Lecture on Primary Hyperparathyroidism

BIOLOGICAL AND

EVIDENCE – BASED

MANAGEMENT OF

PRIMARY

HYPERPARATHYROIDISM

PART I

Normal Physiology

• Calcium Metabolism

• Vitamin D Metabolism

• PTH Biosynthesis and Metabolism

• PTH Actions

• Bone Remodeling

CALCIUM METABOLISM

Total body content of calcium in normal adult approx. 1000g

• >99% within bone crystal structure of hydroxyapatite [Ca

10

(PO

4

)

6

(OH)

2

]

• <1% soluble in intra-and extracellular fluid

• Ca at bone crystal surface is exchangeable

NEER, J Clin Invest 46, 1967

Calcium Absorption

1) Absorbed throughout entire intestine

2) Most efficient in duodenum & proximal jejunum

• Highest levels of Vitamin D dependent Ca binding proteins

•

Lower luminal pH promotes dissociation from food complexes

3) Larger proportion of total Ca absorbed in distal jejunum & ileum due to longer residence times

Bronner. 250, 1986

Bringhurst. 2002

Factors That Affect Calcium

Intestinal Absorption

Absorption

1) Vitamin D [1,25 (OH)

2

D

3

] Increase

– Prime physiologic regulator

2) Increasing Age

3) Estrogen

4) Glucocorticoids

Decrease

Increase

Decrease

Distribution of Calcium in Plasma

• Free Ca 2+ 48%

• Protein Bound Ca

• Albumin accounts for 70% of this fraction

46%

• Associated with diffusible ion complexes

6%

Carr, 1955

Normal Range of Total Serum Calcium

• 8.5 to 10.5 mg/dl

Normal Range of Ionized Serum Calcium

• 1.17 to 1.33 mM

Acid-Base & Serum Protein

Concentration Disorders

1) Metabolic Acidosis

Total Serum Ca

Decreased

2) Malnutrition

3) Cirrhosis

4) Dehydration

5) Multiple Myeloma

Decreased

Decreased

Increased

Increased

Renal Calcium Excretion

• 10,000 mg Ca filtered through glomerulus per day

• Urinary calcium excretion is approx. 200 mg per day

• Only 2% of filtered Ca is normally excreted

Ca Reabsorption in Kidney

Location

1) Prox. & St. Tubules

%

65%

Type

Passive

2) Thick Ascending Limb 10% Passive iPTH Controlled

No

No

3) Thick Ascending Limb 10% Active

4) Distal Convoluted &

Connecting Tubules

10% Active

Yes

Yes

VITAMIN D

Vitamin D

3

Photosynthesis

• Provitamin D

3

(7-DHC) is in cell membranes of epidermal keratinocytes

• UVB light converts Provitamin D

3

Previtamin D

3 by breaking B ring to

• Thermal energy isomerizes Previtamin D

3 to

Vitamin D

3 in cell membrane

Vitamin D

3

Metabolism

• Vitamin D

3 is released into blood from epidermis

• Then transported to liver by Vitamin D binding protein

• Liver Vitamin D-25-hydroxylase converts inert Vitamin D

3 to inert 25(OH)D

3

Vitamin D

3

Metabolism

• Proximal renal tubular cell 25(OH)D

3 hydroxylase converts 25(OH)D

3 to active

1,25(OH)

2

D

3

• 1,25(OH)

2

D

3

, phosphate, Ca inhibit

25(OH)D

3 hydroxylase

• PTH stimulates 25(OH)D

3 hydroxylase

Actions of 1,25(OH)

2

D

3

• Increased Ca absorption in small bowel

• Inhibits 25(OH)D

3 hydroxylase in kidney

• Increases bone mineralization

• Inhibits PTH secretion by parathyroid cells

Dietary Vitamin D

• Ingested vegetal source – Vitamin D

2

• Ingested animal source – Vitamin D

3

• 50% D

2

– D

3 is absorbed by enterocytes and transported by chylomicrons to fat, muscle, liver

Vitamin D Requirements

• Difficult to obtain adequate Vitamin D from diet

• Can obtain sufficient Vitamin D from solar exposure and diet

• Elderly subjects have lower efficacy for UVB light conversion to previtamin D

3

• Elderly subjects have higher Vitamin D RDA of

600 IU or 15 micrograms per day

iPTH

Biosynthesis and Metabolism

Para Thyroid Cell Membrane

Ca Receptor

1) 1,078 AA glycosylated protein

2) Member of G protein-coupled receptor superfamily

3) Large extracellular 7 transmembrane domain

4) Long cytoplasmic tail

Nemeth, 1998

Parathyroid Cell Membrane

Ca Receptor

5) Ligand for receptor is inorganic ion Ca

6) Ca binding to receptor inhibits PTH secretions

Nemeth, 1998

iPTH Gene Consists of 3 Exons on Chromosome 11p15 in

Parathyroid Cell Nucleus

• Exon 1: 85bp, Noncoding

• Exon 2: 90bp, Encodes most AA’s of prepropeptide

• Exon 3: 612bp, Encodes remainder of pro-iPTH

Kronenberg, Rec Prog Hor Res, 42, 1986

pre–pro–PTH MRNA

• Transcribed from PTH gene

(pre-pro-PTH DNA) in Nucleus

• Passes into cytoplasm

• Translated on RER to form pre-pro-PTH

pre-pro-PTH : 115 AA

• pre-, 25 AA (-31 to -6)

• pro-, 6 AA (-6 to 0)

• iPTH, 84 AA (1 to 84)

• prepeptide is cleaved across RER membrane

• propeptide is cleaved in GOLGI Apparatus

• iPTH (1-84) is concentrated in secretory vesicles and granules

Habener; Phys Rev 64, 1984

• Within vesicle/granules, iPTH remains intact or is cleaved to form inactive C-terminal PTH fragment

• iPTH and C-terminal PTH fragments are released from parathyroid cell by exocystosis

• No N-terminal PTH fragments are released from cell

MacGregor, J. Bid Chem 254, 1979

• iPTH ½ life is 2 min.

• <1% of iPTH reaches target organ receptors

• ½ life of inactive C-terminal PTH fragment is several fold more than iPTH

• Concentration of C-terminal PTH fragment exceeds iPTH

Circulating Forms of PTH

• PTH (1-6)

• PTH (1-33)

• PTH (1-36)

•PTH (1-84)

•PTH 7-34

•PTH 34-84

•PTH 37-84


Intact PTH

(iPTH)

PTH (1-84) (human)

H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-

Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-

Asn-Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-Ser-

Gln-Arg-Pro-Arg-Lys-Glu-Asp-Asn-Val-Leu-Val-Glu-Ser-His-Glu-

Lys-Ser-Leu-Gly-Glu-Ala-Asp-Lys-Ala-Asp-Val-Asn-Val-Leu-Thr-Lys-

Ala-Lys-Ser-Gln-OH


N-Terminal Fragments

• PTH(1-6), PTH(1-33), PTH(1-36)

• All active

• All metabolized quickly

• Very low concentrations of <10 -13 mmol/cc

• Little physiologic significance

Potts, 2001

PTH (1-84) (human)

H-Ser-Val-Ser-Glu-Ile-Gln -Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-


Asn-Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-Ser-



Ala-Lys-Ser-Gln-OH

PTH (1-84) (human)



Asn -Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-Ser-



Ala-Lys-Ser-Gln-OH

PTH (1-84) (human)



Asn-Phe-Val-Ala -Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-Ser-



Ala-Lys-Ser-Gln-OH


C-Terminal Fragments

• PTH(34-84), PTH(37-84)

• Formed by iPTH cleavage in parathyroid, liver, kidney

• Increased parathyroid secretion and levels in hypercalcemia

Potts, 2001

PTH (1-84) (human)



Asn -Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-Ser-



Ala-Lys-Ser-Gln-OH

PTH (1-84) (human)



Asn-Phe-Val-Ala -Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-Ser-



Ala-Lys-Ser-Gln-OH


C-Terminal Fragments

• Clearance mostly by glomerular filtration

• Levels elevated in renal failure

• T ½ : 20-40 in

• All inactive

Potts, 2001

Hepatic Metabolism of iPTH

• 70% metabolized by liver in Kupher cells

• iPTH is cleaved between AA 33-34 or 36-37 to form inactive C-terminal PTH fragments

• Free AA are formed

• No N-terminal PTH fragments are formed

Renal Metabolism of iPTH

• 20%; PTH (1-84) is metabolized by kidneys

• Most iPTH is filtered at glomerulus and degraded in tubules forming C-term PTH fragment

• Kidney is only site of clearance of inactive Cterminal PTH fragments formed in parathyroid cell and liver

• Small amount of iPTH binds to kidney PTH receptors

PTH ACTIONS

iPTH Action on Intestines

• No iPTH/PTHrP receptors on intestinal cells

• iPTH indirectly stimulates intestinal absorption of calcium & phosphate via stimulation of renal synthesis of 1,25(OH)

2

D

3

iPTH Actions on Bone

• Osteoclasts are the only cells in bone that can release calcium

• Osteoclasts have no PTH/PTHrP receptors

• iPTH stimulates osteoblasts

• Osteoblasts then increase # and activity of osteoclasts

iPTH Action on Bone

• Net bone resorption is stimulated

• Net release of calcium from bone

iPTH Action on 1,25(OH)

2

D

3

• Renal proximal tubular cell 1 alpha-hydroxylase converts 25(OH)D

3 to 1,25(OH)

2

D

3

• iPTH induces enzyme synthesis by action on this tubular cell PTH/PTHrP receptor

• iPTH induced synthesis requires several hours

• iPTH induced synthesis is blocked by

1,25(OH)

2

D

3

iPTH Action on Phosphate

• Increased bone resorption releases phosphate into circulation

• iPTH reduces phosphate reabsorption in proximal

> distal tubules

• iPTH inhibits renal tubular cell sodium dependent phosphate cotransporter NPT-2

Caverzasio, J.Biol Chem, 1986

BONE REMODELING

Two Main Types of Bone Tissue

1) Compact (Cortical) Bone

•

80% bone mass

• eg. diaphysis of long bones

2) Cancellous Bone

• 20% bone mass

• eg. Vertebral bodies

Kacsoh. Endo Phys. 2000

• Cancellous has larger surface-to-mass ratio than compact bone

• Cancellous bone more active in bone-ECF exchange

• Cancellous bone remodeling renewal rate is 20% per year

• Compact bone remodeling renewal rate is 4% per year


Bone Extracellular Space

1) Osteoid

•

Nonmineralized organic matrix

•

35% bone tissue mass

2) Minerals

•

Ca and Phos in form of hydroxyapatite crystal

Osteoid

Type I Collagen

• 90% of osteoid protein mass

• Large number of prolene-lysine residues

• Pyridinium crosslinks are pyridinoline and deoxypyridinoline that link collagen fibrils

• Formed by osteoblasts

Osteoid

Noncollagenous Matrix Proteins

• 10% of osteoid protein mass

• Produced by osteoblasts and osteoclasts

• Osteocalcin

• Alkaline phospatase (Alk Phos)

• Tartrate-resistant acid phosphatase (TRAP)

• Albumin

Osteoid

1) Collagen

• Found in osteoid and skin

2) Pridinium crosslinks

• Absent in skin

•

Found in osteoid, cartilage, dentin

3) Osteocalcin

•

Produced by osteoblasts

• Regulates mineralization

4) Alk Phos

• Produced by osteoblasts

5) TRAP

• Produced by osteoclasts

Bone Fluid

• Lies between mineralized bone and bone lining cells (osteoclasts)

• Lies between osteoid seam and osteoblasts

• Does not contain hydroxyapatite crystals


Bone Fluid

• Rapidly accessible pool of Ca for ECF

• Crucial environment for osteoid mineralization


Mineralization of Osteoid

1) Matrix vesicles released by osteoblasts into osteoid seams

2) Phase I

• Alk Phos in vesicle membrane increases phos in sap

• Ca binding molecules in vesicle membrane increases Ca in sap

•

Hydroxyapatite crystallization in sap

Mineralization of Osteoid

3) Phase 2

•

Hydroxyapatite crystal perforates membrane and released in bone fluid and osteoid seam

• Crystal proliferates and propagates into the osteoid matrix

NORMAL PARATHYROID GLAND

EMBRYOLOGY, ANATOMY & HISTOLOGY

Parathyroid Embryology

• Originate from Neuroectoderm and endoderm

• Inferior parathyroids and thymus arise from third pharyngeal pouch

• Superior parathyroids arise from fourth pharyngeal pouch in association with the lateral analage of thyroid

Pearse, Clin. Endo, 1976

Clark, Surg Onc Clin N.A., 1998

Parathyroid Embryology

• Parathyroid III descends with thymus to lower border of thyroid

• Parathyroid IV descends with thyroid gland to posterolateral aspect of thyroid at level of cricothyroid cartilage


Anatomy of Parathyroids

1) Superior parathyroid glands

• Located on posteromedial thyroid gland

•

Located within 2cm circumference area

• 1cm superior to intersection of recurrent laryngeal n. and inferior thyroid a.

•

Posterior to recurrent laryngeal n.

2) Inferior parathyroid glands

•

Posterolateral aspect of lower pole thyroid gland

• Inferior to inferior thyroid a.

•

Anterior to recurrent laryngeal n.

Clark, Surg Onc Clin. N.A., 1998

Histology of Normal

Parathyroid Glands

1) Basic cell type – Chief cell

2) Other cells are chief cell morphologic variants due to physiologic activity differences

• Chief cell

•

Oxyphil cell

•

Transitional oxyphil cell

•

Water-clear cell

•

Transitional water-clear cell

Roth, Int Rev Exp Path, 1974

3) Chief Cell

•

Centrally located nucleus

• Moderate amount granular cytoplasm

•

Variable amounts glycogen particles and secretory droplets

• Most abundant cell

•

Two subgroups – dark and light

• Dark chief cells responsible for

PTH synthesis-secretion

Rosai, Jurg Path, 1996

Clark, Surg Onc Clin NA, 1998

4) Oxyphil Cell

•

More abundant cytoplasm

• Deeply granular and acidophilic cytoplasm

•

Many mitochondria

• Few secretory granules

•

Often in nodular collections

• May or may not secrete PTH

Rosai, Surg Path, 1996


5) Transitional Oxyphil Cells

•

Appearance intermediate between chief and oxyphil cells

6) Water-Clear Cells

• Abundant optically clear cytoplasm

•

Sharply defined cell membrane

7) Transitional Water-Clear Cells

• Appearance intermediate between chief and water-clear cells

Roasi, Surgical Path, 1996

8) Cell type distribution in gland is dependent on age

•

Prepuberty – wholly of chief cells

•

Postpuberty – progressive increase in oxyphil cells

9) Adult parenchymal cell content remains relatively constant

10) FOLLICLES and Cysts are seen in 50% of adult glands

Fimelius, Path Res Pract, 1996

Boquist, Lab Invest, 1973

11) Parathyroid gland stromal adipose tissue

•

Appears after puberty

• Increase to 40y age, and then stabilizes

•

Avg. adult content – 30%

• Content varies depending on age, nutrition, activity, body size and composition

•

Fat variability makes it difficult to distinguish normal

– abnormal glands on basis of fat content

Obara, Endocrin Japan, 1990


EPIDEMIOLOGY

Epidemiology

• Incidence – 25 per 100,000 general pop.

• 100,000 new cases annually in U.S.A.

• Incidence increases with age

• Most common 50 to 80 years of age

• Four times more common in women

ETIOLOGY

Monoclonal Cell Expansion in

Adenomas

1) Polymorphism in PRAD 1 Oncogene

2) Polymorphism in VDR Gene

3) Polymorphism D418D of MEN1 Suppressor Gene

• 50% of Adenomas

• Most Common Deranged Gene

Friedman, J. Clin End Met 71, 199?

Carling, Nat Med 1, 1995

Correa, 132, 2002

Etiology

Possible predisposing clinical conditions in case reports

• Hx neck irradiation

• Parathyroid adenoma-hyperplasia

• Familial non-MEN hyperparathyroidism

• Hereditary hyperparathyroidism – jaw tumor syndrome

Shane, J. Clin Endo Metab, 2001

Therapeutic Radiation Exposure

• 49 (11%) of 438 patients with pHPT received childhood ionizing RoRx to neck

• No change in patient presentation

• RoRx exposed patients had more thyroid pathology, 57% vs. 7%

Telelman, 1995

PATHOLOGY

Primary Hyperparathyroidism

Pathology

Single Adenoma

Double Adenoma

Hyperplasia

MENI, MENIIa

Non-MEN

Parathyroid Carcinoma

89%

4%

7%

<0.1%

4%

3%

Hundahl, Cancer, 1999

Van Heerden, Surgery 1996

Pathology of Parathyroid Adenomas

1) Usually have follicular arrangement

2) Usually have varying mitosis, cell, and nuclear size

3) Usually have normal or atrophic rim of parathyroid cells external to hypercellular tissue

4) Second normal gland identified

Carney, Monogr Path, 1993

Pathology of Parathyroid Hyperplasia

1) All parathyroid glands are enlarged

2) Glands may be markedly different in size

3) Chief cell is more common than clear cell hyperplasia

4) Little stromal fat

Kebebew, Surg Onc Clin NA, 1998

CLINICAL PRESENTATION

OF pHPT

1920’s and 1930’s

• Most cases discovered late as severe, symptomatic pHPT

• Classic pHPT described as disorder of “stones, bones, & groans”

• 100% of patients undergoing surgery had osteitis fibrosa cystica

• 80% of patients had nephrolithiasis

• Neuromuscular dysfunction was common

Clark, Surgery, 1999

Albright, AM J Med Sci, 1934

1930’s to 1960’s

• 57% of pHPT pts had nephrolithiasis

• 23% of pts had osteitis fibrosa cystica

• 0.6% of pts were asymptomatic

Cope, NEJM, 1966

Mid 1960’s

• Routine biochemical screening with multichannel laboratory analyzing machines was introduced

• pHPT subsequently dx earlier as mild,

“asymptomatic” pHPT


1984 to 1999

• 80% of pHPT pts were “asymptomatic”

• 17% of pts had nephrolithiasis

• 1.4% of pts had osteitis fibrosa cystica

Silverberg, 2001


• 20% of patients are symptomatic

• 80% of patients are asymptomatic

Symptomatic pHPT

• Osteitis Fibrosa Cystica

• Nephrolithiasis

• Severe Neuromuscular disease

• Acute Hyperparathyroidism

< 2%

15%

Rare

Rare

Silverberg, NEJM, 1999

Asymptomatic pHPT

• Pts with truly asympotmatic pHPT

• Pts with non-specific mild symptoms

Clinical Features of Hypercalcemia

Neurologic

• Lethargy

• Confusion

• Coma Headache

• Depression

• Paranoia

• Muscle weakness

• Hyporeflexia

• Incontinence

• Memory loss

• Hearing loss

• Ataxia

Neuro-Musculoskeletal System

Signs & Symptoms

Muscle weakness

Myalgias

Arthralgias

Paresthesias

Muscle cramps

Chondrocalcinosis

Pseudogout

Osteitis fibrosa cystica

Type II muscle cell atrophy

% pHPT pts

70%

54%

54%

45%

45%

5%

5%

2%

Wells, Curr Prob Surg, 1980

Doherty, Text of Surg, 2001

Central Nervous System

Signs & Symptoms

Mild psych disorders

Depression

Confusion

Poor concentration

Agitation

Coma

Headache

% pHPT pts

15%

10%

5%


Abela, Text Endo Surg, 1997


Gastrointestinal

•Constipation

•Anorexia

•Nausea and vomiting

•Polydipsia

•Weight loss

•Pancreatitis

•Peptic ulcer

•Abdominal pain

Gastrointestinal System

Symptom

Constipation

Cholelithiasis

Peptic ulcer disease

Pancreatitis

Nausea

Vomiting

% pHPT pts

32%

25%

12%

1%


Doherty, Text of Surg, 2001


Cardiovascular

•ECG changes (short QT interval, widened T wave)

•Bradycardia

•Heart block

•Hypertension


Renal

•Polyuria

•Uremia

•Renal colic

•Nephrocalcinosis

Symptom

Nephrolithiasis

Polyuria

Nocturia

Polydypsia

Renal System

% pHPT pts

30%

28%


Dermatologic System

% pHPT pts Signs & Symptoms

Pruritus

Brittle Nails

Calciphylaxis

Sadler, Prin Surg, 1999

Constitutional System

% pHPT pts Signs & Symptoms

Fatigue

Weight loss

Anorexia


Ophthalmologic System

Signs & Symptom

Ocular changes

Band keratopathy

% pHPT pts

100%

> 50%



Other

•Band keratopathy

•Conjunctivitis

•Change in vision

•Pruritus

•Thrombosis

•Myalgia

Diagnosis of pHPT

Serum Calcium Levels

1) Normal range of total serum Ca (tCa) is 8.5-10.5 mg/dl (2.2-2.6 mmol/L)

2) Change in serum albumin concentration by 1g/dl alters tCa by 0.8mg/dL in same direction

3) Change in serum globulin concentration by

1g/dL alters tCa by 0.16 mg/dL in same direction

Budayr, Contemp Surg Residents, 1997

Serum Calcium Levels

4) Change in Serum pH by 0.1 alters tCa by 0.17 mg/dL in same direction

5) Hypercalcemia

•

Mild 10.5-12.0 mg/dL

•

Moderate 12.0-13.5 mg/dL

•

Severe >13.5 mg/dL

6) Mean t Ca in 137 pHPT pts was

10.7 + 0.1 mg/dL (8.5-10.2 mg/dL nl)

Budayr, 1997

Silverberg, Endo Metab Clin NA, 2000

Glendenning, Sir Charles Gairdner Hosp

Perth, Australia

1) Review of 60 surgically proven cases of pHPT

•

50 pt – single or double adenomas

•

10 pt – hyperplasia

• tCa, iCa, iPTH levels

Aust NZ J. Med, 28, 1998

Glendenning - 1998

2) Results

Elevated tCa

Normal tCa

• Elevated iPTH

•

Normal iPTH

Elevated iCa

•

Elevated iPTH

• Normal iPTH

Normal iCa

Total of 60pt

47pts (78%)

13pts (22%)

Total of 60pt

59pt (98%)

8pts (13%)

5pt (8%)

49pt (82%)

11pt (18%)

1pt (2%)

Glendenning - 1998

3) Conclusions

• iCa is superior to tCa in dx of pHPT

• iCa should be used when nl tCa is found in suspected pHPT

• Nl iPTH level in pHPT is relatively common

•

8% pts with pHPT have nl tCa and iPTH

Diagnosis iPTH Assay

1) Produced by Nichols Institute, San Juan

Capistrano, Calif.

2) Two site immunoradiometric (IRMA) or immunochemiluminometric (ICMA) assay

3) Two immunoaffinity purified Ab’s

Slatopolsky, Kidney Intl, 2000


4) One Ab (capture Ab) is immobilized on solid support and binds to C-terminal/mid region epitope, PTH (25-39)

5) Second Ab, labeled with I-125 (IRMA) binds to

N-terminal epitope PTH (7-17)

6) Mid region and C-terminal fragments are not detected by iPTH assay

Slatopolsky, 2000


7) Actually measures biologically active PTH

(1-84) and inactive PTH (7-84)

8) PTH (1-84), also known as cyclase activating

PTH (CAP)

9) PTH (7-84), also know as cyclase inactivating

PTH (CIP)

10) iPTH = 1-84 PTH (CAP) and 7-84 PTH (CIP)

Lepage, Clin Chem, 1998

Cantor, Scantibodies Lab


11) iPTH is elevated in 90% pHPT pts

12) Elevated iPTH and elevated calcium only seen in:

• pHPT

•

Lithium use

•

Thiazide use

•

FHH

Bilezikian, The Parathyroids, 1994

Silverberg, 2001


13) iPTH is in nl range in 10% HPT pts (10-65 pg/cc)

•

Usually upper nl at >45 pg/cc

•

Inappropriately nl in hypercalcemic setting

Silverberg, 2001

Diagnosis

Whole PTH Assay

1) wPTH

2) Produced by Scantibodies Laboratories, Santee,

Calif.

3) Two site IRMA

4) Capture Ab binds to C-terminal/mid region epitope,

PTH (20-28)

5) Labeling Ab (IRMA) binds to N-terminal epitope

PTH (1-6)

Slatopolsky, 2000

Diagnosis

Whole PTH Assay

6) Actually measures only biologically active 1-84

PTH (CAP)

7) wPTH = 1-84 PTH (CAP)

Slatopolsky, 2000

Cantor, Scantibodies Lab

Diagnosis of pHPT

1) 40% of pHPT pts have hypercalciuria

(>400 mg/24hr)

2) Avg in pHPT pts is in upper half of nl


Diagnosis of pHPT

Serum Phosphorous and Chloride Levels

1) 90% pHPT pts have low/low nl phos levels

2) Mean serum phos in 137 pHPT pts was 2.8 + 0.1

(2.5-4.5 mg/dL nl)

3) 805 pHPT pts have high/high nl Cl levels

4) 96% pHPT pts have C1/Phos > 33

5) 92% non-pHPT hypercalcemic pts have Cl/Phos < 30

McHenry, Amer Coll Surg, 2002

Silverberg, Endo Metab Clin NA 2000


Diagnosis of pHPT

Serum Vitamin D Assay

1) 25(OH) D is better than 1,25(OH)D as indicator of Vit D excess or deficiency due to very tight regulation of alpha-1-hydroxylase

2) Mean 25(OH)D level in 137 pHPT pts was

19 +1.0 ng/cc (9-52 ng/cc nl)

3) Mean 1,25(OH)D level in 137 pHPT pts was

54 +2 pg/cc (16-60 pg/cc nl)

4) 1,25(OH)D is elevated in 33% of pHPT pts

Silverberg, Endo Met Clin NA, 2000

Diagnosis of pHPT

Acid-Base Measurement

•

Mild metabolic acidosis often seen

Serum Magnesium Level

•

Mean serum Mg in 137 pHPT pts was

2.0 + 0.1 (1.8-2.4 mg/dL nl)

Urinary CAMP

•

Often elevated in pHPT

•

Variably elevated in hypercalcemia of malignancy


Silverberg, Endo Metab Clin NA 2000


Diagnosis of pHPT

Biochemical Markers of Bone Turnover

1) Bone formation markers

•

Total serum alkaline phosphatase (alk phos)

•

Serum bone-specific isoenzyme of alk phos

•

Serum osteocalcin

Silverberg, 2001

Serum Alkaline Phosphatase

1) Osteoblast product and bone formation marker

2) 15% of pHPT pts have elevated total phos level

3) Mean total alk phos in 137 pHPT pts was 114.0

+5.0 IU/L (<100 IU/L n1)

4) Bone-specific alk phos is more sensitive and elevated in many mild pHPT pts


Clark, Text Endo Surg, 1997

Serum Alkaline Phosphatase

5) Elevation may be indicative of severe skeletal disease

6) pHPT pts with alk phos elevation may develop severe symptomatic post parathyroidectomy hypocalcemia


Serum Osteocalcin

• Osteoblast product

• Bone formation marker

• Generally modestly elevated in pHPT pts

Eastell, J Clin Endo Metab, 1994

Diagnosis of pHPT

Biochemical Markers of Bone Turnover

2) Bone resorption markers

• Urinary hydroxyprolene

• Urinary pyridinoline (PYD)

• Urnary Deoxypyridinoline (DPD)

•

N-telopeptide of type 1 collagen

•

C-telopeptide of type 1 collagen

•

Tartrate resistant acid posphatase (TRAP)


Urinary Hydroxyprolene

1) Collagen break down product

2) Once only available bone resorption marker

3) Frankly elevated in osteitis fibrosa cystica

4) Typically n1 levels in mild pHPT

5) Low sensitivity/specificity in dx of pHPT

6) No longer useful in dx of pHPT

Silverberg, Endo Met Clin Na, 2000

Urinary

Pyridinoline(PYD) and Deoxypyridinoline (DPD)

1) Collagen breakdown products consisting of hydroxypyridinium cross links of collagen

2) Bone resorption marker

3) Mean urinary PYD level in 137 pHPT pts was

46.8 +2.7 (<51.8 nmol/mmol cr nl)

4) Mean urinary DPD level in 137 pHPT pts was

17.6 +1.3 (<14.6 nmol/mmol cr nl)

5) Useful in assessment of pHPT


N-Telopeptides and C-Telopeptides of

Type 1 Collagen

1) Collagen breakdown products

2) Bone resorption markers

3) Limited experience with application towards pHPT

Silverberg, 2001

Tartrate Resistant Acid

Phosphatase (TRAP)

1) Osteoclast product

2) Bone resorption marker

3) Level have been shown to be elevated in pHPT

4) Studies are limited in pHPT

Silverberg, Dyn Bone Cart Metab, 1999

BONE DENSITOMETRY

Dual Energy X-Ray

Absorptiometry

(DEXA)

• Table DEXA machines can measure BMP at hip, spine, radius

• Hip, spine, radius BMD can predict risk of all fractures at all sites

• Hip BMD refers to femoral neck or total hip

• Spine BMD refers to L1 through L3 or L4

Bone Densitometry

• The amount of X-ray energy absorbed by bone reflects the

Ca bone mineral content (BMC)

• BMC divided by bone area exposed is the bone mineral density (BMD)

• BMD = avg. mineral concentration per unit area of bone

• High correlation between BMD and force needed to break bone

Lang. Bone 1997

Relationship of BMD and

Fracture Risk

• Quantified by relative risk per SD (RR/SD)

• RR/SD is increased risk of fracture associated with 1 SD decrease in BMD

• eg. RR/SD of 1.6 means that fracture risk increases 60% for each 1 SD decrease in BMD

• Larger RR/SD implies stronger predictive value of

BMD for fracture risk.

Cummings. JAMA. 2002

Relationship of

BMD and Fracture Risk

(1996, 1999 meta-analysis)

RR/SD

Measurement Site Hip Spine Radius All

Hip 2.6

1.9

1.6 1.6

L-Spine

Radius

1.5

1.9

1.5 1.5

1.5

1.7

1.6

1.4

Cummings, JAMA, 2002

T and Z Scores

• Standard deviation is normal measurement variability in reference population

• The 5 th and 95 th percentile of a group covers about 4 SDs

• For Hip & Spine BMD, 1 SD is about 10-15% of mean value

Cummings. JAMA. 2002

Z Score

Number of SDs below(-) or above(+) mean BMD value for pts of same age

T Score

Number of SDs below mean BMD for young adults 25 to 45 years of age

Cummings, JAMA, 2002

World Health Organization

Definitions for Osteopenia &

Osteoporosis

• Osteopenia – BMD T Score between –1.0 & -2.5

• Osteoporsis – BMD T Score less than –2.5

• These can be at hip, vertebral, radius sites

DIFFERENTIAL DIAGNOSIS

Classification of

Causes of Hypercalcemia

I.

Parathyroid-related

A.

Primary hyperparathyroidism

1) Solitary adenomas

2) Multiple adenomas

3) Familial non-MEN

4) Multiple Endocrine Neoplasia

B.

Lithium therapy

C.

Familial hypocalciuric hypercalcemia

II.

Malignancy associated

Potts, Prin Int Med, 2001

III.

Vitamin D-related

A.

Vitamin D intoxication

B.

Granulomatous disease

IV.

Associated with high bone turnover

A.

Hyperthyroidism

B.

Immobilization

C.

Thiazides

D.

Vitamin A intoxication

V.

Secondary Hyperparathyroidism

VI.

Tertiary Hyperparathyroidism


Multiple Endocrine Neoplasia

Type I (MEN I)

1) Autosomal dominant disorder

•

Gene responsible is on long arm of chromosome 11 (11g 13)

2) Prevalence in population is 0.02 – 0.2/1000

3) Pathologic hyperfunction of two of these three endocrine tissues:

•

Parathyroid gland

• Pituitary gland

•

Pancreatic islet cells

Larsson, Nature, 1988

Wells, Prob Gen Surg, 1997

MEN I

4) HPT occurs in 90% MEN I pts

5) Islet cell tumors occur in 25-75% of MEN I pts

•

Most are gastrinomas presenting as Zollinger-

Ellison syndrome (ZES)

• Less common are insulinomas, glucagonomas, and VIPomas

6) Pituitary tumors occur in 25-75% of Men I pts

•

Most are prolactinomas


MEN I

7) HPT in MEN I pts

•

Most pts develop HPT before onset of islet cell or pituitary tumors

• Almost every pt will develop HPT between 18-40 years of age

• Seen equally in males and females

Benson, Am J Med, 1987

Skogseid, J. Clin Endo Metab, 1991

MEN I

8) Clinical presentation of HPT asymptomatic

Symptomatic

Renal Calculi

Peptic Ulcer Disease

Neuropsychiatric

Muscle Weakness

Bone Disease

Total of 106 pts

49%

51%

35%

8%

8%

5%

2%

Grant, Surgery, 1993

MEN I

9) Pathology of HPT

• Asymetric enlargement of all 4 parathyroid glands as hyperplasia

• Avg. ratio largest : smallest gland is 9.6

• 13% pts have supernumery glands with up to 17 glands reported

•

Ectopic glands are common

•

All glands have chief cell hyperplasia

Marx, Clin Endo, 1991


MEN I

10) Surgical mgmt of HPT

• Subtotal parathyroidectomy (subtotal ptx)

• Total parathyroidectomy with heterotopic autotransplantation into non-dominant forearm (total ptx/at)

•

Identify and biopsy all glands

•

Search for supernumery glands

•

Perform transcervical thymectomy


10) Surgical Mgmt of HPT

MEN I

Recurrent HPT Hypoparathyroidism

Subtotal PTX + 8.8 to 66.6% pts Up to 30% pts

Total PTX/AT

11) PTX should be performed as initial surgery in patients with MEN I, HPT, ZES


Norton, Surgery, 1987

Lithium Associated

Hyperparathyroidism

1) Used in mgmt of bipolar depression and other psychiatric disorders

2) Causes hypercalcemia in 10% of treated patients

3) Acts on parathyroid cell Ca receptor to shift

PTH secretion curve to right

4) Presence of hypercalcemia is independent of dosage, tx duration, lithium toxicity


Abdullah, Brit J Surg, 1999

Lithium Associated HPT

5) In most pts, the HPT is reversible with discontinuing lithium

6) Parathyroid autonomy occurs in susceptible pts on long term lithium tx

7) Lithium may induce parathyroid hyperplasia or promote growth of new or preexisting adenomas


Abdullah, Brit J. Surg, 1999


8) Abdullah, Univ Sydney, Australia

•

Reviewed 49 pts with surgically verified lithium assoc HPT

• Single adenoma – 33 pts

• Hyperplasia – 16 pts

Abdullah, Brit J Surg, 1999


9) Treatment

•

Try alternative medication

•

Surgery if HPT persists following discontinuing lithium

• Surgery if lithium cannot be stopped

•

Surgery involves 4 gland exploration and parathyroidectomy limited to grossly enlarged glands with intra operative iPTH assay


Abdullah, Brit J Med, 1999

Familial Hypocalciuric Hypercalcemia

(FHH)

Genetics

1) Occurs at 1% the frequency of pHPT

2) Autosomal dominant inheritance with nearly 100% penetrance at early age

3) Gene responsible located on chromosome 3 in 90% and chromosome 19 in 10% of cases

4) Gene codes for Ca R in parathyroid cells, kidney cortical thick ascending limb cells, and possibly other tissues

Law, An Int Med, 1985

Brown, Endo Metab Clin NA, 2000

FHH

Pathophysiology

1) 50% reduction in Ca R expression in parathyroid and kidney

2) 10-20% increase in set point for Ca regulated

PTH release

3) Excessive Ca resorption in cortical thick ascending limb

4) Decreased sensitivity to Ca in other organ systems

Brown, 2000

FHH

Laboratory Features

1) Usually mild elevation of ionized and total calcium since birth

2) Usually low normal serum phosphate

3) Usually upper normal or mildly elevated serum Mg

4) Usually normal 25(OH)D and 1,25(OH)

2

D

5) Inappropriately normal iPTH

Brown, 2000

FHH

Renal Function

1) Relative hypocalciuria with relative low 24 hour urinary Ca collection

2) Ratio of Ca clearance to Cr clearance

•

(24hr Uca x Sca)/(24hr Ucr x Scr)

• 80% FHH pts < 0.01

•

80% pHPT pts > 0.01

Marx, Medicine, 1981

FHH

Renal Function

3) Relative hypocalciuria can rarely be seen in pHPT due to:

• Vit D deficiency

•

Low Ca intake

• Thiazide use

•

Lithium use

• Hypothyroidism

Brown, 2000

FHH

Treatment

• Pts are asymptomatic and do not develop complications from hypercalcemia

• Hypercalcemia recurrence rates are very high after parathyroidectomy

• Therefore, surgical intervention should be avoided

Marx, 1981

Brown, 2000

MALIGNANCY ASSOCIATED

HYPERCALCEMIA

Malignancy Associated

Hypercalcemia

(MAHC)

• Most common cause of hypercalcemia in inpatients

• Second most common cause in general population

• 50% 30 day survival rate

Ralson. Ann Int Med. 1990

MAHC

• Humoral Hypercalcemia of Malignancy

• Local Osteolytic

Hypercalcemia

• Authentic Ectopic

Hyperparathyroidism

• Unusual causes

% of pts

80%

20%

Rare

Rare

Stewart. 2001

PTHrP

1) PTHrP gene located on chromosome 12p

2) Limited structural homology between

PTH and PTHrP

3) N-terminal fragments 1-34 PTH/PTHrP have same in vivo effect on Ca

PTHrP

1) PTH/PTHrP interact equivalently with

PTH/PTHrP membrane receptor (PTH1R)

2) PTH1R is G-protein coupled membrane receptor

3) Most PTH/PTHrP actions are mediated through

PTH1R

4) PTH1R gene located on chromosome 3p

HHM

1) Significant hypercalcemia

2) Uncoupling of osteoclastic bone resorption from osteoblastic bone formation

3) Increased PTHrP

4) Decreased PTH

HHM

5) Increased 24 hour urine Ca

6) Decreased 1,25 (OH) D

3

7) Rn Bone Scan shows absence of skeletal metastases

HHM

50% pts have SCC

• Lung • Oropharynx

• Cervix • Vulva

• Esophagus • Skin

• Larynx

HHM

• Renal Ca

• Ovarian Ca

• Bladder Ca

• Breast Ca

• HTLV-1 Lymphoma – 90% associated with HHM

• Pheochromocytomas

• Islet Cell Tumors

LOH

Mechanism of Hypercalcemia

1) Not direct destruction of bone

2) Malignant cells in marrow produce osteoclast activating factors

• Multiple Myeloma – TNF

• Lymphoma – IL – 1

• Breast Cancer – PGE

2

LOH

• Hypercalcemia

• PTH suppression

• 1,25(OH)

2

D

3 suppression

• Non detectable PTHrP

• Increased 24 hour urine Ca

• Usually normal phosphate

LOH

Most Common Malignancies

• Multiple Myeloma

• Leukemia

• Lymphoma

• Breast Cancer

Unusual Causes of MAHC

• 40 pts reported with various types of lymphoma with elevated 1,25 (OH) D

3

Authentic Ectopic

Hyperparathyroidism

1) Now at least 7 convincing case reports

• 2 lung small cell Ca’s

• 1 lung squamous cell Ca

•

1 ovarian clear cell Ca

• 1 thyroid papillary Ca

• 1 thymoma

• 1 neuroendocrine tumor

2) Increased iPTH

3) Undetectable PTHrp

Iguchi, J. Clin End. Metab. - 1998

Vitamin D Intoxication

Related Hypercalcemia

1) 2000 v/d (50 ug/d) is upper limit recommended adult dietary intake

2) Chronic intake of >50,000 v/d is required to cause hypercalcemia

3) Increased intestinal Ca absorption

4) Increased bone resorption

Pott, Prin Int Med, 2001

5) 25(OH)D likely responsible

•

Low biologic activity

• Production not tightly regulated

• Significant elevation in serum 25(OH)D > 100ng/ml

6) 1,25(OH)

2

D not likely responsible

• Most active Vit D metabolite

•

Production tightly regulated at renal

1-alpha-hydroxylase

• Frequently not elevated


7) Treatment

•

Discontinuation Vit D, po Ca restriction, and hydration usually resolves hypercalcemia quickly

• substantial Vit D fat stores may delay resolution for weeks

• 100mg/d hydrocortisone usually resolves hypercalcemia in several days


Granulomatous Diseases

1) Sarcoidosis, tuberculosis, fungal infections, etc.

2) Macrophages in granulomas convert 25(OH)D to

1,25(OH)

2

D at increased rate

3) Increased sensitivity to vitamin D in target organs

4) Low iPTH and 1,25(OH)

2

D levels


Granulomatous Diseases

4) Treatment a) Avoid excessive sunlight exposure b) Limit vitamin D and Calcium intake c) Glucocorticoids (<100 mg/d hydrocortisone) control hypercalcemia

• Block excessive 1,25(OH)

2

D production

• Decreases sensitivity to vitamin D


Hyperthyroidism Associated

Hypercalcemia

• 20% hyperthyroid pts have high normal-mildly elevated Ca, and hypercalciuria

• Hyperthyroidism may be occult to severe

• Due to increased bone turnover, with bone resorption exceeding bone formation

• Mgmt is tx of the hyperthyroidism


Immobilization Associated

Hypercalcemia

• Usually in presence of associated disease

• Due to increased bone turnover, with bone resorption exceeding bone formation

• Hypercalciuria

• Treatment is resumption of ambulation


Thiazide Associated Hypercalcemia

1) Thiazides in normal pts cause transient increase to high normal blood Ca that returns to preexisting levels in 7 days

2) Thiazide assoc hypercalcemia seen in pts tx with thiazides who have high bone turnover rates with resorption exceeding formation



3) eg., hypothyroidism tx with high dose Vit D eg., aggravation of hypercalcemia in pHPT pts

4) Chronic thiazide tx causes hypocalcemia in these pts

•

Increased proximal tubular Na and Ca resorption in response to Na depletion



1) Homeostatic mechanisms in pts with increased bone turnover are ineffective in counteracting the calcium elevating effect of thiazides

2) Thiazide assoc hypercalcemia disappears within days of stopping drug


Vitamin A Intoxication Associated

Hypercalcemia

1) Usually side effect of dietary fadism

2) Due to increased bone turnover, with bone resorption exceeding formation

3) Hypercalcemia (12-14 mg/dl) seen with

50,000 to 100,000 units Vit A/d (10 to 20x MDR)


Vitamin A Intoxication Associated

Hypercalcemia

4) Significantly increased serum Vit A levels

5) Treatment

• Discontinuation of Vit A rapidly resolves hypercalcemia

•

100 mg/d hydrocortisone rapidly resolves hypercalcemia


PARATHYROID CARCINOMA

Pathology

1) Histopathologic criteria:

A. Vascular invasion

B. Capsular invasion

C. Regional +/or distant metastasis

2) Gross criteria:

A. Firm to stony hard mass

B. Adherent to, +/or invading adjacent tissues, eg. Thyroid, nerve, muscle, esophagus

C. Cervical node metastasis

Shane, 2001

Clinical Features

1) Usually present with symptomatic hypercalcemia

•Fatigue

•Weakness

•Wt loss

•Anorexia

•Nausea

•Vomiting

•Polyuria

•Polydypsia

•Bone Pain

Shane, 2001

Clinical Features

2) Prevalence of palpable neck mass – 30-76% pts

3) Prevalence of nephrolithiasis – 56% pts

4) Prevalence of radiologic signs of bone disease –

44 to 91% pts

Van Heerden, Medicine, 1992

Silverberg, Am J. Med, 1990

Shane, 2001

Laboratory Features

1) tCa usually 3-4 mg/dL above normal

2) iPTH usually 3-10 times above normal

3) May have elevated alpha and beta subunits of hCG


Natural History

1) Behaves in indolent, mildly aggressive pattern

2) Recurrent disease presents locally with direct invasion of contiguous neck structures

3) Both lymphatic and hematogenous metastases occur late:

•

Lung – 40%

•

Cervical nodes – 30%

•

Liver – 10%

Shane, 2001

Surgical Treatment

1) When gross findings suggest malignancy at initial operation:

A. En bloc excision of lesion, ipsilateral thyroid lobe and isthmus

B. Resect adjacent tissues adherent to tumor

C. Skeletonization of trachea

D. Ipsilateral central lymph node dissection

Shane, 2001

Surgical Treatment

2) When dx is made post op by histopathologic criteria:

A. Reoperation may not be needed

B. The simple complete resection is often curative

C. Pt can be followed with tCa and iPTH levels every

3mo

Shane, 2001

Management of Recurrent and

Metastatic Carcinoma

1) Tc-99-sestamibi, US, CT, MRI are useful for localization

2) FNA and core bx should be avoided due to potential seeding of tract

3) Resection is primary tx of locally recurrent and distant disease

4) Debulking can offer significant palliation

Shane, 2001

Radiation Therapy

• Parathyroid Carcinoma is not radiosensitive

Chemotherapy

• Results have been disappointing

Shane, 2001

Epidemiology

1) < 0.1% of pHPT pts

2) Ration of women:men is 1:1

3) Avg. age range is 40 to 50y


NATURAL HISTORY OF pHPT:

UNTREATED

AND

POST-PARATHYROIDECTOMY

S. Silverberg, M.D.

Dept. Of Medicine, Columbia Univ, N.Y.

Longitudinal prospective study of pts with asymptomatic mild pHPT

• 52 pts followed for 10y without tx

• 61 pts followed for 10y after parathyroidectomy

NEJM, Oct. 1999

Silverberg, M.D.

Course of Disease Without Treatment

1) No significant change in mean values of:

•

Total serum calcium

•

I PTH

•

Total serum alkaline phosphatase

•

1,25(OH)D

•

24 hour urinary calcium

• DMD at lumbar spine, femoral neck, radius

NEJM, Oct. 1999

Silverberg, M.D.


2) 11/52 pts (21%) had >10% decrease in BMD at one or more sites

3) 14/52 pts (27%) had evidence for disease progression

• Defined as development of one or more indications for parathyroidectomy (NIH, 1990)

NEJM, Oct 1999

Silverberg, M.D.


4) 14/52 pts (27%) – disease progression

•

2 pts developed marked hypercalcemia (> mg/dL)

•

8 pts developed marked hypercalciuria (>400 mg/dL)

•

6 pts developed low cortical bone density (radius Z score less than –2)

NEJM, 1999

Silverberg, M.D.


Site Mean BMD After 10y

Lumbar Spine Significant 12 +3% decrease (p=0.03)

Femoral Neck Significant 14 +4.% decrease (p=0.03)

Radius No significant change

NEJM, 1999

Silverberg, M.D.

Course of Disease Following Parathyroidectomy

Biochemical Features

Serum tCa iPTH

Alk phos

24 hr Urine Ca

% Patients

100% nl

100% nl

100% nl

100% nl

NEJM, 1999

Silverberg, M.D.

Course of Disease Without and With Treatment in Pts with Nephrolithiasis

• 6/8 pts (75%) with nephrolithiasis had one or more stone recurrences without tx over 10 yr

• Difficult to obtain natural tx data o untreated pHPT pts with neophrolithiasis

• 0/12 pts (0%) with nephrolithiasis who underwent parathyroidectomy had stone recurrence over 10y

• In literature - >90% reduction in stone recurrence following parathyroidectomy

NEJM, 1999

Nilsson, Univ Hosp in Uppsala, Sweden

1) Echocardiography in 30 pHPT and in 30 control pts at rest and with exercise a) Measured before parathyroidectomy b) Measured at mean of 13 mo post op

Surgery, 2000


2) PreOp pHPT pts had significantly: a) Higher systolic bp with exercise b) Increased ventricular extrasystoles c) Increased ST depression with exercise d) Increased left ventricular isovolemic relaxation time e) Increased mitral decelleration time f) Increased left ventricular EF g) Increased left ventricular shortening fraction h) Increased left ventricular mass

Surgery, 2000


3) Post Parathyroidectomy a) ST segment exercise depression no longer detected b) Partial reversal of left ventricular isovolemic relaxation time c) Partial reversal of mitral deceleration time d) Partial reversal of LVEF e) Partial reversal of LV shortening fraction


4) Conclusions a) Cardiovascular disease is symptom of pHPT b) Myocardial ischemia and LV dysfunction associated with pHPT can be reversible with surgery

Surgery, 2000

Prager, Univ of Vienna, Austria

1) 20 pts with sporadic pHPT

2) 18 pts with single adenoma

3) 2 pts with double adenoma

4) 0 pts with hyperplasia

5) All 20 pts cured with parathyroidectomy

6) Psychological testing performed pre op,

6 wks post op, and 12 wks post op


4) d2-Test of Attention measured concentration and attentiveness under stress

•

14 rows with 47 figures each

•

Pt identifies relevant figures and crosses them out

•

20 sec per row

Surgery, 2000


5) Numbers Memorizing section of Wilde

Intelligence Test measured retentiveness

• Tester recites series of 5 to 11 digits in identical intervals

•

Pt writes these digits down after verbal presentation

Surgery, 2002


6) Results

• d2-Test showed Concentration Performance significantly improved at 6 and 12 wks post op (p< .05)

•

D2-Test showed Total Number of Items Processed significantly improved at 6 wks post op (p = .0009)

• Wilde Test showed Numbers Memorizing significantly improved at 12 wks post op (p = .0396)

Surgery, 2002


6) Results

•

Linear regression analysis showed no significant correlation for CP changes with pre op Ca, iPTH, age, gender, degree of general symptoms

Surgery, 2002


7) Conclusions

•

This is first study using objective assessment tools to evaluate impact of parathyroidectomy for pHPT on mental performance

•

Significant improvement in cognitive function was demonstrated

Surgery, 2002

Burney, Univ of Mich

1) 155 pts with pHPT

•

86 pts with Ca <10.9 mg/dl

•

69 pts with Ca >10.9 mg/dl

2) SF-36 Health Survey

• Functional health status assessment tool

•

Measures 8 separate domains

3) Both groups had similar marked functional health status impairment preoperatively

Surgery, June 1999


4) Both groups had marked improvement at 2 mo

5) Both groups had additional improvement at 6 mo

6) Both groups returned to normal or near normal in 6 of 8 domains

Surgery, June 1999


7) Conclusion

• Pts with pHPT have significant functional health status impairment independent of Ca level

•

There is dramatic improvement after parathyroidectomy

•

Parathyroidectomy should not be delayed until there is significant hypercalcemia, as recommended in 1990 NIH statement

Surgery, June 1999

Tolpos, Wayne State Univ

1) 53 pts with mild pHPT a) Prospective randomized trial of parathyroidectomy vs. observation b) Ca of 10.1 – 11.5 mg/dl c) Applied SF-36 Health Survey every 6 mo for 24

Surgery, 2000


2) Scores in 2 of 9 domains were significantly improved in surgery vs. observation group a) Social functioning domain b) Role-functioning emotional

Surgery, 2000


3) Conclusions a) The 2 domains detect preclinical pHPT changes b) These 2 domain changes are reversible with parathyroidectomy

Surgery, 2000

Pasieka, M.D.

Univ. of Calgary, Canada

1) Introduced disease specific surgical outcome tool specifically for pHPT

2) 13 symptoms measured by pt as Parathyroidectomy

Assessment of Symptoms scores – PAS scores

3) Sx’s rated from 0 (no sx) to 100 (most extreme)

4) The higher the score, the more symptomatic the pt

World, J. Surg, 2002

Pasieka, M.D.

5) PAS Score Questionnaire

Symptom

1) Pain in the bones

2) Feeling tired easily

3) Mood swings

4)

Feeling “blue” or depressed

5) Pain in the abdomen

6) Feeling weak

7) Feeling irritable

8) Pain in the joints

9) Being forgetful

10) Difficulty getting out of a chair or car

11) Headaches

12) Itchy skin

13) Being thirsty

Score (0-100)

World J. Surg, 2002

Pasieka, M.D.

6) Study enrolled 203 pHPT pts and 58 nontoxic thyroid surgery pts for comparison

A. Scores measured at 7d, 3mo, 12mo post op

B. Control group had no significant change in total

PAS scores

C. Significant reduction in total PAS score observed in pHPT pts

D. No correlation between tCa and iPTH with PAS scores

World J. Surg, 2002

Pasieka, M.D.

7) Conclusion

A. PAS score questionnaire is effective in measuring vague nonspecific sx’s of pHPT

B. Following parathyroidectomy, pts has resolution of these sx’s

C. Parathyroidectomy should be considered for all pts with biochemical evidence of pHPT

World J. Surg, 2002

MEDICAL TREATMENT

Management of Severe Hypercalcemia

• Volume repletion

• Biphosphonates

• Calcitonin

• Gallium nitrate

• Plicamycin

• Phosphate

• High dose glucocorticoids

• Peritoneal or hemodialysis

Bringhurst, Endocrinology, 2003

Volume Repletion

• Correct extracellular volume depletion with IV isotonic saline at 2-4 liters/day

• Diuretics can worsen vol. Depletion and should be discontinued

• Should be used in conjunction with anti-resorptive agents


Biphosphonates

1) Antiresorptive drugs that inhibit osteoclastic bone resorption

2) Drugs of first choice in most situations

3) Pamidronate and Etidronate are available in

U.S.A.


Biphosphonates

4) Pamidronate

•

Dose: 60-90 mg IV over 4-24 hours

•

More reliably normalizes serum Ca often with single dose

• Serum Ca declines rapidly to normal in 2-3 days in

>80% of cases

•

Duration of response ranges from a week to several months


Biphosphonates

4) Pamidronate

•

Dose may be repeated in refractory cases

•

Well tolerated

•

Local pain – swelling at infusion site, low grade fever, transient lymphopenia, hypophosphatemia, hypomagnesemia


Calcitonin

1) Inhibits osteoclast mediated bone resorption

2) Increases renal calcium excretion

3) Rapid onset of action

4) Efficacy limited to a few days possibly due to bone-kidney receptor down-regulation

5) Generally well tolerated


Bringhurst, Text Endocrin, 2003

Gallium Nitrate

1) Inhibits bone resorption by preventing dissolution of hydroxyapatitie crystals

2) Can normalize Ca within 5-7 days

3) Rarely used due to significant nephrotoxicity

4) Not available in USA

Warrell, Ann Int Med, 1987


Plicamycin

1) Formerly mithramycin

2) Inhibits bone resorption

3) Significant hepatic, renal, hematologic toxicity

4) No longer used widely


Phosphate

1) Inhibits osteoclast medicated bone resorption

2) Generalized precipitation of Ca-Phos salts in tissues

3) IV phosphate may cause severe hypocalcemia and hypotension

4) Frequent nausea, abdominal cramps, and diarrhea

5) Not widely used


Dialysis

1) May be required in first 12-24 hours

2) Peritoneal dialysis

3) Hemodialysis employing low or zero-calcium dialysate


Calcimimetics

1) Compounds that mimic +/or potentiate effects of Ca at Ca receptor

2) Type I Calcimimetics

• Conventional receptor agonists

•

Inorganic or organic polycations

• Nonselective

•

Decreased potency

Nemeth, 1998

Type II Calcimimetics

• NPS R-467 and NPS R-568

• Small, organic non-cationic phenylalkylamine compounds

• Selective and potent

Nemeth, 1998

NPS R-467 and NPS R-568

• Inhibit PTH secretion

• Activity is dependent on presence of extracellular

Ca

• Allosteric effectors that increase sensitivity of Ca receptor

• Effectively lower Ca concentrations required to activate Ca receptors

Nemeth, 1998

Silverberg

N. Engl. J. Med. 1997

• Small study

• PO NPS R-568 lowered plasma PTH and

Ca in postmenopausal women with pHPT

Shoback, UCSF

1) Prospective, double-blind, 5 wk trial

2) 10 pts (6 AMG 073, 4 placebo) with pHPT and

Ca levels > 11.0 mg/dl

3) AMG 073 dose of 65 mg po bid x 4 wks

4) 5 week study duration

Abstract, Oct. 2001

Amer Soc Bone Min Res Mtg

Shoback, UCSF

4) AMG 073 Group

• 5 of 6 pts had reduction of serum Ca to normal range with AMG

073

•

Maximal reduction in mean iPTH of approx. 39% seen at 2 to 4 hours post-dose

• Mean iPTH reduction on day 28 of 14.5% at 12 hours post dose

•

Serum Ca returned to predose levels 1 wk after cessation of

AMG 073

• Generally well tolerated

•

Most common adverse events – nausea, abdominal pain, paresthesia

Abstract, Oct. 2001

Amer Soc Bone Min Res Mtg

Shoback, UCSF

5) Placebo Group

•

1 of 4 pts had reduction of serum Ca to normal range

• Mean iPTH on day 28 was increased at 10.6% 12 hours post dose in placebo group

6) Conclusion

• AMG 073 is generally well tolerated

•

AMG 073 was efficacious in reducing serum Ca and iPTH in moderate to severe pHPT

Absract, OCT 2001

Am Soc Bone Min Res Mtg

LOCALIZATION

AND SURGICAL TREATMENT

NUCLEAR MEDICINE

IMAGING

Radiopharmaceuticals

Tc-99 - Sestamibi

Tc-99 - Tetrofosmin

Thallium - 201

Iodine - 123

Tc-99 - Pertechnetate

Tc-99-Sestamibi (Cardiolyte)

1) Sestamibi is monovalent lipophilic cation

(methoxyisobutylisonitrile)

2) Diffuses passively through cell membranes and accumulates in mitochondria following negative membrane potentials

3) Accumulation in abnormal parathyroid is dependent on blood flow, metabolic rate, and pglycoprotein (Pgp) expression

Taylor, Clin Guide Nuc Med, 2000

Tc-99-Sestamibi

4) P-glycoprotein

•

Membrane transport protein

•

Encoded by multidrug resistance gene

•

Responsible for exostosis of chemtx agents

•

Positive P-gp expression may account for

Tc-99-Sestamibi uptake in adenomas

Pattou, Brit J Surg, 1998

Tc-99-Sestamibi

5) High energy photons and short half life increases definition, allows for 3 dimensional images, lowers radiation exposure

6) Given IV

7) No uptake in normal parathyroids

8) Positive uptake in thyroid and abnormal parathyroids

9) More rapid washout from thyroid

Pattou, Brit J Surg, 1998

Tc-99-Tetrofosmin (Myoview)

1) Like sestamibi, this is a lipophilic cation derivative

2) Similar biokinetics and uptake in abnormal parathyroids

3) Less radiation exposure

4) No heating required for preparation

5) Similar preliminary results

6) Slower thyroid washout rate

7) Limited experience


Thallium-201

1) Inorganic cation/K analogue enters cells Na/K trans membrane pump

2) Positive uptake into thyroid and abnormal parathyroids

3) Uptake dependent on blood flow

4) No uptake in normal parathyroids

5) Sensitivity: 26-68%

Mitchell, Surg Clin NA, 1995


Iodine-123

• Usually given po

• Taken up by thyroid

• Not taken up by parathyroid

Technetium-99m-Pertechnetate

• Given IV

• Positive uptake in thyroid

• No uptake in parathyroids



Patient Preparation

• T1-201 – no special prep

• Tc-99-sestamibi – no special prep

• I-123 and Tc-99-pertechnetate thyroid uptake compromised by thyroid meds and recent (4-6wk)

IV iodinated contrast



Radiation Exposure

• Amount of radiation exposure is small and similar to other dx x-rays

• Radiation dose is 5-15% of yearly safe dose for technologists

• Radiation dose is equal to 1-3 yr exposure from normal background radiation

• No restrictions on exposure to others


Imaging Techniques

• Anterior planar views

• Multiple oblique views

• Pinhole images

• Single-photon emission compute tomography (SPECT)


Nuclear Medicine Single

Radiotracer Dual Phase Scan

• Tc-99-sestamibi washes out of normal thyroid tissue faster than from parathyroid adenomas/hyperplasia

• 5-25 mCi given IV

• Immediate image at 5-10 min.

• Delayed images out to 5 hr.

Taylor, Cline Guide Nuc Med, 2000

Nuclear Medicine

Subtraction Scan

• First successful Rn Parathyroid scan was T1-

201/Tc-99-pertechnetate subtraction scan

• Tc-99m-sestamibi has replaced T1-201

• Tc-99-pertechnetate and I-123 thyroid images can be subtracted from Tc-99-sestamibi images of thyroid and parathyroid leaving only parathyroid images

Bergenfelz Surg, 1997

Ultrasonography of Parathyroid Glands

• Best for intra-, juxta-, or infra-thyroidal tumors

• Rarely helpful for ectopic glands

• Cannot image mediastinal glands

• Helpful in identifying coexistent thyroid pathology

Clark, Endo Metab Clin N.A, 2000

US of Parathyroid Glands

• Sensitivity of 65% to 75%

• Relatively inexpensive

• Minimal risk

• Well tolerated

Clark, Endo Metab Clin N.A., 2000

CT Imaging of Parathyroid Glands

• Sensitivity of 42% to 68%

• Helpful in locating ectopic glands

• Expensive

• Small radiation exposure

• Requires IV contrast

• Metallic clips and shoulder artifact can interfere with imaging

Clark, Endo Metab Clin N.A., 2000

Magnetic Resonance Imaging of

Parathyroid Glands

• T1-weighted images - glands have low signal intensity like thyroid and muscle

• T2-weighted images – glands have high signal intensity like fat

• Short tau invasion recovery can differentiate parathyroid from fat

• Gadolinium improves sensitivity

Mitchell, Surg Clin N.A. 1995

Clark, Surg One Clin N.A. 1998

MRI Imaging of Parathyroid Glands

• Overall sensitivity – 57% to 90%

• Helpful in locating ectopic glands

• Requires no IV contrast

• No artifact from metallic clips or shoulders

• Expensive

• Less well tolerated

• Relatively high false positive rate


Selective Venous Catheterization and iPTH Assay

• Helpful for localization in persistent and recurrent hyperparathyroidism when non-invasive imaging is negative or equivocal

• Twofold gradient from peripheral iPTH level is diagnostic at selective catheterization site

• Sensitivity: Up to 80%

• Disadvantages: invasive, expensive

Clark, Endo Metab Clin NA, 2000

Fine Needle Aspiration

1) Method of localization

•

Ultrasound

•

CT

2) Method of sample examination

• Cytology

•

PTH bioassay

• Immunohistochemical PTH staining

Kebebew, Surg Onc Clin NA, 1998

Fine Needle Aspiration

3) Cytology

•

May be difficult to distinguish parathyroid from thyroid cells

•

Accuracy in identifying parathyroid tissue – 60%

4) PTH bioassay accuracy – 100%

5) Immunohistochemical accuracy – 100%

Kebew, Surg Onc Clin NA, 1998

Tikkakoski, J Laryn Otol, 1993

Abati, Hum Path, 1995

1990

National Institute of Health

Consensus Development

Conference on the Diagnosis and

Management of Asymptomatic


Surgery Recommended for

Symptomatic Primary

Hyperparathyroidism

• Osteitis Fibrosa Cystica

• Nephrolithiasis

• Severe Neuromuscular disease

• Acute Hyperparathyroidism

Indications for Surgery

• Total serum Ca>1.0-1.6 mg/dl more than high normal

• More than 30% reduction in Cr clearance not attributable to another cause

• 24 hour urine Ca collection more than 400mg /24 hours

• Distal radius Z score at or below –2

• Age less than 50

J. Bone Min Res. 1991

1990 NIH Guidelines

• 100% of symptomatic pts are surgical candidates

• 37.5% of asymptomatic pts are surgical candidates

• 60% of all pHPT pts are surgical candidates

Bilezikian, Endo Metab Clin NA, 2000

April 8-9, 2002

NIH/NIDDK

Workshop on Asymptomatic Primary

Hyperparathyroidism

Indications For Surgery In pHPT

• All patients who are symptomatic with acceptable operative risk

• Selected asymptomatic patients with acceptable operative risk

Indications for Surgery in

Asymptomatic pHPT

• Total serum Ca 1.0 mg/dl more than high normal

• Persistent elevated serum Cr not attributable to another cause

• Distal radius, hip, lumbar spine T Score at or below –2

• Age less than 50

Dougherty, Amer Col Surg Mtg 2002

Surgery for pHPT

1) Standard open 4-gland exploration

2) Open minimally invasive parathyroidectomy

3) Endoscopic parathyroidectomy

Standard Open 4-Gland Exploration

1) Low anterior transverse neck incision under general anesthesia

2) Explore all 4 glands

3) Excise adenomas

4) Hyperplasia

A. Subtotal parathyroidectomy

B. Total parathyroidectomy with heterotopic autotransplantation into nondominant brachioradialis muscle


5) In hands of experienced endocrine surgeon

A. Cure rate - >95%

B. Positive predictive value of preop localization studies is less than success rate of experienced endocrine surgeon without such studies

C. Preop localization studies not needed

D. Vocal cord paralysis - <1%

E. Permanent hypoparathyroidism - <4%

Bringhurst, Text Endo, 2003

J. Doppman, M.D.

Leading Interventional Radiologist with

Experience in Identifying Occult Endocrine

Neoplasms

“the only localization study needed for initial surgery for hyperparathyroidism is to localize an experienced endocrine surgeon”

Doppman, Ann Surg, 1996


6) In hands of inexperienced endocrine surgeons

A. Cure rates - <95%

B. Major cause of surgical failure

C. Vocal core paralysis – can be much >1%

D. Permanent hypoparathyroidism – can be much > 4%

Bringhurst, Text Endo, 2003

Open Minimally Invasive

Parathyroidectomy

1) Pts most have positive preop Tc-99-sestamibi localization

2) Small unilateral low anterior transverse neck incision next to midline

3) Superficial cervical field block with 20cc 1% lidocaine with 1:100,000 epinephrine and IV propofol sedation

Udelsman, Ann Surg, 2000

OMIP

5) Intraop iPTH monitoring is optional

6) Intraop hand held gamma probe is optional

7) Indications for intraop conversion to 4-gland exploration

A. No adenoma found

B. Inadequate drop in iPTH

C. Inadequate exposure

IntraOperative iPTH Assay

1) Blood samples drawn from peripheral antecubital IV line

2) Preop sample drawn just before incision

3) Preexcision sample drawn after mobilization, and just before parathyroidectomy

4) Postexcision sample drawn at 5 min, 10 min, and prn after parathyroidectomy

Irvin, Op Tech Gen Surg, 1999

Intraoperative iPTH Assay

5) Preexcision iPTH is required

•

Parathyroid manipulation can cause acute rise of iPTH level

•

Parathyroid manipulation can disturb blood supply and cause preexcision fall in iPTH level

6) No further dissection after excision until adequate iPTH drop since manipulation of remaining normal glands may cause rise of iPTH



7) Criteria for iPTH prediction of success

•

Drop of iPTH >50% of highest preop or preexcision baseline within 10 min post excision

•

88% pts meet this criteria at 5 min

• 95% pts meet this criteria at 10 min



Irvin, 1996

Published Interpretation Criteria of Cure

Decreased of > 50% at 5, 10 min. compared to highest baseline level

Chen, 1999 Decrease of > 50% at 5 min.

Thompson, 1999

Starr, 2001

Garner, 1999

Decrease of > 50% at 20 min.

Decrease of > 65% or below upper limit of nl at 5, 10 min.

Decrease of > 50% of highest baseline level and lower than lowest baseline level at any given point (Nichols criteria)

Jaskowiak, 2002

Norman, Univ South Florida

Ex Vivo Radioactivity

Compared to Backround

• Fat

• Lymph Nodes

• Parathyroid Adenoma

Never > 2.2%

Never >2.2%

• Thyroid

• Normal Parathyroids

Never >16%

Never >2.2%

• Hyperplastic Parathyroid Never >16%

Range of 18% to 136%

Surgery, 1999

Norman, Univ South Florida

The 20% Rule

• Radioactive ratios immediately measure metabolic activity of parathyroid tissue

• Any excised parathyroid tissue with >20% of background activity is a solitary parathyroid adenoma and patient is cured

• In this setting, there is no need for 4 gland exploration, frozen section, or intraop iPTH measurement

Surgery, 1999

Saaristo, Univ Hosp of Tampere, Finland

1) 20 pts with pHPT

•

16 pts with solitary adenoma

•

4 pts with hyperplasia

2) Preop Tc-99 sestamibi scanning

3) Standard 4 gland exploration

4) Intraop radioguidance with 10mm Navigator gamma probe

J. Amer Coll Surg, 2002


5) 16 Adenoma PTS

•

Preop scan sensitivity – 81% (13 of 16 pts)

•

Gamma probe sensitivity – 50% (18 of 16 pts)

•

All adenomas detected by gamma probe were detected pre op



6) 4 Hyperplasia Pts

•

Preop scan sensitivity – 100% (4 of 4 pts)

•

Gamma probe sensitivity – 0% (0 of 4 pts)

7) Gamma probe detected only 8 of 32 (25%) of abnormal glands

8) 3 pts with pHPT were excluded due to Navigator malfunction



Conclusions

• In unselected pts scheduled for surgery for pHPT, the preop Tc99- sestamibi scan is more accurate than intraop gamma probe localization

• The intraoperative gamma probe is not recommended for initial pHPT surgery


Inabnet, Mount Sinai

• 60 pts with solitary adenoma localized by Tc99 sestamibi +/or ultrasound

• 18 to 20 mCi Tc99 sestamibi given 1.5 to 3 hours prior to surgery

• 11mm Neoprobe 2000 gamma probe used

• Open minimally invasive parathyroidectomy

• Intraoperative iPTH sampling prior to incision, after isolation, + 5,10, +30 min past excision

Arch Surg, 2002


# of PTS

1) Gamma Probe Unhelpful in pHPT

• Confusing – inaccurate counts

•

Increased activity only over exposed gland

• Equipment failure

•

Isotope administration problems

2) Gamma Probe Helpful in pHPT

17

9

2

1

29(48%)

24(40%)

3) Gamma Probe Unhelpful in Recurrent-Persistent HPT 0(0%)

4) Gamma Probe Helpful in Recurrent-Persistent HPT 6(10%)

5) Pts cured by Radioguided Parathyroidectomy 60(100%)

Arch Surg, 2002


Conclusions

• Findings in this study do not support routine use of intraoperative radioguidance during initial surgery for pHPT

• Radioguidance may be beneficial for persistent or recurrent HPT

Arch Surg, 2002

Radiologic Guided Percutaneous

Alcohol Ablation

1) Selected pts are very ill with poor performance status

2) May require >1 injection

3) Success rate – 80 to 85%

4) Potential for recurrent laryngeal nerve palsy

5) Rarely utilized

Clark, Contmep Surg, 1998

Lecture on Primary Hyperparathyroidism

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