Test Questions

1. Describe the chemical composition of the liver.

2. What role does the liver play in carbohydrate and lipid metabolism?

3. What reactions of metabolism of amino acids and proteins occur in the liver?

4. What is the detoxifying function of the liver?

5. What is the mechanism of neutralization of xenobiotics in the liver?

6. What is the role of the liver in the metabolism of bilirubin?

7. What is the direct and indirect bilirubin?

8. What types of jaundice you know? What are their and symptoms?

9. What tests will distinguish obstructive jaundice from hemolytic jaundice?

13. Regulation of calcium and phosphorus metabolism

An adult human body contains about 1,2 kg of calcium. Calcium salts form the mineral component of bones (99% of total body calcium, 87% of phosphorus). Calcium in the bones is in the form of the mineral hydroxyapatite Са₁₀(РО₄)₆(ОН)₂. Another fund of calcium in the body is Са²⁺ions dissolved in a liquid or combined with proteins of fluids and tissues. There is a constant exchange of calcium between these funds.

Са²⁺ ions are cofactors of many enzymes, together with proteins-modulators are intermediary in the transmission of signals. Calcium is involved in secretion, fertilization, membrane permeability, blood clotting, muscle contraction.

The average adult male consumes 900-1000 mg calcium / day, a woman – 600-700 mg calcium / day, which is absorbed in the digestive tract to 20-40%. A considerable part of the food got calcium passes through the intestines and leaves the body with feces. The remaining 200 mg of calcium which are absorbed in the intestine is eliminated from the body mainly in urine. Normally, the body remains stable balance of calcium.

Calcium absorption in the intestine is carried out by active transport against an electrochemical gradient; by passive diffusion. Calcium is transported across the cell membrane by a vitamin D-dependent calcium-binding protein. Calcium absorption in the intestine in norm is not determined by its entering with food, but hormonal regulation of active transport system. Kidneys are involved in calcium metabolism by filtration and reabsorption.

Calcium metabolism is closely connected with the metabolism of phosphoric acid, which forms poorly soluble calcium salts: phosphate, hydrogen phosphate, dihydrogen phosphate.

Total phosphate of an adult male weighing 70 kg is about 700 grams, ~ 85% of which is in bones and teeth, ~14% are contained within the cells in organic form as a component of ATP and phospholipids. Phosphate in the extracellular fluid is in the form of phospholipids (70%) and inorganic phosphate. In blood plasma phosphates are presented in the form of free ions (80%) or bound to proteins. One of the main functions of inorganic phosphate in the body is buffer function.

The average statistically adult daily consumes 800-1200 mg of phosphorus, 80% of which is absorbed in the intestine, and the same amount is excreted by the kidneys. The basic mechanisms of transport of phosphate in the intestine are an active sodium-dependent transport; passive transport of the concentration gradient. The degree of adaptation of phosphate absorption in the intestine to a change in the consumption of phosphate is low, and therefore the intestine plays a minor role in the homeostasis of phosphates.

The kidneys play a major role in the homeostatic regulation of phosphate balance in the body. Entering of phosphate in the proximal tubule cells is carried out through Na/Pi- cotransporter.

Phosphate can bind free ionized calcium, so if the level of plasma inorganic phosphate increases the calcium content decreases.

The concentration of Са²⁺ ions in interstitial fluid and blood is equal to 9-11 mg/dl. Half of them are Са²⁺ ions in solution, the other half is in complex with albumin. In intracellular fluid concentration of calcium is in the thousands of times smaller. The concentration difference is created mainly Ca-ATPase with the participation of ion channels. Са²⁺ concentration in the blood and interstitial fluid is regulated by endocrine hormones, primarily parathyroid hormone, calcitonin and calcitriol.

Parathyroid hormone is a peptide hormone (84 amino acid residues) formed in the parathyroid glands. The biological activity of parathyroid hormone (PTH) is determined only by the first 32-34 amino acids (counting from the N-terminal end of peptide). This is the most important regulator of calcium homeostasis.

The main target organs of parathyroid hormone are the bones and kidneys. The cell membranes of these organs contain specific receptors of parathyroid hormone related to adenylate cyclase. PTH receptors are also found in the lungs, cardiovascular system, skin, erythrocytes, etc.

Two main mechanisms of action of parathyroid hormone are identified: activation of the system “adenylate cyclase – cyclic AMP (adenosine monophosphate) – protein kinase A” and the system “phosphatidyl inositol – protein kinase C”.

The activation of adenylate cyclase in the bones stimulates the metabolic activity of osteoclasts, bone resorption begins, and inflow of Са²⁺ and phosphates in the blood. In the kidney, PTH increases the reabsorption of Са²⁺ and increases the excretion of renal phosphates. PTH also stimulates the expression of genes and increases the production of a number of local protein factors and prostaglandins.

Synthesis and secretion of PTH are stimulated at lower concentrations of Са²⁺ in the blood. Restoration of normal Са²⁺ concentration in the blood leads to the termination of synthesis and secretion of the hormone. Specific calcium receptors are revealed in parathyroid cells. They provide the sensitivity of the parathyroid glands to changes in serum concentration of calcium, which leads to changes in PTH secretion. In the kidney, Ca-receptor is an important regulator of urinary calcium excretion.

Vitamin D₃ is a precursor of a substance that functions as a steroid hormone – calcitriol. Formation of calcitriol is stimulated mainly by PTH and hypophosphatemia. The conversion of vitamin D to calcitriol occurs with the participation of the liver and kidneys. Specific hydroxylases, which catalyze these reactions, are activated by PTH.

Synthesized in the kidney 1,25(OH)₂D₃ is transferred to the target cells by vitamin D-binding protein, where reacts with a nuclear receptor. Target organs of calcitriol are the small intestine and bones. In the small intestine hormone stimulates the absorption of calcium and phosphates, in bones – calcium mobilization. Calcitriol activates the genes controlling the synthesis of certain proteins, such as calcium-binding protein involved in calcium absorption. Calcitriol may also stimulate the reabsorption of calcium (and phosphate) in the renal tubule. It normalizes the formation of the skeleton and teeth in children, contributes to the preservation of bone structure.

When vitamin D is in deficiency rickets develops in children. It is a disturbance of mineralization of the growing bones, they do not have the normal stiffness, there are a variety of skeletal deformities – curved outward legs, knock-knees, "beads" on the edges, "bird chest", etc. Rickets is usually cured by vitamin D, but there are forms that do not respond to this treatment: they involve a violation of the transformation of vitamin D₃ in calcitriol in the body.

Prolonged intake of excessive amounts of vitamin D (several times more than the norm) leads to bone demineralization, to increase the concentration of calcium in the blood and its deposition in soft tissues, the formation of stones in the urinary tract.

Calcitonin is a hormone peptide (32 amino acids). It is synthesized in the C-cells of parathyroid and thyroid glands. Calcitonin secretion increases with the amount of calcium in the blood. Calcitonin effects due to its effect on specific calcitonin receptors and opposite to PTH effects. The primary target organ for calcitonin is bones, where it inhibits calcium mobilization. It reduces the concentration of calcium in serum. The total contribution of calcitonin in calcium homeostasis is very small compared with the role of PTH and vitamin D.

Other systemic hormones also affect the skeleton, particularly growth hormone, glucocorticoids, thyroid hormones and sex hormones. Several factors have local effects, such as prostaglandins, cytokines.

Changing the calcium concentration in the extracellular fluid leads to a change in its concentration inside the cells: transmembrane gradients of Са²⁺ concentrations are altered; the functioning of the calcium pump, calcium-dependent enzymes and regulatory systems are disrupted.

Convulsions, hyperreflexia, cramps of larynx are observed during hypocalcemia. This is a consequence of lowering the threshold for excitation of nerve and muscle cells. Hypocalcemia may result from malabsorption of calcium in the intestine, such as hypovitaminosis D, with high content of oxalate in the diet or other compounds that bind calcium. Severe hypocalcemia is rare. The most frequent cause of it is hypoparathyroidism caused by damage to the parathyroid glands during operations on the thyroid gland. Neuromuscular excitability is reduced during hypercalcemia, there is nerve function disorder – psychosis, stupor and even coma. Characteristic symptoms are calcification of soft tissues and the formation of stones in the urinary tract. The most common cause of hypercalcemia is hyperparathyroidism as a result of tumor of the parathyroid glands cells, an overdose of vitamin D.