CALCIUM METABOLISM

METABOLISM OF CALCIUM

1. Mineral Metabolism Gandham . Rajeev

2. Minerals are essential for the normal growth & maintenance of the body Essential for calcification of bone, blood coagulation, neuromuscular irritability, acid-base equilibrium, fluid balance & osmotic regulation If the daily requirement is more than 100 mg, they are called major elements or macro minerals If the daily requirement is less than 100 mg, they are called as micro minerals

3. Classification of minerals according to their essentiality Major elements Minor elements Calcium Iron Magnesium Iodine Phosphorous Copper Sodium Manganese Potassium Zinc Chloride Molybdenum Sulfur Selenium   Fluoride

4. Calcium metabolism Most abundant mineral in the human body Total Calcium in the human body is about 1 to 1.5 kg, 99% of which is seen in bone together with phosphate Small amounts in soft tissue & 1% in extracellular fluid Dietary Sources of calcium : Milk is a good source for calcium Egg , fish, cheese, beans, lentils, nuts, cabbage and vegetables are sources for calcium

5. Daily requirement of calcium Adults = 500 mg/day Children’s = 1200 mg/day Pregnancy & lactation = 1500 mg/day After the age of 50, tendency for osteoporosis, prevented by increased calcium (1500 mg/day) & vitamin D (20 μg /day ) Body distribution of Calcium: About 99% of calcium is found in bones It exists as carbonate or phosphate of calcium About 0.5% in soft tissue and 0.1% in extracellular fluid

6. Calcium in plasma is of 3 types Ionized or free or unbound calcium: In blood, 50% of plasma calcium is free & is metabolically active It is required for the maintenance of nerve function, membrane permeability, muscle contraction and hormone secretion Bound calcium: 40% of plasma calcium is bound to protein mostly albumin These two forms are diffusible from blood to tissues

7. Complexed calcium: 10 % of plasma calcium is complexed with anions including bicarbonate, phosphate, lactate & citrate All the three forms of calcium in plasma remain in equilibrium with each other Normal Range: The normal level of plasma calcium is 9-11mg/dl

8. Absorption Mechanism of absorption of calcium: Calcium is taken in the diet as calcium phosphate, carbonate & tartarate About 40% of dietary calcium is absorbed from the gut Absorption occurs form the first & second part of duodenum Absorbed against a concentration gradient & requires energy

9. Requires a carrier protein , helped by calcium-dependent ATPase 400 mg is excreted in stool & 100 mg is excreted through urine Two mechanisms for absorption of calcium: Simple diffusion An active transport - Process involving energy & Ca 2+ pump Both processes require 1, 25 DHCC (Calcitriol) which regulates the synthesis of Ca -binding proteins & transport

10. Factors causing increased absorption Vitamin D: Calcitriol induces the synthesis of carrier protein (Calbindin) in the intestinal epithelial cells & facilitates the absorption of calcium Parathyroid hormone: It increases calcium transport from the intestinal cells by enhancing 1α-hydroxylase activity

11. Acidity: Favors calcium absorption because the Ca -salts, particularly PO 4 & carbonates are quite soluble in acidic solutions In alkaline medium , the absorption of calcium is lowered due to the formation of insoluble tricalcium PO 4 High protein diet: A high protein diet favors calcium absorption If the protein content is low, only 5% may be absorbed

12. Amino acids: Lysine & arginine increases calcium absorption Amino acids increase the solubility of Ca -salts & thus its absorption Sugars and organic acids: Organic acids produced by microbial fermentation of sugars in the gut, increases the solubility of Ca -salts & increases their absorption Citric acid may also increase the absorption of calcium

13. Factors causing decreased absorption Phytic acid : Cereals contain phytic acid (Inositol hexaphosphate ) forms insoluble Ca -salts & decreases the absorption Oxalates: Present in some leafy vegetables, causes formation of insoluble calcium oxalates Fibres : Excess of fibres in the diet interferes with the absorption

14. Malabsorption syndromes: Causing formation of insoluble calcium salt of fatty acid Glucocorticoids : Diminishes intestinal transport of calcium Phosphate : High phosphate content will cause precipitation as calcium phosphate Magnesium : High content of Mg decreases the absorption Ca : P Ratio: 2:1

15. Biochemical functions Development of bones and teeth: Bone is regarded as a mineralized connective tissue Bones also act as reservoir for calcium The bulk quantity of calcium is used for bone and teeth formation Osteoblasts induce bone deposition and osteoclasts produce demineralization

16. Muscles: Calcium mediates excitation & contraction of muscles C 2+ interacts with troponin C to trigger muscle contraction Calcium activates ATPase , increases action of actin and myosin and facilitates excitation-contraction coupling . Calcium decreases neuromuscular irritability. Calcium deficiency causes tetany

17. Nerve conduction: It is necessary for transmission of nerve impulses Blood coagulation: Calcium is known as factor IV in blood coagulation process Prothrombin contains γ- carboxyglutamate residues which are chelated by Ca 2+ during the thrombin formation Calcium is required for release of certain hormones from cells include insulin, parathyroid hormone, calcitonin, vasopressin

18. Activation of enzymes: Calmodulin is a calcium binding regulatory protein, with a molecular weight of 17,000 Daltons Calmodulin can bind with 4 calcium ions Calcium binding leads to activation of enzymes Calmodulin is part of various regulatory kinases Enzymes activated by Ca 2+ include pancreatic lipase, enzymes of coagulation pathway, and rennin

19. Second messenger: Calcium and cAMP are second messengers for hormones e.g. epinephrine in liver glycogenolysis Calcium serves as a third messenger for some hormones e.g , ADH acts through cAMP and then Ca 2+ Myocardium: Ca 2 + prolongs systole In hypercalcemia , cardiac arrest is seen in systole

20. Regulation of plasma calcium level Dependent on the function of 3 main organs B one Kidney I ntestine 3 main hormones Calcitriol Parathyroid hormone Calcitonin Also by GH, glucocorticoids, estrogens, testosterone & thyroid

21. Regulation of plasma calcium level by Calcitriol Role of calcitriol on bone: In osteoblasts of bone, calcitriol stimulates calcium uptake for deposition as calcium phosphate Calcitriol is essential for bone formation Calcitriol along with parathyroid hormone increases the mobilization of calcium and phosphate from the bone Causes elevation in the plasma calcium and phosphate

22. Role of calcitriol on kidneys Calcitriol minimizing the excretion of Ca 2+ & phosphate by decreasing their excretion & enhancing reabsorption Role of calcitriol on intestine: Calcitriol increases the intestinal absorption of Ca 2+ & phosphate C alcitriol binds with a cytosolic receptor to form a calcitriol -receptor complex Complex interacts with DNA leading to the synthesis of a specific calcium binding protein This protein increases calcium uptake by intestine

23. Regulation by parathyroid hormone (PTH ) Parathyroid hormone (PTH) is secreted by two pairs of parathyroid glands Parathyroid hormone (mol. wt. 95,000) is a single chain polypeptide , containing 84 amino acids It is originally synthesized as prepro PTH, whch is degraded to proPTH and, finally, to active PTH The rate of formation & secretion of PTH are promoted by low Ca 2 + concentration

24. Mechanism of action of PTH Action on the bone: PTH causes decalcification or demineralization of bone, a process carried out by osteoclasts. This is brought out by pyrophosphatase & collagenase These enzymes result in bone resorption Demineralization ultimately leads to an increase in the blood Ca 2+ level

25. Action on the kidney PTH increases the Ca 2+ reabsorption by kidney tubules It most rapid action of PTH to elevate blood Ca 2+ levels PTH promotes the production of calcitriol ( 1,25 DHCC) in the kidney by stimulating 1- hydroxyaltion of 25-hydroxycholecalciferol Action on the intestine: It increases the intestinal absorption of Ca 2+ by promoting the synthesis of calcitriol

26. C alcitonin Calcitonin is a peptide containing 32 amino acids lt is secreted by parafollicular cells of thyroid gland The action of CT on calcium is antagonistic to that of PTH C alcitonin promotes calcification by increasing the activity of osteoblasts Calcitonin decreases bone resorption & increases the excretion of Ca 2+ into urine Calcitonin has a decreasing influence on blood calcium

27. Calcitonin, calcitriol & PTH act together

28. Serum Proteins: In hypoalbuminemia , total calcium is decreased In such cases, the metabolically active ionized Ca 2+ is normal & so there will be no deficiency manifestations Alkalosis and Acidosis : Alkalosis favors binding of Ca 2+ with proteins, with consequent lowering of ionized Ca 2+ Total calcium is normal, but Ca 2+ deficiency may be manifested Acidosis favors ionization of Ca 2+ The renal threshold for calcium in blood is 10 mg/dl

29. Hypercalcemia The serum Ca 2+ level >11 mg/dl is called as Hypercalcemia Causes: Hyperparathyroidism: Decrease in serum phosphate (due to increased renal losses) and increase in ALP activity are found in hyperparathyroidism Urinary excretion of Ca 2+ & P resulting in formation of urinary calculi The determination of ionized Ca 2+ ( elevated to 6-9mg/dl) is useful for the diagnosis of hyperparathyroidism

30. Clinical features of hypercalcemia Neurological symptoms such as depression, confusion , inability to concentrate G eneralized muscle weakness G astrointestinal problems such as anorexia, abdominal pain, nausea, vomiting & constipation R enal feature such as polyuria & polydipsia Cardiac arrhythemias

31. Hypocalcemia Decreased serum Ca 2+ < 8.8 mg/dl is called as hypocalcemia Causes: Hypoproteinaemia : If albumin concentration in serum falls, total calcium is low because the bound fraction is decreased Hypoparathyroidism : The commonest cause is neck surgery, idiopathic or due to magnesium deficiency

32. Vitamin D deficiency : May be due to malabsorption or an inadequate diet with little exposure to sunlight Leads to bone disorders, osteomalacia & rickets Renal disease: In kidney diseases, the 1, 25 DHCC ( calcitriol ) is not synthesized due to impaired hydroxylation

33. Pseudohypoparathyroidism : PTH is secreted but there is failure of target tissue receptors to respond to the hormone Clinical features of hypocalcemia : Enhanced neuromuscular irritability Neurologic features such as tingling, tetany , numbness (fingers and toes), muscle cramps Cardiovascular signs such as an abnormal ECG Cataracts

34. Rickets Rickets is a disorder of defective calcification of bones This may be due to a low levels of vitamin D in the body or due to a dietary deficiency of Ca 2+ & P or both The concentration of serum Ca 2+ & P may be low or normal An increase in the activity of alkaline phosphatase is a characteristic feature of rickets

35. Osteoporosis Osteoporosis is characterized by demineraIization of bone resulting in the progressive loss of bone mass After the age of 40-45 , Ca 2+ absorption is reduced & Ca 2+ excretion is increased; there is a net negative balance for Ca 2+ This is reflected in demineralization After the age of 60, osteoporosis is seen There is reduced bone strength and an increased risk of fractures Decreased absorption of vitamin D and reduced levels of androgens/estrogens in old age are the causative factors

36. Thank You