Systemic Inflammatory Molecules Are Associated with Advanced Fibrosis in Patients from Brazil Infected with Hepatitis Delta Virus Genotype 3 (HDV-3).

BACKGROUND AND AIMS: Hepatitis Delta virus (HDV) genotype 3 is responsible for outbreaks of fulminant hepatitis in Northeastern South America. This study investigates if systemic inflammatory molecules are differentially expressed in patients with advanced fibrosis chronically infected with Hepatitis Delta virusgenotype 3(HDV-3). METHODS: Sixty-one patients from the north of Brazil coinfected with hepatitis B virus (HBV)/HDV-3 were analyzed. HDV quantification and genotyping were performed by semi-nested real-time polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP) methodologies. Ninety-two systemic inflammatory molecules (SIMs) were measured by Proximity Extension Assay (PEA) technology. The Shapiro-Wilk, Student's t-test, Mann-Whitney tests, and logistic regression analysis were used when appropriate. RESULTS: The median age was 41 years, and all patients were HBeAg negative. Advanced fibrosis or cirrhosis was diagnosed by histological staging in 17 patients, while 44 presented with minimal or no fibrosis. Advanced necroinflammatory activity correlated positively with serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Established non-invasive fibrosis scores (APRI, FIB-4, and AST/ALT ratio) revealed low sensitivities and positive predictive values (PPVs) with an AUROC maximum of 0.586. Among the 92 SIMs analyzed, MCP.4, CCL19, EN.RAGE, SCF, and IL18 showed a positive correlation with fibrosis stage. A combined score including CCL19 and MCP.4 revealed a sensitivity of 81% and an odds ratio of 2.202 for advanced fibrosis. CONCLUSIONS: Standard non-invasive fibrosis scores showed poor performance in HDV-3 infection. We here suggest that the determination of CCL19 and MCP.4 may be used to identify patients with advanced fibrosis. Moreover, this study gives novel insights into the immunopathogenesis of HDV-3 infection.

Frequência de esteato-hepatite alcoólica em pacientes portadores do vírus de hepatite C / Frequency of alcoholic steatohepatitis in patients with hepatitis C virus

Introdução: o consumo de álcool é um fator de risco bem conhecido para induzir doença crônica do fígado. O álcool também é um cofator na patogênese induzida pelo vírus da hepatite C (VHC). A infecção crônica pelo VHC pode exacerbar a lesão hepática alcoólica por mecanismos que incluem aumento do estresse oxidativo. Portanto o VHC, concomitantemente com o consumo excessivo de álcool, induz diversos mecanismos fisiopatogênicos que contribuem para a diminuição da depuração viral e para a lesão hepática. Objetivos: 1 ­ avaliar a frequência de esteato-hepatite alcoólica em biópsias de pacientes portadores do vírus da hepatite C; 2 ­ estudar os estágios da fibrose hepática nesses pacientes versus pacientes com e sem ingestão de álcool; 3 ­ analisar os escores bioquímicos e antropométricos desses pacientes. Metodologia: estudo de corte transversal, com pacientes acompanhados no núcleo de hepatologia do Hospital Prof. Edgard Santos da Universidade Federal da Bahia, portadores de hepatite C, com laudos de biópsias disponíveis para avaliar presença de esteato-hepatite alcoólica comprovada pelo registro de consumo de gramas de álcool. Foram considerados etilistas homens que consumiam mais de 30 g por dia e mulheres com consumo maior do que 20 g por dia. As variáveis utilizadas basearam-se em critérios histológicos, epidemiológicos e clínicos aplicados a esses pacientes. Resultados: a amostra total de pacientes portadores de hepatite C analisados foi de 335, sendo 100 indivíduos considerados com ingestão elevada de álcool, e 28,9% dos casos da amostra. A presença de esteatose hepática sem esteato-hepatite foi em 34 indivíduos (10,15%), e os casos de esteato-hepatite aparecem em um total de 30 indivíduos (8,96%). A carga viral elevada dos pacientes, tendo como referência >800.000, esteve em n=102, com 30,4% dos casos de VHC. Conclusão: observou-se, na população de estudo, 43 % os portadores de VHC com uso excessivo de alcool, 8,9 6% tinham esteato-hepatiits e 10,15 % esteatose. Além disso, verificou-se que mais da metade desses pacientes (56,6%) apresentaram grau de fibrose moderada e 53,3%, atividade necroinflamatória leve. A comorbidade mais comum observada foi hipertensão arterial sistêmica (HAS), em 40% dos pacientes.

Introduction: alcohol consumption is a well-known risk factor for inducing chronic liver disease, alcohol is also a cofactor in the pathogenesis induced by Hepatitis C Virus (HCV). Chronic HCV infection can exacerbate alcoholic liver damage by mechanisms including increased oxidative stress. Therefore, HCV, concomitantly with excessive alcohol consumption, induces several pathophysiological mechanisms, which contribute to the decrease in viral clearance and liver damage. Objectives: 1 ­ to assess the frequency of alcoholic steatohepatitis in biopsies of patients with the hepatitis C virus, 2 ­ to study the stages of liver fibrosis in these patients versus in patients with or without alcohol intake, 3 ­ analyze biochemical and anthropometric scores of these patients. Methodology: cross-sectional study, with patients monitored at the hepatology center of Hospital Prof. Edgard Santos from the Federal University of Bahia, carriers of hepatitis C with biopsy reports available to assess the presence of alcoholic steatohepatitis proven by recording the consumption of grams of alcohol, considered an alcoholic being a man, who consumed more than 30 g per day and being woman more than 20g a day. The variables used were based on histological, epidemiological and clinical criteria applied to these patients. Results: the total sample of patients with hepatitis C analyzed was (n=335), with n=100 individuals considered to have high alcohol intake, and 28.9% of the cases in the sample. The presence of hepatic steatosis without steatohepatitis was in 34 individuals (10.15%), and cases of steatohepatitis appear in a total of n=30 individuals (8.96%).The high viral load of patients, with >800,000 as reference, was n=102, with 30.4% of cases of HCV. Conclusion: it was observed, in the study population, 43% of HCV carriers with excessive alcohol use, 8.96% had steatohepatitis and 10.15% steatosis. Furthermore, it was found that more than half of these patients (56.6%) had a moderate degree of fibrosis and 53.3% had mild necroinflammatory activity. The most common comorbidity observed was systemic arterial hypertension (SAH), in 40% of patients.

HISTOPATHOLOGICAL, CLINICAL AND EPIDEMIOLOGICAL FEATURES OF HEPATOPORTAL SCLEROSIS IN A REFERRAL CENTER FOR LIVER DISEASE IN NORTHEASTERN BRAZIL.

BACKGROUND: Hepatoportal sclerosis HPS or obliterative portal venopathy (OPV), one of the differential diagnoses for non-cirrohtic portal hypertension, is characterized by the disappearance of the portal branches, portal and septal fibrosis, perisinusoidal fibrosis and regenerative nodular hyperplasia (RNH). It is a spectral disease that may progress to severe portal hypertension. Its etiopathogenesis is still little understood, especially in Brazil, it has been probably misdiagnosed due to its histopatological similarities with the hepatosplenic form of schistosomiasis. OBJECTIVE: To analyze the profile of patients with HPS in Northeastern Brazil and to demonstrate the pathological characteristics of HPS. METHODS: We retrospectively analyzed cases of OPV in liver biopsies and explants from a referral center for liver in Bahia - Brazil. The qualitative and quantitative analysis of the portal tracts and liver parenchyma was made so that comparisons could be done among the HPS findings of our population and the findings described by other authors. RESULTS: From the 62 patients identified with HPS, 42% were male, while 58% were female. The average age at diagnosis was 48.3 years. From this group, we analyzed the liver biopsy of 10 patients whose diagnosis of schistosomiasis could be ruled out. From these 100% (10/10) presented dense portal fibrosis and portal venous obliteration. Liver parenchymal atrophy was present in 60% (6/10) of the patients, sinusoidal dilation was present in 30% (3/10), the presence of portal septa occurred in 50% (5/10) and dense portal fibrosis in all patients analyzed. Nodular regenerative hyperplasia was found in 30% (3/10) of the patients. CONCLUSION: HPS seems to be neglected and misdiagnosed in Brazil, due to its similarities with schistossomiasis. In our study dense portal fibrosis, obliteration of the portal vein branches, parenchymal atrophy, sinusoidal dilatation and parenchymal nodular hyperplasia were the main histopathological findings and were similar to that described in other countries.

Estudo das prevalências de distúrbios metabólicos em pacientes obesos e em portadores de hepatite C / Study of prevalence of metabolic disorders in obese patients and in patients with hepatitis C

Introdução: a infecção crônica pelo vírus da hepatite C (HCV) e a obesidade podem induzir esteatose hepática e diabetes mellitus (DM). Objetivo: avaliar a prevalência de obesidade e de distúrbios metabólicos em pacientes com HCV; estudar a prevalência de HCV e os distúrbios metabólicos em pacientes obesos. Comparar o perfil glicêmico entre os grupos. Metodologia: estudo analítico, com pacientes acompanhados nos ambulatórios de Hepatite C e Obesidade. Variáveis analisadas: glicemia, hemoglobina glicada (A1C), esteatose hepática, HCV, estágio de fibrose hepática e dados sociodemográficos. Resultados: no ambulatório de obesidade 45 pacientes foram avaliados, dos quais 6,7% tinham hepatite C, 40% DM e 61-73% esteatose hepática. As médias das enzimas hepáticas (U/L) foram: AST 22,9; ALT 25,2; FAL 146,5 e GGT 63. Nos obesos com DM, 72,2% apresentavam A1C < 7%. A segunda amostra continha 159 portadores de HCV do ambulatório de hepatologia: 17,9% tinham obesidade, 18,9% DM e 27% esteatose hepática. As médias das enzimas hepáticas (U/L) consistiram em: AST 70,5; ALT 90,6; FAL 108,5 e GGT 131,7. Entre os diabéticos com HCV, 52% não apresentavam A1C < 7%. Conclusão: foi encontrada alta prevalência de hepatite C em pacientes com obesidade (6,7%) quando comparados com a população de Salvador (1,5-1,8%). Os distúrbios metabólicos foram mais frequentes entre obesos, porém os diabéticos com obesidade revelaram A1C menores do que os diabéticos com HCV, sugerindo, neste estudo, que pode existir interferência viral no controle glicídico. A esteatose hepática foi mais prevalente entre obesos.

Introduction: Hepatitis C virus infection (HCV) and Obesity can to induce hepatic steatosis and diabetes mellitus (DM). Objectives: to evaluate the prevalence of obesity and metabolic disorders in HCV viremic patients. To study the prevalence of hepatitis C and metabolic disorders in patients with obesity. To compare glycemic profile between the groups. Methods: analytical study, with patients followed up at hepatitis C and Obesity outpatient clinics patients. Variables studied: blood glucose, glycated hemoglobin (A1C), hepatic steatosis, HCV, hepatic fibrosis stage and sociodemographic data. Results: in Obesity clinic sample 45 patients were evaluated, 6,7% was hepatitis C, 40% DM and 61% -73% hepatic steatosis. Mean of liver enzymes levels (U/L) were: AST 22.9; ALT 25.2; FAL 146.5 and GGT 63. In obese with DM, 72.2% of them were able to maintain A1C < 7%. The second sample contained 159 HCV carriers at the hepatology clinic, 17,9% was Obesity, 18,9% DM and 27% hepatic steatosis. Averages of serum liver enzymes level (U/ L) were: AST 70.5; ALT 90.6; FAL 108.5 and GGT 131.7. Among diabetics with HCV, 52% are unable to maintain A1C < 7%. Conclusions: found high prevalence of hepatitis C in patients with obesity (6.7%) when compared to the population of Salvador (1.5%-1.8%). Metabolic disorders were more frequent in the obese group, but diabetics with obesity have lower A1C values than diabetics with HCV, suggesting, in this study, that there may be a viral interference with glycid control. Liver steatosis is more prevalent among obese people

Características histopatológicas, clínicas e epidemiológicas da esclerose hepatoportal em um centro de referência para doenças do fígado no Nordeste do Brasil / Histopathological, clinical and epidemiological features of hepatoportal sclerosis in a referral center for liver disease in northeastern brazil

ABSTRACT BACKGROUND: Hepatoportal sclerosis HPS or obliterative portal venopathy (OPV), one of the differential diagnoses for non-cirrohtic portal hypertension, is characterized by the disappearance of the portal branches, portal and septal fibrosis, perisinusoidal fibrosis and regenerative nodular hyperplasia (RNH). It is a spectral disease that may progress to severe portal hypertension. Its etiopathogenesis is still little understood, especially in Brazil, it has been probably misdiagnosed due to its histopatological similarities with the hepatosplenic form of schistosomiasis. OBJECTIVE: To analyze the profile of patients with HPS in Northeastern Brazil and to demonstrate the pathological characteristics of HPS. METHODS: We retrospectively analyzed cases of OPV in liver biopsies and explants from a referral center for liver in Bahia - Brazil. The qualitative and quantitative analysis of the portal tracts and liver parenchyma was made so that comparisons could be done among the HPS findings of our population and the findings described by other authors. RESULTS: From the 62 patients identified with HPS, 42% were male, while 58% were female. The average age at diagnosis was 48.3 years. From this group, we analyzed the liver biopsy of 10 patients whose diagnosis of schistosomiasis could be ruled out. From these 100% (10/10) presented dense portal fibrosis and portal venous obliteration. Liver parenchymal atrophy was present in 60% (6/10) of the patients, sinusoidal dilation was present in 30% (3/10), the presence of portal septa occurred in 50% (5/10) and dense portal fibrosis in all patients analyzed. Nodular regenerative hyperplasia was found in 30% (3/10) of the patients. CONCLUSION: HPS seems to be neglected and misdiagnosed in Brazil, due to its similarities with schistossomiasis. In our study dense portal fibrosis, obliteration of the portal vein branches, parenchymal atrophy, sinusoidal dilatation and parenchymal nodular hyperplasia were the main histopathological findings and were similar to that described in other countries.

RESUMO CONTEXTO: Esclerose hepatoportal EHP ou venopatia portal obliterativa VPO, um dos diagnósticos diferenciais para a hipertensão portal não cirrótica, é caracterizada pelo desaparecimento dos ramos portais, fibrose portal e septal, fibrose sinusoidal e hiperplasia nodular regenerativa HNR. A EHP é um doença espectral, que pode progredir para hipertensão portal severa. Sua etiopatologia é ainda pouco compreendida, especialmente no Brasil, onde ela é provavelmente subdiagnoticada devido as suas similaridades com a forma hepatoesplênica da esquistossomose. OBJETIVO: Analizar o perfil dos pacientes com EHP no Nordeste do Brasil, e demontrar as características patológicas da EHP. MÉTODOS: Analisamos restrospectivamente os casos de VPO em biópsias hepáticas e explantes de um centro de referência em fígado na Bahia, Brasil. A análise qualiquantitativa dos tratos portais e parênquima hepático foi realizada, permitindo a comparação entre os nossos paciente e os achados descritos por outros autores. RESULTADOS: Entre os 62 paciente identificados com EHP, 42% era do sexo masculino, 58% era do sexo feminino. A média de idade no diagnótico foi 48,3 anos. Desse grupo, analizamos a biópsia hepática de 10 pacientes nos quais o diagnóstico de esquistossomose pode ser excluído. Desses pacientes, 100% 10/10 se apresentou com fibrose portal densa e obliteração venosa portal. Atrofia do perênquima hepático estava presente em 60% 6/10 dos pacientes, dilatação sinusiodal em 30% 3/10 a presença de septos portais ocorreu em 50% 5/10 e fibrose portal densa foi achada em todos os pacientes. Hiperplasia nodular regenerativa foi encontrada em 30% dos pacientes. CONCLUSÃO: A EHP parece ser negligenciada e subdiagnosticada no Brasil, devido as suas similaridades com esquistossomose. Em nosso estudo, fibrose portal densa, obliteração dos ramos da veia porta, atrofia do parênquima, dilatação sinusoidal e hiperplasia nodular do parênquima foram os principais achados histopatológicos e foram semelhantes aos descritos em outros países.

Comparison of different prognostic scores for patients with cirrhosis hospitalized with SARS-CoV-2 infection.

INTRODUCTION AND OBJECTIVES: Viral infections have been described to increase the risk of decompensation in patients with cirrhosis. We aimed to determine the effect of SARS-CoV-2 infection on outcome of hospitalized patients with cirrhosis and to compare the performance of different prognostic models for predicting mortality. PATIENTS: We performed a prospective cohort study including 2211 hospitalized patients with confirmed SARS-CoV-2 infection from April 15, 2020 through October 1, 2020 in 38 Hospitals from 11 Latin American countries. We registered clinical and laboratory parameters of patients with and without cirrhosis. All patients were followed until discharge or death. We evaluated the prognostic performance of different scoring systems to predict mortality in patients with cirrhosis using ROC curves. RESULTS: Overall, 4.6% (CI 3.7-5.6) subjects had cirrhosis (n = 96). Baseline Child-Turcotte-Pugh (CTP) class was assessed: CTP-A (23%), CTP-B (45%) and CTP-C (32%); median MELD-Na score was 19 (IQR 14-25). Mortality was 47% in patients with cirrhosis and 16% in patients without cirrhosis (P < .0001). Cirrhosis was independently associated with death [OR 3.1 (CI 1.9-4.8); P < .0001], adjusted by age, gender, and body mass index >30. The areas under the ROC curves for performance evaluation in predicting 28-days mortality for Chronic Liver Failure Consortium (CLIF-C), North American Consortium for the Study of End-Stage Liver Disease (NACSELD), CTP score and MELD-Na were 0.85, 0.75, 0.69, 0.67; respectively (P < .0001). CONCLUSIONS: SARS-CoV-2 infection is associated with elevated mortality in patients with cirrhosis. CLIF-C had better performance in predicting mortality than NACSELD, CTP and MELD-Na in patients with cirrhosis and SARS-CoV-2 infection. Clinicaltrials.gov:NCT04358380.

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 < .0001). After excluding patients with history of chronic liver disease, abnormal liver tests on admission were independently associated with death [OR 1.5 (CI 1.1-2.0); P = 0.01], and severe COVID-19 (2.6 [2.0-3.3], P < .0001), both adjusted by age, gender, diabetes, pneumonia and body mass index >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. CLINICALTRIALS.GOV: NCT04358380.

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).

Disease Progression in Patients With Hepatitis C Virus Infection Treated With Direct-Acting Antiviral Agents.

BACKGROUND & AIMS: Little is known about how a sustained virologic response (SVR) to treatment of hepatitis C virus infection with direct-acting antivirals (DAAs) affects patient mortality and development of new liver-related events. We aimed to evaluate the incidence of disease progression in patients treated with DAAs. METHODS: We performed a prospective multicenter cohort study of 1760 patients who received DAA treatment at 23 hospitals in Latin America, from May 1, 2016, through November 21, 2019. We excluded patients with a history of liver decompensation, hepatocellular carcinoma (HCC), or solid-organ transplantation. Disease progression after initiation of DAA therapy included any of the following new events: liver decompensation, HCC, liver transplantation, or death. Evaluation of variables associated with the primary outcome was conducted using a time-dependent Cox proportional hazards models. RESULTS: During a median follow-up period of 26.2 months (interquartile range, 15.3-37.5 mo), the overall cumulative incidence of disease progression was 4.1% (95% CI, 3.2%-5.1%), and after SVR assessment was 3.6% (95% CI, 2.7%-4.7%). Baseline variables associated with disease progression were advanced liver fibrosis (hazard ratio [HR], 3.4; 95% CI, 1.2-9.6), clinically significant portal hypertension (HR, 2.1; 95% CI, 1.2-3.8), and level of albumin less than 3.5 mg/dL (HR, 4.1; 95% CI, 2.3-7.6), adjusted for SVR achievement as a time covariable. Attaining an SVR reduced the risk of liver decompensation (HR, 0.3; 95% CI, 0.1-0.8; P = .016) and de novo HCC (HR, 0.2; 95% CI, 0.1%-0.8%; P = .02) in the overall cohort. CONCLUSIONS: Treatment of hepatitis C virus infection with DAAs significantly reduces the risk of new liver-related complications and should be offered to all patients, regardless of disease stage. Clinicaltrials.gov: NCT03775798.

Drug induced liver damage in a universitary hospital / Lesão hepática induzida por drogas em um hospital universitário

Introdução: lesão hepática induzida por drogas (DILI) é responsável por um amplo espectro de lesão hepática. Clinicamente, esses eventos são apresentados de várias formas e, para alcançar um diagnóstico diferente, outras causas de lesões devem ser excluídas. Objetivo: identificar e caracterizar casos de hepatotoxicidade induzida por medicamentos, fitoterápicos e suplementos alimentares em Hospital Universitário no Brasil. Metodologia: estudo observacional, retrospectivo. Os dados foram coletados em prontuários do Hospital Universitário, entre agosto de 2009, em agosto de 2014. A causalidade das reações medicamentosas suspeitas foi avaliada pelo Conselho de Organizações Internacionais de Ciências Médicas (CIOMS). Resultados: foram selecionados 30 casos suspeitos, 50% do sexo feminino e média de 39 anos. As classes terapêuticas mais comuns foram: anti-infecciosos; agentes antineoplásicos; drogas do sistema nervoso central, esteroides anabolizantes e suplementos herbáceos e dietéticos (HDS). Lesão colestática ou mista foi observada em 73% desses casos; 60% eram altamente prováveis, de acordo com o CIOMS. Conclusão: DILI é causada por uma grande variedade de drogas, suplementos dietéticos e suplementos dietéticos. Anti-infecciosos e quimioterapia foram responsáveis por grande parte da resposta.

Background: drug Induced Liver Injury (DILI) is responsible for wide spectrum of liver injury. Clinically, these events are presented in various forms and for reaching a different diagnosis other injury causes must be excluded. Aim: identify and characterize cases of hepatotoxicity induced by drugs, herbal and dietary supplements in University Hospital in Brazil. Methodology: observational and retrospective study. Was collected in records of University Hospital, between August 2009 at August 2014. The causality of the drug reactions suspected were evaluated Council for International Organizations of Medical Sciences (CIOMS). Results: we selected 30 suspected cases, 50% was female and average was 39 years. the therapeutic classes most common was: anti-infectives; antineoplastic agents; central nervous system drugs, anabolic steroid and herbal and dietary supplements (HDS). Cholestatic or mixed injury was observed in 73% these cases; 60% were highly probable, according to CIOMS. Conclusion: DILI is caused by a wide variety of drugs, dietary supplements and dietary supplements. Anti-infectives and chemotherapy were responsible for much of the response.

Seroepidemiology of hepatitis B in individuals born between 1945-1985 on a Brazilian regional metropolis / Soroepidemiologia da hepatite B em indivíduos nascidos entre 1945-1985 em uma metrópole regional Brasileira

Background: hepatitis B prevalence can be influenced by social/cultural behavior and the Baby Boomer (BB) generation(1945-1964) may have been more susceptible to this infection. Objectives: We investigated the seroprevalence of markers for HBV infection and vaccination and its association with main risk factors. Methodology: a random sample of individuals aged 30-70 years old in a public clinical laboratory from a metropolitan area of Bahia/Brazil were tested for HBsAg/Total Anti-HBc/Anti-HBs/Anti-HBc-IgM and a socio-demographic questionnaire was applied. Results: of the650 participants, 349 were 51-70 yo (BB) and 301 were non-BB. The prevalences were HBsAg (2.3%), Total Anti-HBc (17.1%) and Anti-HBs (27.4%). Anti-HBcIgM (2.7%) was performed in 112 participants sera who had contact/infection with HBV. The laboratory profiles were characterized as susceptibility (68%), vaccine response (14.8%) and contact/infection with HBV (17.2%). BB participants were more susceptible and less vaccinated than non-BB. The higher frequency of contact/infection status was observed in the BB generation. Statistically significant differences were found for the contact/infection status in males(50,9%) illicit drug use (11,6%), syringe/needle sharing (7,1%), and blood transfusion (10,7%). Non-BB with contact/ infection profile reported more tattoo/piercing and BB reported higher use of glass syringes. Conclusion: the majority of the study population was susceptible to infection but participants older than 50 years showed both, a higher frequency of this profile and also a higher frequency of contact/infection status, thus suggesting the need for greater health care attention for this age group.

Introdução: a prevalência de hepatite B pode ser influenciada pelo comportamento sociocultural e a geração Baby Boomer (BB) (1945-1964) pode ter sido mais suscetível a esta infecção. Objetivos: Investigar a soroprevalência de marcadores para a infecção pelo VHB e resposta vacinal e associação com fatores de risco. Metodologia: soro de indivíduos de 30 a 70 anos randomicamente selecionados em um laboratório publico de análises clínicas na área metropolitana do Brasil foram testados para AgHBs/ Anti-HBc Total /Anti-HBs/Anti-HBc-IgM. Todos responderam questionário sociodemográfico contendo perguntas sobre fatores de risco para hepatite B. Resultados: dos 650 participantes, 349 eram BB (51-70 anos) e 301 eram não-BB (30-50 anos). As prevalências estimadas foram: HBsAg (2,3%), Anti-HBs (27,4%). Entre os Anti-HBc Total (17,1%) apenas 2,7% foram Anti-HBc IgM. Os perfis laboratoriais foram caracterizados como suscetibilidade (68%), resposta vacinal (14,8%) e contato com VHB (17,2%). Na distribuição por idade, os BB foram mais susceptíveis, menos vacinados e apresentaram maior frequência de contato/infecção que os não-BB. Diferenças estatisticamente significantes foram encontradas no status contato/infecção e as seguintes variáveis: sexo masculino, uso de drogas ilícitas, compartilhamento de seringas de vidro/agulhas e transfusão de sangue. Não-BB com status contato/infecção relataram ter mais tatuagem/piercing e BB relataram maior uso de seringas de vidro. Conclusão: a maioria da população estudada era suscetível ao VHB, mas os participantes com mais de 50 anos apresentaram tanto uma maior frequência desse status quanto do status contato/ infecção, sugerindo a necessidade de maior atenção à saúde para indivíduos desta faixa etária.

IgG1 and IgG4 antibodies against Core and NS3 antigens of hepatitis C virus.

INTRODUCTION: IgG subclasses involved in the immune response to hepatitis C virus (HCV) antigens have been rarely studied. We investigated the immune response mediated by IgG1 and IgG4 antibodies against the recombinant core and NS3 antigens in patients with chronic hepatitis C. METHODS: Sixty patients infected with HCV genotype 1 without antiviral treatment and 60 healthy subjects participated in the study. Serum levels of alanine aminotransferase, HCV viremia, and the presence of cryoglobulinemia and liver fibrosis were determined. We investigated the serum IgG1 and IgG4 antibodies against recombinant HCV core and NS3 non-structural protein antigens using amplified indirect ELISA. RESULTS: Anti-core and anti-NS3 IgG1 antibodies were detected in 33/60 (55%) and 46/60 (77%) patients, respectively, whereas only two healthy control samples reacted with an antigen (NS3). Anti-core IgG4 antibodies were not detected in either group, while 30/60 (50%) patients had anti-NS3 IgG4 antibodies. Even though there were higher levels of anti-NS3 IgG4 antibodies in patients with low viremia (< 8 × 105 IU/mL), IgG1 and IgG4 antibody levels did not correlate with ALT levels, the presence of cryoglobulinemia, or degree of hepatic fibrosis. High production of anti-core and anti-NS3 IgG1 antibodies was observed in chronic hepatitis C patients. In contrast, IgG4 antibodies seemed to only be produced against the NS3 non-structural antigen and appeared to be involved in viremia control. CONCLUSIONS: IgG1 antibodies against structural and non-structural antigens can be detected in chronic hepatitis C, while IgG4 antibodies seem to be selectively stimulated by non-structural HCV proteins, such as the NS3 antigen.

Atherogenic cytokines and chemokines in chronic hepatitis C are not associated with the presence of cardiovascular diseases.

There appears to be an associative link between chronic hepatitis C (CHC) and cardiovascular diseases (CVDs). However, the exact nature of the relationship between CHC and CVDs has not been elucidated. We investigated the presence of CVDs and the clinical and laboratory alterations associated with these diseases in CHC patients. Twenty-six CHC patients, 35 individuals with atherosclerosis (Athero) and 27 healthy individuals were examined for risk factors for CVD, lipid profile, atherogenic risk indexes, and insulin resistance (IR). Cardiac biomarkers and the chemokines and cytokines involved in atherosclerosis were also evaluated. A higher prevalence of prior acute myocardial infarction was found in the Athero group. Most CHC patients were infected with the hepatitis C virus genotype 1 and exhibited either no hepatic fibrosis or a mild to moderate liver fibrosis. The apolipoprotein B/apolipoprotein A-I and triglyceride/high-density lipoprotein cholesterol ratios and C-reactive protein levels were lower in CHC patients than in the Athero group. Further, IR was elevated in the CHC group and associated with the waist circumference. High GDF-15 levels were observed in the CHC group, which were inversely correlated with APOB levels. Peripheral blood mononuclear cells from CHC patients produced more IFN-γ, TNF-α and IL-6 than CAD PBMC but the production of IL-10 and IL-1ß was similar. CHC and CAD groups presented similar levels of IL-8, MCP-1 and LAP-TGF-ß1. Increased IR, elevated levels of GDF-15, and high production of atherogenic cytokines can be observed in Brazilian CHC patients without association with diabetes and clinical manifestation of cardiovascular diseases.

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.

IgG1 and IgG4 antibodies against core and NS3 antigens of hepatitis C virus

Abstract INTRODUCTION: IgG subclasses involved in the immune response to hepatitis C virus (HCV) antigens have been rarely studied. We investigated the immune response mediated by IgG1 and IgG4 antibodies against the recombinant core and NS3 antigens in patients with chronic hepatitis C. METHODS: Sixty patients infected with HCV genotype 1 without antiviral treatment and 60 healthy subjects participated in the study. Serum levels of alanine aminotransferase, HCV viremia, and the presence of cryoglobulinemia and liver fibrosis were determined. We investigated the serum IgG1 and IgG4 antibodies against recombinant HCV core and NS3 non-structural protein antigens using amplified indirect ELISA. RESULTS: Anti-core and anti-NS3 IgG1 antibodies were detected in 33/60 (55%) and 46/60 (77%) patients, respectively, whereas only two healthy control samples reacted with an antigen (NS3). Anti-core IgG4 antibodies were not detected in either group, while 30/60 (50%) patients had anti-NS3 IgG4 antibodies. Even though there were higher levels of anti-NS3 IgG4 antibodies in patients with low viremia (< 8 × 105 IU/mL), IgG1 and IgG4 antibody levels did not correlate with ALT levels, the presence of cryoglobulinemia, or degree of hepatic fibrosis. High production of anti-core and anti-NS3 IgG1 antibodies was observed in chronic hepatitis C patients. In contrast, IgG4 antibodies seemed to only be produced against the NS3 non-structural antigen and appeared to be involved in viremia control. CONCLUSIONS: IgG1 antibodies against structural and non-structural antigens can be detected in chronic hepatitis C, while IgG4 antibodies seem to be selectively stimulated by non-structural HCV proteins, such as the NS3 antigen.

Adiponectin levels and insulin resistance among patients with chronic hepatitis C.

Chronic hepatitis C virus (HCV) infection is associated with insulin resistance (IR), rapid disease progression, and decreased virological response to antiviral treatment. In addition, obesity is a risk factor for chronic hepatitis C evolution and is associated with IR. As adiponectin is an adipokine that is associated with obesity and IR, this study aimed to investigate serum levels of adiponectin among patients with HCV infection and IR. Thirty-three patients with untreated HCV infection underwent testing of serum adiponectin levels (capture ELISA) and were compared to 30 healthy subjects with similar body mass indexes (BMI). Data were also obtained for several homeostatic model assessment (HOMA) indexes: HOMA-IR, HOMA-ß, and HOMA-adiponectin. Patients with HCV infection had higher adiponectin levels, which predominantly were observed among women. Hyperadiponectinemia was not associated with high BMI. Patients with HCV infection had higher HOMA-IR and HOMA-ß values, although no difference was observed for HOMA-adiponectin. Patients with HCV infection and overweight/obese status had higher HOMA-IR values, although no association was observed for adiponectin levels. Hyperadiponectinemia and IR were not influenced by HCV load or liver fibrosis. The predictors of IR were BMI, glycemia, and serum levels of insulin and non-high-density lipoprotein cholesterol, but not adiponectin levels. Thus, patients with chronic hepatitis C have significant metabolic alterations (hyperadiponectinemia and high HOMA-IR values) that are independent of HCV viremia and liver fibrosis. Among these patients, HOMA-IR but not HOMA-adiponectin was appropriate for diagnosing IR.

Immune response of Th17-associated cytokines by peripheral blood mononuclear cells from patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) chronic infection causes severe cellular immune dysfunction. Here, we investigated the production of Th17-associated cytokines by peripheral blood mononuclear cells (PBMCs) of untreated patients with HCV, patients presenting an early virologic response (EVR) after 12weeks of treatment with interferon-α plus ribavirin with or without HCV protease inhibitors, and patients who were nonresponders to HCV therapy. PBMCs were stimulated with HCV core and nonstructural antigens, and the production of Th17-associated cytokines was measured with a Milliplex MAP immunoassay. Core-stimulated PBMCs from both untreated and nonresponder patients produced interleukin (IL)-17A, and vigorous production of IL-17A in response to NS3 antigen was only verified in the untreated group. Nonresponder patients also produced IL-17F after core antigen stimulation. IL-21 production was unaltered in the three groups of patients, whereas IL-17E and IL-22 were not detected. The production of Th17 cytokines by cells from patients showing an EVR was insignificant. IL-17A and IL-17F levels were not correlated with alanine aminotransferase levels or viremia. However, advanced fibrosis was associated with higher IL-17A production in T0 cells stimulated with core antigen. Untreated patients with HCV and patients who were nonresponders to antiviral treatment differed in their PBMC immune responses of Th17-associated cytokines. The early virological response to antiviral treatment dramatically decreased Th17 immune responses to HCV antigens.

Genotyping of HBV and tracking of resistance mutations in treatment-naïve patients with chronic hepatitis B.

BACKGROUND AND AIMS: Resistance mutation analogs to nucleos(t)ides have been described in treatment-naïve patients with chronic hepatitis B (CHB), with clinical implications. The aim of this study was to investigate primary resistance mutations and genotypes circulating in patients naïve to chronic hepatitis B, in the Northern and Northeastern regions of Brazil. METHODS: We conducted a study of resistance mutations and genotypic characterization of hepatitis B virus (HBV) in 189 treatment-naïve patients chronically infected with HBV. RESULTS: Drug resistance-associated mutations located in the RT domain of the P gene (rtHBV) were found in 6% of the treatment-naïve patients from the Northeastern Region. The mutations were rtA194T, rtL180M + rtM204V, rtS202I, rtM204I, and rtA181S. No patient in the Northern Region had the resistance mutation. In the gene S region, the frequency of vaccine escape mutations was 2.4% in the Northeastern Region and 8.6% in the Northern Region. CONCLUSION: This information before the start of treatment may contribute to clinical decision making, reducing treatment failure and the risk of progression to cirrhosis and hepatocellular carcinoma for CHB.

Mutations associated with drug resistance and prevalence of vaccine escape mutations in patients with chronic hepatitis B infection.

The Brazilian public health system (SUS) has provided antiviral drugs for chronic hepatitis B treatment for over 10 years, but a system for monitoring for drug-related resistance mutations is not available. Determine the presence of HBV mutations associated with resistance to nucleos(t)ide analogs among 81 patients with chronic HBV infection in Salvador-BA-Brazil. HBV-DNA was PCR amplified with primers deduced from the rt domain at the HBV P gene, the sequence extended 1032 bp (from amino acid 1 to 344-rt domain). Those sequences were submitted to the HBV drug resistance database to retrieve each mutation according to the genotype. HBV genotype A1 (85.2%) was the most prevalent, followed by genotype A2 (4.9%), F (6.2%), and C1, D2, and D4 (1.2% each). Six patients (7%) exhibited resistance mutations to LAM, ETV, and TDF: two with patterns L180M + M204V and four with other different patterns: L80I + L180M + M204I; L80V + L180M + M204V; M204I; A194T. All of these mutations were present in patients with genotype A (four A1 and two A2). In addition, four mutations in gene S (three cases with the sI195M mutation and one with the W196L mutation), were detected, corresponding to a rate of 6% of vaccine escape mutations. Althougth the small sample size, an association was found between the occurrence of HBV resistance mutations and HBeAg positivity, co-infection with HIV and a history of treatment for HBV and/or HIV.

Hepatoportal sclerosis related to the use of herbals and nutritional supplements. Causality or coincidence?

 Introduction and aim. Non-cirrhotic idiopathic portal hypertension (NCIPH), also known as hepatoportal sclerosis (HPS) is a disease of uncertain etiology. However, various pathophysiological mechanisms has been postulated, including chronic or recurrent infections and exposure to drugs or toxins. In this context, it appears to be of multifactorial etiology or resulting from a portal vascular endothelium aggression. It is important to consider whether the use of dietary supplements and herbs can trigger or contribute to the occurance of HPS. We report a possible association of HPS with the consumption of herbals and / or dietary supplements. MATERIAL AND METHODS: We describe two cases of HPS in patients without known etiology causes associated with this disease. RESULTS: Both patients were females who were diagnosed with HPS following the consumption of Herbalife® products and putative anorexigenic agents in the form herbals infusions. Image-based analysis and the assessment of the histopathological alterations found in the livers confirmed the diagnosis. The histopatological analysis of liver samples from both patients showed portal tracts enlarged by fibrosis with disappearance or reduction in the diameter of the portal vein branches. In many portal tracts, portal veins branches were replaced by aberrant thin-walled fendiforme vessels. The bile ducts and branches of the hepatic artery show normal aspects. CONCLUSION: After the exclusion of other etiologic factors and a comprehensive analysis of clinical history, consumption of Herbalife® products and anorexigenic agents was pointed-out as a puttative predisposing factor for the development of the disease.