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Gilbert’s Syndrome, Genetic Testing

Gilbert's syndrome is an inherited (genetic) liver disorder that affects the body’s ability to process bilirubin. Bilirubin is a yellow byproduct that occurs naturally as the body breaks down old red blood cells.

People with Gilbert's syndrome do not produce enough liver enzymes to keep bilirubin at normal levels, resulting in higher serum bilirubin levels.

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Bilirubin is a water-insoluble breakdown product of hemoglobin that is transported to the liver, where it is conjugated with glucuronic acid by the uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) enzyme, and then excreted into the bile. Defects in bilirubin conjugation lead to increased levels of unconjugated bilirubin, and inherited disorders of bilirubin metabolism can reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into the bile. Variants in either an exon or the promoter of the UGT1A1 gene can result in UGT1A1 enzyme deficiency and impairment of bilirubin conjugation in hereditary unconjugated hyperbilirubinemia, which includes Gilbert syndrome and Crigler-Najjar syndrome. Gilbert syndrome and Crigler-Najjar syndrome were once considered to be distinct genetic and pathophysiological entities, although both are now attributed to mutations of UGT1A1, but with quantitatively different consequences.

Gilbert syndrome was first described by Augustin Gilbert and Pierre Lereboullet in 1901. It is the most common inherited disorder of bilirubin metabolism, affecting 3% to 12% of the general population (5%–10% of Caucasians), and is primarily characterized by intermittent unconjugated hyperbilirubinemia in the absence of hepatocellular disease or hemolysis, which becomes clinically apparent during fasting, physical exercise, stress, or menstruation.

Some people with Gilbert syndrome also experience abdominal discomfort or tiredness. However, approximately 30 percent of people with Gilbert syndrome have no signs or symptoms of the condition and are discovered only when routine blood tests reveal elevated unconjugated bilirubin levels.

Not everyone with the genetic changes that cause Gilbert syndrome develops hyperbilirubinemia, indicating that additional factors, such as conditions that further hinder the glucuronidation process, may be necessary for the development of the condition. 

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