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 → osteoclast-mediated 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 Ca 15 to 18 mg/dL Fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation, reversible renal tubular defects, increased urination a short QT interval in EKG Ca>13 mg/dL 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 Carcinomas Single adenomas : 89% Double adenomas : 5% Parathyroid chief cell Glandular hyperplasia 6% All four glands are enlarged (upper < lower) Chief cell Carcinomas 1-2% Usually not aggressive Ca 14-15 mg/dL

Etiology- genetic considerations Overactivaion of protooncogenes Cyclin A1/PRAD1 gene, RET Loss of tumor suppressor genes 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 Asymptomatic hypercalcemia Symptomatic hypercalcemia Osteopenia, osteoporosis, nephrolithiasis Osteitis fibrosa cystica or parathyroid crisis Concurrent vitamin D defidiency Osteopenia, osteoporosis, nephrolithiasis evaluaion하는 과정에서 발견 Concurrent vitamin D defidiency를 확인해야 하며, 감소되어있을 경우 이로 인해 PTH 분비가 더욱 증가하며, bone resorption도 증가하게 된다.

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 Nephrolithiasis :15-20% of primary hyperparathyroidism

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 Bone formation marker : bone specific ALP, osteocalcin, type I porcollagen peptides Bone resorption marker : hydroxypyridinium collagen cross-links and telopeptides of type I collagen

Clinical manifestations Neuromuscular manifestations Proximal muscle weakness Muscular atrophy Improve after parathyroidectomy Neuropsychiatric manifestations 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 PTH -> Mg의 renal tubular reabsortion 증가하나, 전체적으로, Mg 감소

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 99m Tc sestamibi scan : 이는 갑상선과 부갑상선 종양의 다른 clearance rate를 이용한 검사법으로 99Tc sestamibi iv 후 15-30분에 조기 영상을 얻고 2-4시갖ㄴ 후 지연 영상을 얻는다. 처음 얻은 영상에서 정상적으로 갑상선, 악하선, 심장, 간에 섭취되며 지연 영상에서는 정상적으로 갑상전 섭취가 보이지 않는다. 부갑상선 병변이 있다면 지연 영상에서 국소성 섭취를 관찰할 수 있다.

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 Subtotal parathyroidectomy : 3 glands: total removal, 4th gland : partial excision

Severe postoperative hypocalcemia 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 Hungry bone syndrome 은 PTH 의 증가로 인해 bone formation과 resorption 에서 전체적으로 Ca의 resortion이 컸으나 수술 후 갑자기 PTH가 감소함에 따라 Ca의 influx가 매우 증가하는 것이다.

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 Ca-P product가 증가해서 artery, joint, soft tissue, viscer 와 같은 곳에서 calcificaion 을 형성함.

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 Sevelamer is a non-calcium-containing phosphate-binding agent. Cinacalcet (Mimpara: Amgen Ltd) is a calcimimetic agent which increases the sensitivity of calcium-sensing receptors to extracellular calcium ions, thereby inhibiting the release of PTH

Treatment Indication for parathyroidectomy Subtotal parathyroidectomy Severe hypercalcemia Progerssive and debilitating hyperparathyroid bone disease Pruritus Progressive extraskeleta calcificaion or calciphylaxis Subtotal parathyroidectomy Total parathyroidectomy and autotransplantation