Calcium metabolism and parathyroid disorders

BONE MINERAL METABOLISM

1. BONE MINERAL METABOLISM GUIDE – Dr. Yogendra Jamra Candidate – Dr.Shivshankar

2. Calcium Metabolism Percentage distribution of total body calcium 1 ECF - 0.1% 2 Intracellular – 1% 3 Bones – Rest (Serve as Reservoirs)

3. Calculation of Corrected Calcium Because calcium binds to albumin and only the unbound calcium is biologically active ,the serum level must be adjusted as follows Corrected Ca 2+ = [4.5 - Plasma Albumin]*0.8 + measured S. Calcium

4. Factors affecting Calcium Concentration 1) Changes in Plasma Protein concentration Increased [protein] Increased total [Ca2+] 2) Changes in Anion concentration Increased [anion] Increased fraction of Ca2+ that is complexed Decreased ionized [Ca2+] 3)Acid base abnormality

5. Blood calcium is tightly regulated by: 1) Principle organ systems: Intestine Bone Kidney 2) Hormones: Parathyroid hormone (PTH) Vitamin D Calcitonin

6. Role Of PTH in Calcium Homeostasis

7. HYPERCALCEMIA Normal Serum calcium: 8.5 mg/dl – 10.5 mg/dl Serum Calcium > 10.5 mg/dl (>2.5 mmol /l) Ionized Calcium > 5.3 mg/dl ( 1.3 mmol /L) Mild: Total Ca 10.5-11.9 mg/dl ( 2.5-3 mmol /l) Ionised 5.6-8 mg/dl ( 1.4-2 mmol /l) Moderate: Total Ca 12-13.9 mg/dl ( 3-3.5 mmol/l) Ionised Ca 8-10 mg/dl ( 2-2.5 mmol /l) Severe: Total Ca 14-16 mg/dl ( 3.5-4 mmol /l) Ionised Ca 10-12 mg/dl ( 2.5-3 mmol /l)

8. Clinical Manifestations of Hypercalcemia Renal Nephrolithiasis Nephrogenic diabetes insipidus Dehydration Nephrocalcinosis Skeleton Bone pain Arthritis Osteoporosis Osteitis fibrosa cystica in hyperparathyroidism ( subperiosteal resorption , bone cysts)

9. Gastrointestinal Nausea, vomiting Anorexia, weight loss Constipation Abdominal pain Pancreatitis Peptic ulcer disease Cardiovascular Hypertension Shortened QT interval on ECG Cardiac arrhythmias Vascular calcification

10. Neuromuscular Impaired concentration and memory Confusion, stupor, coma Lethargy and fatigue Muscle weakness Other Itching Keratitis , conjunctivitis Corneal calcification (band keratopathy )

11. Etiology Parathyroid Related Primary Hyperparathyroidism Lithium Therapy Familial Hypocalciuric Hypercalcemia Malignancy related Solid Tumor (Breast, Lung, Kidney) Hematologic malignancy (Lymphoma, Leukemia) Vitamin D Related Vitamin D Intoxication Increased 1,25(OH)2D ( Sarcoidosis )

12. Associated with high bone turnover Hyperthyroidism Immobilization Thiazides Vitamin A Intoxication Fat Necrosis Associated with Renal failure Severe Secondary Hyperparathyroidism Aluminium Intoxication Milk-Alkali syndrome

13. APPROACH TO HYPERCALCEMIA

14. Serum Calcium must be corrected for serum Albumin before labelling it as hypercalcemia . Among all cases of hypercalcemia , Primary Hyperparathyroidism and Malignancy are the most common causes accounting for more than 90% cases. Therefore diagnostic approach to hypercalcemia typically involves distinguishing between the two.

15. Treatment according to Calcium Levels Calcium level <12 mg/dl Oral Hydration High salt Diet Avoid medications that cause hypercalcemia No treatment at all may be a option

16. Calcium level > 12mg/dl (Severe or Symptomatic) Normal Saline: Initially 200-300ml/hr until patient is euvolemic , then adjust to maintain urine output of 100-150 ml/hr Loop diuretics only after volume repletion in patients with CHF & CKD. Calcitonin , 4 IU/kg – subcutaneously or intramuscularly; repeat every 6-12 hours only if patient is responsive IV Bisphosphonates Zoledronic acid: 4 mg over 15 minutes; 8 mg if second dose is required (not FDA approved) Pamidronate : Given over 2-24 hours, either as 60mg (Ca level, 12-13.5mg/dl) or 90 mg (Ca level, >13.5mg/dl)

17. Indications For Hemodialysis Neurologic Symptoms Calcium level > 18mg dl Acute or Chronic Kidney Disease Congestive Heart Failure

18. Primary Hyperparathyroidism F:M 3:1 Annual Incidence is 0.2% in patients >60 Includes Adenoma MEN Carcinoma Presentation : Asymptomatic hypercalcemia (>50%) Renal stones (20%) Decreased bone density Symptoms of hypercalcemia (<5%)

19. Images show Subperiosteal Bone Resorption along the radial aspects of the middle phalanges. Bone Manifestations in Hyperparathyroidism

20. Image demonstrates subperiosteal resorption that has resulted in severe tuftal resorption .

21. Osteitis Fibrosa Cystica (Brown Tumour ) Manifestated in hyperparathyroidism Represents a reparative cellular process rather than a neoplastic process. Histologically identical to giant cell tumour so it needs to be differentiated. Commonly seen with Secondary Hyperparathyroidism.

22. Pathology In CKD lower serum Ca level lead to a rise in PTH secretion resulting in mobilisation of skeletal calcium through rapid osteoclastic turnover of bone to maintain normal serum calcium levels. In localised regions where bone loss is particularly rapid normal marrow contents may be replaced by haemorrhage, and reparative granulation tissue, with active, vascular, proliferating fibrous tissue, resulting in a brown tumour. Haemosiderin imparts the brown colour

23. Asymptomatic Primary Hyperparathyroidism Most prevalent form of disease Defined as biochemically confirmed hyperparathyroidism with the absence of signs and symptoms typically associated with more severe hyperparathyroidism such as features of renal or bone disease.

24. Guidelines for surgery in Asymptomatic Primary hyperparathyroidism Serum Calcium >1mg/dl (above Normal) 24hr Urinary Calcium No Indication Creatinine Clearance If <60ml/min Bone Density T score <2.5 at any of 3 sites (Spine, distal radius, hip) Age <50 years

25. FAMILIAL HYPOCALCIURIC HYPERCALCEMIA Inherited as Autosomal Dominant Trait Caused by inactivating Mutation in CaSR leading to inappropriate secretion of PTH and excessive reabsorption of Ca in DCT Patients with primary Hyperparathyroidism have <99% Ca reabsorption whereas most patients with FHH have > 99% absorption Differentiating with Primary hyperparathyroidism is important as there is no role of surgery in FHH

26. Calcium/ creatinine clearance ratio of <0.01 is suggestive of FHH. Sequence Analysis of CaSR is commonly performed for Definitive Diagnosis. Generally no treatment is required.

27. Secondary Hyperparathyroidism due to Chronic Renal Failure Impaired production of 1,25(OH)2D is now thought to be the principal factor that causes Calcium Deficiency, Secondary Hyperparathyroidism and bone disease. Resistance to PTH also contributes to Hypocalcemia . Recent findings have indicated that increase in FGF23 production by osteocyte occurs in CKD. FGF23 is potent inhibitor of renal-1alpha hydroxylase so FGF23 dependent reduction in 1,25(OH)2D is important stimulus for development of secondary hyperparathyroidism.

28. Management of Secondary Hyperparathyroidism due to CKD Restriction of phosphate in diet. Avoidance of Aluminium containing phosphate binding antacids to prevent problem of aluminium intoxication. Adequate Calcium intake by mouth usually 1-2g/day and supplementation with 0.25-1mcg/d calcitriol . It is usually recommended to maintain PTH levels between 150-300pg/ml as high PTH may lead to progression to Tertiary Hyperparathyroidism and low PTH levels may lead to Adynamic Bone disease.

29. Tertiary Hyperparathyroidism Tertiary hyperparathyroidism is a state of excessive secretion of PTH after a long period of secondary hyperparathyroidism and resulting in a high blood calcium level. It reflects development of autonomous (unregulated) parathyroid function following a period of persistent parathyroid stimulation. The basis of treatment is still prevention in chronic kidney failure starting medication and dietary restrictions long before dialysis treatment is initiated. The treatment of choice is surgical removal of three and one half parathyroid glands.

30. HYPOCALCEMIA

31. DEFINITION Normal Serum calcium: 8.5 mg/dl – 10.5 mg/dl A decrease in the calcium levels below 8.5mg/dl is termed hypocalcemia

32. LOW PARATHYROID HORMONE LEVELS Parathyroid agenesis Isolated DiGeorge Syndrome Parathyroid destruction Surgical Radiation Infiltration by metastases or systemic diseases Autoimmune Reduced Parathyroid function Hypomagnesemia Activating CaSR mutations

33. HIGH PARATHYROID HORMONE LEVELS ( Secondary Hyperparathyroidism) Vitamin D deficiency or impaired 1,25(OH)2*D production/action Nutritional vitamin D deficiency Renal insufficiency with impaired 1,25(OH)2*D production Vitamin D resistance Parathyroid hormone resistance syndromes PTH receptor mutations Pseudohypoparathyroidism Drugs Calcium chelators Inhibitors of bone resorption Altered vitamin D metabolism (Phenytoin, Ketoconazole) Miscellaneous Acute Pancreatitis Acute Rhabdomyolysis Hungry bone syndrome Osteoblastic metastases

34. Hypocalcemia : Clinical signs Paresthesias Tetany ( carpopedal spasm) Trousseau’s , Chvostek’s signs Seizures Laryngospasm Arrythmia Cataracts , Basal Ganglia Calcification

35. Trousseau’s sign Carpal Spasm may be induced by inflation of BP cuff to 20 mm Hg above the patient’s Systolic BP for 3 minutes.

36. Chvostek Sign Twitching of circumoral muscles in response to gentle tapping of the facial nerve just anterior to the ear.

37. Differential Diagnosis of Hypocalcemia

38. Treatment Acute, symptomatic hypocalcemia : Calcium gluconate , 90 mg or 2.2 mmol IV, diluted in 50 mL of 5% dextrose or 0.9% sodium chloride, given IV over 5 min Continuing hypocalcemia : constant IV infusion (10 ampules of ca or 900 mg of ca in 1 L of 5% dextrose or 0.9% sodium chloride administered over 24 h)

39. Treatment Hypomagnesemia : magnesium supplementation Chronic hypocalcemia due to hypoparathyroidism: calcium supplements (1000–1500 mg/d elemental calcium in divided doses) AND either vitamin D2 or D3 (25,000–100,000 U daily) OR calcitriol [1,25(OH) 2 D, 0.25–2 g/d]

40. Treatment Vitamin D deficiency - vitamin D supplementation N utritional vitamin D deficiency: low doses of vitamin D (50,000 U, 2–3 times per week for several months) V itamin D deficiency due to malabsorption : higher doses (100,000 U/d or more) G oal is to bring serum calcium into the low normal range and to avoid hypercalciuria , which may lead to nephrolithiasis

41. VITAMIN D major steroid hormone involved in mineral ion homeostasis regulation.

42. The 25-hydroxyvitamin D-1α-hydroxylase - expressed in the proximal convoluted tubule cells of the kidney. PTH and hypophosphatemia are the major inducers C alcium , FGF23, and the enzyme’s product 1,25(OH)2D , repress it

43. 1α-hydroxylase is produced by macrophages associated with granulomas and lymphomas. A ctivity of the enzyme is induced by interferon γ and TNF-α but is not regulated by calcium or 1,25(OH)2D; H ypercalcemia,associated with elevated levels of 1,25(OH)2D, may be observed.

44. CAUSES OF IMPAIRED VITAMIN D ACTION

45. Clinical manifestations Mild to moderate vitamin D deficiency is asymptomatic L ong-standing vitamin D deficiency results in - H ypocalcemia -Secondary hyperparathyroidism, -Impaired mineralization of the skeleton -Proximal myopathy

46. RICKETS - In children, before epiphyseal fusion, vitamin D deficiency results in growth retardation associated with an expansion of the growth plate. OSTEOMALACIA - The hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins.

47. DIAGNOSIS Although the normal ranges vary , levels of 25(OH)D <37 nmol /L (<15 ng / mL ) are associated with increasing PTH levels and lower bone density.

48. P rolonged vitamin D deficiency results in hypocalcemia . PTH is a major stimulus for the renal 25(OH)D 1α-hydroxylase, there is increased synthesis of the active hormone, 1,25(OH)2D. Paradoxically , levels of this hormone are often normal in severe vitamin D deficiency. Therefore , measurements of 1,25(OH)2D are not accurate reflections of vitamin D stores and should not be used to diagnose vitamin D deficiency in patients with normal renal function.

49. TREATMENT Recommended daily intake – 600 IU from 1 to 70 years of age, and 800 IU for those over 70 . Toxicity usually is observed only in patients taking doses in the range of 40,000 IU daily .

50. Intact activation of vitamin D initially (50,000 IU weekly for 3–12 weeks), followed by maintenance therapy (800 IU daily ). In patients in whom 1α-hydroxylation is impaired 1,25(OH)2D3 ( calcitriol , 0.25–0.5 μ g/d) and 1 α- hydroxyvitamin D2 (2.5–5 μ g/d ).

51. Pharmacologic doses may be required for maintenance therapy in patients who are taking medications, such as barbiturates or phenytoin ,(accelerate metabolism of or cause resistance to 1,25(OH)2D). Calcium supplementation should include 1.5–2 g/d of elemental calcium . 24-h urinary calcium excretion should be in the range of 100–250 mg/24 h.