CALCIUM BALANCE. James T. McCarthy & Rajiv Kumar

CALCIUM BALANCE James T. McCarthy & Rajiv Kumar

CALCIUM BALANCE TOTAL BODY CALCIUM (~ 1000g in a normal 60 kg adult) - > 99% in bones - ~ 0.6% in the intracellular space - ~ 0.1% in the extracellular space mg/dl meq/l mmol/l TOTAL 9 10 4.5 5,0 2.25 2.5 Ionized Ca 4.2 5.0 2.2 2.5 1.1 1.25 Complexed to anions 0.9 1.0 0.45 0.5 0.22 0.25 Bound to plasma protein (albumin) 3.6 4.0 1.8 2.0 0.9 1.0

CHANGES WITHIN PLASMA CALCIUM FRACTIONS 1. Decrease of albumin conc. by 1g/dL => decrease of total Calcium by 0.35 0.5 meq/l (0.7 1 mg/dl) 2. Alkaline ph=> ionized Ca ++ is bound to HCO 3 and Albumin => reduced ionized Ca ++ 3. Hyponatremia increases Ca ++ binding to albumin; hypernatremia has opposite effect

CALCIUM BALANCE

CALCIUM ABSORPTION FROM GI TRACT 1. 20-40% of normal Calcium intake is absorbed 2. Most of absorption occurs in the duodenum, jejunum, ileum 3. Mechanisms: - passive and facilitated diffusion (50-70%) - active transport ( about 30%) 4. Daily intestinal Calcium secretion: about 200 meq/day 5. Calcium absorption is completed within about 4hours after intake 6. Dietary Calcium intake < 400 mg/day => Calcium deficit 7. Calcium absorption decreases with age

CALCIUM ABSORPTION FROM GI TRACT

7-dehydrocholesterol SKIN Vitamin D3 25-hydroxy-Vitamin D3 LIVER 1,25-hydroxy-Vitamin D3 24,25-hydroxy-Vitamin D3 KIDNEY -PTH -Hypocalcemia -Hypophosphatemia -Hypercalcemia -Hyperphosphatemia

RENAL CALCIUM EXCRETION 25 750 meq/day Filtrable calcium ( ionized + complexed) 97-98% of the filtered calcium is absorbed about 65% in proximal tubules about 15-25% in the thick ascending loop of Henle about 5 15% in the distal convoluted tubule

RENAL CALCIUM REABSORPTION PROXIMAL TUBULES Passive transport (depends on ECF volume) - following sodium & water absorption - following chloride reabsorption Active transport (small amount) - calcium enters the cell via calcium channel - transport depends on concentration gradient - calcium leaves the cell - 3Na + /Ca ++ antiport - Ca ++ ATPase

RENAL CALCIUM REABSORPTION THICK ASCENDING LOOP OF HENLE - paracellular reabsorption - depends on lumen-positive potential difference - reabsorption proportional to sodium transport - stimulated by PTH - blocked by loop diuretics DISTAL CONVOLUTED TUBULE - transcellular transport - calcium enters the cells due to concentration gradient - calcium leaves the cells via 3Na + /Ca ++ antiport - reabsorption inversely proportional to sodium transport - stimulated by thiazide diuretics - stimulated by PTH - stimulated by vitamin D3

CALCIUM SENSING RECEPTORS Parathyroid gland: high Ca ++ => low PTH release Thyroid gland: high Ca ++ => high calcitonin release Proximal tubules: high Ca ++ => inhibition of 1α-hydroxylase Proximal tubules: high Ca ++ => blocks PTH effect on phosphate reabsorption Proximal tubules: high Ca ++ => inhibition of Na-K-ATPase Thick ascending loop of Henle: high Ca ++ => inhibits Na-K-2Cl transport

CALCIUM SENSING RECEPTORS PATHOLOGY 1. Loss of function mutation-> Familial Hypocalciuric Hypercalcemia - autosomal dominant syndrome - hyperparathyroidism - hypercalcemia - low urinary calcium excretion 2. Gain of function mutation - autosomal dominant - hypocalcemia - hypoparathyroidism - high urinary calcium excretion - nephrocalcinosis - nephrolithiasis - progressive renal failure Calcimimetics agents increaseing sensitivity of calcium-sensing receptors Calcilytics agents inactivating calcium-sensing receptors

HYPOCALCEMIA TOTAL CALCIUM < 4.25 meq/l 1. Impaired calcium absorption 2. Increased calcium sequestration 3. Decreased PTH secretion 4. Decreased PTH action

IMPAIRED CALCIUM ABSORPTION Aging (ie. decreased number of receptors for vitamin D 3 ) Malabsorption - intestinal pathology (celiac disease,resection of intestines) - unabsorbed fatty acids => Fatty acids Calcium salts - lack of vitamin D 3 - hyperthyroidism => increased calcium release from bones => hypercalcemia=> low PTH => low vit D 3 - Anticonvulsant drugs (lack of vit.d hydroxylation in liver) - Glucocorticoids - Mg deficiency (impaired PTH secretion, intestinal resistance to vit.d 3 )

INCREASED CALCIUM SEQUESTRATION Hyperphosphatemia - when Ca x Phosphate conc. (mg/dl) product > 60 => deposition of calcium salts Calcium chelation (citrates) Soft tissue deposition - fat tissue necrosis =>precipitation of Calcium salts (acute pancreatitis) Bone deposition - hungry bone syndrome rebuilding of bones after normalization of hyperparathyroidism - osteoblastic metastases of prostate, lung cancer

DECREASED PTH SECRETION/OR ACTION 1. Resistance to PTH action - vitamin D deficiency: impaired absorption, hydroxylation in the liver (anticonvulsant dugs),hydroxylation in kidneys (renal failure, Fanconi syndrome) 2. Magnesium deficiency => impaired PTH release and action on bones 3. Pseudohypoparathyroidism ( abnormal function of PTH receptors) 4. Removal of parathyroid gland

HYPOCALCEMIA - SYMPTOMS 1. Neuromuscular - enhances neuromuscular excitability - paresthesias - hyperreflexia 2. Cardiovascular - arrhytmias - atrial fibrillation - prolonged QT interval - hypotension 3. Bones - fractures - deformations - pain 4. Connective tissue - dry skin, coarse - hair loss - brittle nails - cataract - dental abnormalities

James T. McCarthy & Rajiv Kumar

HYPOCALCEMIA Calcium Phos Vit D 3 PTH phates Hypoparathyroidism LOW HIGH LOW LOW Pseudohypoparathyroidism LOW HIGH LOW HIGH Vitamin D 3 deficiency LOW LOW LOW HIGH Resistance to LOW LOW HIGH HIGH vitamin D 3 Renal Failure LOW HIGH LOW HIGH

HYPOCALCEMIA? Serum phosphate <3.5mg/dL >3.5 mg/dl? Renal function Decreased Normal CRF Low? PTH Normal/High Low? Magnesium Normal Pseudohypoparathyroidism Hypoparathyroidism due to hypomagnesemia Primary Hypoparathyroidism Secondary hypoparathyroidism

HYPOCALCEMIA? Serum phosphate <3.5mg/dL >3.5 mg/dl? FECa High Normal Renal loss? 1,25(OH) 2 D 3 Low High Vitamin D-Dependent Rickets Type I VitaminD-Dependent Rickets Type II

HYPERCALCEMIA TOTAL Calcium > 5.25 meq/l 1. Primary increase in calcium absorption - vitamin D intoxication - granulomatous diseases (ie. Sarcoidosis, tuberculosis) 2. Increased Ca mobilization from bones A. Primary Hyperparathyroidism - parathyroid gland adenoma (80%) - hyperplasia of four glands - parathyroid carcinoma (1%) B. Non-PTH mediated hypercalcemia - hyperthyroidism => stimulation of osteoclasts - release of PTH-related peptide from tumor cells (squamous and oat cell bronchogenic carcinoma, breast cancer, multiple myeloma)

PTH-Related Peptide

James T. McCarthy & Rajiv Kumar

HYPERCALCEMIA Calcium Phos Vit D 3 PTH phates HYPERPARATHYROIDISM HIGH LOW HIGH HIGH PTH-related peptide HIGH LOW NORMAL /LOW LOW Vitamin D 3 excess HIGH HIGH HIGH LOW

HYPERCALCEMIA PTH-Mediated Non-PTH-Mediated Phosphate Low Low/Normal/High Chloride High Normal Metabolic Acidosis Mild Not present Chloride/ >33 <33 Phosphate PTH High Low

HYPERCALCEMIA - SYMPTOMS 1. Neuromuscular - diminished deep tendon reflexes - muscle weakness - depression, lethargy 2. Cardiovascular - positive inotropic effect - hypertension - arrhytmias - shortenning of the QT interval 3. Gastrointestinal - peptic ulcer - pancreatitis 4. Renal - decreased sensitivity to ADH => nephrogenic diabetes insipidus - hypercalciuria => nephrolithiasis - tubulointerstitial nephropathy => distal RTA 5. Bones - hyperparathysoidism => osteitis fibrosa cystica - anemia

PHOSPHATE HOMEOSTASIS Phosphorous in the body (10g/1 kg bw) 85% in bones 14% in the intracellular space 1% in the extracellular space - organic 70% - inorganic 30% Plasma inorganic phosphorous (2.5 4.5 mg/dl) 85% free (HPO 4-2 /H 2 PO 4- = 4:1) 15% bound to albumin or complexed with calcium or magnesium Phosphorous distribution : ICF/ECF 1. pco2 Low pco2 => respiratory alkalosis=> activation of anaerobic glycolysis => phosphorous enters the cells 2. Glucose Glucose uptake into the cells=> activation of glycolysis => phosphorylated intermediates => phosphorous enters the cells

Moshe Levi & Mordecai Popovtzer

PHOSPHATE RENAL EXCRETION 1. About 80% of the filtered phosphorous is reabsorbed - 75% in proximal tubules - 5% in the thick ascending loop of Henle and distal convoluted tubules REGULATION OF PHOSPHATE REABSORPTION STIMULATION Phosphate depletion INHIBITION Phosphate loading Vitamin D 3 Volume contraction Growth hormone Insulin Thyroid hormones PTH and PTH-related peptide Volume expansion Hypercalcemia Hypercapnia Phosphatonins (Fibroblast Growth Factor 23,Fibroblast Growth Factor 7

PHOSPHATONINS - peptides causing phosphaturia - Fibroblast Growth Factor-23 (FGF-23) - secreted Frizzeld Related Protein-4 (sfrp-4) - Matrix Extracelular Phosphoglycoprotein - Fibfrobalst Growth factor-7 (FGF-7) - inhibit Na-Phosphate cotransport in renal epithelial cells - inhibit 1-α-hydroxylase - produced by mesenchymal tumor cells (Tumor Induced Osteomalacia) - produced in genetically determined rickets - X-linked hypophosphatemic rickets - Autosomal dominant hypophosphatemic rickets

High Serum Phosphate Low serum Ca ++ High serum PTH Increased Renal Phosphate excretion Low Renal Vit D3 synthesis Low Instestinal & Renal Phosphate absorption Normal Serum Phosphate

Low Serum Phosphate High serum Ca ++ Low serum PTH Decreased Renal Phosphate excretion High Renal Vit D3 synthesis High Instestinal & Renal Phosphate absorption Normal Serum Phosphate

HYPOPHOSPHATEMIA 1. Internal redistribution - increased insulin - refeeding - respiratory alkalosis - hungry bone syndrome 2. Decreased intestinal absorption - inadequate intake (vitamin D 3 deficiency) - antiacids containing aluminium or magnesium - diarrhea 3. Increased urinary excretion - hyperparathyroidism - vitamin D3 deficiency - Fanconi syndrome - volume expansion - proximal diuretics/osmotic diuresis

HYPOPHOSPHATEMIA SYSTEMIC DISORDERS 1. Central Nervous System - irritability, paresthesias,confusion, coma 2. Cardiovascular System - impaired cardiac contractility 3. Skeletal & Smooth Muscles - myopathy, decreased contractility, rhabdomyolysis 4. Blood - hemolysis, impaired leukocytes phagocytosis and chemotaxis, thrombocytopenia, defective clot retraction 5. Bone - increased bone resorption, rickets, osteomalacia 6. Kidney - decreased GFR, decreased bicarbonates reabsorption, hypercalciuria

HYPERPHOSPHATEMIA 1. Increased phsophorous absorption - phosphorous rich diet - vitamin D 3 intoxication 2. Increased endogenous load - cells necrosis - acidosis 3. Reduced urinary excretion - renal failure - hypoparathyroidism Hyperphosphatemia => low ionized Ca => high PTH and vitamin D 3 - neuromuscular irritability - tetany - hypotension - precipitation of Calcium-Phosphate => vascular calcification, conduction abnormalieties, pruritus