Redução da resistência à insulina após resposta virológica sustentada com agentes antivirais diretos: nem toda população melhora / Insulin resistance reduction after sustained virological response with direct acting antiviral: not every population improves

ABSTRACT BACKGROUND: Hepatitis C virus (HCV) infection is a serious public health problem, that affects approximately 170 million people worldwide. Chronic HCV infection is associated with hepatic insulin resistance and an increased risk of diabetes HCV-infected patients has been well documented. OBJECTIVE: To assess the homeostasis model assessment of insulin resistance (HOMA-IR) index in patients treated with direct acting antiviral (DAAs) medication in the sustained virological response (SVR), categorized by the presence or absence of cirrhosis. METHODS: A prospective study was conducted. Data were collected at the beginning of treatment (t-base) and in the twelfth week after the completion of treatment (t-SVR12). The inclusion criteria were presence of: HCV infection (RNA-HCV positive), age ≥18 years, completion of DAAs' therapy, and presence of diabetes with use of oral hypoglycemic agents. All samples were collected during the study period. The exclusion criteria were: presence of HBV/HIV co-infection, hepatocellular carcinoma at baseline, diabetic patients taking insulin and transplanted patients (liver/kidney). Fibrosis was assessed by hepatic elastography or biopsy (METAVIR). Cirrhosis was determined by clinical results or imaging. HOMA-IR was calculated as fasting insulin (μU/mL) × fasting glucose (mmol/L)/22.5) The patients were divided into two groups: the general study population (all patients, including the diabetic patients) and the special population (patients with normal values of HOMA-IR, which is >2.5, and without diabetes). The delta HOMA-IR value was calculated as: HOMA-IR at t-base - HOMA-IR at t-SVR12. For the descriptive statistical analysis, the paired t-test and generalized linear model assuming the log binding function were performed. A P value of < 0.05 was considered significant. RESULTS: We included 150 patients, and 75 were cirrhotic. The mean age was 55.3±9.97 and body mass index was 27.4±5.18. Twenty-two (14.67%) were diabetic patients using oral hypoglycemic agents, and 17 (11%) were cirrhotic. In the general study population, the mean glucose and HOMA-IR values increased at t-SVR12, but insulin decreased. Delta HOMA-IR was negative at t-SVR12, but there was no significant difference. Excluding diabetic patients and those with normal HOMA-IR values (<2.5), mean glucose, insulin and HOMA-IR decreased at t-SVR12. Delta HOMA-IR decreased significantly at t-SVR12 (P: 0.02). CONCLUSION: In the general population, glucose and HOMA-IR values increased at t-SVR12, but insulin decreased. In the special population, glucose, insulin, HOMA-IR and Delta HOMA-IR decreased at t-SVR12.

RESUMO CONTEXTO: A infecção pelo vírus da hepatite C (VHC) é um grave problema de saúde pública, que afeta aproximadamente 170 milhões de pessoas no mundo. A infecção crônica pelo VHC está associada à resistência à insulina hepática e a um risco aumentado de diabetes. Os doentes infetados pelo VHC foram bem documentados. OBJETIVO: Avaliar o modelo de avaliação da homeostase do índice de resistência à insulina (HOMA-IR) em pacientes tratados com medicação antiviral de ação direta na resposta virológica sustentada (RVS), categorizada pela presença ou ausência de cirrose. MÉTODOS: Foi realizado um estudo prospectivo. Os dados foram coletados no início do tratamento (t-base) e na décima segunda semana após o término do tratamento (t-RVS12). Os critérios de inclusão foram presença de: infecção pelo VHC (RNA-VHC positivo), idade ≥18 anos, conclusão da terapia de antivirais de ação direta e presença de diabetes com uso de hipoglicemiantes orais. Todas as amostras foram coletadas durante o período do estudo. Os critérios de exclusão foram: presença de coinfecção VHB/HIV, carcinoma hepatocelular no início do estudo, pacientes diabéticos em uso de insulina e pacientes transplantados (fígado/rim). A fibrose foi avaliada por elastografia hepática ou biópsia (METAVIR). A cirrose foi determinada por resultados clínicos ou exames de imagem. O HOMA-IR foi calculado como insulinemia de jejum (μU/mL) x glicemia de jejum (mmol/L) /22,5). Os pacientes foram divididos em dois grupos: a população geral do estudo (todos os pacientes, incluindo os diabéticos) e a população especial (pacientes com valores normais de HOMA-IR, que é <2,5 e sem diabetes). O valor do delta HOMA-IR foi calculado como: HOMA-IR no t-base - HOMA-IR no t-RVS12. Para a análise estatística descritiva, foram utilizados o teste t pareado e o modelo linear generalizado, assumindo a função de ligação logarítmica. Um valor de P<0,05 foi considerado significativo. RESULTADOS: Foram incluídos 150 pacientes e 75 eram cirróticos. A idade média foi de 55,3±9,97 e o índice de massa corpórea foi de 27,4±5,18. Vinte e dois (14,67%) eram pacientes diabéticos em uso de hipoglicemiantes orais e 17 (11%) eram cirróticos. Na população geral do estudo, os valores médios de glicose e HOMA-IR aumentaram na t-SVR12, mas a insulina diminuiu. O delta HOMA-IR foi negativo em t-SVR12, mas não houve diferença significativa. Excluindo pacientes diabéticos e aqueles com valores normais de HOMA-IR (<2,5), a média de glicose, insulina e HOMA-IR diminuiu no t-RVS12. O delta HOMA-IR diminuiu significativamente em t-RVS12 (P: 0,02). CONCLUSÃO: Na população geral, os valores de glicose e HOMA-IR aumentaram no t-RVS12, mas a insulina diminuiu. Na população especial, glicose, insulina, HOMA-IR e delta HOMA-IR diminuíram no t-RVS12.

Estudio sobre la sobrecarga de hierro en pacientes con hepatitis C crónica / [A study on hepatic iron overload in chronic hepatitis C patients].

BACKGROUND: Hepatitis C is a worldwide chronic liver disease. Different factors have been found to be associated with an increased progression to severe liver fibrosis, such as alcohol intake higher than 30 g/day, older age at infection and co-infection. Nevertheless, different research centers have found conflicting data concerning the liver iron overload fibrogenic role. AIM: To assess the association between hepatic iron overload and fibrosis stage grades in hepatitis C Virus carriers, hepatic steatosis and demographic variables. METHODS: In this descriptive study we recruited 290 positive anti-HCV and qualitative HCV-RNA, treatment naive chronic hepatitis C outpatients registered fom 2007 to 2009 at the Federal University of Bahia’s Hospital. The variables studied in the liver biopsy results were: 1) fibrosis stage according to META VIR score (F0-F4), 2) iron overload presence or absence according to Perls staining, and 3) presence or absence of steatosis. Fibrosis stages were categorized as mild/moderate (F0-F2) and severe (F3-F4). Exclusion criteria were hepatitis B virus and human immunodeficiency virus co-infection, and primary or secondary hemochromatosis. The statistical analysis was performed using Chi-square and Student’s t tests, with the ssoftware: SPSS 17. A P value < 0.05 was considered as significant. RESULTS: Severe fibrosis was statistically associated with older age, iron overload presence (P = 0.003) and steatosis (P = 0.01). CONCLUSIONS: In this study hepatic iron overload and hepatic steatosis were associated with severe hepatic fibrosis (METAVIR F3-F4).

MTP -493G/T gene polymorphism is associated with steatosis in hepatitis C-infected patients

The reduction of hepatic microsomal transfer protein (MTP) activity results in fatty liver, worsening hepatic steatosis and fibrosis in chronic hepatitis C (CHC). The G allele of the MTP gene promoter, -493G/T, has been associated with lower transcriptional activity than the T allele. We investigated this association with metabolic and histological variables in patients with CHC. A total of 174 untreated patients with CHC were genotyped for MTP -493G/T by direct sequencing using PCR. All patients were negative for markers of Wilson’s disease, hemochromatosis and autoimmune diseases and had current and past daily alcohol intake lower than 100 g/week. The sample distribution was in Hardy-Weinberg equilibrium. Among subjects with genotype 1, 56.8 percent of the patients with fibrosis grade 3+4 presented at least one G allele versus 34.3 percent of the patients with fibrosis grade 1+2 (OR = 1.8; 95 percentCI = 1.3-2.3). Logistic regression analysis with steatosis as the dependent variable identified genotypes GG+GT as independent protective factors against steatosis (OR = 0.4, 95 percentCI = 0.2-0.8; P = 0.01). The results suggest that the presence of the G allele of MTP -493G/T associated with lower hepatic MTP expression protects against steatosis in our CHC patients.

Insulin resistance in non-diabetic patients with chronic hepatitis C: what does it mean? / Resistência insulínica em portadores de hepatite crônica C não diabéticos: qual o significado?

OBJECTIVES: To determine the prevalence of insulin resistance (IR) in non-diabetic patients with chronic hepatitis C, and to assess the association between IR, laboratory parameters and histological findings. SUBJECTS AND METHODS: Eighty-two patients had their serum analyzed for glucose, lipid profile, C-reactive protein (CRP), ferritin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), HOMA-IR, viral load and HCV genotype. Patients with HOMA-IR levels > 2.5 were considered as carriers of insulin resistance. RESULTS: IR was observed in 27 percent of patients and was associated with age, waist circumference and body mass index. IR patients were more likely to have more advanced hepatic fibrosis and necroinflammatory activity, higher levels of aminotransferases and liver steatosis than patients without IR. CONCLUSIONS: Insulin resistance is often present in patients with chronic hepatitis C, and this parameter is associated with more advanced HCV-related hepatic fibrosis.

OBJETIVOS: Em portadores de hepatite crônica C não diabéticos, verificar a prevalência de resistência insulínica (RI) e analisar a associação desta com os parâmetros laboratoriais e histológicos. SUJEITOS E MÉTODOS: Foram incluídos no estudo 82 pacientes, e amostras de sangue foram coletadas para determinação de glicose, perfil lipídico, alanina aminotransferase (ALT), aspartato aminotransferase (AST), ferritina, HOMA-IR, carga viral e genótipo do VHC. HOMA-IR superior a 2,5 foi considerado resistência insulínica. RESULTADOS: RI foi observada em 27 por cento dos pacientes e foi associada a idade, circunferência abdominal e índice de massa corpórea. Quando comparado a pacientes sem RI, aqueles com HOMA-IR superior a 2,5 apresentaram graus mais acentuados de fibrose hepática e atividade necroinflamatória, maiores níveis de aminotransferases e esteatose hepática mais frequente. CONCLUSÕES: É comum a presença de RI em portadores de hepatite crônica C e esta se associa com graus mais avançados de fibrose hepática induzida pelo vírus da hepatite C.

Chronic hepatitis C: hepatic iron content does not correlate with response to antiviral therapy / Hepatite C crônica: concentração hepática de ferro não é correlacionada com a resposta ao tratamento antiviral

The complex interaction between hepatitis C virus infection, iron homeostasis and the response to antiviral treatment remains controversial. The aim of this study was to evaluate the influence of hepatic iron concentration (HIC) on the sustained virological response (SVR) to antiviral therapy in patients with chronic hepatitis C. A total of 50 patients who underwent pretreatment liver biopsy with assessment of HIC by graphite furnace atomic absorption spectroscopy and were subsequently submitted to antiviral treatment with interferon/peginterferon and ribavirin were included in the study. Patients with alcoholism, history of multiple blood transfusion, chronic kidney disease, hemolytic anemia and parenteral iron therapy were excluded. The iron related markers and HIC were compared between those who achieved an SVR and non-responders (NR) patients. The mean age was 45.7 years and the proportion of patients' gender was not different between SVR and NR patients. The median serum iron was 138 and 134 µg/dL (p = 0.9), the median serum ferritin was 152.5 and 179.5 ng/mL (p = 0.87) and the median HIC was 9.9 and 8.2 µmol/g dry tissue (p = 0.51), for SVR and NR patients, respectively. Thus, hepatic iron concentration, determined by a reliable quantitative method, was not a negative predictive factor of SVR in patients with chronic hepatitis C presenting mild to moderate hepatic iron accumulation.

A complexa interação entre infecção pelo vírus da hepatite C, homeostase do ferro e resposta ao tratamento antiviral permanece controversa. O objetivo deste estudo foi avaliar a influência da concentração hepática de ferro (CHF) na resposta virológica sustentada (RVS) à terapia antiviral na hepatite C crônica. Foram incluídos 50 pacientes que foram submetidos à biopsia hepática pré-tratamento com determinação da CHF por espectrofotometria de absorção atômica com forno de grafite e tratados posteriormente com interferon/peginterferon e ribavirina. Pacientes com alcoolismo, história de múltiplas transfusões sanguíneas, doença renal crônica, anemia hemolítica e terapia com ferro parenteral foram excluídos. O perfil de ferro sérico e a CHF foram comparados entre aqueles que atingiram RVS e os não-respondedores (NR). A média de idade dos pacientes foi 45,7 anos e não houve diferença na proporção de homens e mulheres entre os grupos RVS e NR. A mediana do ferro sérico foi 138 and 134 µg/dL (p = 0.9), a mediana da ferritina sérica foi 152,5 e 179,5 ng/mL (p = 0,87) e a CHF mediana foi 9,9 e 8,2 µmol/g de tecido seco (p = 0,51), para pacientes com RVS e NR, respectivamente. Concluindo, a concentração hepática de ferro, determinada por um método quantitativo confiável, não foi um fator preditivo negativo de RVS em pacientes com hepatite C crônica e acúmulo de ferro hepático leve a moderado.

Nitric oxide levels are not changed in saliva of patients infected with hepatitis C virus

O objetivo desta investigacão foi avaliar os níveis de metabólitos do óxido nítrico na saliva de pacientes anti-vírus da hepatite C positivos na tentativa de correlacionar os níveis desses metabólitos com a presenca do VHC na saliva. Foram estudados 39 pacientes anti-VHC positivos (9 com enzimas hepáticas normais, 16 com hepatite crônica e 14 com cirrose hepática) e em 13 controles saudáveis, sem sinais ou sintomas de doenca hepática.O RNA do VHC foi identificado no soro e na saliva através de técnica de RT-PCR e os níveis de óxido nítrico foram avaliados pela quantificacão dos seus metabólitos estáveis, nitratos e nitritos. Os resultados demonstraram que os níveis de nitrito na saliva não diferiram significativamente no grupo anti-VHC positivo em relacão ao grupo controle, nem entre os grupo com presenca ou ausência do RNA do VHC na saliva. Os níveis de nitrito foram mais elevados no grupo com cirrose hepática do que nos grupos controle e anti-VHC positivos, sem cirrose hepática, mas as diferencas não foram estatisticamente significativas. A não observacão de níveis elevados de nitrito na saliva dos pacientes anti-VHC positivos é uma indicacão indireta de que a sialoadenite não deve ser freqüente nesses pacientes ou, se existe, é de intensidade não suficiente para modificar os níves de óxido nítrico na secrecão salivar.

Disfunción tiroidea asociada al tratamiento con interferon alfa en pacientes con hepatitis C crónica / Dysfuction thyroid asociated the treatment qith interferon alpha in patients with hepatitis C chronic

Durante el tratamiento de la Hepatitis C crónica, el interferón alfa es capaz de inducir disfunción tiroidea con varias manifestaciones clinicas. El hipotiroidismo es más común que el hipertiroideismo. Se ha descrito también hipertoroidismo seguido por hipotiroidismo. Los síntomas clínicos varían desde ser subclínico hasta mostrar manifestaciones severas de la enfermedad. La disfunción puede persistir después de descontinar el tratamiento con interferón. Hipotiroidismo es fácilmente controlable con reemplazo con L-thyronina, si es necesario, y la regresión se puede observar luego de omitir el tratamiento con interferón. Los casos casos de hipertiroidismo deben ser bien evaluados. El desarrollo de anticuerpos anti tiroideos o incremento de títulos de dichos anticuerpos ha sido observado durante el tratamiento con interferón alfa, sugiriendo la existencia de mecanismo inmunológico para aclarar la asociación entre la infección por el virus de la hepatitis C y la autoinmunidad tiroidea, y determinar factores de riesgo para el desarrollo de disfunción de ésta glándula durante el tratamiento con interferón

Expression of Transforming Growth Factor beta-1 in Chronic Hepatitis and Hepatocellular Carcinoma Associated with Hepatitis C Virus Infection

BACKGROUND: Transforming growth factor beta-1 (TGF beta 1) has been suggested to play a role in the development, growth or progression of hepatocellular carcinoma (HCC). Genotype and serum titer of HCV also affect the occurrence of HCC in chronic hepatitis C. In this study, we were to evaluate the effects of genotype or serum titer of HCV on the expression of TGF beta 1. We also intended to examine the correlation between the up-regulation of TGF beta 1 and the association with HCC in patients with chronic hepatitis C. METHODS: We studied 19 patients with chronic hepatitis C and 18 with HCC associated with HCV infection. HCV genotype was determined by line probe reverse hybridization assay and the amount of HCV-RNA was quantitated by branched DNA signal amplification assay. Serum TGF beta 1 level was measured by enzyme linked immunosorbent assay. RESULTS: HCV genotypes of patients with HCC were similar to those without it. Serum HCV-RNA titer was higher in genotype 1b than in non-1b (p < 0.05). Serum TGF beta 1 levels were higher in HCC than in chronic hepatitis (p < 0.05). However, there was no significant difference in the serum TGF beta 1 level between genotype 1b and non-1b. Also, it was not correlated with the serum HCV-RNA titer or alanine aminotransferase levels. CONCLUSION: TGF beta 1 seems to be overexpressed in HCC compared to that of chronic hepatitis C: it was not affected by serum ALT levels, genotype or serum HCV titer. It is suggested that TGF beta 1 may be associated with the malignant transformation of hepatocyte or the progression of HCV-associated HCC.