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

Abstract

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.

• Authors: M Filopanti, A M Barbieri, G Mantovani, S Corbetta, V Gasco, M Ragonese, C Martini, F Bogazzi, A Colao, D Ferone, A Peri, F Pigliaru, G Angeletti, M Arosio, P Beck-Peccoz, A G Lania, A Spada
• Journal: European journal of endocrinology (Eur J Endocrinol) Vol. 170 Issue 2 Pg. 247-54 (Feb 2014) ISSN: 1479-683X [Electronic] England
• PMID: 24217933 (Publication Type: Journal Article, Multicenter Study, Observational Study, Research Support, Non-U.S. Gov't)

Chemical References

• Human Growth Hormone
• ADH1B protein, human
• ADH1C protein, human
• Alcohol Dehydrogenase
• UGT1A1 enzyme
• Glucuronosyltransferase
• pegvisomant

Topics

• Acromegaly (complications, drug therapy, genetics)
• Adult
• Alcohol Dehydrogenase (genetics)
• Chemical and Drug Induced Liver Injury (genetics)
• Female
• Genotype
• Glucuronosyltransferase (genetics)
• Human Growth Hormone (adverse effects, analogs & derivatives)
• Humans
• Italy
• Liver Function Tests
• Male
• Middle Aged
• Polymorphism, Genetic
• Retrospective Studies