HYPOCALCEMIA: causes and approach to management

HYPOCALCEMIA: causes and approach to management for internal medicine students

1. HYPOCALCEMIA Dr Rabindra K C Upendra Devkota Memorial National Institute of Neurological and Allied Sciences

2. Objectives of this presentation Brief calcium and its major roles. Elaborate etiology of Hypocalcemia Remind symptoms of Hypocalcemia Highlight treatment of Hypocalcemia

3. What is Calcium? Calcium is an alkaline earth metal with atomic number 20. It is 5 th most abundant element by mass (3.4%) in both the Earth's crust and in seawater. Calcium accounts for  1 to 2 percent  of adult human body weight. Over 99 percent  of total body calcium is found as calcium hydroxyapatite (Ca 10 [PO 4 ] 6 [OH] 2 ) in bones and teeth, where it provides hard tissue with its strength.

4. The calcium ion plays a critical role in normal cellular function and signaling, regulating diverse physiologic processes such as Muscle contraction/Cardiac contractility Neural transmission Membrane stability Hormone secretion Blood coagulation Bone mineralization Thus, extracellular calcium concentrations are maintained within an exquisitely narrow range through a series of feedback mechanisms that involve parathyroid hormone (PTH) and the active vitamin D metabolite 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. Major roles of calcium

5. CALCIUM HOMEOSTASIS Maintained within the narrow normal range. In blood, transported partly by binding to proteins (albumin) and partly to small anions and remaining as free or ionized state. Normal serum calcium: 8.5 to 10.5 mg/dL 2.12 to 2.62 mmol/L Normal ionized calcium: 4.65 to 5.25 mg/dL 1.16 to 1.31 mmol/L

6. Hypocalcemia Hypocalcemia is defined as a total serum calcium concentration < 8.5 mg/dL (< 2.12 mmol/L) in the presence of normal plasma protein concentrations or as a serum ionized calcium concentration < 4.65 mg/dL (< 1.16 mmol/L)

7. CALCIUM HOMEOSTASIS Maintained within the normal range. In blood, transported partly by binding to proteins (albumin) and partly to small anions and remaining as free or ionized state. Normal serum calcium: 8.5 to 10.5 mg/dL 2.12 to 2.62 mmol/L Normal ionized calcium: 4.65 to 5.25 mg/dL 1.16 to 1.31 mmol/L Alteration in albumin level Acid- base disturbances Hormonal imbalances

8. HYPOALBUMINEMIA Reduced serum total calcium with normal serum ionized calcium (pseudo-hypocalcemia) The serum total calcium concentration falls approx. by 0.8mg/dL for every 1g/dL reduction in serum albumin concentration. Calcium = serum calcium + 0.8 (normal albumin – measured albumin) Better directly measure the ionized calcium.

9. HYPOALBUMINEMIA Reduced serum total calcium with normal serum ionized calcium (pseudo-hypocalcemia) The serum total calcium concentration falls approx. by 0.8mg/dL for every 1g/dL reduction in serum albumin concentration. Calcium = serum calcium + 0.8 (normal albumin – measured albumin) Better directly measure the ionized calcium.

10. Acid base imbalances

11. Hormonal regulation of calcium PARATHYROID HORMONE & 2. VITAMIN D

12. Hormonal regulation of calcium PARATHYROID HORMONE & 2. VITAMIN D BONE KIDNEY GIT

13. Hormonal regulation of calcium PARATHYROID HORMONE & 2. VITAMIN D BONE KIDNEY GIT

14. CaSR – CALCIUM SENSING RECEPTOR PARATHYROID GLAND Highly expressed in chief cells Sense variations in serum calcium. Fall in serum calcium is a very potent stimulus leading to PTH release. KIDNEY Important regulator of urinary calcium excretion. Receptors expressed on the basolateral membrane of cells of TALLH Main function to inhibit the calcium reabsorption

15. CaSR – CALCIUM SENSING RECEPTOR PARATHYROID GLAND Highly expressed in chief cells Sense variations in serum calcium. Fall in serum calcium is a very potent stimulus leading to PTH release. KIDNEY Important regulator of urinary calcium excretion. Receptors expressed on the basolateral membrane of cells of TALLH Main function to inhibit the calcium reabsorption INACTIVATING MUTATIONS – FAMILIAL HYPOCALCIURIC HYPERCALCEMIA ACTIVATING MUTATIONS – AUTOSOMAL DOMINANT HYPOCALCEMIA

16. THEREFORE…….. HYPOCALCEMIA MAY OCCUR When PTH secretion is insufficient to normalise the serum calcium When the parathyroid gland and PTH are function are normal HYPOCALCIMIA WITH LOW PTH (PRIMARY HYPOPARATHYROIDISM) HYPOCALCEMIA WITH HIGH PTH (SECONDARY HYPERPARATHYROIDISM)

17. HYPOCALCEMIA WITH LOW PTH DESTRUCTION OF PARATHYROID GLAND ABNORMAL PTH GLAND DEVELOPMENT ALTERED REGULATION OF PTH

18. HYPOCALCEMIA WITH LOW PTH DESTRUCTION OF PARATHYROID GLAND ABNORMAL PTH GLAND DEVELOPMENT ALTERED REGULATION OF PTH

19. DESTRUCTION OF PARATHYROID GLANDS SURGICAL M/C/C of hypoparathyroidism. Can occur after thyroid, parathyroid, or radical neck surgery for head & neck cancer. TRANSIENT / PERMANENT / INTERMITTENT HUNGRY BONE SYNDROME (HBS) AUTO-IMMUNE Acquired hypoparathyroidism not related to surgery. May be permanent. Either immune mediated destruction of PTH gland or may result from activating antibodies to CaSR that decrease PTH secretion. Isolated or a part of autoimmune polyglandular syndrome type I (APS I)

20. DESTRUCTION OF PARATHYROID GLANDS SURGICAL M/C/C of hypoparathyroidism. Can occur after thyroid, parathyroid, or radical neck surgery for head & neck cancer. TRANSIENT / PERMANENT / INTERMITTENT HUNGRY BONE SYNDROME (HBS) AUTO-IMMUNE Acquired hypoparathyroidism not related to surgery. May be permanent. Either immune mediated destruction of PTH gland or may result from activating antibodies to CaSR that decrease PTH secretion. Isolated or a part of autoimmune polyglandular syndrome type I (APS I) OTHER: IRRADIATION INFILTRATIVE DISEASES (hemochromatosis, Wilson disease, metastatic cancer) HIV

21. HUNGRY BONE SYNDROME Sudden increase in calcium uptake by increased osteoblastic activity in bones Parathyroidectomy for hyperparathyroidism Rickets/osteomalacia (vitamin D given without giving calcium) Untreated severe hyperthyroidism following thyroidectomy Acute correction of metabolic acidosis in patients with RTA Institution of antiresorptive therapy in patients with osteoblastic metastasis In cushing syndrome after curative surgery

22. HUNGRY BONE SYNDROME Sudden increase in calcium uptake by increased osteoblastic activity in bones Parathyroidectomy for hyperparathyroidism Rickets/osteomalacia (vitamin D given without giving calcium) Untreated severe hyperthyroidism following thyroidectomy Acute correction of metabolic acidosis in patients with RTA Institution of antiresorptive therapy in patients with osteoblastic metastasis In cushing syndrome after curative surgery SUDDEN CHANGE FROM HIGH BONE TURNOVER STATE LOW BONE TURNOVER STATE

23. HYPOCALCEMIA WITH LOW PTH DESTRUCTION OF PARATHYROID GLAND ABNORMAL PTH GLAND DEVELOPMENT ALTERED REGULATION OF PTH

24. ABNORMAL PARATHYROID GLAND DEVELOPMENT X-linked hypoparathyroidism Autosomal recessive hypoparathyroidism DiGeorge syndrome (velocardiofacial syndrome)

25. HYPOCALCEMIA WITH LOW PTH DESTRUCTION OF PARATHYROID GLAND ABNORMAL PTH GLAND DEVELOPMENT ALTERED REGULATION OF PTH

26. ALTERED REGULATION OF PTH Mutations in the signal peptide sequence of pre-pro-parathyroid hormone (preproPTH). Which impairs the normal processing of preproPTH to PTH. Leading to reduced secretion of PTH from gland. 3 separate autosomal defects CaSR gene mutations (gain of function) Abnormal receptor senses ambient calcium level as excessive, suppresses PTH release, leading to hypocalcemia In kidney, also causes abnormal excessive excretion of calcium. Autosomal Dominant Hypocalcemic Hypercalciuria (ADHH)

27. THEREFORE…….. HYPOCALCEMIA MAY OCCUR When PTH secretion is insufficient to normalise the serum calcium When the parathyroid gland and PTH are function are normal HYPOCALCIMIA WITH LOW PTH (PRIMARY HYPOPARATHYROIDISM) HYPOCALCEMIA WITH HIGH PTH (SECONDARY HYPERPARATHYROIDISM)

28. HYPOCALCEMIA WITH HIGH PTH

29. VITAMIN D DEFICIENCY & RESISTANCE Poor intake or malabsorption coupled with reduced exposure to UV rays. Decreased 25-hydroxylation of vitamin D to form calcidiol in liver. Increased metabolism to inactive metabolites. Decreased hydroxylation of 25-hydroxyvitamin D to 1,25-dihdroxyvitamin D in the kidney. Decreased 1,25-hydroxyvitamin D action

30. CHRONIC KIDNEY DISEASE The M/C/C of an acquired decrease in renal production of 1,25-dihydroxyvitamin D is CHRONIC KIDNEY DISEASE. Hypocalcemia in CKD is also due to occurrence of hyperphosphatemia. Hypocalcemia typically does not occur until end-stage CKD (G5 – eGFR < 15 mL/min/1.73 m2).

31. PTH RESISTANCE (IMPAIRED PTH ACTION) Rare disorder with end organ resistance to PTH action. (Low calcium + high phosphate) with inappropriately high PTH levels. Pathogenesis has been linked to dysfunctional G protein receptor (Gs subunit)

32. EXTRAVASCULAR DEPOSITION HYPERPHOSPHATEMIA Patients with impaired renal excretion or in ARF, increased phosphate intake or excess tissue breakdown. Calcium is deposited mostly in bone, but also in extraskeletal tissue. OSTEOBLASTIC METASTASES Ca breast or prostate cancer. The presumed cause is deposition of calcium in the newly formed bone around the tumor. ACUTE PANCREATITIS Frequent finding in acute pancreatitis. a/w precipitation of calcium soaps in the abdominal cavity. Exact reason is unknown

33. SEPSIS OR SEVERE ILLNESS Incidence of hypocalcemia in critically ill or postsurgical patients is around 80-90%. Usually a/w sepsis and severe burns. Cause :- Reduced PTH secretion Reduced calcitriol production End organ resistance to action of PTH High calcitonin concentration Hypocalcemia is also seen frequently in TSS. Hypomagnesemia + Inflammatory cytokines

34. SURGERY Can occur during and soon after surgery. Most often seen in patients who receive large volumes of blood, because of citrate (normal total calcium with reduced ionised calcium) Other reasons: Volume expansion Hypoalbuminemia. These changes are proportional to the severity of the surgery/anaesthesia procedure. Usually transient.

35. SERUM MAGNESIUM & PTH MILD – MODERATE HYPOMAGNESEMIA PTH RESISTANCE SEVERE HYPOMAGNESEMIA REDUCED PTH SECRETION M/c/c ------- malabsorption, chronic alcoholism, & cisplatin therapy. Other causes – prolonged parenteral fluid administration, diuretic therapy, administration of aminoglycosides. Even though PTH action is low, most patients usually have normal or low phosphate concentrations Hypocalcemia cannot be corrected with calcium; the patients must be given magnesium replacements.

36. Drugs causing hypocalcemia

37. CLINICAL MANIFESTATIONS

38. CLINICAL MANIFESTATIONS ACUTE MANIFESTATIONS DISEASE-SPECIFIC MANIFESTATIONS

39. Features of Hypocalcemia

40. TETANY HALLMARK OF ACUTE HYPOCALCEMIA, as result of neuromuscular irritability. Tetany is a repetitive, high frequency discharges after a single stimulus. Hyperexcitability is seen in all levels of nervous system but most important in PNS. Mild perioral numbness, paresthesia of hands and feet, muscle cramps. Severe carpopedal spasm, laryngospasm, focal or generalised seizures. Seen when total calcium is below 7 – 7.5 (1.8 – 1.9) or ionized calcium below 4.3 (1.1) Tetany is manifestated clinically by both sensory & muscular dysfunction. Symptoms typically begin with perioral & acral paresthesias . Motor symptoms of tetany include stiffness, clumsiness, myalgia, cramps. Typically in hand by carpal spasms

41. SIGNS OF LATENT TETANY TROSSEAU’S SIGN Induction of carpal spasm by inflation of a sphygmomanometer above SBP for 3 minutes. Carpal spasm: Adduction of thumb Flexion of MCP joints Flexion of wrist. Extension of IPP joints. Depends upon the effect of ischemia to increase excitability of the nerve trunk under the cuff. CHVOSTEK’S SIGN Contraction of ipsilateral facial muscles elicitated by tapping the facial nerve just anterior to the ear. The response ranges from twitching of lips to spasm of all facial muscles. Depends on severity Occurs in 10% of normal subjects

42. SIGNS OF LATENT TETANY TROSSEAU’S SIGN Induction of carpal spasm by inflation of a sphygmomanometer above SBP for 3 minutes. Carpal spasm: Adduction of thumb Flexion of MCP joints Flexion of wrist. Extension of IPP joints. CHVOSTEK’S SIGN Contraction of ipsilateral facial muscles elicitited by tapping the facial nerve just anterior to the ear. The response ranges from twitching of lips to spasm of all facial muscles. Depends on severity

43. SEIZURES All types of seizures can be observed in hypocalcemia. May be the sole manifestation. May or may not be associated with tetany.

44. SEIZURES All types of seizures can be observed in hypocalcemia. May be the sole manifestation. May or may not be associated with tetany. PAPILLOEDEMA Can occur in patients with hypocalcemia of any cause. Occurs only with severe hypocalcemia, & reverses with treatment. May or may not be accompanied by high CSF pressure. Rarely optic neuritis is present.

45. SEIZURES All types of seizures can be observed in hypocalcemia. May be the sole manifestation. May or may not be associated with tetany. PAPILLOEDEMA Can occur in patients with hypocalcemia of any cause. Occurs only with severe hypocalcemia, & reverses with treatment. May or may not be accompanied by high CSF pressure. Rarely optic neuritis is present. PSYCHIATRIC MANIFESTATIONS Emotional instability, anxiety, and depression. Confusional states, hallucinations, frank psychosis

46. CARDIOVASCULAR FEATURES Hypotension may complicate hypocalcemia (blood transfusion, low calcium dialysate in RRT) Decreased myocardial perfusion and even CCF have been reported. (reversible). Characteristic : PROLONGATION Of QT INTERVAL (QTc >440ms in men, >460 ms in women) Prolongs phase 2 of the action potential. a/w early after-depolarisations and triggered dysarrhytmias Torsades de pointes (although less common than hypokalemia) Serious arrythmias are rare.

47. CARDIOVASCULAR FEATURES Hypotension may complicate hypocalcemia (blood transfusion, low calcium dialysate in RRT) Decreased myocardial perfusion and even CCF have been reported. (reversible). Characteristic : PROLONGATION Of QT INTERVAL Prolongs phase 2 of the action potential. a/w early after-depolarisations and triggered dysarrhytmias Torsades de pointes (although less common than hypokalemia) Serious arrythmias are rare.

48. DISEASE SPECIFIC MANIFESTATIONS HYPOPARATHYROIDISM Apart from symptoms of hypocalcemia. Unique features pertaining to chronic HPP Basal ganglia calcifications Cataract Dental abnormalities Ectodermal manifestations. Dry skin dementia

49. DISEASE SPECIFIC MANIFESTATIONS HYPOPARATHYROIDISM Apart from symptoms of hypocalcemia. Unique features pertaining to chronic HPP Basal ganglia calcifications Cataract Dental abnormalities Ectodermal manifestations. Dry skin dementia

50. DISEASE SPECIFIC MANIFESTATIONS HYPOPARATHYROIDISM Apart from symptoms of hypocalcemia. Unique features pertaining to chronic HPP Basal ganglia calcifications Cataract Dental abnormalities Ectodermal manifestations. Dry skin dementia

51. DISEASE SPECIFIC MANIFESTATIONS HYPOPARATHYROIDISM Apart from symptoms of hypocalcemia. Unique features pertaining to chronic HPP Basal ganglia calcifications Cataract Dental abnormalities Ectodermal manifestations. Dry skin dementia

52. DISEASE SPECIFIC MANIFESTATIONS PSEUDOHYPOPARATHYROIDISM

53. DISEASE SPECIFIC MANIFESTATIONS VITAMIN D DEFICIENCY CHILDERN -------- RICKETS BONE PAINS X RAY TYPICAL CHANGES MUSCLE WEAKNESS HYPOTONIA MENTAL RETARDATION STUNTED GROWTH ALOPECIA ADULTS -------- OSTEOMALACIA BONE PAINS JOINT PAINS MUSCLE WEAKNESS BONE TENDERNESS WADDLING GAIT RECURRENT FRACTURES

54. DIAGNOSTIC APPROACH TO HYPOCALCEMIA

55. DIAGNOSTIC APPROACH TO HYPOCALCEMIA

56. CONFIRM THE HYPOCALCEMIA REPEAT MEASUREMENT IONISED CALCIUM (GOLD STANDARD) HYPOALBUMINEMIA: CALCIUM CORRECTION

57. DETERMINING THE ETIOLOGY CLINICAL CLUES Family history of hypocalcemia / Personal history of minimal sun exposure Phenotypic appearance History of surgery in the concerned area. Look for associated autoimmunity History of concerned drugs Other pertaining history : CKD, ACUTE PANCTREATITIS, TLS, RHABDOMYOLYSIS.

58. DETERMINING THE ETIOLOGY LABORATORY EVALUATION Serum PTH concentration Phosphate Magnesium Vitamin D metabolites Other

59. (calcidiol) (calcitriol)

60. TREATMENT OF HYPOCALCEMIA

61. THERAPEUTIC APPROACH SEVERE ACUTE AND/OR SYMPTOMATIC HYPOCALCEMIA Symptoms (carpal spasms, tetany) A prolonged QT interval Acute decrease in serum calcium to <7.5 or ionised calcium < 3 even if asymptomatic. INTRAVENOUS CALCIUM IS RECOMMENDED MILDLY SYMPTOMATIC OR CHRONIC HYPOCALCEMIA ORAL CALCIUM SUPPLEMENTATION

62. INTRAVENOUS CALCIUM Initially, IV calcium (1-2 g of calcium gluconate, equivalent to 90 – 180 mg of elemental calcium, in 50 mL of 5% dextrose or NS) infused over 10 – 20 mins. This dose will rise the serum calcium concentration for only two to three hours. Therefore, it should be f/b a slow infusion in patients with persistent hypocalcemia. Calcium gluconate is preferred compared to calcium chloride. IV calcium should be continued until the patient is receiving an effective regimen of oral calcium and vitamin D. 0.5 – 1.5 mg/kg of elemental calcium per hour

63. INTRAVENOUS CALCIUM Initially, IV calcium (1-2 g of calcium gluconate, equivalent to 90 – 180 mg of elemental calcium, in 50 mL of 5% dextrose or NS) infused over 10 – 20 mins. This dose will rise the serum calcium concentration for only two to three hours. Therefore, it should be f/b a slow infusion in patients with persistent hypocalcemia. Calcium gluconate is preferred compared to calcium chloride. IV calcium should be continued until the patient is receiving an effective regimen of oral calcium and vitamin D. 0.5 – 1.5 mg/kg of elemental calcium per hour

64. INTRAVENOUS CALCIUM Initially, IV calcium (1-2 g of calcium gluconate, equivalent to 90 – 180 mg of elemental calcium, in 50 mL of 5% dextrose or NS) infused over 10 – 20 mins. This dose will rise the serum calcium concentration for only two to three hours. Therefore, it should be f/b a slow infusion in patients with persistent hypocalcemia. Calcium gluconate is preferred compared to calcium chloride. IV calcium should be continued until the patient is receiving an effective regimen of oral calcium and vitamin D. 0.5 – 1.5 mg/kg of elemental calcium per hour Always remember the possibility of concurrent hypomagnesemia

65. THERAPEUTIC APPROACH SEVERE ACUTE AND/OR SYMPTOMATIC HYPOCALCEMIA Symptoms (carpal spasms, tetany) A prolonged QT interval Acute decrease in serum calcium to <7.5 or ionised calcium < 3 even if asymptomatic. INTRAVENOUS CALCIUM IS RECOMMENDED MILDLY SYMPTOMATIC OR CHRONIC HYPOCALCEMIA ORAL CALCIUM SUPPLEMENTATION ELEMENTAL CALCIUM OF 1500 – 2000 MG given as either calcium carbonate or calcium citrate in daily divided doses

66. HYPOPARATHYROIDISM Administration of calcium alone is usually transiently effective. Long term management requires addition of vitamin D. Most patients requires lifelong calcium and vitamin D supplementation. Goals : to relieve symptoms to maintain serum calcium in low-normal range (8.0 – 8.5) For those who cannot maintain stable calcium with calcium and vitamin D supplementation, the addition of recombinant human parathyroid hormone (1-84) is an option. No established long term safety Much more expensive.

67. VITAMIN D DEFICIENCY Treated with ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) In the setting of uncomplicated vitamin D deficiency, vitamin D2 or D3 corrects and returns the physiology to normal. Usual practical advice is to treat nutritional vitamin deficiency with 50000-60000 IU of vitamin D2 or D3 weekly for six to eight weeks. Parenteral vitamin D can also be used. Vitamin D metabolites can also be used (calcitriol, calcidiol, etc) are usually preferred in patients with kidney or liver disease.

68. PREVENTION: 600 – 1000 IU (15-25 mcg) once daily HIGH DOSE THERAPY Preferred in patients with 25(OH)D level < 12ng/ml or who are symptomatic. 60000 IU (1500mcg) once weekly for 6 – 12 weeks. Recheck and repeat the dose if necessary LOW DOSE THERAPY Preferred in patients with a serum 25(OH)D level < 20ng/ml. 800 – 1000 IU (20-25 mcg) once daily for 3-4 months MAINTAINANCE DOSING: Once target 25(OH)D levels are achieved, continue maintenance dose of 600-2000 IU (15-50 mcg) OD.

69. AUTOSOMAL DOMINANT HYPOCALCEMIA Increased activity of CaSR in renal tubules, causing normal or high urinary calcium excretion despite serum hypocalcemia. Here, if patient is supplemented with calcium and vitamin D, it can result in more hypercalciuria, nephrocalcinosis, and renal insufficiency. Recombinant PTH can be used. CALCILYTICS: CaSR antagonists By inhibiting the action of calcium on CaSR, they can reset the abnormally low set-point in parathyroid and kidney. But not yet available for human use.

70. RDA of Calcium and Vitamin D 1000 mg-1200 mg daily of calcium. 1500 mg daily of calcium in patients taking long term steroids. 400-800 IU daily of vitamin D.

71. Are My Objectives met? Discussions Questions Comments Remarks