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Gilbert's syndrome, pronounced (zheel-BAYR), often shortened to GS, also called Gilbert-Meulengracht syndrome, is the most common hereditary cause of increased bilirubin and is found in up to 5% of the population (though some gastroenterologists maintain that it is closer to 10%). The main symptom is otherwise harmless jaundice, which does not require treatment, caused by elevated levels of unconjugated bilirubin in the bloodstream (hyperbilirubinemia).

The cause of this hyperbilirubinemia is the reduced activity of the enzyme glucuronyltransferase, which conjugates bilirubin and some other lipophilic molecules. Conjugation renders the bilirubin water-soluble, after which it is excreted in bile into the duodenum.


Gilbert's syndrome is caused by an approximately 70%-75% reduction in the glucuronidation activity of the enzyme Uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UGT1A1). The gene that encodes UGT1A1 normally has a promoter region TATA box containing the allele A(TA6)TAA. Gilbert's syndrome is most commonly associated with homozygous A(TA7)TAA alleles. The allele polymorphism is referred to as UGT1A1*28. In 94% of GS sufferers, mutations in two of the other glucoronyltransferase variations UGT1A6 (rendered 50% inactive) and UGT1A7 (rendered 83% ineffective) are also present. Because of its effects on drug and bilirubin breakdown and because of its genetic inheritance, Gilbert's syndrome can be classed as a minor inborn error of metabolism.

Signs, symptoms and consequences


Gilbert's syndrome produces an elevated level of unconjugated bilirubin in the bloodstream but normally has no serious consequences. 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, especially in the presence of increased hemolysis due to diseases like G6PD deficiency.

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 or brand name Tylenol) 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.

Possible benefits and cardiovascular disease

In the first study on coronary heart disease risk in individuals with GS, a three year span was considered and a significant decrease in incidence of coronary artery disease was found in the subjects . Specifically, people with mildly elevated levels of bilirubin (1.1 mg/dl to 2.7 mg/dl) were at lower risk for CAD and at lower risk for future heart disease.

One research group in the Czech Republic has found a reduced incidence of atherosclerotic disease (hardening of the arteries) in subjects with GS and an inverse relationship between serum bilirubin and cardiovascular disease. They performed a meta-analysis of all studies published up to 2002 on the relationship between bilirubin levels and atherosclerosis. Only males with isolated hyperbilirubinemia (as occurs in GS subjects) were considered. The authors found a close negative relationship between bilirubin levels and the degree of atherosclerosis in the subjects. This beneficial effect is supposedly due to bilirubin IXα's being recognised as a potent antioxidant .

A study by Lin et al. associated moderately elevated levels of bilirubin in people with GS and the (TA)7/(TA)7 genotype with 1/3 the risk for both coronary heart disease and cardiovascular disease as compared to those with the (TA)6/(TA)6 genotype (ie a normal, non-mutated gene locus).

A paper by Schwertner and Vitek summarizes many of the pre-2008 findings between cardiovascular disease and elevated serum bilirubin concentrations. The authors go on to discuss intentional, artificial raising of bilirubin levels as a means of prevention of cardiovascular disease and other oxidative and inflammatory diseases.

Debated signs and diffuse symptoms

Diffuse symptoms, whether connected or not to GS, have been reported in a subset of those affected: 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 (see below). This has led some to dispute whether GS should be classified 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:

  • 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).
  • Viral 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 excluded by the liver-enzymes ALAT, ASAT and albumin being within normal ranges.

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.

Studies of possible symptoms

Historically there has been debate over whether Gilbert's Syndrome has an associated, verifiable set of symptoms aside from jaundice. Clinical studies before the mid 1970's indicated a high prevalence of symptoms in people with GS. Doctors and clinicians at the time attributed such symptoms partly to anxiety, since patients with GS were often misdiagnosed with serious liver disease. Later studies, such as by Bailey et al. in 1977, proposed that selection bias was creating the false impression that GS had a definitive, frequent set of symptoms. The reasoning went: doctors were only seeing the subset of GS patients who presented with symptoms (since these, primarily, would be the only patients in the total group of GS patients who would come to the attention of the medical community)--then, for example, any study which selected from prior patients would tend to favor only the symptomatic subset of the set of people with GS. A 1988 study by Olsson et al. is the only major study of symptoms in people with GS. Its methods included steps to reduce the likelihood of selection bias. The table below outlines studies related to symptoms in GS.

Medical studies related to symptoms of Gilbert's Syndrome
Study GS Diagnostic Criteria Selected From GS Subjects Symptoms Comments
Foulk et al. 1959 1.5 mg/dl prior patients 58 total (51 male), average age of 35 65% complained of fatigue; many complained of gastric disturbances many patients had (mistakenly) received a diagnosis of chronic hepatic disease; authors theorized anxiety contributed to symptoms
Powell et al. 1967 1.1 mg/dl (w/ jaundice or other symptoms) prior patients 42 total (34 male) 69% complained of abdominal pain/discomfort, fatigue or malaise (but relatives with GS were asymptomatic) 78% had been misdiagnosed with hepatitis or gallstones; 24 out of 119 (20%) of the subjects' 1st degree relatives were found to have GS also, all of whom were asymptomatic
Bailey et al. 1977 1.5 mg/dl general population, 23,925 subjects total 6 (all male) no symptoms the primary purpose of this study was testing bimodality of serum-bilirubin the 18,454 men; of the 369 men above the cutoff, 12 were invited back--6 returned and were all asymptomatic; the authors suggested selection bias for high frequency of symptoms in other studies
N. Gitlin 1977 not specified (fasting test) prior patients 26 (19 male), between 14 and 30 years old complaints of recurrent: malaise (66%), asthenia (65%) and abdominal distension (52%) (8% were asymptomatic) the author emphasized the benign nature of the disease (in that it differs from serious liver disease and people would have a normal life expectancy)
Olsson et al. 1988 1.26 mg/dl general population, 2,395 subjects total 48 (24 male), age groups for males: 18-20, 57, 67 while for females: 26,38,50,58,62 subjects were asked if they experienced symptoms that included fatigue, gastric distress, headache and vertigo within the past 3 months; the prevalence of symptoms in the 48 above the cutoff was compared to that in the 2,347 below it the largest study undertaken to look for symptoms of GS in the general population; authors concluded the difference in prevalence of symptoms between those above and below the cutoff was not statistically significant ; authors suggested selection bias as the cause of GS symptom prevalence
Cleary and White 1993 not specified CFS patients 45 (all male), average age: 40 seven (16%) of the men were considered to have GS the authors remark on the high percentage of CFS (chronic fatigue syndrome) patients with GS relative to the percentage of GS in the general population
Valesini et al. 1993 not specified patients with fatigue for > 6 months 57 (16 male) six (11%) of the group were considered to have GS; in a subgroup of 24 with "probable CFS", 4 (16%) were considered to have GS the authors remark on the high percentage of fatigued patients with GS relative to the percentage of GS in the general population

in all studies, care was taken to exclude subjects with overt signs of liver disease--ie the hyperbilirubinemia was considered isolated
these studies used serum bilirubin cutoffs or other non-genetic criteria to make a diagnosis of GS; it was not until the mid 1990's, with the work of eg Bosma et al. [ref to Bosma], that GS was associated with genetic mutations
selecting from prior patients has been argued to carry a selection bias into the frequency of finding symptoms in GS patients
in addition to the possible symptom of intermittent jaundice
a medically benign condition is generally one considered non life-threatening--it may still present with symptoms
each age or age range listed corresponds to a subset of the total sample group (of 2,395), the subset further broken down into subjects above 21 umol/l (considered to have GS) and below 21 umol/l (the control group)
to statistical significance in women, fatigue was more likely in the control group (those w/o GS)
6 of 7 had bilirubin levels > 1.5 mg/dl

Eponym and synonyms

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.

Alternative, less common names for this disorder include:
  • Familial benign unconjugated hyperbilirubinaemia
  • Constitutional liver dysfunction
  • Familial non-hemolytic non-obstructive jaundice
  • Icterus intermittens juvenilis
  • Low-grade chronic hyperbilirubinemia
  • Unconjugated benign bilirubinemia
  • Morbus (disease in Latin)

Notable Sufferers

See also


External links

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