M.I. Lucena

Assessment of drug‐induced liver injury in clinical practice

Currently, pharmaceutical preparations are serious contributors to liver disease, with hepatotoxicity ranking as the most frequent cause for acute liver failure and post‐marketing regulatory decisions. The diagnostic approach of drug‐induced liver injury (DILI) is still rudimentary and inaccurate because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step‐by‐step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage, and the ability to detect the presence of subtle data that favour a toxic aetiology. Clinical and laboratory data may also be assessed with algorithms or clinical scales, which may add consistency to the clinical judgment by translating the suspicion into a quantitative score. The CIOMS/RUCAM instrument is considered at present the best method for assessing causality in DILI, although it could be improved through the use of large database of bona fide DILI cases for validation criteria.

Distinct phenotype of hepatotoxicity associated with illicit use of anabolic androgenic steroids

We have observed an increase in hepatotoxicity (DILI) reporting related to the use of anabolic androgenic steroids (AAS) for bodybuilding.

Antibiotic-Induced Liver Toxicity: Mechanisms, Clinical Features and Causality Assessment

Antibiotics are the therapeutic agents most often associated with hepatotoxicity. However, this is mainly due to the widespread prescription of these drugs. The relative risk of antibiotic-related hepatotoxicity is low. Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult, particularly because some cases occur long after the drug has been stopped. Among the penicillins, amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations. Flucloxacillin ranks as the second highest cause of DILI in many countries. The severity of antibiotic-induced DILI varies widely, with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestatic/mixed type. The pattern is strongly influenced by age. Recently telithromycin (a new generation macrolide) has been linked with DILI, with a typical pattern, which includes abrupt commencement of fever, abdominal pain, jaundice and, in some cases, ascites. Antibiotic-induced DILI appears, in most instances, to be idiosyncratic. Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity.

Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases

Cyproterone acetate (CPA), an anti‐androgenic drug for prostate cancer, has been associated with drug‐induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA‐induced DILI.

Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury.

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies.

Hepatotoxicidad secundaria a fármacos de uso común

Resumen La importancia de las reacciones adversas hepaticas estriba principalmente en su potencial gravedad, no en vano son la causa mas frecuente de retirada de medicamentos del mercado farmaceutico. Las reacciones hepatotoxicas son casi siempre impredecibles (idiosincrasicas), es decir, que ocurren muy raras veces en individuos que toman dosis terapeuticas del compuesto, y no son detectadas casi nunca durante la fase de desarrollo. Aunque el cuadro clinico que se observa mas frecuentemente sea la hepatitis aguda icterica, las lesiones producidas por farmacos pueden simular cualquier enfermedad hepatica conocida. A pesar de que cualquier sustancia ajena al organismo puede ser causa de enfermedad hepatica, hay farmacos con mayor potencial hepatotoxico. Los grupos farmacologicos incriminados mas a menudo en casos de hepatotoxicidad son los antiinflamatorios no esteroideos, entre los cuales el mas comun es el diclofenaco, los antibioticos encabezados por la amoxicilina-acido clavulanico y los antituberculosos. El diagnostico se basa en la sospecha clinica inicial y se sustenta en una anamnesis exhaustiva con una secuencia temporal adecuada y la exclusion de causas alternativas de enfermedad hepatica. Por ultimo, dado que no hay una terapia especifica, salvo excepciones como la N-acetilcisteina, en la intoxicacion por paracetamol el tratamiento fundamental es la deteccion precoz del cuadro con la consiguiente retirada del agente causal. En este articulo se realiza una revision y descripcion de las caracteristicas de las reacciones de hepatotoxicidad producidas por los farmacos mas ampliamente prescritos en la poblacion general, incluyendo analgesicos, antimicrobianos, antidiabeticos, farmacos para el sistema cardiovascular y psicofarmacos.

505 IBUPROFEN-ASSOCIATED HEPATOTOXICITY: ANALYSIS OF A CASE SERIES INCLUDED IN THE SPANISH DILI REGISTRY

504 INSULIN RESISTANCE CONFERS A HIGHER RISK OF PORTAL HYPERTENSION, CIRRHOSIS AND EARLY MORTALITY TO ALCOHOLIC LIVER DISEASE PATIENTS E. Trepo, D. Degre, A. Lemmers, T. Gustot, A. Gerkens, S. Evrard, R. Ouziel, P. Deltenre, M. Adler, J. Deviere, C. Moreno. Department Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Laboratory of Experimental Gastroenterology, Universite Libre de Bruxelles, Brussels, Hopital de Jolimont, Haine-Saint-Paul, Belgium E-mail: christophe.moreno@erasme.ulb.ac.be

P1097 : Distinguishing drug induced autoimmune hepatitis from idiopatic autoimmune hepatitis

M30/CK18-cleavage staining, indicators of hepatocyte apoptosis. Indicators of oxidative stress, including the accumulation of 4-HNEprotein adducts and JNK phosphorylation, were also increased. In contrast, mice deficient in MLK3 were protected from ethanolinduced increases in plasma ALT/AST, pro-inflammatory cytokines and hepatic protein expression of RIP3. Ethanol-induced JNK phosphorylation and oxidative stress were also attenuated in MLK3deficient mice. However, MLK3-deficiency did not affect ethanolinduced steatosis or hepatocyte apoptosis. Conclusions: Taken together, these results suggest that MLK3 participates in the development of ethanol-induced oxidative stress, activation of JNK and induction of necroptotic programmed hepatocyte death. Pharmacological intervention of this pathway could be targeted as a potential therapeutic strategy to suppress necroptosis-induced inflammation and hepatocyte injury in patients with ALD.

P309 PROGNOSTIC MODEL FOR PREDICTING DRUG-INDUCED ACUTE LIVER FAILURE

P309 PROGNOSTIC MODEL FOR PREDICTING DRUG-INDUCED ACUTE LIVER FAILURE R.J. Andrade, M. Robles-Diaz, C. Stephens, I. MedinaCaliz, A. Gonzalez-Jimenez, A.F. Gonzalez, N. Kaplowitz, M.C. Fernandez, M. Romero-Gomez, M. Jimenez-Perez, M. Bruguera, M. Prieto, F. Bessone, N. Hernandez, M. Arrese, M.I. Lucena, Spanish-Latin DILI Registry. Unidad de Gestion Cĺinica de Enfermedades Digestivas, Servicio de Farmacoloǵia Cĺinica, Hospital Universitario Virgen de la Victoria, Instituto de Investigacion Biomedica de Malaga-IBIMA, Universidad de Malaga. CIBERehd, Malaga, Spain; USC Research Center for Liver Diseases, Keck School of Medicine, Los Angeles, CA, United States; Servicio de Farmacia, Hospital de Torrecardenas, Almeŕia, Unidad de Gestion Cĺinica de Enfermedades Digestivas, Hospital Universitario de Valme, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Sevilla, Unidad de Gestion Cĺinica de Enfermedades Digestivas, Hospital Regional Universitario Carlos Haya, IBIMA, Malaga, Instituto de Enfermedades Digestivas y Metabolismo, Hospital Clinic, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Barcelona, Unidad de Gestion Cĺinica de Enfermedades Digestivas, Hospital La Fe. Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd), Valencia, Spain; Facultad de Ciencias Medicas, Servicio de Gastroenteroloǵia y Hepatoloǵia, Hospital Provincial del Centenario. Universidad Nacional de Rosario, Rosario, Argentina; Hospital de Cĺinicas, Cĺinica de Gastroenteroloǵia, Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay; Departamento de Gastroenteroloǵia, Facultad de Medicina Pontificia. Universidad Catolica de Chile, Santiago, Chile E-mail: mrobles@uma.es

Reply: To PMID 24704526.

Reply. Thank you for your interest in our paper and the importance of early identification of an acute liver failure (ALF) outcome in drug-induced liver injury (DILI). We thank you for your questions and the opportunity to clarify a few points. First, the issue of including the International Normalized Ratio (INR) to further improve the prognostic model is important. In the Spanish DILI registry initiated in 1994, INR values were not generally available. Instead, prothrombin time (expressed as percentage) was recorded. However, coagulation data are not always included in routine blood tests or a patient’s first medical consultation. In fact, prothrombin time at onset was missing in a large proportion (approximately 35%) of the DILI cases in our cohort, including 5 of the ALF patients, precluding us from considering this parameter as a component of the algorithm for predicting ALF at onset. Hence, to include prothrombin time as a component of the algorithm for predicting ALF at onset would reduce the total number of DILI episodes substantially and could subsequently reduce the validity of the data outcome. On the other hand, in this study we aimed specifically to predict ALF in patients at DILI recognition by the use of the components of Hy’s law. Nevertheless, we have done a preliminary analysis including prothrombin time (cutoff point, 50%) in our prognostic algorithm. We found that the sensitivity increased to 90% at the expense of a reduced specificity (70%). As pointed out, our prognostic algorithm needs to be further validated in a large, prospective cohort. Whether INR (rather than prothrombin) could either improve or simplify our model requires further study. Second, the King’s criteria are designed to predict survival once the criteria for ALF are met. In contrast, our study was aimed at identifying the risk of ALF at onset, before the actual occurrence of ALF. Third, regarding spontaneous survival in ALF owing to idiosyncratic DILI, only 1 patient in our DILI cohort experienced this. It is in fact stated in our Results (page 111 in the article). Although this case was not included in the analysis, an inclusion would not have changed the findings regarding Hy’s law or the prognostic algorithm.