Calcium Imbalance (Hypocalcemia)

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1. Calcium Imbalance ( Hypocalcemia ) Pabitra Sharma

2. Function of Ca + Mineralization of bone and teeth - bone is mineralized connective tissues. It contain organic ( collagen-protein) and inorganic ( mineral) component . 2. Coagulation of blood Calcium is factor IV in coagulation cascade . Prothrombin factor II contain gla residues. Calcium forms a bridge between gla residue of prothrombim and membrane phospholipids of platelets

3. Function contd … 3. Activation of enzymes - Calmodulin is a calcium binding regulatory protein which bind with 4 calcium ions. 4. Nerves - calcium is necessary for transmission of nerve impulses from pre- synaptic to post- synaptic region 5. Secretion of hormones - calcium mediates secretion of insulin, parathyroid hormone, calcitonin, vasopressin e.t.c from the cells

4. Function contd … 6. Messenger in signal transduction 7. Cardiac contractibility

5. Factors affecting calcium absorption Factors favoring calcium absorption An acidic pH Presence of sugar acids, organic acids and citric acid Presence of Vit D Ca:P ratio- A ratio of dietary Ca : P not more than 2:1 is adequate for optimal absorption, ratio of less than 1 :2 reduces absorption

6. Factors favoring …… State of health and intact mucosa- A healthy adult absorb about 40% of dietary calcium PTH stimulates the activation Vit D, thus indirectly increased absorption of Vit D - High protein diet- Lysine and Agraine causes maximal absorption

7. b) Factors inhibiting absorption of calcium Alkaine pH High fat diet Presence of phytates and oxalates( insoluble calcium salts are formed ) Dietary fiber in excess absorption Excess phosphates, magnesium and iron decrease absorption

8. Factor affecting…. Glucocorticoids reduces intestinal absorption of calcium Calcitonin reduces absorption in directed by inhibiting the activation of Vit D Advancing age and intestinal inflammatory disorders inhibits absorption of calcium

9. Influences on calcium concentrations The plasma pH and the total plasma protein concentration influences the total calcium level Since a significant proportion of calcium in the blood is bound to albumin, it is important to know the Plasma albumin concentration when evaluating the total plasma calcium

10. Influences contd … In general, 0.2 mmol /l must be added to the total calcium concentration for each 1gm/dl decreases in albumin concentration Ionized calcium increases with acidosis, and decreases with alkalosis

11. Contd …. Calcium is the most abundant mineral in the body. Of the body's total calcium, 99% is stored in bone, and serum levels constitute less than 1% . Various factors regulate the homeostasis of calcium and maintain serum calcium within a narrow range. These include parathormone (PTH), vitamin D , hepatic and renal function (for conversion of vitamin D to active metabolites), and serum phosphate and magnesium levels.

12. Serum calcium is present in two forms: the free (ionized) and the bound form . Only about 50% of circulating calcium is present in the physiologically free form . The rest is either bound to proteins (40%) or complexes (10%) with bicarbonate, citrate, and phosphate.

13. The ionized calcium level varies based on the level of serum albumin , blood pH , serum phosphate , magnesium , and bicarbonate levels, the administration of transfused blood containing citrate and free fatty acid content in total parenteral nutrition. The normal range for ionized calcium is 1-1.25 mmol /L (4-5 mg/ dL ).

14. Regulation of calcium homeostasis Three principle hormones are involved in calcium homeostasis Vit D PTH Calcitonin Acting at three target organs Intestine bone and kidney

15. Role of Parathyroid Hormone The actions of PTH are aimed at raising serum calcium. By Increased bone reabsorption by activating osteoclast activity Increasing renal calcium reabsorption by distal renal tubules Increase renal phosphate excretion by decreasing tubule phosphate reabsorption Increase the formation of 1,25- dihydrocholeciferol by increasing the activity of alpha- hydroxyls in the kidney

16. A large amount of calcium is filtered in the kidney, but 99% of the filtered calcium is reabsorbed. About 60% is reabsorbed in the PCT and reminder in Ascending limb. Distal tubules absorption is regulated by PTH Contd ….

17. Roles of PTH PTH is a linear polypeptide containing 84 amino acids residues It is secreted by the chief cells in the four parathyroid glands plasma ionized calcium acts directly on the parathyroid gland in a feed back manner to regulate PTH In hypercalcemia , secretion is inhibited, and the calcium is deposited in the bones In hypocalcemia , PTH secretion is stimulated

18. Role of Vitamin D in calcium homeostasis Vitamin D is a group of closely related sterols produced by the action of UV light Vitamin D3 ( Cholecalciferol ) is produced by the action of sunlight And is converted to 25-hydroxycholecalciferol in the liver The 25- hydroxy-cholaecalciferol is converted in the proximal tubules of the Kidney to the more active metabolite 1,25-hydroxycholecalciferol 1,25-hydroxycholecalciferol synthesis is regulated in a feedback fashion by serum calcium and PTH

19. Role of Calcitonin Calcitonin is a 32 amino acid polypeptide secreted by the Para follicular cells in the thyroid gland It tends to decrease serum calcium concentration and, in general effects opposite to those of PTH The action of Calcitonin are as follows: Inhibits bone reabsorption Increase renal secretion The exact physiological role of calcitonin in calcium homeostasis is uncertain. The effects of calcitonin on bone metabolism are much weaker than those of either PTH or Vitamin D

20. Glucocorticoids and calcium homeostasis Glucocorticoids lower serum calcium levels by inhibiting osteoclast formation and activity. But over long periods they causes Osteoporosis by decreasing bone formation and increasing bone reabsorption. They also decreases the absorption of calcium from the intestine by anti vitamin D action and increased its renal excretion. The decrease in serum calcium concentration increases the secretion of PTH and bone reabsorption is facilitated.

21. Growth hormones and calcium levels Growth hormone increases calcium excretion in the urine It also increases intestinal absorption of calcium and this effects may be greater than The effects on excretion with a resultant positive calcium balance

22. Effects of other hormones on calcium levels Thyroids hormones may cause hypercalcemia , hypercalciuria and in some instances osteoporosis Estrogens prevent osteoporosis, probably by a direct effects on Osteoblasts. Insulin increases bone formation and there is significant bone loss in untreated diabetes

23. Hypocalcemia Hypocalcemia is a laboratory and clinical abnormality that is observed with relative frequency, especially in neonatal pediatric patients . Laboratory  hypocalcemia is often asymptomatic, and its treatment in neonates is controversial. However , children with  hypocalcemia in pediatric intensive care units (PICUs) have mortality rates higher than those of children with normal calcium levels

24. Definition The definition of hypocalcemia is based on both gestational and postnatal age in neonates and is different for children. Calcium data are presented as both mg/ dL and mmol /L (1 mg/ dL = 0.25 mmol /L)

25. Contd …. In children, hypocalcemia is defined as a total serum calcium concentration less than 2.1 mmol /L (8.5 mg/ dL ). In term infants, hypocalcemia is defined as total serum calcium concentration less than 2 mmol /L (8 mg/ dL ) or ionized fraction of less than 1.1 mmol /L (4.4 mg/ dL )  

26. Contd …. I n preterm infants, hypocalcemia is defined as total serum calcium concentration less than 1.75 mmol /L (7 mg/ dL ) is defined as hypocalcemia Symptomatology often manifests when the ionized calcium level falls below 0.8-0.9 mmol /L

27. E tiology Overall, one of the most common causes of hypocalcemia in children is renal failure which results in hypocalcemia because of inadequate 1-hydroxylation of 25-hydroxyvitamin D and hyper- phosphatemia due to diminished glomerular filtration .

28. Contd … Although hypocalcemia is most commonly observed among neonates, it is frequently symptomatic and reported in older children and adolescents, especially in PICU settings. The causes of hypocalcemia can be classified by the child's age at presentation.

29. Classification Early onset neonatal hypocalcemia Early neonatal hypocalcemia , which occurs within 48-72 hours of birth , is most commonly seen in preterm and very low birth weight infants, infants asphyxiated or depressed at birth, infants of diabetic mothers , and the intrauterine growth restricted infants. The mechanisms underlying hypocalcemia caused by these conditions are as follows :

30. Contd … Prematurity : - Possible mechanisms include inadequate nutritional intake D ecreased responsiveness of parathyroid hormone to vitamin D I ncreased calcitonin level I ncreased urinary losses, and hypoalbuminemia leading to a decreased total (but normal ionized) calcium level. 

31. Contd … Birth asphyxia : Delayed introduction of feeds I ncreased calcitonin production I ncreased endogenous phosphate load due to tissue catabolism Renal failure, metabolic acidosis and its treatment with alkali therapy all may contribute to hypocalcemia .

32. Contd … Infants of a diabetic mother : The degree of hypocalcemia is associated with the severity of diabetes in the mother . Magnesium depletion in mothers with diabetes mellitus causes a hypomagnesemic state in the fetus, which induces functional hypoparathyroidism and hypocalcemia in the infant .

33. Contd …. In addition, infants of diabetic mothers have higher serum calcium in utero and this may also suppress the parathyroid gland. A high incidence of birth complications due to microsomal and difficult delivery and, in some cases, higher incidence of preterm birth in infants of diabetic mothers are contributing factors for hypocalcemia .

34. Contd … Intrauterine growth restriction - Infants with intrauterine growth restriction may develop hypocalcemia because of decreased transplacental passage of calcium. - In addition, decreased accretion is present if they are delivered preterm or have experienced perinatal asphyxia as a result of placental insufficiency .

35. Contd.. Late-onset neonatal hypocalcemia This occurs 3-7 days after birth, although occasionally it is seen as late as age 6 weeks. The following are some important causes of late neonatal hypocalcemia : -

36. Contd … Exogenous phosphate load: This is most commonly seen in developing countries. The problem results when the neonate is fed with phosphate-rich formula or cow's milk. Whole cow's milk has 7 times the phosphate load of breast milk (956 vs 140 mg/L in breast milk). This may cause symptomatic hypocalcemia in neonates.

37. Contd … Vitamin D deficiency : In a review of the medical records of 78 term neonates with hypocalcemia , moderate-to-severe late-onset neonatal hypocalcemia developed more often in male infants and Hispanic infants. It was often a sign of coexistent vitamin D insufficiency or deficiency and hypomagnesemia . The newborns respond well to one or more of the following: calcium supplements, calcitriol , low phosphorus formula (PM 60/40), and magnesium supplements for a limited period of time .

38. Contd … Primary immunodeficiency disorder : DiGeorge Syndrome is the most important immunodeficiency disorder to be aware of that is associated with hypocalcemia . DiGeorge Syndrome is a primary immunodeficiency, often but not always, characterized by cellular (T-cell) deficiency, characteristic faces, congenital heart disease and hypocalcemia . Hypoparathyroidism causes hypocalcemia ; 90% of infants with the features of DiGeorge syndrome have a 22q11 chromosomal deletion

39. Contd … Hypocalcemia in infants and children Hypoparathyroidism can result from the following: Aplasia or hypoplasia of parathyroid gland -  DiGeorge syndrome known as velocardiofacial (Shprintzen) syndrome  or 22q11 deletion syndrome; fetal exposure to retinoic acid; complex of vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial and renal abnormalities (VATER/VACTERL);

40. Contd … Parathormone (PTH) receptor defects - Pseudohypoparathyroidism Autoimmune parathyroiditis Infiltrative lesions -  Hemosiderosis , Wilson disease, thalassemia Activating mutations of the calcium-sensing receptor leading to inappropriately suppressed PTH secretion Idiopathic causes Hypoparathyroidism , abnormal vitamin D production or action, and hyperphosphatemia are among the causes of hypocalcemia in infants and children .

41. Contd.. Abnormal vitamin D production or action can be caused by the following: Vitamin D deficiency: Dietary insufficiency and maternal use of anticonvulsants have been reported. Acquired or inherited disorders of vitamin D metabolism Resistance to actions of vitamin D Liver disease: Liver disease can affect 25-hydroxylation of vitamin D; certain drugs ( eg , phenytoin, carbamazepine, phenobarbital, isoniazid, and rifampin) can increase the activity of P-450 enzymes, which can increase the 25-hydroxylation and also the catabolism of vitamin D. Hyperphosphatemia can result from the following :

42. Contd.. Excessive phosphate intake from feeding cow milk or infant formula with improper (low) calcium to phosphate ratio Excessive phosphate intake caused by inappropriate use of phosphate-containing enemas Excessive phosphate or inappropriate Ca:P ratio in total parenteral nutrition Increased endogenous phosphate load caused by anoxia, chemotherapy, or rhabdomyolysis Renal failure

43. Contd.. Other causes of hypocalcemia in infants and children include the following : Malabsorption syndromes Alkalosis: Respiratory alkalosis is caused by hyperventilation; metabolic alkalosis occurs with the administration of bicarbonate, diuretics, or chelating agents, such as the high doses of citrates taken in during massive blood transfusions. Pancreatitis

44. Contd.. Pseudohypocalcemia ( ie , hypoalbuminemia ): Serum calcium concentration decreases by 0.8 mg/ dL for every 1 g/ dL fall in concentration of plasma albumin. “Hungry bones syndrome:" Rapid skeletal mineral deposition is seen in infants with rickets or hypoparathyroidism after starting vitamin D therapy.  

45. Pathophysiology

46. Sign and symptoms Asymptomatic Symptomatic

47. Symptomatic Neuromuscular irritability Myoclonic jerk Jitterinessexaggerated startle seizures

48. Contd.. Cardiac involvement Tachycardia Heart failure Prolonged QT interval Decreased contractibility

49. Contd.. Chronic hypocalcemia may produce the following dermatologic manifestations: Coarse hair Brittle nails Psoriasis Dry skin Chronic pruritus Poor dentition Cataracts

50. Look for Chvosteak’s sign Trousseau’s sign

51. Others Apnea Cyanosis Tachycardia Vomiting Laryngospasm

52. Diagnosis Serum calcium Serum Phosphate Serum Albumin RFT PTH level in serum Parathyroid antibodies ( present in idiopahic hypoparathyrodism ) Vit D serum level Serum magnisium levelX -ray of metacarpals Cardiac enzzumes ABG analysis ECG

53. Management Depend on the underlying cause and severity Administration of calcium alone is only transiently effective Mild asymptomatic cases-often adequate to increase dietary calcium by 1000mg/day Symptomatic: treat immediately

54. Management Prophylactic P reterm , DM mother child, BA- 40mg/kg/day (Elemental calcium)- 4ml/kg/day ( Calcium Gluconate ) Asymptomatic -80ml/kg/day (EC), 8ml/kg/day (CG)

55. Contd.. Symptomatic B olus dose of 2ml/kg/dose (diluted) 5 % dextrose over 10 min under cardiac monitoring C alcium chloride 20mg/kg may be given over 10-30 min

56. Contd.. Hypomagnesemia : Symptomatic hypocalcemia unresponsive to adequate doses of IV calcium therapy is usually due to hypomagnesemia . 2 doses of 0.2 mL/kg of 50% MgSO4 injection, 12 hr apart, deep IM followed by a maintenance dose of 0.2 mL/kg/day of 50% MgSO4, PO for 3 days .

57. Contd.. High phosphate load : These infants have hyperphosphatemia with near normal calcium levels. Exclusive breast-feeding should be encouraged and top feeding with cow’s milk should be discontinued. Phosphate binding gels should be avoided .

58. Vitamin D deficiency states : These babies have hypocalcemia associated with hypophosphatemia due to an intact parathormone response on the kidneys. They benefit from Vitamin D3 supplementation in a dose of 30-60 ng /kg/ day

59. Contd.. Hypoparathyroidism Calcium (50mg/kg/day in 3 divided dose) And 1,25 (OH) vit D3 (0.5- 1 mg/day)

60. Caution Bradycardia Arrhythmia Extravasation Subcutaneous tissues narcosis

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