Download Parathyroid hormone (PTH)

Hyperparathyroidism
내분비 대사 내과
R3 박정은
Parathyroid gland
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갑상전의 상, 하극의 후면에 위치
4개, 간혹 2-8개
황갈색, 난원형의 피막
무게 20-40mg, 길이 4-6 mm,
폭 2-4 mm, 두께 0.5-2 mm
Parathyroid hormone (PTH)
Primary function : maintain the ECF calcium concentration
 Normal range : 10-60 pg/mL
 The hormone acts directly on bone and kidney and indirectly
on intestine
 Serum PTH level : regulated by negative feedback
hypocalcemia → PTH ↑
1) dissolution of bone mineral ↑ (immediate)
2)↓the renal clearance of calcium (immediate)
3) ↑ the efficiency of calcium absorption in the intestine by
stimulating the production of 1,25(OH)2D (maintenance)
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Hormonal control loop for vitamin D metabolism and
function
Harrison 16th p.2246
fig 331-5
Parathyroid hormone (PTH)
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Kidney
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Inhibition of P reabsorption (proximal tubule)
Increased reabsorption of Ca (distal tubule)
stimulation of the renal 25(OH)D-1-hydroxylase
Bone
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Bone calcium release within minutes
increase the number of bone cells, both osteoblasts and
osteoclasts, and to increase the remodeling of bone
Continuous exposure to elevated PTH → osteoclastmediated bone resorption
Intermittent administration of PTH → stimulation of bone
formation
Regulation of PTH
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Calcium sensing receptor
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G protein coupled receptor
Parathyroid gland
Ca ↑ → stimulation of CaSR → suppression of PTH secretion
CaSR gene mutation → hyperparathyroidism
Reduced expression of the CaSR → PTH ↑
: parathyroid adenomas and uremic hyperparathyroidism
Classification of Causes of Hypercalcemia
I. Parathyroid-related
A. Primary hyperparathyroidism
1. Solitary adenomas
2. Multiple endocrine neoplasia
B. Lithium therapy
C. Familial hypocalciuric hypercalcemia
II. Malignancy-related
A. Solid tumor with metastases (breast)
B. Solid tumor with humoral mediation of hypercalcemia (lung, kidney)
C. Hematologic malignancies (multiple myeloma, lymphoma, leukemia)
III. Vitamin D–related
A. Vitamin D intoxication
B. 1,25(OH)2D; sarcoidosis and other granulomatous diseases
C. Idiopathic hypercalcemia of infancy
IV. Associated with high bone turnover
A. Hyperthyroidism
B. Immobilization
C. Thiazides
D. Vitamin A intoxication
V. Associated with renal failure
A. Severe secondary hyperparathyroidism
B. Aluminum intoxication
C. Milk-alkali syndrome
Hypercalcemia
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Ca 11.5 to 12.0 mg/dL
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Ca>13 mg/dL
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Fatigue, depression, mental confusion, anorexia, nausea,
vomiting, constipation, reversible renal tubular defects,
increased urination
a short QT interval in EKG
calcification in kidneys, skin, vessels, lungs, heart, and
stomach
renal insufficiency
Ca 15 to 18 mg/dL
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a medical emergency; coma and cardiac arrest
Primary hyperparathyroidism
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PTH ↑→ disorder of calcium, phosphate, and bone
metabolism
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Annul incidence
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16/100,000 (<1974) → 112/100,000 → 4/100,000
> 45 years old
Female > male
Etiology
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Adenoma
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Glandular hyperplasia
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Single adenomas : 89%
Double adenomas : 5%
Parathyroid chief cell
6%
All four glands are enlarged (upper < lower)
Chief cell
Carcinomas
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1-2%
Usually not aggressive
Ca 14-15 mg/dL
Etiology- genetic considerations
1.
Overactivaion of protooncogenes
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2.
Loss of tumor suppressor genes
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Cyclin A1/PRAD1 gene, RET
MEN1 gene, Rb gene
Multiple endocrine neoplasia syndrome
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MEN 1 : hyperparathyroidism + pituitary tumor +
pancreatic tumor
MEN 2A : hyperparathyroidism + pheochromocytoma +
medullary thyroid ca
MEN 2B : pheochromocytoma + medullary thyroid ca +
mucosal and G-I neuroma
Clinical manifestations
4.
Asymptomatic hypercalcemia
Symptomatic hypercalcemia
Osteopenia, osteoporosis, nephrolithiasis
Osteitis fibrosa cystica or parathyroid crisis
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Concurrent vitamin D defidiency
1.
2.
3.
Clinical manifestations
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Symptoms of hypercalcemia
Renal manifestation
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Decreased GFR
Hypercalciuria
Nephrolithiasis : Calcium oxalate > calcium phosphate
Nephrocalcinosis
Impaired urinary concentrating → polyuria
Reduced fractional phosphate reabsorption →
hypophosphatemia
Increased urinary excretion of magnesium
Clinical manifestations
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Bone manifestation
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Osteitis fibrosa cystica
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Distinctive bone manifestation
Subperiosteal bone resorption on
the radial aspect of the middle
phalanges
↑ Giant multinucleated osteoclasts
Replacement of the cellular and
marrow elements by fibrous tissue
Increased bone turnover
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Low BMD
Cortical bone > trabecular bone
Forearm>hip>spine
Clinical manifestations
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Neuromuscular manifestations
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Neuropsychiatric manifestations
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Proximal muscle weakness
Muscular atrophy
Improve after parathyroidectomy
Elderly patients
Lethargy, depression, psychosis, cognitive dysfuction
Rheumatologic manifestations
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Hyperuricemia and gout
Pseudogout
Calcification of articular cartilage (chondrocalcinosis)
Lab finding
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Hypercalcemia
hypophosphatemia
Hypomagnesemia : hypercalcemia → Mg excretion ↑
Normochromic normocytic anemia
Renal insufficiency
Elevated PTH
Serum parathyroid hormone (PTH) concentrations in
hypercalcemia and hypocalcemia
Clin Endocrinol 2000; 52:329
Image work up
Thyroid sono
 99mTC sestamibi scan
 Neck CT, MRI : ectopic parathyroidism
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→ thyroid sono + 99mTC sestamibi scan :
수술 전 위치 결정에 95% sensitivity
Treatment
Medical surveillance
 Surgical treatment
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Treatment
J of Clin Endocrinolv& Metab :87 ; 5353-5361
Treatment
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Parathyroidectomy
– minimal invasive approach
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thyroid sono + 99mTC sestamibi scan : localization
Intraoperative PTH measurement
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before and at 5 min intervals after removal of a
suspected adenoma
Rapid fall to normal levels of PTH
Multiple gland hyperplasia
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Subtotal parathyroidectomy
Total parathyroidectomy and autotransplantation
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Successful surgery
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Serum calcium decline within 24 hours
Ca falls to low-normal values for 3 to 5 days
Severe postoperative hypocalcemia
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Rare : PTH ↑→ 1,25(OH)2D ↑→ intestinal Ca absortion↑
Ostitis fibrosa cystica or injury to all normal parathyroid glands
Ca <8mg/dL + hyperphosphate : hypoparathyroidism
Hypomagnesemia : impaired PTH secretion
Hungry bone syndrome : increased Ca, P, Mg in bone uptake
Secondary hyperparathyroidism
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Partial resistance to the metabolic actions of PTH
leads to excessive production of PTH
Cause : renal failure, osteomalasia (Vit D deficiency)
Primary hyperparathyoidism : autonomous growth of
parathyroid gland → irreversible
Secondary hyperparathyoidism : adaptive response
of parathyroid gland → reversible
Secondary hyperparathyroidism
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Pathogenesis of 2nd hyperparathyroidism in renal
failure
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Renal failure → phosphate retention
Phosphate ↑ → suppress calcitriol production
Reduced kidney mass → calcitriol production ↓
Calcitriol ↓ → calcium absorption ↓
Hypocalcemia + hyperphospatemia
→ increased Ca-P product
PTH ↑ and proliferation of parathyroid gland
High PTH levels stimulate osteoblasts → high bone turnover
Tertiary hyperparathyroidism
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Hypocalcaemia, low calcitriol and hyperphosphataemia
→ ↑ PTH synthesis and secretion
→ these chronic stimuli persist
→ the parathyroid glands become enlarged
→ function autonomously (CaSR ↓)
→ ↑ secrete PTH even if hypocalcaemia is corrected
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No longer responsive to medical therapy
5% of 2nd HPT
Parathyroid gland hyperplagia
Single or double adenoma (2.6-32%)
Clinical manifestations
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Renal osteodystrophy
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Osteitis fibrosa cystica
Osteomalacia
Adynamic bone disorder
Bone pain
Extraskeletal calcification or calciphylaxis
Pruritus
Treatment
Reverse secondary hyperparathyroidism
→ Reduction of excessive blood phosphate
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Restriction of dietary phosphate : 800-1000mg/D
Oral phosphate binder : Calcium salt, Sevelamer
hydroxylated vitamin D sterols (calcitriol, alfacalcidol)
calcimimetic agent (Cinacalcet)
Parathyroidectomy
Treatment
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Indication for parathyroidectomy
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Severe hypercalcemia
Progerssive and debilitating hyperparathyroid bone disease
Pruritus
Progressive extraskeleta calcificaion or calciphylaxis
1. Subtotal parathyroidectomy
2. Total parathyroidectomy and autotransplantation