MATABOLISM OF CALCIUM & PHOSPHOROUS

MATABOLISM OF CALCIUM & PHOSPHOROUS

1. Calcium Metabolism Gandham . Rajeev

2. Calcium metabolism Sources & RDA Factors affecting calcium absorption Biochemical functions Regulation of plasma calcium Disease states Case report Metabolism of phosphorous Sources & RDA Biochemical functions Disease states RGUHS questions

3. Essential for Normal growth & maintenance of the body Calcification of bone Blood coagulation Neuromuscular irritability Acid-base equilibrium Fluid balance & osmotic regulation Daily requirement is >100 mg/day - macro minerals/macro elements Daily requirement is <100 mg/day - micro minerals/micro elements

4. 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

5. Calcium metabolism Most abundant mineral. Total body calcium is about 1 to 1.5 kg. 99 % is seen in bone together with phosphate & 1 % in ECF Dietary Sources of calcium: Milk is a good source for calcium Egg, fish, cheese, beans, nuts , cabbage and vegetables are good sources for calcium

6. Daily requirement of calcium Adult men & women = 500 mg/day Children’s = 1200 mg/day Pregnancy & lactation = 1500 mg/day Calcium in plasma is of 3 types Ionized or free or unbound calcium Bound calcium Complexed calcium

7. Ionized or free or unbound calcium or diffusible: 5.5 mg/dl In blood, 50% of plasma calcium is free & is metabolically active It is required for Maintenance of nerve function Membrane permeability Muscle contraction Hormone secretion Bound calcium or non diffusible: 4.5 mg/dl 40 % of plasma calcium is bound to proteins – albumin

8. Complexed calcium: 1 mg/dl 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 9-11 mg/dl Urine calcium:100-250 mg/day

9. Absorption From upper small intestine - first & second part of duodenum. About 40% of dietary calcium is absorbed. Absorbed against a concentration gradient & requires energy. Requires a carrier protein, helped by calcium-dependent ATPase .

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 absorption through increased synthesis of calcitriol

11. Acidity favors calcium absorption (enhance solubility of calcium) Amino acids: Lysine & arginine increases calcium absorption Amino acids increase the solubility of Ca-salts & thus its absorption

12. Factors causing decreased absorption Phytates oxalates: Phytates & oxalates form insoluble Ca-salts & decreases the absorption. High phosphate content will cause precipitation as calcium phosphate. Alkaline condition is unfavorable for absorption. Calcium forms insoluble soaps with fatty acids Vitamin D deficiency states.

13. 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 & teeth formation Osteoblasts induce bone deposition & osteoclasts produce demineralization.

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

15. 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 - insulin, parathyroid hormone, calcitonin & vasopressin

16. Activation of enzymes: Calmodulin is a calcium binding regulatory protein. Calmodulin can bind with 4 calcium ions & molecular weight of 17,000 Calcium binding leads to activation of enzymes Enzymes activated by Calcium Glycogen synthase Pancreatic lipase Adenylate cyclase Glycerol 3-P-DH Pyruvate carboxylase PDH & Pyruvate kinase

17. Second messenger: Calcium & 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 & Ca 2 + Myocardium: Ca 2+ prolongs systole. In hypercalcemia , cardiac arrest is seen in systole.

18. Regulation of plasma calcium level Dependent on the function of 3 main organs Bone Kidney Intestine 3 main hormones Calcitriol Parathyroid hormone Calcitonin

19. 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 At low calcium levels, calcitriol along with parathyroid hormone increases the mobilization of calcium & phosphate from the bone Causes elevation in the plasma calcium and phosphate

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

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

22. 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.

23. Action on the kidney PTH increases the Ca 2+ reabsorption by kidney tubules It is 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 .

24. Calcitonin Calcitonin is a peptide containing 32 amino acids. It is secreted by parafollicular cells of thyroid gland. The action of CT on calcium is antagonistic to that of PTH. Calcitonin 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

25. Calcitonin, calcitriol & PTH act together

26. Hypercalcemia The serum Ca 2+ level >11 mg/dl is called as Hypercalcemia . Causes: Hyperparathyroidism: Due to increased activity of parathyroid gland or PTH secreting tumor Increase in calcium & ALP & decrease in phosphate levels. Excretion of calcium & phosphorous in urine. Determination of ionized Ca 2+ (elevated to 6-9 mg/dl) is useful for diagnosis of hyperparathyroidism

27. Clinical features of hypercalcemia Neurological symptoms: Depression , confusion, inability to concentrate Generalized muscle weakness Gastrointestinal problems Anorexia , abdominal pain, nausea, vomiting & constipation Renal feature: calcification of renal tissue Increased myocardial contractility & susceptibility to factures.

28. 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.

29. Vitamin D deficiency: May be due to malabsorption or 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

30. Clinical features of hypocalcemia : Enhanced neuromuscular irritability Neurologic features Tingling , tetany , numbness (fingers & toes), muscle cramps Cardiovascular signs - abnormal ECG Cataracts.

31. 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.

32. Osteoporosis 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+ After the age of 60, osteoporosis is seen There is reduced bone strength & an increased risk of fractures. Decreased absorption of vitamin D & reduced levels of androgens/estrogens in old age are the causative factors.

33. Case report A 5 year old girl had bone deformities such as bow legs and pigeon chest. She had delayed eruption of teeth. The girl was from a strict vegetarian family and she used to take very low amount of milk. Interpret the following laboratory findings. Investigations Report Serum calcium 8.5 mg/dl Serum inorganic phosphate 2.2 mg/dl Serum alkaline phosphatase 175 IU/L Serum calcitriol 12 pg/ml (Reference Range: 15 – 60 pg/ml)

34. Phosphorous Metabolism Gandham . Rajeev

35. Human body contains - 1 kg of phosphorous Body distribution: 80 % of phosphorous is found in bones & teeth in combination with calcium. 15 % of phosphorous is present in soft tissues, as a component of phospholipids, phosphoproteins , nucleic acids & nucleoproteins. 1% is found in ECF, as inorganic form

36. Dietary sources and RDA The food rich in calcium is also rich in phosphorous i.e. milk, cheese, beans, eggs, cereals, fish & meat Milk is good source of phosphorous RDA: Adults: 800 mg/day During pregnancy and lactation: 1,200 mg/day Ca : P of 1:1 is recommended

37. Biochemical functions Phosphorous is essential for formation of bones & teeth It is a constituent of hydroxyapatite in bone & provides structural support. Formation & utilization of high energy phosphate compounds like ATP , ADP, GTP, Creatine phosphate, etc. contains phosphorous. Essential for the formation of Phospholipids , phosphoproteins , nucleic acids, nucleotides

38. Component of nucleotide coenzymes – NAD + , NADP, ATP, ADP Several enzymes & proteins are activated by p hosphorylation & dephosphorylation . Phosphate buffer system is important for maintenance of blood pH Formation of phosphate esters - glucose-6-p.

39. Absorption 90 % of dietary phosphorous is absorbed from small intestine. Absorption is stimulated by both PTH & calcitriol . Excretion: 500 mg of phosphate is excreted through urine per day Renal threshold for phosphorous is 2 mg/dl. Normal range: Plasma phosphorous: 2.5 to 4.5 mg/dl in adults In children’s: 5.0 to 6.0 mg/dl

40. Calcium & phosphorous have reciprocal relationship. In particular, if phosphate rises , calcium falls. Fasting phosphate levels are higher Postprandial decrease of phosphorous is due to the utilization of phosphorous for metabolism.

41. Hypophosphataemia Serum inorganic phosphate concentration <2.5 mg/dl is called as Hypophosphataemia Causes: Decreases intake, Decreased absorption, Increased loss: In the treatment of Diabetes the effect of insulin in causing the shift of glucose into cells also enhances the transport of phosphate into cells, which may result into hypophosphataemia

42. Renal rickets is associates with low phosphate & increased ALP concentration. Congenital defect of tubular phosphate reabsorption, e.g. Fanconi’s syndrome, in which phosphate is lost. Symptoms: Symptoms: Hemolytic anemia, weakness, bone fractures, Muscle pain. Rickets in children’s & osteoporosis in adults may develop.

43. Hyperphosphataemia Increase in serum inorganic phosphate levels than the normal levels is called as hyerphosphataemia Causes: Increased intestinal absorption, decreased renal excretion, cellular release of phosphorous. Symptoms: Chronic renal failure, soft tissue calcification.

44. RGUHS Questions Explain the sources, daily requirement, absorption, biochemical functions & disorders of calcium metabolism. Blood calcium homeostasis. Rickets & osteoporesis . Metabolism of phosphorous.