Primary Adrenal Disease - Emory University Department of Pediatrics

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Primary Adrenal
Disease
Briana Patterson, M.D.
Fellow, Pediatric Endocrinology
Emory University School of
Medicine
Objectives
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Normal adrenal physiology
Common causes of primary adrenal
insufficiency
Evaluation of suspected adrenal insufficiency
Acute and chronic management issues
Normal Adrenals
Adrenal Cortex
Zona Glomerulosa: Mineralocorticoids
Zona Fasiculata: Glucocorticoids
Zona Reticularis: Androgens
Medulla
Adrenal Histology
Reticularis
Glomerulosa
Capsule
Medulla
Fasiculata
Adrenal physiology 1:
HPA axis
Adrenal physiology 2:
Renin-angiotensin system
ACTH
Steroid Biosynthesis
Cholesterol
StAR, 20,22-desmolase
17α-hydroxylase
Pregnenolone
17-OH-Pregnenolone
3βHSD
17α-hydroxylase
Progesterone
21-hydroxylase
DOC
11β-hydroxylase
Corticosterone
18-hydroxylase
18-OH-Corticosterone
18-oxidase
Aldosterone
17,20-lyase
DHEA
3βHSD
3βHSD
17,20-lyase
17-OH-Progesterone
Androstenedione
21-hydroxylase
11-deoxycortisol
aromatase
17βHSD
Estrone
11β-hydroxylase
Cortisol
Testosterone
aromatase
17βHSD
Estradiol
Primary adrenal insufficiency:
Etiologies
Syndromes
Acquired
Congenital
 Autoimmune
 Congenital adrenal  Adrenoleukodystrophy
 Kearns-Sayre
hyperplasia
 AIDS
 Autoimmune
 Wolman disease
 Tuberculosis
polyglandular

Adrenal
hypoplasia
 Bilateral injury
syndrome 1 (APS1)
congenita
 Hemorrhage
 APS2
 Allgrove syndrome
 Necrosis
(AAA)
 Metastasis
 Idiopathic
Primary adrenal insufficiency:
Etiologies
Acquired
 Autoimmune
 AIDS
 Tuberculosis
 Bilateral injury
 Hemorrhage
 Necrosis
 Metastasis
 Idiopathic
Tuberculosis
Adrenal Hemorrhage:
Meningiococcemia
Addison’s Disease
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1st described in 1855 by
Dr. Thomas Addison
Refers to acquired
primary adrenal
insufficiency
Does not confer
specific etiology

Usually autoimmune
(~80%)
Addison’s Disease
Addison’s
Normal
Primary adrenal insufficiency:
Symptoms
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Fatigue
Weakness
Orthostatsis
Weight loss
Poor appetite
Neuropsychiatric
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Apathy
Confusion
Nausea, vomiting
Abdominal pain
Salt craving
Primary adrenal insufficiency:
Physical findings
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Hyperpigmentation
Hypotension
Orthostatic changes
Weak pulses
Shock
Loss of axillary/pubic
hair (women)
Primary adrenal insufficiency:
Physical findings
Primary adrenal insufficiency:
Laboratory findings
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Hyponatremia
Hyperkalemia
Hypoglycemia
Narrow cardiac silhouette on CXR
Low voltage EKG
Primary adrenal insufficiency:
Etiologies
Congenital
 Congenital adrenal
hyperplasia
 Wolman disease
 Adrenal hypoplasia
congenita
 Allgrove syndrome
(AAA)
21-hydroxylase deficiency:
Pathophysiology
CAH: Pathophysiology
Cholesterol
StAR, 20,22-desmolase
17α-hydroxylase
Pregnenolone
17-OH-Pregnenolone
3βHSD
17α-hydroxylase
Progesterone
21-hydroxylase
DOC
11β-hydroxylase
Corticosterone
17,20-lyase
DHEA
3βHSD
3βHSD
17,20-lyase
17-OH-Progesterone
Androstenedione
21-hydroxylase
11-deoxycortisol
Estrone
11β-hydroxylase
Cortisol
Testosterone
18-hydroxylase
18-OH-Corticosterone
18-oxidase
Aldosterone
Estradiol
CAH: Pathophysiology
Cholesterol
StAR, 20,22-desmolase
17α-hydroxylase
Pregnenolone
17-OH-Pregnenolone
3βHSD
17α-hydroxylase
Progesterone
21-hydroxylase
DOC
11β-hydroxylase
Corticosterone
17,20-lyase
DHEA
3βHSD
3βHSD
17,20-lyase
17-OH-Progesterone
Androstenedione
21-hydroxylase
11-deoxycortisol
Estrone
11β-hydroxylase
Cortisol
Testosterone
18-hydroxylase
18-OH-Corticosterone
18-oxidase
Aldosterone
Estradiol
21-hydroxylase deficiency:
Physical exam

Females are unremarkable
other than genitalia

GU exam – Clitoromegaly,
posterior labial fusion, no
vaginal opening

Males appear normal
21-hydroxylase deficiency
CAH

Classification based on enzyme activity
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Classic
 Salt wasting (Complete deficiency)
 Simple virilizing (Significant but partial
defect)
Non Classic

Elevated enzyme levels (Mild deficiency)
Primary adrenal insufficiency:
Etiologies
Syndromes
 Adrenoleukodystrophy
 Kearns-Sayre
 Autoimmune
polyglandular
syndrome 1 (APS1)
 APS2
Primary adrenal insufficiency:
Associated conditions

Autoimmune Polyglandular Syndrome I
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Hypoparathyroidism
Chronic mucocutaneous candidiasis
Atrophic gastritis
Adrenal insufficiency in childhood
Pernicious anemia
Vitiligo
AIRE mutation
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Transcription factor
Affects immune regulation
Primary adrenal insufficiency:
Associated conditions
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Autoimmune Polyglandular Syndrome II
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Autoimmune thyroiditis
Type I diabetes mellitus
Adrenal insufficiency
Pernicious anemia
Premature ovarian failure
Genetic associations
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HLA haplotype, CLTA4
Evaluation
Primary adrenal insufficiency:
Evaluation
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0800 cortisol level
ACTH level
Random cortisol in ill patient
ACTH stimulation test
Suspected CAH

Needs special evaluation
Primary adrenal insufficiency:
Evaluation
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0800 cortisol level
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Levels less than 3 mcg/dL are suggestive of AI
Levels greater than 11 mcg/dL exclude AI
ACTH level
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Elevated in adrenal insufficiency
ACTH readily degraded if not properly processed
Primary adrenal insufficiency:
Evaluation
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Random cortisol in ill patient
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>20 mcg/dL reassuring
Adrenal Autoantibodies
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ACA—adrenal cortex antibody
Anti-21-OH-hydroxylase antibody
Primary adrenal insufficiency:
Evaluation—ACTH Stimulation
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Low dose (1 mcg) test
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Baseline and 30 minute cortisol levels
More physiological ACTH level/stimulation
Useful in central AI
Useful for assessing recovery after chronic steroid
treatment
High dose (250 mcg) test
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Baseline, 30 and 60 minute levels
Can be done IM
Stronger stimulation than 1 mcg test
Primary adrenal insufficiency:
Evaluation—ACTH Stimulation
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Cortisol peaks are controversial
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Reported normals range between 16-25 mcg/dl
Some providers also look at the magnitude of rise
Also use ACTH to help differentiate primary
vs secondary deficiency
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Secondary may respond to high dose, but not low
Primary should fail both high and low dose
Suspected CAH:
Evaluation
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Newborn screening
Call endo before you
treat
Need special evaluation
ACTH stimulation can
be helpful in well
patients with suspected
nonclassic disease
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17-OH progesterone
17-OH pregnenolone
11-deoxycortisol
Deoxycorticosterone
Androstenedione
DHEA
Aldosterone
Cortisol
ACTH
Plasma renin activity
Diagnosis with 17-OH
progesterone
Baseline 10,000 - 90,000
Stimulated 20,000 - 100,000
Baseline
500 - 1,000
Stimulated 2,000-15,000
Baseline
20 - 1,000
Stimulated 200 - 1,000
Treatment
Primary adrenal insufficiency:
Acute treatment
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NS volume resusitation
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Look for/treat hypoglycemia
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25% dextrose
New problem, suspected AI
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Reverse shock
Labssteroids
Established patient with AI
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Steroids
Stress dose steroids
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Loading dose
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50-100 mg/M2 hydrocortisone IV/IM
Small/medium/large approach
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Infants: Hydrocortisone 25 mg
Small children: Hydrocortisone 50 mg
Larger children/teens: Hydrocortisone 100 mg
Continue hydrocortisone with 50-100
mg/M2/day
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Divide q6-8 hours
May be 2-3x home dose
Primary adrenal insufficiency:
Long term treatment
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Daily glucocorticoid replacement (hydrocortisone)
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Daily mineralocorticoid replacement
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10-15 mg/m2/day divided TID
Option to change to prednisone in teen years
Fludrocortisone 0.05-0.2 mg daily
Patient education
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Stress coverage
Emergency steroid administration
 IM hydrocortisone (Solucortef Actovial)
Medic Alert ID
Relative Steroid Potencies
Glucocorticoid Mineralocorticoid
Hydrocortisone
1
++
3-5
+
5-6
0
Dexamethasone
25-50
0
Fludrocortisone
15-20
+++++
Prednisone/
Prednisolone
Methylprednisone
Relative Steroid Potencies
Glucocorticoid Mineralocorticoid
Hydrocortisone
1
++
3-5
+
5-6
-
Dexamethasone
25-50
-
Fludrocortisone
15-20
+++++
Prednisone/
Prednisolone
Methylprednisone
When to consider AI:
Patients at risk…Primary AI
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History of TB
Refractory shock
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Particularly meningococcal disease
Dehydration/shock with hyperpigmentation
Neonate with vomiting/dehydration/shock
Other autoimmune endocrine disease
History consistent with APS1
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Immunodeficiency/chronic mucocutaneous
candidiasis
When to consider AI:
Patients at risk…Secondary AI
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Pituitary trauma/surgery
Brain tumor
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Infiltrative pituitary disease
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Sarcoidosis
Histiocytosis
Congenital pituitary abnormalities
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Craniopharyngioma
Suprasellar germ cell tumor
May have progressive loss of corticotroph function
Chronic glucocorticoid therapy
Adrenal Insufficiency
Summary
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May be primary or secondary
May be congenital or acquired
Treatment is relatively simple
Diagnosis is often controversial
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Baseline cortisol/ACTH before steroids
ACTH stim test if possible
Additional testing if CAH is suspected
Don’t forget to check the blood sugar!
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