Disorders of Calcium, Phosphate, and Magnesium Metabolism PDF

DISORDERS OF CALCIUM, PHOSPHATE AND MAGNESIUM METABOLISM 1 Calcium there are about 1200g of calcium in the body of an adult the largest part is found in bones (99%) in the form of hydroxyapatite The normal concentration of calcium in the plasma is from 2.14 t...

DISORDERS OF CALCIUM, PHOSPHATE AND MAGNESIUM METABOLISM 1 Calcium there are about 1200g of calcium in the body of an adult the largest part is found in bones (99%) in the form of hydroxyapatite The normal concentration of calcium in the plasma is from 2.14 to 2.53 mmol/l Calcium is found in plasma in two forms: - free or ionized form 1.13-1.30 mmol/l - unionized form - bound to inorganic anions, citrates, bicarbonates, phosphates... - bound to proteins Only ionized, free calcium is biologically active. 2 Calcium Calcium The amount of total calcium in the plasma is affected by: protein concentration concentration of free fatty acids anion concentration pH of blood 4 Calcium Protein concentration: calcium intake is reduced in hypoproteinemias and increased in hyperproteinemias the concentration of biologically active ionized calcium is unchanged 5 Calcium Concentration of free fatty acids: increased concentration of free fatty acids (acute pancreatitis, diabetic ketoacidosis, sepsis), causes increased binding of ionized calcium to serum proteins the result is hypocalcemia 6 Calcium Anion concentration: infusion of citrate (anticoagulant), phosphate, and bicarbonate does not change the total amount or concentration of calcium but reduces the amount of ionized calcium 7 Calcium pH : alkalosis reduces the concentration of ionized calcium acydosis increases the concentration of ionized calcium there is constant competition between hydrogen ions and calcium ions for binding sites on proteins 8 Roles of calcium in the body bone formation and teeth neuromuscular excitability muscular contraction hearty rhythm blood coagulation secretion of hormones Liberation of neurotransmitters cofactor in enzymes intracellular secondary messenger 9 Phosphates the total amount of phosphate in the body is from 15 to 20 mmol/l mostly found in bones (hydroxyapatite) and intracellular phosphates (creatine phosphate, ATP, nucleic acids, and phosphoproteins) e extracellular phosphates (phospholipids, phosphate esters, and inorganic phosphate compounds) the normal concentration of phosphorus in the serum is from 0.9 to 1.6 mmol/l 10 The role of phosphate building and teeth production of high energy compounds synthesis of RNA and DNA Synthesis of coenzyme Synthesis of phosphoproteins and phospholipids Activation of enzymes by the process of phosphorylation maintenance of acid-base balance transport of oxygen to tissues (2.3 DPG) 11 Control of calcium and phosphate metabolism The metabolism of calcium and phosphate is closely related to metabolism of skeletal system kidney function and function of the gastrointestinal tract 12 Control of calcium and phosphate metabolism Neurohumoral regulation: parathyroid hormone (parathormone) an active form of vitamin D (calcitriol) calcitonin 13 Control of calcium and phosphate metabolism The concentration of calcium and phosphate in the serum is maintained in a very small range, and the product of their concentration is constant : [Ca] x [HPO4] = const. the calcium level is regulated by controlling the absorption of calcium from the gastrointestinal tract and by controlling the redistribution of calcium between the bone system and the extracellular fluid The level of phosphate in the serum is mainly regulated by the control of phosphate excretion through the kidneys 14 Parathormone synthesized and secreted by the parathyroid glands in response to a reduced concentration of ionized calcium Parathormone achieves direct effects in the bone system and kidneys, and indirect effects by stimulating the synthesis of the active form of vitamin D. vitamin D increases the absorption of calcium in the gastrointestinal tract 15 Regulation of parathormone secretion Calcium receptors on the membrane of parathyroid cells detect changes in the concentration of calcium in the extracellular fluid. Receptors are G-protein coupled receptors: adenylate cyclase ( cAMP) phospholipase C ( inositol phosphate) with reduced concentration Ca 2+ : cAMP increases , IP3 decreases and is secreted PTH. 16 Regulation of parathormone secretion hypocalcemia hypercalcemia (  cAMP ↓IP3): (↓ cAMP  IP3 ): increased release PTH reduced release PTH 17 The mechanism of action of parathormone on bones PTH increases decomposition of bones (Liberation calcium and phosphates ): BONE KIDNEY  Release of cytokines from osteoblasts which stimulates activity of osteoclasts  stimulates stem cells in bones to mature into osteoclasts GIT URINE RESULT : increased calcium releaseand phosphate from bones The effect of PTH on bone depends on the presence of the vitamin D 18 The mechanism of action of parathormone on kidneys increases calcium reabsorption in the kidneys (reduces excretion). increases the excretion of phosphate , BONE KIDNEY and decreases the excretion of hydrogen PTH increases the production of the GIT active form of the vitamin D 3 in the URINE kidneys (absorption of calcium and phosphate in the intestines ) 19 The mechanism of action of parathormone in intestines stimulating the synthesis of the active form of vitamin D Vitamin D stimulates the absorption of BONE KIDNEY calcium and phosphate in intestines GIT URINE 20 The result of the action of the parathyroid hormones 1. increase in calcium concentration inblood 2. reduction of phosphate concentration in blood 21 Vitamin D belongs to the group of liposoluble vitamins and has a steroid structure and binds to nuclear receptors like hormones vitamin D is not even a classic "vitamin" because it can be produced de novo vitamin D has hormone properties because it acts on distant target cells and leads to a response after binding to high- affinity cell receptors vitamin D is not a classic hormone because it is not produced and secreted from the endocrine gland. 22 Vitamin D There are two sources of vitamins D: 1. it is produced in the skin under the influence of UV 2. it is entered through food Two shapes: ergocalciferol (vitamin D2 ) - it is created from ergosterol in plants, it is found in supplements cholecalciferol (vitamin D3) - is found in meat, fish oil and is created in the skin under the influence of UV radiation Ergocalciferol and cholecalciferol - provitamins D 23 Vitamin D vitamin D is inactive, and requires modification to an active metabolite 1,25-( OH ) 2 -D. the first hydroxylation is in the liver and occurs 25-( OH ) -D. 25- ( OH ) - D is transported to kidneys where subject to the second hydroxylation and is formed: 1.25- ( OH ) 2 - D ( calcitriol ) - active form of vitamin D. 24 Vitamin D 25 Mechanism of action of vitamins D on bowels the main mechanism of action of 1,25- ( OH ) 2 -D is an increase absorption of calcium and phosphate from bowels in the intestinal epithelium, it increases the synthesis of transport proteins for calcium → increases calcium absorption 26 Jordy Borer et al. Nephrology 2015; 35 (1) 28-41 Mechanism of action of vitamins D on bones osteoblasts (but not osteoclasts) have receptors for the vitamin D 1,25- ( OH ) 2 - D stimulates the active transport of calcium from osteoblasts into the extracellular fluid ( resorption of calcium and phosphorus from bones ). in bone mineralization prevents demineralization through an inhibitory effect on the synthesis of parathormone 27 Jordy Borer et al. Nephrology 2015; 35 (1) 28-41 Mechanism of action of vitamins D on kidneys reabsorption of calcium and phosphate in the kidneys (reduced excretion) 28 Jordy Borer et al. Nephrology 2015; 35 (1) 28-41 The result of the action of vitamins D absorption of calcium and phosphate from intestines resorption of calcium and phosphate from bones reabsorption of calcium and phosphate in the kidneys (reduced excretion) The final result of the action of vitamin D : calcium ↑ phosphates ↑ 29 Calcitonin is secreted from the parafollicular cells of the thyroid gland Hypercalcemia has the most pronounced effect on the increased secretion of calcitonin, and on the decrease in secretion hypocalcemia the main metabolic effect of calcitonin consists of reducing the level of calcium in the serum 30 Mechanism of action of calcitonin the main place of action of calcitonin are bones and by inhibiting the reabsorption of bone tissue by osteoclasts, calcitonin reduces the level of calcium in the serum (opposite effect compared to parathormone and vitamin D ) calcitonin : reduces the absorption of calcium in the intestines 31 Calcitonin and parathormone 32 Summary: regulation calcium PTH ( most important): Ca 2+ ↑ Calcitonin (transient): Ca 2+ ↓ – increases resorption of bones – increases postponement calcium in – increases reabsorption in kidneys bones – increases absorption in intestines – reduces absorption in intestines (across vitamins D ) – reduces reabsorption of calcium in Vitamin D: Ca 2+ ↑ kidneys – increases absorption in intestines – increases renal reabsorption – increases resorption of bones 33  HYPERCALCIEMIA HYPOCALCEMIA REDUCED INCREASED INCREASED REDUCED CONCENTRATION OF CONCENTRATION OF CONCENTRATION OF CONCENTRATION OF PARATHORMONE CALCITONIN PARATHORMONE CALCITONIN with reduced activation of increased activation of vitamin D in the kidneys vitamin D in the kidneys - decreased intestinal absorption of calcium - increased intestinal absorption of calcium - with reduced renal calcium reabsorption and - increased renal calcium reabsorption and reduced phosphate excretion increased phosphate excretion - with reduced reabsorption of calcium from bones - increased reabsorption of calcium from bones 34 Disorders of calcium metabolism Disorders of serum calcium levels: hypocalcemia hypercalcemia Disorders of urinary calcium excretion: hypercalciuria hypocalciuria 35 Hypocalcemia Hypocalcemia is a condition in which the concentration - of total calcium in the serum is less than 2.14 mmol/l or - concentration of ionized calcium is less than 1.13 mmol/l At the same time, the phosphate concentration in the blood increased reciprocally [Ca] x [HPO 4 ] = const. 36 Etiology of hypocalcemia 1. Reduced intake or absorption of calcium malabsorption (inadequate diet with little calcium or excess phosphorus in the diet) with reduced vitamin D - lack of cholecalciferol - lack of 25-hydroxy-cholecalciferol - lack of 1,25-dihydroxy-cholecalciferol kidney disease - reduced synthesis of the active form of vitamin D and consequently decreased absorption of calcium from the intestines 37 Etiology of hypocalcemia 2. Decreased mobilization of calcium from bones (parathyroid hormone signal dysfunctions) parathyroid gland dysfunction - primary hypoparathyroidism (congenital or acquired) dysfunction of target tissues - pseudohypoparathyroidism and electrolyte imbalance - hypomagnesemia 38 Etiology of hypocalcemia 3. Increased urinary excretion renal insufficiency - retention of phosphate, which results in a decrease in calcium levels - decreased reabsorption of calcium in tubules hyperphosphatemia 39 Etiology of hypocalcemia 4. Increased binding to proteins increased pH - alkalosis reduces the concentration of ionized calcium - there is constant competition between hydrogen ions and ions of calcium for binding sites on proteins increased free fatty acids ( acute pancreatitis, diabetic ketoacidosis, sepsis): - causes increased binding of ionized calcium to serum proteins hyperproteinemia, hyperlipidemia 40 Etiology of hypocalcemia 5. Increased sequestration (deposition) of calcium in tissues increased deposition of calcium in soft tissues - in acute pancreatitis, released lipases cause the formation of large amounts of free fatty acids, which bind calcium and are deposited in tissues, quickly reducing the level of calcium in the serum increased deposition of calcium in the bones - osteoblastic metastases of malignant tumors - hyperphosphatemia - medullary carcinoma of the thyroid gland - removal of parathyroid adenoma in primary hyperparathyroidism 41 Pathophysiological consequences of hypocalcemia hypocalcemia lowers the threshold of the action potential and brings it closer to the resting membrane potential and thus increases neuromuscular excitability f factors affecting the manifestation of hypocalcemia Factor Enhanced effect Reduced effect blood alkalosis acidosis potassium level hyperkalemia hypokalemia 42  Clinical manifestations of hypocalcemia paresthesias in the hands and legs ventricular skeletal spasms muscles arrhythmias Hyperreflexia, osteomalacia tetany ( muscle spasms) bone pains, carpopedal spasm deformities, laryngeal spasm fractures spasms in abdomen hypotension hearty insufficiency 43 Hypocalcemia Hypercalcemia Hypercalcemia is a condition in which the concentration of: - total calcium in the serum is greater than 2.53 mmol/l or - concentration of ionized calcium is greater than 1.3 mmol/l Decreased the concentration of phosphate in the blood [Ca] x [HPO4] = const. 45 Etiology of hypercalcemia 1. Increased intestinal absorption hyperparathyroidism (adenoma, adenocarcinoma, hyperplasia) granulomatous diseases excessive intake of calcium (milk-alkali syndrome) hypervitaminosis D hypophosphatemia 46 Etiology of hypercalcemia 2. Increased resorption of bones hyperparathyroidism (↑ PTH) malignancies (osteolytic metastases, paraneoplastic syndromes, primary bone tumors and malignant blood diseases...) long-term immobilization of the extremities (secondary osteoporosis due to normal reabsorption but reduced bone formation) 47 Etiology of hypercalcemia 3. Endocrine diseases hyperthyroidism hyperthyroidism...conditions in which there are combined disorders: enhanced absorption of calcium from the gastrointestinal tract enhanced release of calcium from the bone system 48 Pathophysiological consequences of hypercalcemia reduced neuromuscular excitability - the threshold for the generation of an action potential increases and neuromuscular membranes become insensitive to depolarization strengthened contractility of the smooth muscle cells of blood vessels - caused by the direct effect of hypercalcemia on the muscle cells of blood vessels 49 Clinical consequences of hypercalcemia nervous system : hypertensive encephalopathy and ischemia muscles : fatigue of the skeletal muscles heart : arrhythmias , arterial hypertension gastrointestinal tract : anorexia, nausea, vomiting; hypercalcemia stimulates the release of gastrin, which causes hypersecretion of gastric juice body fluids and kidney function : reduced ability to concentrate urine leads to natriuresis and polyuria; dehydration soft tissue deposition 50 Disorders of urinary calcium excretion Hypercalciuria (increased calcium excretion) can develop through three mechanisms: increased absorption of calcium in the gastrointestinal tract (increased calcium intake, hypervitaminosis D , sarcoidosis) - ABSORPTIVE HYPERCALCIURIA by increased reabsorption of calcium from the bone system (primary hyperparathyroidism, treatment of hypercalcemia) - REABSORPTION CALCIURIA by increased filtration or reduced reabsorption of calcium in the kidneys (use of vasodilators, dysfunction of proximal tubules induced by heavy metal intoxication) - RENAL HYPERCLACIURIA Hypocalciuria (reduced calcium excretion) – chronic administration of thiazide diuretics, which increase calcium absorption in the distal tubules, causes permanent hypocalciuria. 51 Disorders of phosphate metabolism hypophosphatemia hyperphosphatemia 52 Hypophosphatemia Hypophosphatemia is a condition in which the serum concentration of inorganic phosphate is less than 0.9 mmol/l At the same time, the level of calcium in the blood increased reciprocally [Ca] x [HPO4] = const. 53 Etiology of hypophosphatemia 1. Decreased absorption of phosphate in the gastrointestinal tract 2. Increased renal phosphate excretion 3. Redistribution of phosphate between individual body spaces 54 Etiology of hypophosphatemia 1. Decreased absorption of phosphate in the gastrointestinal tract malabsorption defficiency of the active form of vitamin D chronic alcoholism lack of food intake and infiltrative diseases of the digestive system increased loss : vomiting, diarrhea, use of antacids with magnesium or aluminum 55 Etiology of hypophosphatemia 2. Increased renal phosphate excretion primary hyperparathyroidism hypovitaminosis D kidney disease the use of some medicine 56 Etiology of hypophosphatemia 3. Redistribution of phosphate between individual body places the transfer of phosphate from the extracellular space to the intracellular space occurs during: - respiratory alkalosis - and insulin infusions or - glucose (pulls phosphates into the cell) - and cell expansion - Treatment of acidosis 57 Pathophysiological consequences of hypophosphatemia 1. Reduced oxidative transport capacity in erythrocytes reduced 2,3- DPG, reduced oxygen release in tissues, hypoxia 2. Energetically disturbed metabolism reduced synthesis of ATP from ADP, reduced oxidative phosphorylation in mitochondria, reduced energy supply to cells 3. Disturbed bone mineralization system osteomalacia or rachitis 59 Hyperphosphatemia Hyperphosphatemia is a condition characterized by an increased concentration of inorganic phosphates in the serum (greater than 1.6 mmol/l ). At the same time, the concentration of calcium in the blood was reciprocally reduced [Ca] x [HPO4] = const. 60 Hyperphosphatemia Hyperphosphatemia can be caused by: increased influx of phosphate into the extracellular fluid (exogenous load) transfer of phosphate from intracellular to extracellular space (endogenous load) decreased renal phosphate excretion 61 Etiology of hyperphosphatemia 1. Increased intake and absorption (exogenous load) parenteral or oral intake of phosphate - ingestion of a large amount of milk - administration of phosphate-based drugs and laxatives - phosphate infusion - transfusion of old blood 62 Etiology of hyperphosphatemia 2. Transfer of phosphate from intracellular to extracellular space during massive cell destruction (endogenous load) : therapy with cytostatics crash syndrome hemolysis leukemia 63 Etiology of hyperphosphatemia 3. Decreased renal phosphate excretion reduced glomerular filtration (acute and chronic renal failure) hypoparathyroidism or pseudohypoparathyroidism (due to increased reabsorption in kidney tubules) 64 Pathophysiological consequences of hyperphosphatemia The occurrence of reciprocal hypocalcemia - many of the manifestations of hyperphosphatemia reflect hypocalcemia (paresthesias, tetany, hypotension, cardiac arrhythmias) deposition of phosphate salts in soft tissues 65 Magnesium the largest amount is localized in the intracellular space (about 99%): bones (60%), muscles (35%), CNS, kidneys and liver. only 1% of the total amount of magnesium is found in the extracellular space the normal concentration of magnesium in serum is from 0.65 to 1.05 mmol/l (66% in ionized form ) 66 The roles of magnesium The main roles of magnesium are: metabolic role (metabolism of carbohydrates, proteins and nucleic acids) in maintaining neuromuscular excitability (effect of magnesium on nerve conduction, activation of calcium channels, effect on ion pumps and muscle contraction) factor in numerous enzymatic reactions Calcium and magnesium at the cellular level often exhibit synergistic effects 67 Control of magnesium metabolism The amount of magnesium is regulated by: by controlling the absorption of magnesium from the gastrointestinal tract (vitamin D increases the absorption of magnesium in the small intestine) and control of magnesium excretion through the kidneys (unclear neuroendocrine regulation) on the release of magnesium from the bones (when the concentration of magnesium in the blood decreases) 68 Hypomagnesemia A condition in which the serum concentration of magnesium is less than 0.65 mmol/l 69 Etiology of hypomagnesemia 1. Nutrition and absorption disorders 2. Increased renal excretion of magnesium 3. Endocrine-metabolic disorders 70 Etiology of hypomagnesemia 1. Nutrition and absorption disorders malnutrition and malabsorption vomiting , diarrhea nasogastric suction pancreatic insufficiency with steatorrhea 71 Etiology of hypomagnesemia 2. Increased renal excretion of magnesium hypercalcemia i hypercalciuria aldosteronism osmotic diuresis 72 Etiology of hypomagnesemia 3. Endocrine-metabolic disorders hyperparathyroidism - causes hypercalcemia and consequent hypomagnesemia with the syndrome of "hungry bones " - due to the deposition of calcium, magnesium and phosphate in the skeletal system hypophosphatemia increases urinary excretion of magnesium 73  Syndrome of "hungry bones" This syndrome can lead to severe hypocalcemia too, resulting in symptoms such as tetany, seizures, and cardiovascular complications. Pathophysiological consequences of hypomagnesemia the induction of hypocalcemia - which is manifested by increased neuromuscular excitability - reducing the secretion of parathormone - reducing the effects of parathormone on target tissues - inducing tissue resistance to the effects of vitamin D reduced sodium-potassium ATPase activity - potassium moves to the extracellular space, and sodium accumulates intracellularly energy deficit in cells - deficit of synthesis and use of ATP 75 Hypermagnesemia A condition in which the serum concentration of magnesium is greater than 1.05 mmol/l 76 Etiology of hypermagnesemia 1. Increased magnesium intravenous magnesium ; antacids containing magnesium – exogenous load massive damage cell (crash syndrome) – endogenous load 2. Reduced excretion of magnesium acute and chronic renal insufficiency when using diuretics that increase magnesium reabsorption 77 Pathophysiological consequences of hypermagnesemia block of impulse transmission through the neuromuscular junction reduced neuromuscular excitability Clinical consequences of hypermagnesemia: muscle weakness and hyporeflexia paralysis of skeletal muscles nausea and vomiting and arterial hypotension bradycardia cardiac arrest 78 THANK YOU FOR YOUR ATTENTION 80