Clinical Information

The UGT1A1 gene contains 5 exons and is part of a gene complex located on chromosome 2q37 that encodes several enzymes called uridine diphosphate (UDP)-glucuronosyltransferases. These enzymes perform a chemical reaction called glucuronidation, a major pathway that enhances the elimination of small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble metabolites that can be excreted from the body.

The UGT1A1 enzyme, primarily found in the liver, is responsible for the glucuronidation of bilirubin, converting it from the toxic form of bilirubin (unconjugated bilirubin) to its nontoxic, water-soluble form (conjugated bilirubin). Genetic variants in UGT1A1 may cause reduced or absent UGT1A1 enzymatic activity, resulting in conditions associated with unconjugated hyperbilirubinemia, including Gilbert syndrome and Crigler-Najjar syndrome.(1-4)

Gilbert syndrome is the most common hereditary cause of increased bilirubin and is characterized by total serum bilirubin levels of 1 to 6 mg/dL. Gilbert syndrome is generally considered to be an autosomal recessive trait, although autosomal dominant inheritance has been suggested in some cases. Gilbert syndrome is characterized by a 25% to 50% reduction in glucuronidation activity of the UGT1A1 enzyme, along with episodes of mild intermittent jaundice and the absence of liver disease.(1-3)

Crigler-Najjar (CN) syndrome is an autosomal recessive disorder caused by more severe reductions in UGT1A1 glucuronidation activity and can be subdivided into type 1 and type 2 (CN1 and CN2). CN1 is the most severe form, with complete absence of enzyme activity and total serum bilirubin levels of 20 to 40 mg/dL. Infants with CN1 present with jaundice shortly after birth that persists thereafter.(1,2,4) CN2 is milder than CN1, with at least partial UGT1A1 activity and total serum bilirubin ranging from 6 to 20 mg/dL.(1,2,4) Phenobarbital, a drug that induces synthesis of a number of hepatic enzymes, is effective in decreasing serum bilirubin levels by approximately 25% in patients with CN2; CN1 does not respond to phenobarbital treatment. If left untreated, the buildup of bilirubin in a newborn can cause bilirubin-induced brain damage, known as kernicterus. In addition to phenobarbital, treatments of CN may include phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation.(1,2,4)

In addition to the role of UGT1A1 in bilirubin metabolism, this enzyme also plays a role in drug metabolism. UGT1A1 is involved in the metabolism of irinotecan, a topoisomerase I inhibitor. Irinotecan is a chemotherapy drug used to treat solid tumors, including colon, rectal, and lung cancers. It is a prodrug that forms an active metabolite, SN-38. SN-38 is normally inactivated by conjugation with glucuronic acid followed by biliary excretion into the gastrointestinal tract. If UGT1A1 activity is impaired or deficient, SN-38 fails to become conjugated with glucuronic acid, increasing the concentration of SN-38. This can result in severe neutropenia and diarrhea, which can be life-threatening.(5-8)

Additional drugs have also been associated with an increased risk for adverse outcomes in patients with reduced UGT1A1 enzyme activity. The US Food and Drug Administration drug labels for belinostat, nilotinib, pazopanib, and sacituzumab govitecan contain warnings for an increased risk (incidence) of adverse outcomes or increased bilirubin in patients who have UGT1A1 variants associated with reduced activity.(7) The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice).(8) Additionally, the concentration of several drugs, including dolutegravir and raltegravir, may be increased in patients with reduced UGT1A1 enzyme activity.(7)

In this assay, the UGT1A1 promoter, exons, and exon-intron boundaries are assessed for variants.(5)