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

Prospective Latin American cohort evaluating outcomes of patients with COVID-19 and abnormal liver tests on admission

Introduction & objectives: The independent effect of liver biochemistries as a prognostic factor in patients with COVID-19 has not been completely addressed. We aimed to evaluate the prognostic value of abnormal liver tests on admission of hospitalized patients with COVID-19. Materials & methods: We performed a prospective cohort study including 1611 hospitalized patients with confirmed SARS-CoV-2 infection from April 15, 2020 through July 31, 2020 in 38 different Hospitals from 11 Latin American countries. We registered clinical and laboratory parameters, including liver function tests, on admission and during hospitalization. All patients were followed until discharge or death. We fit multivariable logistic regression models, further post-estimation effect through margins and inverse probability weighting. Results: Overall, 57.8% of the patients were male with a mean age of 52.3 years, 8.5% had chronic liver disease and 3.4% had cirrhosis. Abnormal liver tests on admission were present on 45.2% (CI 42.7–47.7) of the cohort (n = 726). Overall, 15.1% (CI 13.4–16.9) of patients died (n = 244). Patients with abnormal liver tests on admission presented higher mortality 18.7% (CI 15.9–21.7), compared to those with normal liver biochemistries 12.2% (CI 10.1–14.6); P 30. Conclusions: The presence of abnormal liver tests on admission is independently associated with mortality and severe COVID-19 in hospitalized patients with COVID-19 infection and may be used as surrogate marker of inflammation.Fil: Mendizabal, Manuel. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Piñero, Federico. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: 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: Anders, Margarita. Hospital Aleman; ArgentinaFil: Silveyra, María Dolores. Sanatorio Anchorena; ArgentinaFil: Torre, Aldo. Centro Médico ABC; MéxicoFil: Montes, Pedro. Hospital Nacional Daniel A. Carrión; PerúFil: Urzúa, Alvaro. Hospital Clínico de la Universidad de Chile; ChileFil: Pages, Josefina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Toro, Luis G.. Hospitales de San Vicente Fundación de Medellín y Rionegro; ColombiaFil: Díaz, Javier. Hospital Nacional Edgardo Rebagliati Martins; PerúFil: Gonzalez Ballerga, Esteban. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Miranda Zazueta, Godolfino. Instituto Nacional de Ciencias Médicas y Nutrición; MéxicoFil: Peralta, Mirta. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Gutiérrez, Isabel. Centro Médico ABC; MéxicoFil: Michelato, Douglas. Hospital Especializado en Enfermedades Infecciosas Instituto Couto Maia; BrasilFil: Venturelli, Maria Grazia. Hospital Nacional Guillermo Almenara Irigoyen; PerúFil: Varón, Adriana. Fundación Cardio-Infantil; ColombiaFil: Vera Pozo, Emilia. Hospital Regional Dr. Teodoro Maldonado Carbo; EcuadorFil: Tagle, Martín. Clínica Anglo-Americana; PerúFil: García, Matías. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; ArgentinaFil: Tassara, Alfredo. Hospital Aleman; ArgentinaFil: Brutti, Julia. Sanatorio Anchorena; ArgentinaFil: Ruiz García, Sandro. Hospital de Víctor Lazarte Echegaray; PerúFil: Bustios, Carla. Clínica Delgado; PerúFil: Escajadillo, Nataly. Hospital Nacional Almanzor Aguinaga Asenjo; PerúFil: Macias, Yuridia. No especifíca;Fil: Higuera de la Tijera, Fátima. Hospital General de México “Dr. Eduardo Liceaga"; MéxicoFil: Gómez, Andrés J.. Hospital Universitario Fundación Santa Fé de Bogotá; ColombiaFil: Dominguez, Alejandra. Hospital Padre Hurtado; ChileFil: Castillo Barradas, Mauricio. Hospital de Especialidades del Centro Médico Nacional La Raza; MéxicoFil: Contreras, Fernando. No especifíca;Fil: Scarpin, Aldana. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; ArgentinaFil: Schinoni, Maria Isabel. Hospital Alianza; BrasilFil: Toledo, Claudio. Universidad Austral de Chile; ChileFil: Girala, Marcos. Universidad Nacional de Asunción; ParaguayFil: Mainardi, Victoria. Hospital Central De las Fuerzas Armadas; UruguayFil: Sanchez, Abel. Hospital Roosevelt; GuatemalaFil: Bessone, Fernando. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Rubinstein, Fernando Adrian. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Silva, Marcelo Oscar. Universidad Austral. Hospital Universitario Austral; Argentin

Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports

Introduction. Drug-induced liver injury (DILI) remains a major problem for drug development and represents a challenging diagnosis for clinicians. The absence of specific biomarkers for diagnosing DILI precludes the availability of reliable data on the epidemiology of the disease. In this study we aimed to describe the features of idiosyncratic hepatotoxicity reports in Latin American countries.Material and methods. A literature search was performed using the online version of MEDLINE, EMBASE, Scopus, Google Scholar and specific data bases from Latin America (LA) (Scielo, Lilacs) to identify any case report or case series of published DILI from 1996 to 2012. From 1996 to 2012, a total of 176 patients with DILI were published in LA, involving 53 suspicious drugs. The median age in the adult population of these patients was 55 years (17-82) with prevalence of women (67%). Among main therapeutic classes, the rank order was led by non-steroidal anti-inflammatory (61 cases) and systemic antibacterial drugs (37 cases). Nimesulide was the individual drug responsible for the highest number of cases (53), followed by cyproterone acetate (18), nitrofurantoin (17), antituberculous drugs (13) and flutamide (12). Thirty two percent of published cases evolved to acute liver failure (ALF), and half of the subjects required liver transplantation or eventually died.Conclusions. This study represents the first structured attempt to assess the spectrum of DILI profile in LA. The establishment of a Latin American registry to collect prospective DILI cases using a standardized protocol will advance our knowledge about idiosyncratic DILI in this region

Treatment with direct-acting antivirals for HCV decreases but does not eliminate the risk of hepatocellular carcinoma

Background & Aims: Data from Europe and North America have been published regarding the risk of developing hepatocellular carcinoma (HCC) after treatment with direct antiviral agents (DAA). We proposed to evaluate cumulative incidence and associated risk factors for de novo HCC. Methods: This was a prospective multicentre cohort study from Latin America including 1400 F1-F4-treated patients with DAAs (F3-F4 n = 1017). Cox proportional regression models (hazard ratios, HR and 95% CI) were used to evaluate independent associated variables with HCC. Further adjustment with competing risk regression and propensity score matching was carried out. Results: During a median follow-up of 16 months (IQR 8.9-23.4 months) since DAAs initiation, overall cumulative incidence of HCC was 0.02 (CI 0.01; 0.03) at 12 months and 0.04 (CI 0.03; 0.06) at 24 months. Cumulative incidence of HCC in cirrhotic patients (n = 784) was 0.03 (CI 0.02-0.05) at 12 months and 0.06 (CI 0.04-0.08) at 24 months of follow-up. Failure to achieve SVR was independently associated with de novo HCC with a HR of 4.9 (CI 1.44; 17.32), after adjusting for diabetes mellitus, previous interferon non-responder, Child-Pugh and clinically significant portal hypertension. SVR presented an overall relative risk reduction for de novo HCC of 73% (CI 15%-91%), 17 patients were needed to be treated to prevent one case of de novo HCC in this cohort. Conclusions: Achieving SVR with DAA regimens was associated with a significant risk reduction in HCC. However, this risk remained high in patients with advanced fibrosis, thus demanding continuous surveillance strategies in this population.Fil: Piñero, Federico. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Mendizabal, Manuel. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Ridruejo, Ezequiel. Universidad Austral. Hospital Universitario Austral; Argentina. 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: Herz Wolff, Fernando. Universidade Federal do Rio Grande do Sul; BrasilFil: Ameigeiras, Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Anders, Margarita. Hospital Aleman; ArgentinaFil: Schinoni, María Isabel. Universidade Federal da Bahia; BrasilFil: Reggiardo, Virginia. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Palazzo, Ana. Gobierno de la Provincia de Tucumán. Hospital Ángel Padilla; ArgentinaFil: Videla, María. Sanatorio Sagrado Corazón; ArgentinaFil: Alonso, Cristina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Santos, Luisa. Fundación Cardioinfantil; ColombiaFil: Varón, Adriana. Fundación Cardioinfantil; ColombiaFil: Figueroa, Sebastián. Sanatorio Parque; ArgentinaFil: Vistarini, Cecilia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Adrover, Raúl. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos San Roque de Gonnet; ArgentinaFil: Fernández, Nora. Hospital Británico de Buenos Aires; ArgentinaFil: Perez, Daniela. Gobierno de la Provincia de Tucumán. Hospital Ángel Padilla; ArgentinaFil: Tanno, Federico. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Hernández, Nelia. Universidad de la República. Facultad de Medicina. Hospital de Clínicas "Dr. Manuel Quintela"; UruguayFil: Sixto, Marcela. Provincia de Santa Fe. Ministerio de Salud. Hospital "Dr. José María Cullen"; ArgentinaFil: Borzi, Silvia. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal General de Agudos "prof. Dr. Rodolfo Rossi".; ArgentinaFil: Bruno, Andres. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich; ArgentinaFil: Cocozzella, Daniel. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos San Roque de Gonnet; ArgentinaFil: Soza, Alejandro. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Descalzi, Valeria. Fundación Favaloro; ArgentinaFil: Estepo, Claudio. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich; ArgentinaFil: Zerega, Alina. Sanatorio Allende; ArgentinaFil: de Araujo, Alexandre. Hospital de Clinicas de Porto Alegre; BrasilFil: Cheinquer, Hugo. Universidade Federal do Rio Grande do Sul; BrasilFil: Silva, Marcelo. Universidad Austral. Hospital Universitario Austral; Argentin

Decompensated cirrhosis and liver transplantation negatively impact in DAA treatment response: Real-world experience from HCV-LALREAN cohort

Introduction: Although the effectiveness of direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C virus (HCV) has been reported in real-world settings, predictive factors of treatment failure are lacking. Therefore, we sought to explore the baseline predictors of treatment response to DAAs. Methods: This was a prospective multicenter cohort study from the Latin American Liver Research Educational and Awareness Network (LALREAN) including patients who received DAA treatment from May 2016 to April 2019. A multivariate logistic regression model was conducted to identify variables associated with unachieved sustained virological response (SVR), defined as treatment failure (odds ratios [OR] and 95% confidence intervals [CIs]). Results: From 2167 patients (55.2% with cirrhosis) who initiated DAA therapy, 89.4% completed a full-course treatment (n = 1938). Median treatment duration was 12 weeks, and 50% received ribavirin. Definitive suspension due to intolerance or other causes was observed in only 1.0% cases (n = 20). Overall non-SVR12 was 4.5% (95% CI, 3.5-5.7). There were no significant differences in treatment failure according to HCV genotypes and the degree of fibrosis. Independently associated variables with DAA failure were liver function impairment according to the Child-Pugh score B OR, 2.09 (P =.06), Child-Pugh C OR, 11.7 (P <.0001); and liver transplant (LT) recipient OR, 3.75 (P =.01). Conclusion: In this real-life setting, higher DAA treatment failure rates were observed in patients with decompensated cirrhosis and in LT recipients. These predictive baseline factors should be addressed to individualize the appropriate time-point of DAA treatment (NCT03775798; www.clinicaltrials.gov).Fil: 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; Argentina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Piñero, Federico. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Mendizabal, Manuel. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Cheinquer, Hugo. Universidade Federal do Rio Grande do Sul; BrasilFil: Wolff, Fernando Herz. Universidade Federal do Rio Grande do Sul; BrasilFil: Anders, Margarita. Hospital Aleman; ArgentinaFil: Reggiardo, Virginia. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Ameigeiras, Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Palazzo, Ana. Hospital Padilla; ArgentinaFil: Alonso, Cristina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Schinoni, María Isabel. Universidade Federal da Bahia; BrasilFil: Videla Zuain, María Grazia. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; ArgentinaFil: Tanno, Federico. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Figueroa, Sebastián. Hospital Dr. Arturo Oñativia - Salta Capital.; ArgentinaFil: Santos, Luisa. Fundación Cardioinfantil; ColombiaFil: Peralta, Mirta. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Soza, Alejandro. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Vistarini, Cecilia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Adrover, Raúl. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos San Roque de Gonnet; ArgentinaFil: Fernández, Nora. Hospital Británico de Buenos Aires; ArgentinaFil: Perez, Daniela. Hospital Padilla; ArgentinaFil: Hernández, Nelia. Universidad de la República. Facultad de Medicina. Hospital de Clínicas "Dr. Manuel Quintela"; UruguayFil: Estepo, Claudio. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich; ArgentinaFil: Bruno, Andres. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich; ArgentinaFil: Descalzi, Valeria. Fundación Favaloro; ArgentinaFil: Sixto, Marcela. Provincia de Santa Fe. Ministerio de Salud. Hospital "Dr. José María Cullen"; ArgentinaFil: Borzi, Silvia. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal General de Agudos "prof. Dr. Rodolfo Rossi".; ArgentinaFil: Cocozzella, Daniel. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos San Roque de Gonnet; ArgentinaFil: Zerega, Alina. Sanatorio Allende; ArgentinaFil: de Araujo, Alexandre. Hospital de Clinicas de Porto Alegre; BrasilFil: Varón, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Silva, Marcelo. Universidad Austral. Hospital Universitario Austral; Argentin

Drug-Induced Liver Injury in Latin America: 10-year experience of the Latin American DILI (LATINDILI) Network

Background and aims: Latin America is a region of great interest for studying the clinical presentation of idiosyncratic drug-induced liver injury (DILI). A comprehensive analysis of patients enrolled into the LATINDILI Network over a decade is presented. Methods: Demographics, clinical presentation, histological findings and outcome of prospectively recruited DILI cases in the LATINDILI Network were analyzed. Suspected culprit drugs were classified according to the Anatomical Therapeutic Chemical classification. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) scale. Results: Overall, 468 idiosyncratic DILI cases were analyzed (62% women, mean age 49 years). Hepatocellular injury predominated (62%), jaundice was present in 60% of patients and 42% were hospitalized. 4.1% of the cases had a fatal outcome, and 24 (12%) patients developed chronic DILI. The most common drug classes were systemic antiinfectives (31%), musculoskeletal agents (12%), antineoplastic and immunomodulating agents (11%), and herbal and dietary supplements (HDS, 9%). Notably, none of the patients with DILI due to antibacterials or immunosuppressants had a fatal outcome. In fact, Hy's law showed to have drug-specific predictive value, with anti-tuberculosis drugs, nimesulide and HDS associated with the worst outcome, whereas DILI caused by amoxicillin-clavulanate, nitrofurantoin and diclofenac that fulfilled Hy's law did not have a fatal outcome. Conclusion: Features of DILI in Latin America are comparable to other prospective registries. However, the pattern of drugs responsible for DILI differs. An increasing incidence of HDS, with high mortality rate, and likewise nimesulide and nitrofurantoin was noted. Thus, public health policies should raise awareness of the potential adverse effects of these compounds.This work was supported by grants of Instituto de Salud Carlos III (ISCIII), cofounded by Fondo Europeo de Desarrollo Regional – FEDER, cofounded by European Union (grant number PI21/01248; PT20/00127; PT23/00137), and by the Agencia Española de Medicamentos y Productos Sanitarios. CIBERehd and Plataforma de Investigación Clinica are funded by ISCIII. JMPB holds a Rio Hortega contract (CM21/00074) and JSC a Juan Rodés contract (JR21/00066) from ISCIII and cofounded by the European Union. HN holds a postdoctoral research contract funded by Junta de Andalucía (POSTDOC_21_00780). This project has received funding from the European Horizon´s research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement Nº 101095679. This study is funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the manuscript for publication