Gilbert's syndrome

Gilbert's syndrome is a hereditary disease and is transmitted in an autosomal dominant manner. This syndrome is named after the Parisian physician Augustin Gilbert.

In Gilbert's syndrome, the binding of bilirubin to glucuronic acid in the liver decreases to 30% of normal. The bile contains predominantly bilirubin monoglucuronide and, to a lesser extent, diglucuronide. Bolivian squirrel monkeys serve as an experimental model for this disease.

[ 1 ], [ 2 ], [ 3 ], [ 4 ]

Causes of Gilbert's syndrome

Gilbert's syndrome is based on a genetic defect - the presence of an additional TA dinucleotide in the promoter region (A(TA)^TAA) of the gene encoding UDFGT 1*1, which leads to the formation of the region (A(TA)^TAA). This defect is inherited in an autosomal recessive manner, therefore, for the development of the disease, the patient must be homozygous for this allele. It is believed that the elongation of the promoter sequence disrupts the binding of the transcription factor IID, which leads to a decrease in the formation of the UDFGT 1 enzyme. However, a decrease in enzyme synthesis alone is not enough for the development of Gilbert's syndrome; other factors are also necessary, such as latent hemolysis and impaired bilirubin transport in the liver. Therefore, in Gilbert's syndrome, a slight impairment of the excretion of bromsulfalein (BS) and tolbutamide (a drug that is not subject to conjugation) is also noted.

The pathogenesis of the disease is based on the deficiency of the enzyme glucuronyl transferase in hepatocytes, which conjugates bilirubin with glucuronic acid. This leads to a decrease in the uptake and conjugation of bilirubin from the blood and the development of unconjugated hyperbilirubinemia and the appearance of jaundice.

Macroscopically, the liver is not changed in Gilbert's syndrome. Histological and histochemical examination of biopsy specimens reveals deposition of golden-brown pigment (similar to lipofuscin) in hepatocytes, obesity, glycogenesis of nuclei, activation of Kupffer cells, protein dystrophy of hepatocytes, and fibrosis of portal fields. In the early stages, these signs of the disease may not manifest themselves, but they naturally appear at later stages of the disease.

Gilbert's syndrome is observed in 1-5% of the population, 10 times more often in men than in women. The disease is usually detected in adolescence and young age (most often at 11-30 years). Life expectancy in Gilbert's syndrome is not lower than in healthy people, so no treatment is required and the patient only needs to be calmed down. Hyperbilirubinemia persists for life, but there is no increase in mortality.

In many patients, Gilbert's syndrome is first diagnosed after acute viral hepatitis (posthepatitis form of the disease).

[ 5 ], [ 6 ], [ 7 ]

Symptoms of Gilbert's syndrome

The general condition of patients is usually satisfactory. The main complaints are the appearance of jaundice, mild pain and a feeling of heaviness in the right hypochondrium, dyspeptic symptoms (nausea, bitterness in the mouth, loss of appetite, belching), bloating, often bowel disorders (constipation or diarrhea), asthenovegetative manifestations (depressed mood, fatigue, poor sleep, dizziness). The above complaints, as well as the appearance of jaundice, are provoked by stressful situations (emotional stress, heavy physical exertion), episodes of infection in the nasopharynx or biliary tract.

Jaundice is the main symptom of Gilbert's syndrome and has the following characteristic features:

• can be intermittent (occurs periodically after exposure to provoking factors - mental trauma, physical exertion, dietary errors, alcohol consumption, medications, etc.) or chronic;
• the degree of severity of jaundice varies: in many patients it manifests itself only as icterus of the sclera, while in a number of patients there may be a fairly pronounced diffuse matte-yellowish coloration of the skin and visible mucous membranes or only partial coloration of the palms, feet, and armpits;
• in some cases, xanthelasma of the eyelids, facial pigmentation, and scattered pigment spots on the skin are observed;
• In some cases, jaundice may be absent, although the level of bilirubin in the blood is elevated.

Liver enlargement is observed in 25% of patients, with the liver protruding from under the costal arch by 1-4 cm, its consistency is normal, and palpation is painless.

An enlarged spleen may occur in 10% of patients.

Diagnosis of Gilbert's syndrome

1. Complete blood count: usually without significant changes. In 1/3 of patients, hemoglobin may increase to over 160 g/l and the number of erythrocytes, while a decrease in ESR is also observed.
2. General urine analysis: no pathology, urine color unchanged, bilirubin and urobilin tests are negative. Some patients may experience moderate urobilinuria and slight darkening of urine during an exacerbation of the disease.
3. Liver function tests: the bilirubin content in the blood is increased due to the unconjugated (indirect) fraction. The bilirubin level in the blood usually does not exceed 85-100 μmol/l even during periods of exacerbation. In some cases, along with an increase in the content of unconjugated bilirubin, a slight increase in the level of conjugated (direct) bilirubin is observed. This form of Gilbert's syndrome is called alternating and is caused not only by a decrease in the activity of glucuronyl transferase, but also by a violation of bilirubin excretion.

The content of total protein and protein fractions, aminotransferases, alkaline phosphatase, cholesterol, urea, thymol and sublimate test values are usually normal. In some patients, during the period of exacerbation, a slight transient increase in aminotransferase activity and slight hypoalbuminemia are possible. However, it should be noted that changes in liver function tests are usually observed during a long course of the disease and the development of chronic persistent (portal) hepatitis.

4. The life span of red blood cells is normal.
5. Radioisotope hepatography using rose bengal labeled with ¹³¹ I reveals disturbances in the absorptive and excretory functions of the liver.

Special diagnostic tests for Gilbert's syndrome include a fasting test (an increase in serum bilirubin levels during fasting), a phenobarbital test (administration of phenobarbital, which induces liver conjugating enzymes, causes a decrease in bilirubin levels), and a nicotinic acid test (intravenous administration of nicotinic acid, which reduces the osmotic resistance of red blood cells, causes an increase in bilirubin levels).

Thin-layer chromatography reveals a significantly higher proportion (compared to the norm) of unconjugated bilirubin in chronic hemolysis or chronic hepatitis, which is of diagnostic value. Liver biopsy reveals a decrease in the content of conjugating enzymes. However, Gilbert's syndrome can usually be diagnosed without resorting to these special research methods.

The course of Gilbert's syndrome is usually undulating with periods of exacerbation and remission. During an exacerbation, jaundice, subjective manifestations of the disease, and unconjugated hyperbilirubinemia appear or intensify. Gilbert's syndrome lasts for many years; approximately 5 years after the onset of the disease, chronic persistent (portal) hepatitis may develop. In some patients, an inflammatory process may occur in the biliary tract.

[ 8 ]

Diagnostic criteria for Gilbert's syndrome

1. Chronic or intermittent, mild jaundice that appears or intensifies after psycho-emotional stressful situations, physical exertion, alcohol consumption, or dietary errors.
2. Isolated or predominant increase in the content of unconjugated (indirect) bilirubin in the blood.
3. Increased levels of unconjugated bilirubin in the blood of the patient's relatives.
4. Normal lifespan of erythrocytes, no signs of hemolytic anemia (there are no microcytes or microspherocytes in the peripheral blood smear; negative Coombs reaction - no antibodies to erythrocytes).
5. Positive results of the fasting test - limiting the total daily caloric intake to 400 kcal leads to an increase in unconjugated bilirubin in the blood serum during the day by 2 times or more. In hemolytic anemia and other liver diseases, short-term partial fasting does not lead to an increase in hyperbilirubinemia.
6. Normalization of bilirubin levels in the blood under the influence of treatment with phenobarbital (120-180 mg per day for 2-4 weeks), which increases the activity of glucuronyl transferase in hepatocytes.
7. In liver biopsies, glucuronyl transferase activity is reduced.

Serum bilirubin levels can be reduced with phenobarbital, but since jaundice is usually mild, cosmetic benefit from this treatment is limited to a few patients. Patients should be warned that jaundice may occur after intercurrent infections, repeated vomiting, and missed meals. For life insurance purposes, it is important to know that these patients are in the normal risk group.

[ 9 ], [ 10 ], [ 11 ]

Treatment of Gilbert's syndrome

There is no etiotropic treatment for Gilbert's syndrome. In case of exacerbation of the disease, bed or semi-bed rest, plenty of fluids, high-calorie diet and limitation of products containing preservatives are recommended.