Causes of increased bilirubin in the blood

Bilirubin is elevated in the blood in the following situations:

• Increase in the intensity of hemolysis of erythrocytes.
• The defeat of the parenchyma of the liver with a violation of its bilirubin-excretory function.
• Disturbance of the outflow of bile from the bile ducts into the intestine.
• Disturbances in the activity of the enzyme link, which ensures biosynthesis of bilirubin glucuronides.
• Disturbance of hepatic secretion of conjugated (direct) bilirubin in bile.

An increase in the intensity of hemolysis is observed in hemolytic anemia. Hemolysis can also be strengthened with vitamin B _12- deficiency anemia, malaria, massive tissue hemorrhage, pulmonary infarction, with a crushing disorder (unconjugated hyperbilirubinemia). As a result of increased hemolysis, intensive formation of free bilirubin from hemoglobin takes place in the 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 negligible (less than 68.4 μmol / L) due to the high liver capacity for bilirubin conjugation. In addition to increasing bilirubin in hemolytic jaundice, increased isolation of urobilinogen with urine and feces is detected, since it is formed in the intestine in large quantities.

The most common form of unconjugated hyperbilirubinemia is physiological jaundice in newborns. The causes of this jaundice include accelerated hemolysis of erythrocytes and immaturity of the hepatic system of absorption, conjugation (reduced activity of uridine diphosphate glucuronyltransferase), and bilirubin secretion. Due to the fact that bilirubin accumulating in the blood is in the 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 preterm infants it can reach a value of 262 μmol / l. To treat such jaundice, stimulation of the conjugation system of bilirubin with phenobarbital is effective.

Unconjugated hyperbilirubinemia includes jaundice caused by the action of drugs that enhance the breakdown (hemolysis) of erythrocytes, for example, acetylsalicylic acid, tetracycline, etc., and also metabolized with the participation of uridine-diphosphate-glucuronyl transferase.

With parenchymal jaundice, the destruction of hepatocytes occurs, the excretion of direct (conjugated) bilirubin into the bile capillaries is broken and it enters directly into the blood, where its content significantly increases. In addition, the ability of the hepatic cells to synthesize glucuronides of bilirubin decreases, as a result of which the amount of indirect bilirubin also increases. An increase in the concentration in the blood of direct bilirubin 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. The defeat of hepatocytes is accompanied by a violation of their ability to break up to di- and tripyrrols mesobilinogen (urobilinogen) sucked from the small intestine. An increase in the level of urobilinogen in urine can be observed even in the pre-ironic period. In the midst of viral hepatitis, the decrease and even disappearance of urobilinogen in the urine is possible. This is because the increasing stasis of bile in the liver cells leads to a decrease in the release of bilirubin and, consequently, to a decrease in the formation of urobilinogen in the bile ducts. Later, when the function of the liver cells begins to recover, bile is released in large numbers, and urobilinogen appears in large quantities, which in this situation is regarded as a favorable prognostic sign. Sterkobilinogen gets into the big circle of blood circulation and is allocated by kidneys with urine in the form of urobilin.

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

With viral hepatitis, the degree of bilirubinemia correlates to a certain extent with the severity of the disease. Thus, for hepatitis B, with a mild form of the disease, the bilirubin content does not exceed 90 μmol / l (5 mg%), with an average case it is in the range of 90-170 μmol / l (5-10 mg%), with heavy it exceeds 170 μmol / l ( higher than 10 mg%). With the development of the 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, and may be due to the rates of development of viral hepatitis and liver failure.

Unconjugated types of hyperbilirubinemia include a number of rare syndromes.

• Syndrome Krigler-Nayyar type I (congenital non-hemolytic jaundice) is associated with a violation of bilirubin conjugation. At the heart of the syndrome lies the hereditary deficiency of the enzyme uridine-diphosphate-glucuronyltransferase. When studying blood serum, a high concentration of total bilirubin (above 42.75 μmol / l) is detected due to indirect (free). The disease usually ends lethal in the first 15 months, only in very rare cases it can manifest itself in adolescence. The intake of phenobarbital is ineffective, and plasmapheresis only gives a temporary effect. With phototherapy, the concentration of bilirubin in serum can be reduced by almost 50%. The main method of treatment is liver transplantation, which must be performed at a young age, especially if phototherapy is not possible. After organ transplantation, the metabolism of bilirubin normalizes, hyperbilirubinemia disappears, the prognosis improves.
• The Krigler-Nayyar type II syndrome is a rare hereditary disease caused by a less serious defect in the bilirubin conjugation system. Characterized by a benign course compared with type I. The concentration of bilirubin in the serum does not exceed 42.75 μmol / l, the entire accumulating bilirubin refers to the indirect. Differentiate the I and II types of Kriegler-Nayar syndrome by evaluating the effectiveness of phenobarbital treatment by determining the fractions of bilirubin in serum and the content of bile pigments in the bile. In type II (in contrast to type I), the concentrations of total and non-conjugated bilirubin in serum decrease, and the content of mono- and di-glucuronides in the bile increases. It should be noted that the Kriegler-Nayar type II syndrome does not always occur in good quality, and in some cases the concentration of total bilirubin in the blood serum may be above 450 μmol / l, which requires the use of phototherapy in combination with the appointment of phenobarbital.
• Disease Gilbert - a disease caused by a decrease in the absorption of bilirubin by hepatocytes. In such patients, the activity of uridine-diphosphate-glucuronyl transferases is decreased. Gilbert's disease is manifested by a periodic increase in blood concentrations of total bilirubin, 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 hepatic pathology. Diagnostic tests of this syndrome have special diagnostic tests: a test with fasting (increasing the level of bilirubin against fasting), a test with phenobarbital (taking phenobarbital, inducing conjugating enzymes of the liver, causing a decrease in the concentration of bilirubin in the blood), with nicotinic acid (intravenous injection of nicotine acid, which reduces osmotic resistance of erythrocytes and thereby stimulates hemolysis, leads to an increase in the concentration of bilirubin). In clinical practice in recent years, light hyperbilirubinemia, due to Gilbert's syndrome, is detected quite often - in 2-5% of the examined individuals.
• To the parenchymal type of jaundice (conjugated hyperbilirubinemia) refers to the Dabin-Johnson syndrome - chronic idiopathic jaundice. At the heart of this autosomal recessive syndrome lies the violation of the hepatic secretion of conjugated (direct) bilirubin in bile (defect of the ATP-dependent tubular transport system). The disease can develop in children and adults. In the blood serum, the concentration of total and direct bilirubin has been increased for a long time. The activity of alkaline phosphatase and the content of bile acids remain within normal limits. In Dabin-Johnson syndrome, secretion of other conjugated substances (estrogens and indicator substances) is also impaired. This is the basis for the diagnosis of this syndrome with the use of sulfobromphthalein dye (bromsulfalein test). Violation of the secretion of conjugated sulfobromphthalein results in the fact that it again returns to the blood plasma, in which a secondary increase in its concentration is observed (after 120 min after the beginning of the sample the concentration of sulfobromphthalein in the serum is higher than 45 minutes).
• Rotor Syndrome is a form of chronic familial hyperbilirubinemia with an increase in the unconjugated fraction of bilirubin. At the heart of the syndrome lies a combined disturbance of the mechanisms of glucuronidation and transport of bound bilirubin through the cell membrane. In the conduct of the bromsulfalein test, in contrast to the Dabin-Johnson syndrome, there is no secondary increase in the concentration of the dye in the blood.

With obstructive jaundice (conjugated hyperbilirubinemia), biliary exclusion is caused by blockage of the common bile duct with a stone or tumor, as a complication of hepatitis, with primary cirrhosis of the liver, with the use of drugs that cause cholestasis. The increase in pressure in the bile capillaries leads to an increase in the permeability or disruption of their integrity and the entry of bilirubin into the blood. Due to the fact that the concentration of bilirubin in the bile is 100 times higher than in the blood, and bilirubin is conjugated, the concentration of direct (conjugated) bilirubin in the blood sharply rises. Several increased indirect bilirubin. Mechanical jaundice usually leads to an increase in bilirubin in the blood (up to 800-1000 μmol / l). In stool sharply reduced the content of sterocilinogen, complete obturation of the bile duct is accompanied by a complete absence of bile pigments in the feces. If the concentration of conjugated (direct) bilirubin exceeds the renal threshold (13-30 μmol / l), then it is excreted in the urine.

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