Pegvisomant-Induced Liver Injury Is Related to the UGT1A1*28 Polymorphism of Gilbert’s Syndrome

Abstract

Abstract Context: Pegvisomant (PEG) therapy has been associated with drug-induced liver dysfunction in acromegalic patients. The mechanism of its toxicity remains unknown. Objective: The primary objective was to determine whether or not the UGT1A1*28 polymorphism associated with Gilbert’s syndrome influences the development of liver dysfunction during PEG treatment. Design and Setting: A cross-sectional study was conducted in four Spanish university hospitals. Patients: Thirty-six acromegalic patients with active disease, resistant to somatostatin analogs, participated. Results: The prevalence of the UGT1A1*28 homozygous and heterozygous genotypes in acromegalic patients was 14 and 44%, respectively. Ten patients (28%) developed liver function test (LFT) abnormalities. There was a tendency for more frequent liver function abnormalities in males (70% males vs. 30% females, P = 0.058). Carriers of the UGT1A1*28 polymorphism had a higher incidence of LFT abnormalities than the UGT1A1 wild type (43% carriers vs. 7% wild type, P = 0.024). This difference persisted when adjusted in an all-factors multiple regression analysis [coefficient of determination (R2) = 0.463; P = 0.008] for age, gender, alcohol consumption, and UGT1A1*28 polymorphism. A stepwise multivariate likelihood binary logistic regression analysis (R2 = 0.40; P = 0.003) identified male gender (β = 7.21; P = 0.033) and UGT1A1*28 polymorphism (β = 14.1; P = 0.028) as the only significant predictors for the development of LFT abnormalities. Conclusions: The UGT1A1*28 genotype and male gender predict an increased incidence of LFT abnormalities during PEG therapy in acromegaly.