Experience working with interns, young doctors and cadets of advanced training cycles for doctors has shown significant gaps in their knowledge in assessing basic general clinical, biochemical, immunological and other indicators during examinations. Begin
Experience working with interns, young doctors and cadets of advanced training cycles for doctors has shown significant gaps in their knowledge in assessing basic general clinical, biochemical, immunological and other indicators during examinations.
We are starting a series of reviews and articles containing information for laboratory, clinical and differential diagnostics for various pathological conditions.
The first publication is devoted to water-salt metabolism: the exchange of calcium and phosphorus in the body and its disorders.
The functions of calcium in the body include:
The main role in the metabolism of calcium in the human body belongs to bone tissue. In bones, calcium is represented by phosphates - Ca 3 (PO 4) 2 (85%), carbonates - CaCO 3 (10%), salts of organic acids - citric and lactic (about 5%). Outside the skeleton, calcium is found in the extracellular fluid and is practically absent in the cells. The dense matrix of bone, along with collagen, includes calcium phosphate, a crystalline mineral compound close to hydroxyapatite Ca 10 (PO 4) 6 (OH) 2. Some Ca 2+ ions are replaced by Mg 2+ ions, a small part of OH – ions are replaced by fluorine ions, which increase bone strength. The mineral components of bone tissue are in a state of chemical equilibrium with calcium and phosphate ions in the blood serum. Bone cells can accelerate the deposition or, conversely, dissolution of mineral components with local changes in pH, concentration of Ca 2+ ions, HPO 4 2-, and chelating compounds (D. Metzler, 1980). The adult human body contains 1-2 kg of calcium, 98% of which is found in the skeleton (A. White et al., 1981). It makes up about 2% of body weight (approximately 30 mol). The level of calcium in the blood is 9-11 mg/100 ml (2.2-2.8 mmol/l), in the extracellular fluid - about 20 mg/100 ml. The regulation of calcium exchange between extra- and intracellular fluid is carried out by parathyroid hormone, calcitonin, and 1,25-dioxycholecalciferol. As the concentration of calcium ions decreases, the secretion of parathyroid-stimulating hormone (PTH) increases, and osteoclasts increase the dissolution of mineral compounds contained in the bones. PTH simultaneously increases the reabsorption of Ca 2+ ions in the renal tubules. As a result, the level of calcium in the blood serum increases. With an increase in the content of calcium ions, calcitonin is secreted, which reduces the concentration of Ca 2+ ions due to calcium deposition as a result of the activity of osteoblasts. Vitamin D is involved in the regulation process; it is required for the synthesis of calcium-binding proteins necessary for the absorption of Ca 2+ ions in the intestine and its reabsorption in the kidneys. A constant supply of vitamin D is necessary for the normal course of calcification processes. Changes in the level of calcium in the blood can be caused by thyroxine, androgens, which increase the content of Ca 2+ ions, and glucocorticoids, which reduce it. Ca 2+ ions bind many proteins, including some proteins of the blood coagulation system. The proteins of the coagulation system contain calcium-binding sites, the formation of which depends on vitamin K.
In food products, calcium is contained mainly in the form of calcium phosphate, which enters the body. In nature, calcium is found in the form of carbonate, oxalate, tartrate, phytic acid (in cereals).
Calcium deficiency in the body, according to A. White et al. (1981), is often associated with the low solubility of most of its salts.
The authors associate calcification of arterial walls and the formation of stones in the gall bladder, renal pelvis and tubules with the poor solubility of calcium salts. The forms of calcium phosphate according to the degree of increasing solubility are arranged as follows: Ca 3 (PO 4) 2 > CaHPO 4 > Ca (H 2 PO 4) 2.
Calcium phosphates easily dissolve in gastric contents. Maximum calcium absorption occurs in the proximal parts of the small intestine and decreases in the distal parts.
The proportion of calcium absorption is more significant in children (compared to adults), in pregnant and lactating women. Calcium absorption decreases with age and with vitamin D deficiency.
Blood plasma contains fractions of protein-bound (non-diffusing) calcium (0.9 mmol/l) and diffusing: ionized (1.1-1.4 mmol/l) and non-ionized (0.35 mmol/l). Ionized calcium is biologically active; it penetrates cells through membranes; the non-ionized form is associated with proteins (albumin), carbohydrates and other compounds. Inside the cells, the concentration of free calcium is low. Thus, the total concentration of Ca2+ ions in the cytoplasm of erythrocytes is about 3 μM, of which free ions account for less than 1 μM. Calcium ion concentration gradient along different sides from the membrane (from 102 to 105) is maintained by a calcium pump. The very slow reverse diffusion of ions into the cell opposes the pump. Ca2+ refers to secondary messengers - intracellular substances, the concentration of which is controlled by hormones, neurotransmitters, and extracellular signals. Low levels of calcium in cells are maintained by calcium pumps (calcium ATPases) and sodium-calcium exchangers. High activation of Mg 2+ -, Ca 2+ -ATPase is associated with conformational changes in the calcium pump, leading to Ca2+ transfer. A sharp increase in calcium content in the cell occurs when calcium channels or intracellular calcium stores open (the concentration increases to 500-1000 nM with 10-100 nM in an unstimulated cell). The opening of channels can be caused by depolarization of membranes, the action of signaling substances, neurotransmitters (glutamate, ATP), secondary messengers (inositol-1,4,5-triphosphate, cAMP) (Y. Kolman, K. G. Rehm, 2000). The level of calcium in cells increases (5-10 times) in the form of short-term fluctuations (high concentrations of calcium have a cytotoxic effect). In cellular organelles and the cytoplasm of cells there is a large number of proteins that can bind calcium and act as a buffer. The effect of calcium is mediated by “calcium sensors” - special calcium-binding proteins - annexin, calmodulin, troponin. Calmodulin is found in all cells and, when four calcium ions bind, it transforms into an active form that can interact with proteins. C 2+ affects the activity of enzymes, ion pumps, and cytoskeletal components due to the activation of calmodulin.
Hypoalbuminemia does not affect the level of ionized calcium, which varies within a narrow range and thereby ensures the normal functioning of the neuromuscular system. With increasing pH, the proportion of bound calcium increases. During alkalosis, hydrogen ions dissociate from the albumin molecule, which leads to a decrease in the concentration of calcium ions. This may cause clinical symptoms of hypocalcemia, despite the fact that the concentration of total plasma calcium is not altered. The opposite picture (increased concentration of calcium ions in plasma) is observed in acute acidosis. Globulins also bind calcium, although to a lesser extent than albumin.
Components of the regulation of calcium levels in blood plasma include:
The extracellular calcium pool is renewed approximately 33 times during the day (W. J. Marshall, 2002), passing through the kidneys, intestines and bones. And even a small change in any of these flows has a significant effect on the concentration of calcium in the extracellular fluid, including blood plasma. Calcium, which is part of the secretions of the digestive tract, is partially reabsorbed along with dietary calcium.
Disorders of calcium metabolism are accompanied by disturbances of phosphate metabolism and are clinically manifested in changes in the bone skeleton and neuromuscular excitability.
There is an inverse relationship between the content of calcium and phosphorus in the blood serum (a simultaneous increase is observed in hyperparathyroidism, a decrease in rickets in children). With an increased content of phosphorus in food, non-absorbable tribasic calcium phosphate is formed in the gastrointestinal tract. The daily calcium requirement for an adult is 20-37.5 mmol (0.8-1.5 g), in pregnant and lactating women it is twice as high (M. A. Bazarnova et al., 1986). 35 mmol of calcium enters the food canal daily, but only half is absorbed, 50 times slower than sodium, but more intense than iron, zinc, and manganese. Absorption occurs in the small intestine (maximum in the duodenum). Calcium gluconate and lactate are best absorbed. Optimum absorption is observed at pH=3.0. Calcium combines with fatty and bile acids and enters the liver through the portal vein. Transport through the enterocyte membrane into the blood is facilitated by vitamin D. Absorption is reduced by a lack of phosphates (the calcium/phosphorus ratio is important). Absorption is affected by the concentration of Na +, the activity of alkaline phosphatase, Mg 2+ -, Ca 2+ -ATPase, and the content of calcium-binding protein. Calcium is normally excreted from the body through the intestines. Every day, about 25 mmol Ca 2+ is secreted into the food canal by the salivary, gastric and pancreatic glands (M. A. Bazarnova et al., 1986). Calcium excretion in feces persists even with a calcium-free diet (as part of bile). About 270 mmol Ca 2+ is filtered in the kidneys per day. 90% of the calcium filtered in the kidneys is reabsorbed, so overall little is excreted in the urine (excretion increases with increasing calcium concentration in the blood and leads to the formation of kidney stones). Daily excretion ranges from 1.5 to 15 mmol and depends on the circadian rhythm (maximum in the morning), hormone levels, acid-base status, and the nature of food (carbohydrates increase calcium excretion). As the mineral framework of bones is reabsorbed, calcium reabsorption decreases. Bones are a reservoir of calcium: in hypocalcemia, calcium comes from the bones and, conversely, in hypercalcemia, it is deposited in the skeleton.
Calcium ions are important for the course of many processes:
The main sources of calcium are milk, dairy products (cottage cheese, hard cheeses), fish, eggs. It is also found in green vegetables and nuts. One of the sources of calcium is drinking water (up to 350-500 mg in 1 liter). WITH drinking water 10-30% calcium arrives (V.I. Smolyar, 1991). The bioavailability of calcium is improved by fermented milk products and animal proteins; it is reduced by dietary fiber, alcohol, caffeine, excess fat (insoluble compounds are formed), phosphates, and oxalates. An increased content of magnesium and potassium in food inhibits the absorption of calcium: they compete with calcium for bile acids. Vitamin D supplements promote calcium absorption. When treating osteoporosis, simultaneously with the prescription of calcium supplements, it is necessary to compensate for the deficiency of proteins, calciferol, and vitamins.
Hypercalcemia is the result of increased calcium entry into the extracellular fluid from resorbed bone tissue or from food in conditions of decreased renal reabsorption. Most common cause hypercalcemia (90% of cases) are primary hyperparathyroidism, malignant neoplasms. Often hypercalcemia is not clinically apparent. Rare causes of hypercalcemia include (W. Clutter, 1995) granulomatous diseases (including sarcoidosis), hypervitaminosis D, thyrotoxicosis, the use of thiazide diuretics, lithium drugs, milk-alkali syndrome, prolonged immobility, hereditary hypocalciuric hypercalcemia, renal failure. Clinical symptoms of hypercalcemia include:
The most common cause of decreased total serum calcium concentration is hypoalbuminemia.
Calcium metabolism in the body is not disturbed if the content of free calcium is within normal limits. The concentration of free calcium in the serum decreases with hypoparathyroidism, resistance to parathyroid hormone (pseudohypoparathyroidism), vitamin deficiency D, renal failure, severe hypomagnesemia, hypermagnesemia, acute pancreatitis, necrosis of skeletal muscles (rhabdomyolysis), tumor disintegration, and multiple transfusions of citrated blood. Clinical manifestations of hypocalcemia include: paresthesia, a feeling of numbness, muscle cramps, laryngeal spasm, behavioral abnormalities, stupor, positive Chvostek and Trousseau symptoms, prolongation of the Q-T interval on the ECG, cataracts. Moderate hypocalcemia may be asymptomatic.
Hypercalciuria develops with increased dietary calcium intake, vitamin D overdose (increased intestinal resorption), tubular disorders (idiopathic hypercalciuria, renal tubular acidosis), with increased bone tissue breakdown (myeloma, bone tumors, phosphate diabetes, osteoporosis, hyperparathyroidism) .
Hypocalciuria is observed with hypoparathyroidism, hypovitaminosis D, hypocalcemia, and decreased glomerular filtration.
The adult human body contains about 670 g of phosphorus (1% of body weight), which is necessary for bone formation and cellular energy metabolism. 90% of phosphorus, like calcium, is found in the skeleton - bones and teeth (M.A. Bazarnova et al., 1986). Together with calcium, they form the basis of the hard substance of bone. In bones, phosphorus is represented by sparingly soluble calcium phosphate (2/3) and soluble compounds (1/3). Most of the remaining amount of phosphorus is found inside cells, 1% is in extracellular fluid. Therefore, the level of phosphorus in the blood serum does not allow us to judge its total content in the body.
Phosphates are structural elements bone tissue, participate in the transfer of energy in the form of macroergic bonds (ATP, ADP, creatine phosphate, guanine phosphate and others). Phosphorus and sulfur are two elements in the human body that are part of various high-energy compounds. With phosphoric acid glycolysis, glycogenesis, and fat metabolism are carried out. Phosphorus is part of the structure of DNA and RNA, which ensure protein synthesis. It is involved in oxidative phosphorylation, which results in the formation of ATP, and the phosphorylation of some vitamins (thiamine, pyridoxine and others). Phosphorus is also important for the functioning of muscle tissue (skeletal muscle and cardiac muscle). Inorganic phosphates are part of the buffer systems of plasma and tissue fluid. Phosphorus activates the absorption of calcium ions in the intestines. The daily requirement for phosphorus is 30 mmol (900 mg), in pregnant women it increases by 30-40%, during lactation it doubles (M. A. Bazarnova et al, 1986). According to V.I. Smolyar (1991), the need for phosphorus in adults is 1600 mg per day, in children - 1500-1800 mg per day.
Phosphorus enters the human body with plant and animal foods in the form of phospholipids, phosphoproteins and phosphates.
IN plant products(in particular, legumes) contain a lot of phosphorus, but its digestibility is low. Its important sources are meat and fish. In the stomach and intestines, phosphoric acid is split off from organic compounds. Absorption of 70-90% of phosphorus occurs in the small intestine. It depends on the concentration of phosphorus in the intestinal lumen and the activity of alkaline phosphatase (its inhibition reduces phosphorus absorption). Alkaline phosphatase activity increases vitamin D, and phosphate absorption increases parathyroid hormone. Absorbed phosphorus enters the liver, participates in phosphorylation processes, and is partially deposited in the form of mineral salts, which then pass into the blood and are used by bone and muscle tissue (creatine phosphate is synthesized). The normal course of ossification processes and the maintenance of normal bone structure depend on the exchange of phosphates between blood and bone tissue.
In the blood, phosphorus is found in the form of four compounds: inorganic phosphate, organic phosphorus esters, phospholipids and free nucleotides. In blood plasma, inorganic phosphorus is present in the form of orthophosphates, but its concentration in serum is assessed directly (1 mg% phosphorus = 0.32 mmol/l phosphate). It penetrates through semi-permeable membranes and is filtered in the glomeruli. The concentration of inorganic pyrophosphate in blood plasma is 1-10 µmol/l. The content of inorganic phosphorus in the blood plasma of adults is 3.5-4 mg of phosphorus/100 ml, it is slightly higher in children (4-5 mg/100 ml) and in women after menopause. Plasma also contains hexose phosphates, triose phosphates and others. The skeleton is a reservoir of inorganic phosphorus: when its content in plasma decreases, it comes from the skeleton and, conversely, is deposited in the skeleton when its concentration in plasma increases. It is recommended to determine the concentration of phosphorus in the blood serum on an empty stomach: food rich in phosphorus increases it, and carbohydrates and glucose infusion decrease it. Phosphorus is excreted from the body through the intestines and kidneys in the form of calcium phosphate. 2/3 of soluble mono- and disubstituted sodium and potassium phosphates and 1/3 of calcium and magnesium phosphates are excreted in the urine. About 208 mmol of phosphate is filtered in the kidneys per day, and 16-26 mmol is excreted. The ratio of mono- and disubstituted phosphorus salts depends on the acid-base state. With acidosis, monosubstituted phosphates are excreted 50 times more than dibasic phosphates. During alkalosis, disubstituted phosphate salts are intensively formed and released.
Parathyroid hormone reduces the level of phosphorus in the blood serum, inhibiting its reabsorption in the proximal and distal tubules, increasing excretion in the urine. Calcitonin has a hypophosphatemic effect, reducing reabsorption and increasing excretion. 1,25(OH)2D3, enhancing the absorption of phosphate in the intestine, increases its level in the blood, promotes the fixation of phosphorus-calcium salts by bone tissue. Insulin stimulates the entry of phosphate into cells and thereby reduces its content in the blood serum. Growth hormone increases phosphate reabsorption, vasopressin increases excretion.
The exchange of phosphorus and calcium is closely interrelated. It is believed (V.I. Smolyar, 1991) that the ratio between phosphorus and calcium is 1:1-1.5 optimal for joint absorption from food. Hypercalcemia, by reducing the secretion of parathyroid hormone, stimulates the reabsorption of phosphates. Phosphate can combine with calcium and lead to calcium deposition in tissues and hypocalcemia.
If phosphorus metabolism is disrupted, an increase and decrease in phosphorus levels in the blood are detected. Hyperphosphatemia is often observed in renal failure and occurs in hypoparathyroidism, pseudohypoparathyroidism, rhabdomyolysis, tumor breakdown, metabolic and respiratory acidosis. Hyperphosphatemia inhibits the hydroxylation of 25-hydroxycalciferol in the kidneys. Moderate hypophosphatemia is not accompanied by significant consequences. Severe hypophosphatemia (less than 0.3 mmol/l (1 mg%) is accompanied by dysfunction of erythrocytes, leukocytes, muscle weakness (the formation of ATP, 2,3-diphosphoglycerate is impaired). It is observed with alcohol abuse and withdrawal, respiratory alkalosis, impaired absorption of intestines, taking phosphate binders, resuming food intake after fasting, overeating, severe burns, treatment of diabetic ketoacidosis (W. Clutter, 1995). In diabetic ketoacidosis, hypophosphatemia is not a sign of depletion of phosphate stores. Moderate hypophosphatemia (1.0-2 .5 mg%) can be observed with glucose infusion, vitamin D deficiency in food or decreased absorption in the intestine, hyperparathyroidism, acute tubular necrosis, after kidney transplantation, hereditary hypophosphatemia, Fanconi syndrome, paraneoplastic osteomalacia, increased extracellular fluid volume. Respiratory alkalosis can cause hypophosphatemia by stimulating phosphofructokinase activity and the formation of phosphorylated glycolytic intermediates. Chronic hypophosphatemia leads to rickets and osteomalacia.
Hypophosphatemia is manifested by loss of appetite, malaise, weakness, paresthesia in the extremities, and bone pain. Hypophosphaturia is observed with osteoporosis, hypophosphatemic renal rickets, infectious diseases, acute yellow liver atrophy, decreased glomerular filtration, increased phosphorus reabsorption (with PTH hyposecretion).
Hyperphosphaturia is observed with increased filtration and decreased reabsorption of phosphorus (rickets, hyperparathyroidism, tubular acidosis, phosphate diabetes), hyperthyroidism, leukemia, poisoning with salts of heavy metals, benzene, phenol.
Hypocalcemia stimulates the secretion of parathyroid hormone and thereby increases the production of calcitriol. As a result, the mobilization of calcium and phosphates from the bones and their supply from the intestines increases. Excess phosphates are excreted in the urine (PTH has a phosphaturic effect), and the reabsorption of calcium in the renal tubules increases, and its concentration in the blood normalizes. Hypophosphatemia is accompanied by increased secretion of only calcitriol. An increase in its plasma concentration under the influence of calcitriol leads to a decrease in the secretion of parathyroid hormone. Hypophosphatemia leads to stimulation of the absorption of phosphate and calcium in the intestine. Excess calcium is excreted in the urine, since calcitriol enhances calcium reabsorption to a small extent (compared to PTH). As a result of the described processes, the normal concentration of phosphate in the blood plasma is restored regardless of the calcium concentration.
The adult human body contains about 1.2 kg of calcium. Calcium salts form the mineral component of bones (99% of the body's total calcium, 87% of phosphorus). Calcium in bones is in the form of the mineral hydroxyapatite Ca 10 (PO 4) 6 (OH) 2. Calcium is also present in the body in the form of Ca 2+ ions dissolved in liquids or combined with proteins of liquids and tissues. There is a constant exchange of calcium between these two foundations.
Ca 2+ ions are cofactors of many enzymes and, together with modulator proteins, serve as intermediaries in signal transmission. Calcium is involved in secretion, fertilization, membrane permeability, blood clotting, and muscle contraction.
The average adult male consumes 900-1000 mg of calcium per day. adult woman- 600-700 mg, of which up to 20-40% is absorbed in the digestive tract. A significant portion of calcium ingested from food passes through the intestines and leaves the body along with feces. Elimination of calcium from the body occurs primarily through urine. Normally, the body maintains a stable balance of calcium.
Calcium absorption in the intestine occurs due to active transport against electrochemical gradient, due to passive diffusion. Calcium is transported across the cell membrane using vitamin D-dependent calcium binding protein (CBP). The absorption of calcium in the intestine is normally determined not by its intake from food, but by the hormonal regulation of the active transport system. The kidneys are involved in calcium metabolism through filtration and reabsorption.
Calcium metabolism is closely related to the metabolism of phosphoric acid, which forms poorly soluble salts with calcium: phosphate, hydrogen phosphate, dihydrogen phosphate.
The total phosphate of a 70 kg adult male is about 700 g, of which ~85% is found in bones and teeth, ~14% is found intracellularly in organic form as a component of ATP and phospholipids. In extracellular fluids, phosphate is in the form of phospholipids (about 70%) and inorganic phosphate. In blood plasma, phosphates are presented as free ions (80%) or bound to proteins. One of the main functions of inorganic phosphate in the body is its buffering function.
The statistically average adult consumes 800-1200 mg of phosphorus daily, of which about 80% is absorbed in the intestines, and the same amount is excreted by the kidneys. The main mechanisms of phosphate transport in the intestine: active sodium-dependent transport; passive transport along a concentration gradient. The degree of adaptation of intestinal phosphate absorption to changes in phosphate intake is small, and therefore the intestine plays a small role in phosphate homeostasis.
The kidneys play a major role in the homeostatic regulation of phosphate balance throughout the body. The entry of phosphate into the cell of the proximal tubule is carried out through Na/P i - cotransporters.
Phosphate can bind free ionized calcium; therefore, if plasma inorganic phosphate levels increase, calcium levels decrease.
The concentration of Ca 2+ ions in the intercellular fluid and blood is 9-11 mg/dl. Half of them are Ca 2+ ions in a dissolved state, the other half are combined with albumin. In the intracellular fluid, the concentration of calcium is thousands of times less. The concentration difference is created mainly by Ca-ATPase with the participation of a system of ion channels. The concentration of Ca 2+ in the blood and intercellular fluid is regulated by hormones, mainly parathyroid hormone, calcitonin and calcitriol.
Parathyroid hormone is a peptide hormone produced in the parathyroid glands. Contains 84 amino acid residues. The biological activity of parathyroid hormone (PTH) is determined only by the first 32-34 amino acids (counting from the N-terminus of the peptide). It is the most important regulator of calcium homeostasis.
The main target organs of parathyroid hormone are bones and kidneys. The cell membranes of these organs contain specific parathyroid hormone receptors. PTH receptors are also found in the lungs, cardiovascular system, skin, red blood cells, etc.
Two main mechanisms of action of parathyroid hormone have been identified: activation of the adenylate cyclase - cyclic AMP - protein kinase A system and the phosphatidylinositol - protein kinase C system.
In bones, activation of adenylate cyclase stimulates the metabolic activity of osteoclasts, bone resorption begins and the flow of Ca 2+ and phosphates into the blood. In the kidneys, parathyroid hormone increases Ca 2+ reabsorption and increases renal phosphate excretion. PTH also stimulates gene expression and increases the production of several local protein factors and prostaglandins.
The synthesis and secretion of PTH are stimulated by a decrease in the concentration of Ca 2+ in the blood. Restoring the normal concentration of Ca 2+ in the blood leads to the cessation of synthesis and secretion of the hormone. Specific calcium receptors are found in parathyroid cells. They sensitize the parathyroid glands to changes in serum calcium concentration, which leads to changes in PTH secretion. In the kidneys, the Ca receptor is an important regulator of urinary calcium excretion.
Vitamin D 3 is a precursor to a substance that functions as a steroid hormone - calcitriol. The formation of calcitriol is stimulated primarily by PTH and hypophosphatemia. The conversion of vitamin D to calcitriol occurs with the participation of the liver and kidneys. Specific hydroxylases that catalyze these reactions are activated by parathyroid hormone.
Vitamin D-binding protein synthesized in the kidneys by 1,25(OH) 2 D 3 is transported to target cells, where it reacts with a nuclear receptor. The target organs of calcitriol are the small intestine and bones. In the small intestine, the hormone stimulates the absorption of calcium and phosphates, and in the bones - the mobilization of calcium. Calcitriol activates genes that control the synthesis of certain proteins, for example, calcium-binding protein, which is involved in calcium absorption. Calcitriol may also stimulate the reabsorption of calcium (and phosphate) in the renal tubules.
Thus, parathyroid hormone and vitamin D 3 are synergists in relation to the mobilization of calcium from bones and increasing its concentration in the blood.
With a lack of vitamin D, children develop rickets. There is a decrease in the flow of calcium into the blood, a violation of the mineralization of growing bones. Insufficient calcification of the bone leads to various skeletal deformities - curvature of the legs, “rosary” on the ribs, “bird breast”, etc. Rickets is usually cured with vitamin D. However, there are forms of rickets associated with a violation of the conversion of vitamin D 3 in the body into calcitriol. IN in this case Vitamin D administration is ineffective.
Long-term intake of excess amounts of vitamin D (several times more than normal) leads to demineralization of bones and an increase in the concentration of calcium in the blood. At the same time, calcium is intensively absorbed from the intestine - this leads to general hypercalcemia, calcium deposition in soft tissues, and the formation of stones in the urinary tract.
Calcitonin– a peptide hormone synthesized in the C-cells of the parathyroid and thyroid glands. Contains 32 amino acid residues. The secretion of calcitonin (CT) increases with increasing calcium levels in the blood. The effects of CT are due to its effect on specific calcitonin receptors and are opposite to the effects of PTH. The main target organ for calcitonin is bone, where it inhibits calcium mobilization. CT reduces serum Ca concentration. The overall contribution of calcitonin to calcium homeostasis is very small compared to the role of PTH and vitamin D.
Other systemic hormones also have effects on the skeleton, especially growth hormone, glucocorticoids, thyroid hormones, and sex hormones. Some factors have local effects, for example, prostaglandins, cytokines.
A change in the concentration of calcium in the extracellular fluid leads to a change in its concentration inside the cells. As a result, transmembrane gradients of Ca 2+ concentrations change, the functioning of the calcium pump, calcium-dependent enzymes, and a number of regulatory systems is disrupted.
Hypocalcemia– decreased calcium levels in the blood. It may be a consequence of impaired absorption of calcium in the intestine, for example, with hypovitaminosis D, with a high content of calcium-binding compounds (for example, oxalate) in food. Severe hypocalcemia is rare. Its most common cause is hypoparathyroidism, caused by damage to the parathyroid glands during thyroid surgery.
With hypocalcemia, convulsions, hyperreflexes, and laryngeal spasms are observed due to a decrease in the threshold of excitation of nerve and muscle cells.
Hypercalcemia– increased calcium levels in the blood. Most often, its cause is hyperparathyroidism as a result of a tumor of the parathyroid glands; overdose of vitamin D.
Characteristic symptoms of hypercalcemia are soft tissue calcification and the formation of stones in the urinary tract. Neuromuscular excitability decreases; a disorder of nervous functions occurs - psychosis, stupor and even coma.
Control questions
1. Describe the metabolism of calcium and phosphorus in the body.
2. What hormones are involved in the regulation of phosphorus-calcium metabolism?
3. What type of reception predominates in hormones that regulate phosphorus-calcium metabolism?
4. How is vitamin D converted to calcitriol?
5. List the symptoms observed in hypo- and hypercalcemia.
6. What could be the reason for changes in calcium concentration in the blood?
7. Which organs play an important role in the metabolism of calcium and phosphorus?
BIOCHEMISTRY OF BONE TISSUE
Bone- a type of connective tissue characterized by great hardness and mechanical strength. Bone tissue, like other types of connective tissue, consists of cells and extracellular substance. The extracellular substance basically contains an organic matrix structured by a mineral phase. Bone tissue forms bone plates. Depending on the density and location of the plates, compact and spongy bone substances are distinguished. There are three main types of cells in bone tissue: osteoblasts, osteoclasts and osteocytes.
Osteoblast– a bone tissue cell involved in the formation of intercellular substance. Osteoblasts contain a powerful protein synthesis apparatus and a highly developed endoplasmic reticulum. Osteoblasts synthesize organic substances of the bone matrix - procollagen, glycosaminoglycans, protein components of proteoglycans, enzymes, etc.
Osteocyte– a mature process cell of bone tissue, ensuring the integrity of the bone matrix, participating in the regulation of its homeostasis and producing some components of the intercellular substance. Osteocytes are formed from osteoblasts during the formation of bone tissue.
Osteoclast– a giant multinucleated cell of bone tissue that carries out bone tissue resorption: resorption of intercellular substance, demineralization of cartilage, etc. Osteoclasts contain many lysosomes and mitochondria. But they have a poorly developed endoplasmic reticulum and a small number of ribosomes, therefore, RNA synthesis is carried out insignificantly.
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Normally, the main regulators of phosphorus-calcium metabolism are PG, calcitonin and vitamin D. By influencing the skeleton, kidneys and calcium absorption in the intestine, PG ensures a constant concentration of ionized calcium in the extracellular fluid. Even a small, physiological increase in serum PG levels leads to the activation of mature osteocytes and bone resorption.
This process (osteocytic osteolysis) is the main manifestation of the acute effects of PG on the skeleton. With prolonged hypersecretion of PG, the number of osteoclasts increases as a result of their proliferation from mesenchymal bone cells and their activity increases with an increase in the lifespan of each osteoclast. All this is accompanied by osteoclastic resorption of bone tissue, observed, as a rule, in patients with chronic renal failure.
Simultaneously with resorption, the processes of new bone formation occur, and the newly formed bone tissue is richer in cellular elements and less organized than normal bone tissue. As a result of the processes of resorption and new formation, the metabolism of bone tissue during PG hypersecretion is enhanced. Acting on the kidneys, PG reduces the proximal and distal tubular resorption of phosphates, which leads to phosphaturia and hypophosphatemia, as well as Na, HCO3¯ and a number of amino acids, in particular proline. At the same time, PG stimulates the synthesis of 1,25-dihydroxycholecalcifarol in the renal parenchyma.
In contrast to PG, calcitonin, secreted in the interfollicular cells of the thyroid gland, prevents hypercalcemia, reduces the concentration of calcium in the blood and extracellular fluid, reduces the number and activity of osteoclasts in bone tissue and inhibits osteocytic osteolysis. In the kidneys, calcitonin reduces the resorption of phosphates, causing phosphaturia and calciuria and, according to N. Rasmussen et al. (1972), interferes with the synthesis of l,25(OH)2D3. In small concentrations, calcitonin reduces calcium absorption in the intestine.
Vitamin D3 is normally formed in the skin under the influence of ultraviolet light from its predecessor, 7-dehydrocholesterol. The formed vitamin D3, which does not yet have biological activity, is partially deposited in the depot of adipose and muscle tissue and partially undergoes further metabolic transformation.
In the microsomes of liver cells, vitamin D3 is hydroxylated into 25-hydroxycholecalciferol (25ОHD3), the biologically active form of vitamin D3 in circulation. The 25ОHD3 molecule is transferred by serum α2-globulin to the mitochondria of renal cortex cells, where it undergoes secondary hydroxylation with the participation of cytochrome P450 and is converted, depending on the needs of the body, or into l,25(OH)2D3 - an active metabolite of vitamin D3, affecting the absorption of calcium in the intestine and its mobilization from bone tissue, or the relatively inactive metabolite 24,25 (OH)2D3. The synthesis of l,25(OH)2D3 by renal tissue is enhanced by hypophosphatemia, which determines a decrease in the concentration of inorganic phosphorus in the cells of the cortex, and the synthesis of the hormone is inhibited by hyperphosphatemia and calcitonin, which increases the level of phosphorus in the renal cortex.
The content of l,25(OH)2D3 in the kidney tissue changes in two ways: either through the synthesis and degradation of 1-hydroxylase and 24-hydroxylase, which requires several hours, or through a change in the activity of already existing hydrolases, which occurs very quickly under the influence of intracellular calcium, pH, transient increase in PG and other factors. The first pathway ensures permanent regulation of mineral homeostasis due to changes in the absorption of calcium and phosphorus in the intestine and the activity of osteoblasts. The second pathway, since 1,25(OH)2D3 directly affects osteocytes, is important for ensuring the body’s response to various calcemic factors.
In combination with PG, vitamin D3 is involved in bone resorption, enhances the reabsorption of calcium, phosphorus and sodium in the kidneys and affects the absorption of calcium in the small intestine.
In case of renal failure, all links in the hormonal regulation of phosphorus-calcium metabolism are disrupted. Already in the early stages of chronic renal failure, due to increased secretion and slower degradation in the kidneys, the level of immunoreactive PG in the blood of patients increases. Simultaneously with the fall in CP, phosphorus retention occurs, which causes a decrease in ionized calcium in the serum and further enhances the production of PG. An increase in serum PG concentration induces phosphaturia and returns phosphorus levels to normal, which is accompanied by an increase in serum calcium. Thus, at the cost of PG hypersecretion, a new state of phosphorus balance is established.
With a further drop in filtration, this cycle repeats. If phosphorus intake is reduced in proportion to the decrease in CP, then the level of ionized calcium in the serum does not decrease and the secretion of PG does not increase.
In addition to phosphorus retention, the cause of PG hypersecretion in chronic renal failure is the resistance of the skeleton to the calcemic effect of endogenous or exogenous PG. Resistance is manifested by a reduced or normal level of calcium in the serum of patients with chronic renal failure, despite low or normal phosphate levels and increased secretion of PG.
The causes of resistance are secondary hyperparathyroidism, vitamin D3 deficiency, hypermagnesemia and decreased intracellular magnesium. Absorption in the intestines and distribution of vitamin D3 in tissues is not impaired in uremia. In patients with chronic renal failure, the normal level 25ОHD3 in serum, and some decrease is observed only with massive proteinuria, long-term protein restriction in the diet, and severe hyperparathyroidism.
At the same time, l,25(OH)2D3 is not detected in the plasma of patients or its content is sharply reduced. This decrease in l,25(OH)2D3 in uremia and the restoration of its production: after successful kidney transplantation confirm the exclusive role of the kidneys in the formation of l,25(OH)2D3. With l,25(OH)2D3 deficiency, the maturation of bone tissue collagen, the processes of osteoid mineralization are disrupted, and calcium absorption in the intestine is reduced. The last process deserves a more detailed description.
Sodium, potassium and phosphorus are absorbed almost completely in the intestine, and calcium - 25-45% of the amount taken with food. The highest rate of calcium absorption in humans and animals is in the duodenum, however, as a result of the rapid passage of food, the bulk of calcium is absorbed in the jejunum. Calcium can be transported transcellularly or at cell junctions, and the processes of its entry into and exit from the cell are controlled by l,25(OH)2D3. The entry of calcium into the cell is carried out using a calcium-binding protein, the formation of which on the surface of microvilli is induced by 3,25(OH)2D3. Once in the cell, l,25(OH)2D3 stimulates the formation of mRNA, which ensures the synthesis of a number of proteins on ribosomes, including calcium-binding proteins. At the same time, this metabolite enhances the activity of alkaline phosphatase and Ca-stimulated ATPase located in the alkaline border.
There is less data on the mechanisms of calcium transport through the cell and its entry into the blood. It is assumed that this process requires energy, since the release of calcium from the cell occurs against the concentration gradient and occurs with the participation of two ATPases. The activity of one of them is inhibited by ethacrynic acid, and the other by ouabain.
Normally, calcium absorption depends on its intake from food and skeletal mineralization. Absorption is enhanced by lactose and some amino acids - lysine, arginine and tryptophan. Calcium absorption is inhibited by glucocorticoids, which are supposed to inhibit the conversion of 25ОHD3 to l,25(OH)3D3, as well as phytates, which form insoluble complexes with it, and oxalates.
Calcium absorption is better when taken with meals.
Calcium absorption in uremia is sharply reduced, but its negative balance is also determined by other factors - insufficient intake of calcium from food, which in patients on a low protein diet is approximately 1/3 of the amount consumed by healthy individuals, the amount of residual renal function, acidosis, calcium content in the dialysate solution in patients undergoing hemodialysis treatment, some medications, in particular propranolol, cause hypocalcemia by suppressing PG secretion and transcellular calcium transport. S. Liu and H. Chu (1943), who did not observe an improvement in calcium absorption when patients with uremia were prescribed normal doses of vitamin D3, were the first to suggest that impaired calcium absorption in chronic renal failure is associated with acquired resistance to the physiological effects of this vitamin.
Currently, there is numerous experimental data indicating that the occurrence of this resistance is associated with a deficiency of the renal metabolite of vitamin D3 - 1,25(OH)2D3.
The production of l,25(OH)2D3 and the restoration of normal calcium absorption are observed in patients with a normally functioning renal transplant, and in patients undergoing hemodialysis, calcium absorption remains, as a rule, reduced.
Impaired phosphorus-calcium metabolism in uremia is reflected by a variety of bone pathologies that develop in patients with chronic renal failure: osteomalacia, osteitis fibrosa, osteosclerosis, etc., however, combined lesions are more common, for which the term “renal osteodystrophy” is used. Damage to bone tissue is detected already in the early stages of chronic renal failure.
The first manifestations of renal osteodystrophy develop as a result of secondary hyperparathyroidism and are expressed in the appearance of resorption cavities filled with unorganized osteoid; its number increases when CF drops below 40 ml/min. The first signs of osteomalacia, which is characterized by a defect in the mineralization of bone tissue with excessive accumulation of intercellular substance (protein matrix), a several-fold slowdown in the maturation of osteoid and its mineralization, and a decrease in the activity of osteoblasts, are observed in the early stages of chronic renal failure, but a pronounced picture of osteomalacia changes in bones occurs only after a fall EF below 30 ml/min.
A special form of renal osteodystrophy - hyperostosis (osteosclerosis) is a consequence of an increase in bone mass, mainly due to endosteal and, less commonly, cortical bone, which leads to an increase in bone density. Osteosclerosis is determined radiographically when the newly formed osteoid undergoes calcification. Osteosclerosis is observed in different stages of chronic renal failure, but especially often in patients with a predominance of secondary hyperparathyroidism. Since osteosclerosis is relatively rare in primary hyperparathyroidism, a significant role in its origin is attributed to hyperphosphatemia, which can accelerate the transition of osteoclasts to osteoblasts and increase the activity of the latter.
It should be emphasized that with osteosclerosis we're talking about about new bone formation with a disordered structure, which mineralizes in the absence of active metabolites of vitamin D3 and even undergoes hypermineralization, which never happens in bone tissue with a normal structure. Osteosclerosis is much more common in children. Their skeleton contains more disordered bone than that of adults. Because disordered bone traps large amounts of calcium and phosphorus, soft tissue calcification is relatively rare in children.
During hemodialysis treatment, as a result of exposure to a number of additional unfavorable factors, patients not only accelerate the development of the main bone pathology - osteitis fibrosa or osteomalacia, but also often develop new form-dialysis osteopenia, which does not occur in the natural course of renal osteodystrophy.
Osteopenia develops when the balance between bone resorption and new bone formation shifts toward resorption. The development of osteopenia is facilitated by the use of a dialysate solution with a calcium content of less than 1.5 mmol/l, a decrease in physical activity due to both illness and treatment and, as a result, less ultraviolet radiation, and the use of heparin during the hemodialysis procedure, which has osteopenic properties and the ability to reduce ionized calcium, increase PG secretion, often long-term protein restriction in the diet before hemodialysis treatment.
The presence of fluoride in the water used to prepare the dialysate solution, as well as the concentration of phosphorus in the serum of patients, plays a certain role. At phosphorus levels above 2 mmol/L A. Parfitt et al. (1971) observed rapid progression of osteodystrophy, while A. Fornier et al. (1971) while maintaining serum phosphorus concentration less than 2 mmol/l noted an improvement in skeletal condition. It is of interest that the manifestations of dialysis osteopenia do not improve after subtotal parathyroidectomy.
Histologically, osteopenia is characterized by a decrease in endosteal bone as opposed to an increase in endosteal bone in patients not treated with hemodialysis.
The main clinical symptoms of renal osteodystrophy are bone pain and muscle weakness.
If osteomalacia predominates, insufficient calcification of a large mass of osteoid leads to softening of the bones, development of deformities and pathological fractures. In young people with osteomalacia, growth slows down, kyphosis, kyphoscoliosis, and deformation of the pelvic bones and limbs develop due to the restructuring of the metaphyseal zones of the tubular bones. In mature people, bone deformations are less common, but the pain syndrome is more pronounced. X-ray examination of children and adolescents reveals an expansion of the metaepiphyseal zone of provisional calcification, most pronounced in the area of intensive growth (distal metaphysis of the femur).
Looser zones are typical for osteomalacia - symmetrical areas of bone clearing in places of maximum mechanical load: the pubic and ischial bones, the medial edge of the femoral neck, the lesser trochanter, the clavicle. These pseudofractures are also observed in the ribs and long bones.
The earliest radiological sign of renal hyperparathyroidism is considered to be subperiosteal erosions, usually developing on the radial side of the middle phalanx of the II and III fingers of the right hand. At first, the irregularities of the bone edge are difficult to distinguish from the normal version. Subsequently, they worsen, appear on the opposite (ulnar) side of the phalanx, and spread to the distal and proximally adjacent phalanges. In advanced cases, the cortical layer may completely disappear, and the erosive process may deepen to half the thickness of the phalanx. According to V. Wolbach (1947), osteoid protects mineralized bone from the action of osteoclasts. Osteoid is deposited inconsistently along the periosteal surface and therefore the subperiosteal region is the most common site of erosion.
Other typical locations of erosions are the lateral end of the clavicle, the sacroiliac articulation, the pubic fusion, the posterosuperior edge of the ribs, the anteromedial edge of the tibia, and the greater and lesser trochanters of the femur.
Subperiosteal erosions are characterized by loss of compactness of the cortical layer, areas of subcortical bone thinning, and are sometimes combined with cystic degeneration. Patients with osteitis fibrosa often experience fractures of the ribs, femoral neck (for example, during a seizure), compression of the vertebrae, etc.
With osteosclerosis, individual trabeculae first thicken, but later the boundaries of individual trabeculae merge, forming a radiologically dense homogeneous surface. Areas of osteosclerosis occur in the spine, pelvic bones, ribs, cheek bones and long bones of the limbs. In the spine, compacted areas of the upper and lower surfaces of each vertebra, alternating with sparse areas in the vertebral bodies, create a peculiar picture of a “striped” spinal column.
True osteoporosis is rare in uremic patients not receiving hemodialysis treatment. In patients undergoing hemodialysis treatment, changes resembling osteoporosis - thinning of the cortical layer, disappearance of trabeculae, juxtaarticular thinning, but representing dialysis osteopenia, are observed much more often.
Clinically, dialysis osteopenia is characterized by severe pain and numerous fractures that slowly undergo consolidation.
For the diagnosis of osteopenia great importance Along with X-ray methods, there are radio and X-ray densitometric methods that allow you to monitor the mineral density of bone tissue.
With secondary hyperparathyroidism, more often than with osteomalacia, deposits of calcium phosphate salts are found in soft tissues, various organs, and vascular walls. An increase in the phosphorus content in the serum of patients when the product of calcium and phosphorus concentrations exceeds 75, hypermagnesemia, alkalosis developing during hemodialysis, and local tissue damage predispose to the precipitation of salts.
S. Contiguglia et al. (1973) showed that calcifications of soft tissues and blood vessels consist of hydroxyapatite crystals, while amorphous microcrystals of calcium, magnesium and phosphorus are usually found in muscles, heart and lungs. The different composition of calcifications may be due to local tissue factors - the concentration of hydrogen ions, magnesium, calcium and phosphorus. The loss of hydroxyapatite crystals is accompanied by a pronounced fibrotic reaction, while amorphous crystals of calcium, magnesium and phosphorus do not cause it. In peripheral vessels, calcifications are found predominantly in the medial membrane, in contrast to atherosclerotic changes localized in the intima. The radial, ulnar arteries, vessels of the leg, foot and hand are most often affected by calcification.
Vascular calcification may complicate the placement of an arteriovenous graft and create additional difficulties during kidney transplantation. Arterial calcifications resolve slowly after subtotal parathyroidectomy and in patients with a well-functioning graft.
Clinical Nephrology
edited by EAT. Tareeva
In the early childhood(especially in the first year of life) diseases (or conditions) associated with impaired phosphorus-calcium metabolism occupy a leading place.
This is due to the extremely high rates of child development: in the first 12 months of life, body weight increases on average by 3 times, length by 1.5.
Such an intense increase in body size is very often accompanied by an absolute or relative deficiency of calcium and phosphorus in the body.
Various factors lead to the development of calcium- and phosphopenic conditions: deficiency of vitamins (mainly vitamin D), disturbances in the metabolism of vitamin D due to the immaturity of a number of enzyme systems, decreased absorption of phosphorus and calcium in the intestines, as well as their reabsorption in the kidneys, disorders of the endocrine system , regulating phosphorus-calcium metabolism, deviations in microelement status and much more.
Hypercalcemic conditions are much less common. They are, as a rule, iatrogenic in nature, but pose no less a threat to the body than hypocalcemia.
The main indicator characterizing Ca metabolism is its level in the blood, which is normally 2.3–2.8 mmol/l (P content in the blood is 1.3–2.3 mmol/l).
All factors that impair the absorption of calcium in the intestine and reduce its reabsorption in the kidneys cause hypocalcemia, which can be partially compensated by the leaching of Ca from the bones into the blood, which leads to the development of osteomalacia or osteoporosis.
Excessive absorption of Ca in the intestine leads to hypercalcemia, which is compensated by increased deposition in the bones (growth zones) and excretion in the urine.
The body's inability to maintain a normal blood Ca level causes either severe hypocalcemic conditions with manifestations of tetany, or leads to hypercalcemia with a picture of toxicosis, Ca deposition in various tissues and organs.
Its most important source is dairy products: 100 ml of human milk contains 30 mg of Ca, and the same amount of cow's milk contains 120 mg.
The condition of the mucous membrane of the small intestine is important: malabsorption syndromes and enteritis are accompanied by deterioration of absorption. The main regulator of calcium absorption is vitamin D.
The bulk (more than 90%) of calcium and 70% of phosphorus is found in the bones in the form inorganic salts. Throughout life, bone tissue is in a constant process of creation and destruction, caused by the interaction of three types of cells: osteoblasts, osteocytes and osteoclasts. Bones are actively involved in the regulation of Ca and P metabolism, maintaining their stable levels in the blood. With a decrease in the level of calcium and phosphorus in the blood (the product Ca x P is a constant value and equal to 4.5-5.0), bone resorption develops due to the activation of the action of osteoclasts, which increases the flow of these ions into the blood; When this coefficient increases, excessive deposition of salts in the bone occurs.
Half of the Ca contained in the blood is bound to plasma proteins (mainly albumin); of the remaining portion, more than 80% is ionized calcium, capable of passing through the capillary wall into the interstitial fluid. It is the regulator of various intracellular processes, including the conduction of a specific transmembrane signal into the cell and the maintenance of a certain level of neuromuscular excitability. Ca bound to plasma proteins is a reserve for maintaining the required level of ionized calcium.
The main regulators of phosphorus-calcium metabolism, along with vitamin D, are parathyroid hormone (PG) and calcitonin (CT), a thyroid hormone.
“Vitamin D” - ergocalciferol (vitamin D 2) and cholecalciferol (vitamin D 3). Ergocalciferol is found in small quantities in vegetable oil and wheat germ; cholecalciferol – in fish oil, milk, butter, eggs. The physiological daily requirement for vitamin D is quite stable and amounts to 400-500 IU. During pregnancy and lactation breast milk it increases by 1.5, maximum 2 times.
The normal supply of vitamin D to the body is associated not only with its intake from food, but also with its formation in the skin under the influence of UV rays with a wavelength of 280-310 mm. In this case, ergocalciferol is formed from ergosterol (precursor of vitamin D 2), and cholecalciferol is formed from 7-dehydrocholesterol (precursor of vitamin D 3). With sufficient insolation (according to some data, 10 minutes of irradiation of the hands is enough), the amount of vitamin D necessary for the body is synthesized in the skin. With insufficient natural insolation: climatic and geographical features, living conditions (rural area or industrial city), household factors, time of year, etc. The missing amount of vitamin D must come from food or in the form medicines. In pregnant women, vitamin D is deposited in the placenta, which provides the newborn with antirachitic substances for some time after birth.
The main physiological function of vitamin D (i.e., its active metabolites) in the body is the regulation and maintenance of phosphorus-calcium homeostasis in the body at the required level. This is achieved by influencing the absorption of calcium in the intestine, the deposition of its salts in the bones (bone mineralization) and the reabsorption of calcium and phosphorus in the renal tubules.
The mechanism of calcium absorption in the intestine is associated with the synthesis of calcium-binding protein (CaBP) by enterocytes, one molecule of which transports 4 calcium atoms. The synthesis of CaSB is induced by calcitriol through the genetic apparatus of cells, i.e. The mechanism of action of 1,25(OH) 2 D 3 is similar to hormones.
In conditions of hypocalcemia, vitamin D temporarily increases bone resorption, enhances the absorption of Ca in the intestine and its reabsorption in the kidneys, thereby increasing the level of calcium in the blood. In normocalcemia, it activates the activity of osteoblasts, reduces bone resorption and its cortical porosity.
In recent years, it has been shown that cells of many organs have receptors for calcitriol, which thereby participates in the universal regulation of intracellular enzyme systems. Activation of the corresponding receptors through adenylate cyclase and cAMP mobilizes Ca and its connection with the calmodulin protein, which promotes signal transmission and enhances the function of the cell, and accordingly, the entire organ.
Vitamin D stimulates the pyruvate-citrate reaction in the Krebs cycle, has an immunomodulatory effect, regulates the level of secretion of thyroid-stimulating hormone from the pituitary gland, and directly or indirectly (through calcemia) affects the production of insulin by the pancreas.
The second most important regulator of phosphorus-calcium metabolism is parathyroid hormone. The production of this hormone by the parathyroid glands increases in the presence of hypocalcemia, and especially when the concentration of ionized calcium in the plasma and extracellular fluid decreases. The main target organs for parathyroid hormone are the kidneys, bones and, to a lesser extent, the gastrointestinal tract.
The effect of parathyroid hormone on the kidneys is manifested by an increase in the reabsorption of calcium and magnesium. At the same time, phosphorus reabsorption decreases, which leads to hyperphosphaturia and hypophosphatemia. It is also believed that parathyroid hormone increases the ability of the kidneys to form calcitriol, thereby enhancing the absorption of calcium in the intestine.
In bone tissue, under the influence of parathyroid hormone, calcium from bone apatites turns into a soluble form, due to which it is mobilized and released into the blood, accompanied by the development of osteomalacia and even osteoporosis. Thus, parathyroid hormone is the main calcium-sparing hormone. It carries out rapid regulation of calcium homeostasis, constant regulation is a function of vitamin D and its metabolites. The formation of PG is stimulated by hypocalcemia; with a high level of Ca in the blood, its production decreases.
The third regulator of calcium metabolism is calcitonin, a hormone produced by the C-cells of the parafollicular apparatus of the thyroid gland. In terms of its effect on calcium homeostasis, it is a parathyroid hormone antagonist. Its secretion increases when the level of calcium in the blood increases and decreases when it decreases. Diet with big amount calcium in food also stimulates the secretion of calcitonin. This effect is mediated by glucagon, which is thus a biochemical activator of CT production. Calcitonin protects the body from hypercalcemic conditions, reduces the number and activity of osteoclasts, reducing bone resorption, enhances the deposition of Ca in the bone, preventing the development of osteomalacia and osteoporosis, and activates its excretion in the urine. The possibility of an inhibitory effect of CT on the formation of calcitriol in the kidneys is assumed.
Phosphorus-calcium homeostasis, in addition to the three described above (vitamin D, parathyroid hormone, calcitonin), is influenced by many other factors. Microelements Mg, Al are competitors of Ca in the absorption process; Ba, Pb, Sr and Si can replace it in salts found in bone tissue; thyroid hormones, somatotropic hormone, androgens activate the deposition of calcium in the bones, reduce its content in the blood, glucocorticoids contribute to the development of osteoporosis and the leaching of calcium into the blood; Vitamin A is an antagonist of vitamin D during absorption in the intestine. However, the pathogenic influence of these and many other factors on phosphorus-calcium homeostasis manifests itself, as a rule, with significant deviations in the content of these substances in the body.
Violations of phosphorus-calcium metabolism most often occur in young children.
Behind Lately the number of patients with chronic renal pathology has increased. Chronic kidney disease (CKD) is a decrease in kidney function or kidney damage within 3 months. and more. Glomerular filtration rate (GFR) is one of the main markers of decreased kidney function.
The increase in the number of patients with CKD in the world is characterized by an aging population, an increase in the number of patients with diabetes mellitus, and an increase in the number of patients with cardiovascular pathology.
That is why specialists in various fields of medicine are increasingly encountering nephrological patients. There are many challenges in treating a patient with CKD. One of these problems is adequate correction of phosphorus-calcium metabolism.
At the earliest stages of the disease, there is an increase in phosphorus in the body, which leads to a decrease in calcium, and this in turn stimulates the synthesis of parathyroid hormone. This parathyroid hormone can and does reduce the reabsorption of phosphorus in the kidneys. The synthesis of calcitriol, the active form of vitamin D3, is stimulated. Vitamin D3 is produced by hydroxylation of cholecalciferol. As a result, calcidiol and calcitriol are formed. In the kidneys, calcidiol is converted by 1-hydroxylase to calcitriol, which stimulates calcium in the intestines and also, to some extent, causes the removal of calcium from bones.
From the above it follows that parathyroid hormone and calcitriol contribute to the normalization of phosphorus-calcium metabolism.
As CKD progresses, phosphates are retained in the body and after some time the increased amount of calcium in the blood becomes constant. Phosphates stimulate the synthesis of parathyroid hormone and reduce the activity of 1-hydroxylase. Nephrosclerosis also reduces the production of this enzyme. Thus, the synthesis of calcitriol decreases, hypocalcemia develops and the secretion of parathyroid hormone increases.
With the development of secondary hyperparathyroidism, osteodystrophy occurs with a high rate of bone remodeling, the formation of cysts, a decrease in the amount of mineral compounds in the bone, osteomalacia and osteosclerosis.
Osteopathy becomes most pronounced in patients on hemodialysis. Osteodystrophy is mainly manifested by muscle weakness and bone pain. Pathological fractures are common in osteodystrophies.
It has now been established that increased levels of parathyroid hormone in the blood contribute to changes in the skeleton and play an important role in the pathogenesis of vascular calcification, calcification of heart valves, immune dysfunction, the development of anemia, and left ventricular hypertrophy.
Observation and control over the parameters of phosphorus-calcium metabolism in patients with diseases such as chronic kidney disease.
In those patients with GFR below 60 ml/min, such monitoring is mandatory. The following indicators are studied and monitored:
Correction takes place by prescribing an adequate diet and drug therapy. If GFR is below 30-40 ml/min, it is necessary to limit foods that contain phosphorus: fish, eggs, liver, nuts, coffee, chocolate, beer, cola. If the diet is ineffective and the level of parathyroid hormone and phosphates in the blood is maintained, drugs that bind phosphates in the intestines are used. The most commonly used are calcium carbonate or calcium acetate. First, 1-1.5 g is prescribed three times a day. The drug is taken with meals. The body should receive no more than 2 g of elemental calcium per day. In children, this dose increases to 2.5 g per day. Therapeutic measures are carried out under strict control of the levels of parathyroid hormone, calcium and phosphorus.
In case of severe hyperphosphatemia, antacids are used that adsorb excess phosphorus, but antacids cannot be used for a long time, since those drugs that contain aluminum can accumulate in the form of its hydroxide in the bones, which leads to aluminum intoxication.
During therapy, calcium levels should be normal. If its amount is reduced, the dose of the drug is increased and vitamin D is added. Vitamin D should only be used when the amount of calcidiol is known.
The half-life of calcidiol ranges from 25 to 30 days. The level of calcidiol in the blood indicates the body's supply of vitamin D. When calcidiol decreases below 30 ng/ml, clinical symptoms of vitamin D deficiency may develop, and these are osteomalacia and hypocalcemia.
In patients on hemodialysis, a deficiency of calcitriol and calcidiol was detected in 78%, and in almost 20% of patients, vitamin D deficiency was detected in a severe form.
If calcidiol decreases below 30 ng/ml, replacement treatment with ercogalciferol is carried out. If the level is above 30 ng/ml, calcitriol (vitamin D3) is used.
When CKD progresses to stage 5, only calcitriol or its analogues are used as replacement therapy. The most common in use is the precursor to calcitriol - alfacalcidiol.
This compound is represented by cholecalciferol, hydroxylated in the first position. When alphacalcidiol enters the stomach, it is absorbed and converted to the form of calcitriol. This drug is not hydroxylated by the kidneys, which makes it possible to use this drug in patients with CKD.
When eliminating calcitriol deficiency, the vicious circle of development of secondary hyperparathyroidism occurs in the disease chronic kidney disease.
Alphacalcidiol is used at the beginning of therapy at 0.25 mcg per day. The drug is titrated under strict control of the levels of parathyroid hormone, phosphorus and calcium in the blood plasma.
When parathyroid hormone decreases by a third and when calcium and phosphorus levels are normal, the dosage of alphacalcidiol is doubled. When parathyroid hormone reaches its normal values, the dosage of the drug is reduced by half. When parathyroid hormone decreases below the lower limit of normal, treatment with alfacalcidiol is terminated.
When treating with vitamin D preparations, it is necessary to avoid the development of hypercalcemia and hyperphosphatemia.
Hypercalcemia manifests itself:
Chronic vitamin D intoxication causes calcification of soft tissues, internal organs and blood vessels. If hypercalcemia develops during treatment, the drugs should be temporarily discontinued. If there is a persistent increase in calcium in the blood, they resort to dialysis for 3 weeks, forced diuresis, calcitonin.
The drug may interact with other medicines. For example, the risk of hypercalcemia increases when calcium supplements are prescribed with thiazide diuretics. Alphacalcidiol and digoxin increase the risk of developing intoxication with cardiac glycosides.
