calcium homeostasis by dr anita teli

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Calcium Homeostasis :

Calcium Homeostasis Speaker: Dr Anita Teli PG Chairperson: Dr C.M.Kulkarni Asst Prof Date & Time : 1 st Dec 2010,10.30 am BLDE University Bijapur

Physiological & Biochemical functions:

Physiological & Biochemical functions Development of teeth & bone Neuromuscular excitation Blood coagulation Membrane integrity & plasma membrane transport: Mediation of intracellular action of hormones Activation of enzymes Release of hormones & neurotransmitters Calmodulin mediated action of calcium Regulation of secretory processes Action on heart: by acting on myocardium it prolongs systole . Calcium is believed to be involved in the cell to cell contact & adhesion BLDE University Bijapur

Distribution in the body:

Distribution in the body Most abundant among the minerals in the body. Major divalent cation in the body. Total content in an adult man is 1 to 1.5 kg. Approx 99% of body calcium is found in the bone & remaining 1% of the calcium is present inside the cells & only 0.1- 0.2% is present in the ECF. BLDE University Bijapur

Calcium in bones:

Calcium in bones Calcium in bones is present in 2 pools : Pool of stable calcium : much larger ( 99% of total bone calcium). Is formed by calcium present in the stable mature bones. It represents the calcium pool that is not readily exchangeable, but can mobilized only through action of PTH . 2) . Pool of readily exchangeable calcium : is much smaller only 1% of the total bony Ca & consists of labile (young) newly formed bone. BLDE University Bijapur

Calcium in Plasma:

Calcium in Plasma Total plasma calcium: 10mg% ( 9-11mg%) Non diffusible form - 4mg% Diffusible forms - 6mg% BLDE University Bijapur

Dietary requirements:

Dietary requirements Adult men & women – 800mg/day Women during pregnancy, lactation & post-menopause- 1500mg/day Children (1-18yrs) 800-1200mg/day Infants (<1yrs) 300-500mg Dietary sources: Best sources – milk & milk products. Good sources- beans, leafy vegetables, cabbage, fish, egg yolk Cereals contain only small amounts of calcium. But cereals are the staple diet in India. Therefore form the major source of calcium in the Indian diet BLDE University Bijapur

Calcium balance:

Calcium balance The overall calcium homeostasis ( calcium balance) or normal daily calcium turn over is maintained by an interplay of following processes: Absorption of ingested calcium Exchange of calcium between bone & ECF. Secretion of calcium from ECF Excretion of calcium in fecal matter & urine. BLDE University Bijapur

D :

D BLDE University Bijapur

Mechanism of absorption:

Mechanism of absorption Normally about 75-80% of daily intake is absorbed from the upper small intestine. Absorbed by an active transport mechanism. Steps involved: Entry of calcium inside the enterocyte across its luminal border occurs by active transport mechanism involving a membrane bound carrier that is activated by Vit D ( calcibindin ) Transport of calcium out of the cell into interstitium from where its absorbed into blood capillaries by Ca 2+ ATPase active transport system & by a Na + - Ca 2+ exchange system BLDE University Bijapur

Factors promoting & inhibiting calcium absorption:

Factors promoting & inhibiting calcium absorption Acidity in stomach Bile & bile salts Presence of phosphate in adequate amounts Hypocalcemia Vit D, PTH, GH High protein diet Presence of alkalies Reduced secretion of bile salts Excess of inorganic phosphate,oxalate & pytates. Hypercalcemia BLDE University Bijapur

Regulation of calcium absorption:

Regulation of calcium absorption Absorption is well regulated to maintain plasma calcium levels with in a narrow range. Vit D & PTH play main role in regulation of calcium absorption. Importance of Ca:P ratio : This ratio is imp for calcification of bones. The product of Ca & P ( mg/dl) in children is about 50 & in adults it is around 40. This product is less then 30 in rickets. BLDE University Bijapur

Exchange of calcium between bone & ECF:

Exchange of calcium between bone & ECF The ECF contains about 1000mg of calcium which is in dynamic equilibrium with the calcium present in the bone. Two types of exchange occurs between bone & ECF : Rapid exchange : Rapid exchange occurs between the ECF & the readily exchangeable pool of calcium. The significance not known. Slow exchange: Slow exchange occurs between ECF & larger pool of stable calcium. Concerned with bone remodelling by constant interplay of bone resorption & deposition BLDE University Bijapur

Hormonal regulation of plasma ca level:

Hormonal regulation of plasma ca level Calcitropic hormones: three primarily involved in ca homeostasis are 1}Parathyroid hormone (PTH) 2}Calcitriol active form of Vit D (1,25(OH) 2 cholecalciferol 3}calcitonin Parathyroid hormone related protein (PTHrP) Growth hormones has stimulatory effect on bone deposition sex hormones have inhibitory effects on bone resorption Glucocorticoids have stimulatory effect on bone resorption BLDE University Bijapur

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Parathyroid hormone (PTH) Ivar Sandstrom discovered PT gland in 1880. In 1926,Collip isolated PTH BLDE University Bijapur

Structure ,Synthesis and secretion of PTH:

Structure ,Synthesis and secretion of PTH PTH is single chain polypeptide containing 84 AA & MW 9500 Synthesis: It is synthesized as preproPTH with 115 AA inside the ER , cleaved into proPTH containing 90 AA. In the Golgi apparatus proPTH is broken again to form mature PTH with 84 AA. Storage of PTH for 1hr. First 35 AA are biologically active. Secretion: Released from chief cells by exocytosis in response to decrease in plasma ionised calcium concentration that is sensed by calcium receptors in the PTH cells .The release of hormone is mediated by cAMP BLDE University Bijapur

Regulation of PTH secretion:

Regulation of PTH secretion Role of plasma ionised calcium Role of serum Mg 2+ concentration Role of plasma phosphate concentration Role of Vitamin D BLDE University Bijapur

Plasma level ,half life and degradation :

Plasma level ,half life and degradation Plasma level of PTH -130pg/ml. The normal PTH level in serum is 10-60ng/lt Half life of PTH in plasma - 5-8 minutes Degradation: occurs in rapidly in the peripheral tissues . Mainly split in the liver. BLDE University Bijapur

Mechanism of action:

Mechanism of action PTH binds to a membrane receptor protein on the target cells ( bones, kidneys and intestine) and activates adenyl cyclase to liberate cAMP. cAMP in turn increases intracellular calcium that promote the phosphorylation of proteins by kinases BLDE University Bijapur

Actions of PTH:

Actions of PTH PTH - calcium levels & Phosphate levels Action on bones : PTH stimulate calcium and phosphate resorption from bones by 2 processess : Rapid phase of demineralization Slow phase of demineralization Mechanism of dimeralization : PTH induces pyrophosphatase in the osteoclasts , no of osteoclasts also increased & they release lactate into surrounding medium which solubilize salts, secretion of collagenase causes loss of matrix. BLDE University Bijapur

Actions on kidney:

Actions on kidney Increases the reabsorption of calcium from ascending limb of loop of henle & distal tubules. Inhibition of phosphate reabsorption in the proximal tubule. Produces phosphaturia & hypophosphatemia . Inhibits reabsorption of sodium & bicarbonate in the proximal tubule. Stimulates reabsorption of Mg 2+. 5. Stimulates synthesis of calcitriol . BLDE University Bijapur

Actions on intestines:

Actions on intestines Increases both calcium & phosphate absorption by indirectly increasing the synthesis of 1,25 (OH) 2 D 3 . BLDE University Bijapur

Vitamin D:

Vitamin D Term Vit D refers to a group of closely related steroids produced by action of ultraviolet light on certain pro vitamins. Sources of Vit D 3: fish, fish liver oils, egg yolk. Milk is not a good source. Daily requirement – 400 IU or 10µg. Countries with good sunlight recommended dietary allowance is 200 IU or 5µg. Half life is short around 10 hrs Vit D 3 is the major storage & circulatory form. Transported in blood bound to Vit D binding proteins (DBP). BLDE University Bijapur

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BLDE University Bijapur

Role of calcitriol in calcium homeostasis.:

Role of calcitriol in calcium homeostasis. Calcitriol regulates plasma levels of Calcium & phosphate by acting at 3 diff sites: Intestine Bone Kidney. Mechanism of action: Calcitriol acts by exerting its effect on gene expression in the target cells by binding with intracellular receptors. Its receptor is found both in the cytoplasm & nucleus. BLDE University Bijapur

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BLDE University Bijapur

Action on intestine.:

Action on intestine. Helps calcium absorption from the intestine by its actions : Increases calcium permeability at brush border by causing changes in the membrane phospholipids. b). Induces synthesis of calcium dependent ATPase which helps to pump calcium out of the cells. c). Induces synthesis of calcium binding protein Calbindin . d). Promotes entry of calcium into subcellular organelles BLDE University Bijapur

Actions on bone:

Actions on bone Increases bone resorption as well as bone mineralization. Bone resorption : calcitriol receptors are present on osteoblasts. Receptor calcitriol complex on the osteoblasts releases cytokines that stimulates recruitment, differentiation & fusion of precursors of osteoblasts which cause bone resorption for which PTH is also required. Bone mineralization : maintains levels of Calcium & phosphate & calcium phosphate ion product in the normal range by causing bone resorption. This ion product is imp in bone calcification. Increases osteoblastic proliferation, alkaline phosphatase secretion & osteoclastin synthesis. Lack of Vit D is associated with defective mineralization of cartilage as well as bone. BLDE University Bijapur

Action on kidneys:

Action on kidneys Increases the reabsorption of calcium & phosphate by increasing the no of calcium pumps. BLDE University Bijapur

Calcitonin :

Calcitonin Synthesized in the C cells or parafollicular cells of the thyroid gland. Constitute 0.1% of epithelial cells of thyroid gland. Origin – neural crest Structure : straight chain polypeptide , 32 AA, MW-3500. Secreted in response to elevated plasma calcium levels. Plasma levels 10-20pg/ml. can increase to 2 to 10 fold after an acute rise in plasma calcium conc. as little as 1mg/dl. Half life – less then 10 min. Largely degraded & cleared by the kidney. BLDE University Bijapur

Regulation of secretion:

Regulation of secretion Increase in plasma calcium conc. Calcium levels above 9.5mg/dl leads to calcitonin synthesis. Gastrointestinal hormones: gastrin, CCK, glucagon & secretin have been reported to stimulate calcitonin secretion. 3. β – adrenergic agonists, dopamine & estrogen stimulate calcitonin secretion . BLDE University Bijapur

Actions & physiological role of calcitonin:

Actions & physiological role of calcitonin Calcitonin : calcium levels Action on bone : - Opposes the bone resorptive action of PTH. - Inhibits the osteoclastic activity, binding to membrane receptors on the osteoclasts & decreases its activity. - No of osteoclasts also reduced. -Inhibits calcium permeability of osteoclasts & osteoblast cells & thereby inhibit active transport of calcium from bone cells to ECF. 2. Action on kidney : Increases the loss of calcium & phosphate in urine BLDE University Bijapur

Applied aspects :

Applied aspects Hypercalcemia : Blood calcium level is >11mg/dl Causes Conditions associated with hypercalcemia & raised PTH levels -primary hyperparathyroidism -chronic renal failure 2. Conditions associated with hypercalcemia & low or undetectable PTH levels - hypercalcemia of malignancy -familial hypercalcemia - sarcoidosis -hyperthyroidism - thiazide diuretics BLDE University Bijapur

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Symptoms and Signs Only 20 % people exhibit signs of hypercalcemia Calcium may be precipitated in urine leading to recurrent bilateral urinary calculi. Ectopic calcification seen in renal tissue, pancreas, arterial walls & muscle. Increased solutes in urine lead to polyuria. Pathological fracture of bone. BLDE University Bijapur

Hypocalcemia :

Hypocalcemia Serum calcium level is less than 8.8mg/dl. If serum calcium level is less than 8.5mg/dl –mild tremors If less than 7.5mg/dl –tetany PTH deficiency acquired Thyroidectomy Parathyroidectomy Hypomagnesemia Irradiation Infiltrative Developmental defect of parathyroid glands (DiGeorge) BLDE University Bijapur

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PTH Resistance Pseudohypoparathyroidism Congenital defect Absent metacarpal, short stature, round face, mental disability Target organ unresponsiveness to PTH Serum PTH levels high BLDE University Bijapur

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Vitamin D Deficiency Nutritional deficiency and lack of skin exposure Osteomalacia Adult Proximal muscle weakness Rickets Type 1 Hereditary vitamin D deficiency due to lack of 1-alpha hydroxylase Rickets Type II :Target organ unresponsiveness to vitamin D due to defect in receptor BLDE University Bijapur

Tetany :

Tetany Refers to clinical condition due to increased neuromuscular excitibility. Causes Hypocalcaemia Hypomagnesaemia Alkalosis reduces ionic calcium . Tetany may be latent or manifest. In manifest tetany sign & symptoms depend on the age of the pt BLDE University Bijapur

Clinical features :

Clinical features In children: Carpopedal spasm Laryngeal stridor due to spasm of laryngeal muscles. Convulsions & even death due to associated asphyxia. Visceral features-intestinal cramps, biliary sapasm , bronchosapsm , profuse sweating. Adult patients Paraesthesias i.e. tingling sensation in the peripheral parts of limbs or around mouth. Carpopedal spasm are less common Laryngeal stridor & convulsions very rare . BLDE University Bijapur

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Latent tetany : typical signs & symptoms of tetany are absent, but can be unmasked by following provocative tests: Trousseau’s sign Chvostek’s sign Management: -Intravenous injection of 20 ml 0f 10% calcium gluconate . -Treatment of underlying cause of hypocalcemia . BLDE University Bijapur

Metabolic bone diseases:

Metabolic bone diseases Rickets Osteomalacia osteoporosis BLDE University Bijapur

Rickets :

Rickets Occurring in children due to deficiency of Vit D in which there is defective calcification of bone matrix. Causes & types : Vit D deficiency rickets - dietary deficiency of Vit D. deficient synthesis in the skin- due to inadequate exposure to sunlight Vit D resistant rickets Type I Vit D resistant rickets- inactivating mutations in the gene for renal hydroxylase resulting in non formation of calcitriol . No response to vit D but normal response to calcitriol . Type II Vit D resistant rickets : inactivating mutations of the gene for calcitriol . No response to both Vit D & calcitriol . BLDE University Bijapur

Pathogenesis of defective bone mineralization:

Pathogenesis of defective bone mineralization Vit D deficiency leads to poor intestinal absorption of calcium & decreased reabsorption of calcium & phosphate from renal tubules. There is failure of mineralization of organic bone matrix & ossification is retarded The cartilage cells persist & go on multiplying giving rise to broad irregular cartilagenous zone which can be felt as marked projection on the surface. The matrix between cartilage cells & new bone does not become adequately mineralized resulting in softness of bones BLDE University Bijapur

Clinical features:

Clinical features Craniotabes: small rounded areas in the membranous bones of skull which yield under pressure. Widening of wrist – epiphyseal widening of lower end of radius. Rickety rosary – beading of costochondral junction of ribs. Frontal bossing & posterior flattening of skull. Harrison’s sulcus: indentation of lower ribs at the site of attachment of diaphragm. Bowing of legs & knock knees when the child starts walking. Kyphosis & pelvic deformities BLDE University Bijapur

Biochemical changes:

Biochemical changes Low levels of plasma calcium & phosphate. Product of plasma calcium & phosphate is decreased to 30. Serum alkaline phosphatase levels are high Plasma calcitriol levels are low or absent. Management : Calcium & Vit D. Therapeutic doses of Vit D – 1000 – 5000 IU daily for 6-8 weeks followed by 200-400 IU daily BLDE University Bijapur

Osteomalacia:

Osteomalacia Adult counterpart of rickets. Characterized by defective mineralization of the adult bone in which epiphyseal growth plates are already closed. Causes: Vit D deficiency Other causes: primary non mineralization defect defective matrix synthesis Clinical features : Diffuse skeletal pain & bony tenderness. Muscle weakness Waddling gait due to proximal muscle weakness. Pseudofractures in flat bones or in ends of long bones. BLDE University Bijapur

Osteoporosis :

Osteoporosis Is characterized by reduction of bone mass per unit volume with normal ratio of bone matrix & minerals. Develops due to mismatch of bone resorption & bone remodelling process. The bone resorption being in excess Etiology Immobilization Hyperthyroidism Hyperthyroidism & cushing’s syndrome Bone secondaries Chronic renal failure. : BLDE University Bijapur

Characteristic features:

Characteristic features Bone density is reduced. In radiographs the affected bones show clear glass appearance. Incidence of fractures is increased, particularly Colles fracture, vertebral bodies & hips. Serum calcium & phosphate level are usually normal . Increased urinary excretion of calcium & hydroxy proline . Treatment: Calcium intake Moderate exercise Biphophanates - etidronate BLDE University Bijapur

References :

References Indu Khurana. Text book of medical physiology. Endocrinal control of calcium metabolism & bone physiology. Pg724-750. D M Vasudevan. Text book medical Physiology. 4 th edition. Pg 222. Text book of medical physiology- Guyton Review of medical physiology- Ganong BLDE University Bijapur

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thank you BLDE University Bijapur

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