Gilbert's Syndrome

Gilbert syndrome is a hereditary disease and is transmitted by an autosomal dominant type. This syndrome is named in honor of the Parisian therapist Augustine Gilbert. 

In Gilbert's syndrome, the binding of bilirubin to glucuronic acid in the liver is reduced to 30% of normal. In bile, the content of predominantly monoglycuronide bilirubin and, to a lesser extent, diglucuronide, increases. The experimental model of this disease is Bolivian squirrel monkeys.

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Causes of Gilbert's Syndrome

At the heart of Gilbert's syndrome is a genetic defect-the presence on the promoter site (A (TA) ^ TAA) of the gene encoding UDFGT 1 * 1, an additional dinucleotide of TA, which leads to the formation of a site (A (TA) ^ TAA). This defect is inherited by autosomal recessive type, therefore for the development of the disease the patient must be homozygous for this allele. It is believed that the extension of the promoter sequence disrupts the binding of the transcription factor IID, which leads to a decrease in the formation of the enzyme UDPGT 1. However, only reduction in the synthesis of enzymes is insufficient for the development of Gilbert's syndrome; it is also necessary to have other factors, for example, latent hemolysis and disruption of bilirubin transport in the liver. Therefore, in Gilbert's syndrome, there is also a slight disruption in the release of bromsulfalein (BS) and tolbutamide (a drug that does not undergo conjugation).

At the heart of the pathogenesis of the disease is the insufficiency in the hepatocytes of the enzyme glucuronyltransferase, which conjugates bilirubin with glucuronic acid. This leads to a decrease in the capture from the blood and conjugation of bilirubin and the development of non-typed hyperbilirubinemia and the appearance of jaundice.

Macroscopically, the liver is not changed in Gilbert's syndrome. Histological and histochemical studies of biopsy specimens show a deposition in the hepatocytes of a golden brown pigment (similar to lipofuscin), obesity, glycogenesis of nuclei, activation of Kupffer cells, hepatocyte protein dystrophy, portal field fibrosis. In the early period, these signs of the disease may not appear, but they naturally appear in later terms 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 found in adolescents and young adults (most often in 11-30 years). Life expectancy in Gilbert's syndrome is not lower than in healthy people, therefore, no treatment is required and the patient needs only to calm down. Hyperbilirubinemia persists for life, but no increase in mortality.

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

[6], [7], [8]

Symptoms of Gilbert's Syndrome

The general condition of patients is usually satisfactory. The main complaints are the appearance of jaundice, uneasy pain and a feeling of heaviness in the right hypochondrium, dyspeptic phenomena (nausea, bitterness in the mouth, loss of appetite, eructation), bloating, often stools (constipation or diarrhea), astheno-vegetative manifestations (depressed mood, fatigue, poor sleep, dizziness). These complaints, as well as the appearance of jaundice, are provoked by stressful situations (emotional stress, heavy physical stress), episodes of infection in the nasopharynx or bile ducts.

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

• it may be intermittent (it occurs periodically after exposure to provoking factors - mental trauma, physical activity, bias in the diet, alcohol intake, medications, etc.) or chronic;
• the severity of jaundice varies: in many patients it manifests itself only with the sclera, in a number of patients a sufficiently pronounced diffuse matte-icteric staining of the skin and visible mucous membranes or only partial staining of the palms, feet, axillary hollows;
• in some cases xanthelasms of the eyelids, pigmentation of the face, scattered pigment spots on the skin are observed;
• in some cases, jaundice may be absent, although the level of bilirubin in the blood is increased.

Liver enlargement is observed in 25% of patients, while the liver protrudes from under the costal arch by 1-4 cm, its consistency is usual, palpation is painless.

Enlargement of the spleen can be in 10% of patients.

Diagnosis of Gilbert's Syndrome

1. General blood test: usually without significant changes. In 1/3 of patients, hemoglobin can increase in excess of 160 g / l and the number of erythrocytes, while a decrease in ESR is also observed.
2. The general analysis of urine: without pathology, the color of urine is not changed, the samples for bilirubin and urobilin are negative. In some patients in the period of exacerbation of the disease, moderate urobilinuria and a slight darkening of urine are possible.
3. Functional tests of the liver: the content of bilirubin in the blood is increased due to the unconjugated (indirect) fraction. The level of bilirubin 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 syndrome is called alternating and is caused not only by a decrease in the activity of glucuronyltransferase, but also by a violation of bilirubin excretion.

The content of total protein and protein fractions, aminotransferases of alkaline phosphatase, cholesterol, urea, indices of thymol and sulemic samples, as a rule, are normal. In some patients in the exacerbation period, a slight transient increase in aminotransferase activity, a slight hypoalbuminemia, is possible. However, it should be noted that changes in functional liver samples are usually observed with a prolonged course of the disease and the development of chronic persistent (portal) hepatitis.

4. The lifespan of erythrocytes is normal.
5. Radioisotope hepatography using Bengal pink, labeled ¹³¹ I, reveals impaired absorption and excretory functions of the liver.

Special diagnostic tests for Gilbert syndrome include a fasting test (increasing serum bilirubin level against fasting), a phenobarbital test (taking phenobarbital inducing conjugating liver enzymes, lowering the level of bilirubin), a sample with nicotinic acid (intravenous nicotinic acid, which reduces osmotic resistance of erythrocytes, causes an increase in the level of bilirubin).

Thin layer chromatography reveals a significantly higher proportion (in comparison with the norm) of unconjugated bilirubin in chronic hemolysis or chronic hepatitis, which is of diagnostic significance. With liver biopsy, a decrease in the content of conjugating enzymes is revealed. However, Gilbert's syndrome usually can be diagnosed without resorting to these special methods of investigation.

The course of Gilbert's syndrome is usually wavy with periods of exacerbation and remission. During an exacerbation, jaundice appears or worsens, subjective manifestations of the disease and unconjugated hyperbilirubinemia. Gilbert syndrome lasts for many years, approximately 5 years after the onset of the disease, chronic persistent (portal) hepatitis can form. In some patients, it is possible to join the inflammatory process in the biliary tract.

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Diagnostic criteria for Gilbert's syndrome

1. Chronic or intermittent, blurred jaundice, manifested or enhanced after psychoemotional stress situations, physical stress, alcohol intake, dietary errors.
2. Isolated or predominant increase in the content of unconjugated (indirect) bilirubin in the blood.
3. An increase in the level of unconjugated bilirubin in the blood from relatives of the patient.
4. Normal life span of erythrocytes, absence of signs of hemolytic anemia (in the smear of peripheral blood there are no microcytomas, microspherocytes, negative Coombs reaction - no antibodies to erythrocytes).
5. Positive results of the sample with fasting - the restriction of the total daily calorific value of 400 kcal leads to an increase in unconjugated bilirubin in the blood serum during the day by 2 times or more. With hemolytic anemia and other liver diseases, a short-term partial fasting does not lead to an increase in hyperbilirubinemia.
6. Normalization of the level of bilirubin in the blood under the influence of treatment with phenobarbital (120-180 mg per day for 2-4 weeks), which increases the activity of glucuronyltransferase in hepatocytes. 
7. In hepatic biopsy samples, the activity of glucuronyltransferase has been reduced.

The level of bilirubin in the serum can be reduced with phenobarbital, but since jaundice is usually slightly expressed, the cosmetic effect of such treatment is noted only in a few patients. It is necessary to warn patients that jaundice can appear after intercurrent infections, repeated vomiting and missed food intake. For life insurance of such patients it is important to know that they belong to the group of usual risk.

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Treatment of Gilbert's syndrome

Etiotropic treatment of Gilbert's syndrome is absent. When the disease worsens, it is recommended to have a bed or half-bed regime, plenty of drink, a high calorie diet and a restriction of foods that contain preservatives.