Acute liver injury (ALI) is a major reason for stopping drug development or removing drugs from the market. Hospitalisation for ALI is relatively rare for marketed drugs, justifying studies in large-scale databases such as the nationwide Système National des Données de Santé (SNDS), which covers 99% of the French population.
SNDS was queried over 2010–2014 for all hospital admissions for acute toxic liver injuries not associated with a possible other cause, using a case–population approach. Exposures of interest were drugs dispensed from 7 to 60 days before date of admission. Individual drugs were analysed by their frequency (if five or more cases) and by the ratio of exposed cases to the number of exposed subjects and to exposed patient-time in the general population over the same timeframe.
Over 5 years, 4807 cases of ALI were identified, mean age 54.5, 59% women, 76% exposed to at least one of 249 different drugs. Drugs most commonly identified were non-overdose paracetamol (31% of cases), esomeprazole or omeprazole (18%), phloroglucinol, domperidone, co-amoxiclav, furosemide, and atorvastatin (more than 250 cases each). When compared to population exposures, the highest per-person risks were observed with antimycobacterial antibiotics, with one case for 1000 or fewer users, followed by colestyramine and erythromycin (around 1/5300), antiepileptic drugs, anticoagulants, and anti-Alzheimer drugs (1/6000–1/10,000 users). When a person-time approach was considered, the drugs with the highest per-tablet risk were still the antituberculosis drugs, followed by a number of other antibiotics.
This nationwide study describes drugs associated with ALI, according to absolute population burden and per-patient and per-tablet risk. Some of these associations may be spurious, others causal, and others yet were unexpected. Systematic analysis of drug classes will look for outliers within each class that could raise signals of unexpected hepatic toxicity.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Gulmez SE, Larrey D, Pageaux GP, Bernuau J, Bissoli F, Horsmans Y, et al. Liver transplant associated with paracetamol overdose: results from the seven-country SALT study. Br J Clin Pharmacol. 2015;80(3):599–606.
Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, Jove J, et al. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study. Drug Saf. 2013;36(2):135–44.
Gulmez SE, Larrey D, Pageaux GP, Lignot-Maleyran S, de Vries C, Sturkenboom M, et al. Methodology for a multinational case-population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT). Eur J Clin Pharmacol. 2013;69(3):605–16.
Keisu M, Andersson TB. Drug-induced liver injury in humans: the case of ximelagatran. Handb Exp Pharmacol. 2010;196:407–18.
Reuben A, Koch DG, Lee WM, Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a US multicenter, prospective study. Hepatology. 2010;52(6):2065–76.
Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349(5):474–85.
Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet. 2010;376(9736):190–201.
Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 1999.
David S, Hamilton JP. Drug-induced liver injury. US Gastroenterol Hepatol Rev. 2010;1(6):73–80.
Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731–9.
Zimmerman HJ. The spectrum of hepatotoxicity. Perspect Biol Med. 1968;12(1):135–61.
Zimmerman HJ. Drug-induced liver disease. Drugs. 1978;16(1):25–45.
Gulmez SE, Lignot-Maleyran S, de Vries CS, Sturkenboom M, Micon S, Hamoud F, et al. Administrative complexities for a European observational study despite directives harmonising requirements. Pharmacoepidemiol Drug Saf. 2012;21(8):851–6.
Donati M, Conforti A, Lenti MC, Capuano A, Bortolami O, Motola D, et al. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case–control study in Italy. Br J Clin Pharmacol. 2016;82(1):238–48.
Douros A, Bronder E, Andersohn F, Klimpel A, Thomae M, Sarganas G, et al. Drug-induced liver injury: results from the hospital-based Berlin case–control surveillance study. Br J Clin Pharmacol. 2015;79(6):988–99.
Sabate M, Ibanez L, Perez E, Vidal X, Buti M, Xiol X, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther. 2007;25(12):1401–9.
Sobhonslidsuk A, Poovorawan K, Soonthornworasiri N, Pan-Ngum W, Phaosawasdi K. The incidence, presentation, outcomes, risk of mortality and economic data of drug-induced liver injury from a national database in Thailand: a population-base study. BMC Gastroenterol. 2016;16(1):135.
Gulmez SE, Unal US, Lassalle R, Chartier A, Grolleau A, Moore N. Risk of hospital admission for liver injury in users of NSAIDs and nonoverdose paracetamol: preliminary results from the EPIHAM study. Pharmacoepidemiol Drug Saf. 2018. https://doi.org/10.1002/pds.4640.
Bezin J, Duong M, Lassalle R, Droz C, Pariente A, Blin P, et al. The national healthcare system claims databases in France, SNIIRAM and EGB: powerful tools for pharmacoepidemiology. Pharmacoepidemiol Drug Saf. 2017;26(8):954–62.
Moore N, Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, et al. Choice of the denominator in case population studies: event rates for registration for liver transplantation after exposure to NSAIDs in the SALT study in France. Pharmacoepidemiol Drug Saf. 2013;22(2):160–7.
Bezin J, Girodet PO, Rambelomanana S, Touya M, Ferreira P, Gilleron V, et al. Choice of ICD-10 codes for the identification of acute coronary syndrome in the French hospitalization database. Fundam Clin Pharmacol. 2015;29(6):586–91.
Gilleron V, Gasnier-Duparc N, Hebbrecht G. Certification des comptes: une incitation à la traçabilité des processus de contrôle. Revue Hospitaliere de France. 2018;582:42–6.
Aladjidi N, Jutand MA, Beaubois C, Fernandes H, Jeanpetit J, Coureau G, et al. Reliable assessment of the incidence of childhood autoimmune hemolytic anemia. Pediatr Blood Cancer. 2017;64(12).
Bosco-Lévy P, Duret S, Picard F, Dos Santos P, Puymirat E, Gilleron V, et al. Diagnostic accuracy of the international classification of disease 10th revision codes of heart failure in administrative database Pharmacoepidemiol Drug Saf. 2018 (in press).
Daveluy A, Miremont-Salame G, Kostrzewa A, Couret A, Lacoin L, Lecomte C, et al. Identification of abuse and dependence cases through a hospital database. Pharmacoepidemiol Drug Saf. 2012;21(12):1344–9.
Gouverneur A, Dolatkhani D, Rouyer M, Grelaud A, Francis F, Gilleron V, et al. Agreement between hospital discharge diagnosis codes and medical records to identify metastatic colorectal cancer and associated comorbidities in elderly patients. Rev Epidemiol Sante Publique. 2017;65(4):321–5.
Theophile H, Laporte JR, Moore N, Martin KL, Begaud B. The case-population study design: an analysis of its application in pharmacovigilance. Drug Saf. 2011;34(10):861–8.
Capella D, Pedros C, Vidal X, Laporte JR. Case-population studies in pharmacoepidemiology. Drug Saf. 2002;25(1):7–19.
Moore N, Gulmez SE, Blin P, Lassalle R, Jove J, Theophile H, et al. Relative risks from case-population data. Epidemiology. 2013;24(6):935–6.
Institut national de la statistique et des études économiques. Pyramides des âges (Population totale par sexe et âge—France et France métropolitaine). https://www.insee.fr/fr/statistiques/1913143?sommaire=1912926&q=pyramide+des+ages. Accessed 22 Oct 2018
Duong M, Gulmez SE, Salvo F, Abouelfath A, Lassalle R, Droz C, et al. Usage patterns of paracetamol in France. Br J Clin Pharmacol. 2016;82(2):498–503.
Duong M, Salvo F, Pariente A, Abouelfath A, Lassalle R, Droz C, et al. Usage patterns of ‘over-the-counter’ vs. prescription-strength nonsteroidal anti-inflammatory drugs in France. Br J Clin Pharmacol. 2014;77(5):887–95.
Moride Y, Abenhaim L. Evidence of the depletion of susceptibles effect in non-experimental pharmacoepidemiologic research. J Clin Epidemiol. 1994;47(7):731–7.
Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993;46(11):1331–6.
Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323–30.
Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002;36(2):451–5.
Rosa H, Prudente MS, Cardoso VM. Paracetamol hepatic necrosis and its prevention by cholestyramine. Arq Gastroenterol. 1984;21(4):164–6.
Siegers CP, Moller-Hartmann W. Cholestyramine as an antidote against paracetamol-induced hepato- and nephrotoxicity in the rat. Toxicol Lett. 1989;47(2):179–84.
Singhal R, Harrill AH, Menguy-Vacheron F, Jayyosi Z, Benzerdjeb H, Watkins PB. Benign elevations in serum aminotransferases and biomarkers of hepatotoxicity in healthy volunteers treated with cholestyramine. BMC Pharmacol Toxicol. 2014;3(15):42.
Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA. 1994;271(13):992–8.
Johnson DF Jr, Hall WH. Allergic hepatitis caused by propionyl erythromycin ester of lauryl sulfate. N Engl J Med. 1961;14(265):1200–2.
Pessayre D, Benhamou JP. Hepatotoxicity of erythromycin derivatives. Br Med J. 1979;1(6174):1357.
Brauer R, Douglas I, Garcia Rodriguez LA, Downey G, Huerta C, de Abajo F, et al. Risk of acute liver injury associated with use of antibiotics Comparative cohort and nested case–control studies using two primary care databases in Europe. Pharmacoepidemiol Drug Saf. 2016;25(Suppl 1):29–38.
Ferrer P, Amelio J, Ballarin E, Sabate M, Vidal X, Rottenkolber M, et al. Systematic review and meta-analysis: macrolides- and amoxicillin/clavulanate-induced acute liver injury. Basic Clin Pharmacol Toxicol. 2016;119(1):3–9.
Moore N, Masson H, Noblet C, Joannidès R. What medicines do patients really take? A comparison of free form vs oriented questionnaires. Post Mark Surveill. 1993;7:355–62.
Moore N, Pierfitte C, Pehourcq F, Lagnaoui R, Begaud B. Comparison of patient questionnaires, medical records, and plasma assays in assessing exposure to benzodiazepines in elderly subjects. Clin Pharmacol Ther. 2001;69(6):445–50.
Duong M, Abouelfath A, Lassalle R, Droz C, Blin P, Moore N. Coronary events after dispensing of ibuprofen: a propensity score-matched cohort study versus paracetamol in the French nationwide claims database sample. Drug Saf. 2018;41(11):1049–58.
The authors wish to thank ADERA, the non-profit organisation that provides legal, administrative and human resources support to Bordeaux PharmacoEpi.
Conflict of interest
Nicholas Moore, Stéphanie Duret, Adeline Grolleau, Régis Lassalle, Vanessa Barbet, Mai Duong, Nicolas Thurin, Cécile Droz-Perroteau, and Sinem Ezgi Gulmez have no conflicts of interest that are directly relevant to the content of this study. All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organisation for the submitted work and no other relationships or activities that could appear to have influenced the submitted work. Bordeaux PharmacoEpi receives funding from various pharmaceutical companies and governmental bodies to conduct research on marketed drugs at the request of regulatory authorities or as a consequence of research grant applications. None of these concern the subject at hand.
This study was supported by an unconditional public joint grant from Direction Générale de la Santé (DGS), from Mission recherche de la Direction de la recherche, des etudes, de l’évaluation et des statistiques (MiRe-DREES) of Caisse Nationale d’Assurance Maladie des Travailleurs Salariés (CNAMTS), Régime Social Indépendants (RSI) and Caisse Nationale de Solidarité́ pour l’Autonomie (CNSA), as part of the general call for projects by IReSP (Appel à Projets, Institut de Recherche en Santé Publique), no. 2013-29. It was designed, conducted and analysed independently by the Bordeaux PharmacoEpi Research Platform, CIC Bordeaux CIC1401.
In accordance with the French regulations, this study received authorisation from the Institute of Health Data (Institut des Données de Santé) and from the French Data Protection Commission (Commission Nationale de l’Informatique et des Libertés). This study was registered with ENCePP (http://www.encepp.eu), at the European Medicines Agency (EMA, London, UK), with the registration number ENCEPP/SDPP/7549.
About this article
Cite this article
Moore, N., Duret, S., Grolleau, A. et al. Previous Drug Exposure in Patients Hospitalised for Acute Liver Injury: A Case-Population Study in the French National Healthcare Data System. Drug Saf 42, 559–572 (2019). https://doi.org/10.1007/s40264-018-0752-1