Gilbert's syndrome

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Overview
Gilbert's syndrome (pr. Zhil-bear), often shortened to the acronym GS, is the most common hereditary cause of increased bilirubin, and is found in up to 5% of the population. The main symptom is otherwise harmless 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 glucuronyltransferase which conjugates bilirubin and some other lipophilic molecules. Conjugation renders the bilirubin water-soluble and suitable for excretion via the kidneys.

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

In German literature, it is commonly associated with Jens Einar Meulengracht.

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 UGT1A1 normally has a promoter region TATA box containing the allele A(TA6)TAA. Gilbert's syndrome is associated with homozygous A(TA7)TAA alleles. The allele polymorphism is referred to as UGT1A1*28.

Jaundice
Gilbert's syndrome produces an elevated level of unconjugated bilirubin in the bloodstream but normally this has no serious consequence. Mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic.

It has been reported that GS may contribute to an accelerated onset of neonatal jaundice.

Some patients report experiencing unpleasant physical symptoms during episodes of high bilirubin levels. They may report meal-related fatigue, tremors, nausea, and abdominal pain, with jaundice. Because patients may be unaware of their condition but conscious of apparent jaundice, they may present these symptoms at urgent-care facilities needlessly.

Detoxification of certain drugs
The enzymes that are defective in GS (UGT1A1) are also responsible for some of 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 UGT1A1.

While paracetamol (acetaminophen) is not metabolized by UGT1A1, it is metabolized by one of the other enzymes also deficient in some people with GS. A subset of people with GS may have an increased risk of paracetamol toxicity.

Reduced risk of ischemic heart disease
One research group in the Czech Republic has found a reduced incidence of atherosclerotic disease in subjects with GS. This is supposed to be due to bilirubin IXα being recognised as a potent antioxidant.

Diffuse symptoms
Many people report diffuse symptoms related to GS - feeling tired all the time (fatigue), difficulty maintaining concentration, loss of appetite, abdominal pain, loss of weight and others -, but no clear adverse symptoms related to elevated levels of unconjugated bilirubin have been found in adults during scientific studies. . This has led some to dispute whether GS should classify as a disease.

Exclusion of other conditions
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:

Normal levels of total bilirubin (conjugated and unconjugated) are under 20 mmol/dL. Patients with GS show predominantly elevated unconjugated bilirubin, while conjugated is usually in normal ranges and form less than 20% of the total. Levels of bilirubin in GS patients should be between 20 mmol/dl and 80 mmol/dl (or, divided by 17.1 to express these numbers in mg/dL, between 1.17 and 4.68 mg/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.
 * Hemolysis can be excluded by a full blood count, haptoglobin, lactate dehydrogenase levels and the absence of reticulocytosis (elevated reticulocytes in the blood would usually be observed in haemolytic anaemia).
 * Hepatitis can be excluded by negative blood samples for antigens specific to the different hepatitis vira.
 * Cholestasis can be excluded by the absence of lactate dehydrogenase, low levels of conjugated bilirubin and ultrasound scan of the bile ducts.
 * More severe types of glucoronyl transferase disorders like Crigler-Najjar syndrome (types I and II). These are much more severe, with 0-10% UGT1A1 activity, with sufferers at risk of brain damage in infancy (type I) and teenage years (type II).
 * Other diseases of the liver can be exluded by the liver-enzymes ALT, AST and albumin being within normal ranges.

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

More severe types of glucoronyl 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).

Findings specific to Gilbert's syndrome
Patients with GS show predominantly elevated unconjugated bilirubin, while conjugated is usually within normal ranges and form less than 20% of the total. Levels of bilirubin in GS patients is reported to be from 20 μmol/dl to 90 μmol/dl (1.2 to 5.3 mg/dL) compared to the normal amount of < 20 μmol/dL. GS patients will have a ratio of unconjugated/conjugated (indirect/direct) bilirubin that is commensurately higher than those without GS.

The level of total bilirubin is often increased if the blood sample is taken after fasting for two days, and a fast can therefore be useful diagnostically. If the total bilirubin does in fact increase while fasting, the patient can then be given low doses of phenobarbital when fasting has ended, and following samples should show a decrease in total bilirubin toward normal levels.

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
 * Morbus Meulengracht