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Bilirubin, resulting from the breakdown of heme, is a water-insoluble toxic compound. Uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1) is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.(1) Genetic mutations in the UGT1A1 gene may cause reduced or absent UGT1A1 enzymatic activity resulting in hyperbilirubinemia (eg, Gilbert syndrome, Crigler-Najjar).
Gilbert syndrome, found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL).(2) Gilbert syndrome is caused by a 25% to 50% reduced glucuronidation activity of the UGT1A1 enzyme and characterized by episodes of mild intermittent jaundice and the absence of liver disease.
Crigler-Najjar (CN) types I and II are inherited causes of severe unconjugated hyperbilirubinemia. CN type I is associated with no UGT1A1 enzymatic activity and usually presents as intense jaundice in the first days of life and persists thereafter.(3) Type II is a milder form in which bilirubin levels are <20mg/dL. 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 CN type II; CN type I does not respond to phenobarbital treatment. If left untreated, the buildup of bilirubin in a newborn can cause kernicterus, bilirubin-induced brain damage. Treatments of CN include: phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation. Phototherapy becomes ineffective at later ages and liver transplantation should occur prior to the onset of brain damage (before phototherapy becomes ineffective).
The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. Currently there are more than 130 known mutations in UGT1A1, with 45 mutations that cause a decrease in UGT1A1 enzyme activity. In this assay, the promoter, exons, exon-intron boundaries, and a region in the distal promoter called the "phenobarbital response enhancer module," which is associated with transcriptional activity of the gene, are assessed for polymorphisms and mutations.(4)
Identifying individuals who are at risk of hyperbilirubinemia
Confirmation of a diagnosis of Gilbert or Crigler-Najjar syndromes
Verification of carrier status for Gilbert or Crigler-Najjar syndromes
An interpretive report is provided.
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
UGT1A1 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient’s UGT1A1 status.
An alternative splice site for exon 5 (referred to as exon 5b) has been discovered and described in the literature. This new exon is described to have a decrease in enzymatic activity (compared with exon 5a: previously known as exon 5), but little is known about the frequency of exon 5b or how it impacts hyperbilirubinemia. Currently, we are not testing or sequencing exon 5b; we continue to monitor the literature for new information on exon 5b.
Absence of a detectable gene mutation or polymorphism does not rule out the possibility that the patient may have a genetic cause for increased unconjugated bilirubin.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
An interpretive report will be provided.
1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136-158
2. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733
3. Costa E, Vieira E, Martins M, et al: Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis 2006;36:91-97
4. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41