A. González-Jiménez

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.

Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury

BACKGROUND & AIMS Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. METHODS 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. RESULTS Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis. CONCLUSIONS One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. LAY SUMMARY Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis.

The value of serum aspartate aminotransferase and gamma‐glutamyl transpetidase as biomarkers in hepatotoxicity

The current definition of the pattern of liver injury in hepatotoxicity (DILI) is given by the R (ratio) value, dividing alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in upper limits of normal at DILI onset. We aimed to explore the validity of using aspartate aminotransferase (AST) and gamma‐glutamyl transpeptidase (GGT) as biomarkers of hepatocelullar and cholestatic damage, respectively, when calculating the R value.

Herbal and Dietary Supplement-Induced Liver Injuries in the Spanish DILI Registry

Background & Aims There have been increasing reports of liver injury associated with use of herbal and dietary supplements, likely due to easy access to these products and beliefs among consumers that they are safer or more effective than conventional medications. We aimed to evaluate clinical features and outcomes of patients with herbal and dietary supplement‐induced liver injuries included in the Spanish DILI Registry. Methods We collected and analyzed data on demographic and clinical features, along with biochemical parameters, of 32 patients with herbal and dietary supplement‐associated liver injury reported to the Spanish DILI registry from 1994 through 2016. We used analysis of variance to compare these data with those from cases of liver injury induced by conventional drugs or anabolic androgenic steroid‐containing products. Results Herbal and dietary supplements were responsible for 4% (32 cases) of the 856 DILI cases in the registry; 20 cases of DILI (2%) were caused by anabolic androgenic steroids. Patients with herbal and dietary supplement‐induced liver injury were a mean age of 48 years and 63% were female; they presented a mean level of alanine aminotransferase 37‐fold the upper limit of normal, 28% had hypersensitivity features, and 78% had jaundice. Herbal and dietary supplement‐induced liver injury progressed to acute liver failure in 6% of patients, compared with none of the cases of anabolic androgenic steroid‐induced injury and 4% of cases of conventional drugs. Liver injury after repeat exposure to the same product that caused the first DILI episode occurred in 9% of patients with herbal and dietary supplement‐induced liver injury vs none of the patients with anabolic androgenic steroid‐induced injury and 6% of patients with liver injury from conventional drugs. Conclusion In an analysis of cases of herbal and dietary supplement‐induced liver injury in Spain, we found cases to be more frequent among young women than older patients or men, and to associate with hepatocellular injury and high levels of transaminases. Herbal and dietary supplement‐induced liver injury is more severe than other types of DILI and re‐exposure is more likely. Increasing awareness of the hepatoxic effects of herbal and dietary supplements could help physicians make earlier diagnoses and reduce the risk of serious liver damage.

Hepatic Damage by Natural Remedies

The rising burden of herbal and dietary supplement hepatotoxicity (HILI) is a growing concern in Western countries. The estimated incidence of HILI in well-designed prospective studies ranges from less than 1 to 3 individuals per 100,000 inhabitants/year. Herbal hepatotoxicity has a particular signature encompassing female predominance, hepatocellular type of damage with markedly elevated transaminases on presentation, more common unintentional rechallenge, and a greater risk of death/liver transplantation. Herbal hepatotoxicity recognition is particularly challenging for hepatologists because of the often hidden herbal consumption, difficulties in identifying the causative herbal component, and the possibility of contamination, adulteration, and misidentification, which preclude a proper adjudication and lead to inaccurate reporting of cases in scientific journals. Collaborative efforts to retrieve detailed phenotypic data and biological samples of patients with HILI would facilitate genomic and other molecular approaches for a better understanding of host risk factors and, hopefully, for biomarker identification.

Hepatic Safety of Atypical Antipsychotics: Current Evidence and Future Directions

The newer atypical antipsychotic agents (AAPs) represent an attractive therapeutic option for a wide range of psychotic disorders, including schizophrenia and bipolar mania, because of the reduced risk of disabling extrapyramidal symptoms. However, their growing use has raised questions about their tolerability over the endocrine, metabolic, and cardiovascular axes. Indeed, atypical antipsychotic drugs are associated, to differing extents, with mild elevation of aminotransferases related to weight gain, AAP-induced metabolic syndrome, and nonalcoholic fatty liver disease. Although the hepatic safety of new AAPs seems improved over that of chlorpromazine, they can occasionally cause idiosyncratic liver injury with varying phenotypes and, rarely, lead to acute liver failure. However, AAPs are a group of heterogeneous, chemically unrelated compounds with distinct pharmacological and pharmacokinetic properties and substantially different safety profiles, which precludes the notion of a class effect for hepatotoxicity risk and highlights the need for an individualized therapeutic approach. We discuss the current evidence on the hepatotoxicity potential of AAPs, the emerging underlying mechanisms, and the limitations inherent to this group of drugs for both establishing a proper causality assessment and developing strategies for risk management.

The influence of drug properties and host factors on delayed onset of symptoms in drug-induced liver injury

Most patients with drug‐induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry.

High Prevalence of Ibuprofen Drug-induced Liver Injury in Spanish and Latin-American Registries.

*Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Málaga, Spain; Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; Unidad de Gestión Clínica de Aparato Digestivo Intercentros, Hospitales Universitarios Virgen Macarena-Virgen del Rocio, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Seville, Spain; kHospital Provincial del Centenario, Facultad de Medicina, Universidad Nacional de Rosario, Rosario, Argentina; Servicio de Aparato Digestivo, Hospital Morales Meseguer, Murcia, Spain; Department of Immunology, Complutense University School of Medicine, Madrid, Spain; **Hospital 12 de Octubre Health Research Institute (i+12), Madrid, Spain; Unidad de Investigación Clínica y Ensayos Clínicos Instituto de Investigación Biomédica de Málaga, Plataforma Spanish Clinical Research Network, Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Málaga, Spain

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