Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients

Context: Hepatotoxicity is one of the most serious adverse effects in acromegalic patients treated with pegvisomant (PEG-V). Recent studies have found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome. Objective: To determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment. Design and setting: Multicenter observational retrospective study conducted in 13 tertiary care endocrinology units in Italy. Patients: A total of 112 patients with active disease resistant to somatostatin analogs (SSTa) and 108 controls were enrolled. Interventions: Clinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping. Results: No differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT), abnormalities and overt hepatotoxicity developed in 17 and 4.5% of patients respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratio=1.25; P=0.04) and the number of concomitant medications, other than SSTa (B=3.9; P=0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found. Conclusions: UGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.