Sinem Ezgi Gulmez1,2,3, Nicholas Moore4,5,6, Georges-Philippe Pageaux7, Severine Lignot8,9, Yves Horsmans10, Bruno Stricker11, Jacques Bernuau12, Franco Bissoli13, Douglas Thorburn14, Jean-Louis Montastruc15, Sophie Micon8,9, Fatima Hamoud8,9, Régis Lassalle8,9, Jérémy Jové8,9, Patrick Blin8,9, Dominique Larrey7. 1. Department of Pharmacology, University of Bordeaux, 33000 Bordeaux, France. sinemezgi.gulmez@u-bordeaux2.fr 2. INSERM CIC-P0005, 33000, Bordeaux, France. sinemezgi.gulmez@u-bordeaux2.fr. 3. INSERM CIC 0005 Pharmaco-épidémiologie, Service de Pharmacologie, Université Bordeaux Segalen, Bâtiment Le Tondu-Case 41, 146, Rue Léo Saignat, 33076, Bordeaux Cedex, France. sinemezgi.gulmez@u-bordeaux2.fr. 4. Department of Pharmacology, University of Bordeaux, 33000, Bordeaux, France. nicholas.moore@pharmaco.u-bordeaux2.fr. 5. INSERM CIC-P0005, 33000, Bordeaux, France. nicholas.moore@pharmaco.u-bordeaux2.fr. 6. INSERM CIC 0005 Pharmaco-épidémiologie, Service de Pharmacologie, Université Bordeaux Segalen, Bâtiment Le Tondu-Case 41, 146, Rue Léo Saignat, 33076, Bordeaux Cedex, France. nicholas.moore@pharmaco.u-bordeaux2.fr. 7. CHU Hôpital Saint-Eloi, INSERM1040-IRB, 34000, Montpellier, France. 8. Department of Pharmacology, University of Bordeaux, 33000, Bordeaux, France. 9. INSERM CIC-P0005, 33000, Bordeaux, France. 10. Département d'Hépatogastroentérologie, Université Catholique de Louvain, Bruxelles, Belgium. 11. Department of Epidemiology, Erasmus Medical Centre, 3015 CE, Rotterdam, The Netherlands. 12. Hepatology Department, Beaujon Hospital, Clichy, France. 13. Department of Internal Medicine and Cardiology, Clinica San Gaudenzio, Novara, Italy. 14. Liver Transplantation Hepatobilliary Unit, Royal Free Hampstead NHS Trust, London, NW3-2QG, UK. 15. Pharmacologie médicale et clinique, CHU et Faculté de Médecine de Toulouse, INSERM 1027, 31000, Toulouse, France.
Abstract
BACKGROUND: Several methods have been proposed to assess causality in drug-induced liver injury but none have been tested in the specific context of acute liver failure leading to transplantation (ALFT). OBJECTIVE: We took advantage of the Study of Acute Liver Transplant (SALT), a European case-population study of ALFT, to test different causality scales. METHODS: Causality was assessed by experts in SALT, a 7-country case-population study from 2005 to 2007 of adult otherwise unexplained ALFT, for all drugs found within 30 days prior to the date of initial symptoms of liver disease (index date), using information content, causality scales, and data circuit determined from a pilot study, Salome. RESULTS: The consensus points from Salome were to provide full data on drugs including international non-proprietary name (INN) and doses except for non-steroidal anti-inflammatory drugs (NSAIDs) and to use the World Health Organization (WHO) causality scale. In SALT, among the 9,479 identified patients, 600 (6.3%) were cases of ALFT, of which 187 had been exposed to drugs within 30 days, without overdose. In 130 (69.5%) of these the causality score was possible, probable, or highly probable. CONCLUSION: In ALFT cases, once other clinical causes have been excluded and drug exposure established within 30 days, the main discriminant characteristic for causality will be previous knowledge of possible hepatotoxicity.
BACKGROUND: Several methods have been proposed to assess causality in drug-induced liver injury but none have been tested in the specific context of acute liver failure leading to transplantation (ALFT). OBJECTIVE: We took advantage of the Study of Acute Liver Transplant (SALT), a European case-population study of ALFT, to test different causality scales. METHODS: Causality was assessed by experts in SALT, a 7-country case-population study from 2005 to 2007 of adult otherwise unexplained ALFT, for all drugs found within 30 days prior to the date of initial symptoms of liver disease (index date), using information content, causality scales, and data circuit determined from a pilot study, Salome. RESULTS: The consensus points from Salome were to provide full data on drugs including international non-proprietary name (INN) and doses except for non-steroidal anti-inflammatory drugs (NSAIDs) and to use the World Health Organization (WHO) causality scale. In SALT, among the 9,479 identified patients, 600 (6.3%) were cases of ALFT, of which 187 had been exposed to drugs within 30 days, without overdose. In 130 (69.5%) of these the causality score was possible, probable, or highly probable. CONCLUSION: In ALFT cases, once other clinical causes have been excluded and drug exposure established within 30 days, the main discriminant characteristic for causality will be previous knowledge of possible hepatotoxicity.
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