse, leprosy, etc.) can cause CN
by the occurrence of inflammation in foot, associated with
° Manifest
fracture and dislocation of the bones and joints of the foot, and
especially of the mid- and hind-foot
that a person with neuropathy is predisposed to exag° Hypothesized
gerated release of proinflammatory cytokines (IL-1β, TNF-α) and
consequent activation osteoclasts through the RANKL-NFkappaB
pathway
■ Neuropathy is associated with decreased release of neuropeptides (e.g., calcitonin gene-related peptide [CGRP]) that oppose
the RANKL-NFkappaB activation
■ When the affected person continues to bear weight on the
inflamed foot (because of reduced protective sensation), the process of inflammation and resultant bone breakdown continues,
leading to the skeletal damage that characterizes the condition
■ The condition can also be triggered by other causes of inflammation such as infection, ulceration, or surgery
• Diagnosis
The
diagnosis should be suspected and actively pursued in any
° person
with neuropathy who presents with foot or ankle inflammation with or without obvious associated deformity, which occurs
spontaneously or following minimal trauma
• Management
role of surgery in the acute phase is not established
° The
experts manage CN simply by immobilizing the foot in a
° Most
nonremovable, below-knee fiberglass cast
■ The cast needs to be changed after a few days (because there
will be a rapid resolution of local inflammation), and then
replaced every 1−2 weeks for a period of months
■ The duration of casting may be up to 12 months, sometimes
longer
■ Patients often suffer marked frustration and depression because
of the limitation of their activity
48565_ST06_251-352.indd 318
5/1/13 9:32 PM
References
°
°
°
°
°
319
Secondary ulceration complicates the deformity in approximately
25% and can itself be complicated by osteomyelitis
Gross deformity or intractable infection may lead to below-knee
amputation
Although some experts have recommended the use of bisphosphonates, available data suggest that bisphosphonates may actually
delay resolution
The condition eventually settles although it may occur on contralateral side in approximately 20% of patients
■ Long-term ipsilateral recurrence is very uncommon
Late corrective surgery may be used to minimise the deformity
REFERENCES
Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society
of America clinical practice guideline for the diagnosis and treatment of
diabetic foot infections. Clin Infect Dis, 2012;54:e132–73.
Rogers LC, Frykberg RG, Armstrong DG, et al. The Charcot foot in diabetes.
Diabetes Care, 2011;34(9):2123−9.
48565_ST06_251-352.indd 319
5/1/13 9:32 PM
48565_ST06_251-352.indd 320
5/1/13 9:32 PM
56 ■ HYPOGLYCEMIA DISORDERS
Kevin Donohue, DO and Serge Jabbour, MD
DEFINED BY WHIPPLE’S TRIAD
• Symptoms/signs consistent with hypoglycemia
• PG concentration <55 mg/dL (not a fingerstick glucose)
• Relief of symptoms after the PG is raised
SYMPTOMS
• Neurogenic symptoms are the result of adrenergic response, i.e.,
release of NE, Epi, and acetylcholine, in response to hypoglycemia
• Neuroglycopenic symptoms are the result of CNS glucose deprivation
TABLE 56.1 Neurogenic Versus Neuroglycopenic Symptoms
Neurogenic Symptoms
Sweating
Tremulousness
Palpitations
Anxiety and confusion
Hunger
Neuroglycopenic Symptoms
Confusion, irritability
Psychotic behavior
Motor incoordination, paresis
Diplopia
Seizure, coma
CLASSIFICATION OF HYPOGLYCEMIAS IN ADULTS
• Fasting hypoglycemia
insulin, insulin secretagogues (sulfonylureas, glinides),
° Drugs:
ethanol (interferes with gluconeogenesis), quinine, gatifloxacin,
pentamidine (direct injury to pancreatic β cells with subsequent
insulin release)
illnesses: sepsis (including malaria); hepatic, renal, or
° Critical
cardiac failure; inanition (all decrease glycogen stores and impair
gluconeogenesis)
deficiency: cortisol, glucagon, and Epi (associated with
° Hormone
poor glycogenolysis and gluconeogenesis)
Nonislet
cell
bulky mesenchymal or epithelial tumors pro° ducing large tumors:
amounts of IGF-2 with insulin-like activity (alternative
hypothesis is that the tumors utilize large amounts of glucose)
Endogenous hyperinsulinism, insulinoma, β-cell hypertrophy/
° hyperplasia,
autoantibody to insulin or insulin receptor (excess
insulin production)
48565_ST06_251-352.indd 321
5/1/13 9:32 PM
322
Hypoglycemia Disorders
• Reactive (postprandial) hypoglycemia: delayed insulin release after a
meal has been absorbed, occurs 4−6 hours after eating
bypass (PGB): nesidioblastosis
° Postgastric
pancreatogenous hypoglycemia syndrome (NIPHS):
° Noninsulinoma
β-cell hypertrophy
• Factitious hypoglycemia: surreptitious or even malicious administration of insulin or an insulin secretagogue
• Artifactual hypoglycemia: incorrect collection of blood samples or
interfering substances in the blood causing glycolysis in vitro (i.e.,
leukemia, chronic hemolytic anemia, etc.)
DIAGNOSIS
• Document Whipple’s triad (draw labs before administering glucose)
• Labs: glucose, insulin, C-peptide, proinsulin, insulin secretagogue
screen, β hydroxybutyrate (and if indicated: ethanol, insulin antibodies, and IGF-2)
• If unable to draw labs during a spontaneous episode, perform 72-hour
fast
serum glucose, insulin, and β hydroxybutyrate every 6 hours
° Check
until blood glucose <60
frequency of lab draws to every 2 hours until blood
° Increase
glucose <45, then check glucose, insulin, proinsulin, C-peptide,
and β hydroxybutyrate
IV glucagon injection given after labs drawn to relieve symp° 1-mg
toms and correct hypoglycemia (check PG 10, 20, and 30 minutes
after glucagon injection)
TABLE 56.2. Results
C-Peptide Insulin
Insulinoma. NIPHS,
PGBH
Sulfonylurea
Exogenous insulin
Nonislet cell tumors
Insulin autoimmune
48565_ST06_251-352.indd 322
Proinsulin SU Screen
↑
↑
↑
–
↑
↓
↓
↑
↑
↓
↑
↓
↓
+
–
–
↑
↑
↑
–
Misc.
↑ IGF-2
+ insulin
antibody
5/1/13 9:32 PM
Treatment 323
IMAGING (LOCALIZING STUDIES)
• CT, MRI, and transabdominal ultrasonography can detect most
insulinomas
imaging does not rule out insulinoma (proceed with arte° Negative
rial calcium stimulation)
• Arterial calcium stimulation
gluconate is selectively injected into the gastroduodenal,
° Calcium
splenic, and superior mesenteric arteries with concurrent sampling
of insulin in the hepatic vein
■ Can distinguish between a focal abnormality (insulinoma) and
a diffuse process (Islet cell hypertrophy/nesidioblastosis) when
imaging is negative
■ Also used to localize nonimaged but focal lesion and aid surgical
resection
TREATMENT
• Acute episode
patient awake and able to take oral meds: glucose tabs (~15 g) or
° If4-ounce
juice or soda
patient not able to take oral meds but has IV access: ½ amp
° IfD50
IV (1/2 amp = 12.5 g)
patient cannot take oral meds and no IV access: glucagon 1 mg
° IfSQ/IM
° Repeat glucose level in 15 minutes, repeat treatment if needed
• Carefully review patient’s medications, and remove any possible
offending agents (e.g., insulin, insulin secretagogues, fluoroquinolones)
• Consider and correct any underlying critical illness (e.g., AI, sepsis,
and liver failure)
• Preferred treatment for insulinoma is surgical resection based on
imaging and/or arterial calcium stimulation
• Preferred treatment for NIPHS is medical management with an
α-glucosidase inhibitor, diazoxide, calcium channel blocker, β blocker
or octreotide; or partial pancreatectomy guided by imaging and arterial
calcium stimulation if medical therapy fails to relieve symptoms
• If patient has insulin antibodies, consider anti-inflammatory agents,
steroids, and referral to an endocrinologist
48565_ST06_251-352.indd 323
5/1/13 9:32 PM
324
Hypoglycemia Disorders
REFERENCES
Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of
adult hypoglycemic disorders: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab, 2009;94(3):709−28.
Guettier JM, Gorden P. Hypoglycemia. Endocrinol Metab Clin North Am,
2006;35(4):753−6.
Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: risk
factors and outcomes. Crit Care Med, 2007;35(10):2262−7.
Murad MH, Coto-Yglesias F, Wang AT, et al. Clinical review: drug-induced
hypoglycemia: a systematic review. J Clin Endocrinol Metab,
2009;94(3):741−5.
48565_ST06_251-352.indd 324
5/1/13 9:32 PM
57 ■ LIPID ESSENTIALS
Charlotte Boney, MD
LIPID PROFILE REFLECTS THE LIPOPROTEINS CARRYING
CHOLESTEROL AND TRIGLYCERIDE
• Total cholesterol (TC) largely reflects LDL and HDL; fasting has no
effect on TC and HDL levels
• LDL can be measured directly or estimated by the Friedewald equation
(LDL = TC – HDL − TG/5), which is accurate only when TG are
<400 mg/dL
• HDL is measured directly; if elevated, it is a protective factor in CVD
and can be a significant proportion of TC
• TG measured in the fasting state largely reflects very low-density
lipoproteins (VLDL); in the nonfasting state, TG reflects chylomicrons
(CM), which are synthesized from dietary fat; TG carried in CM can take
8−10 hours to return to baseline after eating
• Plasma lipoproteins contain cholesterol esters (CE), some free
cholesterol (FC), and TG in precise proportions as well as specific
apolipoproteins that confer structure and function (enzyme cofactor,
receptor binding). See Table 57-1.
• Lipoprotein (a) is not measured in a lipid profile, but is a modified LDL
particle that is an independent risk factor for CVD. Its unique lipoprotein Apo(a) has substantial homology to plasminogen
TABLE 57.1 Lipoprotein Structure and Function
Lipoprotein
Chylomicron
(CM)
CM Remnant
VLDL
% Cholesterol % TG
5
85
20
60
20
55
Major Protein Source
ApoB48
Diet
(intestine)
ApoB48, ApoE Plasma
(derived
from CM
hydrolysis)
ApoB100,
Liver
ApoE
Function
Deliver FFA
to tissues
Deliver FFA
to liver
Deliver FFA
to tissue;
pick up CE
from HDL
(continues)
48565_ST06_251-352.indd 325
5/1/13 9:32 PM
326
Lipid Essentials
TABLE 57.1 (continued )
Lipoprotein
Intermediate
– density
lipoprotein
(IDL)
LDL
HDL
Lipoprotein (a)
% Cholesterol % TG
Major Protein Source
35−40
20−25 ApoB100,
Plasma
ApoE
(derived
from VLDL
hydrolysis)
60
5
ApoB100
Plasma
(derived
from IDL
hydrolysis)
20
5
ApoAI, ApoCI, Liver,
ApoCII
intestine
60
5
ApoB100,
Apo(a)
Function
Deliver FFA
to tissue;
pick up CE
to form LDL
Deliver CE to
tissues
Return CE
to liver;
transfer CE
to VLDL/
IDL to form
LDL
Liver: Apo(a) Promotes
linked to
thrombosis
LDL at cell
surface
PLASMA LIPOPROTEINS ARE DETERMINED
BY 3 INTERRELATED PATHWAYS
• Transport of dietary or exogenous fat (Figure 57.1)
are synthesized in the intestine from dietary fat and hydrolyzed
° CM
in plasma by lipoprotein lipase (LPL), releasing FFA for uptake by
peripheral tissues and adipose tissue
remnants are removed quickly by the binding of apolipoprotein
° CM
E to the remnant receptor, delivering TG to the liver for repackaging
as VLDL
in the pathway can occur due to mutations in LPL or
° Defects
its cofactor apolipoprotein C-II. These defects result in lipemic
plasma and increased risk of pancreatitis but not increased CVD.
Defects in the lipoprotein ApoE can produce excess remnants,
which lower LDL clearance and elevate TG, increasing risk of
pancreatitis and CVD
48565_ST06_251-352.indd 326
5/1/13 9:32 PM
Plasma Lipoproteins Are Determined by 3 Interrelated Pathways
327
Dietary Fat and
Cholesterol
Intestine
Liver
Chylomicrons
CM–Remnant
LPL
FFA
Peripheral
Tissue
Adipose
Tissue
FIGURE 57.1 Exogenous (Dietary) Pathway
• Transport of hepatic or endogenous fat (Figure 57.2)
is synthesized and secreted from the liver and contains
° VLDL
mostly TG, some CE, and the lipoprotein ApoB100. VLDL undergoes
hydrolysis by LPL and picks up CE from HDL by cholesterol ester
transport protein (CETP) to become intermediate density lipoprotein
(IDL), which is further hydrolyzed by LPL and hepatic lipase (HL)
with transfer of more CE from HDL by CETP to become LDL
is removed from the blood by binding of ApoB100 to the LDL
° LDL
receptor (LDLR) on tissues, including liver. Oxidized LDL particles
are taken up by scavenger receptors on macrophages, promoting
foam cell formation, inflammation, and CVD. Small, dense LDL is
more prone to the scavenger pathway and is taken up more slowly
by the LDLR
is synthesized and secreted from the liver and contains
° VLDL
mostly TG, some CE, and the lipoprotein ApoB100. VLDL undergoes
hydrolysis by LPL and picks up CE from HDL by CETP to become IDL,
which is further hydrolyzed by LPL and HL with transfer of more CE
from HDL by CETP to become LDL
48565_ST06_251-352.indd 327
5/1/13 9:32 PM
328
Lipid Essentials
°
°
°
LDL is removed from the blood by binding of ApoB100 to the LDLR
on tissues, including liver. Oxidized LDL particles are taken up by
scavenger receptors on macrophages, promoting foam cell formation, inflammation, and CVD. Small, dense LDL is more prone to the
scavenger pathway and is taken up more slowly by the LDLR
The hepatic cholesterol pool is determined by endocytosis of
LDL bound to its receptor, de novo cholesterol synthesis, and CE
delivered by CM and bile. HMG Co-A reductase is the rate-limiting
step in cholesterol synthesis and the target of “statin” cholesterollowering therapy. Treatments that decrease the intracellular
cholesterol pool, such as dietary restriction or statin therapy,
increase LDLR expression and thus decrease circulating LDL levels.
Defects in this pathway may be genetic (single defects in the LDLR
or the LDLR ligand ApoB100; polygenic defects that increase VLDL
production or reduce LDL clearance) or acquired (VLDL overproduction from excessive dietary fat, poor LPL activity due to insulin
resistance impairs VLDL metabolism). Defects can increase levels
of TG or LDL or both
Peripheral
Tissue
Liver
LDL
LPL, HL CETP (HDL)
VLDL
IDL
LPL
FFA
Peripheral
Tissue
Adipose
Tissue
FIGURE 57.2 Endogenous Pathway
48565_ST06_251-352.indd 328
5/1/13 9:32 PM
Plasma Lipoproteins Are Determined by 3 Interrelated Pathways
329
• Reverse cholesterol transport (Figure 57.3)
HDL (nHDL) particles are synthesized in the liver and intes° Nascent
tines and acquire FC from cells via the cholesterol transport protein
ATP-binding cassette transporter A1 (ABCA1). Lecithin cholesterol
acyltransferase (LCAT) converts FC to CE to form a stable, mature
HDL (also referred to as HDL 3)
delivers CE back to the liver (“reverse cholesterol transport”)
° HDL
or to cholesterol-requiring tissues via its specific receptor, scavenger receptor B-1 (SR-B1). Its major lipoprotein, ApoA1, has crucial
functions, including structure, binding the HDL receptor SR-B1 and
activating LCAT
also transfers CE via CETP to VLDL and IDL particles to
° HDL
form LDL
in this pathway include mutations in ABCA1 (Tangier
° Defects
Disease), ApoA1, and LCAT (“Fish eye” disease), all of which result
in very low HDL levels and increased CVD risk. Acquired defects,
such as insulin resistance, increase HDL clearance by the kidney to
lower HDL levels. Elevated ApoA1 or deficiency in CETP results in
high levels of HDL, which is cardioprotective
Adrenal Testis
Ovary
Peripheral
Tissue
Liver
HDL
CE
LDL
LCAT
nHDL
FC
ABCA1
CETP
VLDL
FIGURE 57.3 Reverse cholesterol (HDL) Pathway
REFERENCES
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). JAMA, 2001;285(19):2486−97.
Knopp RH. Drug treatment of lipid disorders. N Engl J Med, 1999;341(7):498−511.
Kwiterovich, PO. The American Journal of Cardiology, Volume 86, Issue 12,
Supplement 1, 21 December 2000, Pages 5–10.
48565_ST06_251-352.indd 329
5/1/13 9:32 PM
48565_ST06_251-352.indd 330
5/1/13 9:32 PM
58 ■ LIPID DISORDERS
Rajesh M. Kabadi, MD and Perry J. Weinstock, MD
LIPID COMPONENTS
• Cholesterol is a fat-like substance that is present in cell membranes
• Precursor of bile acids and steroid hormones
• Travels in the blood as distinct particles called lipoproteins
° LDL
■ Accounts for 60−70% of plasma cholesterol
■ Contains a single apolipoprotein: ApoB-100
■ Major atherogenic lipoprotein
■ Primary target for treatment per National Cholesterol Education
Program (NCEP) guidelines
° HDL
■ Accounts for 20−30% of plasma cholesterol
■ Made up of two apolipoproteins: ApoA-I and A-II
■ Inversely correlated with risk for CHD
■ Felt to protect against development of atherosclerosis
° VLDL
■ Contains 10−15% of total serum cholesterol
■ Produced by liver
■ Triglyceride-rich precursor of LDL
■ Major lipoproteins are: ApoB-100, ApoCs (C-I, C-II, C-III), and
ApoE
■ Atherogenic, especially VLDL remnants
IDL
° ■ Resides between VLDL and LDL
■ In usual practice it is included in the LDL measurement
■ Like VLDL, tends to be atherogenic
° Chylomicrons
■ Triglyceride (TG) rich
■ Formed in the intestine from dietary fat
■ Same apolipoproteins as VLDL except ApoB-48 instead of B-100
CLASSIFICATION OF TOTAL CHOLESTEROL AND LDL CHOLESTEROL
• LDL: the primary target for cholesterol lowering therapy
LDL is a strong risk factor for CHD and stroke
° Elevated
angiographic trials have shown that LDL-lowering reduces
° Various
the volume of plaque
° NCEP classification
48565_ST06_251-352.indd 331
5/1/13 9:32 PM
332
Lipid Disorders
TABLE 58.1 Classifi cation of Total Cholesterol and LDL Cholesterol
<200
200−239
≥240
70*
<100
100−129
130−159
160−189
≥190
Total Cholesterol
Desirable
Borderline high
High
LDL Cholesterol
Optional goal in very high-risk individuals*
Optimal
Near optimal
Borderline high
High
Very high
*Very high risk: recent MI or known CAD + history of DM, metabolic syndrome, or current smoking.
TABLE 58.2 Triglyceride Level Categories
Triglyceride Category
Normal
Borderline−high
High
Very high
Levels
<150 mg/dl
150−199
200−499
>500
• TG: energy storage unit of fatty acids
well-defined risk factor for CHD in women
° Particularly
in blood primarily as VLDL
° Carried
° May cause pancreatitis when >500 mg/dL
• VLDL: major carrier of TG derived from the endogenous pathway
atherogenic remnant lipoproteins as it gives up triglycer° Produces
ides to become IDL
• IDL: result of action of lipoprotein lipase on VLDL to liberate free fatty
acids
• HDL: responsible for reverse cholesterol transport
levels (<40 mg/dL) → increased CAD morbidity/mortality
° Low
° High level (≥60 mg/dL:) → decreased CAD morbidity/mortality
• Non-HDL: defined as Total Cholesterol minus HDL and is equivalent to
total of VLDL, IDL, and LDL
° Useful clinical measure when TG >200 mg/dL
48565_ST06_251-352.indd 332
5/1/13 9:32 PM
Classifi cation of Total Cholesterol and LDL Cholesterol 333
TABLE 58.3 Frederickson’s Classifi cation of Lipoprotein Disorders
Type
I
IIa
IIb
III
IV
V
Serum Elevation
Cholesterol and
triglycerides
Cholesterol
Cholesterol and
triglycerides
Cholesterol and
triglycerides
Triglycerides
Cholesterol and
triglycerides
Syndrome
Familial hyperchylomicronemia
Lipoprotein
Elevation
CMs
Familial hypercholesterolemia
LDL
Familial combined hyerplipdemia LDL and VLDL
Dysbetalipoproteinemia
IDL
Familial hypertriglyceridemia
Metabolic syndrome
VLDL
VLDL and CMs
• Type I (familial hyperchylomicronemia)
elevated fasting plasma TG levels, mainly chylomicrons
° Severely
or absent LPL activity or ApoC-II activity
° Reduced
Associated
recurrent bouts of pancreatitis, eruptive
° xanthomas,with:
xerostomia, or xerophthlamia; occasionally behavioral
disturbances
centered around diet and lifestyle modification (low-fat
° Treatment
diet, avoidance of alcohol)
Fibrate
therapy
also be particularly effective and especially
° reduces the riskcan
of pancreatitis in such individuals
• Type II
types: both involve elevated LDL (may exceed >220 mg/dL in
° Two
adults)
■ Type IIa (familial hypercholesterolemia)
• Elevation in LDL only
■ Type IIb (familial combined hyperlipidemia)
• Elevation in LDL and VLDL
risk of developing CAD in men in the third and fourth decades
° High
and 10 years later in women
■ Treatment end points revolve around CAD risk factors
clinically with premature CAD, corneal arcus, xanthomas
° Manifest
over extensor tendons, xanthelasmas
° Autosomal dominant transmission
48565_ST06_251-352.indd 333
5/1/13 9:32 PM
334
Lipid Disorders
• Type III (dysbetalipoproteinemia)
genetic disorder (defect in ApoE)
° Rare
with increased CHD risk and CVA at young age
° Associated
Characterized
elevation of remnant lipoprotein particles
° ■ Lab findings:byincreased
total cholesterol, TG, and IDL; reduced
HDL; LDL measurements usually unreliable
findings: tuberous xanthomas and striated palmar
° Clinical
xanthomas
Treatment
involves diet and medical therapy
° ■ Dietary modifi
cation with special attention to
• Low-fat diets, especially saturated fats and trans fats
• Restriction of carbohydrates
• Increased fiber
■ Correction of metabolic abnormalities (diabetes, obesity,
hypothyroid)
■ Medical therapy includes the use of fibrate drugs, statins, and
niacin
• Type IV (familial hypertriglyceridemia)
VLDL-related serum TG level
° Elevated
with diabetes
° Association
Association
with CHD is not as strong as with type II disorders
° No specific physical
exam findings
° Treatment centered around
lifestyle modifications
° ■ Limit alcohol and encourage
low-fat dieting
■ Increasing physical activity
therapy is second-line if lifestyle modification fails, and
° Medical
includes niacin, fibrates, fish oil
• Type V
elevation in plasma TG levels (both VLDL and CMs)
° Severe
associated with: high-fat diet, obesity, diabetes
° Usually
modification generally advised
° Dietary
As
previously,
fibrates and nicotinic acid are effective treatment
° options
48565_ST06_251-352.indd 334
5/1/13 9:32 PM
Common Pharmacologic Therapies 335
TABLE 58.4 ATP III LDL-C Goals and Cutpoints for Therapy
Risk Category
High: CHD‡ or CHD§
risk equivalents
(10 year risk >20%)
Moderately high: 2+
risk factors (10 year
risk 10–20%)
Moderate: 2+ risk
factors (10 year risk
<10%)
Low: 0−1 risk factors
(10-year risk <10%)
Initiate TLC* Pharmacologic
LDL-C Goal (mg/dL) (mg/dL)
Therapy (mg/dL) †
<100 (optional <70) ≥100
≥100 (consider drug
option if <100)
<130
≥130
≥130 (consider drug
option if 100−129)
<130
≥130
≥160
<160
≥160
≥190
Risk factors include cigarette smoking, hypertension (BP >140/90), low HDL (<40 mg/dL), family history
of premature CAD (first-degree male relative <55 yrs old; first-degree female relative <65 yrs), and age
(men ≥45, women ≥55).
* TLC = therapeutic lifestyle changes.
† Drug therapy should be sufficient to achieve 30−40% LDL reduction.
‡ CHD = history of MI, unstable angina, stable angina, revascularization, or evidence of ischemia.
§ CHD risk equivalents: clinical manifestations of noncoronary forms of atherosclerotic disease (PAD,
AAA, carotid artery disease), diabetes.
COMMON PHARMACOLOGIC THERAPIES
• HMG-CoA reductase inhibitors (“statins”)
formation of mevalonate, rate-limiting step in sterol
° Prevent
synthesis
■ Body responds by increasing LDL receptors
■ End result is decreased LDL production and increased clearance
referred to as “statin” drugs (see Table 58.5)
° Commonly
Ant-infl
ammatory effects as well
°
48565_ST06_251-352.indd 335
5/1/13 9:32 PM
48565_ST06_251-352.indd 336
Simvastatin* Rosuvastatin Pravastatin Fluvastatin Lovastatin
10 mg
20 mg
40 mg
20 mg
20 mg
40 mg
80 mg
40 mg
40 mg
5 mg
80 mg
80 mg
10 mg
20 mg
40 mg
Pitavastatin
1 mg
2 mg
4 mg
~% LDL ↓
30%
38%
41%
47%
55%
63%
*Recent FDA warning recommends limiting the use of simvastatin doses >40 mg; should not exceed 10-mg dose with diltiazem, verapamil, and
amiodarone; should not exceed 20-mg dose with amlodipine, ranolazine.
10 mg
20 mg
40 mg
80 mg
Atorvastatin
TABLE 58.5 Common Statin Forms and Their Doses
336
Lipid Disorders
5/1/13 9:32 PM
Common Pharmacologic Therapies 337
•
•
•
•
side effects include transaminitis and myositits
° Common
■ Liver function should be monitored at regular intervals for all
patients on statin therapy
■ If suspicion for myositis, serum CPK levels should be obtained
Metabolized
cytochrome P-450 system
° ■ Inhibitors byof the
this system will increase statin levels in the plasma
Cholesterol absorption inhibitor (Ezetimibe)
selective uptake of cholesterol and other sterols at intestinal
° Limits
epithelial level
LDL cholesterol numerically but data do not demonstrate
° Improves
improvement in CHD outcomes
Bile acid–binding resins
colestipol, and colesevelam
° Cholestyramine,
bile acid resorption at intestinal level
° Inhibit
therapy for patients with severe hypercholesterolemia
° Adjunctive
caused by increased LDL
■ Can be taken in conjunction with statin therapy
effects are gastrointestinal discomfort, constipation, fullness
° Side
■ May interfere with absorption of other medications
• Other medications should be taken 1 hour before or 3 hours
after administration of bile acid–binding resin
Fibric acid derivatives (“Fibrates”)
in treatment of hypertriglyceridemia and in low HDL
° Indicated
states
Interacts
with
PPARα, which regulates transcription of LPL, ApoC-III,
° and ApoA-I genes
include gemfibrozil and fenofibrate
° Examples
side effects include
° Common
■ Abdominal discomfort
■ Transaminitis
■ Erectile dysfunction
■ When administering gemfibrozil concurrently with statin therapy,
may increase risk of rhabdomyolysis due to interference with
statin elimination
Nicotinic acid (Niacin)
Indicated
° levels for increasing HDL levels, lowering TG, and lowering LDL
effective doses include 1500–3000 mg/day in divided
° Typical
separate doses
Common
side effects include flushing, hyperuricemia, hyperglyce° mia, acanthosis
nigricans, and gastritis
■ Usually started at low doses with plan to titrate to maximum over
2–3 weeks due to side effect tolerability
■ Slow-release formulations also aid with tolerability but may be
associated with liver toxicity, particularly at doses exceeding 2 g
■ Flushing may be attenuated by pretreatment with aspirin
48565_ST06_251-352.indd 337
5/1/13 9:32 PM
338
Lipid Disorders
°
°
The Coronary Drug Project had previously shown that use of niacin
improved mortality at 15 years
Recent data (AIM-HIGH study) have called into question the
concept that the addition of niacin to statin therapy would improve
CHD outcomes
REFERENCES
AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients
with low HDL cholesterol levels receiving intensive statin therapy. N Engl J
Med, 2011;365(24):2255−67.
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). JAMA, 2001;285(19):2486−97.
FDA. “Drug Safety and Availability > FDA Drug Safety Communication:
New restrictions, contraindications, and dose limitations for Zocor
(simvastatin) to reduce the risk of muscle injury.” 12/15/11. FDA. 6/28/12.
Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm
Frederickso DS, Lees RS. A system for phenotyping hyperlipoproteinemia.
Circulation, 1965;31:321−7.
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials
for the National Cholesterol Education Program Adult Treatment Panel III
guidelines. Circulation, 2004;110(2):227−39.
Quehenberger O, Dennis EA. The human plasma lipidome. N Engl J Med,
2011;365(19):1812−23.
48565_ST06_251-352.indd 338
5/1/13 9:32 PM
59 ■ ESSENTIALS OF ADIPOSE TISSUE
ENDOCRINOLOGY
Mark Herman MD and Eleftheria Maratos-Flier MD
TYPES OF ADIPOSE TISSUE
• White adipose tissue
with predominantly large solitary lipid droplet
° Adipocytes
for energy storage
° Adapted
■ Storage of dietary fat as triglyceride
■ Conversion of excess dietary glucose to fatty-acids for storage
(de novo lipogenesis)
functions
° Other
■ Insulation
■ Mechanical cushion
■ Regulation of appetite, energy expenditure, and hypothalamicpituitary axes via leptin secretion
■ Metabolism of sex steroids
• Brown adipose tissue
with small, multilocular lipid droplets
° Adipocytes
in mitochondria
° Rich
° Adapted for thermogenesis
• Beige or Brite Cells
adipocytes with an intermediate phenotype
° White
° May participate in thermogenesis
ENDOCRINE REGULATION OF LIPID STORAGE
AND RELEASE IN ADIPOCYTES
• Chylomicrons or VLDL deliver triglyceride to adipose tissue depots
• The activity of lipoprotein lipase (LPL) present on the luminal surface
of adipose tissue vascular endothelial cells is stimulated by insulin
and hydrolyzes triglyceride to release free fatty acids
• FFAs are transported across the adipocyte membrane by diffusion
and/or facilitation by fatty acid transporters with the assistance of
intracellular fatty acid binding proteins
• Insulin stimulates translocation of the insulin-responsive glucose
transporter (Glut4) to the adipocyte plasma membrane to permit
adipocyte glucose uptake. This glucose is used to produce glycerol3-phosphate, which is then esterified with fatty acyl-CoAs to form
triglyceride for storage purposes
48565_ST06_251-352.indd 339
5/1/13 9:32 PM
340
Essentials of Adipose Tissue Endocrinology
• Insulin inhibits lipolysis by multiple mechanisms including decreasing cAMP
levels through induction of a phosphodiesterase, which catabolizes cAMP
• Catecholamines bind to β-adrenergic receptors, which activate cAMPdependent Protein Kinase A (PKA); this phosphorylates perilipin, a lipid
droplet surface protein, and hormone-sensitive lipase (HSL), resulting
in hydrolysis of triglyceride to glycerol and FFAs
ADIPOSE TISSUE DERIVED EFFERENT SIGNALS
• Adipokines: adipocyte-derived secreted proteins with endocrine or
paracrine functions
related proteins: leptin (see below), TNFα, IL-6
° Cytokine
involved in fibrinolysis: PAI-1, tissue factor
° Proteins
Complement
related proteins: adipsin, adiponectin (see below)
° Others: resistin,
RBP4, FGF21
°
• Enzymes involved in steroid metabolism
Aromatase
(conversion
androgens to estrogens)
° 17βHSD (conversion of of
to testosterone)
° 11βHSD1 (conversion ofandrostenedione
inactive to active glucocorticoids)
°
• Nonesterified fatty acids released as a result of lipolysis
LEPTIN
• A circulating peptide hormone with structural homology to cytokines
• Secreted into the circulation in proportion to adipose tissue mass and
is also regulated acutely by nutritional status
• Effects of leptin are mediated through actions on leptin receptors
present in the hypothalamus
• Its primary role is to serve as a signal of energy sufficiency
levels rapidly decline with weight loss
° Leptin
decline in leptin levels increase appetite and reduce energy
° Aexpenditure
• A decline in leptin suppresses the thyroid and gonadal axes
• Other functions
regulates immune function, hematopoiesis, angiogenesis,
° Leptin
and bone development
• Rare genetic mutations in leptin cause morbid obesity which are
reversible with leptin
• Leptin is ineffective at reducing weight in most obese humans due to a
state of leptin resistance associated with high circulating leptin levels
ADIPONECTIN
• Adipocyte secreted protein that circulates at high concentrations
in multimeric complexes, which suppresses hepatic glucose production
• Circulating levels decrease in obesity and increase with weight loss or
thiazolidinedione treatment
48565_ST06_251-352.indd 340
5/1/13 9:32 PM
Adipose Tissue Endocrinology in Obesity
341
OBESITY
• Defined as excess adiposity
• Produced by a combination of adipocyte hyperplasia and hypertrophy
• Clinical definitions
BMI >25 kg/m2
° Overweight:
Obesity:
BMI
>30
kg/m2
°
• A key component of the “metabolic syndrome,” which is a cluster of
cardiovascular disease risk factors including hypertriglyceridemia,
hypertension, low HDL-C, and insulin resistance (see Chapter 61,
Metabolic Syndrome)
• Increased risk for early mortality with increasing obesity
• Rapidly increasing prevalence over the last three decades
the United Sates, the prevalence of obesity is >30%
° In
explanation for the rapidly increasing prevalence of obesity
° The
remains uncertain. Potential contributors include
■ Environmental factors: changes in diet and exercise
■ Genetic factors: may contribute to ~60 % of the variation in BMI
in a population
• Variants in the melanocortin 4 receptor (MC4R) gene and
the fat mass and obesity−associated (FTO) gene account for
~2% of the variation in BMI
• Genome wide association scans have identified an additional
8 genetic loci associated with BMI; however, variants in
these genes appear to account for only a small fraction of the
heritability of BMI
ADIPOSE TISSUE ENDOCRINOLOGY IN OBESITY
• In obesity, adipocytes are resistant to the effects on insulin to inhibit
lipolysis, resulting in an increase in the release of FFAs; increased circulating FFAs can contribute to the development of insulin resistance
in muscle and liver
• Obesity is a state of leptin resistance
• Decreased adiponectin secretion in obesity may contribute to insulin
resistance
• Increased TNFα and RBP4 secretion in obesity may contribute to
insulin resistance
• Increased adipose tissue inflammation obesity may contribute to
insulin resistance
• Expression of Glut4, the insulin-responsive glucose transporter, is
down-regulated in adipocytes in obese patients contributing to insulin
resistance
48565_ST06_251-352.indd 341
5/1/13 9:32 PM
342
Essentials of Adipose Tissue Endocrinology
LIPODYSTROPHIES
• Disorders characterized by selective or generalized absence or loss of
body fat
• May be genetic or acquired and partial or generalized
• The most prevalent form of lipodystrophy is associated with HIV infection and treatment with highly active antiretroviral therapy (HAART),
particularly protease inhibitors
• Causes insulin resistance and its associated complications such as
DM, hypertriglyceridemia, and often severe hepatic steatosis
• Use of a methylated form of leptin is currently under investigation as
replacement therapy of several varieties of lipodystrophy
REFERENCES
Barbatelli G, Murano I, Madsen L, et al. The emergence of cold-induced
brown adipocytes in mouse white fat depots is determined predominantly
by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol
Metab, 2010;298(6):E1244−53.
Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of
lipolysis in adipocytes. Annu Rev Nutr, 2007;27:79−101.
Fawcett KA, Barroso I. The genetics of obesity: FTO leads the way. Trends
Genet, 2010;26(6):266−74.
Garg A. Clinical review: lipodystrophies: genetic and acquired body fat
disorders. J Clin Endocrinol Metab, 2011;96(11):3313−25.
Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol
Metab, 2004;89(6):2548−56.
48565_ST06_251-352.indd 342
5/1/13 9:32 PM
60 ■ OBESITY MANAGEMENT
David W. Lam, MD and Robert T. Yanagisawa, MD
PATHOPHYSIOLOGY
• Obesity involves a complex interaction between genetics, behavior,
and environment. Ultimately, it results from chronic energy imbalance
where intake exceeds expenditure.
intake can be estimated with dietary journals reviewed
° Energy
by the practitioner or a registered dietician; accuracy hinges on
patient motivation and perceptions of intake
expenditure is a product of the resting metabolic rate (RMR)
° Energy
and a physical activity factor
■ Resting metabolic rate (kcal/day) = 10 X weight (kg) + 6.25 X
height (cm) – 5.0 X age (yr) + s (s = 5 for males and –161 for
females)
■ Physical activity factor (range 1.2–1.9): sedentary = 1.2, moderate exercise 3–5x/wk = 1.55, extra active = 1.90
energy intake and expenditure helps patients concep° Calculating
tualize and quantify the efficacy of caloric reductions in diet and
increasing physical exercise
• Pathologic and iatrogenic factors can contribute to obesity and make
treatment more difficult
conditions: Cushing’s syndrome, hypothyroidism, PCOS,
° Pathologic
and hypothalamic obesity
Iatrogenic
causes:
antipsychotics (thioridazine, clozapine, olanzap° ine, risperidone, lithium),
tricyclic antidepressants, antiepileptic
(carbamazepine, valproate), antidiabetic drugs (insulin, sulfonylureas, thiazolidinediones), and glucocorticoids
DIAGNOSIS
• BMI = weight (kg)/height (m) squared
• BMI is the current standard for classification of obesity by the WHO
and the National Heart, Lung, and Blood Institute
(BMI 25.0–29.9)
° Overweight
class I (BMI 30.0–34.9)
° Obesity
Obesity
class
II (BMI 35.0–39.9)
° Obesity class III
(BMI ≥40.0)
°
• Increased BMI and waist circumference (WC) are independently associated with increased risk for type 2 DM, hypertension, and CVD
48565_ST06_251-352.indd 343
5/1/13 9:32 PM
344
Obesity Management
• Relative risk varies depending on population sampled; however,
patients with a BMI ≥25.0, males with WC >102 cm and females with
WC > 88 cm should be evaluated for possible comorbid conditions
• Sole use of BMI has limitations in muscular patients and those with
significant loss of muscle mass. In addition it has ethnic limitations,
particularly with Asian populations (e.g., Asian males with WC >90
cm and Asian females with WC >80 cm are considered higher risk).
Despite these limitations, BMI cut-offs are still recommended for
international use
CLINICAL PRESENTATION
TABLE 60.1 History at Clinical Presentation of Obesity
History Components
• Age of onset of obesity
• Weight loss attempts including
methods, successes, and failures
• Food intake with attention to skipped
meals, portion size, beverage choices,
food consumed between scheduled
meals, and dining out
• Physical activity including duration,
intensity, and frequency of activities
• Triggers for increased food
consumption and decreased physical
activity
• Perceived impact of obesity on health
and body image
• Willingness and motivation to lose
weight
• Medications and supplements
• Targeted review of systems to evaluate
for secondary contributors of obesity
such as hypothyroidism and Cushing’s
syndrome
Evaluate for Comorbidities
•
•
•
•
•
Coronary heart disease
Type 2 DM
Sleep apnea
Nonalcoholic steatohepatitis
PCOS
Assess Factors Increasing CVD Risk
• Tobacco use
• Hypertension
• Hyperlipidemia (LDL >160, LDL
130–159 with 2 additional risk factors,
HDL <35)
• Impaired fasting glucose
• Family history of CAD (Men ≥45,
women ≥55)
• Physical examination
weight, WC (measured at the level of the iliac crest at the
° Height,
end of expiration) should be measured in addition to standard vital
signs.
complete physical examination should be performed with specific
° Aattention
to signs that maybe consistent with a secondary contributor of obesity such as Cushing’s syndrome and hypothyroidism
48565_ST06_251-352.indd 344
5/1/13 9:32 PM
Treatment 345
• Laboratory evaluation
LFTs, TSH, fasting lipid panel, fasting BG
° Electrolytes,
clinically suspected, a 24-hour urine-free cortisol or midnight
° Ifsalivary
cortisol should be collected to screen for Cushing’s disease
TREATMENT
• Patient involvement and investment are critical for success; goals
of treatment and a treatment plan should be made jointly with the
patient and discussed at each visit
• Injury prevention should be reviewed and the necessity for pretreatment cardiovascular assessment should be determined by the
practitioner
• Goals of therapy
10% decrease from baseline weight with a rate between 1 and 2
° Apounds
per week is recommended for initial weight loss
adjustment may be required after initial weight loss because
° Plan
of an adjustment of the energy balance
• Lifestyle modifications
° Diet
■ Total energy intake should be reduced by 500–1000 kcal/day for
obese patients and 300–500 kcal/day for overweight patients;
intake from fat should be limited to 25–35% of the total
■ Education for the patient on appropriate food choices, reading
food labels, and making healthy decisions when dining out is
essential
■ Weight loss from diet is more related to the restriction of energy
intake over specific macronutrient modification (e.g., low fat or
low carbohydrate diets)
Exercise
° ■ 30 minutes of moderate-to-vigorous physical activity 5–7 days
a week is recommended. Moderate intensity: 3.0–5.9 Metabolic
Equivalent of Tasks (METS) (walking 3 miles/hour = 3.3 METS).
Vigorous intensity: >6.0 METS (running at 6 miles/hour = 6 METS)
■ Exercise can offset lean body mass loss and the lowering of the
RMR from caloric restriction; in addition, exercise leads to more
percent weight lost as fat compared to caloric restriction
Cognitive
therapy (CBT) and behavioral weight loss
° (BWL) are behavioral
psychological interventions for weight management
■ CBT seeks to identify emotions that facilitate overeating and
manage patient expectations
■ BWL includes self-monitoring and reinforcing positive diet/
exercise behaviors
48565_ST06_251-352.indd 345
5/1/13 9:32 PM
346
Obesity Management
TABLE 60.2 Pharmacotherapy for Obesity
Class of Medication
Intestinal fat
absorption inhibitor
(orlistat*)
CNS stimulants/
appetite
suppressants
(benzphetamine*,
diethylpropion*,
phendimetrazine*,
phentermine*)
Appetite
suppressant,
selective serotonin
(5-HT2c) agonist
(lorcaserin*)
Effi cacy
5–10 kg loss,
less for over the
counter.
Variable
Side Effects
Indication
Oily spotting,
Long-term treatment
intestinal cramps, of obesity
gas, loose stools
Short-term
Palpitations,
treatment of
increased blood
pressure, insomnia. obesity (less than
• Scheduled drugs 12 weeks)
given abuse
potential.
5% body weight
loss
Biguanide
(metformin)
0.6–2.7 kg loss
Alpha-glucosidase
inhibitors
(Acarbose,
miglitol)
GLP-1 analogs
(exenatide,
liraglutide)
0.5 kg loss
(1–3 years)
Headache, Upper
BMI ≥30 or
respiratory
BMI ≥27 with
infection (URI)
weight-related
symptoms.
comorbidity
Consider baseline
echocardiogram
(ECHO)
Abdominal
Type 2 DM
discomfort,
diarrhea, anorexia
Abdominal pain,
Type 2 DM
flatulence,
diarrhea
Amylin mimetic
(pramlintide)
1.5 kg loss
1.8–6.0 kg loss
Nausea, vomiting, Type 2 DM
dyspepsia.
Serious reactions:
pancreatitis
Nausea, vomiting, Type 2 DM
anorexia
*Approved by United States Food and Drug Administration (FDA) for the treatment/management of obesity
°
°
Most nutraceutical supplements lack rigorous scientific data demonstrating their safety and efficacy in weight loss. It is important to
educate patients regarding the use of nutraceutical supplements
Dietary fiber (25 g/day for women and 38 g/day for men) may
enhance weight loss by slowing the absorption of macronutrients
and decreasing appetite
48565_ST06_251-352.indd 346
5/1/13 9:32 PM
References
347
• Surgical treatment of obesity
surgery should be considered in patients with BMI
° Bariatric
≥40 kg/m2, or BMI ≥35 kg/m2 with a significant obesity-related
comorbidity
should have preoperative measurement of iron, vitamins
° Patients
B12, C, and D, and zinc. Postoperatively they should be screened
for complications at 6 months and then annually
TABLE 60.3 Surgical Treatment of Obesity
Procedure
Gastric banding
Excess Body
Weight Loss
46%
Type 2 DM
Resolution
57%
Sleeve gastrectomy
55%
80%
Gastric bypass
60%
80%
Biliopancreatic
diversion/
duodenal switch
64%
95%
Micronutrient
Complications
Vitamins C, D,
B12, B6, Folate,
and Iron
Zinc, Vitamin D,
Folate, Vitamin
B12, Iron
Iron, Folate,
Vitamins A, B1,
B12, B6, C, D,
E, Zinc
Vitamins A, B12, D,
E, K, Iron, Zinc,
Selenium, Copper,
Folate
REFERENCES
Bray GA. Medications for weight reduction. Med Clin North Am,
2011;95(5):989−1008.
Donnelly JE, Blair SN, Jakicic JM, et al. American College of Sports Medicine
Position Stand. Appropriate physical activity intervention strategies for
weight loss and prevention of weight regain for adults. Med Sci Sports
Exerc, 2009;41(2):459−71.
Laddu D, Dow C, Hingle M, Thomson C, Going S. A review of evidence-based
strategies to treat obesity in adults. Nutr Clin Pract, 2011;26(5):512−25.
48565_ST06_251-352.indd 347
5/1/13 9:32 PM
348
Obesity Management
Leblanc ES, O’Connor E, Whitlock EP, Patnode CD, Kapka T. Effectiveness
of primary care-relevant treatments for obesity in adults: a systematic
evidence review for the U.S. Preventive Services Task Force. Ann Intern
Med, 2011;155(7):434−47.
Mechanick JI, Kushner RF, Sugerman HJ, et al. American Association of
Clinical Endocrinologists, The Obesity Society, and American Society for
Metabolic & Bariatric Surgery Medical guidelines for clinical practice for
the perioperative nutritional, metabolic, and nonsurgical support of the
bariatric surgery patient. Endocr Pract, 2008;14(Suppl 1):1−83.
Strohmayer E, Via MA, Yanagisawa R. Metabolic management following
bariatric surgery. Mt Sinai J Med, 2010;77(5):431−45.
48565_ST06_251-352.indd 348
5/1/13 9:32 PM
61 ■ METABOLIC SYNDROME
George A. Bray, MD
INTRODUCTION
• Metabolic syndrome is a cluster of risk factors that predict the risk for
cardiovascular and metabolic disease
• A list of the primary components and other factors that are often
present but not included in the definition of metabolic syndrome are
shown in Table 61-1
• Metabolic syndrome is highly prevalent in obese individuals
• The higher the number of abnormal components, the greater is the risk
of cardiometabolic diseases
glucose alone may be as good as the metabolic syndrome in
° Fasting
predicting diabetes
° Low HDL-C and elevated BP are strong predictors of CVD
• Acarbose has a stronger association with diabetes than with CHD
TABLE 61.1 Features of the Metabolic Syndrome
Major Components
Abdominal obesity
Glucose intolerance
High triglycerides
Low HDL-cholesterol
High blood pressure
Insulin resistance
Factors Frequently Found
Microalbuminuria
Small dense LDL
Inflammatory markers
Thrombotic factors
Endothelial dysfunction
Hyperuricemia
PREVALENCE
• The prevalence of the metabolic syndrome has been estimated at
23.7% of the adult population or 47 million US adults
• The prevalence increases with age
in those aged 20–29 years
° 6.7%
in those aged 60–69 years
° 43.5%
42%
in
people older than 70 years
°
• The overall prevalence is similar in men and women (24.0% versus
23.4%)
• Ethnic variation with higher prevalence in African-American and
Mexican-American women (57%) and men (30%)
48565_ST06_251-352.indd 349
5/1/13 9:32 PM
350
Metabolic Syndrome
DIAGNOSIS
• The NCEP Adult Treatment Panel III has provided defining values for
5 components of the metabolic syndrome including WC, plasma TG,
plasma HDL-C, fasting glucose, and BP. When 3 of the 5 criteria are
abnormal, the patient has metabolic syndrome
• Other diagnostic criteria for metabolic syndrome were developed by the
WHO and the International Diabetes Federation
• The agreed upon international diagnostic criteria are shown below.
The diagnosis requires that 3 of the 5 measures listed in below be
abnormal and allows different definitions of WC to be employed. In
general, WC >40 inches (102 cm) in men and >35 inches (88 cm) in
women is the risk level in the US
criteria for The Metabolic Syndrome (Drug treatments
° International
for any of these conditions are considered alternate indicator criteria)
■ ↑ waist circumference (population- and country-specific definitions)
■ ↑ triglycerides (≥ 150 mg/dL)
■ ↓ HDL-cholesterol (Males, < 40 mg/dL; Females, <50 mg/dL)
■ ↑ blood pressure (>130 mm Hg systolic and/or > 85 mm Hg
diastolic)
■ ↑ fasting blood glucose (> 100 mg/dL)
CLINICAL PRESENTATION
• Obesity, hypertension, dyslipidemia, and hyperglycemia
• Focus history on symptoms of diabetes and its complications, obesity
and its complications, CAD (angina), and polycystic ovary syndrome
(PCOS)
• Other complications include cognitive decline in the elderly, fatty liver
disease, obstructive sleep apnea, gout, and chronic kidney disease
• Complete physical examination, including height, weight, waist
circumference, and BP
LABORATORY TESTING
• Fasting lipid profile (TC, LDL-C, HDL-C, and TG)
• Fasting glucose
TREATMENT
• Weight loss will improve all of the markers of the metabolic syndrome
and reduces the risk of developing diabetes
• Diet and exercise is the first step in management
48565_ST06_251-352.indd 350
5/1/13 9:32 PM
References
351
• Surgically induced weight loss via laparoscopic gastric banding or
gastric bypass can be particularly effective in reversing diabetes and
metabolic syndrome (Table 61.2)
• If BP, dyslipidemia, diabetes, or IGT persist, they may need to be
treated individually
TABLE 61.2 The Effect of Substantial Weight Loss After Surgery on the Incidence
of the Metabolic Syndrome in Randomized Control Trials
Study Population
Mild-to-moderately obese
adults (BMI 30–35)
Obese adults with type 2
diabetes
Obese adolescents
Reduction in the
Incidence of Diabetes
Signifi cance
From 40% → 3%
P = 0.006
97% → 28%
P < 0.001
36% → 0%
P = 0.03
REFERENCES
Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome:
a joint interim statement of the International Diabetes Federation
Task Force on Epidemiology and Prevention; National Heart, Lung, and
Blood Institute; American Heart Association; World Heart Federation;
International Atherosclerosis Society; and International Association for
the Study of Obesity. Circulation, 2009;120(16):1640−45.
Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after
bariatric surgery: systematic review and meta-analysis. Am J Med,
2009;122(3):248−56.
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive Summary of The Third Report of The
National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). JAMA, 2001;285(19):2486−97.
Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome
among US adults: findings from the third National Health and Nutrition
Examination Survey. JAMA, 2002;287(3):356−9.
Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current
state of the evidence. Diabetes Care, 2008;31(9):1898−904.
Franssen R, Monajemi H, Stroes ES, Kastelein JJ. Obesity and dyslipidemia.
Endocrinol Metab Clin North Am, 2008;37(3):623−33.
Gu D, Reynolds K, Wu X, et al. Prevalence of the metabolic syndrome and
overweight among adults in China. Lancet, 2005;365(9468):1398−405.
Koster A, Leitzmann MF, Schatzkin A, et al. Waist circumference and mortality. Am J Epidemiol, 2008;167(12):1465−75.
48565_ST06_251-352.indd 351
5/1/13 9:32 PM
352
Metabolic Syndrome
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive
protein and low-density lipoprotein cholesterol levels in the prediction of
first cardiovascular events. N Engl J Med, 2002;347(20):1557−65.
Sjöström L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and
cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med,
2004;351(26):2683−93.
48565_ST06_251-352.indd 352
5/1/13 9:32 PM
SECTION VII: MISCELLANEOUS
48565_ST07_353-368.indd 353
5/1/13 9:32 PM
48565_ST07_353-368.indd 354
5/1/13 9:32 PM
62 ■ PANCREATIC NEUROENDOCRINE
TUMORS AND CARCINOID SYNDROME
Matthew H. Kulke, MD
PATHOPHYSIOLOGY
• Neuroendocrine tumors (NETs) are generally subcategorized as either
carcinoid tumors or pancreatic endocrine tumors
• The release of substances such as serotonin, gastrin, glucagon, and
insulin into the systemic circulation results in the unique systemic
syndromes associated with NETs
• NETs can be further classified according to histology. The majority are
well-differentiated and pursue a relatively indolent course. A minority,
however, are poorly differentiated and pursue an aggressive course;
these tumors are treated with aggressive surgery and/or traditional
chemotherapy
TABLE 62.1 Histologic Classifi cation of Neuroendocrine Tumors
Differentiation Grade
Low grade
(G1)
Mitotic Ki-67
Count
Index
<2 per ≤2%
10 HPF
Traditional
Carcinoid, islet
cell, pancreatic
(neuro)
endocrine
tumor
Intermediate
2–20
per
3–20%
Carcinoid,
Well10 HPF
atypical
differentiated grade (G2)
carcinoid,
islet cell,
pancreatic
(neuro)
endocrine
tumor
High grade >20 per >20 % Small cell
(G3)
10 HPF
carcinoma
Poorly
differentiated
48565_ST07_353-368.indd 355
ENETS, WHO
Neuroendocrine
tumor,
grade 1
Neuroendocrine
tumor,
grade 2
Neuroendocrine
carcinoma,
grade 3,
small cell
Large cell
Neuroendocrine
neuroendocrine carcinoma
carcinoma
grade 3, large
cell
5/1/13 9:32 PM
356 Pancreatic Neuroendocrine Tumors and Carcinoid Syndrome
CLINICAL PRESENTATION
• Pancreatic NET
NET may arise either sporadically or, less commonly, in
° Pancreatic
patients with MEN-1
clinical presentations of pancreatic endocrine tumors
° The
are diverse and are often related to symptoms of hormonal
hypersecretion (Table 62.2)
tests and initial treatment of symptoms of hormonal
° Diagnostic
hypersecretion depend on the type of tumor (Table 62.2)
TABLE 62.2 Clinical Presentation and Initial Treatment of Pancreatic
Neuroendocrine Tumors
Tumor
Insulinoma
Symptoms or Signs
Hypoglycemia resulting in
intermittent confusion,
sweating, weakness,
nausea; loss of
consciousness may occur
in severe cases
Glucagonoma
Rash (necrotizing migratory
erythema), cachexia,
diabetes, deep venous
thrombosis
VIPoma, Verner-Morrison
Profound secretory
syndrome, WDHA
diarrhea, electrolyte
syndrome
disturbances
Gastrinoma,
Acid hypersecretion
Zollinger-Ellison syndrome resulting in refractory
peptic ulcer disease,
abdominal pain, and
diarrhea
Diagnostic Tests
Insulin/glucose ratio;
C-peptide; 48–72 hour
inpatient fast if necessary
Serum glucagon
Serum VIP
Basal gastrin; stimulated
gastrin level if basal
gastrin inconclusive
• Carcinoid tumors
commonly used classification scheme groups carcinoid tumors
° Aaccording
to their presumed derivation from the embryonic gut:
foregut (bronchial and gastric), midgut (small intestine and
appendiceal), and hindgut (rectal)
clinical presentation and management of these tumors varies,
° The
depending upon their site of origin (see Table 62.3)
48565_ST07_353-368.indd 356
5/1/13 9:32 PM
Diagnosis
357
TABLE 62.3 Clinical Presentation of Carcinoid Tumors
Tumor
Foregut
Bronchial Carcinoids
Gastric Carcinoids
Midgut
Small Intestine
Carcinoids
Appendiceal Carcinoids
Hindgut
Rectal Carcinoids
Symptom
Cough, hemoptysis, post-obstructive pneumonia,
Cushing’s syndrome. Carcinoid syndrome rare
Usually asymptomatic and found incidentally
Intermittent bowel obstruction or mesenteric ischemia.
Carcinoid syndrome common when metastatic.
Usually found incidentally; may cause carcinoid syndrome
when metastatic
Either found incidentally or discovered due to bleeding,
pain, and constipation; rarely cause hormonal symptoms,
even when metastatic
DIAGNOSIS
• Laboratory esting
5-Hydroxyindole acetic acid (5-HIAA) levels
° Urinary
■ Elevated levels of 5HIAA in a 24-hour urine collection are highly
specific for carcinoid tumors, but not particularly sensitive
■ 5-HIAA levels are generally elevated in patients with primary
midgut carcinoid tumors but not useful in patients with either
foregut (bronchial, gastric) or hindgut (rectal) carcinoid tumors
that only rarely secrete serotonin
chromogranin A (CGA)
° Serum
■ Serum CGA concentrations are a more sensitive marker than
urinary 5-HIAA levels in patients with carcinoid tumors, and can
also be used as a marker in patients with both functional and
nonfunctional pancreatic endocrine tumors
■ However, CGA is nonspecifi c and may be elevated in patients on
PPIs, with chronic renal disease, and in other medical conditions
of specific hormones (glucagon, vasoactive intestinal
° Measurement
peptide (VIP), insulin, gastrin) may be helpful in the diagnosis and
follow-up of patients with specific secretory symptoms related to
the hormone of interest
• Imaging
type and sequence of diagnostic imaging tests depend in part
° The
on tumor stage (localized versus metastatic) and the suspected
location of the primary tumor
48565_ST07_353-368.indd 357
5/1/13 9:32 PM
358 Pancreatic Neuroendocrine Tumors and Carcinoid Syndrome
°
°
°
For evaluation of suspected localized disease, direct imaging with
the potential for diagnostic biopsy is preferred
■ Endoscopic ultrasound may be helpful both to visualize and
facilitate biopsy in patients with pancreatic NET
■ Bronchoscopy can be used to diagnose patients with bronchial
carcinoid
■ Colonoscopy is appropriate in patients with suspected rectal or
small bowel carcinoid tumors
Patients with localized disease or suspected metastatic disease
should generally be evaluated first with cross sectional imaging
■ CT scanning remains the standard cross-sectional imaging technique for baseline staging of patients with neuroendocrine tumors
■ NET liver metastases are often hypervascular and may become
isodense relative to the liver with the administration of IV contrast materials. CT scans should thus be performed both before
and after the administration of IV contrast agents. If CT results
are inconclusive or CT is not easily feasible, MRI scan is highly
sensitive for liver metastases and may be used for staging
Somatostatin receptor scintigraphy is generally used as an adjunct
to cross-sectional imaging at baseline. It is not generally used or
recommended for the routine follow-up of patients with neuroendocrine tumors
■ With the exception of insulinomas (of which only 50% express
type 2 somatostatin receptors), over 90% of NETs, including
nonfunctioning pancreatic tumors and carcinoid tumors, contain
high concentrations of somatostatin receptors, and can be
imaged with a radiolabeled form of the somatostatin analogue
octreotide (111-indium pentetreotide)
■ The uptake of radiolabeled octreotide is also predictive of a clinical response to therapy with somatostatin analogues
GENERAL MANAGEMENT APPROACH
• Surgery is the only curative treatment option for patients with NETs,
and should be considered for patients with localized disease; the type
and extent of surgery is dependent on the location and size of the tumor
• Treatment for patients with advanced disease focuses both on treatment of symptoms of hormone hypersecretion (if present) and direct
antitumor therapies
TREATMENT OF SYMPTOMS OF HORMONAL
HYPERSECRETION BY TUMOR TYPE
• Insulinoma: diazoxide is generally used as an initial treatment to
stabilize blood glucose levels. Recent data suggest that everolimus
may have a direct and rapid effect in improving glucose control
48565_ST07_353-368.indd 358
5/1/13 9:32 PM
Systemic Treatment Options for Tumor Control 359
•
•
•
•
Somatostatin analogues are not universally effective in treating
patients with insulinoma and should be used with caution
Glucagonoma: somatostatin analogues are generally effective in treating symptoms associated with glucagon hypersecretion
VIPoma: somatostatin analogues are generally effective in treating the
diarrhea associated with VIP hypersecretion
Gastrinoma: PPIs are generally used first-line; the addition of octreotide can also be considered
Carcinoid syndrome: the flushing and diarrhea associated with
carcinoid syndrome has been attributed to serotonin secretions, and is
generally highly responsive to treatment with somatostatin analogues
TREATMENT OF PATIENTS WITH HEPATIC-PREDOMINANT
METASTATIC DISEASE
• In selected cases, metastatic liver disease can be surgically resected
• Hepatic arterial embolization is commonly used as a palliative technique in patients with hepatic metastases who are not candidates for
surgical resection, and can be performed with or without the administration of concurrent chemotherapy. More recently, radioembolization
has also shown promise in patients with advanced NETs
SYSTEMIC TREATMENT OPTIONS FOR TUMOR CONTROL
• Somatostatin analogues
improved time to tumor progression in patients with
° Octreotide
advanced small bowel carcinoid tumors and is often used first-line
to slow tumor growth in this setting
• Interferon α
α has been used as a treatment for advanced carcinoid
° Interferon
for several decades
not approved for this indication in the United States, reports
° While
suggest that single-agent IFN therapy can provide symptomatic
control of carcinoid syndrome, and induce a biochemical response
in at least 30–35% of patients
studies evaluating the efficacy and toxicity of interferon
° Prospective
in advanced neuroendocrine tumors have been limited by relatively
small patient numbers
• Cytotoxic chemotherapy
chemotherapy has, in general, been minimally active
° Cytotoxic
in patients with advanced carcinoid tumors; most studies have
focused on regimens incorporating streptozocin, dacarbazine, or
temozolomide
contrast to carcinoid tumors, pancreatic NETs are clearly respon° In
sive to cytotoxic chemotherapy; active regimens include those
containing streptozocin or temozolomide
48565_ST07_353-368.indd 359
5/1/13 9:32 PM
360 Pancreatic Neuroendocrine Tumors and Carcinoid Syndrome
• Molecularly targeted therapy
targeted therapies, including VEGF pathway inhibi° Molecularly
tors and the mammalian target of rapamycin (mTOR) inhibitor
everolimus, are currently under investigation for the treatment of
advanced carcinoid tumors
a TKI-targeted against the VEGF receptor and related
° Sunitinib,
receptors, was approved for use in patients with advanced
pancreatic NET
mTOR inhibitor everolimus is approved for use in patients with
° The
advanced pancreatic NET. Everolimus may also independently
improve glycemic control in patients with functioning insulinomas
REFERENCES
Chan JA, Kulke MH. New Treatment Options for Patients with Advanced
Neuroendocrine Tumors. Curr Treat Options Oncol, 2011;12:136–48.
Halperin DM, Kulke MH. Management of Pancreatic Neuroendocrine Tumors.
Gastroenterol Clin North Am, 2012;41:119–31.
Kulke MH, Benson AB 3rd, Bergsland E, et al. Neuroendocrine tumors. J Natl
Compr Canc Netw, 2012;10(6):724−64.
48565_ST07_353-368.indd 360
5/1/13 9:32 PM
63 ■ AUTOIMMUNE POLYGLANDULAR
SYNDROMES AND MULTIPLE ENDOCRINE
NEOPLASIAS
Catherine J. Owen, MBBS, MRCP, MRCPCH, PhD
AUTOIMMUNE POLYGLANDULAR SYNDROMES (APS)
• Encompass a wide spectrum of clinical diseases, whereby more than
one organ-specific autoimmune disease occurs in an affected individual
TABLE 63.1 Comparison of Features in APS1 and APS2
APS2
Age of onset
Adulthood (16–40 + yrs)
Female : male ratio 3:1
Main manifestations Addison’s disease + either
hypothyroidism or type 1
diabetes
Aetiology
Prevalence
Multifactorial — multiple
genes (including HLA,
CTLA-4, CYP21B) and
environmental factors.
Familial clustering.
4–5/100,000
APS1
Childhood (4–10 yrs)
1:1
Candidiasis,
hypoparathyroidism,
Addison’s disease (2 of 3 OR
1 + 2 minor manifestations)
Monogenic (autosomal
recessive) – AIRE gene
mutation (important role
in central induction of
self-tolerance).
Very rare estimated 3 per million
AUTOIMMUNE POLYGLANDULAR SYNDROMES TYPE 2 (APS2)
• The presence of autoimmune primary adrenal insufficiency (AI) with
either autoimmune thyroid disease (AITD) or type 1 diabetes
Clinical Presentation of APS2
• AI occurs in 100% and is the first endocrine abnormality in ~50%
• AITD (usually hypothyroidism) occurs in 70–90%
• Type 1 DM in 30–50%
• Complete triad (AI, AITD, and type 1 DM) noted in 10%
48565_ST07_353-368.indd 361
5/1/13 9:32 PM
362
Autoimmune Polyglandular Syndromes and Multiple Endocrine Neoplasias
• Other autoimmune conditions may also be associated (Table 63.2)
TABLE 63.2 Other Autoimmune Conditions Associated with APS2
More Common
Manifestations
(1–20 %)
Pernicious anemia
Gonadal failure
(male and female)
Vitiligo
Alopecia
Autoimmune
hepatitis
Malabsorption
(inc. celiac disease)
Sjögren syndrome
Neoplasia
Rare Manifestations
Endocrine
Pituitary involvement,
hypophysitis, empty sella
syndrome,
late-onset hypoparathyroidism
Gastrointestinal Ulcerative colitis, primary bilary
cirrhosis
Dermatological
Granuloma annulare, dermatitis
herpatiformis
Neurology
Myositis, myasthenia gravis,
neuropathy, stiff man syndrome
Other
Sarcoidosis, serositis, selective IgA
deficiency, idiopathic heart block,
idiopathic thrombocytopenia
purpura, rheumatoid arthritis
• Related conditions
APS2: presence of AITD or type 1 DM with adrenal
° Incomplete
autoantibodies; or patients with AI with thyroid and/or islet cell
autoantibodies (but not overt AITD or type 1 DM)
■ Many will develop APS2 in the future; around 30% with positive
adrenal antibodies will develop AI over the next 6 years
APS
3: association of AITD with an autoimmune disease other
° thantype
AI
Diagnosis of APS2
• History and examination essential
about family history of autoimmunity
° Ask
patients with a single autoimmune disease are at risk for others
° All
of disorders and age of onset is unpredictable
° Number
follow-up is needed to decrease morbidity and mortality,
° Long-term
especially from undiagnosed AI
• Autoantibody screening depends on the likelihood of finding another
autoimmune disease and of reducing morbidity and mortality
50% have second autoimmune endocrinopathy, so screen
° AI:
for AITD and type 1 DM at diagnosis and at periodic intervals.
Autoantibodies (i.e., TPO, GAD65, insulin, islet cell, and IA-2) can
develop at any time, so period screening is indicated even if initial
testing is negative. The optimal interval for retesting is not clear.
Some advocate checking antibodies every 5 years in adults, with
further testing yearly if positive. However, others recommend yearly
TSH testing with or without antibody screening.
with type 1 DM: at risk for AITD, therefore screen annually
° Patients
with TSH; only screen for other conditions if clinical concern
48565_ST07_353-368.indd 362
5/1/13 9:32 PM
Autoimmune Polyglandular Syndromes Type 2 (APS2)
363
AITD: rarely develop a second autoimmune condition, there° Isolated
fore only do autoantibody screening if clinical concern, not routinely
intermittent autoantibody screening in women with
° Consider
premature ovarian insufficiency or young patients with vitiligo
Family
members
° biochemically should also be assessed clinically and
• Clear link between the presence of organ-specific autoantibodies and
the progression to disease; often a latent period of months or years
• Screen antibody-positive patients annually as per the individual condition
• Also investigate if clinical symptoms suggestive of associated autoimmune condition as antibodies not 100% sensitive
TABLE 63.3 Screening Tools (Both Autoantibodies and End-Organ Testing) for the
Main Diseases Associated with the Autoimmune Polyglandular Syndromes
Disease Component
AI
AITD
T1DM
Hypoparathyroidism
Gonadal failure
Autoimmune hepatitis
Autoimmune gastritis/
pernicious anaemia
Celiac disease
Associated
Autoantibodies
End-Organ Testing
P450c21, P450scc, P450c17 BP, U&E, ACTH, plasma
renin activity, annual
synacthen test
Thyroid peroxidase,
fT3, fT4, and TSH
thyroglobulin, thyrotropin
receptor
GAD65, insulin, 1A-2, islet cell HbA1c, fasting blood glucose
Possibly the calciumSerum Ca2+, phosphate, PTH
and Mg2+
sensing receptor
P450c17, P450scc
Gonadotropin levels,
testosterone/estradiol
CYP1A2*, CYP2A6, AADC*,
LFTs
LKM
H/K-ATPase of gastric
CBC
parietal cells, intrinsic factor
Endomysial,
Intestinal biopsy
transglutaminase, gliadin
Autoantibodies marked * are almost exclusive to APS1 and thus helpful in differentiating APS1 from other
autoimmune diseases.
#
The presence of anemia on complete blood count requires further investigation with ferritin, transferrin,
and serum iron levels if the anemia is microcytic, and vitamin B12 levels if macrocytic.
P450c21, steroid 21-hydroxylase; P450scc, cholesterol side-chain cleaving enzyme; P450c17, steroid
17α-hydroxylase; GAD65, glutamic acid decarboxylase 65; 1A-2, tyrosine phosphatase-like protein 1A-2;
CYP1A2, cytochrome P450 1A2; CYP2A6, cytochrome P450 2A6; AADC, aromatic L-amino acid decarboxylase; LKM, liver–kidney microsomal.
• Other key points
and ↓ insulin dose in type 1 DM: consider AI
° Recurrent hypoglycemia
in AI, TSH levels often ↑ (~5−10 mU/L) in absence of
° Conversely,
thyroid disease, as cortisol inhibits thyrotrophin release
48565_ST07_353-368.indd 363
5/1/13 9:32 PM
364
Autoimmune Polyglandular Syndromes and Multiple Endocrine Neoplasias
Management of APS2
• Hormone replacement or other therapies for the component diseases
of APS2 are similar whether the disease occurs in isolation or in
association with other conditions, and disorders should be treated as
they are diagnosed
patients with AITD and subclinical adrenocortical failure, LT4
° In
initiation can precipitate an adrenal crisis (by ↑ cortisol clearance)
AUTOIMMUNE POLYGLANDULAR SYNDROMES TYPE 1 (APS1)
• Autosomal recessive condition, also known as the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome (APECED)
Clinical Presentation of APS1
• Three major manifestations: chronic mucocutaneous candidiasis
(CMC), autoimmune hypoparathyroidism, and AI
• Spectrum of associated endocrine and nonendocrine minor manifestations
TABLE 63.4 Major and Minor Manifestations Associated with APS1 Frequencies
Seen in North American and European Patients Are Shown in Parentheses
Major
Manifestations
Minor
Manifestations
—
Chronic mucocutaneous candidiasis (72–
100%), autoimmune hypoparathyroidism
(76–93%), autoimmune adrenal failure
(73–100%)
Endocrine
Hypergonadotrophic hypogonadism
(17–69%), AITD (4–31%), type 1 DM
(0–33%), pituitary defects (7%)
Gastrointestinal
Pernicious anemia (13–31%),
malabsorption (10–22%), cholelithiasis
(44%), chronic active hepatitis (5–31%)
Dermatological
Vitiligo (8–31%), alopecia (29–40%),
urticarial-like erythema with fever (15%)
Ectodermal Dysplasia Nail dystrophy (10–52%), dental enamel
hypoplasia (40–77%), tympanic
membrane calcification (33%)
Other
Keratoconjunctivitis (2–35%), hypo/
asplenia (15–40%)
• CMC tends to develop in infancy, hypoparathyroidism ~age 7, and AI
by 13 years
three major manifestations occur in ~60% of subjects
° All
is often mild and intermittent, may need to ask about
° CMC
specifically
Hypoparathyroidism
is often the first endocrine feature of APS1
° AI can develop gradually,
ciencies of cortisol and aldosterone
° can appear in either orderdefi
up to 20 years apart
48565_ST07_353-368.indd 364
5/1/13 9:32 PM
Clinical Presentation of MEN-1
365
• Minor manifestations present throughout life, until about the fifth decade
number of disease components is 4 but can be up to 10
° Median
active hepatitis varies from asymptomatic to cirrhosis or
° Chronic
fulminant hepatic failure with a potentially fatal outcome. Beware
↑ transaminase levels
• Great variability in the clinical picture makes diagnosis challenging
Diagnosis of APS1
• Clinical diagnosis requires 2 of the 3 major manifestations OR 1 major
and 2 minor manifestations OR 1 major manifestation + affected sibling
• Confirm with DNA screening for autoimmune regulator (AIRE) mutations and autoantibody screen
genetic testing often looks for only the most common muta° Since
tions, a negative result may not exclude the diagnosis
Interferon autoantibodies (IFN-α and IFN-ω) have almost 100%
° prevalence
in APS1 and are disease-specific, so should be measured to help identify those with negative genetic screening
• After diagnosis, close follow-up is essential, as some manifestations
(particularly AI and chronic active hepatitis) are life threatening
components recognized by standard surveillance methods
° New
of autoantibodies indicates need for at least annual
° Presence
screening for the relevant condition
° Absence of antibodies does not exclude disease development
• All siblings should be assessed
Management of APS1
• Treat individual disorders
• Treat oral candidiasis because of the risk of oral carcinoma
• Ca 2+ levels in APS1 hypoparathyroidism are often labile, probably due
to malabsorption
frequently (2–3 times monthly) and maintain around lower
° Monitor
end of the normal range (2.0–2.2 mmol/L) to avoid hypercalciuria
2+
2+
° ↓ Mg may contribute to resistance to Ca and require replacement
• In AI, alteration of the HC dose changes Ca2+ absorption
2+
° ↑ Ca may be the first sign of the AI developing
• Avoid live vaccines in view of underlying immunodeficiency
MULTIPLE ENDOCRINE NEOPLASIAS (MEN)
• Autosomal-dominant disorders, with high penetrance, leading to development of glandular hyperplasia and malignant neoplasia of endocrine organs
CLINICAL PRESENTATION OF MEN-1
• Association of parathyroid hyperplasia (>90%), pituitary adenomas
(15–50%) and pancreatic islet cell tumours (60–80%)
May also develop carcinoid, adrenocortical hyperplasia, and lipomas
°
• ~50% present <20 years of age
• Hypercalcemia due to hyperparathyroidism most common presenting
feature
48565_ST07_353-368.indd 365
5/1/13 9:32 PM
366
Autoimmune Polyglandular Syndromes and Multiple Endocrine Neoplasias
CLINICAL PRESENTATION OF MEN-2
• Associated with MTC, subdivided into
MTC with pheochromocytoma (50%) and/or hyperparathy° MEN-2A:
roidism (~35%)
MEN-2B
(rarer):
with pheochromocytoma, multiple mucosal
° neuromas (mainlyMTC
tongue and GI tract), Marfanoid habitus and dysmorphic facies, with multiple facial neuroma leading to thickened
lips and eyelids
■ MTC presents earlier and is more aggressive in MEN-2B
° Familial MTC: MTC alone
TABLE 63.5 Main Endocrine Associations in MEN-1 and MEN-2 Together with
Their Clinical Presentation and Screening/Diagnostic Tools
Important
Points
Occurs in
>90% of
cases
Prolactinoma
60% pituitary
tumours in
MEN-1
GH-secreting
Acromegaly,
IGF-1, GH
25% pituitary
tumour
gigantism
tumours in
MEN-1
ACTHCushing’s
Urinary-free
<15% pituitary
secreting or
disease
cortisol, 9 AM tumours in
nonfunctioning
and midnight MEN-1
cortisol
Insulinoma
Hypoglycaemia Glucose/
~30%
insulin
pancreatic
tumours in
MEN-1
Organ
Neoplasia
Parathyroid Hyperparathyroidism
Pituitary
MEN-1 Pancreas
Gastrinoma
PP producing,
VIP producing
Screening/
Symptoms
Diagnosis
Bones and joint Ca2+, PTH
pain, renal
stones
Galactorrhea, Prolactin
hypogonadism
Zollinger-Ellison Gastrin
syndrome
~50%
pancreatic
tumours in
MEN-1, main
cause death
Usually
Plasma PP and Rare, most other
asymptomatic, VIP, imaging
pancreatic
diarrhea
tumors are
nonfunctioning
(continues)
48565_ST07_353-368.indd 366
5/1/13 9:32 PM
Diagnosis of MEN-2
367
TABLE 63.5 (continued)
Organ
Neoplasia
Parathyroid Hyperparathyroidism
Thyroid
Medullary
carcinoma
Adrenal
Phaeochromocytoma
Symptoms
Bones and
joint pain,
renal stones
Neck mass
MEN-2
Hypertension,
headache,
adrenergic
paroxysms
Screening/
Diagnosis
Ca2+, PTH
Important
Points
Occurs in
~35% of
cases
Calcitonin
Occurs in nearly
100% fg
MEN-2 cases
Catecholamine Occurs in 50%
measurement of cases,
and/or
frequently
imaging
bilateral, rarely
malignant
DIAGNOSIS OF MEN-1
• Due to inactivating mutation of tumor suppressor gene MEN-1.
• In 70%, MEN-1 mutation is identified, the remainder diagnosed clinically
test if ≥2 MEN-1 associated tumors or positive family his° Genetic
tory of MEN-1. Age of screening children depends on family wishes
and local practice
• Once diagnosed, regular screening can detect tumors ~10 years before
symptom onset
• If patient with known mutation, begin screening at age 5 with history,
examination and annual Ca2+ and PTH, add in PRL, IGF-1 and pancreatic ultrasound after age of 10. Other tests only performed in children
if clinically indicated
• Begin screening for pancreatic neuroendocrine markers ~aged 20 by
annual measurement of gastrin, VIP, glucagon, pancreatic polypeptide,
CGA, insulin, and glucose. Also pancreas MRI every 3 years, pituitary
MRI every 3–5 years, and chest CT or MRI every 1–2 years
• If screen positive, further studies, including imaging, are necessary
DIAGNOSIS OF MEN-2
• MEN-2 caused by a gain of function mutation of the RET proto-oncogene
• Early genetic testing important as prophylactic thyroidectomy can
prevent MTC
• Close relationship between mutation and phenotype, with different
RET gene mutations correlating with time of onset of MTC, aggressiveness of MTC, and the presence or absence of other endocrine tumors
thyroidectomy recommended for all patients
° Complete
of surgery (age < 1 yr, 1–5 yrs, 5–10 yrs) depends on the
° Timing
particular RET mutation
° Annual calcitonin level also recommended
48565_ST07_353-368.indd 367
5/1/13 9:32 PM
368
Autoimmune Polyglandular Syndromes and Multiple Endocrine Neoplasias
• Annually screen for pheochromocytoma with fractionated urine or
plasma MNs
• Annually screen for primary hyperparathyroidism with serum calcium
• Genetically test all those with sporadic MTC, as 5–10% RET mutation
positive
MANAGEMENT OF MEN
• As per the individual condition or tumor, preferably by a multidisciplinary
team involving the relevant specialists experienced in managing MEN
• Other key points
gradually involves multiple glands, so need
° Hyperparathyroidism
subtotal (3½ glands) parathyroidectomy or total parathyroidectomy
with gland reimplantation in forearm
syndrome has high mortality from peptic ulcer
° Zollinger-Ellison
disease
MEN-2, complete thyroidectomy is recommended, as develop° In
ment of MTC is inevitable and has a poor prognosis once clinically
evident
REFERENCES
Burgess J. How should the patient with multiple endocrine neoplasia type 1
(MEN 1) be followed? Clin Endocrinol (Oxf), 2010;72(1):13−6.
Husebye ES, Perheentupa J, Rautemaa R, Kämpe O. Clinical manifestations
and management of patients with autoimmune polyendocrine syndrome
type I. J Intern Med, 2009;265(5):514−29.
Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol,
2009;161(1):11−20.
Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: known and novel aspects of the syndrome. Ann N Y Acad
Sci, 2011;1246:77−91.
Lankisch TO, Jaeckel E, Strassburg CP. The autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy or autoimmune polyglandular syndrome
type 1. Semin Liver Dis, 2009;29(3):307−14.
Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev
Endocrinol, 2010;6(5):270−7.
Owen CJ, Cheetham TD. Diagnosis and management of polyendocrinopathy
syndromes. Endocrinol Metab Clin North Am, 2009;38(2):419−36.
Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam
Cancer, 2010;9(3):449−57.
48565_ST07_353-368.indd 368
5/1/13 9:32 PM
INDEX
Note: Italicized page locators indicate figures; tables are noted with t
A
Abdominal scan, 138
α blockade, preoperative
management, 140
ACC. See Adrenocortical
carcinoma
ACCORD, 294
Acromegaly
clinical presentation, 19–20
diagnostic evaluation, 20–21
management, 21–24
medical therapy options, 24t
pathophysiology, 19
physical exam, 20
signs and symptoms of, 20
testing for, 23t
ACTH. See Adrenocorticotropic
hormone
ACTH-dependent Cushing’s
syndrome, 123, 126
ACTH-independent Cushing’s
syndrome, 123, 126
Actonel, 192t, 198
Acute adrenal crisis, AI, 120
Acute coronary syndrome,
DM in, 300
Acute illness, NTIS, 70
Acute treatment of
hypercalcemia, 172
ADA. See American Diabetes
Association
ADA Standards of Medical Care in
Diabetes (2013), 298
Adenohypophysis. See Anterior
pituitary
ADH. See Antidiuretic hormone
Adipocytes, release in, 339–340
Adipokines, 340
Adiponectin, 340
48565_IDXx_369-396.indd 369
Adipose tissue endocrinology,
essentials of
adiponectin, 340
derived efferent signals, 340
endocrine regulation of lipid
storage, 339–340
leptin, 340
lipodystrophies, 342
obesity, 341
types of, 339
Adjuvant mitotane for tumors, 157
Adjuvant radiotherapy
for adrenocortical carcinoma, 158
for craniopharyngiomas, 35
Adrenal adenoma, 127
Adrenal androgens, 115
replacement, 119
Adrenal cortex, 113
Adrenalectomy, 96
Adrenal essentials
anatomy, 113
function of hormones, 115–116
histology, 113
hormone synthesis, 113, 114
regulation of adrenal function,
114–115
Adrenal incidentaloma, 136
adrenal masses, 149
benign vs. malignant adrenal
masses, 151, 152
hormone hypersecretion
assessment, 149
patients
evaluation and management
with, 151, 152
history and follow-up of, 153
pheochromocytoma, 149–150
primary aldosteronism, 150
SCS, 150
5/1/13 9:35 PM
370
Index
Adrenal insufficiency (AI)
acute adrenal crisis, 120
with AITD, 362
causes of, 117
chronic treatment of, 119–120
critical illness-related
corticosteroid
insufficiency, 121
diagnosis of, 118–119
HC dosing conditions, 120
patient education and “sick day
management,” 120
symptoms and finding in, 117t
Adrenal medulla, 113
Adrenal steroidgenesis, 114
Adrenal ultrasound, 235
Adrenocortical carcinoma (ACC)
adjuvant mitotane/radiotherapy
and follow-up, 157–158
advanced disease, 158
clinical presentation, 155–157
epidemiology and
pathophysiology, 155
hormonal evaluation, 156t
initial therapy and surgical
approach, 157
mitotane effect on endocrine
function, 158–159
pathological evaluation, 157
staging for adult, 156t
Adrenocorticotropic hormone
(ACTH)
deficiency, 9, 9t
manifestations of, 8t
Adult care, transition from pediatric
to, 30
Adult growth hormone deficiency
(AGHD)
causes of, 25
clinical presentation, 25–26, 26t
diagnosis, 27
GH replacement therapy in,
recommendations for, 29t
imaging, 29
management, 29
provocative dynamic tests for, 28t
signs and symptoms of, 26t
48565_IDXx_369-396.indd 370
Adults
classification of hypoglycemia in,
321–322
DM screening in, 259
Adult Treatment Panel III, 299t
ADVANCE, 294
AGHD. See Adult growth hormone
deficiency
AI. See Adrenal insufficiency
AIT. See Amiodarone-induced
thyrotoxicosis
AITD. See Autoimmune thyroid
disease
Aldosterone antagonists, 150
Aldosterone-producing
adenoma, 150
Alemtuzumab, 76
Alendronate (Fosamax), 192t, 197
Alpha-glucosidase inhibitors, 346t
Aluminum-based antacids, 74
American Diabetes Association
(ADA)
for DM, 259, 264–266
guidelines for ill patients, 300
lipid management
recommendations, 298t
American Thyroid Association (ATA),
89, 90
Aminobisphosphonates, 197
Amiodarone
hypothyroidism, 75
pharmacology, 75
Amiodarone-induced thyrotoxicosis
(AIT)
classification, 75
diagnosis, 75
management, 75–76
Amylin mimetic (pramlintide), 346t
Anaplastic thyroid cancers (ATCs)
clinical presentation, 97
diagnostic evaluation, 98–99
differences between PDTC
and, 99t
external radiation therapy,
100–101
on FNAB, 98t
management, 100
5/1/13 9:35 PM
Index
pathophysiology, 97
signs and symptoms of, 98t
surgery, 100
treatment options and
suggestions, 101t
Anatomical imaging of
pheochromocytoma, 138
Androgen replacement
adrenal, 119
risks of, 213–215, 214t–215t
Androgens, 223
Angiotensin-converting enzyme
inhibitors (ACEIs), 297, 304
Angiotensin-II receptor, 304
Anorgasmia, 220
Anterior pituitary, 3
cells and hormones, 5–6
control of, 4
Antiadrenal medical therapy, 128
Antiandrogens, 230, 236–237
Antibiotic therapy for STI, 317
Antibody testing, glycemia
in DM, 260
Anticonvulsant therapy, 290
Antidepressants, 290
Antidiabetic medications,
noninsulin, 262t–263t
Antidiuretic hormone (ADH)
deficiency, 9t, 10
manifestations of, 8t
Antihyperglycemic medications,
cardiovascular
considerations of,
295t–296t
Antiplatelet therapy, 299
Appendiceal carcinoids tumors, 357t
APS. See Autoimmune polyglandular
syndromes
Aredia, 197
Arginine test for GH secretion
in adults, 28t
Arginine vasopressin receptor
(AVPR) antagonists, 40
ARR testing. See Plasma
aldosterone/renin ratio
testing
Arterial calcium stimulation, 323
48565_IDXx_369-396.indd 371
371
Arteries, blood supply, 113
Artifactual hypoglycemia, 322
Aspirin therapy, 299
Asymptomatic primary
hyperparathyroidism,
parathyroidectomy in,
171, 172t
ATA. See American Thyroid
Association
ATCs. See Anaplastic thyroid
cancers
Atherosclerosis, 293, 294
ATP-binding cassette transporter
A1 (ABCA1), 329
ATP III LDL-C, goals and cutpoints
for therapy, 335t
Autoantibody, screening of,
362–363
Autocrine regulation, 204
Autoimmune adrenalitis, 117
Autoimmune polyendocrinopathy–
candidiasis–ectodermal
dystrophy syndrome
(APECED), 364
Autoimmune polyglandular
syndromes (APS), 361
diseases associated with, 363t
type 1 (APS1)
clinical presentation of,
364–365
diagnosis of, 365
features in, 361t
major and minor
manifestations associated
with, 364t
management of, 365
type 2 (APS2)
autoimmune conditions
associated with, 362t
clinical presentation of,
361–362
diagnosis of, 362–363
features in, 361t
management of, 364
Autoimmune thyroid disease (AITD),
AI with, 362
Autoimmune thyroiditis, 103
5/1/13 9:35 PM
372
Index
Autosomal recessive condition.
See autoimmune
polyendocrinopathy–
candidiasis–ectodermal
dystrophy syndrome
(APECED)
B
Barbiturates, 74
Bariatric surgery for obesity, 347
Basal insulin, 264–265
β blockade, preoperative
management, 140
Behavioral weight loss
(BWL), 345
Beige cells, 339
Bexarotene, 77
Bicarbonate, hyperglycemic
emergencies
management, 274
Biguanides, 295t, 346t
Bilateral adrenalectomy, Cushing’s
syndrome, 128
Bilateral inferior petrosal sinus
sampling (IPSS), 127
Bilateral primary aldosteronism,
131, 133, 134
Bile acid–binding resins, 337
Bile acid sequestrants, 74
Biliopancreatic diversion/duodenal
switch for obesity, 347t
Biopsy, 358
Blood glucose control, 287,
304, 305
Blood pressure (BP), 136
close monitoring, 141
control, 287
Blood supply, 3, 113
Blood tests for male infertility,
218–219
BMD. See Bone mineral density
Body mass index (BMI), 259,
343–344
Bolus insulin, 265
Bone
calcitonin, 167
metabolism, 190
48565_IDXx_369-396.indd 372
Paget’s disease of. See Paget’s
disease of bone
PTH, 165
Bone mineral density (BMD)
by DEXA, 189t
maintenance of, 242
Boniva, 192t
Breastfeeding, 306
Brite cells, 339
Bronchial carcinoids tumors, 357t
Bronchoscopy, 358
Brown adipose tissue, 339
Bulbourethral glands, 202
Burned out Paget’s disease, 195
BWL. See Behavioral weight loss
C
CAH. See Congenital adrenal
hyperplasia
Calcidiol, 165
Calcifediol, 165
Calcitonin, 96, 167, 192t
Calcitonin receptor (CTR), 167
Calcium balance, maintenance of,
163–164
Calcium carbonate, 73
Calcium gluconate, 323
Calcium infusion, 183
Calcium intakes, 163, 164t
Calcium metabolism essentials
calcitonin, 167
calcium balance, maintenance
of, 163–164
PTH, 164–165
vitamin D, 165–166
Calcium-sensing receptor
(CaSR), 163
Carbamazepine, 74
treatment for central DI, 45
Carcinoembryonic antigen
(CEA), 96
Carcinoid syndrome, 359
Carcinoid tumors
clinical presentation,
356–357, 357t
diagnosis, 357–358
5/1/13 9:35 PM
Index
general management
approach, 358
hepatic-predominant metastatic
disease treatment, 359
hormonal hypersecretion
treatment symptoms of,
358–359
pathophysiology, 355
treatment options for control of,
359–360
Cardiovascular complications, 196
Cardiovascular disease (CVD), 311
management in prediabetes, 312
in type 2 diabetes
antiplatelet therapy, 299
CHD screening, 300
DM in acute coronary
syndrome, 300
dyslipidemia, 298
glycemic control, 294
hypertension management, 297
lipid guidelines, 298, 298t
NCEP, 299t
overview, 293
pathophysiology, 293, 294
risk factors, 300
Cardiovascular health, maintenance
of, 243
Carney complex, 86
Catecholamine
neurotransmitters, 221
Catecholamine-producing
tumors, 135
Catecholamines
binding to β-adrenergic
receptors, 340
function of adrenal hormones, 116
synthesis, 113
CBT. See Cognitive behavioral
therapy
C-cell hyperplasia (CCH), 93
C cells, 49
CEA. See Carcinoembryonic antigen
Central diabetes insipidus, 43
etiologies of, 43t
interpretation of test results, 44
treatment, 45
48565_IDXx_369-396.indd 373
373
Central hypothyroidism, causes
of, 63
Cerebral edema, 275
Cervical factors, female infertility,
245, 246, 249
CETP. See Cholesterol ester
transport protein
CGA. See Chromogranin A
Charcot neuroosteoarthropathy
background, 317–318
diagnosis, 318
management, 318–319
pathophysiology, 318
CHD. See Coronary heart disease
Chemotherapy, 141
Chlorpropamide, treatment for
central DI, 45
Cholecalciferol, 165
Cholesterol, 331
absorption inhibitor, 337
lipoproteins carrying, 325
Cholesterol esters (CE), 325
Cholesterol ester transport protein
(CETP), 327, 329
Cholestyramine, 74
Chromogranin A (CGA), 357
Chronic hypercalcemia, symptoms
of, 170, 170t
Chronic illness, NTIS, 70
Chronic mucocutaneous candidiasis
(CMC), 364
Chronic treatment
of AI, 119–120
for hypercalcemia, 172
Chvostek’s sign, 182
Chylomicrons (CM), 326, 331, 339
Clofibrate, treatment for central
DI, 45
Clomiphene
citrate, 248
resistance to, 248
CMC. See Chronic mucocutaneous
candidiasis
CNS stimulants/appetite
suppressants, 346t
Cognitive behavioral therapy (CBT),
for obesity, 345
5/1/13 9:35 PM
374
Index
Colonoscopy, 358
Combined oral contraceptives, 230
Computed tomography (CT)
scans, 156
abdominal, 138
adrenal, 126, 133
anatomical imaging, 138
of chest, 94
of neck, 57, 99
for NET liver metastases, 358
parathyroid, 177
Congenital adrenal hyperplasia
(CAH)
clinical presentation, 144–145
laboratory testing and
diagnostic evaluation,
145, 145t
management, 145–147
pathophysiology, 143–144, 143
types of, 144
Congenital hypothyroidism, 63
Conivaptan, 40
Connecting peptide
(C-peptide), 253
glycemia in DM, 260
Coronary heart disease (CHD),
screening, 300
Correction-dose insulin, 308–309
Corticotrophin-releasing hormone
(CRH) testing, 127
Corticotrophs, 6
Cosmetic therapies for
hirsutism, 237
Cosyntropin stimulation test
(CST), 118
Counter-regulatory hormones, 255
Cowden’s syndrome, 86
CPA. See Cyproterone acetate
C-peptide. See Connecting peptide
Craniopharyngiomas
background, 34
management, 35
presentation and
evaluation, 35
CST. See Cosyntropin stimulation
test
Cushing’s disease, 126–128
48565_IDXx_369-396.indd 374
Cushing’s syndrome, 95
causes, management of,
127–128
clinical features, 123
diagnostic strategy, 124–125
differential diagnosis, 126–127
etiologies, 123
standard diagnostic tests for,
125–126
Cyproterone acetate (CPA), 236
Cytokines, 69
Cytotoxic chemotherapy, 359
D
Debulking surgery, 141
Deficient hormones, manifestations
of, 8t
Demeclocycline, managing SIADH, 39
Denosumab (Prolia), 192t
DEXA. See Dual-energy X-ray
absorptiometry
Dexamethasone, 118
DI. See Diabetes insipidus
Diabetes
hypoglycemia in
acute treatment of, 279
classification of, 277
etiologies, 277–278
prevention of, 279
preexisting. See Preexisting
diabetes
in pregnancy
classification, 303
diagnosis of GDM, 303–304
management of, 304–305
postnatal care, 305–306
preconception care, 304
prenatal considerations for, 305
risk factors for GDM, 303
type 1
glycemic management in,
264–265
TDD of, 264
type 2
cardiovascular disease in.
See Cardiovascular disease,
in type 2 diabetes
5/1/13 9:35 PM
Index
glycemic management in,
265–267
Diabetes insipidus (DI)
clinical manifestations, 43
definition, 43
diagnosis, 44
etiologies of, 43t
treatment, 45
types of, 43
Diabetes mellitus (DM), 255
in acute coronary syndrome, 300
ADA for, 259
background, 257
drug-induced, 258
gestational, 259
glycemia in, 260
pharmaceutical options
for, 261t
type 1
glycemic management in,
264–265
pathophysiology and clinical
presentation of, 257
type 2
glycemic management in,
265–266
pathophysiology and clinical
presentation of, 257–258
recommendations for
delay, 312
Diabetes prevention
associated conditions, 311
clinical presentation, 311
diagnostic evaluation, 311t
pathophysiology, 311
Diabetic cardiomyopathy, 294
Diabetic foot ulceration and
infection
background, 315
long-term care, 317
management of, 316
osteomyelitis, 317
pathophysiology, 315–316
Diabetic ketoacidosis (DKA), 257
diagnosis, 272t
evaluation, 272, 272t
laboratory abnormalities, 273
48565_IDXx_369-396.indd 375
375
management, 273–274, 274t
complications of, 274–275
pathophysiology, 271
resolution of, 275
transition from IV insulin
infusion, 275
typical precipitating factors, 272
Diabetic nephropathy
clinical presentation, 286
diagnostic evaluation, 286
epidemiology, 285
management, 287
pathophysiology, 285
risk factors, 285
stages of, 286t
Diabetic retinopathy
clinical presentation, 281
diagnostic evaluation, 281
management, 282
nonproliferative and
proliferative, 281
pathophysiology, 281
retinal findings, 282t
Diet
for metabolic syndrome, 350
for obesity, 345
Dietary fiber, 346
Differentiated thyroid cancer
(DTC), 85
features indicating risk of
recurrence of, 90t
initial treatment of, 89–90
Diminished ovarian reserve
(DOR), 249
Discontinue oral antidiabetic
agents, 307
Distal sensory neuropathy, 316
Distal symmetrical neuropathy, 315
Distal symmetric polyneuropathy
(DSPN)
clinical presentation, 289
management of, 290
pathophysiology, 289
screening and monitoring of,
289–290
DKA. See Diabetic ketoacidosis
DM. See Diabetes mellitus
5/1/13 9:35 PM
376
Index
Dopamine, 77
Dopamine agonists
for acromegaly, 22, 24t
for nonfunctioning
macroadenomas, 33
for ovulation, 16
treatment for
hyperprolactinemia, 15
DOR. See Diminished ovarian reserve
Doxazosin, 140
DPP-4 inhibitors, 296t
Drospirenone, 230, 237
Drug-induced DM, 258
Drugs affecting thyroid function
absorption, 73–74
causing central
hypothyroidism, 77
directly, 75–77
hormone metabolism, 74
DSPN. See Distal symmetric
polyneuropathy
DTC. See Differentiated thyroid
cancer
Dual-energy X-ray absorptiometry
(DEXA), BMD by, 189t
Dysbetalipoproteinemia, 334
Dyslipidemia, 298
E
Early postnatal period, 202
EBRT. See External beam radiation
therapy
Ectopic ACTH syndrome, 128
Eflornithine cream, hirsutism, 237
Ejaculatory duct, 202
Ejaculatory dysfunction, 217, 219
11-hydroxylase deficiency (11OHD),
144, 147
Endocrine
function, 201
in MEN-1 and MEN-2, 366t–367t
pancreas, 253–255
Endocrinopathies, 217
therapies for, 219–220
Endogenous fat. See Transport
of hepatic fat
Endometrium, menstrual cycle, 224t
48565_IDXx_369-396.indd 376
Endoscopic ultrasound, 358
Energy expenditure,
calculating, 343
Energy intake, calculating, 343
Enteral feeding, 309
Enzymes in steroid
metabolism, 340
Epididymis, 202
Erectile dysfunction, 220
Ergocalciferol, 165
Estradiol, 222
Estrogen, 221, 222
HRT, 192t
skeletal protection, 178
symptoms of deficiency, 240
Euvolemia, 38
Everolimus, mTOR inhibitor, 360
Evista, 192t
Exercise
for metabolic syndrome, 350
for obesity, 345
Exocrine function, 201
Exogenous fat. See Transport
of dietary fat
External beam radiation
therapy (EBRT), 85,
96, 141
Extracellular fluid (ECF) volume,
classification of
hypoosmolality by, 38
Ezetimibe, 337
F
Factitious hypoglycemia, 322
Factitious thyrotoxicosis, 53t
Familial combined
hyperlipidemia, 333
Familial hyperaldosteronism
type I, 131
type II, 131
Familial hypercholesterolemia, 333
Familial hyperchylomicronemia, 333
Familial hypertriglyceridemia, 334
Familial medullary thyroid cancer
(FMTC), 93
Family planning, 243
Fasting hypoglycemia, 321
5/1/13 9:35 PM
Index
Female infertility. See also Male
infertility
causes of, 245
clinical presentation, 246
diagnostic evaluation, 246–247
management, 247–249
pathophysiology, 245
preconception counseling, 247
treatment of, 248
Female reproduction essentials
development in embryo, 221
menopause, 224–226
menstrual cycle hormones,
221–224, 223t–224t,
225 –226
puberty, 221
Ferriman Gallwey hirsutism scoring
system, 234, 235
Fibrates. See Fibric acid derivatives
Fibric acid derivatives, 337
Fibroblast growth factor (FGF), 5
Finasteride, 237
Fine needle aspiration (FNA),
81, 151
5-Hydroxyindole acetic acid
(5-HIAA), 357
Fludrocortisone suppression
testing, 133
Fluid restriction, managing
SIADH, 39
Flutamide, 237
FMTC. See Familial medullary
thyroid cancer
FNA. See Fine needle aspiration
Follicles, 49
Follicular stimulating hormone
(FSH), 222
deficiency, 9t, 10
manifestations of, 8t
Follicular thyroid carcinoma
(FTC), 85
clinical presentation and
diagnosis, 87
definition, 85
epidemiology, 85
long-term management, 90–91
pathogenesis, 86
48565_IDXx_369-396.indd 377
377
pathological features, 86–87
persistent/recurrent disease
management, 91–92
prognosis, 87–88
risk factors, 85–86
TNM classification, 88
Forteo, 192t
Fosamax, 192t, 197
Fracture, risk factors for, 191t
Frederickson’s classification of
lipoprotein disorders, 333t
type I, 333
type II, 333
type III, 334
type IV, 334
type V, 334
Free cholesterol (FC), 325
Free fatty acids, 339
Free thyroxine index (FTI), 52t
FTC. See Follicular thyroid
carcinoma
FTI. See Free thyroxine index
Fuel homeostasis, insulin
roles in, 255
Fuel metabolism, essentials,
253–255
Functional imaging,
pheochromocytoma, 138
G
Gastric banding procedure for
obesity, 347t
Gastric bypass procedure for
obesity, 347t
Gastric carcinoids tumors, 357t
Gastrinoma, 359
GDM. See Gestational diabetes
mellitus
Genetic testing,
pheochromocytoma,
138, 139
Gestation, 202
Gestational diabetes mellitus
(GDM), 259
diagnosis of, 303–304
risk factors for, 303
women with, 305–306
5/1/13 9:35 PM
378
Index
GH receptor antagonist, 22, 23, 24t
Glucagon
actions of, 254
secretion, hypoglycemia
lack, 278
test for GH secretion in
adults, 28t
Glucagon-like peptide 1 (GLP-1)
analogs, 346t
receptor agonists, 296t
Glucagonoma, 359
Glucocorticoid-remediable
aldosteronism (GRA), 131,
133, 134
Glucocorticoids, 77, 114, 115,
237, 309
equivalency chart for, 120t
replacement of AI, 119
Glucose, 307, 339
Glycemia in DM, diagnosis and
management of, 260
Glycemic control
in type 1 diabetes, 264–265
in type 2 diabetes, 265–266, 294
Glycemic issues in hospitalized
patients
in ICU, 309–310
outside ICU, 307–309
Goiter effects, lithium, 76
Gonadotrophs, 6
Gonadotropin, 249
Gonadotropin-releasing hormone
(GnRH), 221, 237
regulation of, 203
GRA. See Glucocorticoid-remediable
aldosteronism
Granulomatous disease, 172
Graves’ disease, 53t
Growth hormone (GH)
manifestations of, 8t
measurement of, 20–21
replacement therapy
in AGHD, 29t
Growth hormone deficiency (GHD),
25–26, 26t
in adults. See Adult growth
hormone deficiency
48565_IDXx_369-396.indd 378
Growth hormone–releasing
hormone (GHRH), 28t
Gynecomastia
clinical presentation, 206
diagnostic evaluation, 206
history and physical examination
in, 206t
management, 207
pathogenesis of, 205t
H
HAAF. See Hypoglycemia-associated
autonomic failure
HDDST. See High-dose
dexamethasone test
HDL. See High-density lipoprotein
Hemoglobin A1c, glycemia in
DM, 260
Hepatic cholesterol pool,
determination of, 328
Hepatic-predominant metastatic
disease, 359
Heterogeneous syndrome, 227
HHS. See Hyperosmolar
hyperglycemic state
High-density lipoprotein (HDL),
325, 331, 332
High-dose dexamethasone test
(HDDST), 126
Highly active antiretroviral therapy
(HAART), 342
High-risk patients, benefit from
metformin, 312
Hirsutism
clinical presentation, 233–235
diagnostic evaluation, 235
management, 236–238
pathophysiology, 233
in PCOS, 230
HMG-CoA reductase inhibitors,
335–337, 336t
Hormonal assessment for pituitary
hypofunction, 9t
Hormone hypersecretion
assessment for, 149
biochemical evaluation for, 153
treatment symptoms of, 358–359
5/1/13 9:35 PM
Index
Hormone replacement, 9–10
thyroid, 71, 73–77
Hormone replacement therapy
(HRT), 242
for females, 10
Hormones
counter-regulatory, 255
of menstrual cycle, 221–224,
223t–224t
secretion, adrenal
incidentalomas, 153
Hospitalized patients outside, ICU,
307–309
HPA axis. See Hypothalamicpituitary-adrenal axis
HPT axis. See Hypothalamicpituitary-thyroid (HPT) axis
H2 receptor antagonists, 73
Hungry bone syndrome, 181
Hurthle cell cancer, 87
Hydrocortisone (HC), 146
dosing conditions of AI, 120
IV, 67
Hyperandrogenism, 227–228
OCPs reducing, 236
Hypercalcemia
clinical presentation, 170
crisis, 178
diagnostic evaluation, 170–172
incidence, 169
management, 172
pathophysiology, 169–170
Hyperchloremic acidosis, 275
Hyperfunction, screening for, 32
Hyperglycemia for patients in ICU,
309–310
Hyperglycemic emergencies
diagnosis, 272t
evaluation, 272, 272t
laboratory abnormalities, 273
management, 273–274, 274t
complications of, 274–275
pathophysiology, 271
resolution of, 275
transition from IV insulin
infusion, 275
typical precipitating factors, 272
48565_IDXx_369-396.indd 379
379
Hyperosmolar hyperglycemic
state (HHS)
diagnosis, 272t
evaluation, 272, 272t
laboratory abnormalities, 273
management, 273–274, 274t
complications of, 274–275
pathophysiology, 271
resolution of, 275
transition from IV insulin
infusion, 275
typical precipitating
factors, 272
Hyperparathyroidism, 94
clinical presentation, 176
diagnostic evaluation,
176–178
management, 178
pathophysiology, 175
Hyperprolactinemia, 220
pathophysiology, 13
symptoms due to, 13t, 14
Hypertension, 131, 141
management, 297
monitor for, 312
Hyperthyroidism
clinical features of, 54
in pregnancy
clinical presentation, 106
diagnosis, 106
etiology and
pathophysiology, 105
laboratory evaluation, 106
management, 107
subclinical, 60–61
Hypertonic saline, managing
SIADH, 39
Hypertrichosis, 233
Hypervolemia, 38
Hypocalcemia
clinical presentation, 182
diagnostic evaluation scheme
for, 183, 183
laboratory testing, 182–183
management, 183, 184
pathophysiology, 181
specific causes, 181
5/1/13 9:35 PM
380
Index
Hypoglycemia, 253, 274
development of, 271
disorders
classification in adults,
321–322
defined, 321
diagnosis, 322
imaging, 323
neurogenic vs. neuroglycopenic
symptoms, 321t
treatment, 323
lack of, 278
in patients with diabetes
acute treatment of, 279
classification of, 277
definition, 277
etiologies of, 277
prevention of, 279
symptoms of, 277
treatment of, 268, 300
Hypoglycemia-associated
autonomic failure (HAAF),
risk factors for, 278
Hypogonadism, prevalence of,
211–212
Hypokalemia, 131, 274
Hyponatremia treatment guidelines
for SIADH, 41
Hypoosmolality
classification by ECF
volume, 38
clinical presentation, 37
diagnostic evaluation, 38
pathophysiology, 37
Hypophyseal portal vessels, 3
Hypopituitarism
background, 7
causes of, 7
clinical presentation, 7–8
diagnostic evaluation, 9
hormone replacement, 9–10
pathophysiology, 7
screening for, 32
surgery for, 33
Hypotension, 141
Hypothalamic-pituitary-adrenal
(HPA) axis, 115
48565_IDXx_369-396.indd 380
Hypothalamic-pituitary-testicular
axis, 203
in male, 209, 209
Hypothalamic-pituitary-thyroid
(HPT) axis, 69, 70
Hypothalamopituitary disease, 219
Hypothyroidism, 75, 76
background, 63–64
clinical presentation of, 64t
diagnosis, 64
myxedema coma, 66–67
in pregnancy
clinical presentation, 103
diagnosis, 104
etiology and
pathophysiology, 103
laboratory evaluation, 104
management, 104–105
screening for, 103
subclinical, 66
treatment, 65–66
Hypovolemia, 38
I
Ibandronate (Boniva), 192t
ICU
hospitalized patients outside,
307–309
patients in, 309–310
Idiopathic hirsutism, 233
Idiopathic hyperandrogenemia, 233
IDL. See Intermediate density
lipoprotein
Imatinib, 74
Immobilization, 172
Impaired Fasting Glucose (IFG), 311
Impaired Glucose Tolerance
(IGT), 311
IMRT. See Intensity-modulated
radiation therapy
Inactivating enzyme. See Type 3
deiodinase (D3) catalyses
Infection, diabetic foot, 315–317
Infertility, 146
female. See Female infertility
male. See Male infertility
in PCOS, 231
5/1/13 9:35 PM
Index
Insulin
actions of, 253
defects, 257–258
basal, 264, 265
bolus, 265
cardiovascular considerations
of, 296t
excess, 277
formulations, 261t
hyperglycemic emergencies
management, 274
initial dose of, 309
measurements, 253
mixtures of, 308t
preparations of, 308t
protocol for initiating, 308
roles in fuel homeostasis, 255
TDD of, 275
use in pregnancy, 305
Insulin-like growth factor-1 (IGF-1)
testing, 20
Insulin-lowering medications, 237
Insulinoma, 358–359
Insulin pump. See SQ insulin
Insulin resistance, pathophysiology
of, 293
Insulin-responsive glucose
transporter (Glut4), 339
Insulin therapy, 305
multiple-dose, 264
Insulin tolerance test (ITT)
for AGHD, 27, 28t
for diagnosis of AI, 118
Intensity-modulated radiation
therapy (IMRT), 100
Interferon-α, 76–77, 359
Interleukin-2, 77
Intermediate/long-acting
insulin, 308t
Intermediate density lipoprotein
(IDL), 327, 331, 332
Interpretation of test for diagnosis
of DI, 44
Interstitial compartment,
testes, 201
Intestinal fat absorption
inhibitor, 346t
48565_IDXx_369-396.indd 381
381
Intraoperative hypertensive crisis,
140–141
Intrauterine insemination (IUI), 249
Intravenous (IV) fluids,
hyperglycemic emergencies
management, 273–274
Intravenous (IV) insulin infusion,
transition from, 275
Intravenous (IV) insulin protocols
for patients in ICU,
309–310
Intravenous (IV) saline infusion
testing, 132
In vitro fertilization (IVF), 249
Iodine, 53t
deficiency, 63
Islets of Langerhans, 253
Isotonic saline, managing
SIADH, 39
ITT. See Insulin tolerance test
IUI. See Intrauterine insemination
IVF. See In vitro fertilization
K
Ketoacidosis
development of, 271
diabetic. See Diabetic
ketoacidosis
Kidney
calcitonin, 167
PTH, 165
L
Lactotrophs, 5
LADA. See Latent autoimmune
diabetes of adults
Lanthanum carbonate, 73
Laser photocoagulation, 282
Latent autoimmune diabetes
of adults (LADA), 258
LCAH. See Lipoid CAH
LDL. See Low-density lipoprotein
LDLR. See Low-density lipoprotein
receptor
Leptin, 340
Leydig cells, 201
5/1/13 9:35 PM
382
Index
Lifestyle modifications, treatment
for obesity, 345
Lipid
control, 287
disorders
components, 331
pharmacologic therapies, 335,
336t, 337–338
TC and LDL cholesterol,
classification, 331–335
essentials, 325–329
guidelines, 298, 298t
Lipid-poor adrenal tumors, 151
Lipodystrophies, 342
Lipoid CAH (LCAH), 144, 147
Lipomastia, 205
Lipoprotein
disorders, Frederickson’s
classification of,
333–334, 333t
lipid profile reflects, 325
structure and function,
325t–326t
Lipoprotein lipase (LPL),
326, 339
Lithium
effects, 76
mechanisms, 76
Liver metastases, NETs, 358
Long-term care, diabetic
foot ulceration and
infection, 317
Low-density lipoprotein (LDL), 325,
327–328, 331
Low-density lipoprotein (LDL)
cholesterol
ATP III, goals and cutpoints for
therapy, 335t
classification of, 331–335, 332t
Low-density lipoprotein receptor
(LDLR), 327
LPL. See Lipoprotein lipase
Luteinizing hormone (LH), 222
deficiency, 9t, 10
manifestations of, 8t
Lymphoma, 172
48565_IDXx_369-396.indd 382
M
Macroadenomas, 16, 19
nonfunctioning, 33
Magnetic resonance imaging
(MRI) scan
anatomical imaging, 138
craniopharyngiomas, 35
for NET liver metastases, 358
pituitary, 127
tumor size monitored, 16
Malabsorption syndromes,
evaluation of, 186
Male factors, causes of infertility,
245, 247, 249
Male infertility. See also Female
infertility
clinical presentation, 218
definition of, 217
diagnostic evaluation,
218–219
diagnostic imaging, 219
pathophysiology of, 217
treatment of, 219–220
Male reproduction essentials
neuroendocrine regulation,
203–204
reproductive outflow tract, 202
sexual differentiation, 202–203
testes, 201
Males
hypothalamic-pituitarytesticular axis in,
209, 209
testosterone replacement for, 10
Mammalian target of rapamycin
(mTOR) inhibitor
everolimus, 360
Mammosomatotrophs, 6
Maturity-onset diabetes of the
young (MODY), 258
clinical presentation of, 267,
269t–270t
diagnostic evaluation, 267
management, 268
pathophysiology of, 267,
268t–269t
5/1/13 9:35 PM
Index
Medical comorbidities,
management for
acromegaly, 23
Medical nutrition therapy
(MNT), 312
Medical therapy for acromegaly, 22
Medullary thyroid cancer (MTC)
clinical features, 95
clinical presentation, 94
diagnosis, 94
epidemiology, 93
features of, 93t
follow-up, 96
pathophysiology, 93
staging, 95
therapy, 95–96
Meiosis arrests, 221
MEN. See Multiple endocrine
neoplasias
Menopause, 224–226
Menstrual abnormalities, 228
Menstrual cycle hormones,
221–224, 223t–224t,
225 –226
Menstrual irregularity in PCOS, 231
Metabolic syndrome
clinical presentation, 350
component of, 341
diagnosis, 350
features of, 349t
incidence in randomized control
trials, 351t
international criteria for, 350t
laboratory testing, 350
prevalence of, 349
treatment, 350–351
Metanephrine (MN) testing,
interpretation of, 137
Metformin, 230, 237, 305, 312, 346t
Metyrosine, 140
Miacalcin, 198
Microadenomas, 16
nonfunctioning, 32–33
Mineralocorticoid, 114, 116
antagonist, 147
replacement of AI, 119
48565_IDXx_369-396.indd 383
383
Mitotane effect on endocrine
function, 158–159
MNT. See Medical nutrition therapy
MODY. See Maturity-onset diabetes
of the young
Molecularly targeted therapy, 360
Monitoring serum in hospitalized
patients with SIADH,
41–42
Motor, distal symmetrical
neuropathy, 315
MTC. See Medullary thyroid cancer
Multiple-dose insulin therapy, 264
Multiple endocrine neoplasias-1
(MEN-1)
clinical presentation of, 365, 366
diagnosis of, 367
endocrine associations in, 366t
Multiple endocrine neoplasias-2
(MEN-2)
clinical presentation of, 366, 367
diagnosis of, 367–368
endocrine associations in, 367t
Multiple endocrine neoplasias
(MEN)
management of, 368
Myxedema coma, 66
diagnosis, 67
management, 67
N
Nascent HDL (nHDL), 329
National Cholesterol Education
Program (NCEP) Adult
Treatment Panel III,
299t, 350
Neoplastic cell, 196
Nephrogenic diabetes insipidus, 43
etiologies of, 43t
interpretation of test results, 44
treatment, 45
Nephropathy, diabetic. See Diabetic
nephropathy
NETs. See Neuroendocrine tumors
Neuroendocrine regulation,
203–204
5/1/13 9:35 PM
384
Index
Neuroendocrine tumors (NETs), 355
classification of, 355t
liver metastases, 358
pancreatic. See Pancreatic
neuroendocrine tumors
Neurohypophysis. See Posterior
pituitary
Neurologic symptoms, 196
Neuropathy
CN complication of, 318
distal sensory, 316
distal symmetrical, 315
Niacin. See Nicotinic acid
Nicotinic acid, 337–338
Nonesterified fatty acids, 340
Nonfunctioning macroadenoma
management of, 33–34
signs or symptoms of, 33
Nonfunctioning microadenoma
management of, 33
presentation and natural
history, 32
Nonfunctioning pituitary adenomas
management of, 33–34
presentation and natural history
of, 32–33
Non-high-density lipoprotein, 332
Noninsulin antidiabetic
medications, 262t–263t
Noninsulinoma pancreatogenous
hypoglycemia syndrome
(NIPHS), 323
Nonislet cell tumors, 321
Nonproliferative diabetic
retinopathy, 281
Non-ST elevation myocardial
infarction (NSTEMI), 300
Nonsteroidal anti-inflammatory
drugs (NSAIDs), 45
Nonthyroidal illness syndrome
(NTIS)
background, 69
diagnostic evaluation, 70–71
management, 71
pathophysiology, 69–70
treatment of, 71
TSH levels, 70–71
48565_IDXx_369-396.indd 384
Normocalcemic
hyperparathyroidism, 176
NSAIDs. See Nonsteroidal antiinflammatory drugs
NSTEMI. See Non-ST elevation
myocardial infarction
NTIS. See Nonthyroidal illness
syndrome
O
Obesity
adipose tissue endocrinology
in, 341
clinical definitions, 341
male infertility, 220
management
clinical presentation,
344–345, 344t
diagnosis, 343–344
pathophysiology, 343
treatment, 345–347
pharmacotherapy for, 346t
rapidly increasing prevalence, 341
roles of, 255
surgical treatment of, 347, 347t
OCPs. See Oral contraceptive pills
ODS. See Osmotic demyelination
syndrome
Oral contraceptive pills (OCPs), 242
reducing hyperandrogenism, 236
Oral contraceptives, 236
Oral salt loading, 132
Osmoreceptors, 3
Osmotic demyelination syndrome
(ODS), 41
Osteitis deformans. See Paget’s
disease of bone
Osteomyelitis, 317
Osteoporosis
bone metabolism, 190
definition, 189–190
epidemiology, 189
medical therapy for use in, 192t
risk factors for, 191, 191t
screening, 191
secondary causes of, 190t
treatment, 191–192
5/1/13 9:35 PM
Index
Osteoporotic fractures, 189
Ovarian hormones, menstrual
cycle, 223
Ovarian ultrasound, 145
Ovary, menstrual cycle, 223
Overnight metyrapone test, 118
Ovulation induction, 248
Ovulatory dysfunction, 245,
246, 248
Oxytocin, 5
P
PAD. See Peripheral arterial disease
Paget’s disease of bone
assessment of therapeutic
response, 197–198
clinical presentation, 195–196
diagnostic evaluation, 196
etiology, 195
management, 197–198
pathophysiology, 195
physical examination, 196
Painful subacute thyroiditis, 53t
Painless thyroiditis, 76
Pamidronate (Aredia), 197
Pancreas
endocrine, 253–255
nonimmune causes of, 258
Pancreatic islets, 253
Pancreatic neuroendocrine
tumors (NETs)
clinical presentation,
356–357, 356t
diagnosis, 357–358
general management
approach, 358
hepatic-predominant metastatic
disease treatment, 359
hormonal hypersecretion
treatment symptoms of,
358–359
pathophysiology of, 355
treatment of, 356t, 359–360
Panretinal photocoagulation, 282
Papillary thyroid carcinoma (PTC)
clinical presentation and
diagnosis, 87
48565_IDXx_369-396.indd 385
385
definition, 85
epidemiology, 85
long-term management,
90–91
pathogenesis, 86
pathological features, 86–87
persistent/recurrent disease
management, 91–92
prognosis, 87–88
risk factors, 85–86
TNM classification, 88
Paracrine regulation, 204
Parathyroidectomy, 96
in asymptomatic primary
hyperparathyroidism,
171, 172t
Parathyroid gland anatomy, 164
Parathyroid hormone (PTH),
164–165, 171
Parathyroid hormone 1-receptor
(PTH-1R), 164
Parenteral feeding, 309
Patient education of AI, 120
PCOS. See Polycystic ovary
syndrome
PDTC. See Poorly differentiated
thyroid cancer
Pelvic ultrasound, 235, 241
Perimenopause, 224
Peripheral arterial disease
(PAD), 315
Peritoneal factor, female infertility,
245, 247, 249
P450-oxidoreductase deficiency
(PORD), 144, 147
PG. See Plasma glucose
Pharmacological therapy,
57–58, 192
hirsutism, 236
for lipid disorders, 335–338
treatment goals with, 312
Pharmacotherapy
for obesity, 346t
for Paget’s disease of bone,
197–198
Phenoxybenzamine, 140
Phenytoin, 74
5/1/13 9:35 PM
386
Index
Pheochromocytoma, 94
adrenal incidentalomas,
149–150
clinical presentation, 136
diagnostic evaluation
anatomical imaging, 138
functional imaging, 138
genetic testing, 138, 139
screening test strategy, 137
follow-up, 141
malignant
pheochromocytomas, 141
management
operative, 140–141
postoperative, 141
preoperative, 140
pathophysiology, 135
Phosphate, hyperglycemic
emergencies
management, 274
PHPT. See Primary
hyperparathyroidism
Physical activity factor, energy
expenditure, 343
PI. See Pituitary incidentalomas
Pituitary essentials
basic facts, 3
control of, 3–5, 4
function, 5–6
MRI, 127
Pituitary hormones, menstrual
cycle, 223
Pituitary hypofunction, hormonal
assessment for, 9t
Pituitary incidentalomas (PI)
definition of, 31
differential diagnosis, 31
evaluation, 31–32
management, 32
Plasma aldosterone/renin ratio
(ARR) testing,
131–132
Plasma calcium, 163
Plasma catecholamines, 137
Plasma chromogranin A, 137
Plasma glucose (PG), glycemia
in DM, 260
48565_IDXx_369-396.indd 386
Plasma lipoproteins, 325
determined by
reverse cholesterol transport,
329, 329
transport of dietary fat,
326, 327
transport of hepatic fat,
327–328, 328
Plasma methoxytyramine, 137
Plateau response, 198
POCT glucose. See Point-of-care
testing glucose
POI. See Primary ovarian
insufficiency
Point-of-care testing (POCT)
glucose, 307
glycemia in DM, 260
Polycystic ovaries, characteristics
of, 229
Polycystic ovary syndrome
(PCOS)
background, 227
definitions, 227
hirsutism in, 230
imaging, 229
infertility in, 231
investigations, 228–229
management of, 229–230
menstrual irregularity in, 231
signs, 228
symptoms, 227–228
Poorly differentiated thyroid
cancer (PDTC)
clinical presentation, 97
diagnostic evaluation, 98–99
differences between ATC
and, 99t
external radiation therapy,
100–101
management, 100
pathophysiology, 97
surgery, 100
PORD. See P450-oxidoreductase
deficiency
Positron emission tomography
(PET) scanning,
pheochromocytoma, 138
5/1/13 9:35 PM
Index
Posterior pituitary, 3
control of, 4
hormones, 5
Postnatal care, 305–306
Postpartum thyroiditis
clinical presentation, 109
diagnostic evaluation, 109
etiology and
pathophysiology, 109
in pregnancy, 109
treatment and monitoring, 110
Postprandial hypoglycemia. See
Reactive hypoglycemia
PPI. See Proton pump inhibitors
Pramlintide. See Amylin mimetic
Preconception care of women with
diabetes, 304
Prediabetes
associated conditions, 311
clinical presentation, 311
diagnostic evaluation, 311t
management of CVD in, 312
pathophysiology, 311
treatment goals with
pharmacologic
therapy, 312
Preexisting diabetes, women with,
304, 306
Pregnancy, 16
diabetes in. See Diabetes,
in pregnancy
thyroid disorders in. See Thyroid
disorders in pregnancy
21OHD, 144
Premixed insulin for
DM, 261t
Pressure sores on heel, 315
Primary AI, 117, 118
Primary aldosteronism, 150
ARR testing, 131–132
clinical presentation, 131
confirmatory testing options,
132–133
management, 134
subtype differentiation, 133
subtypes of, 131t, 132t
unilateral vs. bilateral, 133
48565_IDXx_369-396.indd 387
387
Primary hyperparathyroidism
(PHPT), 94, 169, 172
clinical presentation, 176
pathophysiology, 175
symptomatic, 176
treatment in, 178
in young adults/children, 177
Primary hypothyroidism,
causes of, 63
Primary medical therapy for
acromegaly, 21
Primary ovarian insufficiency (POI)
clinical presentation, 239–240
definition, 239
diagnostic evaluation,
240–241
management, 241–243
pathophysiology, 239
Primary polydipsia, 43, 44
diagnosis, 44
treatment, 45
Primary testicular defect
in sperm production, 217
therapies for, 219
Progesterone, 222
Progestins, 236
Prolactin (PRL)
inhibition of, 13
levels during pregnancy, 16
Prolactinemia
clinical presentation, 13–14
diagnostic evaluation, 14
follow-up, 16
pathophysiology, 13
treatment, 15
Prolactinomas
diagnostic evaluation, 14
pathophysiology, 13
treatment, 15
Prolia, 192t
Proliferative diabetic
retinopathy, 281
Prostate glands, 202
Proton pump inhibitors (PPI), 73
Provocative tests
for diagnosis of DI, 44
for GH secretion in adults, 28t
5/1/13 9:35 PM
388
Index
Pseudogynecomastia, 205
Psuedo-Cushing’s syndrome, 124
PTC. See Papillary thyroid carcinoma
Puberty, 203, 221
R
Radiation therapy (RT)
for acromegaly, 23
Cushing’s syndrome, 128
external, 100–101
for prolactinemia, 15
Radioactive iodine therapy, 58–59
Raloxifene, 74
Rapid-acting insulin for DM, 261t, 265
Rapid/short-acting insulin, 308t
Reactive hypoglycemia, 322
Rearranged during transfection
(RET), 93
Reclast, 192t, 197
Rectal carcinoids tumors, 357t
Regulation of adrenal function,
114, 115
Renal fluid excretion, increased, 40
Reproductive outflow tract, 202
Resting metabolic rate (RMR), 343
RET. See Rearranged during
transfection
Retinopathy, diabetic. See Diabetic
retinopathy
Reverse cholesterol transport,
329, 329
Rifampicin, 74
Risedronate (Actonel), 192t, 198
RMR. See Resting metabolic rate
S
Salmon calcitonin (Miacalcin), 198
Screening guidelines for men
and women, 191, 191t
Scrotal ultrasound, 219
SCS. See Subclinical Cushing’s
syndrome
Secondary adrenal insufficiency
(AI), 117, 119
Secondary hyperparathyroidism,
175, 176
48565_IDXx_369-396.indd 388
Sellar imaging, male infertility, 219
Seminal fluid analysis for male
infertility, 218–219
Seminal vesicle, 202
Seminiferous tubules, 201
Sensory, distal symmetrical
neuropathy, 315
Sequential gene testing, clinical
algorithm for, 138, 139
SERM-Raloxifene (Evista), 192t
Sertoli cells, 201
Serum calcium, 182
Serum chromogranin A (CGA), 357
Serum 25-hydroxyvitamin D, 186
Serum osmolality and sodium, for
diagnosis of DI, 44
Serum phosphorous, 177
Sevelamer hydrochloride, 73
17-hydroxylase/17,20-lyase
deficiency (17OHD),
144, 147
Sex hormone–binding globulin
(SHBG), variations in,
212, 212t
Sexual differentiation, 202–203
Sexual disorders, 217
therapies for, 220
Short-acting insulin for DM, 261t
“Sick day management” of AI, 120
Silent subacute thyroiditis, 53t
Skeletal X-rays, 196
Sleeve gastrectomy procedure
for obesity, 347t
Small intestine carcinoids
tumors, 357t
Soft tissue infection (STI), 316–317
Somatostatin
analogues, 24t, 359
for acromegaly, 22
for nonfunctioning
macroadenomas, 34
receptor scintigraphy, 358
Somatotrophs, 5
Sperm defect transport, 217
therapies for, 219
Spironolactone, 147, 236
Sporadic tumors, 141
5/1/13 9:35 PM
Index
SQ insulin
therapy, 264–265
transitioning from IV insulin to,
275, 310
Standards of Medical Care in
Diabetes, 300
ST elevation myocardial infarction
(STEMI), 300
Steroid biosynthesis pathway, 143
Steroidgenesis, adrenal, 114
Steroid metabolism, enzymes
involved in, 340
STI. See Soft tissue infection
Struma ovarii, 53t
Subclinical Cushing’s syndrome
(SCS), 150
Subclinical hyperthyroidism,
60–61
Subclinical hypothyroidism, 66
Sucralfate, 74
Sulfonylureas, 295t
Sunitinib, 360
Superovulation, 249
Surgery
for acromegaly, 21
ATC, 100
for DTC, 89
gynecomastia, 207
for hyperthyroidism, 59
MTC, 95
for nonfunctioning
macroadenomas, 33
persistent/recurrent
disease, 91
transsphenoidal, 15
Syndrome of inappropriate
antidiuretic hormone
secretion (SIADH)
clinical criteria, 39
disorders associated with, 39
monitoring serum in hospitalized
patients with, 41–42
treatment
arginine vasopressin receptor
antagonists, 40
demeclocycline, 40
fluid restriction, 39
48565_IDXx_369-396.indd 389
389
hypertonic saline, 39
isotonic saline, 39
tolvaptan, 40–41
urea, 40
Systemic arterial blood supply, 3
Systemic chemotherapy, 159
T
TBG. See Thyroid hormone binding
globulin
TC. See Total cholesterol
TDD. See Total daily dose
Technetium bone scan, 196
Teriperatide (Forteo), 192t
Tertiary hyperparathyroidism,
175, 176
Testes, 201
Testicular descent, 202
Testing
for acromegaly, 23t
antibody, 260
CRH, 127
end-organ, 363t
fludrocortisone suppression, 133
genetic, 138
glycemic, 229
interpretation of MN, 137
plasma ARR, 131–132
Testosterone, 212
deficiency in men
androgen replacement, risks
of, 213, 214t–215t, 215
assays/tests, 212
chronic conditions with
hypogonadism prevalence,
211–212
diagnosis, 212–213
etiology, 210t, 213t
history, 211
pathophysiology, 209
physical exam, 211
prevalence, 209
screening for, 211–212
replacement for males, 10
therapy, avoidance, 213
Thiazide diuretics, treatment for
central DI, 45
5/1/13 9:35 PM
390
Index
Thiazolidinediones, 295t
3β-hydroxysteroid dehydrogenase
deficiency (3βHSDD),
144, 147
THRT. See Thyroid hormone
replacement therapy
Thyroglobulin (Tg), 49
Thyroid absorption, drugs affecting,
73–74
Thyroid cancer
clinical presentation, 108
diagnosis and management, 108
etiology and
pathophysiology, 107
history of, 109
Thyroid disorders in pregnancy
hyperthyroidism
clinical presentation, 106
diagnosis, 106
etiology and
pathophysiology, 105
laboratory evaluation, 106
management, 107
hypothyroidism
clinical presentation, 103
diagnosis, 104
etiology and
pathophysiology, 103
laboratory evaluation, 104
management, 104–105
screening for, 103
postpartum thyroiditis
clinical presentation, 109
diagnostic evaluation, 109
etiology and
pathophysiology, 109
treatment and monitoring, 110
thyroid nodules and thyroid
cancer
clinical presentation, 108
diagnosis and
management, 108
etiology and
pathophysiology, 107
history of, 109
Thyroid dysfunction, male
infertility, 220
48565_IDXx_369-396.indd 390
Thyroid essentials
anatomy of, 49
histology of, 49
physiology of, 49–50
Thyroid FNA, decision-making
for, 81t
Thyroid function
drugs affecting, 73–77
tests
anatomy of, 49
histology of, 49
physiology of, 49–50
use and interpretation of,
51–52t
Thyroid hormone
effect of drugs on, 71t
metabolism, drugs affecting, 74
resistance, 53t
therapy, 67
Thyroid hormone binding globulin
(TBG), 51t
Thyroid hormone replacement
therapy (THRT), 73
Thyroid nodule
clinical presentation, 108
diagnosis and management, 108
etiology and
pathophysiology, 107
evaluation
clinical presentation, 79–80
diagnostic evaluation, 80–81
epidemiology and
pathophysiology, 79
malignancy risk by cytologic
diagnosis, 82t
management, 81–82
history of, 109
Thyroid-stimulating hormone
(TSH), 51t
conditions of, 54–55t
deficiency, 9t, 10
manifestations of, 8t
suppression, 91
Thyroid storm, treatment of, 60, 60t
Thyrotoxicosis
clinical presentation of, 54
diagnosis, 54–57
5/1/13 9:35 PM
Index
etiology and pathophysiology
of, 53
management options of, 57–59
subclinical hyperthyroidism,
60–61
thyroid storm, 60
Thyrotrophs, 6
TNM. See Tumor node metastasis
Tolvaptan, 40–41
Total cholesterol (TC), 325,
331–335, 332t
Total daily dose (TDD)
calculation, 309
of insulin, 275
in type 1 diabetes, 264
Total thyroxine, 51t
Toxic adenoma/toxic goiter, 53t
Transient receptor potential
channels, 166
Transport of dietary fat, 326, 327
Transport of hepatic fat,
327–328, 328
Transrectal ultrasound, 219
Transsphenoidal surgery
for acromegaly, 21
for prolactinemia, 15
Triglyceride
categories, 332t
lipoproteins carrying, 325
Trophoblastic disease, 53t
Trousseau’s sign, 182
TSH-secreting pituitary adenoma, 53t
T3 resin uptake (T3RU), 52t
Tubal factors, female infertility,
245, 246, 248
Tumor node metastasis (TNM)
classification, 88
staging, 88t, 99, 100t
Tumors
carcinoid. See Carcinoid tumors
pancreatic neuroendocrine. See
Pancreatic neuroendocrine
tumors
21-hydroxylase deficiency
(21OHD), 144
adult, 146–147
child/adolescent, 146
48565_IDXx_369-396.indd 391
391
newborn, 146
treatment principles, 145–146
Type 1 deiodinase (D1) catalyses, 69
Type 2 deiodinase (D2) catalyses, 69
Type 3 deiodinase (D3) catalyses, 69
Type 1 diabetes
glycemic management in, 264–265
TDD of, 264
Type 2 diabetes
cardiovascular disease in. See
Cardiovascular disease,
in type 2 diabetes
glycemic management in, 265–267
U
UA. See Unstable angina
UAE. See Urinary albumin excretion
UK Prospective Diabetes Study
(UKPDS), 294
Ulceration, diabetic foot, 315–317
Unilateral primary aldosteronism,
131, 133, 134
Unstable angina (UA), 300
Urea, managing SIADH, 39
Urinary albumin excretion (UAE),
categories of, 285, 286t
Urinary 5-Hydroxyindole acetic acid
(5-HIAA), 357
Urine catecholamines, 137
Urology, 215
Uterine factors, female infertility,
245, 246, 249
V
VADT, 294
Vascular endothelial growth
factor (VEGF), 86
Vasomotor, 315
Vasopressin, 5
Veins, 113
Venous drainage, 3
Very low-density lipoproteins
(VLDL), 325, 327, 331,
332, 339
VIPoma, 359
Visual field testing for PI, 32
5/1/13 9:35 PM
392
Index
Vitamin D, 165–166
deficiency, 181
clinical presentation, 186
diagnosis, 186
management, 186–187
pathophysiology, 185
prevalence of, 185
risk factors for, 185
recommended intakes
for, 166t
Vitamin D receptor (VDR), 166
VLDL. See Very low-density
lipoproteins
W
Waist circumference, increased, 343
Water deprivation test for diagnosis
of DI, 44
48565_IDXx_369-396.indd 392
Weight-based insulin regimen,
308–309
Weight loss
from diet, 345
effect of substantial, 351
PCOS management, 229–230
Weight reduction, hirsutism, 236
Werner syndrome, 86
Whipple’s triad, 321
White adipose tissue, 339
World Health Organization (WHO), 189
Z
Zoledronic acid, 192t, 197
Zometa, 192t
Zona fasciculata, 113
Zona glomerulosa, 113
Zona reticularis, 113
5/1/13 9:35 PM