Causes of increased bilirubin in the blood

Bilirubin in the blood is elevated in the following situations:

• Increased intensity of erythrocyte hemolysis.
• Damage to the liver parenchyma with disruption of its bilirubin-excreting function.
• Violation of the outflow of bile from the bile ducts into the intestines.
• Disturbances in the activity of the enzyme link that ensures the biosynthesis of bilirubin glucuronides.
• Impaired hepatic secretion of conjugated (direct) bilirubin into bile.

Increased intensity of hemolysis is observed in hemolytic anemias. Hemolysis can also be enhanced in vitamin B12 _- deficiency anemias, malaria, massive tissue hemorrhages, pulmonary infarctions, and crush syndrome (unconjugated hyperbilirubinemia). As a result of increased hemolysis, free bilirubin is intensively formed from hemoglobin in reticuloendothelial cells. At the same time, the liver is unable to form such a large amount of bilirubin glucuronides, which leads to an increase in free bilirubin (indirect) in the blood and tissues. However, even with significant hemolysis, unconjugated hyperbilirubinemia is usually insignificant (less than 68.4 μmol/l) due to the high capacity of the liver to conjugate bilirubin. In addition to increased bilirubin, hemolytic jaundice is accompanied by increased excretion of urobilinogen in urine and feces, since it is formed in the intestines in large quantities.

The most common form of unconjugated hyperbilirubinemia is physiological jaundice in newborns. The causes of this jaundice include accelerated hemolysis of red blood cells and immaturity of the liver system of absorption, conjugation (reduced activity of uridine diphosphate glucuronyl transferase) and secretion of bilirubin. Due to the fact that bilirubin accumulating in the blood is in an unconjugated (free) state, when its concentration in the blood exceeds the level of albumin saturation (34.2-42.75 μmol/l), it is able to overcome the blood-brain barrier. This can lead to hyperbilirubinemic encephalopathy. In the first day after birth, the concentration of bilirubin often increases to 135 μmol/l, in premature infants it can reach 262 μmol/l. For the treatment of such jaundice, stimulation of the bilirubin conjugation system with phenobarbital is effective.

Unconjugated hyperbilirubinemia includes jaundice caused by the action of drugs that increase the breakdown (hemolysis) of red blood cells, for example, acetylsalicylic acid, tetracycline, etc., as well as those metabolized with the participation of uridine diphosphate glucuronyl transferase.

In parenchymatous jaundice, hepatocytes are destroyed, the excretion of direct (conjugated) bilirubin into the bile capillaries is impaired, and it enters directly into the blood, where its content increases significantly. In addition, the ability of liver cells to synthesize bilirubin glucuronides decreases, as a result of which the amount of indirect bilirubin also increases. An increase in the concentration of direct bilirubin in the blood leads to its appearance in the urine due to filtration through the membrane of the renal glomeruli. Indirect bilirubin, despite the increase in concentration in the blood, does not enter the urine. Damage to hepatocytes is accompanied by a violation of their ability to destroy mesobilinogen (urobilinogen) absorbed from the small intestine to di- and tripyrrols. An increase in the content of urobilinogen in the urine can be observed even in the pre-icteric period. At the height of viral hepatitis, a decrease and even disappearance of urobilinogen in the urine is possible. This is explained by the fact that increasing stagnation of bile in liver cells leads to a decrease in the excretion of bilirubin and, consequently, to a decrease in the formation of urobilinogen in the biliary tract. Later, when the function of liver cells begins to recover, bile is excreted in large quantities, and urobilinogen again appears in large quantities, which in this situation is regarded as a favorable prognostic sign. Stercobilinogen enters the systemic circulation and is excreted by the kidneys with urine in the form of urobilin.

The main causes of parenchymatous jaundice include acute and chronic hepatitis, liver cirrhosis, toxic substances (chloroform, carbon tetrachloride, paracetamol), massive spread of cancer in the liver, alveolar echinococcus and multiple liver abscesses.

In viral hepatitis, the degree of bilirubinemia correlates to a certain extent with the severity of the disease. Thus, in hepatitis B, in a mild form of the disease, the bilirubin content does not exceed 90 μmol / l (5 mg%), in a moderate form it is within 90-170 μmol / l (5-10 mg%), in a severe form it exceeds 170 μmol / l (above 10 mg%). With the development of hepatic coma, bilirubin can increase to 300 μmol / l or more. It should be borne in mind that the degree of increase in bilirubin in the blood does not always depend on the severity of the pathological process, but can be due to the rate of development of viral hepatitis and liver failure.

Unconjugated types of hyperbilirubinemia include a number of rare syndromes.

• Crigler-Najjar syndrome type I (congenital non-hemolytic jaundice) is associated with a disorder of bilirubin conjugation. The syndrome is based on a hereditary deficiency of the enzyme uridine diphosphate glucuronyl transferase. Blood serum examination reveals a high concentration of total bilirubin (above 42.75 μmol/l) due to indirect (free). The disease usually ends fatally in the first 15 months, only in very rare cases can it manifest itself in adolescence. Phenobarbital is ineffective, and plasmapheresis gives only a temporary effect. Phototherapy can reduce the concentration of bilirubin in the blood serum by almost 50%. The main method of treatment is liver transplantation, which should be performed at a young age, especially if phototherapy is impossible. After organ transplantation, bilirubin metabolism is normalized, hyperbilirubinemia disappears, and the prognosis improves.
• Crigler-Najjar syndrome type II is a rare hereditary disorder caused by a less severe defect in the bilirubin conjugation system. It is characterized by a more benign course compared to type I. The concentration of bilirubin in the blood serum does not exceed 42.75 μmol/l, all accumulating bilirubin is indirect. Differentiation between types I and II of Crigler-Najjar syndrome is possible by assessing the effectiveness of phenobarbital treatment by determining the bilirubin fractions in the blood serum and the content of bile pigments in the bile. In type II (in contrast to type I), the concentrations of total and unconjugated bilirubin in the blood serum decrease, and the content of mono- and diglucuronides in the bile increases. It should be noted that Crigler-Najjar syndrome type II does not always proceed benignly, and in some cases the concentration of total bilirubin in the blood serum may be higher than 450 μmol/L, which requires phototherapy in combination with the administration of phenobarbital.
• Gilbert's disease is a disease caused by decreased absorption of bilirubin by hepatocytes. In such patients, the activity of uridine diphosphate glucuronyl transferases is reduced. Gilbert's disease is manifested by a periodic increase in the concentration of total bilirubin in the blood, rarely exceeding 50 μmol/l (17-85 μmol/l); these increases are often associated with physical and emotional stress and various diseases. At the same time, there are no changes in other indicators of liver function, there are no clinical signs of liver pathology. Special diagnostic tests are of great importance in the diagnosis of this syndrome: a fasting test (an increase in bilirubin levels during fasting), a phenobarbital test (taking phenobarbital, which induces conjugating enzymes of the liver, causes a decrease in the concentration of bilirubin in the blood), with nicotinic acid (intravenous administration of nicotinic acid, which reduces the osmotic resistance of red blood cells and thereby stimulates hemolysis, leads to an increase in the concentration of bilirubin). In clinical practice in recent years, mild hyperbilirubinemia caused by Gilbert's syndrome has been detected quite often - in 2-5% of examined individuals.
• Dubin-Johnson syndrome, chronic idiopathic jaundice, belongs to the parenchymatous type of jaundice (conjugated hyperbilirubinemia). This autosomal recessive syndrome is based on a disorder of hepatic secretion of conjugated (direct) bilirubin into bile (a defect of the ATP-dependent transport system of the canaliculi). The disease can develop in children and adults. The concentration of total and direct bilirubin in the blood serum is elevated for a long time. The activity of alkaline phosphatase and the content of bile acids remain within normal limits. In Dubin-Johnson syndrome, the secretion of other conjugated substances (estrogens and indicator substances) is also impaired. This is the basis for the diagnosis of this syndrome using the dye sulfobromophthalein (bromsulfalein test). Disruption of the secretion of conjugated sulfobromophthalein leads to its return to the blood plasma, in which a secondary increase in its concentration is observed (120 minutes after the start of the test, the concentration of sulfobromophthalein in the serum is higher than after 45 minutes).
• Rotor syndrome is a form of chronic familial hyperbilirubinemia with an increase in the unconjugated fraction of bilirubin. The syndrome is based on a combined disorder of the mechanisms of glucuronidation and transport of bound bilirubin through the cell membrane. When conducting a bromsulphalein test, in contrast to Dubin-Johnson syndrome, a secondary increase in the concentration of the dye in the blood does not occur.

In obstructive jaundice (conjugated hyperbilirubinemia), bile excretion is impaired due to blockage of the common bile duct by a stone or tumor, as a complication of hepatitis, in primary cirrhosis of the liver, when taking drugs that cause cholestasis. Increased pressure in the bile capillaries leads to increased permeability or disruption of their integrity and the entry of bilirubin into the blood. Due to the fact that the concentration of bilirubin in bile is 100 times higher than in the blood, and bilirubin is conjugated, the concentration of direct (conjugated) bilirubin in the blood increases sharply. Indirect bilirubin is slightly elevated. Mechanical jaundice usually leads to an increase in bilirubin in the blood (up to 800-1000 μmol/l). The content of stercobilinogen in feces decreases sharply, complete obstruction of the bile duct is accompanied by a complete absence of bile pigments in feces. If the concentration of conjugated (direct) bilirubin exceeds the renal threshold (13-30 μmol/l), it is excreted in the urine.

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