1. Hyperparathyroidism
내분비 대사 내과
R3 박정은

2. 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 mm

3. Parathyroid hormone (PTH)
Primary function : maintain the ECF calcium concentration
Normal range : 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)

4. Hormonal control loop for vitamin D metabolism and function
Harrison 16th p.2246
fig 331-5

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

6. 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

7. 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

8. 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

9. 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

10. 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 mg/dL

11. 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

12. 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.

13. 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

14. 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

15. 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)

16. Lab finding Hypercalcemia hypophosphatemia
Hypomagnesemia : hypercalcemia → Mg excretion ↑
Normochromic normocytic anemia
Renal insufficiency
Elevated PTH
PTH -> Mg의 renal tubular reabsortion 증가하나, 전체적으로, Mg 감소

17. Serum parathyroid hormone (PTH) concentrations in hypercalcemia and hypocalcemia
Clin Endocrinol 2000; 52:329

18. 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.

19. Treatment
Medical surveillance
Surgical treatment

20. Treatment
J of Clin Endocrinolv& Metab :87 ;

21. 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

22. 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.

23. 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

24. 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

25. 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%)

26. 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.

27. Treatment Reverse secondary hyperparathyroidism
→ Reduction of excessive blood phosphate
Restriction of dietary phosphate : mg/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

28. 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