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1. HYPERCALCEMIA Dr. V. Naga Jyothi Dr. K . Akhil Vardhan Dr. P. Kalyan

2. Relatively a common clinical problem   Affects 0.5 – 1% of the general population.  Often a incidental finding. Sometimes can cause a life threatening entity called  hypercalcemic crisis 99% of total body calcium is distributed among bones, remaining 1% circulates throughout the body.

3. According to level of corrected total calcium value, HYPERCALCEMIA can be classified as ➢ Mild hypercalcemia  ( corrected total calcium is 10.5 – 12 mg/dL) ➢ Moderate hypercalcemia  ( corrected total calcium is 12 – 14 mg/dL) ➢ Severe hypercalcemia   ( corrected calcium is >14 mg/dL)

4. HYPERCALCEMIA OCCURS WHEN ENTRY OF CALCIUM INTO THE CIRCULATION>EXCRETION OF CALCIUM INTO THE URINE OR DEPOSITION INTO BONES Accelerated Bone Resorption Excessive Gastrointestinal Absorption Decreased Renal Excretion

5. Causes of Hypercalcemia  Excessive PTH production  Primary hyperparathyroidism (adenoma, hyperplasia, rarely carcinoma)  Tertiary hyperparathyroidism (long-term stimulation of PTH secretion in renal insufficiency Ectopic PTH secretion (very rare)  FHH  Alterations in CaSR function (lithium therapy)  Hypercalcemia of malignancy  Overproduction of PTHrP (many solid tumors )  Lytic skeletal metastases (breast, myeloma)  

6. Excessive 1,25(OH)2  D production  Granulomatous diseases (sarcoidosis, tuberculosis, silicosis)  Lymphomas  Vitamin D intoxication  Primary increase in bone resorption  Hyperthyroidism   Immobilization   Excessive calcium intake  Milk-alkali syndrome  Total parenteral nutrition 

7. Other causes  Endocrine disorders (adrenal insufficiency, pheochromocytoma, VIPoma )  Medications (thiazides, vitamin A, antiestrogens ) 

8. PRIMARY HYPERPARATHYROIDISM •Due to PTH-mediated osteoclastic activation and bone resorption. •Solitary adenoma >>>> parathyroid hyperplasia >>>> parathyroid carcinoma. •Occur as an isolated entity or may be a part of hereditary diseases. •Patients typically have relatively minor elevations in calcium (usually less than 11) , and some patients have mostly high normal values with intermittent hypercalcemia. •Severe hypercalcemia is very infrequent.

9. FAMILIAL HYPOCALCIURIC HYPERCALCEMIA Inherited as autosomal dominant trait.   •Mutation in the CaSR gene, leading to abnormal sensing of blood calcium by PTH glands and renal tubules.   •Leading to increased PTH secretion + increased calcium Reabsorption .    

10. PRIMARY HYPER-PARATHYROIDISM FAMILIAL HYPOCALCIURIC HYPERCALCEMIA Family History Negative Positive Fractional excretion of calcium >0.02 <0.01 Symptoms of hypercalcemia May be symptomatic Asymptomatic Parathyroid Sestamibi Scan Usually shows a single Parathyroid Adenoma No abnormal parathyroid tissue demonstrable

11. TERTIARY HYPERPARATHYROIDISM In some patients, with advanced and prolonged renal failure, parathyroid hyperplasia may gradually progress to  autono mous overproduction   of PTH that is not suppressible by elevated serum calcium concentration. This entity is called as  tertiary hyperparathyroidism .

12. HYPERCALCEMIA IN CKD •Excessive use of calcium and phosphate •Tertiary hyperparathyroidism •Immediate post renal transplantation

13. MALIGNANCY RELATED HYPERCALCEMIA Common(10%), often severe and difficult to manage. Occurs in patients with many malignancies, both solid tumours and leukemias.   Mechanisms ; • Tumour secretion of PTHrP  ( humoral hypercalcemia of malignancy ) •Osteolytic metastases with local release of cytokines. •Tumour production of 1,25 hydroxy vitamin D (calcitriol)

14. MORE VITAMIN D                                                         MORE INTESTINAL CALCIUM ABSORPTION.   CAUSES •Chronic excessive ingestion ( >40,000 – 1,00,000 IU per day) •Excessive use of topical calcipotriol for dermatologic conditions. •Consumption of milk which is inadvertently excessively fortified with vitamin D. HYPERVITAMINOSIS D

15. HYPERCALCEMIA IN CHRONIC GRANULOMATOUS DISEASES Due to excess synthesis 1 alpha hydroxylase by activated macrophages  Macrophages in granulomatous tissue convert 25(OH)D to 1,25(OH)D in an accelerated rate.  PTH levels may be low and increased levels of 1,25(OH) vitamin D

16. HYPERCALCEMIA IN CHRONIC GRANULOMATOUS DISEASES 1.Sarcoidosis 2.Tuberculosis 3.Berylliosis 4.Coccidioidomycosis 5.Paracoccidiodomycosis 6.Histoplasmosis 7.Candidiasis 8.Langerhans-cell histiocytosis 9.Leprosy

17. THYROTOXICOSIS • Mild hypercalcemia in 15 – 20% of thyrotoxic patients. •Due to thyroid-hormone mediated increase in bone resorption •Typically resolves after treatment ACROMEGALY • Hypercalcemia is reportedly present in 5-10% of patients with acromegaly. •It is usually PTH-dependent, as a result of coexistent parathyroid adenoma or hyperplasia, which are common in individuals with Multiple endocrine neoplasia •However, there are few cases reported of non-PTH dependent hypercalcemia a/w acromegaly.

18. PHEOCHROMOCYTOMA • Hypercalcemia is a rare complication of pheochromocytoma. •It can be due to concurrent hyperparathyroidism or to the pheochromocytoma itself. ADRENAL INSUFFICIENCY • Hypercalcemia occurs in occasional patients with Addisonian crisis. •Increased bone resorption + volume contraction + increased tubular reabsorption +  Hemo-concentration . •Appears also to be mediated by, at least in part, by thyroid hormone via a process normally inhibited by glucocorticoids

19. THIAZIDE DIURETICS • Thiazide diuretics lowers urinary calcium excretion, an effect that is useful in the treatment of patients with hypercalciuria and recurrent nephrolithiasis . • This effect rarely causes hypercalcemia in normal persons but can lead to hypercalcemia in patients with underlying hyperparathyroidism and other diseases with high bone-turnover .

20. LITHIUM • Seen in patients receiving chronic lithium therapy. •Mainly due to increased PTH secretion due to an increase in the set point at which calcium suppresses PTH release. •Sometimes, lithium can unmask the underlying  hyperpearathyroidism . THEOPHYLLINE TOXICITY • Mild to moderate. •Responds to beta adrenergic agonists (similar in hyperthyroidism) .

21. CLINICAL MANIFESTATIONS ASYMPTOMATIC                             SYMPTOMATIC 1 . NEUROPSYCHIATRIC DISTURBANCES   2.GASTROINTESTINAL DYSFUNCTION   3.RENAL DYSFUNCTION   4.CARDIOVASCULAR DISEASE   5.MUSCULOSKELETAL DISEASE.

22. NEUROPSYCHIATRIC DISTURBANCES MILD:   anxiety, depression, and cognitive dysfunction. • SEVERE:  lethargy, confusion, stupor and coma.   •Mostly seen in patients with primary hyperparathyroidism. •These symptoms are more likely to occur in older adults and in those with rapidly rising calcium concentrations. 

23. GASTROINTESTINAL SYMPTOMS MORE COMMON :     Constipation, Anorexia and Nausea   LESS COMMON :        Peptic ulcer disease and Pancreatitis.

24. MUSCULOSKELETAL SYMPTOMS • PROFOUND MUSCLE WEAKNESS. •DEFICIENT FINE MOTOR MOVEMENTS •BONE PAINS •REDUCTION IN CORTICAL BONE MASS

25. RENAL MANIFESTATIONS NEPHROGENIC DI •Defect in concentrating ability causing polyuria and polydipsia. •Mechanism appears to be down-regulation of aquaporin-2 channels, secondary tubulo interstitial injury. •Underlying dehydration worsens the hypercalcemia.

26. NEPHROLITHIASIS   • Whenever the hypercalcemia and hypercalciuria is long standing. •Can also cause the distal(type1) renal tubular acidosis.

27. RENAL INSUFFICIENCY Related to the degree and duration of hypercalcemia. •Reversible: due to direct renal vasoconstriction and natriuresis-induced volume contraction. • Irrerevrsible : calcification, degeneration and necrosis of the tubular cells and eventual tubular atrophy. • m/c/c cause of renal failure in sarcoidosis is  nephrocalcinosis

28. CARDIOVASCULAR MANIFESTATIONS ACUTE HYPERCALCEMIA •Directly shortens the myocardial action potential, which is reflected in a shortened QT interval. •Some cases of SVT and VT has been described . •ST elevation mimicking myocardial infarction has also been reported.

29. LONG STANDING HYPERCALCEMIA • As occurs in hyperparathyroidism •Lead to cardiac abnormalities, including deposition of calcium in heart valves, coronary arteries, and myocardial fibres; hypertension & cardiomyopathy

30. PHYSICAL FINDINGS OF HYPERCALCEMIA • BAND KERATOPATHY   •A reflection of subepithelial calcium phosphate deposits in cornea.   •Extends as a horizontal band across the cornea in the area that is exposed between eyelids

31. DIAGNOSTIC APPROACH TO HYPERCALCEMIA CONFIRM HYPERCALCEMIA DETERMINING THE ETIOLOGY

32. CONFIRM THE HYPERCALCEMIA • REPEAT MEASUREMENT   • CORRECTED FOR ALBUMIN   • REVIEW THE PREVIOUS VALUES.   • IONISED CALCIUM MEASUREMENT.

33. Degree and duration of hypercalcemia   T he presence of longstanding asymptomatic hypercalcemia is more suggestive of primary hyperparathyroidism, and also raises the possibility of FHH.   •Primary hyperparathyroidism is often associated with borderline or mild hypercalcemia (11-12)   •Values above 13 are unusual in PHPT, although they do occur, they are more common in patients with malignancy-associated hypercalcemia

34. DETERMINING THE ETIOLOGY Clinical findings that favour PHTPT • Asymptomatic patient with chronic hypercalcemia. •Postmenopausal woman. •A normal physical examination. •No other obvious cause of hypercalcemia •A family history of hyperparathyroidism. •And evidence of MEN

35. Hypercalcemiaof malignancy •More higher concentration, and a more rapid increase •Advanced disease and poor prognosis Review of diet and drugs

36. ONCE HYPERCALCEMIA IS CONFIRMED MEASUREMENT OF SERUM PTH Elevated PTH Minimally elevated PTH. Low-Normal Or low PTH PRIMARY HYPERPARATHYROIDISM NON –PTH MEDIATED HYPERCALCEMIA

37. If no clinically apparent malignancy or other causes Then measure PTHrP 1,25 Dihyroxy vitamin D 25 Hydroxy vitamin D

38. OTHER TESTS SERUM PHOSPHATE   Low or low-normal  •Hyperparathyroidism •Hypercalcemia of malignancy  • Elevated/ high-normal •Vitamin d toxicity, immobilisation, thyrotoxicosis •Metastatic bone disease

39. URINARY CALCIUM EXCRETION Normal/high-normal/elevated • Hyperparathyroidism •Hypercalcemia of malignancy   Hypocalciuria  (<100mg/day) with hypercalcemia •FHH (FECa < 1%) •Thiazide diuretics •Milk-alkali syndrome

40. TREATMENT OF HYPERCALCEMIA Therapeutic approach Mild(<12) – does not require any treatment Moderate (12-14) Chronic - does not require any treatment Acute- more aggressive treatment Severe –(>14) more aggressive treatment

41. MILD/CHRONIC MODERATE HYPERCALCEMIA Patients with asymptomatic or mildly symptomatic hypercalcemia do not require immediate treatment. However, they should be advised to avoid factors that can aggravate hypercalcemia, like: Thiazide diuretics Lithium carbonate Calcium supplements

42. Vitamin D supplements Multivitamins containing calcium Volume depletion Prolonged bedrest or inactivity A high calcium diet

43. SEVERE HYPERCALCEMIA Volume Expansion Calcitonin Bisphoshonates

44. VOLUME EXPANSION WITH ISOTONIC SALINE •Isotonic saline for 24-48 hours corrects the possible volume depletion due to hypercalcemia-induced urinary salt wasting.  Rate of saline infusion depends on •Age of the patient • Comorbidities • Edema A reasonable regimen is administration of isotonic saline at an initial rate of 200 -300 ml/hr that is then adjusted to maintain the urine output at 100-150 ml/hr

45. In the absence of renal or heart failure, loop diuretic therapy to directly increase calcium excretion is not recommended  Saline therapy rarely normalises the serum calcium concentration in patients with more than mild hypercalcemia. Concurrent treatment with bisphosphonates with or without calcitonin is typically required to treat moderate to severe hypercalcemia.

46. CALCITONIN MECHANISM: reducing bone resorption via  interefernce  with osteoclast function increasing renal calcium excretion  Administered either IM or SC with initial dose of  4Units/kg.  If  hypocalcemic  response is noted in 4-6 hours, then the patient is calcitonin sensitive and dose is repeated every 12 hours for next 24-48 hours.  If response is not-satisfactory, dose may be increased to 8Units/kg every 6-12 hours.

47. The efficacy of calcitonin is limited to the first 48 hours.  Because of its limited duration of action, calcitonin is most useful in symptomatic patients with calcium >14mg/dL, when combined with hydration

48. BISPHOSPHONATES Relatively non-toxic compounds, and are more potent than calcitonin and saline in reducing calcium levels. They have become the preferred agents for management of hypercalcemia due to excessive bone resorption from variety of causes including malignancy-related hypercalcemia.

49. Their maximum effect is seen in 2-4 days, so that they are usually given in conjunction with saline or calcitonin.  They have also been used to PREVENT hypercalcemia and adverse skeletal events, particularly in metastatic cancer to bone

50. PRETREATMENT COSIDERATIONS Always review vitamin D and creatinine levels prior to administering bisphosphonates . •Hypercalcemia with concomitant vitamin D deficiency are more likely to develop  hypocalcemiaafter treatment.  If creatinine is increased, the bisphosphonates should be infused at a slower rate, and in some cases, at a reduced rate.

51. CHOICE OF DRUG AND DOSING ZOLENDRIC ACID (4mg over 15 mins)   • PAMIDRONATE (60-90 mg over 24 hours)   • IBANDRONATE (2-6 mg over 2 hours)   • CLODRONATE

52. SIDE EFFECTS & PRECAUTION •Flu-like syndrome •Ocular inflammation • Hypocalcemia • Hypophosphatemia •Impaired renal function •Osteonecrosis of jaw •Atypical femur fracture.

53. DOSING IN RENAL IMPAIRMENT •Potential nephrotoxic drugs. •Creat > 4.5, cautious when using iv bisphosphonate . •Adequate hydration + lower dose + slow infusion.    

54. BISPHOSPHONATES CONTRAINDICATED IN Severe renal impairment Allergy to drugs  PATIENTS WITH REFRACTORY TO BISPHOSPHONATES In these cases Denosumab is an option

55. DENOSUMAB • Mab against RANK-L   •60mg/120mg SC initial dosing.   •More risk of  hypocalcemia  ( espif renal  impairement )   But unlike BPs, no restriction in renal failure.

56. Gallium nitrate Hypocalcemic agent that inhibits bone resorption. Mainly used for malignancy related hypercalcemia 100-200/m2 surface area for 5 consecutive days Efficacy better than calcitonin and equal to etidronate Nephrotoxic

57. Mithramycin / Plicamycin Cytotoxic antibiotic used mainly in the therapy of embryonic tumours of testis in old days. This drug also reduces serum calcium as an additional benefit. Potentially a toxic agent

58. IF NOTHING IS WORKING  CONSIDER DIALYSIS WITH LITTLE OR LOW CALCIUM IN THE DIALYSATE ( HEMODIALYSIS /PERITONEAL)

59. DISEASE SPECIFIC THERAPIES HYPERPARATHYROIDISM The treatment is typically parathyroidectomy or monitoring for complications of primary hyperparathyroidism. The  calcimimetic   CINACANCET reduces serum calcium and also reduces bone pains

60. HYPERPARATHYROIDISM The treatment is typically parathyroidectomy or monitoring for complications of primary hyperparathyroidism.  The  calcimimetic   CINACANCET reduces serum calcium and also reduces bone pains

61. GRANULOMATOUS DISEASE LOW CALCIUM DIET  TREATMENT OF CAUSE  GLUCOCORTICOIDS (prednisolone 20-40 mg per day)

62. HYPERVITAMINOSIS D STOP VITAMIN D tablets or supplements.   Calcitriol -  its short lasting, so just stopping the drug, increasing fluid intake.   Calcidiol - lasts longer, more aggressive therapy such as glucocorticoids and/or bisphosphonates are used.

63. THANK YOU