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.

Hepatotoxicidad secundaria a “productos naturales”: análisis de los casos notificados al Registro Español de Hepatotoxicidad / No disponible

Introducción: la toxicidad hepática asociada al uso crecientede productos de “remedios naturales” es un fenómeno emergente.Objetivos: valoración de las características epidemiológicas,clínicas y demográficas de los casos de hepatotoxicidad secundariosa productos herbales (PH) y suplementos dietéticos(SD).Pacientes y métodos: análisis de los casos de hepatotoxicidaddebida a PH y SD incluidos en el Registro Español de Hepatotoxicidad.Resultados: trece casos de un total de 521 casos (2%) dereacciones adversas hepáticas incluidas en el registro entre1994 y 2006, eran secundarios a PH/SD, representando el décimogrupo terapéutico responsable por orden de frecuencia,por delante de analgésicos, ansiolíticos y antipsicóticos. Nuevepacientes (69%) eran mujeres y la edad media fue de 45 años.Nueve pacientes (69%) presentaron ictericia. El tipo de dañomás frecuente fue el hepatocelular (12; 92%) y un 31% de loscasos presentaron datos de hipersensibilidad. La sustancia máscomúnmente involucrada en los casos de daño hepático fue laCamellia sinensis (23%) seguida de Rhamnus purshianus eisoflavonas (Fitosoja®, Biosoja®) con dos casos cada uno (15%).Tres casos (23%) presentaron re-exposición positiva.Conclusiones: la hepatotoxicidad originada por PH/SD noes excepcional, y su perfil es la hepatitis aguda hepatocelular ictéricapredominantemente en mujeres. La frecuente ocurrenciade reexposición positiva en estos pacientes indica un bajo índicede sospecha y un retraso o ausencia de diagnóstico de estetipo de reacción adversa

Background: toxic liver damage associated with the use ofnatural remedies is a growing health problem.Objectives: to analyze the demographics, and clinical andepidemiological characteristics of patients developing liver injuryrelated to these remedies.Patients and methods: all DILI cases associated with the useof herbal remedies (HR) or dietary supplements (DS) submitted tothe Spanish Registry were analyzed. Type of liver damage, severity,and outcome were specifically evaluated.Results: thirteen cases out of 521 DILI cases (2%) submittedto the Spanish Liver Toxicity Registry between 1994 and2006 were related to HR/DS, which ranked as the 10th therapeuticgroup with a greater number of cases and above painkillers, anxiolytics, and antipsychotic drugs. Nine patients (69%)were female (mean age 45 years). Nine cases (69%) had jaundiceat presentation. The predominating type of liver damagewas hepatocellular (12; 92%), and 31% of cases exhibited thecommon features of hypersensitivity. Camellia sinensis (3,23%) was the main causative herb, followed by Rhamnus purshianusand isoflavones (Fitosoja®, Biosoja®) (2 cases each,15%). Three cases (23%) were rechallenged with the offendingproduct.Conclusions: the incidence of hepatic damage related toHR/DS is not so rare, the most common profile of affected patientsbeing a woman with acute hepatocellular hepatitis. Lowsuspicion regarding the putative role of herbs in hepatotoxicitymakes diagnosis more difficult, and probably increases the incidenceof inadvertent rechallenge in these patients

[An analysis of the causes, characteristics, and consequences of reexposure to a drug or compound responsible for a hepatotoxicity event]. / Análisis de las causas, características y consecuencias de la reexposición al fármaco o compuesto responsable de un episodio de hepatotoxidad.

INTRODUCTION: reexposure to a causal agent represents a potentially serious event in hepatotoxicity. OBJECTIVES: to assess the characteristics and outcome of cases with positive reexposure. MATERIAL AND METHODS: a retrospective study of cases with evidence of positive reexposure included in Registro Español de Hepatopatías Asociadas a Medicamentos, and an analysis of their relation to demographic and clinical variables, causality, course, and consequences. RESULTS: of a total of 520 cases 31 (6%) met reexposure criteria. Fatal outcomes, needs for admission, and mean recovery time were all higher for hepatocellular-type toxic injury. The most commonly identified drug class was antibiotics. On most occasions (73%) reexposure to the causal compound escaped notice because of: absence of index case diagnosis, lack of information to patients and their physicians, and (12%) development of cross reactions between structurally similar drugs. CONCLUSIONS: accidental reexposure to a drug or a structurally-related compound after an initial hepatotoxicity event is common and may have serious consequences, particularly in hepatocellular-type toxicity. Careful history taking and reflecting diagnostic suspicion in the initial episode s record may reduce the incidence of this iatrogenic event.

Análisis de las causas, características y consecuencias de la reexposición al fármaco o compuesto responsable de un episodio de hepatotoxicidad / No disponible

Introducción: la reexposición al agente causal constituye unincidente potencialmente grave en hepatotoxicidad.Objetivos: evaluar las características y la evolución de los casoscon reexposición positiva.Material y métodos: estudio retrospectivo de una serie decasos con evidencia de reexposición positiva incluidos en el RegistroEspañol de Hepatopatías Asociadas a Medicamentos, analizandosu relación con variables demográficas y clínicas, causalidad,evolución y consecuencias.Resultados: de un total de 520 casos, 31 (6%) cumplían loscriterios de reexposición. La evolución fatal, la necesidad de hospitalizacióny el tiempo medio de recuperación fueron mayores enla lesión tóxica de tipo hepatocelular. El grupo farmacológicoidentificado con mayor frecuencia fue el de los antibióticos. En lamayoría de los casos la reexposición con el compuesto responsablefue inadvertida (73%) debido a: la ausencia de diagnóstico delcaso índice, la carencia de información al paciente o a su médicoy también (12%) por el desarrollo de una reacción cruzada entrefármacos estructuralmente similares.Conclusiones: la reexposición accidental a un mismo fármacoo a otro estructuralmente relacionado tras un primer episodiode hepatotoxicidad no es infrecuente y sus consecuencias puedenser graves, especialmente en el tipo de lesión hepatocelular. Unaminuciosa historia clínica y la sospecha diagnóstica reflejada en elinforme del primer episodio podrían disminuir la incidencia deeste evento iatrogénico

Introduction: reexposure to a causal agent represents a potentiallyserious event in hepatotoxicity.Objectives: to assess the characteristics and outcome of caseswith positive reexposure.Material and methods: a retrospective study of cases withevidence of positive reexposure included in Registro Español deHepatopatías Asociadas a Medicamentos, and an analysis of theirrelation to demographic and clinical variables, causality, course,and consequences.Results: of a total of 520 cases 31 (6%) met reexposure criteria.Fatal outcomes, needs for admission, and mean recovery timewere all higher for hepatocellular-type toxic injury. The most commonlyidentified drug class was antibiotics. On most occasions(73%) reexposure to the causal compound escaped notice becauseof: absence of index case diagnosis, lack of information topatients and their physicians, and (12%) development of cross reactionsbetween structurally similar drugs.Conclusions: accidental reexposure to a drug or a structurally-related compound after an initial hepatotoxicity event is commonand may have serious consequences, particularly in hepatocellular-type toxicity. Careful history taking and reflectingdiagnostic suspicion in the initial episode’s record may reduce the incidence of this iatrogenic event (AU)

[Liver injury induced by "natural remedies": an analysis of cases submitted to the Spanish Liver Toxicity Registry]. / Hepatotoxicidad secundaria a "productos naturales": análisis de los casos notificados al Reigstro Español de Hepatotoxicidad.

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.

[Genotype and phenotypic expression of hereditary hemochromatosis in Spain]. / Genotipo y expresión fenotípica de la hemocromatosis hereditaria en España.

INTRODUCTION: The prevalence of C282Y homozygosity in patients with hereditary hemochromatosis (HH) has been reported to be markedly lower in the Mediterranean Basin than in northern Europe. In Spain, the available data are contradictory and limited to small series in specific regions. The objective of this study is to determine the prevalence of the 2 main HFE gene mutations in a large series of unrelated Spanish patients with HH from different geographical origins. PATIENTS AND METHOD: The criteria for HH diagnosis were: repeat serum transferrin saturation index (> 45% plus C282Y homozygosity and/or hepatic iron index (> 1.9 of dry liver weight in non-cirrhotic patients or (> 4.1 in patients with liver cirrhosis. Cases in related individuals were excluded. Demographic data, clinical expression, iron parameters and HFE gene mutations (C282Y and H63D) were assessed in 222 patients. RESULTS: A total of 83.3% of patients were C282Y homozygous and 5% were compound heterozygous (C282Y/H63D). No significant differences in phenotypic expression or in the frequency of C282Y homozygosity were observed between patients born in the North and South of Spain. CONCLUSION: The genotypic and phenotypic expression of HH in Spain is very similar to that reported in Northern Europe. Thus, the genetic heterogeneity described in some Southern European regions cannot be considered a common feature to all countries of the Mediterranean Basin.

[Tetrabamate-induced hepatotoxicity. Report of seven cases and literature review]. / Hepatotoxicidad por tetrabamato. Presentación de 7 casos y revisión de la bibliografía.

OBJECTIVES: Analysis of all cases of tetrabamate (Atrium)-induced hepatotoxicity reported in the Andalusian Registry of drug-induced liver disorders and comparison with cases reported in the literature. MATERIAL AND METHOD: Information was gathered in a structured protocol. The causal role of tetrabamate was estimated in each case using the diagnostic scale of the Council for International Organizations of Medical Sciences (CIOMS). RESULTS: Of 327 cases of hepatotoxicity, 7 (2%) were due to tetrabamate. The mean age was 57 years (4 men). In 57% of the cases, the presenting symptom was tremor. The latency period was between 15 and 730 days. Liver damage was mainly cytolytic without signs of hypersensitivity. In all cases outcome was favorable with complete recovery between 60 and 120 days. The CIOMS diagnostic scale rated a causal role of tetrabamate as highly probable in six cases and as probable in one. CONCLUSION: Tetrabamate can induce hepatotoxicity, probably due to an idiosyncratic metabolic mechanism. Because of this finding and the existence of more appropriate therapeutic alternatives, tetrabamate should not be used in the treatment of alcohol withdrawal.

Flutamide-induced hepatotoxicity: report of a case series.

OBJECTIVE: To evaluate the characteristics of flutamide induced hepatotoxicity. MATERIAL AND METHODS: In this retrospective study we have analyzed all cases of flutamide hepatotoxicity submitted to the Andalucian Registry of drug-induced liver disease. Data were collected using a structured reporting form. Causality assessment was performed using two clinical scales: the standard CIOMS scale and the recently developed María and Victorino scale. RESULTS: Nine of 185 patients (4.9%) were identified. In 8 male patients, mean age 75 years (range 65-83), flutamide was indicated for palliative therapy of disseminated prostatic carcinoma, and in one young female (14 years) was given for the treatment of facial hirsutism. The mean duration of the flutamide therapy was 151 days (range 4-443). All patients presented with overt liver injury, the most frequent features being asthenia, anorexia, weight loss, nausea, vomiting and jaundice. No patient showed hypersensitivity features. In two patients (22%) the hepatic damage evolved to fulminant liver failure, one of them undergoing a liver transplantation and the other subsequently died. An additional patient died of a non-hepatic related cause when his liver function was improving. Causality assessment by the two clinical scales did not exclude any case, but the two patients who died where classified as unlikely by the María and Victorino scale. CONCLUSIONS: Flutamide can induce severe acute hepatitis, probably due to an idiosyncratic metabolic mechanism. Liver tests monitoring should probably be mandatory during the first months of flutamide therapy and the drug withdrawn if transaminases began to increase.

Hepatotoxicidad por flutamida: análisis de una serie / Flutamide-induced hepatotoxicity: report of a case series

Objetivo: evaluar las características de la hepatotoxicidad por flutamida.Material y métodos: análisis de 9 casos de toxicidad hepática secundaria a este fármaco remitidos al Registro Andaluz de Hepatopatías asociadas a medicamentos. La información se recogió en un protocolo estructurado. La imputabilidad de la flutamida se estimó en cada uno de los casos por dos escalas diagnósticas; Council for International Organization of Medical Sciences (CIOMS) y una recientemente validada (María y Victorino).Resultados: 9 de 185 casos (4,9 por ciento) de hepatotoxicidad remitidos al registro eran debidos a flutamida. En 8 pacientes varones con edad media de 75 años (rango 65-83), la flutamida se indicó para la paliación del carcinoma de próstata metastásico, y en una mujer de 14 años para el tratamiento del hirsutismo facial. El tiempo medio de duración del tratamiento fue de 151 días (rango 4-433). El episodio de hepatotoxicidad tuvo expresión clínica en todos los pacientes, siendo las manifestaciones más frecuentes: astenia, anorexia, pérdida de peso, náuseas, vómitos e ictericia. Ningún paciente presentó manifestaciones de hipersensibilidad. Dos pacientes (22 por ciento) presentaron fallo hepático fulminante, falleciendo uno y realizándose transplante hepático en el otro. Un tercer paciente falleció cuando la lesión hepática estaba en fase de resolución. No hubo ningún caso excluido en la evaluación de im putabilidad, pero los dos casos de éxitus fueron clasificados como dudosos por la escala de María y Victorino. Conclusiones: flutamida puede producir hepatitis aguda grave, ocasionalmente fulminante, por un mecanismo presuntamente de idiosincrasia metabólica. Debería monitorizarse el perfil hepático durante los primeros meses de tratamiento con flutamida, suspendiéndose el fármaco en caso de detectarse alteraciones (AU)

Pharmacokinetics of netobimin and microsomal metabolism of albendazole in infected gerbils with Echinococcus granulosus.

A comparison of the pharmacokinetic profiles of netobimin (NTB), albendazole sulfoxide (ABZSO) and albendazole sulfone (ABZSO2) was performed in gerbils (Meriones unguiculatus) with intra-abdominal hydatidosis and in healthy gerbils. The infection was developed after peritoneal inoculation of protoscolices of Echinooccus granulosus from sheep. Plasma concentrations of NTB, ABZSO and ABZSO2 were measured by HPLC after oral administration of 50 mg NTB kg(-1). The results showed an incomplete biotransformation of NTB over the experimental time; and this increased in infected animals. ABZSO and ABZSO2 pharmacokinetic profiles were unaffected and were similar in both non-infected and infected animals. Both hepatic and intestinal microsomal sulfoxidase activities were measured. Since infected gerbils induced hepatic activity and decreased intestinal activity, the total activity was not different in infected and non-infected animals. In summary, intra-abdominal hydatid disease affected the pharmacokinetic profile of NTB, but ABZSO and ABZSO2 plasma concentrations were not different in infected and non-infected gerbils.

Acute liver injury associated with the use of ebrotidine, a new H2-receptor antagonist.

BACKGROUND/AIM: Ebrotidine is a new H2-receptor antagonist marketed in Spain in early 1997 and withdrawn in July 1998. We report 11 cases of acute liver injury related to ebrotidine and submitted to a Regional Registry of Hepatotoxicity between June 1997 and August 1998. METHODS: In all cases a structured protocol was used to ascertain the role of ebrotidine and to exclude other causes (viral, immunologic, metabolic) of liver injury. RESULTS: All patients showed clinical symptoms of acute hepatitis, with a marked increase in aminotransferase activities (ALT values ranging from 15 to 91 times the upper limit of normal). Total bilirubin values were also greatly increased (mean 16 mg/dl), and the liver injury was defined as hepatocellular. Features of hypersensitivity were absent. Liver biopsy was done in three patients. Histopathological examination revealed mainly centrozonal necrosis (two cases) or massive necrosis (one patient). Withdrawal of the drug was followed by a gradual improvement in liver dysfunction, except in one patient who developed fulminant hepatic failure and died. There was a positive response to rechallenge in one patient after an inadvertent drug administration. CONCLUSION: Ebrotidine therapy seems to be associated with severe acute liver injury, and therefore its benefit/risk ratio is unfavorable. The relative rareness and unpredictability of the injury, the lack of dose-relationship and the absence of hallmarks of drug allergy are suggestive of an idiosyncratic metabolic mechanism.

Use of prenatal phenobarbital in the prevention of subependymal/intraventricular hemorrhage in premature infants.

BACKGROUND: Subependymal/intraventricular hemorrhage (SE/IVH) is a frequent cause of disability and mortality. METHODS: This is a prospective, randomized, double-blind study which included 100 pregnant Mexican women who need to interrupt their pregnancy within 28-32 weeks of gestation. One group was given a single dose of intravenous (IV) phenobarbital 10 micrograms/kg (phenobarbital group, n = 50), and the other was provided with diluted distilled water (control group). Measurements of phenobarbital serum concentrations were taken by both mother and newborn, and head sonograms were applied during the first 24 hours, at the 3rd and 7th days of life. RESULTS: The sample was made up of 42 newborns in the phenobarbital group, and 46 in the control group; the newborns had phenobarbital levels of 11.5 5.7 g/microliter at birth, and of 9.5 +/- 5.9 g/microliter 24 hours later. SE/IVH was found in 12 patients from the phenobarbital group and in 29 from the control group (p < 0.005), the first group were 11 mild SE/IVH (2 grade I, and 9 grade II), and 26 in the control group (4 grade I, and 22 grade II), p < 0.005. Severe hemorrhages were similar between groups. A larger frequency of SE/IVH was found in the newborn group which received mechanical ventilation (p = 0.0008). CONCLUSIONS: Prenatal phenobarbital can reduce the SE/IVH frequency in premature infants younger than 32 weeks at birth. Its main effect could be shown in patients with mechanical ventilation.

[Drug use among students in Cali, Colombia]. / Uso de drogas entre estudiantes de Cali, Colombia.

The use of alcohol, tobacco, marihuana, cocaine, and bazuco was examined in a cross-sectional study of a random sample of 512 secondary-school students enrolled in public and private schools in Cali, Colombia. The overall prevalence of use for any of these substances was 59.38% in the public schools and 36.96% in the private schools (z = 4.6, P less than 0.05). The probability of finding an alcohol user was about 55.26%. The frequency of use for all the substances was 18.9% in the public schools and 7.46% in the private ones. Experience with marihuana, cocaine, and bazuco was more frequent in the public schools. The average age of users (19.91 years) was higher than that of non-users (16.25 years): t = 8.34, P less than 0.05. Students in the public schools with a family history of mental illness had almost a ninefold greater risk of being substance users (RR = 8.84, IC 95% = 1.22-3.37); among students in the private schools, having personal conflicts with authority figures (teachers and the police) was a significant risk factor (RR = 2.03, IC 95% = 1.22-3.37).