Transcript Document

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(PO4)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
1) Vitamin D [1,25 (OH)2D3]
–
Absorption
Increase
Prime physiologic regulator
2) Increasing Age
Decrease
3) Estrogen
Increase
4) Glucocorticoids
Decrease
Distribution of Calcium in Plasma
• Free Ca 2+
48%
• Protein Bound Ca
46%
• Albumin accounts for 70% of this fraction
• Associated with diffusible ion
complexes
Carr, 1955
6%
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
Decreased
3) Cirrhosis
Decreased
4) Dehydration
Increased
5) Multiple Myeloma
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
%
Type
1) Prox. & St. Tubules
65%
Passive
No
2) Thick Ascending Limb
10%
Passive
No
3) Thick Ascending Limb
10%
Active
Yes
4) Distal Convoluted &
10%
Active
Yes
Connecting Tubules
iPTH Controlled
VITAMIN D
Vitamin D3 Photosynthesis
• Provitamin D3 (7-DHC) is in cell
membranes of epidermal keratinocytes
• UVB light converts Provitamin D3 to
Previtamin D3 by breaking B ring
• Thermal energy isomerizes Previtamin D3 to
Vitamin D3 in cell membrane
Vitamin D3 Metabolism
• Vitamin D3 is released into blood from
epidermis
• Then transported to liver by Vitamin D
binding protein
• Liver Vitamin D-25-hydroxylase converts
inert Vitamin D3 to inert 25(OH)D3
Vitamin D3 Metabolism
• Proximal renal tubular cell 25(OH)D3
hydroxylase converts 25(OH)D3 to active
1,25(OH)2D3
• 1,25(OH)2D3, phosphate, Ca inhibit
25(OH)D3 hydroxylase
• PTH stimulates 25(OH)D3 hydroxylase
Actions of 1,25(OH)2D3
• Increased Ca absorption in small bowel
• Inhibits 25(OH)D3 hydroxylase in kidney
• Increases bone mineralization
• Inhibits PTH secretion by parathyroid cells
Dietary Vitamin D
• Ingested vegetal source – Vitamin D2
• Ingested animal source – Vitamin D3
• 50% D2 – D3 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 D3
• 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 (1-84)
• PTH (1-6)
• PTH (1-33)
• PTH (1-36)
•PTH 7-34
•PTH 34-84
•PTH 37-84
Circulating Forms of PTH
Intact PTH
(iPTH)
PTH (1-84) (human)
H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-AsnSer-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-HisAsn-Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-SerGln-Arg-Pro-Arg-Lys-Glu-Asp-Asn-Val-Leu-Val-Glu-Ser-His-GluLys-Ser-Leu-Gly-Glu-Ala-Asp-Lys-Ala-Asp-Val-Asn-Val-Leu-Thr-LysAla-Lys-Ser-Gln-OH
Circulating Forms of PTH
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-AsnSer-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-HisAsn-Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-SerGln-Arg-Pro-Arg-Lys-Glu-Asp-Asn-Val-Leu-Val-Glu-Ser-His-GluLys-Ser-Leu-Gly-Glu-Ala-Asp-Lys-Ala-Asp-Val-Asn-Val-Leu-Thr-LysAla-Lys-Ser-Gln-OH
PTH (1-84) (human)
H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-AsnSer-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-HisAsn-Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-SerGln-Arg-Pro-Arg-Lys-Glu-Asp-Asn-Val-Leu-Val-Glu-Ser-His-GluLys-Ser-Leu-Gly-Glu-Ala-Asp-Lys-Ala-Asp-Val-Asn-Val-Leu-Thr-LysAla-Lys-Ser-Gln-OH
PTH (1-84) (human)
H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-AsnSer-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-HisAsn-Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-SerGln-Arg-Pro-Arg-Lys-Glu-Asp-Asn-Val-Leu-Val-Glu-Ser-His-GluLys-Ser-Leu-Gly-Glu-Ala-Asp-Lys-Ala-Asp-Val-Asn-Val-Leu-Thr-LysAla-Lys-Ser-Gln-OH
Circulating Forms of PTH
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)
H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-AsnSer-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-HisAsn-Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-SerGln-Arg-Pro-Arg-Lys-Glu-Asp-Asn-Val-Leu-Val-Glu-Ser-His-GluLys-Ser-Leu-Gly-Glu-Ala-Asp-Lys-Ala-Asp-Val-Asn-Val-Leu-Thr-LysAla-Lys-Ser-Gln-OH
PTH (1-84) (human)
H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-AsnSer-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-HisAsn-Phe-Val-Ala-Leu-Gly-Ala-Pro-Leu-Ala-Pro-Arg-Asp-Ala-Gly-SerGln-Arg-Pro-Arg-Lys-Glu-Asp-Asn-Val-Leu-Val-Glu-Ser-His-GluLys-Ser-Leu-Gly-Glu-Ala-Asp-Lys-Ala-Asp-Val-Asn-Val-Leu-Thr-LysAla-Lys-Ser-Gln-OH
Circulating Forms of PTH
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)2D3
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)2D3
• Renal proximal tubular cell 1 alpha-hydroxylase
converts 25(OH)D3 to 1,25(OH)2D3
• 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)2D3
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
Kacsoh. Endo Phys. 2000
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
Kacsoh. Endo Phys. 2000
Bone Fluid
• Rapidly accessible pool of Ca for ECF
• Crucial environment for osteoid mineralization
Kacsoh. Endo Phys. 2000
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
Clark, Surg Onc Clin N.A., 1998
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
Clark, Surg Onc Clin NA, 1998
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
Clark, Surg Onc Clin NA, 1998
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%
4%
3%
<0.1%
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
Clark, Surgery, 1994
1984 to 1999
• 80% of pHPT pts were “asymptomatic”
• 17% of pts had nephrolithiasis
• 1.4% of pts had osteitis fibrosa cystica
Silverberg, 2001
Primary Hyperparathyroidism
• 20% of patients are symptomatic
• 80% of patients are asymptomatic
Symptomatic pHPT
• Osteitis Fibrosa Cystica
< 2%
• Nephrolithiasis
15%
• Severe Neuromuscular disease
Rare
• Acute Hyperparathyroidism
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%
Wells, Curr Prob Surg, 1980
Abela, Text Endo Surg, 1997
Clinical Features of Hypercalcemia
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%
Wells, Curr Prob Surg, 1980
Doherty, Text of Surg, 2001
Clinical Features of Hypercalcemia
Cardiovascular
•ECG changes (short QT interval, widened T wave)
•Bradycardia
•Heart block
•Hypertension
Clinical Features of Hypercalcemia
Renal
•Polyuria
•Uremia
•Renal colic
•Nephrocalcinosis
Renal System
Symptom
Nephrolithiasis
Polyuria
Nocturia
Polydypsia
% pHPT pts
30%
28%
Wells, Curr Prob Surg, 1980
Dermatologic System
Signs & Symptoms
Pruritus
Brittle Nails
Calciphylaxis
% pHPT pts
Sadler, Prin Surg, 1999
Constitutional System
Signs & Symptoms
Fatigue
Weight loss
Anorexia
% pHPT pts
Sadler, Prin Surg, 1999
Ophthalmologic System
Signs & Symptom
Ocular changes
Band keratopathy
% pHPT pts
100%
> 50%
Sadler, Prin Surg, 1999
Clinical Features of Hypercalcemia
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%)
8pts (13%)
5pt (8%)
Total of 60pt
59pt (98%)
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
Diagnosis
iPTH Assay
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
Diagnosis
iPTH Assay
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
Diagnosis
iPTH Assay
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
Diagnosis
iPTH Assay
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)
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
Silverberg, Endo Metab Clin NA, 2000
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
Budayr, Contemp Surg Residents, 1997
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
McHenry, Amer Coll Surg, 2002
Silverberg, Endo Metab Clin NA 2000
Budayr, Contemp Surg Residents, 1997
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
Silverberg, Endo Met Clin NA, 2000
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
McHenry, Amer Coll Surg, 2002
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)
Silverberg, Endo Metab Clin NA, 2000
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
Silverberg, Endo Met Clin NA, 2000
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)
Measurement Site
Hip
L-Spine
Radius
Hip
2.6
1.5
1.5
RR/SD
Spine Radius All
1.9
1.6
1.6
1.9
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 5th and 95th 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.
II.
Primary hyperparathyroidism
1) Solitary adenomas
2) Multiple adenomas
3) Familial non-MEN
4) Multiple Endocrine Neoplasia
B.
Lithium therapy
C.
Familial hypocalciuric hypercalcemia
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
Potts, Prin Int Med, 2001
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 ZollingerEllison syndrome (ZES)
• Less common are insulinomas,
glucagonomas, and VIPomas
6) Pituitary tumors occur in 25-75% of Men I pts
• Most are prolactinomas
Wells, Prob Gen Surg, 1997
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
Clark, Surgery, 1992
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
Wells, Prob Gen Surg, 1997
MEN I
10) Surgical Mgmt of HPT
Recurrent HPT
Subtotal PTX + 8.8 to 66.6% pts
Hypoparathyroidism
Up to 30% pts
Total PTX/AT
11) PTX should be performed as initial surgery in patients
with MEN I, HPT, ZES
Wells, Prob Gen Surg, 1997
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
Potts, Prin Int Med, 2001
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
Potts, Prin Int Med, 2001
Abdullah, Brit J. Surg, 1999
Lithium Associated HPT
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
Lithium Associated HPT
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
Potts, Prin Int Med, 2001
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)2D
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
% of pts
• Humoral Hypercalcemia
of Malignancy
80%
• Local Osteolytic
Hypercalcemia
20%
• Authentic Ectopic
Hyperparathyroidism
Rare
• Unusual causes
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) D3
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 – PGE2
LOH
• Hypercalcemia
• PTH suppression
• 1,25(OH)2D3 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) D3
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
•
•
•
6)
Low biologic activity
Production not tightly regulated
Significant elevation in serum 25(OH)D > 100ng/ml
1,25(OH)2 D not likely responsible
•
•
•
Most active Vit D metabolite
Production tightly regulated at renal
1-alpha-hydroxylase
Frequently not elevated
Pott, Prin Int Med, 2001
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
Pott, Prin Int Med, 2001
Granulomatous Diseases
1) Sarcoidosis, tuberculosis, fungal infections, etc.
2) Macrophages in granulomas convert 25(OH)D to
1,25(OH)2D at increased rate
3) Increased sensitivity to vitamin D in target organs
4) Low iPTH and 1,25(OH)2D levels
Potts, Prin Int Med, 2001
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)2D production
• Decreases sensitivity to vitamin D
Potts, Prin Int Med, 2001
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
Potts, Prin Int Med, 2001
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
Pott, Prin Int Med, 2001
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
Potts, Prin Int Med, 2001
Thiazide Associated Hypercalcemia
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
Potts, Prin Int Med, 2001
Thiazide Associated Hypercalcemia
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
Potts, Prin Int Med, 2001
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)
Pott, Prin Int Med, 2001
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
Pott, Prin Int Med, 2001
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
•Vomiting
•Weakness
•Polyuria
•Wt loss
•Polydypsia
•Anorexia
•Bone Pain
•Nausea
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
Shane, J. Clin Endo Metab, 2001
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
Shane, J. Clin Endo Metab, 2001
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.
Course of Disease Without Treatment
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.
Course of Disease Without Treatment
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.
Course of Disease Without Treatment
Site
Lumbar Spine
Femoral Neck
Radius
Mean BMD After 10y
Significant 12 +3% decrease (p=0.03)
Significant 14 +4.% decrease (p=0.03)
No significant change
NEJM, 1999
Silverberg, M.D.
Course of Disease Following Parathyroidectomy
Biochemical Features
% Patients
Serum tCa
iPTH
Alk phos
24 hr Urine Ca
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
Nilsson, Univ Hosp
in Uppsala, Sweden
2) PreOp pHPT pts had significantly:
a)
b)
c)
d)
e)
f)
g)
h)
Higher systolic bp with exercise
Increased ventricular extrasystoles
Increased ST depression with exercise
Increased left ventricular isovolemic relaxation time
Increased mitral decelleration time
Increased left ventricular EF
Increased left ventricular shortening fraction
Increased left ventricular mass
Surgery, 2000
Nilsson, Univ Hosp
in Uppsala, Sweden
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
Nilsson, Univ Hosp
in Uppsala, Sweden
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)
2)
3)
4)
5)
6)
20 pts with sporadic pHPT
18 pts with single adenoma
2 pts with double adenoma
0 pts with hyperplasia
All 20 pts cured with parathyroidectomy
Psychological testing performed pre op,
6 wks post op, and 12 wks post op
Prager, Univ of Vienna, Austria
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
Prager, Univ of Vienna, Austria
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
Prager, Univ of Vienna, Austria
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
Prager, Univ of Vienna, Austria
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
Prager, Univ of Vienna, Austria
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
Burney, Univ of Mich
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
Burney, Univ of Mich
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
Tolpos, Wayne State Univ
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
Tolpos, Wayne State Univ
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)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
Score (0-100)
Pain in the bones
Feeling tired easily
Mood swings
Feeling “blue” or depressed
Pain in the abdomen
Feeling weak
Feeling irritable
Pain in the joints
Being forgetful
Difficulty getting out of a chair or car
Headaches
Itchy skin
Being thirsty
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
Bringhurst, Endocrinology, 2003
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.
Bringhurst, Endocrinology, 2003
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
Bringhurst, Endocrinology, 2003
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
Bringhurst, Endocrinology, 2003
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
Shane, J. Clin Endo Metab, 2001
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
Bringhurst, Text Endocrin, 2003
Plicamycin
1) Formerly mithramycin
2) Inhibits bone resorption
3) Significant hepatic, renal, hematologic toxicity
4) No longer used widely
Bringhurst, Text Endocrin, 2003
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
Bringhurst, Text Endocrin, 2003
Dialysis
1) May be required in first 12-24 hours
2) Peritoneal dialysis
3) Hemodialysis employing low or zero-calcium
dialysate
Bringhurst, Text Endocrin, 2003
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
Taylor, Clin Guide Nuc Med, 2000
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
Radiopharmaceuticals
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
Taylor, Clin Guide Nuc Med, 2000
Radiopharmaceuticals
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
Taylor, Clin Guide Nuc Med, 2000
Radiopharmaceuticals
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
Taylor, Clin Guide Nuc Med, 2000
Imaging Techniques
• Anterior planar views
• Multiple oblique views
• Pinhole images
• Single-photon emission compute tomography (SPECT)
Taylor, Clin Guide Nuc Med, 2000
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 T1201/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
Clark, Surg Onc Clin N.A., 1998
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
Primary Hyperparathyroidism
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
Standard Open 4-Gland Exploration
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
Standard Open 4-Gland Exploration
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%
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
Irvin, Op Tech Gen Surg, 1999
Intraoperative iPTH Assay
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, Op Tech Gen Surg, 1999
Intraoperative iPTH Assay
Published Interpretation Criteria
of Cure
Irvin, 1996
Decreased of > 50% at 5, 10 min.
compared to highest baseline level
Chen, 1999
Decrease of > 50% at 5 min.
Thompson, 1999
Decrease of > 50% at 20 min.
Starr, 2001
Decrease of > 65% or below upper limit
of nl at 5, 10 min.
Garner, 1999
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
Thyroid
Normal Parathyroids
Hyperplastic Parathyroid
Parathyroid Adenoma
Never > 2.2%
Never >2.2%
Never >16%
Never >2.2%
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
Saaristo, Univ Hosp
of Tampere, Finland
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
J. Amer Coll Surg, 2002
Saaristo, Univ Hosp
of Tampere, Finland
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
J. Amer Coll Surg, 2002
Saaristo, Univ Hosp
of Tampere, Finland
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
J. Amer Coll Surg, 2002
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
Inabnet, Mount Sinai
# of PTS
1)
2)
3)
4)
5)
Gamma Probe Unhelpful in pHPT
• Confusing – inaccurate counts
17
• Increased activity only over exposed gland
9
• Equipment failure
2
• Isotope administration problems
1
Gamma Probe Helpful in pHPT
Gamma Probe Unhelpful in Recurrent-Persistent HPT
Gamma Probe Helpful in Recurrent-Persistent HPT
Pts cured by Radioguided Parathyroidectomy
29(48%)
24(40%)
0(0%)
6(10%)
60(100%)
Arch Surg, 2002
Inabnet, Mount Sinai
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