UGT1A1*28 relationship with abnormal total bilirubin levels in chronic hepatitis C patients

Abstract

Gilbert syndrome (GS) is a frequent benign clinical condition, marked by intermittent unconjugated hyperbilirubinemia, mostly due to the polymorphism uridine diphosphate-glucuronosyltransferase 1A1∗28 (UGT1A1∗28). Hyperbilirubinemia has been reported in a GS patient undergoing hepatitis C treatment, and other UGT isoforms polymorphisms have been linked to worse outcomes in viral hepatitis. Yet, little is known to GS contributions’ to the liver disease scenario. Our aim was to assess UGT1A1 genotypes’ frequency in chronic hepatitis C (CHC) patients and correlate with total bilirubin (TB). This is a case–control study in a large tertiary medical center. Cases were CHC patients confirmed by hepatitis C virus (HCV)–polymerase chain reaction. Exclusion criteria were hepatitis B virus or human immunodeficiency virus (HIV) coinfection. Control were healthy blood donors. UGT1A1 promoter region gene genotyping was performed, and bilirubin serum levels were available for HCV patients. Genotypes and alleles frequencies were similar in case (n = 585; P = 0.101) and control groups (n = 313; P = 0.795). Total bilirubin increase was noticed according to thymine–adenine repeats in genotypes (P < 0.001), and the TB greater than 1 mg/dL group had more UGT1A1∗28 subjects than in the group with TB values <1 mg/dL (18.3 vs 5.3; P < 0.001). Bilirubin levels are linked to the studied polymorphisms, and this is the first time that these findings are reported in a chronic liver disease sample. Among patients with increased TB levels, the frequency of UGT1A1∗28 is higher than those with normal TB. Personalized care should be considered to GS, regarding either abnormal bilirubin levels or drug metabolism.

UGT1A1 (TA)n promoter genotype: Diagnostic and population pharmacogenetic marker in Serbia

“…Atazanavir-associated hyperbilirubinemia has been described in GS patients receiving therapy for HIV [ 38 ] and in chronic myeloid leukemia treatment with nilotinib [ 39 ]. Hyperbilirubinemia has been reported in GS patients undergoing hepatitis C treatment [ 40 ]. However, if genetic testing shows that the patients are carriers of UGT1A1 GS risk genotypes, they should not be excluded from clinical trials despite increased bilirubin values but should be treated, taking into account UGT1A1 (TA) n promoter genotype-related higher bilirubin levels.…”

Significance of UGT1A1*28 Genotype in Patients with Advanced Liver Injury Caused by Chronic Hepatitis C

“…The frequency of UGT1A1 *28 genotype in this study was high in both groups- patients with CHC 23.8% and healthy blood donors 16.7%. These frequencies are among the highest of the published data in blood donors ranging from 5% in Iceland, 10% in Portugal, 11.6% in Spain, 15.3% in Croatia and especially compared to Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5% (5, 13, 29). The recognized prevalence is probably much lower than the real frequencies of the mutations, making GS underdiagnosed, due to incomplete penetrance and other acquired or inherited conditions affecting bilirubin metabolism, which can also alter clinical manifestation (30).…”

“…These genetic variations in UGT1A1 gene are the most common cause of mild hereditary intermittent unconjugated hyperbilirubinemia-Gilbert syndrome (GS) (4). The in sertion of thymine-adenine (TA) repeats in the pro moter region (wild type consists of 6 TA repeats), reduces gene transcription by 67–82%, with sub sequent reduction of enzyme activity by 20–30% (5). UGT1A1 *28 variant allele contains 7 TA repeats, and individuals with GS possess 7/7 homozygous genotype with two UGT1A1 *28 alleles.…”

“…Although GS is considered a benign condition, new pharmacogenetic discoveries have shown that certain UGT1A1 alleles are responsible for adverse outcomes and higher risks for breast and colorectal cancer due to decreased detoxification of carcinogens. Higher risks for severe drug reactions (irinotecan, nilotinib, pazopanib, belino stat, atazanavir) have been documented in patients with certain homozygous UGT1A1 alleles and reduced enzyme activity (5, 6, 7, 8, 9, 10). Pretreatment pharmacogenomic testing can greatly assist in individualizing therapy and might prompt special caution /different treatment options, due to a higher risk of side effects such as jaundice, diarrhea and neutropenia (11).…”

Frequência de polimorfismos nos genes responsáveis pela absorção, distribuição, metabolismo e excreção (ADME) de medicamentos na população brasileira

“…Assim, a presença de mutação no gene UGT1A1 em pacientes hepatopatas pode levar ao aumento da bilirrubina sérica, supervalorizando o acometimento hepático da condição patológica (37) . Outros dados sugerem que a variação genética da região promotora do gene UGT1A1 é alta entre pacientes com bilirrubina maior que 1mg/dL, e que a genotipagem para UGT1A1*28 deve ser considerada na avaliação dos pacientes com hepatite C crônica com hiperbilirrubinemia (38) . FONTE: Sim, 2013 (39) Figura 3.…”