Pathogenesis of hypotrophy

The pathogenesis of hypotrophy is complex. Despite the diversity of etiological factors, it is based on a chronic stress reaction - one of the universal non-specific pathophysiological reactions of the body that occurs in many diseases, as well as with prolonged exposure to various damaging factors.

The impact of stress factors causes complex changes and a complex reaction of all links of the neuroendocrine-immune system, leading to a radical restructuring of metabolic processes and a change in the reactivity of the body. The child's basal metabolic rate increases sharply and the need for energy and plastic material increases significantly.

Increased protein and calorie requirements in children with pathology)

State	Clinical manifestations	Need
		Energy, %	Protein, %
Healthy	None	100	100
Mild stress	Anemia, fever, mild infection, minor surgery	100-120	150-180
Moderate stress	Musculoskeletal injury, exacerbation of chronic disease	120-140	200-250
Significant stress	Sepsis, severe trauma, major surgery	140-170	250-300
Severe stress	Severe burns, rapid rehabilitation in case of hypotrophy	170-200	300-400

The hormonal response in hypotrophy is combined, but the catabolic direction of the processes prevails. An increase in the level of catecholamines, glucagon and cortisol (powerful catabolic hormones) leads to increased lipolysis and protein destruction with the mobilization of amino acids (primarily from skeletal muscles), as well as to the activation of hepatic gluconeogenesis. In addition, the activity of thyroid hormones increases, an increase in the level of antidiuretic hormone and the development of hyperaldosteronism are noted, which significantly changes the electrolyte balance in the body of a child with hypotrophy. In addition to catabolic hormones, the production of anabolic hormones also increases, in particular STH, but its concentration increases against the background of a low level of somatomedins and insulin-like growth factor, which completely neutralizes its activity. The level of another anabolic hormone - insulin - is usually reduced in hypotrophy, in addition, its activity is impaired at the receptor and post-receptor level. Possible causes of insulin resistance in hypotrophy:

• significant increase in the activity of counter-insular hormones;
• high serum levels of non-esterified fatty acids against the background of activated lipolysis;
• electrolyte imbalance in the form of decreased levels of chromium, potassium and zinc.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ]

Water-electrolyte imbalance

Such neuroendocrine regulation disorders in children with hypotrophy lead to significant changes in the internal environment of the body and body composition. The level of general hydration increases sharply: the water content in the body increases by 20-25% and reaches 89% of the total body weight, while in children this figure does not normally exceed 60-67%. The hydration level increases due to both intracellular and (to a greater extent) extracellular fluid. At the same time, a redistribution of fluid in the body is observed: mainly fluid is concentrated in the interstitial space, and the BCC decreases sharply (to 50% of the normal level), which is probably associated with the development of hypoalbuminemia and a decrease in the osmotic pressure of blood plasma in children with hypotrophy.

A decrease in the BCC causes a decrease in renal plasma flow and filtration, which stimulates a further increase in the production of antidiuretic hormone and aldosterone and the retention of sodium and water in the body, closing a vicious circle. In children with hypotrophy, a sharp excess of sodium in the body is noted even in the absence of edema, and sodium accumulates mainly in the intercellular space. The content of total sodium in the body with hypotrophy increases almost 8 times, while its serum level may remain within the normal range or be slightly elevated. The level of total potassium in the body decreases to 25-30 mmol / kg, in a healthy child this figure is 45-50 mmol / kg. A decrease in the content of total potassium is directly related to the inhibition of protein synthesis and sodium retention in the body. With hypotrophy, the level of other minerals also decreases: magnesium (by 20-30%), phosphorus, iron, zinc, copper. A deficiency of most water- and fat-soluble vitamins is noted.

Changes in protein metabolism

Protein metabolism is subject to the greatest changes in hypotrophy. The total protein content in the body of a child with hypotrophy decreases by 20-30%. A decrease in both muscle (by 50%) and visceral protein pools is noted. The total albumin level in the body decreases by 50%, but the extravascular albumin pool is actively mobilized and returns to circulation. The concentration of most transport proteins in the blood plasma decreases: transferrin, ceruloplasmin, retinol-binding protein. The level of fibrinogen and most blood coagulation factors (II, VII, X, V) decreases. The amino acid composition of the protein changes: the level of essential amino acids decreases by 50%, the proportion of amino acids with a branched side chain decreases, the content of valine decreases by 8 times. Due to the suppression of lysine and histidine catabolism, their level remains virtually unchanged. The content of alanine and other glycogenic amino acids in the body increases significantly due to the breakdown of muscle proteins and an increase in transaminase activity in muscle tissue.

Changes in protein metabolism are gradual and adaptive. The body adapts to a significantly reduced protein flow from the outside, and a child with hypotrophy experiences “conservation” of its own protein metabolism. In addition to inhibition of synthesis, albumin breakdown slows down by an average of 50%. The half-life of albumin doubles. With hypotrophy, the efficiency of amino acid reutilization in the body increases to 90-95%, while normally this figure does not exceed 75%. Enzymatic activity of the liver increases with simultaneous inhibition of urea production and excretion (up to 65-37% of the normal level). Muscle protein is actively used to maintain adequate levels of serum and liver protein pools. In muscle tissue, inhibition of synthetic activity develops, and urinary excretion of creatinine, hydroxyproline, and 3-methylhistidine increases.

[ 8 ], [ 9 ], [ 10 ], [ 11 ]

Changes in fat metabolism

Due to increased lipolysis, a threefold decrease in the volume of adipose tissue is observed in children with hypotrophy. Fats are actively used for gluconeogenesis processes, which leads to a decrease in the serum level of triglycerides, cholesterol and phospholipids. Very low-density lipoproteins are practically absent in the blood plasma, and the concentration of low-density lipoproteins is significantly reduced. Due to a deficiency of apoproteins, a lack of lysine, choline and carnitine in the body, lipoprotein synthesis is disrupted. A pronounced deficiency of essential fatty acids is noted. Reduced lipoprotein lipase activity leads to a disruption in the utilization of triglycerides in tissues; triglyceride overload (their content increases by 40%) with an insufficient amount of low-density lipoproteins negatively affects liver function, which leads to the development of ballooning and fatty degeneration of hepatocytes.

[ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ]

Changes in the gastrointestinal tract

Dystrophic changes in the small intestinal mucosa lead to villus atrophy and disappearance of the brush border. The secretory function of the digestive glands is impaired, the acidity of the gastric juice decreases, and the production and activity of digestive enzymes and biliary secretions are inhibited. The barrier function of the intestinal mucosa suffers: intercellular interaction of enterocytes is impaired, the production of lysozyme and secretory immunoglobulin A is inhibited. Due to dystrophy of the muscular layers of the intestinal wall, intestinal motility is impaired, general hypotension and dilation with periodic waves of antiperistalsis develop. Such changes in the gastrointestinal tract lead to the development of maldigestion, malabsorption, ascending bacterial contamination of the small intestine and worsening of BEM.

[ 20 ], [ 21 ], [ 22 ], [ 23 ], [ 24 ], [ 25 ], [ 26 ], [ 27 ], [ 28 ], [ 29 ]

Changes in the cardiovascular system

In children with hypotrophy, the cardiovascular system is characterized by a tendency to develop centralization of blood circulation, which occurs against the background of hypovolemia and is manifested by a hyperdynamic reaction of the myocardium, pulmonary hypertension, spastic state of precapillary arterioles, and impaired microhemocirculation with signs of "sludge syndrome" in microvessels. Hemodynamic disorders are pathogenetically associated with a chronic stress reaction. With hypotrophy of I and II degrees, increasing sympathicotonia and increasing activity of the central regulatory circuit are noted, with III degree - "failure of adaptation", decentralization of regulation with a transition to autonomous levels. With a severe form of hypotrophy, a negative chronotropic effect, a tendency to hypotension, bradycardia and a high risk of hypovolemic shock are noted. However, infusion therapy should be used with extreme caution, since due to high tissue hydration, changes in the microcirculatory bed and the development of sodium-potassium imbalance, there is a high risk of rapid development of cardiovascular failure and sudden death syndrome due to asystole.

[ 30 ], [ 31 ], [ 32 ], [ 33 ], [ 34 ], [ 35 ], [ 36 ], [ 37 ]

Changes in the immune system

In children with hypotrophy, transient secondary immunodeficiency (metabolic immunodepression) develops. The pathogenetic link in the disturbances of immunological reactivity in hypotrophy is metabolic shifts associated with a pronounced deficiency of plastic material (protein), instability of carbohydrate metabolism with peaks of transient hyperglycemia and switching of metabolism mainly to lipid metabolism. Disturbances of both innate and acquired immunity are noted. Disturbances of innate immune protection in hypotrophy mostly concern microcytic phagocytosis. Due to impaired maturation of neutrophils and their mobilization from the bone marrow, the number of circulating neutrophils in hypotrophy decreases slightly, but their functional activity suffers significantly: the chemitactic and opsonizing activity of neutrophils is suppressed, their ability to lyse phagocytosed bacteria and fungi is impaired. The function of macrophages suffers slightly. Hypotrophy does not lead to significant disruptions of the complement system, but when an infection is superimposed, the latter is quickly depleted. A decrease in the number and lytic activity of NK cells is noted. In acquired immunity, the cellular link of immune defense is most damaged in hypotrophy. Both the primary and secondary cellular immune responses are suppressed. The absolute number of T cells, especially CD4, decreases, and the CD4/CD8 ratio is disrupted. The level of immunoglobulins is usually unchanged, but these antibodies have low affinity and specificity.

[ 38 ], [ 39 ], [ 40 ], [ 41 ]

Kwashiorkor

Kwashiorkor is a special type of hypotrophy, in its development a significant role is given to a predominantly carbohydrate diet with a sharp deficit of protein food and the layering of a secondary infection against the background of insufficient nutrition and impaired adaptation, which causes a significant restructuring of metabolic processes in the body and, first of all, the protein-synthetic function of the liver. In the liver, the synthesis of visceral transport proteins (such as albumin, transferrin, lipoproteins) is blocked and the production of acute phase proteins necessary for ensuring the inflammatory response of the body is activated. Against the background of a deficit of transport proteins, hypooncotic edema and fatty degeneration of the liver quickly develop. Kwashiorkor, like other forms of hypotrophy, is a manifestation of a classic stress reaction, but its development is accelerated, therefore the homeostasis disorders described above are also true for this form of hypotrophy, but they are more acute and intense.