Hepatotoxicidad inducida por clozapina: reporte de caso y revisión breve de la literatura

Introducción: Los antipsicóticos son medicamentos que pueden producir elevaciones transitorias de las enzimas hepáticas. La clozapina es un antipsicótico atípico usado en el tratamiento de la esquizofrenia refractaria a los antipsicóticos convencionales y existe evidencia que puede producir elevaciones de las transaminasas hepáticas, expresión de dafño hepático con patrón hepatocelular. Métodos: Reporte de caso y revisión no sistemática de la literatura relevante. Presentación del caso: Una mujer de 39 años con diagnóstico de esquizofrenia paranoide acudió a un servicio de urgencias de un hospital general por náuseas, vómitos e ictericia que apareció tras el inicio de clozapina. No hubo mejoría clínica de la paciente durante la hospitalización, que falleció a los 44 días de su ingreso. Revisión de la literatura: La clozapina puede elevar las cifras de función hepática de manera transitoria y asintomática. Hay criterios clínicos para recomendar la suspensión de este antipsicótico. Conclusiones: Este caso es el tercero en la literatura que registra un desenlace fatal tras un cuadro de hepatotoxicidad inducido por clozapina. © 2021 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.

Introduction: Antipsychotics are drugs that can produce transient elevations of hepatic enzymes. Clozapine is an atypical antipsychotic used in treatment-resistant schizophrenia and there is evidence that it can produce elevations of hepatic transaminases, expression of liver damage in a hepatocellular pattern. Methods: Case report and non-systematic review of the relevant literature. Case presentation: A 39-year-old woman with a diagnosis of paranoid schizophrenia attended the emergency department of a general hospital for nausea, vomiting and jaundice that appeared after the initiation of clozapine. There was no clinical improvement during hospitalization, and death occurred after 44 days. Literature review: Clozapine can increase the liver enzyme levels transiently and asymptomatically; however, there are clinical criteria that recommend the withdrawal of the antipsychotic. Conclusions: This is the third case reported in the literature of a fatal outcome of clozapine-induced hepatotoxicity.

Perfil epidemiológico de pacientes intoxicados con acetaminofén con intenciones suicidas / Epidemiological profile of patients intoxicated with acetaminophen for suicidal purposes / Perfil epidemiológico de pacientes intoxicados com acetaminofen (Paracetamol) com intenções suicidas

Objetivo: este estudio busca describir los individuos evaluados por sobredosis de acetaminofén entre 2019 y 2020 en un centro de referencia de trasplante hepático en Colombia. Metodología: estudio derivado del análisis secundario de historias clínicas entre el 1.º de enero de 2019 y el 31 de diciembre de 2020. Los criterios de inclusión abarcan individuos con ingestión aguda y voluntaria de dosis tóxicas de acetaminofén (>4 g/día). Resultados: sesenta y tres casos, 68% mujeres, 67% menores de 18 años y 54% estudiantes. Reportó historia personal de enfermedad psiquiátrica el 60% y el 35% al menos un intento de suicidio previo. La mediana de dosis de acetaminofén fue 15g, 46% refirieron co-ingesta de otras sustancias y 13% estaba bajo efecto de sustancias psicoactivas. El 57% tenía la intención clara de suicidarse, así como 81% vomitó antes de acudir al servicio de urgencias, 22% recibió medidas de descontaminación y 10% no recibió N - acetilcisteína. Quince individuos desarrollaron lesión hepática aguda, nueve con criterios de severidad. Conclusiones: la población era predominantemente joven, la historia de enfermedad psiquiátrica fue muy prevalente y la mayoría refirieron un evento vital que explicara el comportamiento impulsivo de consumo. Ninguno desarrolló criterios para trasplante hepático, lo cual podría explicarse por la edad de los individuos, los episodios de vómito temprano, y la ausencia de enfermedad hepática crónica o de consumo de sustancias hepatotóxicas.

Objective: this study aims to describe patients with overdose intake of acetaminophen between 2019 and 2020 at a reference center for liver transplantation in Colombia. Methodology: study derived from a secondary analysis of the clinical records between January 1st, 2019, to December 31st, 2020. Inclusion criteria were individuals with voluntary acute ingestion of toxic doses of acetaminophen (>4 g/day). Results: sixty-three cases, 68% women, 67% <18-year-old, and 54% students. 60% had personal history of psychiatric illness and 35% reported at least one previous suicide attempt. The median dose of acetaminophen was 15g, 46% referred to co-ingestion with other substances and 13% were under the effect of any psychoactive substance. 57% had a clear intention of suicide. 81% vomited before the arrival to the emergency room, 22% received decontamination intervention with gastric lavage or activated charcoal, and 10% did not receive any dose of N-Acetylcysteine. Fifteen individuals developed an acute liver injury, nine with severity criteria. Conclusions: the population was predominantly young, the personal history of psychiatric disease was highly prevalent, and most of the cases referred a vital event that explains the impulsive behavior in acetaminophen consumption. None developed criteria for liver transplantation, and this could be explained by the young age of the individuals, the episodes of early vomiting, and the absence of chronic liver disease or hepatotoxic substance consumption.

Objetivo:este estudo busca descrever os indivíduos avaliados por sobredose de acetaminofen entre 2019 e 2020 num centro de referência de transplante hepático na Colômbia. Metodologia: estudo derivado da análise secundário de histórias clínicas entre o dia 1.º de janeiro de 2019 e 31 de dezembro de 2020. Os critérios de inclusão abrangem indivíduos com ingestão aguda e voluntária de dose tóxicas de acetaminofen (>4 g/dia).Resultados:sessenta e três casos, 68% mulheres, 67% menores de 18 anos e 54% estudantes. Reportou história pessoal de doença psiquiátrica, 60% e 35% pelo menos uma tentativa de suicídio prévio. A média de dose de acetaminofen foi de 15g, 46% referiram com ingestão de outras sustâncias e 13% estava sob efeito de sustâncias psicoativas. 57% tinham a intenção clara de suicidar-se, assim como 81% vomitou antes de acudir ao serviço de urgências, 22% receberam medidas de descontaminação e 10% não recebeu N - acetilcisteína. Quinze indivíduos desenvolveram lesão hepática aguda, nove com critérios de severidade. Conclusões: a população era predominantemente jovem, a história de doençapsiquiátrica foi muito prevalente e a maioria referiram um evento vital que explicasse o comportamento impulsivo de consumo. Nenhum desenvolveu critérios para transplantehepático, o qual se poderia explicar pela idade dos indivíduos, os episódios de vómito precoce, e a ausência de doença hepática crónica ou de consumo de sustâncias hepatotóxicas.

Colestasis inducida por anabólicos: reporte de caso y revisión de la literatura / Anabolic-induced cholestasis: case report and literature review

La función metabólica y de excreción está determinada principalmente por la actividad hepática, esto predispone al hígado a lesión inducida por toxicidad, en donde la disfunción es mediada directa o indirectamente por xenobióticos y/o sus metabolitos. La enfermedad hepática inducida por fármacos (DILI) es una condición poco frecuente, que se relaciona hasta con el 50% de las insuficiencias hepáticas agudas, y de ahí su importancia. La lesión directa puede estar dirigida a hepatocitos, conductos biliares y estructuras vasculares; no obstante, diferentes xenobióticos pueden interferir con el flujo de bilis mediante el bloqueo directo de proteínas de trasporte en los canalículos. Actualmente no existen marcadores absolutos para el diagnóstico de esta entidad y las manifestaciones clínicas pueden ser variables, desde el espectro de alteraciones bioquímicas en ausencia de síntomas, hasta insuficiencia hepática aguda y daño hepático crónico, por lo cual es principalmente un diagnóstico de exclusión basado en evidencia circunstancial. A partir de esta inferencia, se han desarrollado escalas y algoritmos para evaluar la probabilidad de lesión hepática inducida por medicamentos, tóxicos, herbales o suplementos. En la mayoría de los casos, es característico que la condición del paciente mejore cuando se elimina el fármaco responsable del daño. Aunque el patrón colestásico generalmente tiene mejores tasas de supervivencia en comparación con otros patrones, también se asocia con un alto riesgo de desarrollar enfermedad hepática crónica o ser el desencadenante de manifestaciones inmunológicas en el hígado. Se presenta el caso clínico de un paciente con patrón colestásico de DILI por uso de esteroides anabólicos.

Metabolic and excretory function is determined mainly by liver activity which can make this organ susceptible to toxic injury, where dysfunction is directly or indirectly mediated by xenobiotics and/ or their metabolites. Drug-induced liver disease (DILI) is a rare condition, which is associated with up to 50% of acute liver failure, and hence its importance. Direct injury can be directed to hepatocytes, bile ducts, and vascular structures, however, different xenobiotics can interfere with bile flow by directly blocking transport proteins in the canaliculi. Currently there are no definite markers for the diagnosis of this condition, and clinical manifestations can be variable, including biochemical changes in the absence of symptoms to acute liver failure and chronic liver damage, which makes it mainly an exclusion diagnosis based on clinical evidence. Scales and algorithms have been developed to assess the probability of drug, toxic, herbal, or supplement-induced liver injury. In most cases, the patient's condition typically improves when the drug responsible for the injury is removed. Although the cholestatic pattern generally has better survival rates compared to other patterns, it is also associated with a high risk of developing chronic liver disease or acting as a trigger for immune disorders in the liver. The clinical case of a patient with a cholestatic pattern of DILI due to the use of anabolic steroids is presented.

Application of Serum DBIL,TBIL,DBIL/TBI Detection in the Diagnosis of Drug-induced Liver Injury / 现代检验医学杂志

Objective To analyze the functions of total bilirubin(TBIL)and direct bilirubin(DBIL),DBIL/TBIL detection in the diagnosis of drug-induced liver injury(DILI).Methods The clinical data and laboratory examination results of the pa-tients with drug-induced liver disease in Shaanxi Provincial People's Hospital were collected from January 2014 to December 2016.The factors were assessed by uni-variate and multivariate logistic regression analysis.Results In all,162 cases identi-fied as DILI were included in the study.The main causative group of drugs was Chinese herb(about 88 cases,54.3%).A-mong these 162 cases,124 cases(76.5%)were hepatocellular damage type,30 cases(18.5%)cholestatic damage type and 8 cases(4.9%)mixed type damage.It showed that the complete recovery occurred in 120 patients(74.1%)and the non-re-covery occurred in 41(25.3%),of which one death(0.6%).The binary logistic regression analysis identified the jaundice, DBIL,TBIL and DBIL/TBIL as independent factors of the non-recovery of DILI.Conclusion The main causative group of drugs was Chinese herb and the hepatocellular damage type was the commonest one.What's more,whether the case pro-gress into non-recovery one,was related to jaundice,TBIL,DBIL and DBIL/TBIL.

Medicamentos causantes de hepatotoxicidad en el embarazo: revisión estructurada / A Structured Review of Hepatotoxic Medicines during Pregnancy

Objetivo: identificar los medicamentos y determinar las principales características asociadas con hepatotoxicidad por medicamentos en el embarazo. Método: revisión estructurada en PubMed/Medline, EMBASE y Web of Science utilizando los términos: Drug induced liver injury OR Hepatotoxicity AND Pregnancy. La búsqueda incluyó artículos en inglés, español, humanos, entre 2005 y 2015, con información sobre hepatotoxicidad por medicamentos en el embarazo. Fueron excluidos los artículos sin relación con embarazo o hepatotoxicidad, asociados con otras causas de enfermedad hepática o con hepatotoxicidad por otras sustancias. La información del medicamento y las características de los pacientes fueron registradas en una tabla. La probabilidad de la aparición de hepatotoxicidad fue valorada y agrupada en tres categorías: definida, probable y posible; para algunos medicamentos fue determinada por el método RUCAM. Resultados: fueron identificados 488 artículos, de los cuales 46 fueron seleccionados. Fueron identificados también 12 medicamentos (acetaminofeno, alfametildopa, labetalol, metotrexato, saquinavir, nevirapina, propiltiouracilo, metimazol, carbimazol, nitrofurantoína, ácido acetilsalicílico y piperidolato) con probabilidad de causar hepatotoxicidad en el embarazo. Algunas características asociadas con los fármacos fueron: tiempo de aparición de las reacciones, semanas de embarazo (3-36), factores de riesgo (edad y enfermedades crónicas), manifestaciones clínicas (elevación de transaminasas, prurito, ictericia) y desenlaces (trasplante de hígado, muertes materna y fetal). Conclusión: los medicamentos acetaminofeno, alfametildopa, labetalol, metotrexato, saquinavir, nevirapina, propiltiouracilo, metimazol, carbimazol, nitrofurantoína, ácido acetilsalicílico y piperidolato podrían causar hepatotoxicidad en pacientes embarazadas. Además de la dosis y del tiempo de exposición al fármaco, la edad y el tiempo de gestación podrían influir en la presentación y gravedad de la hepatotoxicidad

Objective: The aim of this study is to identify hepatotoxic drugs and determine the main characteristics of drug hepatotoxicity in pregnancy. Method: We conducted a structured review of PubMed/Medline, EMBASE and Web of Science using the terms “Drug induced liver injury” OR Hepatotoxicity AND Pregnancy. The search included articles in English and Spanish with information on hepatotoxic drugs in pregnancy that were posted between 2005 and 2015. Items not related to pregnancy or hepatotoxicity or which were related to other causes of liver disease or to hepatotoxicity due to other substances were excluded. Drug information and patient characteristics were recorded in a table. The probability of occurrence of hepatotoxicity was assessed and grouped into three categories: defined, probable, and possible. The categories of some drugs were determined with the RUCAM method. Results: We identified 488 articles of which 46 were selected. Twelve agents that are potentially heaptotoxic for pregnant women were identified: acetaminophen, alpha-methyldopa, methotrexate, methotrexate, saquinavir, nevirapine, propylthiouracil, methimazole, carbimazole, nitrofurantoin, acetylsalicylic acid and piperidolate. Some characteristics associated with the drugs were time of reaction onset, weeks of pregnancy (3-36), risk factors (age and chronic diseases), clinical manifestations (elevation of transaminases, pruritus, and jaundice) and outcomes (liver transplantation and death of mother and/or fetus). Conclusion: Acetaminophen, alpha-methyldopa, labetalol, methotrexate, saquinavir, nevirapine, propylthiouracil, methimazole, carbimazole, nitrofurantoin, acetylsalicylic acid and piperidolate can cause hepatotoxicity in pregnant patients. In addition to dosage and exposure time, patient age and gestation time can influence presentation and severity of hepatotoxicity

Hepatotoxicidad: patrón colestásico inducido por fármacos / Hepatotoxicity: A Drug-Induced Cholestatic Pattern

La enfermedad hepática inducida por fármacos (DILI) es una condición poco frecuente; sin embargo, explica el 40%-50% de las insuficiencias hepáticas agudas. Su patrón es colestásico en un 20%-40%, causado por la inhibición de los transportadores que regulan la síntesis biliar; esta reducción en la actividad es mediada directa o indirectamente por los medicamentos y sus metabolitos, por polimorfismos genéticos y otros factores de riesgo del paciente. Sus manifestaciones van desde las alteraciones bioquímicas en ausencia de síntomas, hasta la insuficiencia hepática aguda y el daño hepático crónico. Aunque no existe un examen o marcador que indique el diagnóstico absoluto de la enfermedad, se han desarrollado escalas y algoritmos que permiten valorar la probabilidad de DILI colestásica, y otras pruebas que por su complejidad y costo no son de uso rutinario. Por lo anterior, es principalmente un diagnóstico de exclusión basado en evidencia circunstancial. El patrón colestásico de DILI presenta una mejor tasa de supervivencia general pero un mayor riesgo de desarrollo de enfermedad hepática crónica. En la mayoría de los casos, el cuadro del paciente mejora con el retiro del medicamento responsable del daño; la hemodiálisis y el trasplante deben considerarse solo para casos selectos. No se ha probado la eficacia de otras terapias. En este artículo se profundizará en la fisiopatología, la presentación clínica, bioquímica e histopatológica, además del diagnóstico, manejo y pronóstico de este tipo de colestasis.

Although drug induced liver disease is a rare condition, it explains 40% to 50% of all cases of acute liver failure. In 20% to 40% of the cases, the pattern is cholestatic and is caused by inhibition of the transporters that regulate bile synthesis. This reduction in activity is directly or indirectly mediated by drugs and their metabolites and/or by genetic polymorphisms and other risk factors of the patient. Its manifestations range from biochemical alterations in the absence of symptoms to acute liver failure and chronic liver damage. Although there is no absolute test or marker for diagnosis of this disease, scales and algorithms have been developed to assess the likelihood of cholestatic drug induced liver disease. Other types of evidence are not routinely used because of their complexity and cost. Diagnosis is primarily based on exclusion using circumstantial evidence. Cholestatic drug induced liver disease has better overall survival rates than other patters, but there are higher risks of developing chronic liver disease. In most cases, the patient’s condition improves when the drug responsible for the damage is removed. Hemodialysis and transplantation should be considered only for selected cases. The effectiveness of other therapies is unproven. This article will delve into the pathophysiology, biochemistry, and histopathology and the clinical presentation of the disease and will discuss diagnosis, management and prognosis of this type of cholestasis.

Computed tomography findings of hepatic veno-occlusive disease caused by Sedum aizoon with histopathological correlation

This study investigated the value of computed tomography (CT) in the diagnosis and treatment of hepatic veno-occlusive disease (HVOD) caused by Sedum aizoon (SA). The clinical manifestations, treatment results, imaging findings, and histological findings of the liver were analyzed in 39 patients with HVOD caused by SA. Hepatomegaly, liver dysfunction, abdominal effusion, and geographic density changes on liver CT scans were found in all 39 patients. The pathological findings of histological liver examination included swelling and point-like necrosis of liver cells, significant expansion and congestion of the sinuses, endothelial swelling, and wall thickening with incomplete lumen occlusion of small liver vessels. CT geographic density changes were confirmed by histological examination of the liver in 18 patients. Sixteen patients with small amounts of ascites that started within 4 weeks of treatment recovered completely or significantly improved after symptomatic and supportive treatment. However, only 43.75% of the patients with larger amounts of ascites improved following symptomatic and supportive treatment. In conclusion, liver CT examination is a valuable, safe, and noninvasive tool for the diagnosis of HVOD caused by SA. In selected cases, liver CT examination may replace liver biopsy and histological analysis.

Effect of Atorvastatin Combined with Methylprednisolone on Liver Function of Nephrotic Syndrome Patients / 中国药房

OBJECTIVE:To observe the effect of atorvastatin combined with methylprednisolone on the liver function of ne-phrotic syndrome patients. METHODS:The data of 93 patients with primary nephritic syndrome were retrospectively analyzed and divided into atorvastatin group,methylprednisolone group and combination group by different medication. Atorvastatin group was orally given atorvastatin 20 mg at bedtime,once a day+aspirin;methylprednisolone group was orally given methylprednisolone 0.8 mg/kg in the early morning,once a day+aspirin;combination group was given atorvastatin+methylprednisolone+aspirin(the same usage and dosage with the above-mentioned groups). The course was 4 weeks. The clinic data was observed,including ALT,AST, GGT,TB and DB before and after treatment,the incidence of patients with drug-induced liver disease and prognosis of patients with drug-induced liver disease. RESULTS:After treatment,the ALT,AST and GGT in atorvastatin group and combination group were significantly higher than before,with significant difference(P0.05). There was no significant dif-ference in the elevated rate of ALT among groups(P>0.05);the incidence of drug-induced liver disease in combination group was significantly higher than atorvastatin group and methylprednisolone group,with significant difference(P<0.05). ALT in combina-tion group was significantly decreased and returned to pretreatment levels after atorvastatin withdrawal and 2 weeks of hepatoprotec-tants treatment for 7 patients with drug-induced liver disease. CONCLUSIONS:Atorvastatin combined with methylprednisolone has high risk on liver function in the treatment of nephrotic syndrome. Pretreatment levels can be recovered by both drug withdrawal and symptomatic treatment.

Diagnosis and treatment of hepatic veno-occlusive disease induced by sedum aizoon in HBsAg positive patients / 中华临床感染病杂志

Objective To review the diagnosis and treatment of hepatic veno-occlusive disease(HVOD)induced by sedum aizoon in HBsAg positive patients. Methods Clinical data of 35 HBsAg positive cases who took sedum aizoon decoction and developed HVOD were collected, the clinical manifestation, imaging examination, histological examination of liver puncture biopsy, and the outcomes of patients were reviewed. Results Hepatomegaly, liver dysfunction, abdominal effusion and map-like density changes in liver CT scan were observed in 35 patients. Liver biopsy wag performed in 17 patients. In histopathological examination, the swelling and point-like necrosis of liver cells, expansion and congestion of sinus, endothelial swelling, wall thickening, incomplete lumen occlusion of small liver vascular were observed. Map-like density changes in liver CT scan were found in all 17 patients who were diagnosed by histological examination. Fifteen patients presented small amount of ascites within 4 weeks of onset, 13 of whom recovered or improved after treated with low-molecular weight heparin and albumin; while among the remaining 20 patients. only half of them were benefited from the same treatments. Conclusion HVOD can be diagnosed by liver CT scan instead of histological examination; treatment of patients in early stage may improve the outcome.

Systematic Review on Reduced Glutathione in the Treatment of Drug-induced Liver Disease / 中国药房

OBJECTIVE: To evaluate the efficacy of reduced glutathione in the treatment of drug-induced liver disease. METHODS: Literatures were retrieved from PubMed, Medline, EMBASE, Cochrane Library, CBM, VIP, CNKI databases by computer and from relevant Chinese medical journals by hand. Trial selection, quality evaluation and information extraction were performed according to including and excluding criteria. Meta-analysis was conducted using RevMan 5.0 software. RESULTS: The meta-analysis of 13 included RCTs showed that total effective rate, ALT and total bilirubin in trial group were significantly different from control group(P

Correlation Analysis of 113 Patients with Drug-induced Liver Disease / 中国药房

OBJECTIVE: To analyze 113 patients with drug-induced liver disease(DILD) so as to clinically validate the international generally-accepted diagnostic criteria.METHODS: 113 DILD cases were reviewed and categorized according to international generally-accepted diagnostic criteria and then graded separately by Maria clinical scale and DDW-J scale to analyze the correlations.RESULTS: 113 out of 822 patients with liver diseases were DILD(13.7%),among whom 17 were of hepatocellular type(15.0%),92 cholestasis type(81.5%) and 4 mixed type(3.5%).Application of Maria clinical scale and DDW-J scale led to different number of DILD cases diagnosed.DILD were mostly induced by antihyperlipidemic drugs and immunosuppressants followed by anticoagulant drugs.CONCLUSION: DDW-J scale,which is more close to clinical diagnostic criteria,contributed to the standardization of the diagnostic criteria of DILD,yet it has its limitations as well.