Gilbert's disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype

Hepatology. 2006 Nov;44(5):1324-32. doi: 10.1002/hep.21361.


Gilbert's disease leads to intermittent non-hemolytic hyperbilirubinemia by a reduction of hepatic bilirubin glucuronidation associated with the presence of the UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism. It is considered benign because it does not result in hepatocellular damage. However, pharmacogenetic analyses have linked UGT1A1*28 to drug toxicity and cancer predisposition. The protease inhibitor atazanavir (ATV) is an inhibitor of hepatic UGT activity leading to hyperbilirubinemia in individual patients. Whether this is linked specifically to UGT1A1*28 or to more complex variants influencing glucuronidation is unclear. One hundred and six ATV-treated patients were characterized and genotyped for UGT1A1*28, the UGT1A3 (-66C) and UGT1A7 (-57G) promoter variants, and UGT1A7(129K/131K). ATV treatment increased median bilirubin levels from 10 to 41 micromol/L (P = .001) with hyperbilirubinemia exceeding 43 micromol/L in 37%. Hyperbilirubinemia over 43 micromol/L was significantly associated not only with UGT1A1*28 but also with UGT1A3-66C, UGT1A7-57G, and UGT1A7(129K/131K), although these variants do not naturally occur in linkage dysequilibrium in blood donors. Homozygous combinations of UGT1A1*28 with the other variants increased from 7.4% (normal bilirubin to 42 micromol/L) to 41% to 46.1% (43 to >85 micromol/L), and 100% (>85 micromol/L). All six patients with hyperbilirubinemia greater than 85 micromol/L were homozygous for all four variants identifying a haplotype inherited on a single allele. In conclusion, the genetic variant associated with Gilbert's disease is identified as part of a haplotype of four UGT1A variants spanning three genes at the UGT1A gene locus. This haplotype predisposes to hyperbilirubinemia in ATV treatment and may have an additional role as a pharmacogenomic risk factor for drug therapy.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Atazanavir Sulfate
  • Female
  • Genetic Variation
  • Gilbert Disease / complications
  • Gilbert Disease / genetics*
  • Glucuronosyltransferase / genetics*
  • HIV Infections / complications
  • HIV Infections / drug therapy
  • HIV Infections / genetics
  • HIV Protease Inhibitors / adverse effects*
  • HIV Protease Inhibitors / therapeutic use
  • Haplotypes
  • Humans
  • Hyperbilirubinemia / etiology*
  • Male
  • Middle Aged
  • Oligopeptides / adverse effects*
  • Oligopeptides / therapeutic use
  • Polymorphism, Single Nucleotide
  • Pyridines / adverse effects*
  • Pyridines / therapeutic use


  • HIV Protease Inhibitors
  • Oligopeptides
  • Pyridines
  • Atazanavir Sulfate
  • Glucuronosyltransferase