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Hyperparathyroidism 내분비 대사 내과 R3 박정은 Parathyroid gland 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) Hormonal control loop for vitamin D metabolism and function Harrison 16th p.2246 fig 331-5 Parathyroid hormone (PTH) Kidney Inhibition of P reabsorption (proximal tubule) Increased reabsorption of Ca (distal tubule) stimulation of the renal 25(OH)D-1-hydroxylase Bone 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 Calcium sensing receptor 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 Ca 11.5 to 12.0 mg/dL Ca>13 mg/dL 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 a medical emergency; coma and cardiac arrest Primary hyperparathyroidism PTH ↑→ disorder of calcium, phosphate, and bone metabolism Annul incidence 16/100,000 (<1974) → 112/100,000 → 4/100,000 > 45 years old Female > male Etiology Adenoma Glandular hyperplasia Single adenomas : 89% Double adenomas : 5% Parathyroid chief cell 6% All four glands are enlarged (upper < lower) Chief cell Carcinomas 1-2% Usually not aggressive Ca 14-15 mg/dL Etiology- genetic considerations 1. Overactivaion of protooncogenes 2. Loss of tumor suppressor genes Cyclin A1/PRAD1 gene, RET MEN1 gene, Rb gene Multiple endocrine neoplasia syndrome 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 Concurrent vitamin D defidiency 1. 2. 3. Clinical manifestations Symptoms of hypercalcemia Renal manifestation 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 Bone manifestation Osteitis fibrosa cystica 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 Low BMD Cortical bone > trabecular bone Forearm>hip>spine Clinical manifestations Neuromuscular manifestations Neuropsychiatric manifestations Proximal muscle weakness Muscular atrophy Improve after parathyroidectomy Elderly patients Lethargy, depression, psychosis, cognitive dysfuction Rheumatologic manifestations Hyperuricemia and gout Pseudogout Calcification of articular cartilage (chondrocalcinosis) Lab finding 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 → thyroid sono + 99mTC sestamibi scan : 수술 전 위치 결정에 95% sensitivity Treatment Medical surveillance Surgical treatment Treatment J of Clin Endocrinolv& Metab :87 ; 5353-5361 Treatment Parathyroidectomy – minimal invasive approach thyroid sono + 99mTC sestamibi scan : localization Intraoperative PTH measurement before and at 5 min intervals after removal of a suspected adenoma Rapid fall to normal levels of PTH Multiple gland hyperplasia Subtotal parathyroidectomy Total parathyroidectomy and autotransplantation Successful surgery Serum calcium decline within 24 hours Ca falls to low-normal values for 3 to 5 days Severe postoperative hypocalcemia 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 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 Pathogenesis of 2nd hyperparathyroidism in renal failure 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 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 No longer responsive to medical therapy 5% of 2nd HPT Parathyroid gland hyperplagia Single or double adenoma (2.6-32%) Clinical manifestations Renal osteodystrophy Osteitis fibrosa cystica Osteomalacia Adynamic bone disorder Bone pain Extraskeletal calcification or calciphylaxis Pruritus Treatment Reverse secondary hyperparathyroidism → Reduction of excessive blood phosphate Restriction of dietary phosphate : 800-1000mg/D Oral phosphate binder : Calcium salt, Sevelamer hydroxylated vitamin D sterols (calcitriol, alfacalcidol) calcimimetic agent (Cinacalcet) Parathyroidectomy Treatment Indication for parathyroidectomy Severe hypercalcemia Progerssive and debilitating hyperparathyroid bone disease Pruritus Progressive extraskeleta calcificaion or calciphylaxis 1. Subtotal parathyroidectomy 2. Total parathyroidectomy and autotransplantation