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Aims: Detection and characterization of idiosyncratic drug-induced liver injury (DILI) currently rely on standard liver tests, which are suboptimal in terms of specificity, sensitivity and prognosis. Therefore, DILI diagnosis can be delayed, with important consequences for the patient. In this study, we aimed to evaluate the potential of osteopontin, cytokeratin-18 (caspase-cleaved: ccK18 and total: K18), α-glutathione- S-transferase and microRNA-122 as new DILI biomarkers. Methods: Serial blood samples were collected from 32 DILI and 34 non-DILI acute liver injury (ALI) cases and a single sample from 43 population controls without liver injury (HLC) and analysed using enzyme-linked immunosorbent assay (ELISA) or single-molecule arrays. Results: All biomarkers differentiated DILI and ALI from HLC with an area under receiver operator characteristic curve (AUC) value of >0.75 but were less efficient in distinguishing DILI from ALI, with ccK18 (0.79) and K18 (0.76) demonstrating highest potential. However, the AUC improved considerably (0.98) for ccK18 when comparing DILI and a subgroup of autoimmune hepatitis cases. Cytokeratin-18, microRNA- 122 and α-glutathione-S-transferase correlated well with traditional transaminases, while osteopontin correlated most strongly with the international normalized ratio (INR). Conclusions: ccK18 appears promising in distinguishing DILI from autoimmune hepatitis but less so from other forms of acute liver injury. Osteopontin demonstrates prognostic potential with higher levels detected in more severe cases regardless of aetiology, Consejería de Salud y Familia de la Junta de Andalucía, Grant/Award Numbers: PI- 0274-2016, P18-RT-3364, Instituto de Salud Carlos III (ISCIII) cofounded by Fondo Europeo de Desarrollo Regional - FEDER, Grant/Award Numbers: PI19/00883, PI18/00901, UMA18-FEDERJA-193; Universidad de Málaga/CBUA

The identification of specific human leukocyte antigen (HLA) risk alleles in drug-induced liver injury (DILI) points towards an important role of the adaptive immune system in DILI development. In this study we aimed to corroborate the role of an adaptive immune response in DILI through immunophenotyping of leukocyte populations and immune checkpoint expressions. Blood samples were collected from adjudicated DILI (n=12), acute viral hepatitis (VH, 13), acute autoimmune hepatitis (AIH, 9) and acute liver injury of unknown etiology (UKE, 15) at day 1 (recognition), day 7 and day >30. Blood samples from non-alcoholic fatty liver disease patients (NAFLD, 20) and healthy liver controls (HLC, 54) were extracted at one time point. Leukocyte populations and immune checkpoint expressions were determined based on cell surface receptors, except for CTLA-4 that was determined intracellularly, using flow cytometry. At recognition DILI demonstrated significantly higher levels of activated helper T-cell (p

Acute liver injury and progression to acute liver failure can be life-threatening conditions that require prompt careful clinical assessment and therapeutic management.The aim of this article is to review the safety and side effect profile of pharmacological therapies used in the treatment of acute liver injury with specific focus on hepatic toxicity. We performed an extensive literature search with the terms 'acute liver injury,' 'acute liver failure,' 'therapy,' 'safety,' 'adverse reactions' and 'drug induced liver injury.' A thorough discussion of the main drugs and devices used in patients with acute liver injury and acute liver failure, its safety profile and the management of complications associated to therapy of these conditions is presented.Several pharmacological approaches are used in acute liver injury and acute liver failure in an empirical basis. Whilst steroids are frequently tried in serious drug-induced liver injury there is concern on a potential harmful effect of these agents because of the higher mortality in patients receiving the drug; hence, statistical approaches such as propensity score matching might help resolve this clinical dilemma. Likewise, properly designed clinical trials using old and new drugs for subjects with serious drug-induced liver injury are clearly needed.

Old patients with hepatotoxicity have been scarcely studied in idiosyncratic drug-induced liver injury (DILI) cohorts. We sought for the distinctive characteristics of DILI in older patients across age groups. A total of 882 DILI patients included in the Spanish DILI Registry (33% ≥65 years) were categorized according to age: “young” (

Drug-induced liver injury (DILI) is an adverse reaction to many drugs in common use that in a liver transplantation (LT) recipient may cause graft dysfunction and may even lead to graft loss and the need for retransplantation. However, several potential clinical scenarios, such as graft rejection and infection, can confound the diagnosis of suspected DILI in the setting of LT. This makes causal assessment of a new liver injury more uncertain and has traditionally precluded collection of bona fide cases of DILI affecting LT patients in prospective DILI registries and cohorts. Although no studies have yet determined a greater susceptibility of the transplant patient to DILI, these patients nevertheless present certain risk factors that can theoretically increase the risk of DILI. These include the fact that these patients are polymedicated, use drugs that are potentially hepatotoxic, and can have coexisting hepatitis B or C viruses in addition to other factors found in nontransplant patients, such as genetic variants. Therefore, awareness is crucial of any potential hepatotoxic effect of drugs used in the LT recipient and their possible implication in any case of liver dysfunction. In the present article, we review the most common drugs used in LT recipients from a liver safety perspective and address the main pitfalls in attributing causality in this clinical setting. We also affirm the need for further research and collaboration in this somewhat neglected topic in the field of DILI.

Alcohol-related liver disease (ARLD) is the most prevalent cause of advanced liver disease and liver cirrhosis in Europe, including Spain. According to the World Health Organization the fraction of liver cirrhosis attributable to alcohol use in Spain is 73.8% among men and 56.3% among women. ARLD includes various stages such as steatohepatitis, cirrhosis and hepatocellular cancer. In addition, patients with underlying ARLD and heavy alcohol intake may develop alcoholic hepatitis, which is associated with high mortality. To date, the only effective treatment to treat ARLD is prolonged withdrawal. There are no specific treatments, and the only treatment that increases life expectancy in alcoholic hepatitis is prednisolone. For patients with alcoholic hepatitis who do not respond to treatment, some centres offer the possibility of an early transplant. These clinical practice guidelines aim to propose recommendations on ARLD taking into account their relevance as a cause of advanced chronic liver disease and liver cirrhosis in our setting. This paper aims to answer the key questions for the clinical practice of Gastroenterology, Hepatology, as well as Internal Medicine and Primary Health Centres, making the most up-to-date information regarding the management and treatment of ARLD available to health professionals. These guidelines provide evidence-based recommendations for the clinical management of this disease.

BACKGROUND AND OBJECTIVES: Corticosteroids are often empirically used to treat idiosyncratic hepatotoxicity with severe features. Interestingly, intravenous methylprednisolone (MP) is increasingly being recognized as being responsible for liver injury. We aimed to characterize MP-induced liver injury by analyzing demographical, clinical, laboratory and outcome data of three MP-induced hepatotoxicity cases and compared this information with that of previously published cases. CASE SERIES: Three females with multiple sclerosis (MS) were treated intravenously with MP, mean daily dose 767 mg. Liver damage occurred 2 to 6 weeks after exposure. Severity was mild to moderate. Two patients suffered positive rechallenge. LITERATURE REVIEW: We identified 50 published cases of MP hepatotoxicity. Most of these cases were female (86%) and main treatment indications were MS (29 cases) and Graves' ophthalmopathy (13 cases). Hepatocellular damage predominated and mean time to onset was 6 weeks. Four patients died and rechallenge occurred in 19 cases. CONCLUSION: MP pulses can induce severe liver injury, often with an autoimmune phenotype, particularly in patients with MS and Graves' ophthalmopathy. Consequently, these patient groups should have liver tests monitored when treated with MP to provide safer patient care.

[Background & Aims] Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period., [Methods] Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected., [Results] A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974–0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994–0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy’s law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%)., [Conclusions] AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management., [Lay summary] Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes., The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI19/00883, PI16/01748, PI18/00901, PI18/01804, PI-0285-2016, PI-0274-2016, PI-0310-2018, PT17/0017/0020) and Agencia Española del Medicamento. CIBERehd and Plataforma ISCIII Ensayos Clinicos are funded by Instituto de Salud Carlos III. MRD holds a Joan Rodes (JR16/00015)/Acción B clinicos investigadores (B-0002-2019) and JSC a Rio Hortega (CM17/00243) research contract from ISCIII and Consejería de Salud de Andalucía.

Background Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations. Objectives: To evaluate clinical, laboratory features and outcome in HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network. Methods A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity. Results From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p = .04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p = .008 and p = .021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p = .026), and had more severe and fatal/liver transplantation outcomes (21% vs 12% vs 13%; p = .005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%). Conclusions HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver transplantation than DILI related to conventional drugs.

Drug induced liver injury (DILI) is a relatively rare hepatic condition in response to the use of medications, illegal drugs, herbal products or dietary supplements. It occurs in susceptible individuals through a combination of genetic and environmental risk factors believed to modify drug metabolism and/or excretion leading to a cascade of cellular events, including oxidative stress formation, apoptosis/necrosis, haptenization, immune response activation and a failure to adapt. The resultant liver damage can present with an array of phenotypes, which mimic almost every other liver disorder, and varies in severity from asymptomatic elevation of liver tests to fulminant hepatic failure. Despite recent research efforts specific biomarkers are not still available for routine use in clinical practice, which makes the diagnosis of DILI uncertain and relying on a high degree of awareness of this condition and the exclusion of other causes of liver disease. Diagnostic scales such as the CIOMS/RUCAM can support the causality assessment of a DILI suspicion, but need refinement as some criteria are not evidence-based. Prospective collection of well-vetted DILI cases in established DILI registries has allowed the identification and validation of a number of clinical variables, and to predict a more severe DILI outcome. DILI is also in need of properly designed clinical trials to evaluate the efficacy of new DILI treatments as well as older drugs such as ursodeoxycholic acid traditionally used to ameliorate cholestasis or corticosteroids now widely tried in the oncology field to manage the emergent type of hepatotoxicity related to immune checkpoint inhibitors.

Background and Aims: Drug-induced liver injury (DILI) presents with a wide phenotypic spectrum requiring an extensive differential diagnosis. Hepatitis E virus (HEV) is not systematically ruled out during acute hepatitis assessment in Spain. The aims of this study were to establish the role of HEV infection and its phenotypic presentation in patients initially suspected of DILI and to determine the anti-HEV seroprevalence rate. Methods: An analysis of 265 patients with suspected DILI and considered for enrolment in the Spanish DILI Registry and 108 controls with normal liver profiles was undertaken. Anti-HEV Immunoglobulin (Ig) G antibodies were analyzed in serum from all subjects. In those with serum samples extracted within 6 months from liver damage onset (n=144), HEV antigen (Ag) and anti- HEV IgM antibodies were tested in duplicate by ELISA. In addition, RT-PCR was performed externally in 8 patients. Results: Out of 144 patients, 12 (8%) were positive for anti-HEV IgM, mean age 61 years. Underlying hepatic diseases (OR=23.4, p20 folds upper limit of normal (OR=10.9, p=0.002) were associated with the diagnosis of acute hepatitis E. The overall anti-HEV IgG seroprevalence rate was 35%, evenly distributed between patients with suspected DILI (34%), and controls (39%). Conclusions: HEV seroprevalence and acute hepatitis E rates are relatively high in Spain. A search for active HEV infection is therefore advised in patients assessed for suspicion of DILI, particularly in patients with underlying liver diseases and high transaminase levels. The present study has been supported by grants of the Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional FEDER (contract numbers: FIS PI0274-2016, PI-0285- 2016, PI 18-01804, PI 18-00901, PT17/0017/0020, CM17/00243, JR16/00015, B-0002-2019, UMA-18-FEDERJA-193 and by the Agencia Española del Medicamento. SCReN and CIBERehd are funded by Instituto de Salud Carlos III. European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network, IMI2-Translational Safety Biomarker Pipeline (TransBioLine). The funding sources had no involvement in the study design, in the collection, analysis, and interpretation of data, in the writing of the report or in the decision to submit the manuscript for publication

Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight loss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville.

Introduction: In 2011, the Latin-American DILI-Network (LATINDILIN) set up under the guidance of the Spanish DILI Registry a network of hepatologists to prospectively identify and characterize DILI patients. Aim: To evaluate the drugs more frequently associated with DILI in LA, clinical phenotype and outcome. Methods: Demographics, clinical and biochemical parameters of all cases included in the LATINDILI Network were analysed according to the type of liver injury (hepatocellular, Hep; cholestatic, Chol and mixed, Mix). Results: 404 DILI cases were included. Anti-infectives (31%), musculoskeletal system drugs (13%) and herbal products (9.2%) were the main causative therapeutic drug classes. Mean age was 49 years (female sex, 61%). Hep injury predominated (62%) whereas Chol and Mix patterns were 24% and 15% of cases, respectively. Chol patients (mean age 56y) were older than Hep and Mix cases (47 and 50, p

Introduction: Idiosyncratic drug-induced liver injury (DILI) is a complex hepatic condition whose diagnosis is challenging due to lack of specific biomarkers. Objectives: We aimed to evaluate serum metabolomic differences between patients with DILI and with other causes of liver injury in search for specific DILI biomarkers. Methods: Metabolomic profiles of serum samples from 26 Spanish DILI patients, 34 with non-DILI acute liver injury (ALI) and 48 healthy controls, were analyzed using UHPLC-MS. To assess changes in disease progression, DILI and ALI patients were followed-up from detection (visit 1), one week (visit 2) and >30 days (visit 3). Data were analyzed using Shapiro-Wilk, Student's t and Wilcoxon tests. Results: Several amino acids, fatty acids (FAs), LPI and bile acids were increased, whereas the glycerophospholipids MEPE and MAPC were decreased (p0,05). Conclusion: Most metabolomic differences are found at times closer to DILI recognition (visits 1&2), although abnormal values of FAs remain during recovery. Some FAs species and the amino acids taurine, Phe-Phe glutamic acid, lysine, tryptophan and alanine seem promising DILI biomarker candidates that should be further explored. Funding: CIBERehd, ISCiii-FEDER PI18/00901, PI19/00883.

Drug-induced liver injury (DILI) is a rare, unpredictable, and potentially serious adverse reaction. It is induced by many drugs, herbs, and dietary supplements and represents a diagnostic challenge to clinicians. Older people (aged 65 years and older) are often polymedicated, and their declining physiological function affects drug pharmacokinetics. There is no consistent evidence that age is a general risk factor for DILI; however, age might be a risk factor with specific medications, with antimicrobials and cardiovascular drugs being the most likely medications to cause DILI in older people. Ageing influences DILI phenotypes, making cholestatic damage and chronic DILI more likely. In older people with DILI, comorbidities act as confounding causes and account for higher mortality unrelated to the liver. There are no specific therapies for DILI and supportive measures are still the mainstay of management. This Review highlights current advances and gaps in DILI epidemiology, mechanisms, and diagnosis that are pertinent to older individuals.

Idiosyncratic drug-induced liver injury (DILI) remains one of the most important causes of drug attrition both in the early phases of clinical drug development and in the postmarketing scenario. This is because, in spite of emerging data on genetic susceptibility variants associated to the risk of hepatotoxicity, the precise identification of the individual who will develop DILI when exposed to a given drug remains elusive.In this review, we have addressed recent progress made and initiatives taken in the field of DILI from a safety perspective through a comprehensive search of the literature.Despite the substantial progress made over this century, new approaches using big data analysis to characterize the true incidence of DILI are needed and to categorize the drugs' hepatotoxic potential. Genetic studies have highlighted the role of the adaptive immune system yet the mechanisms leading adaptation versus progression remain to be elucidated. There is a compelling need for development and qualification of sensitive, specific, and affordable biomarkers in DILI to foster drug development, patient treatment stratification and, improvement of causality assessment methods. Gaining mechanistic insights in DILI is essential to uncover therapeutic targets and design prospective clinical trials with appropriate endpoints.

RESUMEN En el año 2016 se detectó en la provincia de Málaga un brote de hepatitis A en pacientes con características epidemiológicas especiales, con un predominio de sujetos del sexo masculino. Presentamos 51 casos de hepatitis A aguda con una media de edad de 35,7 años, el 90% varones, con un 55% de casos que reconocían haber mantenido relaciones sexuales con otros hombres en los últimos dos meses. La mitad de ellos requirieron ingreso hospitalario por coagulopatía significativa en el momento del diagnóstico, sin evolución a fallo fulminante, ni encefalopatía en ningún caso. Cuatro casos presentaban ascitis al diagnóstico. Este brote se suma a otros dos publicados en Reino Unido y Holanda con un número de casos similar y epidemiológicamente muy parecidos, lo cual refuerza la importancia de la vigilancia epidemiológica y la necesidad de vacunación en esta población de riesgo, así como de campañas informativas a la población para prevenir la enfermedad. ABSTRACT In 2016, an outbreak of hepatitis A was identified in the Malaga province among patients with specific epidemiological characteristics, which were predominantly males. This is a report of 51 subjects with acute hepatitis A and a mean age of 35.7 years, 90% were male and 55% of cases were men who had had sex with other men within the last two months. Half of them required hospitalization for significant coagulopathy at diagnosis and no cases progressed to fulminant failure or encephalopathy. Four patients had ascites at the time of diagnosis. This outbreak adds to those reported in the United Kingdom and the Netherlands with a similar number of cases and epidemiology. These studies highlight the importance of epidemiological surveillance, the need for vaccination in this particular at risk population and the need for informative campaigns in order to prevent this disease.

Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight toss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville. (C) 2018 Elsevier Espana, S.L.U. All rights reserved.

Summary Background We have observed an increase in hepatotoxicity (DILI) reporting related to the use of anabolic androgenic steroids (AAS) for bodybuilding. Aim To characterise phenotype presentation, outcome and severity of AAS DILI. Methods Data on 25 cases of AAS DILI reported to the Spanish (20) and Latin-American (5) DILI Registries were collated and compared with previously published cases. Results AAS DILI increased from representing less than 1% of the total cases in the Spanish DILI Registry in the period 2001–2009 to 8% in 2010–2013. Young men (mean age 32 years), requiring hospitalisation, hepatocellular injury and jaundice were predominating features among the AAS cases. AAS DILI caused significantly higher bilirubin values independent of type of damage when compared to other drug classes (P = 0.001). Furthermore, the cholestatic AAS cases presented significantly higher mean peak bilirubin (P = 0.029) and serum creatinine values (P = 0.0002), compared to the hepatocellular cases. In a logistic regression model, the interaction between peak bilirubin values and cholestatic damage was associated with the development of AAS-induced acute kidney impairment (AKI) [OR 1.26 (95% CI: 1.035–1.526); P = 0.021], with 21.5 ×ULN being the best bilirubin cut-off point for predicting AKI risk (AUCROC 0.92). No fatalities occurred. Conclusions Illicit recreational AAS use is a growing cause of reported DILI that can lead to severe hepatic and renal injury. AAS DILI is associated with a distinct phenotype, characterised by considerable bilirubin elevations independent of type of damage. Although hepatocellular injury predominates, acute kidney injury develops in cholestatic cases with pronounced jaundice.

Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

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.

A chronic adverse reaction may occur in some instances of drug-induced liver injury (DILI), even despite drug cessation. In our study, we obtained records from a Spanish registry and evaluated cases of DILI with biochemical evidence of long-term damage. Chronic outcome was defined as a persistent biochemical abnormality of hepatocellular pattern of damage more than 3 months after drug withdrawal or more than 6 months after cholestatic/mixed damage. Data on 28 patients with a chronic clinical evolution (mean follow-up 20 months) between November 1995 and October 2005 were retrieved (18 female; overall mean age 55 yr) and accounted for 5.7% of total idiosyncratic DILI cases (n = 493) submitted to the registry. The main drug classes were cardiovascular and central nervous system (28.5% and 25%, respectively), which, in contrast, represented only 9.8% and 13%, respectively, of all DILI cases. The most frequent causative drugs were amoxicillin–clavulanate (4 of 69 cases), bentazepam (3 of 7 cases), atorvastatin (2 of 7 cases), and captopril (2 of 5 cases). Patients with cholestatic/mixed injury (18 of 194 cases [9%]) were more prone to chronicity than patients with hepatocellular injury (10 of 240 cases; P < .031). In the case of chronic hepatocellular injury, 3 patients progressed to cirrhosis and 2 to chronic hepatitis. In the cholestatic/mixed group, liver biopsy indicated cirrhosis in 1 patient and ductal lesions in 3 patients. In conclusion, cholestatic/mixed type of damage is more prone to become chronic while, in the hepatocellular pattern, the severity is greater. Cardiovascular and central nervous system drugs are the main groups leading to chronic liver damage. (HEPATOLOGY 2006;44:1581–1588.)

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.

Drug-induced idiosyncratic liver disease (DIILD) depends largely on host susceptibility factors. Small studies support the genetic influence of human leukocyte antigen (HLA) class II molecules on the predisposition to DIILD. We sought associations between HLA-DRB and -DQB alleles and DIILD considered collectively or according to the biochemical expression of liver damage. We studied a total of 140 patients with a definitive or probable diagnosis of DIILD, as assessed with the Council for International Organizations of Medical Sciences scale, with 635 volunteer bone marrow and blood donors serving as controls. HLA-DRB1* and -DQB1* genotyping was performed by hybridization with sequence-specific oligonucleotides after genomic amplification. The group with DIILD did not differ from control subjects with regard to the distribution of HLA-DRB and -DQB antigens. The frequencies of alleles DRB1*15 (35.4% vs. 18.6% of controls; P = .002; odds ratio [OR] 2.31) and DQB1*06 (61.5% vs. 40.8%; P = .001; OR 2.32) were significantly increased in patients with the cholestatic/mixed type of liver damage in comparison to healthy subjects. By contrast, frequencies of alleles DRB1*07 (16.9% vs. 35.4%; P = .003; OR 0.37) and DQB1*02 (32.3% vs. 55.8%; P = .0003; OR 0.39) were significantly decreased. In conclusion, there is no association between any specific HLA allele and the propensity to develop DIILD. However, the genetic influence associated with HLA class II alleles appears to play a role in the biochemical expression of liver injury in cholestatic/mixed hepatotoxicity and may explain why a given drug may cause different patterns of liver damage. (HEPATOLOGY 2004;39:1603–1612.)

Introducción: la reexposición al agente causal constituye un incidente potencialmente grave en hepatotoxicidad. Objetivos: evaluar las características y la evolución de los casos con reexposición positiva. Material y métodos: estudio retrospectivo de una serie de casos con evidencia de reexposición positiva incluidos en el Registro Español de Hepatopatías Asociadas a Medicamentos, analizando su relación con variables demográficas y clínicas, causalidad, evolución y consecuencias. Resultados: de un total de 520 casos, 31 (6%) cumplían los criterios de reexposición. La evolución fatal, la necesidad de hospitalización y el tiempo medio de recuperación fueron mayores en la lesión tóxica de tipo hepatocelular. El grupo farmacológico identificado con mayor frecuencia fue el de los antibióticos. En la mayoría de los casos la reexposición con el compuesto responsable fue inadvertida (73%) debido a: la ausencia de diagnóstico del caso índice, la carencia de información al paciente o a su médico y también (12%) por el desarrollo de una reacción cruzada entre fármacos estructuralmente similares. Conclusiones: la reexposición accidental a un mismo fármaco o a otro estructuralmente relacionado tras un primer episodio de hepatotoxicidad no es infrecuente y sus consecuencias pueden ser graves, especialmente en el tipo de lesión hepatocelular. Una minuciosa historia clínica y la sospecha diagnóstica reflejada en el informe del primer episodio podrían disminuir la incidencia de este evento iatrogénico.

BACKGROUND: toxic liver damage associated with the use of natural remedies is a growing health problem. OBJECTIVES: to analyze the demographics, and clinical and epidemiological characteristics of patients developing liver injury related to these remedies. PATIENTS AND METHODS: all DILI cases associated with the use of herbal remedies (HR) or dietary supplements (DS) submitted to the Spanish Registry were analyzed. Type of liver damage, severity, and outcome were specifically evaluated. RESULTS: thirteen cases out of 521 DILI cases (2%) submitted to the Spanish Liver Toxicity Registry between 1994 and 2006 were related to HR/DS, which ranked as the 10th therapeutic group with a greater number of cases and above pain killers, anxiolytics, and antipsychotic drugs. Nine patients (69%) were female (mean age 45 years). Nine cases (69%) had jaundice at presentation. The predominating type of liver damage was hepatocellular (12; 92%), and 31% of cases exhibited the common features of hypersensitivity. Camellia sinensis (3, 23%) was the main causative herb, followed by Rhamnus purshianus and isoflavones (Fitosoja(R), Biosoja(R)) (2 cases each, 15%). Three cases (23%) were rechallenged with the offending product. CONCLUSIONS: the incidence of hepatic damage related to HR/DS is not so rare, the most common profile of affected patients being a woman with acute hepatocellular hepatitis. Low suspicion regarding the putative role of herbs in hepatotoxicity makes diagnosis more difficult, and probably increases the incidence of inadvertent rechallenge in these patients. Language: es

August 2015 e123 Assessment and Drug Research, Coimbra, Portugal; and University of Coimbra, School of Pharmacy, Coimbra, Portugal Background: Drugs either used in the treatment of ocular or systemic pathologic conditions have the potential to cause adverse events in the eye and to affect ocular functions. Ocular adverse events are the fewest adverse events studied and assessed in post-marketing surveillance. The investigation of the regulatory actions resulting from the identification of serious ocular disorders associated with the use of drugs, irrespective of being locally or systemically administered, during the last decade, is of utmost importance given its implication for the clinical practice. Material and Methods: The websites of four health regulatory authorities were reviewed to identify safety alerts issued on ocular adverse events. Safety alerts were included if they have been issued between January 2005 and December 2014. Only safety alerts on drugs with market authorization were considered for inclusion. Results: Thirty-eight safety alerts were included in the study. “Urologicals” (n = 11; 29%), followed by “Drugs used in diabetes”, “Antibacterials for systemic use”, “Antioneplastic agents”, and “Ophthalmologicals” were the most frequent suspected drugs evaluated in the safety alerts (n = 4; 10%, each). The most frequently evaluated adverse events were “Visual disorders NEC” (n = 12; 32%), including visual impairment, diplopia, and blurred vision. The majority (n = 25; 66%) of the safety alerts were supported by postmarketing spontaneous reports. The most commonly updated drug label section was the “Warnings and Precautions” section (n = 33; 87%), followed by the “Adverse reactions” section (n = 26; 68%). Conclusion: Ocular adverse events newly identified during this decade come mostly from systemic drugs, some of them marketed for several years. Physicians should be aware of drug-induced adverse effects in the eye in order to avoid as soon as possible their progression, which can lead to visual impairment.

We report a patient who developed cholestatic hepatitis shortly after starting therapy with irbesartan, one of the new, recently marketed angiotensin II antagonists. Serological studies and ultrasonography ruled out viral hepatitis and extrahepatic obstructive jaundice, respectively. A percutaneous liver biopsy showed a portal inflammatory infiltrate with eosinophils and marked cholestatic features in the perivenular area. Irbesartan was discontinued and the patient's jaundice resolved slowly over a period of several weeks, although mild biochemical cholestasis lasted for more than 1 year. There have been seven prior cases of angiotensin II antagonist-induced hepatotoxicity reported in the literature. A class warning for hepatotoxicity for these compounds should probably be considered.