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Endo 1.16 Endocrine control of calcium and phosphate metabolism • Calcium and phosphate in the body • Endocrine control of calcium and phosphate • Causes of hyper- and hypocalcaemia • Hyperparathyroidism • Vitamin D deficiency • Endocrine control of bone turnover osteoporosis and osteomalacia Functions of Calcium • • • • • • • Bone growth and remodelling Secretion Muscle contraction Blood clotting Co-enzyme Stabilization of membrane potentials Second messenger/stimulus response coupling Distribution of calcium in the body Skeleton - 99% Intracellular - 1% Extracellular - 0.1% Ionized 45% Ca2+ 2.2-2.6 mmol/l Bound to Plasma proteins 45% PTH, Vit D Ions e.g. Phosphate, lactate, HCO3- 10% Functions of phosphate [ H2PO4- and HPO42-] • Element in: High energy compounds e.g. ATP Second messengers e.g. cAMP • Constituent of: DNA/RNA, phospholipid membranes, bone • Intracellular anion • Phosphorylation (activation) of enzymes Distribution of phosphate Skeleton - 90% Intracellular - 5% Extracellular - <0.03% 50% free 0.8-1.2 mmol/l 50% bound Controlled by kidneys + effects of PTH Daily turnover of calcium and phosphate based on an intake of 1000mg/day Ca2+ 1 Pi PTH, Vitamin D Ca2+ Ca2+ .B Bound and free in equilibrium Reduced plasma proteins and alkalosis Acidosis Ca2+ Ca2+ Bone - an important store of calcium, phosphate and other ions Osteolysis - calcium is taken up from the extracellular fluid into the osteocytes and transported to the bone surface Bone remodelling Control of calcium and phosphate PTH and vitamin D increase Ca2+ and decrease Pi Calcitonin decreases Ca2+ Parathyroid glands • 4 glands on upper and lower poles of each lobe of the thyroid gland • Supernumerary glands not uncommon (source of PTH excess?) • 30-50 mg weight • Chief cells and oxyphill cells • Supplied by blood from thyroid arteries (thyroid surgery) Synthesis of parathyroid hormone 84 a.a. protein Sensing circulating calcium concentrations and control of PTH secretion Functions of PTH BONE • Stimulates osteolytic osteolysis • Stimulates bone resorption KIDNEY • Increases Ca2+ reabsorption, decreases phosphate, HCO3- and Na+ reabsorption • Increases 1a-hydroxylase enzyme (25, OH-D 1,25 OH-D) ? Hyperparathyroidism hypercalcaemia CLINICAL MANIFESTATIONS OF HYPERCALCAEMIA • Neurological - lethargy, confusion, loss of • • • • • appetite Psychiatric - depression, hallucination GI - vomiting, constipation, anorexia Renal - nephrogenic diabetes insipidus Cardiovascular - increased contractility, shortened ventricular systole Rheumatological - joint and bone pains Bone erosion hyperparathyroidism BIOCHEMICAL ANALYSIS OF HYPERPARATHYROIDISM • SERUM MEASUREMENTS High PTH, calcium, alkaline phosphatase Decreased phosphate, decreased bicarbonate hyperchloraemic acidosis • URINE MEASUREMENTS Increased calcium, phosphate and cAMP Major causes of hypercalcaemia • 1o Hyperparathyroidism • Malignancy (PTHrp) Some other causes: • Vitamin D related e.g. excess; • sarcoidosis, tuberculosis and other granulomatous diseases, excess intake • High bone turnover e.g. hyperthyroidism, immobilization • Renal failure Parathyroid hormone related peptide (PTHrp) • 3 splice variants from a single gene • synthesized in various tissues • discovered in patients with cancers of squamous cell origin Does not stimulated renal conversion of 25hydroxycholecalciferol Unlike PTH Synthesis of active vitamin D One hydroxylation in liver - C25 Second hydroxylation in kidney - C1 Vitamin D receptors Actions of Vitamin D in Calcium homeostasis • Increases Ca2+ absorption in the gut Calcium absorbed by: active uptake/extrusion endocytosis/exocytosis trans-cellular route All require CaBP’s - synthesis stimulated by Vitamin D • Synergises with PTH on bone • Inhibits PTH synthesis • Inhibits 1a-hydroxylase Absorption of calcium from the gut Other actions of vitamin D • Stimulates differentiation of monocytes to macrophages • Inhibits proliferation of T and B lymphocytes • Anti-proliferative action on skin cells (psoriasis?) • Anti-proliferative action on certain tumours • Increases production of 17b hydroxysteroid dehydrogenase (oestradiol --> oestrone) • Stimulates hair growth (alopecia?) Causes of Vitamin D deficiency Pseudo • Liver/kidney disease (synthesis) • Resistance to hormone (receptor) (Rickets) • Mal-absorption • Dietary insufficiency • Poor exposure to sunlight Typical signs and symptoms of Vitamin D deficiency • Aches and pains in bones • Proximal myopathy • Mild hypocalcaemia - 2o hyperparathyroidism • Hypophosphataemia and hyperchloraemic acidosis • Bone deformities - osteomalacia Pseudohypoparathyroidism • 1942 - Fuller Albright - hypocalcaemic and hyperphosphataemic: PTH resistance • Defect in stimulatory G protein (Type 1a) • Albright’s Hereditary Osteodystrophy (AHO) short stature, short neck and fingers, obesity • Other types not associated with abnormal Gs Receptor/signal transduction defects? Some causes and treatment of hypocalcaemia Causes • Vitamin D deficiency (2o hyperprathyroidism) • Hypoparathyroidism (thyroid surgery) • Pseudohypoparathyroidism • Neonatal • Activating mutation of Ca2+ receptor Treatment • Vitamin D - oral (injectable): cheap • Calcium - acutely PTH (recombinant): expensive - osteoporosis? Osteoporosis - loss of bone mass Osteomalacia - loss of bone mineralization Bone remodelling and the action of vitamin D and PTH Vit D PTH Vit D PTH Osteoporosis - low bone mass and microarchitectural deterioration of bone tissue • Endocrine: hypogonadism, glucocorticoid excess, hyperthyroidism • Haematopoietic disease: e.g. leukaemia, sickle cell disease • Connective tissue disease: • Drug induced: e.g. heparin, anticonvulsants • Renal disease • Nutritional: eg malabsorption Bone density and age