Profile of herbal and dietary supplements induced liver injury in Latin America: A systematic review of published reports

Hepatotoxicity related to HDS is a growing global health issue. We have undertaken a systematic review of published case reports and case series from LA from 1976 to 2020 to describe the clinical features of HDS related hepatotoxicity in this region. We search in PubMed, Web of Science, Scopus and specific LA databases according to PRISMA guidelines. Only HILI cases published in LA that met criteria for DILI definition were included. Duplicate records or reports that lacked relevant data that precluded establishing causality were excluded. Finally, 17 records (23 cases) were included in this review. Centella asiatica, Carthamus tinctorius, and Herbalife® were the most reported HDS culprit products, the main reason for HDS consumption was weight loss. The clinical characteristics of HDS hepatotoxicity in our study were compared to those of other studies in the USA, Europe and China showing a similar signature with predominance of young females, hepatocellular damage, a high rate of ALF and mortality, more frequent inadvertent re-challenge and chronic damage. This study underscores the challenge in causality assessment when multi-ingredients HDS are taken and the need for consistent publication practice when reporting hepatotoxicity cases due to HDS, to foster HDS liver safety particularly in LA

Drug-induced liver injury: A management position paper from the Latin American Association for Study of the liver

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) is an uncommon cause of liver disease presenting with a wide range of phenotypes and disease severity, acute hepatitis mimicking viral hepatitis to autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes. Disease severity ranges from asymptomatic liver test abnormalities to acute liver failure. DILI has been traditionally classified in predictable or intrinsic (dose-related) or unpredictable (not dose-related) mechanisms. Few prospective studies are assessing the real prevalence and incidence of hepatotoxicity in the general population. DILI registries represent useful networks used for the study of liver toxicity, aimed at improving the understanding of causes, phenotypes, natural history, and standardized definitions of hepatotoxicity. Although most of the registries do not carry out population-based studies, they may provide important data related to the prevalence of DILI, and also may be useful to compare features from different countries. With the support of the Spanish Registry of Hepatotoxicity, our Latin American Registry (LATINDILI) was created in 2011, and more than 350 DILI patients have been recruited to date. This position paper describes the more frequent drugs and herbs-induced DILI in Latin America, mainly focusing on several features of responsible medicaments. Also, we highlighted the most critical points on the management of hepatotoxicity in general and those based on findings from our Latin American experience in particular.Fil: Bessone, Fernando. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Hospital Nacional del Centenario; ArgentinaFil: Hernandez, Nelia. Hospital de Clinicas Dr. Manuel Quintela; UruguayFil: Tagle, Martin. Universidad Peruana Cayetano Heredia; PerúFil: Arrese, Marco. Pontificia Universidad Católica de Chile; ChileFil: Parana, Raymundo. Universidade Federal da Bahia; BrasilFil: Mendez-Sánchez, Nahum. Fundacion Clinica Medica Sur; México. Universidad Nacional Autónoma de México; MéxicoFil: Ridruejo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Mendizabal, Manuel. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Dagher, Lucy. Policlinica Metropolitana; VenezuelaFil: Contreras, Fernando. Universidad Pedro Henriquez Urena; República DominicanaFil: Fassio, Eduardo. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Pesoa, Mario. Hospital de Clincas; BrasilFil: Brahm, Javier. Clinica Las Condes; ChileFil: Silva, Marcelo. Universidad Austral. Hospital Universitario Austral; Argentin

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

Los datos sobre la reexposición positiva en la lesión hepática inducida por fármacos (DILI) idiosincrásica son escasos. Apuntamos a analizar la presentación clínica, el resultado y los fármacos asociados con la reexposición positiva en dos registros DILI. Se incluyeron casos de los registros DILI español y latinoamericano. De 1418 pacientes con DILI idiosincrásico, 58 casos tuvieron una nueva exposición positiva (4,1%). Pacientes con positivo la nueva exposición tuvo una duración más corta de la terapia (p=0,001) y latencia (p=0,003). En pacientes con reexposición, los niveles de aspartato transaminasa aumentaron (p=0,026) y mostraron un tiempo prolongado de recuperación (p=0,020), aunque no se observaron diferencias en términos de resultados fatales. El principal fármaco implicado en la reexposición fue amoxicilina-clavulanato (17%). La mayoría de los eventos de reexposición fueron involuntarios (71%). Usando ambos existentes definiciones de reexposición positiva, hubo cuatro casos que cumplieron exclusivamente con los criterios actuales y cinco que sólo cumplen con la definición histórica. Todos los casos de nueva impugnación positiva, independientemente del patrón de daño, cumplió con los criterios de alanina transaminasa (ALT) ≥3 veces el límite superior de lo normal (LSN) y/o fosfatasa alcalina (ALP) ≥2 veces el LSN.Funding for open access charge: Universidad de Málaga / CBU

Serious liver injury induced by Nimesulide: an international collaboration study reporting 57 cases

Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to analyze the clinical phenotype, outcome, and histological features of nimesulide-induced liver injury (nimesulide-DILI). We analyzed 57 cases recruited from the Spanish and LATIN DILI registries. Causality was assessed by the RUCAM scale. Mean age of the whole case series was 59 years (86% women) with a median time to onset of 40 days. A total of 46 patients (81%) were jaundiced. Nimesulide-DILI pattern was hepatocellular in 38 (67%), mixed in 12 (21%), and cholestatic in 7 (12%) cases. Transaminases were elevated with a mean of nearly 20-fold the upper limit of normality (ULN), while alkaline phosphatase showed a 2-fold mean elevation above ULN. Total bilirubin showed a mean elevation of 13-fold the ULN. Liver histology was obtained in 14 cases (25%), most of them with a hepatocellular pattern. Median time to recovery was 60 days. Overall, 12 patients (21%) developed acute liver failure (ALF), five (8.8%) died, three underwent liver transplantation (5.3%), and the remaining four resolved. Latency was ≤15 days in 12 patients (21%) and one patient developed ALF within seven days from treatment initiation. Increased total bilirubin and aspartate transaminase levels were independently associated with the development of ALF. In summary, nimesulide-DILI affects mainly women and presents typically with a hepatocellular pattern. It is associated with ALF and death in a high proportion of patients. Shorter (≤15 days) duration of therapy does not prevent serious nimesulide hepatotoxicity, making its risk/benefit ratio clearly unfavorable.The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional - FEDER (contract numbers: PI18-00901; PI 18/01804; PT20/00127) and Agencia Española del Medicamento. Plataforma ISCiii de Investigación Clínica and CIBERehd are funded by ISCIII. MRD holds a Joan Rodes (JR16/00015)/Acción B clinicos investigadores (B-0002-2019) research contract from ISCIII and Consejería de Salud de Andalucía, IAA holds a Sara Borrell research contract from the National Health System, ISCIII (CD 20/00083)

Clinical presentation, causative drugs and outcome of patients with autoimmune features in two prospective DILI registries

Background & aims: Idiosyncratic drug-induced liver injury (DILI) with autoimmune features is a liver condition with laboratory and histological characteristics similar to those of idiopathic autoimmune hepatitis (AIH), which despite being increasingly re-ported, remains largely undefined. We aimed to describe in-depth the features of this entity in a large series of patients from two prospective DILI registries. Methods: DILI cases with autoimmune features collected in the Spanish DILI Registry and the Latin American DILI Network were compared with DILI patients without autoimmune features and with an independent cohort of patients with AIH. Results: Out of 1,426 patients with DILI, 33 cases with autoimmune features were identified. Female sex was more frequent in AIH patients than in the other groups (p= .001). DILI cases with autoimmune features had significantly longer time to onset (p< .001) and resolution time (p= .004) than those without autoimmune features. Interestingly, DILI patients with autoimmune features who relapsed exhibited significantly higher total bilirubin and transaminases at onset and absence of peripheral eosinophilia than those who did not relapse. The likelihood of relapse increased over time, from 17% at 6 months to 50% 4 years after biochemical normalization. Statins, nitrofurantoin and minocycline were the drugs most frequently associated with this phenotype. Conclusions: DILI with autoimmune features shows different clinical features than DILI patients lacking characteristics of autoimmunity. Higher transaminases and total bilirubin values with no eosinophilia at presentation increase the likelihood of relapse in DILI with autoimmune features. As the tendency to relapse increases over time, these patients will require long-term follow-up.Instituto de Salud Carlos III; Fondo Europeo de Desarrollo Regional— FEDER, Grant/Award Number: UMA18- FEDERJA-193, PI18/00901, PI19/00883 and PI21/01248; Consejería de Salud y Familia de la Junta de Andalucía, Grant/Award Number: P18-RT- 3364 and PI- 0310- 2018; Agencia Española del Medicamento; Sara Borrell, Grant/Award Number: CD20/00083; Rio Hortega, Grant/Award Number: CM21/00074; Garantía Juvenil, Grant/Award Number: SNGJ5Y6-09; Junta de Andalucía and European Social Fund; European Cooperation in Science and Technology; Universidad de Málaga/CBUA Funding for open access charge: Universidad de Málga / CBU

Herbal and dietary supplements-induced liver injury in Latin America: Experience from the LATINDILI Network

Background: Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations. Objectives: To evaluate clinical, laboratory features and outcome in HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network. Material and methods: A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity. Results: From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p=0.04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p=0.008 and p=0.021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p=0.026), and had more severe and fatal/liver transplantation outcome (21% vs 12% vs 13%; p=0.005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%). Conclusions: HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver-transplant than DILI related to conventional drugs.The present study has been supported by grants of the Andalusian Health Service (SAS) (contract number: PI-0285-2016). Instituto de Salud Carlos III co-funded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: (PI-0274-2016, PI-0285-2016, PI-0310-2018, PI18-00901, PI18/01804). IAA holds a Sara Borrell research contract from the National Health System, ISCiii (CD 20/00083), and by the Agencia Española del Medicamento. CIBERehd is funded by Instituto de Salud Carlos III

Acute dystonia after injection of pegylated interferon alpha-2b

Universidade Federal de São Paulo, Sch Med, São Paulo, BrazilUniv Fed Bahia, Sch Med, Salvador, BA, BrazilUniv São Paulo, Sch Med, São Paulo, BrazilUniversidade Federal de São Paulo, Sch Med, São Paulo, BrazilWeb of Scienc

Prevalence of non-organ-specific autoantibodies in a rural community from northeastern Brazil: a population-based study

Non-organ-specific autoantibodies (NOSA) are well-recognized diagnostic markers of autoimmune hepatitis (All-l) and primary biliary cirrhosis (PBC), but can also be observed in patients with viral hepatitis as well as in healthy subjects. The aim of this study was to evaluate the prevalence of NOSA in subjects living in a rural community in Brazil and to correlate their occurrence with the presence of liver disease. Seven hundred twenty-five apparently healthy subjects were randomly selected for assessment of antinuclear (ANA), anti-smooth muscle (SMA), antimitochondrial (AMA), anti-liver/kidney microsome type 1, and anti-liver cytosol type 1 antibodies. Subjects with those NOSA were evaluated for the presence of AIH, PBC, and viral hepatitis. Reactivities for all NOSA, SMA, ANA, and AMA were detected, respectively, in 14, 10, 4, and 0.1% of subjects, with a mean titer of 1:40. NOSA-positive subjects were significantly older and more frequently females. No correlation was observed between the occurrence of NOSA and PBC. AIH, or viral hepatitis. The prevalence of NOSA in Brazilians was 14%. They were usually low titer. NOSA were more frequently observed in females and older subjects and their presence was not correlated with the presence of AIH, PBC, or viral hepatitis. (C) 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.National Research Council (CNPq) of BrazilNational Research Council of Brazil (CNPq)Centro de Pesquisas Goncalo Moniz, Fundacao Oswaldo Cruz (FIOCRUZ)Centro de Pesquisas Goncalo Moniz, Fundacao Oswaldo Cruz (FIOCRUZ