Gilbert's syndrome

Gilbert's syndrome (pr. Zhil-bear), often shortened to the acronym GS, the most common hereditary cause of increased bilirubin, is found in about 5% of the population. The main symptom is otherwise harmless mild jaundice which does not require treatment, caused by elevated levels of unconjugated bilirubin in the bloodstream (hyperbilirubinemia).

The source of this hyperbilirubinemia is reduced activity of the enzyme which conjugates bilirubin and some other lipophillic molecules. Conjugation renders the bilirubin water-soluble and suitable for excretion via the kidneys.

Gilbert's syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and co-workers in 1901.

Pathogenesis

Gilbert's syndrome is caused by approximately 30%-50% reduced glucuronidation activity of the enzyme Uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UGT1A1). The gene which encodes UGT1AT normally has a promoter region containing the allele A(TA₆)TAA. Gilbert's syndrome is associated with homozygous A(TA₇)TAA alleles.

Signs and symptoms

Gilbert's syndrome produces an elevated level of unconjugated bilirubin in the bloodstream but normally has no serious consequence. Rarely, mild jaundice may appear.

Some patients report experiencing unpleasant physical symptoms during episodes of high bilirubin levels. They may report persistent or meal-related fatigue, dizziness, tremors, nausea, abdominal pain, and "brain fog", with or without jaundice. Because patients may be unaware of their condition but conscious of apparent jaundice, they may present these otherwise harmless symptoms at urgent-care facilities needlessly.

Gilbert's syndrome also reduces the liver's ability to detoxify certain drugs. For example, Gilbert's syndrome is associated with severe diarrhea and neutropenia in patients who are treated with irinotecan, which is metabolized by this enzyme.

While paracetamol (acetaminophen) is not metabolized by UGT1A1, it is metabolized by one of the other enzymes also deficient in most people with GS. Metabolism of paracetamol is thus reduced by 31%, leaving liver-toxic metabolites in the body for longer periods.

Diagnosis

While this syndrome is considered harmless, it is clinically important because it may be confused with much more dangerous liver conditions. However, these will show other indicators of liver dysfunction. Haemolysis can be excluded by a full blood count and lactate dehydrogenase levels. Liver biopsy is rarely necessary. The onset of GS is often in childhood or early adulthood.

Normal levels of total bilirubin (conjugated and unconjugated) are under 20 mmol/dl. Patients with GS show only elevated unconjugated bilirubin, while conjugated is in normal ranges and forms less that 20% of the total. Levels of bilirubin in GS patients should be between 20 mmol/dl and 80 mmol/dl. GS patients will have a ratio of unconjugated/conjugated (indirect/direct) bilirubin that is commensurately higher than those without GS. Other liver enzymes are expected to be similar between patients with and without GS. Complete liver enzyme tests are ordered in order to assure the correct diagnosis.

The level of total bilirubin is often increased if the blood sample is taken while fasting.

More severe types of gluconitril transferase disorders like GS are Crigler-Najjar syndrome (types I and II). These are much more severe and cause brain damage in infancy (type I) and teenage years (type II).

External links

Action on Gilbert's Syndrome - the UK organisation helping people with Gilbert's Syndrome
Gilbert's web - patient forum
GilbertsSyndrome.com - collection of information on Gilbert's Syndrome, including symptom survey
English + German Gilberts Syndrome Forum - patient forum

Synonyms

Alternative, less common names for this disorder are as follows:

Familial benign unconjugated hyperbilirubinaemia
Constitutional liver dysfunction
Familial non-hemolytic non-obstructive jaundice
Icterus intermittens juvenilis
Low-grade chronic hyperbilirubinemia
Unconjugated benign bilirubinemia

References

Gilbert A, Lereboullet P. La cholemie simple familiale. Sem Med 1901;21:241-3.
Extract from "Total Wellness" by Dr. Joseph Pizzorno
Gilbert's Syndrome Fact Sheet at AllRefer Health
Gilbert's Web Food Recommendations
Liver Detoxification Pathway from Liver Doctor Website

Footnotes

Eponymous diseases | Gastroenterology | Hepatology | Genetic disorders | Syndromes

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