Advances in clinical diagnosis and treatment of drug-induced liver injury in children / 中华肝脏病杂志

Drug-induced liver injury (DILI) is one of the most common adverse drug reactions that may seriously threaten the health of children and is receiving increasing clinical attention day by day. There is still no independent diagnosis and treatment guideline for DILI in children, but its clinical features are not completely similar to those in adults. This article reviews the epidemiology, clinical features, diagnosis, and treatment progress in order to provide a reference for the management of DILI in children.

Comparative analysis of clinical diagnosis and treatment guidelines for drug-induced liver injury at home and abroad / 中华肝脏病杂志

Drug-induced liver injury influencing factors are complex and have diverse clinical manifestations. Simple and reliable diagnostic methods are still deficient, and further classification of toxicological mechanisms is required. There are numerous pertinent discrepancies between domestic and international guidelines aimed at drug-induced liver injury diagnosis and treatment, with partial to no consensus on the content. The American Gastroenterological Association's 2021 Clinical Guidelines, the Asia-Pacific Association for the Study of the Liver's 2021 Consensus Guidelines, the Council for International Organizations of Medical Sciences' 2020 International Consensus, the European Society's Hepatology Committee's 2019 Clinical Practice Guidelines, and the 2015 Chinese Medical Association Guidelines are five influential clinical guidelines on drug-induced liver injury at home and abroad. The epidemiology, risk factors, diagnosis and evaluation, treatment management, and other contents, particularly traditional Chinese medicine, were compared and analyzed using other relevant consensus opinions or guidelines in order to improve understanding and provide a reference for clinical diagnosis and treatment of drug-induced liver injury.

Standardize the diagnosis and treatment of drug-induced liver injury, and strengthen clinical and translational research / 中华肝脏病杂志

As a liver disease with the most complex clinical phenotype, drug-induced liver injury (DILI) poses great challenges in diagnosis and management in clinical practice. Although guidelines based on the latest research advances can provide clinicians with guidance on the identification, diagnosis, and management of DILI, the overall level of evidence in this field is relatively low and high-level evidence is limited. Therefore, we should interpret guidelines with caution and look forward to more clinical and translational research to address the huge unmet clinical needs in DILI.

Chinese guideline for diagnosis and management of drug-induced liver injury (2023 version) / 中华肝脏病杂志

Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, anti-neoplastic drugs), and signal and assessment of DILI in clinical trials.

Hepatotoxicidad grave inducida por sertralina / Sertraline-induced severe hepatotoxicity

We report the case of a 19-year-old patient, with a history of traumatic liver damage, but with a normal liver profile at her first discharge; 1 month after the event, with post-traumatic stress disorder, treatment with 25 mg of sertraline was started every day; one month later, she develops severe hepatotoxicity without a specific etiology. According to the Naranjo algorithm, it is attributed as a probable case of sertraline hepatotoxicity. Management is carried out with support measures and suspension of the medication, and the patient recovers until she is asymptomatic, currently has normal liver tests

Reportamos el caso de una paciente de 19 años, con antecedentes de daño hepático traumático, pero con un perfil hepático normal en su primer alta; después de 1 mes del evento, con trastorno de estrés postraumático se inició tratamiento con 25 mg diarios de sertralina; un mes después, desarrolla una hepatotoxicidad severa sin etiología determinada. De acuerdo con el algoritmo de Naranjo, se atribuye como caso probable de hepatotoxicidad por sertralina. El manejo se realiza con medidas de apoyo y suspensión del medicamento, y la paciente se recupera hasta que se encuentra asintomática, actualmente tiene pruebas hepáticas normales

Antioxidant and hepatoprotective effects of ethanolic and ethyl acetate stem bark extracts of Copaifera multijuga (Fabaceae) in mice / Efeitos antioxidante e hepatoprotetor dos extratos brutos etanólico e acetato de etila da casca do caule da Copaifera multijuga(Fabaceae) em camundongos

The properties of oil-resin of copaiba, Copaifera multijuga are commonly mentioned in the literature, but there are few studies on extracts from its stem bark. We evaluated the antioxidant effects of ethanolic (EE) and ethyl acetate (EA) crude stem bark extracts from copaiba and compared them to rutin in a paracetamol (PCM)-induced oxidative stress model in mice. All test comparisons differed significantly. Hepatic catalase (CAT) and glutathione-S-transferase (GST) activity decreased in the PCM group, and there was an increase of protein carbonyls in the liver, kidney and brain. However, the protein carbonyls decreased in the liver for the PCM + EE group, in the kidneys for the PCM + EA and PCM + Rutin groups, and in the brain for all treatments. Hepatic GSH decreased in the PCM group and increased in the PCM + EE group. The extracts showed a positive effect on ascorbic acid (ASA), since they were able to restore the levels of parameters that had been changed by PCM. There was an increase of ALT and AST activity in the plasma within the PCM group. Even though ALT decreased in the PCM + Rutin, PCM + EE and PCM + EA groups, EE and EA did not have an effect on AST. The strongest antioxidant effect was observed for EE, due to the presence of the phenolic compounds epicatechin and epiafzelechin, as well as the highest concentration of total phenols and an excellent antioxidant potential observed in the DPPH· test.

As propriedades do óleo-resina da copaíba, Copaifera multijuga são comumente citadas na literatura, mas há poucos estudos sobre extratos da casca do caule. Avaliamos os efeitos antioxidantes de extratos brutos etanólico (EE) e acetato de etila (EA) da casca do caule da copaíba e os comparamos à rutina no modelo de estresse oxidativo induzido por paracetamol (PCM) em camundongos. Todas as comparações de teste diferiram significativamente. A atividade da catalase hepática (CAT) e da glutationa-S-transferase (GST) diminuiu no grupo PCM, e houve um aumento de proteínas carboniladas no fígado, rim e cérebro. No entanto, as proteínas carboniladas diminuíram no fígado para o grupo PCM + EE, nos rins para os grupos PCM + EA e PCM + rutina, e no cérebro para todos os tratamentos. A GSH hepática diminuiu no grupo PCM e aumentou no grupo PCM + EE. Os extratos mostraram um efeito positivo sobre o ácido ascórbico (ASA), uma vez que foram capazes de restaurar os níveis dos parâmetros que foram alterados pelo PCM. Houve um aumento da atividade de ALT e AST no plasma dentro do grupo PCM. Embora a ALT tenha diminuído nos grupos PCM + rutina, PCM + EE e PCM + EA, EE e EA não afetaram a AST. O efeito antioxidante mais forte foi observado para o EE, provavelmente devido à presença dos compostos fenólicos epicatequina e epiafzelequina, assim como à maior concentração de fenóis totais e um excelente potencial antioxidante observado no teste DPPH·

Drug-induced Liver Injury Caused by Ipragliflozin Administration with Causality Established by a Positive Lymphocyte Transformation Test (LTT) and the Roussel Uclaf Causality Assessment Method (RUCAM): A Case Report

ABSTRACT A 75-year old male patient had been regularly visiting our hospital for the management of his type 2 diabetes mellitus since he was diagnosed at age 64 years. When he developed hypoglycemic episodes with sulfonylurea, ipragliflozin (50 mg/day) was started to replace the sulfonylurea therapy. However, 49 days after starting ipragliflozin, his AST increased from 13 to 622 U/L, ALT increased from 9 to 266 U/L, ALP increased from 239 to 752 U/L, and γ-GTP increased from 19 to 176 U/L. ZTT was 3.5 U, TTT was 0.4 U, and total bilirubin was 0.7 mg/dL. IgM hepatitis A antibody, hepatitis B antigen, hepatitis C virus antibody, IgM CMV antibody, and IgM EB VCA antibody were negative, whereas a lymphocyte transformation test for ipragliflozin was positive. Abdominal CT scan showed mild fatty liver but no sign of nodular lesions. Following admission to our hospital, he received liver supportive therapy with the discontinuation of ipragliflozin therapy. He was discharged from the hospital 18 days later with AST and ALT levels reduced to 20 U/L and 13 U/L, respectively. Based on the clinical presentation of this patient, it is highly important to monitor liver function along with other possible clinical complications (e.g., dehydration, ketosis, and urinary tract infection) associated with SGLT2 inhibitor therapy.

Amoxycillin Clavulanic Acid Induced Hepatotoxicity.

Drug-related hepatotoxicity is a serious health problem, with broad implications for patients, healthcare providers, the pharmaceutical industry and governmental regulatory agencies. Herein we report a rare case of amoxycillinclavulanic acid combination induced liver injury of cholestatic pattern in 40 years old, well educated male patient. Patient gave history that though other drugs were given to him by his physician for fever with chills & rigors, malaise, bodyache, except amoxycillin-clavulanic acid combination all other drugs were well tolerated previously by the patient, without appearance of jaundice. So jaundice in this patient was most probably due to amoxycillinclavulanic acid combination. Though severe liver injury is rare, proper history should be taken while prescribing amoxycillin-clavulanic acid combination. Attention must be paid to potential side-effects of the drugs and close follow-up with patients is a medical necessity to evaluate adverse reactions, especially in case of amoxycillinclavulanic acid combination.

Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na+-K+-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na+-K+-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na+-K+-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

[Assessment of crocin toxicity on the rat liver]

Crocin, the carotenoid isolated from saffron, has numerous medicinal properties which include anticancer and antioxidant activities. Some antioxidants, such as carotenoids, can act as pro-oxidants at higher dosages and therefore induce tissue damage. In this situation antioxidant defense systems in the liver activate to prevent tissue damage. This study investigates the possible toxic effects of crocin on the liver of normal rats. Normal rats were randomly divided into four groups. Group 1 was treated with normal saline as the control and groups 2 to 4 were treated different doses of 50, 100 and 200 mg/kg crocin intraperitoneally once a week for four weeks. Animals were killed one week after the last injection. Serum profile of the rats that included ALT, AST, ALP, urea, uric acid and creatinine, as well as the activity of antioxidant enzymes [SOD, CAT and GPx], GSH content, and lipid and protein oxidation by measurement of MDA and protein carbonyl levels were assessed in the liver. In addition, we conducted histopathological examinations of the liver specimens. We studied different crocin concentrations that have been used to treat various diseases. There were no significant changes in serum parameters, GSH, MDA, protein carbonyls and activities of CAT and SOD at the different crocin concentrations. Histopathological examination did not show any changes in the liver. Only the higher dose [200 mg/kg] decreased GPx activity which might be reversible over the long-term. Crocin, at the studied doses showed no toxic effects on the rat liver

Efecto de Noni C sobre el daño hepático inducido por tetracloruro de carbono en ratas / Effect of Noni C on the carbon tetrachloride-induced hepatic damage in rats

Introducción: las enfermedades hepáticas son un serio problema de salud. El estudio de agentes de origen natural que disminuyan el daño hepático inducido por sustancias químicas ha despertado un interés especial. Objetivo: evaluar el efecto del Noni C sobre el daño hepático inducido por tetracloruro de carbono, en modelo experimental desarrollado en ratas Wistar machos. Métodos: se realizó estudio experimental y se usó como control positivo el tetracloruro de carbono a dosis de 0,3 mL/kg de peso, intraperitoneal, durante 3 días; y como control negativo solución salina. Se utilizaron 4 dosis (85, 130, 170 y 215 mg/kg de peso) de Noni C durante 6 días, postratamiento con tetracloruro de carbono. Se determinaron niveles de transaminasa glutámico pirúvica y glutámico oxalacética; también lesión hepática como tumefacción celular, hepatitis reactiva, esteatosis y necrosis. Resultados: se obtuvo reducción significativa de las transaminasas glutámico pirúvica y glutámico oxalacética a las dosis de 85 y 170 mg/kg de Noni C, y ausencia de necrosis y esteatosis en los grupos tratados con las dosis de 170 y 215 mg/kg de peso. Conclusiones: en los grupos tratados con Noni C disminuyó el daño hepático inducido por el tetracloruro de carbono

Introduction: liver diseases are a serious health problem. The study of natural agents that can reduce the chemical substance-induced hepatic damage has aroused a particular interest. Objective: to evaluate the effect of Noni C on the carbon tetrachloride-induced hepatic damage in an experimental model developed in male Wistar rats. Methods: An experimental study was conducted in which the positive control was carbon tetrachloride at a dose of 0.3 mL/kg of weight, intraperitoneally administered for 3 days, and the negative control was saline solution. Four doses of Noni C(85, 130, 170 and 215 mg/kg of weight) were administered for 6 days, after treatment with the carbon tetrachloride. glutamic piruvic and glutamic oxaloacetic transaminase levels were determined, as well as hepatic lesions such as cell tumors, reactive hepatitis, steatosis and necrosis. Results: glutamic piruvic and glutamic oxaloacetic transaminases levels significantly decreased at doses of 85 and 170 mg/kg of Noni C, and no necrosis or steatosis was observed in the groups treated with 170 and 215 mg/kg doses. Conclusions: the carbon tetrachloride-induced hepatic damage diminished in the groups treated with Noni C

Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats / Transplante de hepatócitos recém-isolados em um modelo de hepatotoxicidade induzida por acetaminofeno em ratos

CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7) hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.

CONTEXTO: O transplante de hepatócitos é uma modalidade terapêutica atrativa para doenças hepáticas como alternativa ao transplante hepático ortotópico. OBJETIVO: Investigar a factibilidade do uso de hepatócitos frescos isolados de ratos em um modelo de hepatotoxicidade induzida por paracetamol. MÉTODOS: Hepatócitos foram isolados de ratos Wistar machos e transplantados 24 horas após a administração de paracetamol em receptores fêmeas. As ratas receberam 1x10(7) hepatócitos ou tampão salina fosfato pela veia porta ou no baço e foram sacrificadas após 48 horas. RESULTADOS: Os níveis de alanina aminotransferase medidos durante o experimento não diferiram entre os grupos em nenhum momento. Análises moleculares e histológicas demonstraram a presença de hepatócitos no fígado dos animais transplantados pelo baço ou pela veia porta. CONCLUSÃO: Os dados indicam a factibilidade e eficácia do transplante de hepatócitos no fígado ou baço em um modelo de hepatotoxicidade leve induzida por paracetamol.

Evaluation of prophylactic and therapeutic effects of silymarin on acute toxicity due to tetracycline severe overdose in cats: a preliminary study

The aim of the present study was to determine the protective action of silymarin on acute toxicity due to tetracycline severe overdose in cats. Thirty healthy cats were randomly allotted into five equal groups. Cats in group A were given tetracycline [single dose 120 mg/kg, p.o.]; group B consisted of cats that received silymarin [single dose 30 mg/kg, p.o.] concurrent with tetracycline administration; groups C, D and E were treated as group B, but silymarin was administered 4, 12 and 24 h after tetracycline administration, respectively. The serum concentrations of alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], lactate dehydrogenase [LDH], BUN, serum creatinine and total and direct bilirubin were measured before tetracycline administration and 4, 12, 24 and 72 h later. A single oral administration of tetracycline increased, significantly, serum concentrations of ALT, AST, ALP, LDH in all cats of group A, after 24 h [P<0.001]. In groups B and C, levels of serum enzyme activities remained within normal values. In group D, there were changes in levels of serum enzyme activities, but the difference was not significant [P>0.05]. In group E, levels of serum enzyme activities were significantly higher than normal values [P<0.05]. The difference was significant between groups A and E with groups B and C for the serum enzymes [P<0.05]. In conclusion, silymarin can protect liver tissue against hepatotoxicity in cats with tetracycline severe overdose, particularly in the first 4 h after exposure

Hepatotoxicidad por drogas: reporte de un caso y revisión de literatura / Drug-induced liver injury: a case report and literature review

La Hepatotoxicidad por drogas se define como una lesión hepática asociada a deterioro de la función de éste órgano, secundaria a exposición a una droga u otro agente no infeccioso. Es un cuadro infrecuente, pero puede determinar graves lesiones hepáticas y una mortalidad considerable si no se detecta a tiempo. Es labor del clínico mantener un alto Índice de sospecha al enfrentarse a un paciente con alteraciones hepáticas de reciente comienzo y uso concomitante de medicamentos. En el presente articulo se expone el caso clínico de un paciente masculino, 48 años de edad, con Depresión Severa en tratamiento con Sertralina, Clonazepam, Risperidona, Lamotrigna y Acido Valproico. Ingresó al Hospital de Talca con diagnostico de Síndrome Colestásico cuyo estudio demostró serología para VHB y VHC negativa y ecotomografía abdominal normal. Presentó buena respuesta clínica y de laboratorio a la suspensión de las drogas. El cuadro fue compatible con Hepatotoxicidad por drogas.

Preventive and curative effects of calendula-officinal's leaves extract on acetaminophen-induced hepatotoxicity

To asses the hepatoprotective potential of leaves of Calendula officinalis against experimentally produced liver damage in animals using acetaminophen as model hepatotoxin. This study was conducted at Department of Pharmacy, University of Peshawar. Preliminary experiments were performed in mice to estimate the protective effect of plant material against lethal dose of acetaminophen [1gm/kg]. Acute toxicity of plant material up to a dose of 3 gm was assessed in mice to note any behavioural changes and mortality. Hepatic damage in rats was induced by oral acetaminophen [640 mg/kg]. The effect of methanolic extract of leaves of Calendula officinalis was investigated against acetaminophen-induced hepatic damage in 30 male, albino rats. Acetaminophen produced 100% mortality at a dose of 1 gm/kg in mice, while pretreatment of mice with Calendula officinalis [l.0 gm/kg] reduced the death to 30%. Pretreatment of rats with leaves extract [500 mg/kg orally, four doses at 12 hours interval] prevented [p<0.05] the acetaminophen [640 mg/kg] induced rise in serum transaminase [GOT GPT], serum bilirubin and serum alkaline phosphatase. Post treatment with three successive doses of leaves extract [500 mg/kg, 6 hourly] restricted the hepatic damage induced by acetaminophen [P<0.05]. These results indicate that the crude extract of Calendula officinalis leaves exhibits hepatoprotective action

Hepatite por propiltiouracil: apresentaçäo de dois casos com evoluçöes diversas / Hepatitis by propylthiouracil: report of 2 cases with various evolutions

Os autores apresentam dois casos de hepatite tóxica por uso de propiltiouracil (PTU), com evoluções diversas. Uma paciente desenvolveu icterícia e alterações de transaminases, que desapareceram com a suspensão do medicamento. Outra paciente apresentou-se com quadro de hemorragia digestiva alta, insuficiência hepática e evoluiu rapidamente para o óbito. Os dois casos mostraram sorologias negativas para hepatites virais. Os autores chamam atenção para a importância da orientação ao paciente quanto à possibilidade de desenvlver icterícia em uso de PTU e, nos casos de hepatotoxicidade, da pronta suspensão do uso da droga e acompanhemento clínico do paciente.

Tratamento homeopático da hepatotoxicose aguda induzida por tetracloreto de carbono em coelhos / Homeopatic treatment of acute carbon tetrachloride induced hepatotoxicity in rabbits

Quinze (15) coelhos (Oryctolagus cuniculus) foram submetidos à intoxicaçäo pelo tetracloreto de carbono na dosagem de 0,5 ml/kg de peso corporal, dose única, administrado por sonda gástrica. Foram realizadas as dosagens de alanina amino tranferase (ALT), aspartato amino transferase (AST), fosfatase alcalina (FA) e gama glutamil tranferase (GGT) antes e durante o experimento. Vinte e quatro (24) horas após a intoxicaçäo, os coelhos foram divididos aleatoriamente em três grupos de 5 animais. Cada grupo recebeu um tratamento diferente durante 13 dias. O grupo I foi tratado com tetracloreto de carbono diluído na 30ª centesimal hahnemanniana (30 CH), uma vez ao dia. O grupo II recebeu Phosphorus 30 CH, também uma vez ao dia. O grupo III desempenhou o papel de controle, recebendo diariamente uma dose de placebo, pelo mesmo período de tempo que os grupos anteriores. Os resultados das concentraçöes séricas de ALT, AST, GGT e FA foram submetidos à análise estatística. A variaçäo da concentraçäo de todas as enzimas foi significativa entre os dias, mas nem todas variaram significativamente entre os grupos considerados. O tetracloreto de carbono 30 CH foi capaz de acelerar a recuperaçäo do quadro de hepatite tóxica aguda determinada pela reduçäo dos níveis de ALT. O tratamento com Phosphorus 30 CH mostrou-se incapaz seja de reverter o quadro de hepatite tóxica, seja de acelerar a regeneraçäo hepática.