HYPERCALCEMIA

1. HYPERCALCEMIA Dr R V S N Sarma., M.D., M.Sc., Consultant Physician and Chest Specialist visit: www.drsarma.in

2. Hypercalcemia • Commonly encountered in Practice • Diagnosis often is made incidentally • The most common causes are primary hyperparathyroidism and malignancy • Diagnostic work-up includes measurement of serum calcium, intact parathyroid hormone (I-PTH), h/o any medications • Hypercalcemic crisis is a life-threatening emergency

3. Important Issues • Most often asymptomatic – Incidental Dx • Mild Hypercalcemia is asymptomatic • Most important cause is hyper parathyroid • DD is needed to decide the treatment • Optimal step by step evaluation is a must.

4. Physiology of Calcium • 98% of the body calcium is in the skeleton • Only 2% is circulation and only half of this is free calcium (ionized Ca++) • This only is physiologically active • The reminder 1% is bound to proteins • Direct measurement of free Calcium ??

5. Calcium Homeostasis

6. Calcium Homeostasis

7. Calcium Metabolism (1,000 mg/day)

8. How They control Ca Levels

9. Corrected Serum Calcium Corrected total calcium (mg%) = [(Measured total calcium mg%) + {(4.4 - measured albumin g%) x 0.8}] Example: [12.0 + {(4.4 – 2.4) x 0.8}] = [ 12.0 + (2 x 0.8)] = 12.0 + 1.6 = 13.6 mg%

10. Vitamin D Metabolism Supplements Vitamin D 2 Calcitriol (Active)

11. Formation of Calcitriol

12. Calcium Homeostasis

13. Hypercalcemia Grading

14. Hypercalcemia

15. Causes of Hypercalcemia

16. The Two Important Causes • More than 90 percent of hypercalcemia cases are Primary hyperparathyroidism and malignancy • These conditions must be differentiated early to provide optimal treatment & accurate prognosis • Humoral hypercalcemia of malignancy implies a very limited life expectancy — only a matter of weeks • Primary hyperparathyroidism has a benign course.

17. Parathyroid hormone-related • Primary hyperparathyroidism • Sporadic, familial, associated with Multiple Endocrine Neoplasia (MEN I or II) • Tertiary hyperparathyroidism • Associated with chronic renal failure • PTH  due to Vitamin D deficiency

18. Vitamin D-related • Vitamin D intoxication • Iatrogenic Vitamin D injections • Usually 25-hydroxyvitamin D2 in over-the-counter supplements • Granulomatous disease – Sarcoidosis, Berylliosis, Tuberculosis • Hodgkin’s lymphoma

19. Malignancy • Humoral hypercalcemia of malignancy (mediated by PTHrP) – common cause • Solid tumors, especially lung, head and neck squamous cancers • Renal Cell Carcinoma (RCC) • Local osteolysis (mediated by cytokines) • Multiple Myeloma • Breast cancer

20. Medications • Thiazide diuretics (usually mild) - common • Lithium for depressive illnesses • Milk-alkali syndrome (calcium + antacids) • Vitamin A intoxication (including analogs used to treat acne)

21. Endocrine Diseases • Hyperthyroidism • Adrenal insufficiency • Acromegaly • Pheochromocytoma

22. Genetic and Other disorders • Familial hypocalciuric hypercalcemia (FHH) mutated calcium-sensing receptor gene • Immobilization, with high bone turnover (e.g., Paget’s disease, bedridden child) • Recovery phase of Rhabdomyolysis

23. Hypercalcemia - Clinical

24. Clinical Features Renal “stones” • Nephrolithiasis • Nephrogenic Diabetes Insipidus • Dehydration • Nephrocalcinosis

25. Clinical Features Skeleton “bones” • Bone pains • Arthritis • Osteoporosis • Osteitis fibrosa cystica in HPTH

26. Clinical Features Abdominal “Moans” • Nausea, vomiting • Severe anorexia, weight loss • Constipation (not relieved by Rx.) • Abdominal pain (vague and diffuse) • Pancreatitis • Peptic ulcer disease

27. Clinical Features Psychological “Groans” • Impaired concentration • Impaired memory, Depression • Confusion, stupor, coma • Lethargy and severe fatigue • Extreme muscle weakness • Corneal calcification (band keratopathy)

28. Clinical Features contd… Cardiovascular • Hypertension, Increased risk of CHD • ECG changes of shortened QT interval, PR prolonged, QRS widened, ST , Bradycardia • Cardiac arrhythmias; Vascular calcification Others • Itching (Generalized Pruritus) • Keratitis, conjunctivitis

29. Algorithmic Approach Normal calcium Hypocalcemia

30. Algorithmic Approach

31. Algorithmic Approach Endocrine

32. Serum Ca++ and I-PTH

33. Hyperparathyroidism • Increased screening for serum Ca++ and • Wider availability of I-PTH assay • 80% of cases single parathyroid adenoma • Usually benign adenoma or hyperplasia • Rarely parathyroid cancer • High PTH in the setting of hypercalcemia • Slowly progressive – Sestamibi N-scan • 25% require surgery – RLN paralysis

34. Sestamibi Nuclear Scan 64 yrs male - “hyper parathyroid storm” with a serum calcium level of 16.4 mg%

35. Criteria for Surgery • Serum calcium level > 12 mg % at any time • Episodes of hyper parathyroid crisis • Marked hypercalciuria (urinary Ca++ > 400 mg /day) • Nephrolithiasis; Impaired renal function • Osteitis fibrosa cystica – Thinning of cortical bone • Reduced bone density by DEXA scan (Z score < 2) • Classic neuromuscular symptoms, Proximal muscle weakness and atrophy, Hyper reflexia and ataxia • Age younger than 50 years

36. Vitamin D Related • 25 OH - Vitamin D2 is the supplemental Vit D • Level of 25 OH – Vitamin D3 is to be measured • Macrophages in the granulomas, lymphomas cause extra renal conversion of 25 OH form to the1,25 hydroxy derivative –the active Calcitriol • PTH levels are suppressed; Calcitriol levels  • Stop the offending use of Vitamin D • Glucocorticoids – for over one month or more • Manage hypercalcemia vigorously

37. Hypercalcemia of Malignancy • Most commonly mediated by systemic PTHrP • Humoral Hypercalcemia of malignancy • PTHrP mimics the bone & renal effects of PTH • Normal Calcitriol and suppressed PTH levels • Excessive bone lysis due to primary or bone secondaries can cause hypercalcemia • MM and metastatic Br Ca present in this way. • In Osteolytic hypercalcemia, SAP is markedly  • Hodgkin’s lymphoma –  production of Calcitriol

38. Medications and Hypercalcemia • Thiazide diuretics increase renal calcium resorption and cause mild hypercalcemia • Resolves after discontinuing the drug • Thiazide unmasks hyperparathyroidism • Milk–alkali syndrome – Ca + Antacids • Lithium –  the set point for PTH  • Excess Vitamin A -  bone resorption and causes hypercalcemia.

39. Other Causes of Hypercalcemia • FHH – Familial Hypocalciuric Hypercalcemia • AD – 100% penetrance – Ca-R gene mutation • Moderate hypercalcemia with normal/  PTH • 24 hour urinary calcium is very low • No benefit from parathyroidectomy • High bone turnover in Paget’s disease or prolonged immobilization • Recovery phase of Rhabdomyolysis

40. Treatment • Ca <12 but > 10.3 mg% – no appreciable clinical benefit – they need evaluation • Any patient with Serum Ca > 12 mg% should be aggressively treated • Ca > 14 mg% is Hypercalcemic crisis • Always correct the Ca value for Sr Albumin

41. The Four Rx Modalities

42. Hydration and Diuresis • Vigorous I.V. Nacl Diuresis – N Saline • Adequate hydration – urine out put must be maintained 200 ml/hour = 5 L /day • The safest and most effective treatment of Hypercalcemic crisis is saline rehydration • Once the urine out put is maintained – give I.V. Furosemide – a loop diuretic in low doses of 10 to 20 mg • ERT - might be beneficial in PMW – new RCT

43. Calcitonin • In severe hypercalcemia refractory to saline diuresis • Calcitonin (Zycalcit, Miacalcin) 6 -8 U/kg IM/SC (400 i.u) given every six hours. • This treatment has a rapid onset but short duration of effect • Patients develop tolerance to the calcium-lowering effect of Calcitonin.

44. Bisphosphonates • Zoledronic acid (Zometa) - 4 mg IV diluted in 100 ml of N Saline - over at least 15’ once a M • Pamindronate (Pamidria) - 60 mg IV infusion over 4 h initial – repeated after a month • Etidronate (Didronel) - 7.5 mg/kg IV over 4 h daily for 3-7 d; dilute in at least 250 ml of sterile N Saline • They inhibit bone resorption, inhibit the Osteoclastic activity.

45. Other Rx Options • Dialysis for refractory Hypercalcemic crisis • Parathyroidectomy for adenomas • Rx. of the underlying cause – Eliminate drugs • Plicamycin (Mithracin) 25 mcg/kg/d IV for 4 d • Gallium nitrate (Ganite) 100 mg/m2/d IV for 5 days in 1 L of NS or 5% Dextrose • Cinacalcet (Sensipar) - 30 mg PO od – (increases sensitivity of calcium sensing receptor)

46. Take Home Points • Hypercalcemia is often asymptomatic • Screen all suspected by doing Sr Calcium • If elevated, do I-PTH and follow algorithm • 90% Hyperparathyroidism and malignancy • Vitamin D toxicity is an important cause • Thiazide diuretics common cause, Vitamin A • Adequate hydration - N Saline + Furosemide • Calcitonin + Zoledronic acid main stay of Rx.