CALCIUM BALANCE. James T. McCarthy & Rajiv Kumar

Transcription

1 CALCIUM BALANCE James T. McCarthy & Rajiv Kumar

2 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 , Ionized Ca Complexed to anions Bound to plasma protein (albumin)

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

4 CALCIUM BALANCE

5 CALCIUM ABSORPTION FROM GI TRACT % 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

6 CALCIUM ABSORPTION FROM GI TRACT

7 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

8 RENAL CALCIUM EXCRETION 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

9 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

10 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

11 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

12 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

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

14 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 )

15 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

16 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

17 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

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19 James T. McCarthy & Rajiv Kumar

20 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

21 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

22 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

23 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)

24 PTH-Related Peptide

25 James T. McCarthy & Rajiv Kumar

26 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

27 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

28 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

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30 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 ( 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

31 Moshe Levi & Mordecai Popovtzer

32 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

33 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

34 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

35 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

36 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

37 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

38 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