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HORMONAL CONTROL OF CALCIUM and PHOSPHORUS METABOLISM HORMONES INVOLVED… 1,25 Dihydrocholecalciferol Parathyroid hormone Calcitonoin Parathyroid hormone related protein { PTHrP} Miscellaneous hormones : Glucocorticoids, Growth hormone, Estrogen CALCIUM & PHOSPHATE METABOLISM NORMAL VALUES Total body calcium – 1100 g {27.5 mol / L} 99 % in bones Plasma calcium : 9 – 11 mg / dL {5 m Eq / L or 2.5 mmol / L} Ionized calcium – 50 % {1.2 mmol / L} Protein bound – 41 % {1.0 mmol / L} Complexed with anions – 9 % {0.2 mmol / L} FUNCTIONS OF CALCIUM FREE IONIZED CALCIUM Blood coagulation Muscle contraction Transmission of nerve impulses Formation of skeleton ,etc. Calcium • Regulate neuromuscular excitability • Blood coagulation • Secretory processes • Membrane integrity • Plasma membrane transport • Enzyme reactions • Release of hormones and neurotransmitters • Bone mineralization Calcium Homeostasis EFFECTS OF ALTERED CALCIUM HYPOCALCEMIA • Nerve and muscle cells becomes hyperexcitable. increased neuronal membrane permeability to Na + channels HYPOCALCEMIC TETANY – latent or manifest Calcium at 6 mg / dL --- TETANY at 4 mg / dL --- LETHAL Alkaline pH – tetany at higher values. SIGNS OF MANIFEST TETANY CARPOPEDAL SPAM • Laryngeal stridor • Convulsions • Visceral features like intestinal spasm, bronchospasm and profuse sweating. Obstetric hand / Main d’ acconcheur hand LATENT TETANY • CHVOSTEK’S SIGN • TROUSSEAU’S SIGN HYPERCALCEMIA CALCIUM LEVEL > 12 mg / dL • Nervous system is depressed • Reflex activities are sluggish • Decreased QT interval • Lack of appetite CALCIUM IN BONE Two types 1. Readily exchangeable reservoir {500 mmol of Ca2+ is exchanged} 2. Stable calcium {7.5 mmol of Ca2+ is exchanged} CALCIUM IN KIDNEYS • 98 % - 99 % is reabsorbed 60 % in PCT 40 % in Ascending limb of LOH Distal tubule PARATHYROID HORMONE CALCIUM IN GIT • 30 – 80 % of ingested calcium is absorbed • Actively transported out of the intestinal cells with the help of Ca 2+ dependent ATPase 1,25 Vitamin D3 • Increased plasma calcium – decreased absorption from the gut • Decreased by phosphates and oxalates and alkalis • Increased by high protein diet DIET 25mmol (1000 mg) BONE RAPID EXCHANGE ABSORPTION GIT 15 mmol SECRETION 500 mmol ECF 35 mmol REABSORPTION 12.5 mmol 7.5 mmol FECES 22.5mmol EXCHANGEABLE 100 mmol REABSORPTION 247.5 mmol GLOMERULAR FILTRATE 250 mmol URINE 2.5 mmol STABLE 27,200 mmol PHOSPHATE METABOLISM NORMAL VALUES • Total body phosphate – 500 to 800 g. • 85 – 90 % in skeleton • Plasma phosphate – 12 mg / dL 2/3rd – organic 1/3rd – inorganic {Pi} ex. PO43- , HPO42-, H2PO42- FUNCTIONS ATPase , c AMP , 2-3, DPG Phosphorylation and Dephosphorylation BONE: 3 mg of PO4 enters and is again reabsorbed. KIDNEYS: 85 % - 90 % of filtered Pi is reabsorbed by Active Transport in PCT Overflow mechanism PTH GIT • Absorbed in duodenum and small intestine by Active transport and passive diffusion. • Absorption is linear to dietary intake. • All PO4 excreted in urine. VITAMIN D 3 FORMATION OF VITAMIN D3 7 DEHYDROCHOLESTEROL SUNLIGHT PREVITAMIN D3 VITAMIN D3 CHOLECACIFEEROL 25 HYDROXYLASE LIVER 25- HYDROXY CHOLECALCIFEROL 24 α HYDROXYLASE 1 α HYDROXYLASE KIDNEY 24, 25 DIHYDROXY CHOLECALCIFEROL 1, 25 DIHYDROXY CHOLECALCIFEROL MECHANISM OF ACTION • 1,25 – dihydroxycholecalciferol is a steroid compound (secosteroid) • Acts via the steroid receptor superfamily • Exposes the DNA – binding domain and results in increased transcription of some mRNAs. ACTIONS OF VITAMIN D3 1. Promotes intestinal calcium absorption BY 1. Formation of calcium binding protein (calbindin) 2. Formation of calcium stimulated ATPase 3. Formation of alkaline phosphatase 25-HYDROXYLASE 2. Promotes phosphate absorption by the intestines • As a direct effect • Calcium acts as a transport mediator for phosphate. 3. Decreases renal excretion of calcium & phosphate • Increases reabsorption of Ca and PO4 by the renal tubules 4. Increases both bone resorption and bone mineralization BONE RESORPTION – by stimulating PTH. Calcitriol receptors are present in osteobasts Receptor – calcitriol complex – stimulate osteoblasts --- activation & differentiation of osteoclasts. BONE MINERALIZATION – by stimulation osteoblasts and alkaline phosphatase secretion REGULATION OF SYNTHESIS PTH 25 –OH D3 24,25- (OH)2 D3 Ca 1,25 (OH)2 D3 BONE & INTESTINES PO4 RICKETS & OSTEOMALACIA VITAMIN D deficiency in children and adults - defective bone mineralization and calcification - failure to deliver adequate Ca and PO4 FEATURES: Weakness and bowing of weight bearing bones, dental defects and hypocalcemia. Responsive to Vitamin D therapy. VITAMIN D RESISTANT RICKETS: mutations in the gene coding for the enzyme 1 α HYDROXYLASE Rickety rosary STRUCTURE • FOUR parathyroid glands located behind the thyroid gland • 6 x 3 x 2 mm • Two types of cells 1. Chief cells 2. Oxyphil cells CHEMISTRY Pre pro PTH ( 115 aa) Pro PTH ( 90 aa ) PTH ( 84 aa ) Normal plasma PTH 10 -55 pg / mL Half life – 10 mins ACTIONS OF PTH I. Increases calcium and phosphate absorption from the bones II. Decreases excretion of calcium by the kidneys III. Increases the excretion of phosphate by the kidneys IV. Increases intestinal absorption of calcium and phosphate. INCREASED PLASMA CALCIUM Hyperfunction (Recklinghausen’s disease) - Hypercalciemia - hypophosphatemia hyperphosphaturia osteoporosis Accumulation of Са in tissues Hypofunction - hypocalciemia hyperphosphatemia hypophosphaturia tetanus Hyperparathyroidism: adenoma or hyperplasia or ectopic Hypocalcemia DISORDERS OF PTH • HYPOPARATHYROIDISM • HYPERPARATHYROIDISM primary and secondary • PSEUDOHYPOPARATHYROIDISM HYPOPARATHYROIDISM • • • • Body calcium level decreases Osteoclasts are inactive Sudden removal – signs of tetany appears Responds to treatment with PTH or Vitamin D3 PSEUDOHYPOPARATHYROIDISM PTH is normal Defect is in PTH receptors Not responsive to hormone therapy PRIMARY HYPERPARATHYROIDISM • Tumors – adenoma of parathyroid glands • More common in women. • Extreme osteolytic resorption calcium and phosphate levels. Bone : Punched out cystic areas in the bone filled by osteoclasts – osteoclast tumors ‘ osteitis fibrosa cystica’ Serum Alkaline phosphatase is elevated. Hypercalcemia: P. Calcium – 12 – 15 mg / dL CNS depression, muscle weakness, constipation, abdominal pain, peptic ulcer, lack of appetite etc… Metastatic calcification: CaHPO4 crystals are deposited in renal tubules, lung alveoli, thyroid glands etc… Renal stones: Calcium phosphate and also calcium oxalate stones SECONDARY HYPERPARATHYROIDISM • Increased levels of PTH is the result of compensatory mechanism to hypocalcemia • Due to chronic renal disease or deficiency of Vitamin D 3 • Produced by the parafollicular cells / C cells of thyroid gland. • Remnants of ultimobrachial body. STRUCTURE: Molecular weight – 3500 and has 32 aminoacids. In brain “Calcitonin gene related polypeptide ( CGrP)” is formed. Calcitonin - Is synthesized by parafollicular cells of thyroid gland -Affects the metabolism of Са and Р -Promotes the transferring of Са2+ from blood into bones -Inhibits reabsorption of Р in kidneys (decreases the content of Р in blood due to its excretion with urine) Increase of calcitonin - hypocalciemia - hypophosphatemia - hyperphosphaturia Decrease of calcitonin - hypercalciemia - hyperphosphatemia - hypophosphaturia • STIMULUS : Increased plasma calcium Others: β adrenergic agonists, dopamine and estrogen, GASTRIN, CCK, glucagon.. • ACTIONS: Decreases absorptive action of osteoclasts Deposits exchangeable Ca in bone salts Decreases the formation of osteoclasts • CLINICAL USE: Used in the treatment of PAGET’S DISEASE. OSTEOPOROSIS Diminished bone matrix due to poor oeteoblastic activity Causes: 1. Lack of physical stress 2. Malnutrition 3. Postmenopausal lack of estrogen 4. Old age 5. Lack of Vitamin C 6. Cushing’s syndrome OTHER HORMONES PARATHYROID HORMONE RELATED PROTEIN ( PTHrP) • Produced by different tissues of our body • Binds to PTH receptors • Marked effect on growth and development of cartilage in utero. • Cartilage growth is stimulated by a protein called “Indian hedgehog” • Other uses : Brain – prevents excitotoxic damage Placenta – transports calcium • Defect in PTHrP – severe skeletal deformities. GLUCOCORTICOIDS Lowers plasma calcium by inhibiting osteoclasts. Over Long periods – osteoporosis Inhibit protein synthesis in osteoblasts,thereby synthesis of organic matrix Inhibit absorption of Ca and Po4 from the gut and facilitate its excretion in the kidneys. GROWTH HORMONE Increases intestinal absorption of Calcium “Positive calcium balance” IGF – I Stimulates protein synthesis in bone. THYROID HORMONE Hypercalcemia, Hypercalciuria and Osteoporosis. ESTROGENS Prevents osteoporosis by inhibiting certain cytokines INSULIN Increases bone formation