PTH related disorders

1. PTH related disorders Simona Glasberg, MD Neuroendocrine Tumors Unit,Endocrinology & Metabolism Service,Hadassah-Hebrew University Medical Center, Jerusalem, Israel Course in Endocrinology, Year 4, HUJI, 31/10/2013

2. Introduction -The parathyroid glands • small endocrine glands in the neck that produce parathyroid hormone (PTH). • humans usually have four parathyroid glands, located in variable manner on the posterior surface of the thyroid gland, or, in rare cases, within the thyroid gland itself or in the chest (mediastinum) or even the thymus. • control the amount of Ca in the blood and within the bones.

3. Parathyroid hormone- physiology • The primary function of PTH is to maintain the extracellular fluid (ECF) calcium concentration within a narrow normal range. • PTH acts • directly on bone (Ca resorbtion) and kidney (Ca re-absorption) • indirectly on the intestine through its effects on synthesis of 1,25(OH)-D • in turn, PTH production is closely regulated by the concentration of serum ionized calcium and vitamin D. increase serum Ca

4. Calcium (through the Ca-SR) and vitamin D (through its nuclear receptor)- reduce PTH release and synthesis.

5. Hyperparathyroidism (HPT) • excess production of PTH • is a common cause of hypercalcemia • is usually the result of autonomously functioning adenomas, or hyperplasia.

6. Hypocalcaemia, as might be induced by calcium-deficient diets, is counteracted by an increased secretion of PTH  (1)increased rate of dissolution of bone mineral  increased flow of calcium from bone into blood (2)reduced renal clearance of calcium, returning more of the calcium filtered at the glomerulus into ECF (3)increased efficiency of calcium absorption in the intestine by stimulated production of 1,25(OH)2D  Immediate control  Steady state

7. PTH actions on kidneys • Inhibition of phosphate absorbtion (proximal tubule) • Augmentation of calcium reabsorbtion (distal tubule) • Stimulation of the renal 25- (OH) D3 1-alpha-hydroxylase.

8. As much as 12 mmol (500 mg) calcium is transferred between the ECF and bone each day • PTH acts as a homeostatic hormone to preserve calcium concentration in blood at the cost of bone demineralization.

9. PTH actions on bone • PTH-mediated changes in bone calcium release can be seen within minutes. • The chronic effects of PTH are to: • increase the number of bone cells, both osteoblasts and osteoclasts, and to increase the remodeling of bone • Continuous exposure to elevated PTH (as in hyperparathyroidism) leads to increased osteoclast- mediated bone resorption.

10. PTH actions on bone, cont. • However, the intermittentadministration of PTH, elevating hormone levels for 1–2 hours each day, leads to a net stimulation of bone formation rather than bone breakdown. • Striking increases, especially in trabecular bone in the spine and hip, have been reported with the use of PTH in combination with estrogen. • PTH(1-34) (teriparatide, Forteo Eli Lilly) as monotherapy caused a highly significant reduction in fracture incidence in a worldwide placebo-controlled trial.

11. PTH actions on bone - how it works? • Osteoblasts(or stromal cell precursors), which have PTH/PTHrP receptors, are crucial to this bone-forming effect of PTH. • Osteoclasts, which mediate bone breakdown, lack such receptors. PTH-mediated stimulation of osteoclasts is indirect, acting in part, through cytokines released from osteoblasts to activate osteoclasts • In experimental studies of bone resorption in vitro, osteoblasts must be present for PTH to activate osteoclasts to resorb bone

12. PTH - Structure • PTH is an 84-amino-acid single-chain peptide. The amino-terminal portion, PTH(1–34), is critical for the biologic actions of the molecule.

13. PTH - Biosynthesis, Secretion, and Metabolism • Hypocalcemia  Minutes secretion of preformed hormone. • Sustained hypocalcemia  Hours PTH mRNA expression Dayscellular replication increase gland mass.

14. PTH - Secretion • PTH secretion increases steeply to a maximum value of about five times the basal rateas calcium concentration falls from normal to the range of 1.9–2 mmol/L (7.5–8 mg/dL) (measured as total calcium). • Severe intracellular magnesium deficiency impairs PTH secretion.

15. PTH - availability • Rapid (minutes) changes in PTH availability depends on the proteolytic destruction of preformed hormone (posttranslational regulation of hormone production) • High calcium increases • Low calcium inhibit the proteolytic destruction of PTH stores. Ca PTH

16. Ca++ sensing receptor (CaSR) • a G protein-coupled receptor (GPCR). • serves for the ECF calcium control of PTH secretion. • its stimulation by high Ca levels suppresses PTH secretion. • is present in PT glands and the calcitonin-secreting cells of the thyroid (C cells), as well as in other sites such as brain and kidney.

17. CaSR - mutations • Heterozygous point mutations associated with loss-of-function cause the syndrome of FHH, in which the blood calcium abnormality resembles that observed in hyperparathyroidism but with hypocalciuria. • Heterozygous gain-of-function mutations cause a form of hypocalcemia resembling hypoparathyroidism.

18. PTH - Metabolism • Most of the proteolysis of hormone occurs in the liver and kidney.

19. PTHrP (Parathyroid hormone-related protein) • Same receptor as PTH • Important in fetal life

20. PTHrP • Most cell types produce PTHrP, including brain, pancreas, heart, lung, mammary tissue, placenta, endothelial cells, and smooth muscle. • PTHrP is responsible for most instances of hypercalcemia of malignancy - a syndrome that resembles HPT but without elevated PTH levels. • In fetal animals, PTHrP directs transplacental calcium transfer, and high concentrations of PTHrP are produced in mammary tissue and secreted into milk, but the biologic significance of the very high concentrations of this hormone in breast milk is unknown.

21. in adults • PTHrP appears to have little influence on calcium homeostasis • in disease states (e.g., large tumors, especially of the squamous cell type as well as renal cell carcinomas), there is massive overproduction of PTHrP and hypercalcemia.

22. Calcitonin • Antagonist to PTH • Limited physiologic significance in humans (no need for replacement) • Tumor marker – MTC • Adjunctive treatment in severe hypercalcemia and in Paget's disease of bone • Calcitonin from salmon, which is used therapeutically, is 10–100 times more potent than mammalian forms in lowering serum calcium

23. Hypercalcemia I. Parathyroid-related II. Malignancy-related Primary Hyperparathyroidism 1.Adenoma(s) 2. Hyperplasia (MEN) 3. Carcinoma Lithium therapy Familial hypocalciuric hypercalcemia (FHH) Solid tumor with bone metastases (breast) Solid tumor with humoral mediation of hypercalcemia (lung, kidney) Hematologic malignancies (multiple myeloma, lymphoma, leukemia)

24. Hypercalcemia III. Vitamin D - related IV. High bone turnover Vitamin D intoxication 1,25(OH)2D: sarcoidosis and other granulomatous diseases Idiopathic hypercalcemia of infancy Hyperthyroidism Immobilization Thiazides Vitamin A intoxication

25. False positive Hypercalcemia • hemoconcentration during blood collection • elevation in serum proteins such as albumin • No need for fasting

26. Hypercalcemia - Clinical features • Asymptomatic  usually due to PHPT. • Malignancy-associated hypercalcemia  the disease is usually not occult • The interval between detection of hypercalcemia and death, especially without vigorous treatment, is often <6 months.

27. Hypercalcemia - Signs & symptoms Fatigue Depression Mental confusion Anorexia, nausea, vomiting Constipation Reversible renal tubular defects Increased urination A short QT interval in the ECG Cardiac arrhythmias

28. Hypercalcemia - Signs & symptoms • More common at calcium levels >2.9–3 mmol/L (11.5–12 mg/dL) • >3.2 mmol/L (13 mg/dL), calcification in kidneys, skin, vessels, lungs, heart, and stomach occurs and renal insufficiency may develop, particularly if blood phosphate levels are normal or elevated due to impaired renal function. • Severe hypercalcemia, usually defined as 3.7–4.5 mmol/L (15–18 mg/dL), can be a medical emergency; coma and cardiac arrest can occur.

29. Primary Hyperparathyroidism (PHPT)

30. PHPT - Natural history & incidence • High PTH, Hypercalcemia, hypo-phosphatemia. • Patients may present with multiple signs and symptoms, including recurrent nephrolithiasis, peptic ulcers, mental changes, and, less frequently, extensive bone resorption. • The diagnosis is frequently made in patients who have no symptoms and minimal, if any, signs of the disease other than hypercalcemia and elevated levels of PTH. The manifestations may be subtle, and the disease may have a benign course for many years or a lifetime.

31. PHPT - Incidence • The incidence is 1 in 800 people. This rate is much higher in women over 50: 1 in 250. • The disease has a peak incidence between the third and fifth decadesbut occurs in young children and in the elderly. • At young ages, hyperparathyroidism is often caused by a familial hyperparathyroidism syndromes. • has been reported in patients with a history of irradiation to the head and neck (eg, for the treatment of childhood malignancy, for the treatment of benign conditions, or after nuclear power plant accidents).

32. PHPT - Etiology • Most often - isolated adenomas • Hyperplasia - in hereditary syndromes such as MEN syndromes. • Carcinoma < 1%

33. Solitary Adenomas • A single abnormal gland is the cause of PHPT in ~85% • Double adenomas are reported.

34. Hereditary Syndromes and Multiple Parathyroid Tumors • In ~15% of patients, all glands are hyperfunctioning (parathyroid hyperplasia) - usually hereditary and associated with other endocrine abnormalities. • MEN 1 (Wermer's syndrome): hyperparathyroidism ,tumors of the pituitary and pancreas. • MEN 2A:pheochromocytoma, MTC, PHPT • MEN 2B usually lacks hyperparathyroidism; has additional associated features such as multiple neuromas. • The hyperparathyroidism jaw tumor (HPT-JT) syndrome occurs in families with parathyroid tumors (sometimes carcinomas) in association with benign jaw tumors - often termed non-syndromic familial isolated hyperparathyroidism (FIHP).

35. Adenomas - Pathology • Most often located in the inferior parathyroid glands • 6 -10% ectopic: thymus, thyroid, pericardium, or behind the esophagus. • Usually 0.5–5 g in size but may be as large as 10–20 g (normal glands weigh 25 mg on average). • Chief cells are predominant in both hyperplasia and adenoma.

36. Parathyroid carcinoma • Often not aggressive. Long-term survival without recurrence is common if at initial surgery the entire gland is removed without rupture of the capsule. • Recurrent parathyroid carcinoma is usually slow-growing with local spread in the neck, and surgical correction of recurrent disease may be feasible. • The diagnosis of carcinoma is often made in retrospect. HPT from a parathyroid carcinoma is usually more severe clinically.

37. Genetic Defects Associated with Hyperparathyroidism • Mutations in the Menin tumor suppressor gene (MEN1) . • Over 1300 mutations have been reported to date. • The MEN1 phenotype is inherited via an autosomal-dominant pattern and is associated with neoplasms of the pituitary gland, the parathyroid gland, and the pancreas. Crystal Structure of Human Menin

38. Genetic Defects Associated with Hyperparathyroidism, cont. • Retinoblastoma (Rb) gene • a tumor-suppressor gene located on chr 13q14, initially associated with retinoblastoma, but implicated in other neoplasias, including parathyroid carcinoma • HRPT2 gene • sporadic parathyroid carcinomas frequently have HRPT2 mutations. • some patients with apparently sporadic parathyroid carcinoma carry germ-line mutations in HRPT2 and may have the HPT-JT syndrome or a phenotypic variant. • RET encodes a tyrosine kinase type receptor; • specific inherited germ-line mutations lead to a constitutive activation of the receptor- MEN 2

39. PHPT - Signs and symptoms • In series in which patients are followed without operation, as many as 80% are classified as without symptoms. • Kidney involvement, due either to deposition of calcium in the renal parenchyma or to recurrent nephrolithiasis, was present in 60–70% of patients prior to 1970. • With earlier detection, renal complications occur in <20% of patients in many large series. Renal stones are usually composed of either calcium oxalate or calcium phosphate. • In occasional patients, repeated episodes of nephrolithiasis or the formation of large calculi may lead to urinary tract obstruction, infection, and loss of renal function. Nephrocalcinosis may also cause decreased renal function and phosphate retention.

40. PHPT - Bone involvement • The distinctive bone manifestation is osteitis fibrosa cystica, which occurred in 10–25% of patients in series reported 50 years ago. • Histologically, the pathognomonic features are: • an increase in the giant multinucleated osteoclasts in scalloped areas on the surface of the bone (Howship's lacunae) • replacement of the normal cellular and marrow elements by fibrous tissue. • X-ray changes include resorption of the phalangeal tufts and replacement of the usually sharp cortical outline of the bone in the digits by an irregular outline (subperiosteal resorption). • In recent years, osteitis fibrosa cystica is very rare, due to the earlier detection of the disease.

42. Cortical bone density is reduced while trabecular (cancellous) bone density, especially in the spine, is relatively preserved (distal radius…)

43. PHPT - Neurologic manifestations • Neuropsychiatric • Neuromuscular- proximal muscle weakness, easy fatigability, and atrophy of muscles, complete regression of neuromuscular disease after surgical correction of the hyperparathyroidism

44. PHPT – GIT manifestations • Sometimes subtle and include vague abdominal complaints and disorders of the stomach and pancreas • MEN 1 - duodenal ulcer may be the result of associated pancreatic tumors that secrete excessive quantities of gastrin (ZES) • Pancreatitis has been reported in association with hyperparathyroidism, but the incidence and the mechanism are not established.

45. Asymptomatic PHPT (APHPT) Biochemically confirmed hyperparathyroidism (elevated or inappropriately normal PTH levels despite hypercalcemia) with the absence of signs and symptoms typically associated with more severe hyperparathyroidism such as features of renal or bone disease.

46. APHPT - Issues of concern • Potential for cardiovascular deterioration • The presence of subtle neuropsychiatric symptoms • Longer-term status of skeletal integrity in patients not treated surgically. • The current consensus is that medical monitoring rather than surgical correction of hyperparathyroidism may be justified in certain patients. • The evidence of eventual (>8 years) deterioration in BMD after a decade of relative stability.

47. Guidelines for Surgery in APHPT

48. Guidelines for Monitoring in APHPT

49. APHPT - Diagnosis • Elevated PTH level • Asymptomatic hypercalcemia • Phosphate is usually low but may be normal, especially if renal failure has developed

50. Treatment: PHPT • Surgical excision of the abnormal parathyroid tissue is the definitive therapy for this disease. • The conventional parathyroidectomy procedure was neck exploration with general anesthesia; this procedure is being replaced in many centers, whenever feasible, by an outpatient procedure with local anesthesia, termed minimally invasive parathyroidectomy. • Parathyroid exploration is challenging and should be undertaken by an experienced surgeon