Interpretation on Consensus on drug-induced liver injury by CIOMS Working Group:liver injury attributed to herbal and dietary supplements / 中国中药杂志

With the increase in the medical level, the improvement of adverse drug reaction(ADR) monitoring systems, and the enhancement of public awareness of safe medication, drug safety incidents have been frequently reported. Drug-induced liver injury(DILI), especially liver injury attributed to herbal and dietary supplements(HDS), has globally attracted high attention, bringing great threats and severe challenges to the people for drug safety management such as clinical medication and medical supervision. Consensus on drug-induced liver injury had been published by the Council for International Organizations of Medical Sciences(CIOMS) in 2020. In this consensus, liver injury attributed to HDS was included in a special chapter for the first time. The hot topics, including the definition of HDS-induced liver injury, epidemiological history, potential risk factors, collection of related risk signals, causality assessment, risk prevention, control and management were discussed from a global perspective. Based on the previous works, some experts from China were invited by CIOMS to undertake the compilation of this chapter. Meanwhile, a new causality assessment in DILI based on the integrated evidence chain(iEC) method was widely recognized by experts in China and abroad, and was recommended by this consensus. This paper briefly introduced the main contents, background, and characteristics of the Consensus on drug-induced liver injury. Significantly, a brief interpretation was illustrated to analyze the special highlights of Chapter 8, "Liver injury attributed to HDS", so as to provide practical references for the medical staff and the researchers who worked on either Chinese or Western medicine in China.

Mechanism of hepatotoxicity induced by ethanol extract of Dysosma versipellis based on "quantity-weight-evidence" network toxicology / 中国中药杂志

In this study, the toxicological/pharmacological research method of "quantity-weight-evidence" network was first proposed and practiced to supplement the existing methodology of network toxicology. We transformed the traditional qualitative network into a quantitative network in this study by attributing weights to toxic component content and target frequency, which improved the reliability of data and provided a research idea for the systematic safety evaluation and toxicological research of Chinese medicinal herbs. Firstly, 50% ethanol extract of Dysosma versipellis(DV) was administrated to rats via gavage and the potential hepatotoxic components were identified by serum pharmacochemistry. Then, the component targets were obtained from SwissTargetPrediction, PharmMapper and other online databases, and the target weights were given according to the relative content of components and target fishing frequency. Meanwhile, the targets of hepatotoxicity were predicted from online databases such as Comparative Toxicology Database(CTD) and GeneCards. Subsequently, protein-protein interaction analysis and KEGG pathway enrichment were performed with the STRING database. Finally, the quantitative network of "toxic components-weighted targets-pathways" was constructed. Eleven potential toxic compounds were predicted, including podophyllotoxin, podophyllotoxone, deoxypodophyllotoxin, and 6-methoxypodophyllotoxin. A total of 106 hepatotoxic targets and 65 weighted targets(e.g., Cdk2, Egfr, and Cyp2 c9) were identified. The results of Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment showed that these targets could act on PI3 K-AKT, MAPK, and Ras signaling pathways to play a role in inflammatory response and oxidative stress. However, traditional network toxicology showed that 51 targets such as AKT1, Alb, and Stat3 may lead to hepatotoxicity by mediating inflammation and cell proliferation. In conclusion, we proposed "quantity-weight-evidence" network toxicology in this study and used it to study the mechanism of DV-induced hepatotoxicity in rats. This study confirms the feasibility of this new methodology in toxicological evaluation and further improves the systematic evaluation of the safety of Chinese medicinal herbs.

Bavachin enhances NLRP3 inflammasome activation induced by ATP or nigericin and causes idiosyncratic hepatotoxicity / 医学前沿

Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.

Landscape of Hepatobiliary Adverse Drug Reactions Related to Preparations Containing Psoraleae Fructus and Its Application in Pharmacovigilance / 中国结合医学杂志

OBJECTIVE@#To analyze clinical feature and information of medication to explore the risk signals of preparations containing Psoraleae Fructus (BGZP) related with hepatobiliary adverse drug reactions (ADR), in order to reinforce pharmacovigilance.@*METHODS@#A retrospective study was conducted based on hepatobiliary ADR related with BGZP from the China Adverse Drug Reaction Monitoring System in years from January 2012 to December 2016. Serious and general ADRs were analyzed and assessed.@*RESULTS@#There were 355 cases of hepatobiliary ADR related to BGZP. Both the amount of cases and the proportion of serious ADR showed an increasing growth by years (P<0.05). It was found that 10.43% of 355 cases may be involved with irrational drug use, including overdose, repeated medication, and combination of multiple drugs. There were 190 cases which used BGZP (non-combination), and they were mainly for common in diseases caused by abnormal immune activation (accounting for 40.53% of the total cases). Especially at the age group with the most cases with age of 41-50 years, the cases associated with immunological diseases of female were obviously more than that of male (P<0.05). The latency of hepatobiliary ADR related to BGZP ranged from 1 to 386 days, and the median latency was 27.5 days, along with the range of cumulative dose (0.45-520.02 g) as well as the daily dose (0.09-2.64 g/d) after the conversion.@*CONCLUSIONS@#Cases of hepatobiliary ADR related to BGZP showed significant individual differences, and there was no correlation between drug usage duration and dosage and the occurrence of hepatobiliary ADR. It may be similar with idiosyncratic drug-induced liver injury, and recommended that BGZP should be used with more caution under monitoring liver function, especially in female patients with immunological diseases.

Flucloxacillin-Induced Hepatotoxicity - Association with HLA-B*5701

SUMMARY Drug-induced liver injury (DILI) to flucloxacillin is rare and is classified as idiosyncratic, as it is dependent on individual susceptibility, unpredictable, and dose-independent. The authors present the case of a 74 - year - old man with a history of monoclonal gammopathy under investigation and alcoholic habits of 24 g/day, with asthenia, anorexia, nausea, abdominal discomfort, and fever with three days of evolution. He was treated with two courses of antibiotic therapy with flucloxacillin to erysipelas previously (3 months and 2 weeks before admission). Lab tests showed serum AST levels of 349 U/L, ALT 646 U/L, alkaline phosphatase 302 U/L, GGT 652 U/L, total bilirubin 3.3 mg/dL and direct bilirubin 2.72 mg/dL. Infectious, autoimmune, and metabolic causes were ruled out. Magnetic resonance cholangiopancreatography showed normal results. Liver biopsy showed mild multifocal (predominantly microvesicular) steatosis; marked changes in the centrilobular areas (sinusoidal dilatation, marked congestion, hemorrhage, and multifocal hepatocyte collapse); expansion of the portal areas with the formation of bridges; proliferated bile ducts and inflammatory infiltrate of variable density, predominantly mononuclear type. The HLA-B*5701 screening test was positive. Hepatic biochemical tests remain abnormal with a significative increase in total bilirubin, which reached levels of 24.1 mg/dL, with the development of jaundice, pruritus, and choluria. DILI was assumed, and the patient was treated with ursodeoxycholic acid. There was favorable evolution, without evidence of blood coagulation dysfunction or encephalopathy. The analytic normalization was, however, slow, with evolution to chronicity. The authors present this case to remind the possibility of moderate/severe drug-induced liver injury to flucloxacillin, an antibiotic commonly used in clinical practice and association with the HLA-B * 5701 allele reported in the literature.

RESUMO A hepatotoxicidade à flucloxacilina é rara e classifica-se como idiossincrática, uma vez que é dependente da suscetibilidade individual, não expectável e independente da dose. Apresentamos o caso de um homem, 74 anos, antecedentes de gamapatia monoclonal e hábitos alcoólicos de 24 g/dia, com quadro de astenia, anorexia, náuseas, desconforto abdominal e febrícula com três dias de evolução. Referência a dois ciclos de antibioterapia com flucloxacilina por erisipela (três meses e duas semanas antes da admissão). Analiticamente com AST 349 U/L, ALT 646 U/L, FA 302 U/L, GGT 652 U/L, bilirrubina total 3,3 mg/dL, bilirrubina direta 2,72 mg/dL. Excluídas etiologias infecciosa, autoimune, metabólica, bem como patologia das vias biliares por colangio-RM. Biópsia hepática mostrou esteatose multifocal ligeira (predominantemente microvesicular); alterações acentuadas nas áreas centrolobulares (dilatação sinusoidal, congestão acentuada, hemorragia e colapso multifocal de hepatócitos); expansão das áreas portais com constituição de pontes; ductos biliares proliferados e infiltrado inflamatório de densidade variável, predominantemente de tipo mononucleado. Tipagem de HLA-B*5701 positiva. Agravamento analítico atingindo bilirrubina total 24,1 mg/dL, com desenvolvimento de icterícia, prurido e colúria. Admitida a hepatotoxicidade, iniciou terapêutica com ácido ursodesoxicólico. Verificou-se evolução favorável, sem evidência de coagulopatia ou encefalopatia. A normalização analítica foi, no entanto, lenta, com evolução para cronicidade. Os autores apresentam este caso para alertar para a possibilidade de hepatotoxicidade moderada a grave à flucloxacilina, antibiótico de uso comum na prática clínica e associação com o alelo HLA-B*5701 relatada na literatura.

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

Eficácia hepatoprotetora do extrato metanólico de Indigofera suffruticosa (Mill) em lesão hepática induzido por paracetamol em camundongos / Hepatoprotective efficacy of methanolic extract of indigofera suffruticosa (mill) on paracetamol-induced liver damage in mice

ABSTRACT BACKGROUND: Indigofera suffruticosa Mill (Fabaceae) is abundant in northeastern Brazil and popularly used in the treatment of infectious and inflammatory processes. Several biological properties, such as anti-inflammatory, anticancer, antitumor, hepatoprotective and low toxicity, are reported for this plant. OBJECTIVE: This study investigated hepatoprotective activity and the antioxidant effect of methanolic extract of I. suffruticosa leaves (MEIS) on Swiss albino mice submitted to experimental models of acetaminophen-induced liver injury. METHODS: MEIS (50 mg/kg; p.o.) was standardized according to the LD50 and its hepatoprotective property on Swiss albino mice evaluated during a 7-day period. On the eighth day, the acetaminophen-induced hepatic injury was performed. Histomorphometric analysis of liver tissue, antioxidant activity and serum levels of alanine aminotransferase (AST), aspartate aminotransferase (ALT) and bilirubin were measured. RESULTS: MEIS (50 mg/kg; p.o.) restored serum enzyme levels and results were close to those of positive control (silymarin) when compared to the negative control. Histopathological and histomorphometric analyzes confirmed MEIS hepatoprotective activity, showing reorganization of structural units of cells, nuclei and sinusoidal capillaries of hepatocytes, reducing the damage on liver tissue and increasing organ regeneration rate. MEIS showed high antioxidant potential at concentrations of 1000 and 500 µg/mL. CONCLUSION: This study suggests that MEIS has hepatoprotective activity and high antioxidant potential.

RESUMO CONTEXTO: Indigofera suffruticosa Mill (Fabaceae) é abundante no nordeste do Brasil e popularmente utilizada no tratamento de processos infecciosos e inflamatórios. Várias propriedades biológicas, como anti-inflamatório, anticâncer, antitumoral, hepatoprotetor e baixa toxicidade, são relatadas para esta planta. OBJETIVO: Este estudo investigou a atividade hepatoprotetora e o efeito antioxidante do extrato metanólico de folhas de I. suffruticosa (MEIS) em camundongos albinos suíços submetidos a modelos experimentais de lesão hepática induzida por paracetamol. MÉTODOS: O MEIS na dose de 50 mg/kg (via oral) foi padronizado de acordo com a LD50 e sua propriedade hepatoprotetora em camundongos albinos Swiss avaliados durante um período de sete dias. No oitavo dia, a lesão hepática foi induzida por paracetamol em todos grupos pre-tratados. Foram medidos os níveis sericos enzimaticos, alanina aminotransferase, aspartato aminotransferase e bilirrubina, análise histomorfométrica do tecido hepático e atividade antioxidante. RESULTADOS: O MEIS restaurou os níveis séricos de enzimas e os resultados foram próximos aos do controle positivo (silimarina) quando comparados ao controle negativo. As análises histopatológicas e histomorfométricas confirmaram a atividade hepatoprotetora do MEIS, mostrando reorganização das unidades estruturais das células, núcleos e capilares sinusoidais dos hepatócitos, reduzindo os danos no tecido hepático e aumentando a taxa de regeneração de órgãos. O MEIS apresentou alto potencial antioxidante nas concentrações de 1000 e 500 µg/mL. CONCLUSÃO: Este estudo sugere que I. suffruticosa tem atividade hepatoprotetora e alto potencial antioxidante.

Segurança e tolerabilidade de Nintedanibe em pacientes com fibrose pulmonar idiopática no Brasil / Safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis in Brazil

RESUMO Objetivo Ensaios clínicos mostraram que 150 mg de Nintedanibe duas vezes ao dia reduzem a progressão da doença em pacientes com Fibrose Pulmonar Idiopática (FPI), com um perfil de efeitos adversos que é controlável para a maioria dos pacientes. Antes da aprovação do Nintedanibe como tratamento para a FPI no Brasil, um Programa de Acesso Expandido (PEA) foi iniciado para fornecer acesso precoce ao tratamento e avaliar a segurança e a tolerância do Nintedanibe para este grupo de pacientes. Métodos Foram elegíveis para participar da PEA pacientes com diagnóstico de FPI nos últimos 5 anos, com capacidade vital forçada (CVF) ≥ 50% do previsto e capacidade de difusão dos pulmões para monóxido de carbono (DLco) 30%-79% do previsto. Os pacientes receberam Nintedanibe 150 mg, 2 vezes ao dia (bid). As avaliações de segurança incluíram eventos adversos que levaram à suspensão permanente do Nintedanibe e eventos adversos graves. Resultados O PEA envolveu 57 pacientes em 8 centros. A maioria dos pacientes era do sexo masculino (77,2%) e brancos (87,7%). No início do estudo, a média de idade foi de 70,7 (7,5) anos e a CVF foi de 70,7 (12,5%) do previsto. A média de exposição ao Nintedanibe foi de 14,4 (6,2) meses; a exposição máxima foi de 22,0 meses. Os eventos adversos frequentemente relatados pelo pesquisador como relacionados ao tratamento com Nintedanibe foram diarreia (45 pacientes, 78,9%) e náusea (25 pacientes, 43,9%). Os eventos adversos levaram à suspensão permanente do Nintedanibe em 16 pacientes (28,1%) que passaram por um evento adverso grave. Conclusões No PEA brasileiro, o Nintedanibe apresentou um perfil aceitável de segurança e tolerância em pacientes com FPI, condizendo com dados de ensaios clínicos.

ABSTRACT Objective Clinical trials have shown that nintedanib 150 mg twice daily (bid) reduces disease progression in patients with idiopathic pulmonary fibrosis (IPF), with an adverse event profile that is manageable for most patients. Prior to the approval of nintedanib as a treatment for IPF in Brazil, an expanded access program (EAP) was initiated to provide early access to treatment and to evaluate the safety and tolerability of nintedanib in this patient population. Methods Patients with a diagnosis of IPF within the previous five years, forced vital capacity (FVC) ≥ 50% predicted and diffusing capacity of the lungs for carbon monoxide (DLco) 30% to 79% predicted were eligible to participate in the EAP. Patients received nintedanib 150 mg bid open-label. Safety assessments included adverse events leading to permanent discontinuation of nintedanib and serious adverse events. Results The EAP involved 57 patients at eight centers. Most patients were male (77.2%) and white (87.7%). At baseline, mean (SD) age was 70.7 (7.5) years and FVC was 70.7 (12.5) % predicted. Mean (SD) exposure to nintedanib was 14.4 (6.2) months; maximum exposure was 22.0 months. The most frequently reported adverse events considered by the investigator to be related to nintedanib treatment were diarrhea (45 patients, 78.9%) and nausea (25 patients, 43.9%). Adverse events led to permanent discontinuation of nintedanib in 16 patients (28.1%). Sixteen patients (28.1%) had a serious adverse event. Conclusion In the Brazilian EAP, nintedanib had an acceptable safety and tolerability profile in patients with IPF, consistent with data from clinical trials.

Hepatotoxicidad colestásica asociada al uso de quimioterapia en esquema con lomustina: reporte de un caso y revisión de la literatura / Colestasic hepatotoxicity associated with the use of chemotherapy in scheme with lomustine: case report and literature review

Drug-induced liver injury (DILI) is a rare entity associated with high morbidity and mortality. It includes a broad spectrum of clinical patterns, from acute hepatitis to cirrhosis. Among the common associated drugs are antimicrobial like anti-TBC, antineoplastic, CNS agents and non-steroidal anti-inflammatory drugs. Establishing causality between DILI and a certain drug is a challenge. Some scoring systems have been evaluated, considering RUCAM score as the gold standard. We present the case of a 35-year-old woman with a history of a high-grade glioma treated with surgery and chemotherapy with lomustine, procarbazine and vincristine. She evolved with altered liver tests, predominantly cholestatic pattern, but asymptomatic. Etiologic study negative and abdominal imaging were normal. The liver biopsy was compatible with 40% ductopenia, without inflammatory elements. We consider DILI associated with the use of lomustine, with RUCAM score suggesting. After discontinuing chemotherapy and using ursodeoxycholic acid for the treatment of cholestasis there was an improvement in liver tests. There is limited evidence in the literature regarding hepatotoxicity associated with lomustine, mainly in experimental animal models. Cases of cholestatic hepatotoxicity have been described with the use of other similar nitrosureas. In relation to procarbazine and vincristine, DILI is reported mainly reversible and predominantly with hepatocellular pattern, not consistent with our case. We find it interesting to communicate with review of the literature about it.

El daño hepático inducido por drogas (DILI) es una entidad poco frecuente, con alta morbimortalidad asociada. Incluye un amplio espectro de patrones clínicos, desde hepatitis aguda a cirrosis. Dentro de los fármacos frecuentemente asociados se encuentran antibióticos como anti-TBC, agentes antineoplásicos, de acción en el SNC y anti-inflamatorios no esteroidales. Establecer una causalidad entre DILI y una determinada droga constituye un desafío. Para ello, se han evaluado diversos sistemas de puntuación, considerándose gold estándar el RUCAM score. Se presenta el caso de una mujer de 35 años de edad con antecedentes de glioma de alto grado operado y en quimioterapia con lomustina, procarbazina y vincristina. En su evolución presenta alteración de pruebas hepáticas de predominio colestásico de manera asintomática, con estudio etiológico causal negativo e imagenológico normal. La biopsia hepática fue compatible con ductopenia de 40% sin elementos inflamatorios. Se plantea DILI asociado al uso de lomustina con un score de RUCAM sugerente, decidiéndose interrumpir sus ciclos de quimioterapia e inicia tratamiento con ácido ursodesoxicólico, presentando mejoría progresiva de pruebas hepáticas. Existe evidencia limitada en la literatura en relación a hepatotoxicidad asociada a este fármaco, principalmente en modelos experimentales, y con el uso de otras nitrosureas similares se han descrito casos de hepatotoxicidad de predominio colestásico. En relación con procarbazina y vincristina existen reportes de DILI principalmente reversible y con patrón de predominio hepatocelular, lo que no es concordante con nuestro caso, por lo cual nos parece de interés comunicarlo con revisión de la literatura al respecto.

Drug Induced Liver Injury at a Tertiary Hospital in India: Etiology, Clinical Features and Predictors of Mortality

ABSTRACT Introduction and aims. Drug-induced liver injury (DILI) is rare; however, it is one of the important causes of acute liver failure which results in significant morbidity or mortality. Material and methods. Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months or until normalization of liver tests. Causality assessment was done by applying the Roussel Uclaf Causality Assessment Method model. Results. We collected data from 82 individuals diagnosed with DILI at our hospital from 2014 through 2015 (41 men; median age, 38 years). The most commonly implicated drugs were antitubercular therapy (ATT) (49%), antiepileptic drugs (12%), complementary and alternative medicine (CAM) in 10%, antiretroviral drugs (9%) and non-steroidal anti-inflammatory drugs (6%). 8 out of 13 deaths were liver related. Also, liver related mortality was significantly higher for ATT DILI (17.5%) vs. those without (2.4%) (P = 0.02). There was no significant difference in overall as well as liver related mortality in hepatocellular, cholestatic or mixed pattern of injury. Laboratory parameters at one week after discontinuation of drug predicted mortality better than those at the time of DILI recognition. On multivariate logistic regression analysis, jaundice, encephalopathy, MELD (Model for end stage liver disease) score and alkaline phosphatase at one week, independently predicted mortality. Conclusion. DILI results in significant overall mortality (15.85%). ATT, anti-epileptic drugs, CAM and antiretroviral drugs are leading causes of DILI in India. Presence of jaundice, encephalopathy, MELD score and alkaline phosphatase at one week are independent predictors of mortality.(AU)

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.

Hepatotoxicity by herbs: a practical review of a neglected disease / Hepatotoxicidad por hierbas: una revisión práctica de una enfermedad subestimada

Herbs are commonly used worldwide for the treatment of various diseases, constituting a multi-billion dollar market. Unfortunately, hepatotoxicity induced by herbs is also common. The true incidence and prevalence are not known. There is need for more strict regulations andexperimental and pre-clinical studies regarding its efficacy and safety. There is no gold standard for the diagnosis of herbs-induced liver injury (HILI) and it constitutes a diagnostic challenge for the clinician, whereestablishing causality could be cumbersome. Clinical presentation varies from asymptomatic cases with mildly abnormal liver tests to fulminant liver failure requiring liver transplantation. In this review, we will discuss the epidemiology, clinical manifestations, challenges and diagnostic approach of HILI and will also present some exemplary cases from the University of Miami, Division of Hepatology.

Las hierbas y productos derivados son comúnmente usados alrededor del mundo para el tratamiento de varias enfermedades, constituyendo un mercado multibillonario. Desafortunadamente, hepatotoxidad inducida por estos productos también es común. Existe la necesidad de regulaciones más estrictas, y de estudios experimentales y pre-clínicos acerca de su eficacia y seguridad. No existe un gold-standard para el diagnóstico de injuria hepática inducida por hierbas (HILI), constituyendo un reto diagnóstico para el clínico, donde el establecer una relación de causalidad puede resultar muy difícil. La presentación clínica puede variar desde casos asintomáticos con enzimas hepáticas levemente elevadas hasta casos de falla hepática fulminante requiriendo transplante hepático. En esta revisión, discutiremos brevemente la epidemiologia, manifestaciones clínicas, retos y aproximación diagnostica de la injuria hepática inducida por hierbas y finalmente mostraremos algunos casos ejemplares extraídos de nuestro archivo en la División de Hepatología de la Universidad de Miami.

Abacavir-induced liver toxicity

Abstract Abacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine.

Daño hepático agudo inducido por claritromicina. A propósito de un caso / Acute liver injury induced by clarithromycin, case report

Introducción: El daño hepático por fármacos es una lesión secundaria al uso de medicamentos. Posee una baja incidencia, representando la causa más común de muerte por falla hepática aguda. Es importante el diagnóstico y tratamiento precoz para evitar resultados desfavorables. Presentación del caso: Mujer de 73 años, con antecedentes de Hipertensión arterial en tratamiento, colecistectomizada; cursó neumonía adquirida en la comunidad de presentación atípica en tratamiento con claritromicina 500mg/12 horas y al cuarto día de tratamiento presentó ictericia, coluria, hipocolia y astenia. Al examen físico presentó dolor a palpación en hemiabdomen derecho y hepatomegalia. Los exámenes en urgencias mostraron una marcada alteración de las pruebas hepáticas, con leucocitos de 9.020/mm3 y 8% de eosinófilos. Se solicitó ecotomografía abdominal que no evidenció obstrucción de vía biliar. Durante la hospitalización se descartó serología para Virus Hepatitis A, B, C, Epstein Barr, Citomegalovirus y Virus de la Inmunodeficiancia Humana (VIH), junto con un perfil inmunológico no patológico. Se complementó con colangioresonancia que no evidenció obstrucción de la vía biliar, por lo que se indicó biopsia hepática que concluyó "daño hepático secundario a fármacos''. Se suspendió claritromicina, evolucionando favorablemente dándose de alta al séptimo día. Discusión: La claritromicina es un antibiótico usado ampliamente para tratar las infecciones bacterianas, sin embargo, es capaz de inducir daño hepático. El diagnóstico del daño hepático por fármacos es difícil, requiriéndose alto índice de sospecha, en donde las manifestaciones clínicas, la eosinofilia y el descarte de otras patologías son fundamentales para plantear el diagnóstico.

Introduction: Drug induced liver injury (DILI), is a drug hepatotoxicity, with low incidence. However represents the most common cause of death secondary to acute liver failure. Assertive diagnosis and early treatment is important to avoid adverse results. Case report: A 73-year-old woman, with arterial hypertension and cholecystectomy, who suffered community acquired pneumonia with atypical presentation, was treated with clarithromycin 500 mg twice a day. She manifested jaundice, choluria, hipocholia and fatigue after the fourth day in treatment. Additional, physical examination: at palpation showed right and upper abdominal pain, and hepatomegaly. During the emergency room, laboratory tests showed significant alterations in liver function. Total leukocyte count 9020 with 8% eosinophils. Abdominal ultrasound was negative for biliary obstruction. During hospitalization, markers for autoimmune liver disease were non pathological, and viral serologies (Hepatitis A, B, C viruses, Epstein Barr, Cytomegalovirus and Human immunodeficiency virus) were negative. Biliary obstruction was negative according Magnetic resonance cholangiopancreatography. Liver biopsy showed "drug induced liver injury". Clarithromycin was suspended, and the patient achieved clinical improvement and she was discharge at the 7th day. Discussion: Clarithromycin is an antibiotic widely used for several bacterial infections, capable of induced hepatotoxicity. Diagnosis of DILI is difficult, that requires high index of clinical suspicion. Clinical manifestations, eosinophilia and diferential diagnoses are key for an assertive diagnosis

Effects of perinatal exposure to nonylphenol on delivery outcomes of pregnant rats and inflammatory hepatic injury in newborn rats

The current study aimed to investigate the effects of perinatal exposure to nonylphenol (NP) on delivery outcome of pregnant rats and subsequent inflammatory hepatic injury in newborn rats. The pregnant rats were divided into 2 groups: control group (corn oil) and NP exposure group. Thirty-four pregnant rats were administered NP or corn oil by gavage from the sixth day of pregnancy to 21 days postpartum, with blood samples collected at 12 and 21 days of pregnancy and 60 days after delivery. The NP concentration was measured by HPLC, with chemiluminescence used for detection of estrogen and progesterone levels. Maternal delivery parameters were also observed. Liver and blood of the newborn rats were collected and subjected to automatic biochemical detection of liver function and blood lipid analyzer (immunoturbidimetry), and ultrastructural observation of the hepatic microstructure, with the TNF-α and IL-1β hepatic tissue levels evaluated by immunohistochemistry. Compared with the control group, the pregnant and postpartum serum NP and estradiol levels of the mother rats in the NP group were significantly increased, together with lowered progesterone level, increased number of threatened abortion and dystocia, and fewer newborn rats and lower litter weight. Serum and hepatic NP levels of the newborn rats measured 60 days after birth were significantly higher than those of the control group, as well as lower testosterone levels and increased estradiol levels. When observed under electron microscope, the hepatocyte nuclei of the control group were large and round, with evenly distributed chromatin. The chromatin of hepatocytes in the NP group presented deep staining of the nuclei, significant lipid decrease in the cytoplasm, and the majority of cells bonded with lysate. The results of immunohistochemistry showed that there was almost no TNF-α or IL-1β expression in the hepatocytes of the control group, while the number of TNF-α-, PCNA-, and IL-1β-positive cells in the NP group was increased, with higher integral optical density than the control group. Compared to the control group, the serum levels of alanine aminotransferase, aspartate aminotransferase, triglyceride and low-density lipoprotein in the newborn rats of the NP group were significantly increased. There was no significant difference in the serum level of high-density lipoprotein or cholesterol between the groups. Perinatal exposure to NP can interfere with the in vivo estrogen and progesterone levels of pregnant rats, resulting in threatened abortion, dystocia and other adverse delivery outcomes. High liver and serum NP levels of the newborn rats led to alteration of liver tissue structure and function. The NP-induced hepatotoxicity is probably mediated by inflammatory cytokines TNF-α and IL-1α.

Hepatotoxicidad asociada a hierbas y productos nutricionales de origen botánico / Herbals and herbal nutritional products hepatotoxicity

Las hierbas y otros productos de origen botánico, han sido utilizados por siglos en diversas culturas con fines medicinales y dietéticos. Contrario a la creencia de ser productos naturales y seguros, su potencial hepatotóxico es reconocido en diversos estudios a nivel mundial, lo que constituye un problema de salud que amerita mayor atención. La prevalencia reportada de hepatotoxicidad asociada a productos botánicos es variable y depende de diversos factores como población estudiada, período y diseño del estudio. Se han reportado un total de 60 productos a base de hierbas con fines medicinales y dietéticos, que pueden causar lesión hepática; sin embargo, el mecanismo fisiopatológico no está completamente dilucidado. Su cuadro clínico y características histológicas, no difieren de la lesión hepática asociada a medicamentos y la mayoría de los pacientes tienen un patrón de lesión hepatocelular. El diagnóstico se hace por exclusión, representando un desafío clínico importante, por lo que resulta fundamental la sospecha clínica y el diagnóstico diferencial de otras patologías agudas y crónicas. De allí que las investigaciones futuras están orientadas a mejorar los métodos diagnóstico existentes e introducir nuevas tecnologías toxicológicas, genéticas e inmunológicas. El manejo es complejo y representa un reto para el especialista puesto que no existe antídoto; el manejo se basa en suspender el uso del producto y en el tratamiento sintomático que disminuya la progresión a la falla hepática aguda fulminante.

Herbs and other botanicals have been used in different cultures with medicinal and dietary purposes for centuries. Contrary to the belief of being natural and safe products, their hepatotoxic potential is recognized in several studies worldwide, and represent a health problem that deserves greater attention. The reported prevalence of hepatotoxicity associated with botanicals is variable and depends on various factors such as population, period and design of the study. There have been reports of a total of 60 products with herbal medicinal and dietary purposes, which may cause liver damage; however, the pathophysiological mechanisms involved are not fully elucidated. Their clinical and histological features, not unlike liver injury associated with drugs in most patients, have a pattern of hepatocellular injury. Diagnosis is by exclusion, and represents a clinical challenge. It is essential the clinical suspicion and the differential diagnosis with other acute and chronic conditions. Hence, future researches are aimed at improving existing diagnostic methods and introducing new toxicological, genetic and immunological technologies. Treatment is complex and presents a challenge for the specialist, as there are no antidotes. Management based on the discontinued use of the product and in the symptomatic treatment, decreases the progression to an acute fulminant hepatic failure.

Dapsone in the treatment of pemphigus vulgaris: adverse effects and its importance as a corticosteroid sparing agent

Pemphigus vulgaris is an autoimmune disease characterized by suprabasal blisters with acantholysis, which has a fatal course in a large number of untreated patients. Systemic corticosteroid therapy is considered first-line therapy. Adjuvant treatment with the goal of sparing corticosteroids include, among others, dapsone. This drug is not without side effects and its use requires clinical and laboratory control. We present a patient with PV initially managed with suboptimal dose of prednisone, evolving into drug-induced hepatitis after introduction of dapsone.