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

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

Research output: Contribution to journalArticle

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Abstract

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), abnormalitiesandoverthepatotoxicity developed in 17and4.5%ofpatients respectively. Logistic andlinear regressionanalyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratioZ1.25; PZ0.04) and the number of concomitant medications, other than SSTa (BZ3.9; PZ0.03). 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.

Original languageEnglish
Pages (from-to)247-254
Number of pages8
JournalEuropean Journal of Endocrinology
Volume170
Issue number2
DOIs
Publication statusPublished - Feb 2014

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Alcohol Dehydrogenase
Liver Function Tests
Liver
Genes
Alleles
Somatostatin
Gilbert Disease
Therapeutics
Endocrinology
Tertiary Healthcare
Italy
Observational Studies
Liver Diseases
Retrospective Studies
Genotype
pegvisomant
DNA

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients. / Filopanti, M.; Barbieri, A. M.; Mantovani, G.; Corbetta, S.; Gasco, V.; Ragonese, M.; Martini, C.; Bogazzi, F.; Colao, A.; Ferone, D.; Peri, A.; Pigliaru, F.; Angeletti, G.; Arosio, M.; Beck-Peccoz, P.; Lania, A. G.; Spada, A.

In: European Journal of Endocrinology, Vol. 170, No. 2, 02.2014, p. 247-254.

Research output: Contribution to journalArticle

Filopanti, M, Barbieri, AM, Mantovani, G, Corbetta, S, Gasco, V, Ragonese, M, Martini, C, Bogazzi, F, Colao, A, Ferone, D, Peri, A, Pigliaru, F, Angeletti, G, Arosio, M, Beck-Peccoz, P, Lania, AG & Spada, A 2014, 'Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients', European Journal of Endocrinology, vol. 170, no. 2, pp. 247-254. https://doi.org/10.1530/EJE-13-0657
Filopanti, M. ; Barbieri, A. M. ; Mantovani, G. ; Corbetta, S. ; Gasco, V. ; Ragonese, M. ; Martini, C. ; Bogazzi, F. ; Colao, A. ; Ferone, D. ; Peri, A. ; Pigliaru, F. ; Angeletti, G. ; Arosio, M. ; Beck-Peccoz, P. ; Lania, A. G. ; Spada, A. / Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients. In: European Journal of Endocrinology. 2014 ; Vol. 170, No. 2. pp. 247-254.
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abstract = "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), abnormalitiesandoverthepatotoxicity developed in 17and4.5{\%}ofpatients respectively. Logistic andlinear regressionanalyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratioZ1.25; PZ0.04) and the number of concomitant medications, other than SSTa (BZ3.9; PZ0.03). 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.",
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T1 - Role of UGT1A1 and ADH gene polymorphisms in pegvisomant-induced liver toxicity in acromegalic patients

AU - Filopanti, M.

AU - Barbieri, A. M.

AU - Mantovani, G.

AU - Corbetta, S.

AU - Gasco, V.

AU - Ragonese, M.

AU - Martini, C.

AU - Bogazzi, F.

AU - Colao, A.

AU - Ferone, D.

AU - Peri, A.

AU - Pigliaru, F.

AU - Angeletti, G.

AU - Arosio, M.

AU - Beck-Peccoz, P.

AU - Lania, A. G.

AU - Spada, A.

PY - 2014/2

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N2 - 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), abnormalitiesandoverthepatotoxicity developed in 17and4.5%ofpatients respectively. Logistic andlinear regressionanalyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratioZ1.25; PZ0.04) and the number of concomitant medications, other than SSTa (BZ3.9; PZ0.03). 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.

AB - 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), abnormalitiesandoverthepatotoxicity developed in 17and4.5%ofpatients respectively. Logistic andlinear regressionanalyses showed an association between LFT abnormalities during the follow-up visit and prior events of LFT abnormalities in medical history (odds ratioZ1.25; PZ0.04) and the number of concomitant medications, other than SSTa (BZ3.9; PZ0.03). 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.

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