Gilberts Syndrome & Gilberts Disease

Gilbert's syndrome, 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 (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 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, after which it is excreted in bile into the duodenum.

Eponym

Gilbert's syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and co-workers in 1901.[1][2]

In German literature, it is commonly associated with Jens Einar Meulengracht.[3]


Pathogenesis

Gilbert's syndrome is caused by approximately 30%-50% reduced glucuronidation activity of the enzyme Uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UGT1A1).[4][5] 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.[6] The allele polymorphism is referred to as UGT1A1*28.


Signs and symptoms

Gilbert's syndrome produces an elevated level of unconjugated bilirubin in the bloodstream but normally has no serious consequence. Mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise asymptomatic. [7][8]

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 UGT1A1.[9]

While paracetamol (acetaminophen) is not metabolized by UGT1A1,[10] it is metabolized by one of the other enzymes also deficient in some people with GS.[11][12] A subset of people with GS may have an increased risk of paracetamol toxicity.[12][13]


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. 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). 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 μmol/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 μmol/dl and 80 μmol/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.

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

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).


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



See also
Crigler-Najjar syndrome
Dubin-Johnson syndrome
Rotor syndrome


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