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 Blood coagulation Muscle contraction Transmission of nerve impulses Formation of skeleton,etc. FREE IONIZED CALCIUM

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 Obstetric hand / Main d’ acconcheur hand Laryngeal stridor Convulsions Visceral features like intestinal spasm, bronchospasm and profuse sweating.

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 Ca 2+ is exchanged} 2. Stable calcium {7.5 mmol of Ca 2+ 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 Increased plasma calcium – decreased absorption from the gut Decreased by phosphates and oxalates and alkalis Increased by high protein diet 1,25 Vitamin D 3

GLOMERULAR FILTRATE 250 mmol DIET 25mmol (1000 mg) GIT FECES 22.5mmol ABSORPTION 15 mmol SECRETION 12.5 mmol REABSORPTION mmol ECF 35 mmol URINE 2.5 mmol BONE EXCHANGEABLE 100 mmol STABLE 27,200 mmol RAPID EXCHANGE 500 mmol REABSORPTION 7.5 mmol

PHOSPHATE METABOLISM

NORMAL VALUES Total body phosphate – 500 to 800 g. 85 – 90 % in skeleton Plasma phosphate – 12 mg / dL 2/3 rd – organic 1/3 rd – inorganic {Pi} ex. PO 4 3-, HPO 4 2-, H 2 PO 4 2- FUNCTIONS ATPase, c AMP, 2-3, DPG Phosphorylation and Dephosphorylation

BONE: 3 mg of PO 4 enters and is again reabsorbed. KIDNEYS: 85 % - 90 % of filtered Pi is reabsorbed by Active Transport in PCT PTH Overflow mechanism

G I T Absorbed in duodenum and small intestine by Active transport and passive diffusion. Absorption is linear to dietary intake. All PO 4 excreted in urine.

VITAMIN D 3

FORMATION OF VITAMIN D 3

7 DEHYDROCHOLESTEROL PREVITAMIN D3 VITAMIN D3 CHOLECACIFEEROL 25- HYDROXY CHOLECALCIFEROL 25 HYDROXYLASE LIVER 24, 25 DIHYDROXY CHOLECALCIFEROL 1, 25 DIHYDROXY CHOLECALCIFEROL KIDNEY 1 α HYDROXYLASE 24 α HYDROXYLASE SUNLIGHT

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 D 3 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 PO 4 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 25 –OH D 3 1,25 (OH) 2 D3 BONE & INTESTINES Ca PO 4 PTH 24,25- (OH) 2 D3

RICKETS & OSTEOMALACIA VITAMIN D deficiency in children and adults - defective bone mineralization and calcification - failure to deliver adequate Ca and PO 4 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 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 D 3 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: CaHPO 4 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 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 Po 4 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