Rechallenge in idiosyncratic drug-induced liver injury: An analysis of cases in two large prospective registries according to existing definitions.

INTRODUCTION: Data on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. METHODS: Cases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. RESULTS: Of 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. CONCLUSIONS: Episodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

MICROBIOTA INSIGHTS IN CLOSTRIDIUM DIFFICILE INFECTION AND INFLAMMATORY BOWEL DISEASE.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation that includes Crohn´s disease (CD) and ulcerative colitis (UC). Although the etiology is still unknown, some specific factors have been directly related to IBD, including genetic factors, abnormal intestinal immunity, and/or gut microbiota modifications. Recent findings highlight the primary role of the gut microbiota closely associated with a persistent inappropriate inflammatory response. This gut environment of dysbiosis in a susceptible IBD host can increasingly worsen and lead to colonization and infection with some opportunistic pathogens, especially Clostridium difficile. C. difficile is an intestinal pathogen considered the main cause of antibiotic-associated diarrhea and colitis and an important complication of IBD, which can trigger or worsen an IBD flare. Recent findings have highlighted the loss of bacterial cooperation in the gut ecosystem, as well as the pronounced intestinal dysbiosis, in patients suffering from IBD and concomitant C. difficile infection (CDI). The results of intestinal microbiota studies are still limited and often difficult to compare because of the variety of disease conditions. However, these data provide important clues regarding the main modifications and interrelations in the complicated gut ecosystem to better understand both diseases and to take advantage of the development of new therapeutic strategies. In this review, we analyze in depth the gut microbiota changes associated with both forms of IBD and CDI and their similarity with the dysbiosis that occurs in CDI. We also discuss the metabolic pathways that favor the proliferation or decrease in several important taxa directly related to the disease.

Can chronic stretching change the muscle-tendon mechanical properties? A review.

It is recognized that stretching is an effective method to chronically increase the joint range of motion. However, the effects of stretching training on the muscle-tendon structural properties remain unclear. This systematic review with meta-analysis aimed to determine whether chronic stretching alter the muscle-tendon structural properties. Published papers regarding longitudinal stretching (static, dynamic and/or PNF) intervention (either randomized or not) in humans of any age and health status, with more than 2 weeks in duration and at least 2 sessions per week, were searched in PubMed, PEDro, ScienceDirect and ResearchGate databases. Structural or mechanical variables from joint (maximal tolerated passive torque or resistance to stretch) or muscle-tendon unit (muscle architecture, stiffness, extensibility, shear modulus, volume, thickness, cross-sectional area, and slack length) were extracted from those papers. A total of 26 studies were selected, with a duration ranging from 3 to 8 weeks, and an average total time under stretching of 1165 seconds per week. Small effects were seen for maximal tolerated passive torque, but trivial effects were seen for joint resistance to stretch, muscle architecture, muscle stiffness, and tendon stiffness. A large heterogeneity was seen for most of the variables. Stretching interventions with 3- to 8-week duration do not seem to change either the muscle or the tendon properties, although it increases the extensibility and tolerance to a greater tensile force. Adaptations to chronic stretching protocols shorter than 8 weeks seem to mostly occur at a sensory level.

Expert clinical management of autoimmune hepatitis in the real world.

BACKGROUND: High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM: To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS: A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS: Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS: There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.

Use of (18)F-FDG PET/CT in the preoperative evaluation of patients diagnosed with peritoneal carcinomatosis of ovarian origin, candidates to cytoreduction and hipec. A pending issue.

PURPOSE: To evaluate the clinical usefulness of the results obtained with (18)F-FDG PET/CT in relation to CT in the preoperative staging of patients with peritoneal carcinomatosis secondary to primary or recurrent ovarian cancer candidates to cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC). MATERIAL AND METHODS: A retrospective study comparing the results obtained with CT and (18)F-FDG PET/CT in the preoperative evaluation of a series of 59 patients was performed. In all patients the peritoneal carcinomatosis index (PCI) was determined by preoperative radiological CT and 18F-FDG PET/CT and compared with surgical PCI, which was considered as reference. RESULTS: Of the 59 patients studied, in 55 peritoneal carcinomatosis presences were confirmed (4 patients had complete responses to neoadjuvant chemotherapy). The mean surgical, CT and 18F-FDG PET/CT PCI was 9.46±7.70, 3.69±3.96 and 2.25±1.02, respectively. In the global disease detection, CT showed a higher positive likelihood ratio (LR+) than (18)F-FDG PET/CT (15.3, 95% CI 8.35-28.04 vs. 3.47, 95% CI 3.36-5.11) and a lower negative likelihood ratio (LR-) than 18F-FDG PET/CT (0.67, 95% CI 0.61-0.73 vs. 0.82, 95% CI 0.76-0.88). In every region of the abdomen the CT showed a greater LR+ than 18F-FDG PET/CT and a lower LR- than 18F-FDG PET/CT. CONCLUSIONS: CT showed the best diagnostic results compared to (18)F-FDG PET/CT to confirme the presence of peritoneal disease. The lower performance of the (18)F-FDG PET/CT suggests that the main utility of (18)F-FDG PET/CT is to evaluate a possible metastatic extraperitoneal spread of the disease.

In vivo quantification of the shear modulus of the human Achilles tendon during passive loading using shear wave dispersion analysis.

The shear wave velocity dispersion was analyzed in the Achilles tendon (AT) during passive dorsiflexion using a phase velocity method in order to obtain the tendon shear modulus (C 55). Based on this analysis, the aims of the present study were (i) to assess the reproducibility of the shear modulus for different ankle angles, (ii) to assess the effect of the probe locations, and (iii) to compare results with elasticity values obtained with the supersonic shear imaging (SSI) technique. The AT shear modulus (C 55) consistently increased with the ankle dorsiflexion (N = 10, p < 0.05). Furthermore, the technique showed a very good reproducibility (all standard error of the mean values <10.7 kPa and all coefficient of variation (CV) values ⩽ 0.05%). In addition, independently from the ankle dorsiflexion, the shear modulus was significantly higher in the proximal location compared to the more distal one. The shear modulus provided by SSI was always lower than C55 and the difference increased with the ankle dorsiflexion. However, shear modulus values provided by both methods were highly correlated (R = 0.84), indicating that the conventional shear wave elastography technique (SSI technique) can be used to compare tendon mechanical properties across populations. Future studies should determine the clinical relevance of the shear wave dispersion analysis, for instance in the case of tendinopathy or tendon tear.

Effects of hip and head position on ankle range of motion, ankle passive torque, and passive gastrocnemius tension.

Ankle joint range of motion (ROM) is notably influenced by the position of the hip joint. However, this result remains unexplained. Thus, the aim of this study was to test if the ankle passive torque and gastrocnemius muscle tension are affected by the hip and the head positions. The torque and the muscle shear elastic modulus (measured by elastography to estimate muscle tension) were collected in nine participants during passive ankle dorsiflexions performed in four conditions (by combining hip flexion at 90 or 150°, and head flexed or neutral). Ankle maximum dorsiflexion angle significantly decreased by flexing the hip from 150 to 90° (P < 0.001; mean difference 17.7 ± 2.5°), but no effect of the head position was observed (P > 0.05). Maximal passive torque and shear elastic modulus were higher with the hip flexed at 90° (P < 0.001). During submaximal ROM, no effects of the head and hip positioning (P > 0.05) were found for both torque and shear elastic modulus at a given common ankle angle among conditions. Shifts in maximal ankle angle due to hip angle manipulation are not related neither to changes in passive torque nor tension of the gastrocnemius. Further studies should be addressed to better understand the functional role of peripheral nerves and fasciae in the ankle ROM limits.

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

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.

Provocative mechanical tests of the peripheral nervous system affect the joint torque-angle during passive knee motion.

This study aimed to determine the influence of the head, upper trunk, and foot position on the passive knee extension (PKE) torque-angle response. PKE tests were performed in 10 healthy subjects using an isokinetic dynamometer at 2°/s. Subjects lay in the supine position with their hips flexed to 90°. The knee angle, passive torque, surface electromyography (EMG) of the semitendinosus and quadriceps vastus medialis, and stretch discomfort were recorded in six body positions during PKE. The different maximal active positions of the cervical spine (neutral; flexion; extension), thoracic spine (neutral; flexion), and ankle (neutral; dorsiflexion) were passively combined for the tests. Visual analog scale scores and EMG were unaffected by body segment positioning. An effect of the ankle joint was verified on the peak torque and knee maximum angle when the ankle was in the dorsiflexion position (P < 0.05). Upper trunk positioning had an effect on the knee submaximal torque (P < 0.05), observed as an increase in the knee passive submaximal torque when the cervical and thoracic spines were flexed (P < 0.05). In conclusion, other apparently mechanical unrelated body segments influence torque-angle response since different positions of head, upper trunk, and foot induce dissimilar knee mechanical responses during passive extension.

Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry.

OBJECTIVES: The hepatotoxic potential of statins is controversial. The objectives of this study were to describe the relative frequency of hepatotoxicity caused by statins and the phenotypes found in Spain. PATIENTS AND METHODS: The incidence of hepatotoxicity attributed to statins in the Spanish Hepatotoxicity Registry (REH) were studied and compared with those attributed to other drugs. RESULTS: Between April 1994 and August 2012, the REH included a total of 858 cases of which 47 (5.5 %) were attributed to statins. Of these, 16 were due to atorvastatin (34 %); 13 to simvastatin (27.7 %); 12 to fluvastatin (25.5 %); 4 to lovastatin (8.5 %) and 2 to pravastatin (4.3 %). Statins represented approximately half of the cardiovascular group which occupied 3rd place (10 %), after anti-infectious agents (37 %) and central nervous system drugs (14 %). The hepatocellular pattern was predominant, especially in the simvastatin group (85%), the cholestatic/mixed pattern was more frequent with fluvastatin (66 %) and had a similar distribution to atorvastatin. Patients with statin-induced toxicity were older (62 years versus 53 years, p < 0.001) and more often demonstrated anautoimmune hepatitis phenotype (8.5 % versus 1.4 %, p < 0.003). CONCLUSIONS: Statins are not a common cause of hepatotoxicity in Spain. Atorvastatin is the statin involved in the greatest number of incidents. The liver injury pattern varies among the different statins. The hepatitis phenotype with autoimmune features appears to be a characteristic signature of statin-induced hepatotoxicity.

Hepatitis C virus infection alters lipid metabolism depending on IL28B polymorphism and viral genotype and modulates gene expression in vivo and in vitro.

Hepatitis C virus (HCV) interacts with lipid receptors to enter the cell, circulates as lipoviroparticle and is secreted as VLDL. We aimed to investigate the role of the rs12979860 polymorphism in the IL28B gene in 143 with chronic hepatitis C genotype 1, 144 infected with genotype 3, 90 genotype 4 and 413 noninfected individuals on lipid profile and to test the impact of HCV infection in an in vitro model on VLDL biosynthesis-related gene expression rs12979860 polymorphism was analysed using real-time PCR coupled to Fluorescence Resonance Energy Transfer (FRET). Huh7.5 (rs12979860 CT) and Huh7 (genotype CC) cells were infected with JFH-1 particles and serum from patients infected with genotypes 1 and 3. Gene expression of apolipoprotein B (apoB), microsomal triglyceride transfer protein (MTP), acetyl CoA carboxylase (ACC), diacylglycerol acyltransferase 2 (DGAT2), diacylglycerol acyltransferase 1 (DGAT1) and low-density lipoprotein receptor (LDLr) genes were determined by semiquantitative RT-PCR in vivo and in vitro. Genotype CC rs12979860 polymorphism was associated with significantly higher serum LDL and total cholesterol levels in patients with hepatitis C genotype 1 but not in patients with hepatitis C genotype 3, genotype 4 and control (noninfected) population. Genotype CC was more often seen in genotype 3 and healthy people in comparison with genotype 1; P = 0.001. In vitro results showed that HCV infection promotes lipid metabolism gene expression induction depending on viral genotype, but to a lesser extent in cells with CT genotype. These results demonstrate that IL28B genotype influences lipid metabolism in patients with hepatitis C but not in noninfected and it seems to be viral genotype-mediated. HCV infection modifies lipid-related genes expression (DGAT1 and DGAT2) in cultured cells based on viral genotype and IL28 polymorphism.

Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression.

Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual's level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values=0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention.

Case definition and phenotype standardization in drug-induced liver injury.

Drug-induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH).

Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis.

BACKGROUND & AIMS: Multiple instances of DILI in the same patient with drugs of similar structure or function as well as completely unrelated drugs are not well understood and poorly documented. We have sought evidence of the frequency and characteristics of patients who have experienced two DILI episodes due to different drugs. METHODS: All cases of DILI systematically collected in the Spanish DILI Registry between 1994 and 2009 were retrieved. Data on demographics, clinical, laboratory and pathological findings, and outcome were analyzed. RESULTS: Nine patients (mean age 67 years, four women) out of 742, 1.21%, had evidence of two DILI episodes caused by different drugs. In four cases DILI was associated with structurally related drugs and in an additional two cases the drugs had a common target. In another case, unrelated antibiotics were implicated. In only two cases, the two drugs/herbals were not related in structure or function. All but one patient exhibited hepatocellular damage. The type of damage was consistent in both DILI episodes. Four cases presented as autoimmune hepatitis (AIH) in the second episode. CONCLUSIONS: Multiple episodes of DILI in association with different drugs occur infrequently. In each individual, the type of injury was similar during the two DILI episodes, regardless of the causative drug. Second episodes of DILI are more likely to be associated with features of AIH. It remains uncertain if this is drug-induced unmasking of true AIH or DILI with autoimmune features. These cases illustrate the dilemma faced by clinicians in distinguishing these possibilities.

Hepatotoxicidad por antibióticos: actualización en 2008 / Hepatotoxicity by antibiotics: update in 2008

Aunque los antibióticos son los fármacos más común- mente implicados en reacciones hepatotóxicas impredecibles en la bibliografía, el riesgo potencial es bajo teniendo en cuenta su amplísimo uso. No obstante, entre las penicilinas, amoxicilina-ácido clavulánico es la causa más frecuente de hepatotoxicidad en cohortes de pacientes con lesión hepática tóxica no restringida a agentes específicos, constituyendo entre un 12,8 y un 14% de los casos, y la causa más frecuente de hospitalización por reacción adversa hepática. La incidencia de hepatotoxicidad inducida por amoxicilina- ácido clavulánico ha sido calculada en 9,91 por cada 100.000 prescripciones y la presentación clínica es variada, siendo el patrón de lesión influenciado por la edad, predominando el hepatocelular entre sujetos jóvenes y el colestásico/mixto entre sujetos de edad avanzada. Entre los macrólidos, la eritromicina es un ejemplo clásico de fármaco inductor de colestasis tóxica. La telitromicina, un macrólido de nueva generación, ha creado una importante alerta por la descripción de un elevado número de incidencias de hepatotoxicidad en un corto período de tiempo, con una firma característica que incluye fiebre y dolor abdominal de comienzo brusco, ictericia y ascitis en algunos casos. Las tetraciclinas pueden producir esteatosis microvesicular en forma dependiente de la dosis, especialmente cuando son administradas por vía intravenosa, y la minociclina es capaz de provocar una lesión hepática tóxica indistinguible de la hepatitis autoinmune tipo I. Las quinolonas, a pesar de ser extensivamente utilizados en pacientes con cirrosis hepática e infecciones de la vía biliar han sido muy infrecuentemente relacionadas con la producción de lesión hepática tóxica (AU)

Although antibiotics are the most commonly incriminated drugs in instances of hepatotoxicity in medical literature. However, it is mainly due to its wide prescription and the absolute risk of hepatotoxicity related to antibiotic use is thought to be low. Nevertheless, among the different penicillins, amoxicillin-clavulanate is the single leading drug involved in hepatotoxicity in cohorts of patients with drug- induced liver injury (DILI), representing between 12.8% to 14% of the cases. It is the most frequent cause of hospitalization for DILI. The incidence of amoxicillin-clavulanate induced hepatotoxicity has been estimated to be 9.91 per 100 000 users and its clinical presentation varies, the type of injury strongly influenced by age, with the hepatocelullar pattern predominating in younger patients and the cholestatic/mixed ones in older subjects. Among macrolides, erythromycin is a classical example of drug capable of inducing cholestatic injury. Recently, concern has arisen regarding telithromycin, a new generation macrolide, is hepatotoxic came from the identification of several cases of DILI related to this drug, with a typical signature, including abrupt commence of fever, abdominal pain, jaundice and ascites in some cases. Tetracyclines, especially in intravenous high doses, may be associated with dose-dependent microvesicular steatosis, and minocycline has been involved in an autoimmune like type I hepatitis. Quinolones, in spite of their extensive use in patients with cirrhosis and biliary infections, have been very rarely associated with hepatotoxicity (AU)

[Hepatotoxicity by antibiotics: update in 2008]. / Hepatotoxicidad por antibióticos: actualización en 2008.

Although antibiotics are the most commonly incriminated drugs in instances of hepatotoxicity in medical literature. However, it is mainly due to its wide prescription and the absolute risk of hepatotoxicity related to antibiotic use is thought to be low. Nevertheless, among the different penicillins, amoxicillin-clavulanate is the single leading drug involved in hepatotoxicity in cohorts of patients with drug-induced liver injury (DILI), representing between 12.8% to 14% of the cases. It is the most frequent cause of hospitalization for DILI. The incidence of amoxicillin-clavulanate induced hepatotoxicity has been estimated to be 9.91 per 100,000 users and its clinical presentation varies, the type of injury strongly influenced by age, with the hepatocelullar pattern predominating in younger patients and the cholestatic/mixed ones in older subjects. Among macrolides, erythromycin is a classical example of drug capable of inducing cholestatic injury. Recently, concern has arisen regarding telithromycin, a new generation macrolide, is hepatotoxic came from the identification of several cases of DILI related to this drug, with a typical signature, including abrupt commence of fever, abdominal pain, jaundice and ascites in some cases. Tetracyclines, especially in intravenous high doses, may be associated with dose-dependent microvesicular steatosis, and minocycline has been involved in an autoimmune like type I hepatitis. Quinolones, in spite of their extensive use in patients with cirrhosis and biliary infections, have been very rarely associated with hepatotoxicity.