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Gilbert's syndrome (// zheel-BAIR), 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%). A major characteristic is jaundice, supposedly 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 a few other lipophilic molecules. Conjugation renders the bilirubin water-soluble, after which it is excreted in bile into the duodenum.
Signs and symptoms
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. This situation can be especially dangerous if not quickly treated as the high bilirubin causes irreversible neurological disability in the form of kernicterus.
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 names Panadol, 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.
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. These researchers went on to perform a meta-analysis of data available up to 2002, and confirmed that the incidence of atherosclerotic disease (hardening of the arteries) in subjects with GS had a close and inverse relationship to the serum bilirubin. This beneficial effect was attributed to bilirubin IXα which is recognised as a potent antioxidant, rather than confounding factors such as high-density lipoprotein (HDL) levels.
This association was also seen in long-term data from the Framingham Heart Study. Moderately elevated levels of bilirubin in people with GS and the (TA)7/(TA)7 genotype was associated with 1/3 the risk for both coronary heart disease and cardiovascular disease as compared to those with the (TA)6/(TA)6 genotype (i.e. a normal, non-mutated gene locus).
Signs and Symptoms
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, itching (with no rash), and others, but scientific studies found no clear pattern of adverse symptoms related to the elevated levels of unconjugated bilirubin in adults (see below). There is consequently debate about whether GS should be classified as a disease. Gilbert's syndrome has, however, been linked to an increased risk of gallstones.
Gilbert's syndrome is a phenotypic effect, characterized by mild jaundice due to increased unconjugated bilirubin, that arises from several different genotypic variants of the gene for the enzyme responsible for changing bilirubin to the conjugated form.
Gilbert's syndrome is characterized by a 70–80% reduction, rather than more severe loss of activity, in the glucuronidation activity of the enzyme, uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UDP-glucuronosyltransferase 1A1, or UGT1A1). The UGT1A1 gene is located on human chromosome 2.
There are considerably in excess of 100 variants of the UGT1A1 gene, designated as UGT1A1*n (where n is the general chronological order of discovery), either of the gene itself or of its promoter region. The UGT1A1 gene is associated with a TATA box promoter region ; this region most commonly contains the genetic sequence A(TA6)TAA; this variant accounts for about 50% of alleles in many populations. There are however several allelic polymorphic variants of this region, the most common adding another dinucleotide repeat TA to the promoter region, so that it is thus referred to as A(TA7)TAA, being also called UGT1A1*28; this common variant accounts for about 40% of alleles in some populations, but is seen less often, approximately 3% of alleles, in southeast and east Asian people and Pacific Islanders.
In most populations, Gilbert's syndrome is most commonly associated with homozygous A(TA7)TAA alleles. In 94% of GS cases, two other glucuronosyltransferase enzymes, UGT1A6 (rendered 50% inactive) and UGT1A7 (rendered 83% ineffective), are also affected.
However, Gilbert's syndrome can arise without TATA box promoter polymorphic mutations; in some populations, particularly healthy southeast and east Asians, Gilbert's syndrome is more often a consequence of heterozygote missense mutations (such as Gly71Arg also known as UGT1A1*6, Tyr486Asp also known as UGT1A1*7, Pro364Leu also known as UGT1A1*73) in the actual gene coding region, which may be associated with significantly higher bilirubin levels.
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.
People with GS predominantly have elevated unconjugated bilirubin, while conjugated bilirubin is usually within the normal range and is less than 20% of the total. Levels of bilirubin in GS patients are reported to be from 20 μM to 90 μM (1.2 to 5.3 mg/dL) compared to the normal amount of < 20 μM. 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 further increased if the blood sample is taken after fasting for two days, and a fast can therefore be useful diagnostically. A further conceptual step that is rarely necessary or appropriate is to give a low dose of phenobarbital: the bilirubin will decrease substantially.
There are also tests that detect DNA mutations of UGT1A1 by polymerase chain reaction or DNA fragment sequencing.
While this syndrome is considered harmless, it is clinically important because it may give rise to a concern about a blood or liver condition, which could be more dangerous. However, these conditions have additional indicators:
- 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 viruses.
- 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 glucuronyl 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).
- Dubin–Johnson syndrome and Rotor syndrome, which are rarer autosomal recessive disorders that are characterized by an increase of conjugated bilirubin.
- In GS, unless another disease of the liver is also present, the liver enzymes ALAT and ASAT, as well as albumin, are within normal ranges.
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
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