Evaluation of drug-induced liver injury as etiology for acute liver failure in Brazil.

INTRODUCTION AND OBJECTIVES: Little is known about the etiology of acute liver failure (ALF) in Latin America. The objective of this paper is to investigate the main etiologies of ALF in Brazil, including Drug Induced Liver Injury (DILI) using stringent causality criteria. PATIENTS OR MATERIAL AND METHODS: All the cases of individuals who underwent liver transplantation (LT) in 12 centers in Brazil for ALF were reviewed. When DILI was stated as the cause of ALF, causality criteria were applied on site by the main investigator in order to rule out other etiologies. RESULTS: 325 individuals had ALF mainly for unknown reasons (34%), DILI (27%) and AIH (18%). Reassessment of the 89 cases of DILI, using stringent causality criteria, revealed that in only 42 subjects could DILI be confirmed as the cause of ALF. Acetaminophen (APAP) toxicity (n = 3) or DILI due to herbal and dietary supplements (HDS) (n = 2) were not commonly observed. CONCLUSIONS: Undetermined etiology and DILI are the main causes of ALF in Brazil. However, APAP toxicity and DILI due to HDS are mostly uncommon.

CURING HEPATITIS C WITH THE NEW DIRECT ACTING ANTIVIRALS DID NOT IMPROVE INSULIN RESISTANCE AFTER ONE YEAR.

BACKGROUND: Chronic hepatitis C still figures as an important cause of morbidity among the Brazilian population, and is closely associated with metabolic disturbances, including insulin resistance (IR), which can be evaluated by the Homeostatic Model Assessment (HOMA-IR). IR may entail lower sustained virologic response (SVR) on certain therapeutic regimens and faster progression to advanced hepatic fibrosis. With the arrival of the direct acting agents (DAA) in hepatitis C treatment, there is an increased need in observing the impact in patients' IR profile while using such therapies. OBJECTIVE: - 1) To compare the results of HOMA-IR in patients affected by chronic hepatitis C before treatment with DAA and 12 months after finishing it with SVR. 2) To evaluate the evolution of weight after curing chronic hepatitis C. METHODS: We included patients older than 18 from two tertiary care in Curitiba - PR, of both sexes, with chronic hepatitis C, treated with DAA, from July 2015 to September 2017. We also evaluated the patients' levels of fasting insulin, fasting glucose and glycated hemoglobin before starting treatment and 12 months after finishing it. We also used epidemiologic data, such as age, sex, hepatic fibrosis degree, body mass index, abdominal circumference, viral genotype and the presence of diabetes mellitus before and after treatment. IR was assessed before and after treatment and calculated by the HOMA-IR score. Insulin resistance was defined by a HOMA-IR greater than 2.5. We excluded patients who lost follow-up, those who did not achieve SRV and those who did not have a laboratory profile. The results of quantitative variables were described by means, medians, and standard deviations. P values <0.05 indicated statistical significance. RESULTS: We included 75 patients in this study, with a mean age of 55.2 years and 60% of males. Forty-three patients had advanced fibrosis. Twenty one (28%) had a previous diabetes mellitus diagnosis. We identified 31 (41.3%) patients with IR before antiviral treatment, and this number increased to 39 (52%) after 12 months of finishing treatment, according to HOMA-IR. There was no statistic difference between insulin, glucose and HOMA-IR measurements before and after curing hepatitis C. We observed a weight gain in patients shortly after curing hepatitis C, but this did not persist at the end of the study. We also had no significant difference in IR prevalence when viral genotype was concerned. CONCLUSION: In this study, there was no statistically significant difference between HOMA-IR results in patients before and 12 months after treatment for hepatitis C. Even though patients gained weight after the cure, this was not statistically significant after a year (P=0.131).

A cura da hepatite C crônica com os novos antivirais de ação direta não resultou em melhora da resistência insulínica a curto prazo / Curing hepatitis c with the new direct acting antivirals did not improve insulin resistance after one year

ABSTRACT BACKGROUND: Chronic hepatitis C still figures as an important cause of morbidity among the Brazilian population, and is closely associated with metabolic disturbances, including insulin resistance (IR), which can be evaluated by the Homeostatic Model Assessment (HOMA-IR). IR may entail lower sustained virologic response (SVR) on certain therapeutic regimens and faster progression to advanced hepatic fibrosis. With the arrival of the direct acting agents (DAA) in hepatitis C treatment, there is an increased need in observing the impact in patients' IR profile while using such therapies. OBJECTIVE: - 1) To compare the results of HOMA-IR in patients affected by chronic hepatitis C before treatment with DAA and 12 months after finishing it with SVR. 2) To evaluate the evolution of weight after curing chronic hepatitis C. METHODS: We included patients older than 18 from two tertiary care in Curitiba - PR, of both sexes, with chronic hepatitis C, treated with DAA, from July 2015 to September 2017. We also evaluated the patients' levels of fasting insulin, fasting glucose and glycated hemoglobin before starting treatment and 12 months after finishing it. We also used epidemiologic data, such as age, sex, hepatic fibrosis degree, body mass index, abdominal circumference, viral genotype and the presence of diabetes mellitus before and after treatment. IR was assessed before and after treatment and calculated by the HOMA-IR score. Insulin resistance was defined by a HOMA-IR greater than 2.5. We excluded patients who lost follow-up, those who did not achieve SRV and those who did not have a laboratory profile. The results of quantitative variables were described by means, medians, and standard deviations. P values <0.05 indicated statistical significance. RESULTS: We included 75 patients in this study, with a mean age of 55.2 years and 60% of males. Forty-three patients had advanced fibrosis. Twenty one (28%) had a previous diabetes mellitus diagnosis. We identified 31 (41.3%) patients with IR before antiviral treatment, and this number increased to 39 (52%) after 12 months of finishing treatment, according to HOMA-IR. There was no statistic difference between insulin, glucose and HOMA-IR measurements before and after curing hepatitis C. We observed a weight gain in patients shortly after curing hepatitis C, but this did not persist at the end of the study. We also had no significant difference in IR prevalence when viral genotype was concerned. CONCLUSION: In this study, there was no statistically significant difference between HOMA-IR results in patients before and 12 months after treatment for hepatitis C. Even though patients gained weight after the cure, this was not statistically significant after a year (P=0.131).

RESUMO CONTEXTO: A hepatite C crônica ainda figura como importante causa de morbimortalidade na população brasileira, e está associada a alterações metabólicas, incluindo a resistência insulínica (RI), que pode ser avaliada pelo índice HOMA-IR. A RI pode inclusive implicar em menores taxas de reposta virológica sustentada (RVS) em certos regimes terapêuticos e à uma mais rápida progressão para fibrose hepática avançada. Com o advento dos novos antivirais de ação direta (DAA) oferecidos para hepatite C, há crescente necessidade de observar o impacto dos mesmos no perfil de RI em pacientes submetidos à tais terapêuticas. OBJETIVO: - 1) Comparar os valores do HOMA-IR dos pacientes com hepatite C crônica antes do tratamento com os DAAS com os valores deste índice após 12 meses do término do tratamento com RVS. 2) Avaliar evolução do peso após obtenção da cura da hepatite C crônica. MÉTODOS: Foram incluídos pacientes maiores de 18 anos de dois serviços terciários de Curitiba - PR, de ambos os sexos, portadores de hepatite C crônica, com tratamento com os antivirais de ação direta, no período de julho de 2015 a setembro de 2017. Tais pacientes também foram submetidos a dosagem dos níveis de insulina de jejum, glicemia de jejum e hemoglobina glicada antes de iniciar o tratamento da hepatite C e até 12 meses após o término. Também foram utilizados dados como idade, sexo, grau de fibrose hepática, índice de massa corporal, circunferência abdominal, genótipo viral e presença de diabetes mellitus antes e depois do tratamento. A RI foi estimada antes e após 12 meses do término do tratamento e calculada pelo HOMA-IR. Os resultados de variáveis quantitativas foram descritos por médias, medianas, valores mínimos, valores máximos e desvios padrões. Valores de P<0,05 indicaram significância estatística. RESULTADOS: Foram incluídos 75 pacientes no estudo com média de idade de 55,2 anos, sendo 60% do sexo masculino. Destes pacientes, 43 tinham fibrose avançada. Vinte e um (28%) pacientes tinham o diagnóstico de diabetes mellitus. A RI foi observada em 31 (41,3%) pacientes antes do tratamento antiviral, sendo que este número aumentou para 39 (52%) de acordo com a dosagem do HOMA-IR 12 meses após o término do tratamento. Não houve diferença estatística entre os valores de insulina, glicemia e HOMA-IR antes e após a cura da hepatite. Houve um ganho de peso inicial após a obtenção da cura da hepatite C, mas que não se manteve ao final do estudo. CONCLUSÃO: Não foi vista diferença estatística significante entre os valores do HOMA-IR apresentados pelos pacientes portadores de hepatite C crônica antes do tratamento e 12 meses após a cura da doença. Embora tenha ocorrido ganho de peso após obtenção da cura da doença, este não se deu de forma estatisticamente significativa (P=0,131) ao final de um ano.

EVALUATION OF PROGRESSION OF HEPATIC FIBROSIS IN A GROUP OF PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE ACCOMPANIED FOR 10 YEARS.

BACKGROUND: Non-alcoholic fatty liver disease has been progressively diagnosed in the general population as a consequence of the increased prevalence of obesity and type 2 diabetes mellitus, its main risk factors. It is characterized by accumulation of fat in the hepatocytes associated with lobular inflammation and balonization, which can lead to cirrhosis and hepatocarcinoma. Thus, a characterization and follow-up of a progression of the fibrosis level of these patients becomes important, being that the transient hepatic elastography is a reliable method for this evaluation with a measure of the kapa index. OBJECTIVE: To evaluate the progression of hepatic fibrosis through elastography in patients with non-alcoholic fatty liver disease. METHODS: Patients who had previously performed hepatic biopsy and noninvasive scores for non-alcoholic steatohepatitis (NASH) and fibrosis were included in the study. These same subjects were then submitted to current clinical evaluation, laboratory and liver elastography tests, defining the level of liver fibrosis, about 10 years after the first evaluation. RESULTS: Data were analyzed for 66 patients previously submitted to liver biopsy. Of these, 16 were not found, four could not participate because they were debilitated due to hepatic cirrhosis, two had died from an automobile accident and five from complications of cirrhosis of the liver. Therefore, of the 50 patients with a known history, 9 (18%) had died of cirrhosis or were unable to attend the examination because of their liver disease. The remaining population was predominantly female (61.5%), mean age of 63 years, being overweight, dyslipidemia (76.9%), disorders of the glycemic profile (76.9%), and metabolic syndrome (82.1%). Of the 39 cases evaluated, 35% had the same degree of fibrosis at the initial evaluation (biopsy) and at the current evaluation (elastography), 33% had an increase in the degree of fibrosis and another 30% had a decrease in the degree of fibrosis. Twenty-eight patients had NASH at baseline. Regarding these patients, it was observed in the current evaluation, that 25% remained stable in the degree of fibrosis, 39% progressed, and 35% regressed. CONCLUSION: Despite some limitations of our study, such as the small number of patients, and the use of two different methods of evaluation (biopsy and elastography), the data obtained allow us to conclude that of the 39 evaluated cases, 33% (13) presented progression of fibrosis and the total group of 50 patients, 42% had cirrhosis or died due to liver disease. The presence of NASH on hepatic biopsy did not prove to be, in our study, a predictive of the evolution of hepatic fibrosis in the patients.

Avaliação da progressão da fibrose hepática em um grupo de pacientes com doença hepática gordurosa não alcoólica acompanhados por 10 anos / Evaluation of progression of hepatic fibrosis in a group of patients with non-alcoholic fatty liver disease accompanied for 10 years

ABSTRACT BACKGROUND: Non-alcoholic fatty liver disease has been progressively diagnosed in the general population as a consequence of the increased prevalence of obesity and type 2 diabetes mellitus, its main risk factors. It is characterized by accumulation of fat in the hepatocytes associated with lobular inflammation and balonization, which can lead to cirrhosis and hepatocarcinoma. Thus, a characterization and follow-up of a progression of the fibrosis level of these patients becomes important, being that the transient hepatic elastography is a reliable method for this evaluation with a measure of the kapa index. OBJECTIVE: To evaluate the progression of hepatic fibrosis through elastography in patients with non-alcoholic fatty liver disease. METHODS: Patients who had previously performed hepatic biopsy and noninvasive scores for non-alcoholic steatohepatitis (NASH) and fibrosis were included in the study. These same subjects were then submitted to current clinical evaluation, laboratory and liver elastography tests, defining the level of liver fibrosis, about 10 years after the first evaluation. RESULTS: Data were analyzed for 66 patients previously submitted to liver biopsy. Of these, 16 were not found, four could not participate because they were debilitated due to hepatic cirrhosis, two had died from an automobile accident and five from complications of cirrhosis of the liver. Therefore, of the 50 patients with a known history, 9 (18%) had died of cirrhosis or were unable to attend the examination because of their liver disease. The remaining population was predominantly female (61.5%), mean age of 63 years, being overweight, dyslipidemia (76.9%), disorders of the glycemic profile (76.9%), and metabolic syndrome (82.1%). Of the 39 cases evaluated, 35% had the same degree of fibrosis at the initial evaluation (biopsy) and at the current evaluation (elastography), 33% had an increase in the degree of fibrosis and another 30% had a decrease in the degree of fibrosis. Twenty-eight patients had NASH at baseline. Regarding these patients, it was observed in the current evaluation, that 25% remained stable in the degree of fibrosis, 39% progressed, and 35% regressed. CONCLUSION: Despite some limitations of our study, such as the small number of patients, and the use of two different methods of evaluation (biopsy and elastography), the data obtained allow us to conclude that of the 39 evaluated cases, 33% (13) presented progression of fibrosis and the total group of 50 patients, 42% had cirrhosis or died due to liver disease. The presence of NASH on hepatic biopsy did not prove to be, in our study, a predictive of the evolution of hepatic fibrosis in the patients.

RESUMO CONTEXTO: A doença hepática gordurosa não alcoólica vem sendo diagnosticada com frequência progressivamente maior na população geral, como consequência do aumento da prevalência da obesidade e do diabetes mellitus tipo 2, considerados seus principais fatores de risco. Caracteriza-se por acúmulo de gordura nos hepatócitos associada à inflamação lobular e balonização, podendo levar à cirrose e hepatocarcinoma. Desta forma, torna-se importante a caracterização e acompanhamento do nível de fibrose hepática destes pacientes, sendo que a elastografia hepática transitória, tem se mostrado um método confiável para esta avaliação com a medida do índice kapa. OBJETIVO: Avaliar a progressão da fibrose hepática através de elastografia em pacientes com doença hepática gordurosa não alcoólica. MÉTODOS: Foram incluídos no estudo pacientes que haviam realizado anteriormente biópsia hepática e cálculo de escores não invasivos para avaliação de esteato-hepatite não alcoólica (EHNA) e fibrose. Estes mesmos indivíduos foram então submetidos à avaliação clínica, laboratorial e exame de elastografia hepática atuais, definindo o nível de fibrose hepática, cerca de 10 anos após a primeira avaliação. RESULTADOS: Foram analisados dados relativos a 66 pacientes previamente submetidos a biópsia hepática. Destes, 16 não foram localizados, quatro não puderam participar por estarem incapacitados em função de cirrose hepática, dois haviam falecido por acidente automobilístico e cinco, por complicações de cirrose hepática. Portanto, do grupo de 50 pacientes com evolução conhecida, nove (18%) haviam falecido por cirrose ou estavam incapacitados de comparecer ao exame em função de sua doença hepática. A população restante era predominantemente do sexo feminino (61,5%), com idade média de 63 anos, apresentando sobrepeso, dislipidemia (76,9%), distúrbios do metabolismo glicêmico (76,9%) e síndrome metabólica (82,1%). Dos 39 casos avaliados, 35% tiveram o mesmo grau de fibrose na avaliação inicial (biópsia) e na avaliação atual (elastografia), 33% tiveram aumento no grau de fibrose e outros 30% tiveram diminuição no grau de fibrose. Vinte e oito pacientes apresentavam EHNA na avaliação inicial. Em relação a esses pacientes observou-se na avaliação atual que, 25% mantiveram-se estáveis no grau de fibrose, 39% progrediram e, 35% regrediram. CONCLUSÃO: Apesar de algumas limitações do nosso estudo, como o pequeno número de pacientes e o uso de dois métodos diferentes de avaliação (biópsia e elastografia), os dados obtidos nos permitem concluir que dos 39 casos avaliados, 33% apresentaram progressão da fibrose e do grupo total de 50 pacientes, 42% apresentam cirrose ou faleceram em decorrência de doença hepática. A presença de EHNA à biópsia hepática não se mostrou um dado capaz, no nosso estudo, de predizer a evolução da fibrose hepática nos pacientes.

Importância da medida dos níveis de infliximabe em pacientes com doença inflamatória intestinal: uma coorte Brasileira / Importance of measuring levels of infliximab in patients treating inflammatory bowel disease in a brazilian cohort

ABSTRACT BACKGROUND: Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases. In such pathologies, there is an increased production of alpha tumor necrosis factor (TNF-α). Patients, in whom the conventional immunosuppressant treatment fails, require the use of immunobiological therapy, such as anti-TNF-α, a monoclonal antibody. Infliximab is an anti-TNF-α drug, a chimerical immunoglobulin, with a murine component, which is responsible for the generation of immunogenicity against the drug and formation of anti-TNF-α antibodies. The presence of anti-drug antibodies may be responsible for adverse events and reduction of the drug's effectiveness. Patients with inflammatory bowel diseases undergoing therapy with biological medication, such as infliximab, can relapse overtime and this may not be translated into clinical symptoms. Thus, there is a need for a method to evaluate the efficacy of the drug, through the measurement of serum infliximab levels, as well as antibodies research. OBJECTIVE: This study aimed to measure serum infliximab levels and anti-infliximab antibodies in patients with inflammatory bowel diseases post-induction phase and during maintenance therapy, and describe the therapeutic modifications that took place based on the serum levels results. METHODS: It was a retrospective study, that included forty-five patients, with a total of 63 samples of infliximab measurement. RESULTS: Twenty-one patients had an adequate infliximab serum level, 31 had subtherapeutic levels and 11 had supratherapeutic levels. Seven patients had their medication suspended due to therapeutic failure or high levels of antibodies to infliximab. CONCLUSION: In conclusion, only a third of the patients had adequate infliximab levels and 36% presented with subtherapeutic levels at the end of the induction phase. Therapy optimization occurred based in about 46% of the samples results, demonstrating the importance of having this tool to help the clinical handling of patients with inflammatory bowel diseases ongoing biologic therapy.

RESUMO CONTEÚDO: Doença de Crohn e retocolite ulcerativa são doenças inflamatórias intestinais crônicas. Nelas, ocorre aumento da produção de fator de necrose tumoral alfa (TNF-α). Pacientes que falham no tratamento convencional imunossupressor, requerem uso de terapia imunobio­lógica, que são anticorpos monoclonais, principalmente os anti-TNF-α. O infliximabe é uma droga anti-TNF-α, uma imunoglobulina quimérica, com componente murino. Este é responsável pela imunogenicidade da droga e a formação de anticorpos. Presença de anticorpos antidroga pode ser responsável pelos eventos adversos e redução da eficácia da droga. Pacientes com doenças inflamatórias intestinais, em terapia imunossupressora com medicação biológica como o infliximabe, podem ter recaída da doença e muitas vezes isso não se relaciona com a sintomatologia do paciente. Por isso há a necessidade de um método de avaliação do efeito da droga como a dosagem do nivel sérico do infliximabe, bem como da pesquisa de anticorpos. OBJETIVO: O estudo tem como objetivo conhecer os níveis séricos do infliximabe e dos anticorpos anti-infliximabe em pacientes com doença inflamatória intestinal em terapia de manutenção ou pós-indução e descrever as condutas terapêuticas que foram modificadas em função dos níveis séricos de infliximabe e anticorpos para infliximabe. MÉTODOS: Trata-se de estudo restrospectivo, com análise da dosagem dos níveis séricos de infliximabe e anticorpos para Infliximabe. Foram incluídos 45 pacientes, num total de 63 coletas de dosagem de infliximabe. RESULTADOS: Vinte e um paciente estavam com o nível sérico de infliximabe adequado, níveis subterapêuticos em 31 pacientes e níveis supraterapêuticos em 11 pacientes. Sete pacientes tiveram a medicação suspensa por falha terapêutica ou altos níveis de anticorpos para infliximabe. CONCLUSÃO: Apenas um terço dos pacientes apresentavam níveis adequados de infliximabe e 36% dos pacientes apresentavam níveis subterapêuticos ao término da indução. Em cerca de 46% das amostras a conduta adotada se baseou nos níveis de infliximabe e anticorpos para infliximabe demonstrando a importância de se ter esta ferramenta para auxílio no manejo clínico dos pacientes portadores de doenças inflamatórias intestinais em terapia biológica.

IMPORTANCE OF MEASURING LEVELS OF INFLIXIMAB IN PATIENTS TREATING INFLAMMATORY BOWEL DISEASE IN A BRAZILIAN COHORT.

BACKGROUND: Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases. In such pathologies, there is an increased production of alpha tumor necrosis factor (TNF-α). Patients, in whom the conventional immunosuppressant treatment fails, require the use of immunobiological therapy, such as anti-TNF-α, a monoclonal antibody. Infliximab is an anti-TNF-α drug, a chimerical immunoglobulin, with a murine component, which is responsible for the generation of immunogenicity against the drug and formation of anti-TNF-α antibodies. The presence of anti-drug antibodies may be responsible for adverse events and reduction of the drug's effectiveness. Patients with inflammatory bowel diseases undergoing therapy with biological medication, such as infliximab, can relapse overtime and this may not be translated into clinical symptoms. Thus, there is a need for a method to evaluate the efficacy of the drug, through the measurement of serum infliximab levels, as well as antibodies research. OBJECTIVE: This study aimed to measure serum infliximab levels and anti-infliximab antibodies in patients with inflammatory bowel diseases post-induction phase and during maintenance therapy, and describe the therapeutic modifications that took place based on the serum levels results. METHODS: It was a retrospective study, that included forty-five patients, with a total of 63 samples of infliximab measurement. RESULTS: Twenty-one patients had an adequate infliximab serum level, 31 had subtherapeutic levels and 11 had supratherapeutic levels. Seven patients had their medication suspended due to therapeutic failure or high levels of antibodies to infliximab. CONCLUSION: In conclusion, only a third of the patients had adequate infliximab levels and 36% presented with subtherapeutic levels at the end of the induction phase. Therapy optimization occurred based in about 46% of the samples results, demonstrating the importance of having this tool to help the clinical handling of patients with inflammatory bowel diseases ongoing biologic therapy.

Hepatite E crônica - relato de um caso brasileiro / Chronic hepatitis E - a brazilian case report

Hepatite é a quinta forma conhecida de hepatites humanas virais. Apesar de ser muito incomum em nossa prática clínica, a incidência em países ocidentais vem aumentando. O vírus da Hepatite E (HVE) pode estar relacionado à doença aguda, falência hepática, hepatite crônica e cirrose. O HVE é um RNA vírus, com 5 genótipos descritos (1, 2, 3, 4 e 5), sendo que quatro deles podem afetar humanos. Além das manifestações hepáticas, o genótipo 3 pode também levar a manifestações extra-hepáticas, como alterações neurológicas, renais e reumatológicas. O diagnóstico pode ser difícil porque existem poucos testes validados e ainda com baixa sensibilidade e especificidade. A hepatite aguda não precisa ser tratada, já a hepatite E crônica deve ser tratada. Relatamos aqui um caso brasileiro de Hepatite E crônica em um paciente imunossuprimido.

Hepatitis E is the fifth known form of human viral hepatitis. Although not very common in our clinical practice, the incidence in Western countries is increasing. Hepatitis E virus (HEV) may be related to acute illness, liver failure, chronic hepatitis and cirrhosis. HEV is an RNA virus, with 5 described genotypes (1,2,3,4,5), 4 of them can affect humans. Besides liver manifestations, genotype 3 is also related to extra-hepatic manifestations, such as neurological, renal and rheumatological. The diagnosis may be difficult because of the low availability of tests and due to low sensibility and specificity. The acute illness does not have to be treated, but the chronic one does. We presente here a Brazilian case of chronic hepatitis E in an immunosuppressed patient.