Lipoproteína de alta densidade e hipertensão arterial sistêmica estão associados à atividade necroinflamatória hepática em pacientes com hepatite C crônica / High-density lipoprotein cholesterol and systemic arterial hypertension are associated with hepatic necroinflammatory activity in patients with chronic hepatitis c

ABSTRACT Background: Approximately 71 million people are chronically infected with hepatitis C virus (HCV) worldwide. A significant number of these individuals will develop liver cirrhosis and/or hepatocellular carcinoma. Beyond the liver, there is a sizeable body of scientific evidence linking cardiovascular disease and chronic hepatitis C (CHC); however, the biological mechanisms behind the concurrence of these conditions have not been completely clarified yet. Objective: To evaluate associations between hepatic histology, clinical comorbidities and lipid profile in patients with CHC. To investigate associations between liver histology and demographic, nutritional, biochemical and virological parameters. Methods: Eight-five patients with CHC prospectively underwent hepatic biopsy. Liver fragments were obtained from each patient by percutaneous route using a Menghini needle. Fibrosis was evaluated according to the METAVIR scoring system, as follows: F0, no fibrosis; F1, fibrous portal expansion; F2, fibrous portal widening with few septa; F3, bridging fibrosis with architectural distortion; and F4, liver cirrhosis. The activity was classified based on the degree of lymphocyte infiltration and hepatocyte necrosis, from A0 to A3. The diagnosis of liver disease was based on clinical, biochemical, histological, and radiological methods. The data were analyzed by logistic regression models. Results: This cross-sectional study included 85 outpatients followed at the tertiary care ambulatory centre with a mean age of 57.2±10.7 years and 45 (52.9%) were females. There were 10 patients with cirrhosis. Patients with a METAVIR F3-F4 were significantly older (P=0.02) and had higher levels of ALT (P=0.0006), AST (P<0.0001), γ-GT (P=0.03) and bilirubin (P=0.001) and higher prothrombin time than patients with F0-F2 score. Albumin levels (P=0.01) were significantly lower in METAVIR F3-F4. Age (OR=1.09; 95%CI=1.02-1.16; P=0.02), steatosis (OR=4.03; 95%CI=1.05-15.45; P=0.04) and high-density lipoprotein cholesterol (HDL-C) <60 mg/dL (OR=7.67; 95%CI=1.71-34.49; P=0.008) were independently associated with fibrosis. Hypertension (OR=6.36; 95%CI=1.31-30.85; P=0.02) and HDL-C <60 mg/dL (OR=9.85; 95%CI=2.35-41.39; P=0.002) were independently associated with necroinflammatory activity. Hypertension (OR=6.94; 95%CI=1.92-25.05; P=0.003) and HDL-C <60 mg/dL (OR=3.94; 95%CI=1.27-12.3; P=0.02) were associated with interface inflammatory activity. Triglycerides (TG ≥150 mg/dL) remained associated with lobular inflammatory activity. Conclusion: cholesterol levels <60 mg/dL were independently associated with necroinflammatory activity in chronic hepatitis C. Patients with hypertension are at an increased risk of developing necroinflammatory activity.

RESUMO Contexto: Aproximadamente 71 milhões de pessoas estão infectadas pelo vírus da hepatite C em todo o mundo. Um número significativo desses indivíduos desenvolverá cirrose hepática e/ou carcinoma hepatocelular. Além do fígado, há evidências científicas que associam doenças cardiovasculares e hepatite C crônica; no entanto, os mecanismos biológicos implicados na ocorrência dessas condições ainda não foram completamente esclarecidos. Objetivo: Avaliar a associação entre histologia hepática, comorbidades clínicas e perfil lipídico em pacientes com hepatite C crônica. Investigar associações entre histologia hepática e parâmetros demográficos, nutricionais, bioquímicos e virológicos. Métodos: Oitenta e cinco pacientes com hepatite C crônica foram prospectivamente submetidos à biópsia hepática. Biópsias hepáticas foram obtidas de cada paciente por via percutânea com agulha de Menghini. A fibrose foi avaliada de acordo com o sistema de pontuação METAVIR, como segue: F0, sem fibrose; F1, expansão portal fibrosa; F2, alargamento portal fibroso com poucos septos; F3, fibrose em ponte com distorção arquitetônica; e F4, cirrose hepática. A atividade foi classificada com base no grau de infiltração de linfócitos e necrose de hepatócitos, de A0 a A3. O diagnóstico da doença hepática foi baseado em métodos clínicos, bioquímicos, histológicos e radiológicos. Os dados foram analisados por modelos de regressão logística. Resultados: Neste estudo transversal, realizado em um ambulatório do hospital universitário, foram incluídos 85 pacientes que tinham média de idade de 57,2±10,7 anos, sendo 45 (52,9%) do sexo feminino. Havia 10 pacientes com cirrose. Os pacientes com METAVIR F3-F4 eram significativamente mais velhos (P=0,02) e tinham níveis mais elevados de ALT (P=0,0006), AST (P<0,0001), γ-GT (P=0,03) e bilirrubina (P=0,001) e, maior tempo de protrombina do que pacientes com escore F0-F2. Os níveis de albumina (P=0,01) foram significativamente mais baixos naqueles classificados como METAVIR F3-F4. Idade (OR=1,09; IC95%=1,02-1,16; P=0,02), esteatose (OR=4,03; IC95%=1,05-15,45; P=0,04) e HDL-C <60 mg/dL (OR=7,67; 95%IC=1,71-34,49; P=0,008) foram independentemente associados à fibrose. Hipertensão (OR=6,36; IC95%=1,31-30,85; P=0,02) e HDL-C <60 mg/dL (OR=9,85; IC95%=2,35-41,39; P=0,002) foram independentemente associados à atividade necroinflamatória. Hipertensão (OR=6,94; IC 95%=1,92-25,05; P=0,003) e HDL-C <60 mg/dL (OR=3,94; IC95%=1,27-12,3; P=0,02) foram associados à atividade inflamatória de interface. Os triglicerídeos (TG >150 mg/dL) permaneceram associados à atividade inflamatória lobular. Conclusão: Níveis de coleterol HDL <60 mg/dL foram independentemente associados à atividade necroinflamatória na hepatite C crônica. Pacientes com hipertensão têm risco aumentado de desenvolver atividade necroinflamatória.

Diferentes níveis protéicos na dieta de girinos de rã-touro (Lithobates catesbeianus) e seus efeitos sobre o tecido hepático / Different protein levels in the diet of bullfrog tadpoles (Lithobates catesbeianus) and its effects on the liver tissue

Para verificação da ocorrência de alterações morfológicas no fígado, foram coletados dez animais de cada dieta, no 30º dia (1º período experimental) e no 60º dia (2º período experimental), sendo esse, o último dia do período experimental e início do clímax da metamorfose. Os girinos foram distribuídos em delineamento experimental inteiramente casualizado (DIC) com três tratamentos: dieta experimental com 32,68% de proteína bruta e duas dietas comerciais com 37,92% e 57,53% de proteína bruta. Os órgãos coletados foram fixados em solução de Bouin e depois submetidos às práticas da rotina histotecnológica e coradas com hematoxilina - Eosina (HE). Na avaliação microscópica do fígado foram encontradas diversas alterações morfológicas como: Desorganização e vacuolização de hepatócitos, infiltrado inflamatório mononuclear periportal, multifocal e difuso, infiltrado inflamatório eosinofílico, congestão, hemorragia, hemólise e necrose. As alterações hepáticas encontradas neste estudo sugerem que as dietas utilizadas para os girinos de rã-touro, não atenderam suas necessidades dietéticas, afetando a homeostasia dos mesmos, comprometendo assim, sua sanidade.(AU)

To verify the occurrence of liver morphological changes, bullfrog tadpoles were fed three diets: an experimental diet with 32.68% crude protein and two commercial diets with 37.92% and 57.53% crude protein. Tadpoles were distributed into a completely randomized design (CRD) with three treatments and four replications. Liver samples were collected twice, on the 30th and 60th day of the experiment. Tadpole livers were fixed in Bouin's solution, then subjected to routine histotechnology procedures, and stained with hematoxylin - eosin (HE). Microscopic evaluation of liver tissue showed several morphological changes like disorganization and vacuolization of hepatocytes; periportal, multifocal and diffuse mononuclear inflammatory infiltrate, eosinophilic inflammatory infiltration, congestion, hemorrhage, hemolysis and necrosis. The liver changes found in this study suggest that diets used for bullfrog tadpoles, did not meet their dietary needs, what affected their homeostasis, thus compromising their health.(AU)

Histologia do fígado de tilápia do Nilo (Oreochromis niloticus) alimentados com dietas contendo silagem biológica de pescado / Histology liver in Nile tilapia (Oreochromis niloticus) fed diets with fish silage

Este estudo teve como objetivo avaliar as possíveis alterações histopatológicas hepática de tilápias do Nilo alimentadas com dietas contendo silagem biológica de pescado com diferentes concentrações protéicas. Foram utilizados 180 juvenis alimentados com dietas contendo três níveis de proteína (20, 24 and 28% PB), e duas proporções de silagem biológica (» e ½) durante 75 dias. Os fragementos de fígado foram fixados em Bouin e inclusos em Histosec®. Posteriorente foram cortados em microtomo com espessura de 2 a 5µm. O método utilizado para coloração foi hematoxilina/eosina e PAS. Os cortes histológicos foram analisados em microscopio de luz. O desarranjo na morfologia do fígado dos peixes alimentados com silagem biológica foi influenciado pelos altos níveis protéicos, e pelo aumento ½ de proporções de proteínas de origem animal das dietas. Foi observado que a variação dos hepatócitos está diretamente ligada com o tipo da dieta fornecida para os peixes. Nos peixes alimentados com as dietas contendo 28% PB, o fígado apresentou desarranjo da estrutura cordonal dos hepatócitos, pontos de necrose e deslocamento do núcleo para periferia. Níveis elevados de silagem biológica de pescado provoca alterações deletérias no fígado. O nível de proteína adequado para manter o desenvolvimento associado à saúde do peixe é de 24%PB.(AU)

This study aimed to evaluate possible histopathological liver of tilapia fed diets containing fish silage and level protein. Sample of 180 fed with tilapia fingerlings fed with diets containing three protein levels (20, 24 and 28% CP), and Proportions residue fermented silage of tilapia (» and ½) of were analyzed during 75 days. The tissue fragments were fixed in Bouin and included in Histosec®. After that, between 2 to 5µm slices were done in a rotation microtome. The methods used for tissue analysis were hematoxilin/eosin and PAS. The histological slices were examined under light microscope (Olympus BX-50). The disarray in the morphology of the liver of fish fed biological silage was influenced by high protein levels, and increased proportions of ½ of animal protein diets. It was observed that the variation of hepatocytes is directly related to the type of diet for fish. In fish fed diets containing 28% CP, the liver showed disruption of the structure cordon of hepatocytes, necrosis and shifting points of the core to the periphery. Elevated levels of biological fish silage cause deleterious changes in the liver. The level of protein required to maintain the health of the associated development fish is 24% crude protein.(AU)

Anti-hepatitis C virus treatment may prevent the progression of liver fibrosis in non-responder human immunodeficiency virus/hepatitis C virus coinfected patients

AIM: To evaluate changes in liver histology in patients with human immunodeficiency virus/hepatitis C virus coinfection non-responders to a suboptimal Interferon+Ribavirine regimen. MATERIALS AND METHODS: We investigated 49 patients with two sequential liver biopsies: 18 were non-responders to Interferon+Ribavirine treatment (Group hepatitis C virus Rx) administered after the 1st liver biopsy who underwent a 2nd liver biopsy after a median period of 3.92 year and 31 were patients who remained untreated for hepatitis C virus disease (Group hepatitis C virus untreated) after the 1st liver biopsy because of refusal and underwent a 2nd liver biopsy after a median period of 5.05-years. Most patients in both groups were under highly active antiretroviral therapy. At the time of 1st liver biopsy similar degrees of necro-inflammation, fibrosis and steatosis were observed in both groups. Changes in liver lesions between 1st and 2nd liver biopsys were adjusted for different intervals between liver biopsys by a mathematic formula. RESULTS: Liver fibrosis did not change in 88.9% of patients in Group hepatitis C virus Rx and in 77.4% in Group hepatitis C virus untreated. A marked deterioration in liver fibrosis was observed in 5 (16%) patients in Group hepatitis C virus untreated and in none in Group hepatitis C virus treated. Necro-inflammation and steatosis remained substantially unchanged in both groups. CONCLUSION: Liver histology remained substantially unchanged in human immunodeficiency virus/hepatitis C virus patients non-responder to anti-hepatitis C virus therapy over 4 years observation, suggesting an effective anti-hepatitis C virus early treatment for all hepatitis C virus/human immunodeficiency virus coinfected patients who can reasonably tolerate therapy. .

Hepatitis B virus genotypes in Southeast Brazil and its relationship with histological features

Data concerning the relationship between hepatitis B virus (HBV) genotypes and liver histology are scarce. The aim of this study was to compare HBV non-B and non-C genotypes according to demographic features, clinical status, HBV-DNA levels and liver histology in Rio de Janeiro. One hundred twenty one consecutive chronic HBV-infected patients were enrolled during two-year period and data were prospectively collected. Sera were tested for HBV genotyping using restriction fragment length polymorphism. Liver biopsy was obtained from patients with either increased alanine aminotransferase (ALT) or HBV-DNA levels. Genotype A was the most common, found in 82 (68%) patients, followed by F in 19 (15%), D in 17 (14%), B in one (1%) and C in two (2%). There was no association between HBV genotypes A, D and F and gender (p = 0.37), age (p = 0.78), race (p = 0.22), mode of infection (p = 0.94), HB "e" antigen status (p = 0.37) and HBV-DNA levels (p = 0.47). The ALT levels were lower in genotype D (75%) compared with A (47%) and F (55%) (p = 0.05). Liver biopsy showed lower inflammation [histological activity index (HAI) = 4] and fibrosis (F) (= 0) scores in genotype D than in genotypes A (HAI = 5, p < 0.001; F = 2, p = 0.008) or F (HAI = 5, p = 0.009; F = 2, p = 0.01). Genotype A was the most prevalent in chronic HBV-infected patients and genotype D patients presented with less intense liver disease.

Histological and immunohistochemical features in fatal acute fulminant hepatitis E.

Background: Hepatitis E is being increasingly recognized as an emerging infection in developed countries. Data on histological findings and nature of inflammatory cell infiltrate in liver in this disease are quite sparse. Aims: This study was planned to study the histological features and the type of inflammatory infiltrate in liver biopsies of patients with acute fulminant hepatitis E. Materials and Methods: We retrieved postmortem liver biopsies of 11 Indian patients with fulminant hepatitis E, and compared these with biopsies from seven patients with fulminant hepatitis B. Results : Biopsies from acute fulminant hepatitis E showed varying degrees of hepatocyte necrosis, mixed portal and lobular inflammation, accompanied by bile ductular proliferation, lymphocytic cholangitis, Kupffer cell prominence, cholestasis, apoptotic bodies, pseudo-rosette formation, steatosis, and presence of plasma cells in portal tracts. Interface hepatitis was more frequent in acute hepatitis B than in acute hepatitis E (100% vs 20%; P<0.05). These findings differ from those reported in cases with autochthonous hepatitis E in Europe. On immunohistochemistry, lymphocyte infiltrate consisted predominantly of CD3 + T cells in both hepatitis E and hepatitis B; these cells contained a predominant cytotoxic (CD8 + ) cell subpopulation in 81.8% of cases with hepatitis E and in 50% of cases with hepatitis B. Conclusion: Our findings suggest that histological changes in HEV infection may vary with geographical location because of prevalent HEV genotypes, and that CD8 + lymphocytes play a role in HEV-induced liver injury.

Changes in Glycogen and Glycosaminoglycan Levels in Hepatocytes of Iduronate-2-Sulfatase Knockout Mice before and after Recombinant Iduronate-2-Sulfatase Supplementation

PURPOSE: Mucopolysaccharidosis II (MPS II) is a lysosomal storage disorder caused by a deficiency of iduronate-2 sulfatase (IdS), which is involved in the degradation of glycosaminoglycan (GAG). In this study, the frequency of fasting hypoglycemia in patients with MPS II was investigated and changes in accumulation of glycogen and GAG in the hepatocytes of IdS-knockout (KO) mice were evaluated before and after recombinant IdS enzyme replacement therapy (ERT). MATERIALS AND METHODS: Plasma glucose levels were evaluated after an 8-hour fast in 50 patients with MPS II. The IdS-KO mice were divided into three groups (group 2; saline, group 3; 0.15 mg/kg of IdS, and group 4; 0.5 mg/kg of IdS); wild-type mice were included as controls (group 1). ERT was initiated intravenously at four weeks of age, and continued every week until 20 weeks of age. RESULTS: The mean glucose level after an 8-hour fast was 94.1 +/- 23.7 mg/dL in the patients with MPS II. Two (4%) out of 50 patients had fasting hypoglycemia. For the mice, GAG in the lysosomes nearly disappeared and glycogen particles in the cytoplasm were restored to the normal range in group 4. CONCLUSION: Glucose metabolism in patients with MPS II appeared to function well despite hepatocytic GAG accumulation and hypothetical glycogen depletion. A higher dose of IdS infusion in MPS II mice led to disappearance of lysosomal GAG and restoration of glycogen to the cytoplasm of hepatocytes.

Evaluation of the histopathological hepatic lesions and opportunistic agents in Brazilian HIV patients / Avaliação das alterações histológicas hepáticas e infecções oportunistas em pacientes brasileiros infectados pelo HIV

INTRODUCTION: to evaluated the type histopathological hepatic lesions and opportunistic agents in Brazilian HIV-infected patients. METHODS: we examined 52 percutaneous liver biopsies of 50 HIV-infected patients who had at least two of the following conditions: fever of unknown origin, unexplained severe emaciation, hepatomegaly or abnormal liver chemistry. The specimens were cultured for mycobacteria and fungi and stained by standard procedures. RESULTS: reactive patterns, granulomatous hepatitis and chronic active hepatitis were verified in 28 (54 percent), 11 (21 percent) and 8 (15 percent) of the patients respectively. Opportunistic infections were diagnosed in 18 (36 percent) patients: mycobacteria in 12 (24 percent), Cryptococcus neoformans in 5 (10 percent) patients and mycobacteria and yeast was isolated from the same liver fragment in one patient. CONCLUSIONS: mycobacteriosis was the most common opportunistic infection and liver tissue culture is an important method to detect opportunistic agents, even in the absence of histological lesions.

INTRODUÇÃO: avaliar os tipos de lesões histopatológicas e infecções oportunistas de Brasileiros infectados pelo HIV. MÉTODOS: Foram analisadas 52 biópsias hepáticas percutâneas de 50 pacientes que apresentavam pelo menos duas das alterações: febre de origem indeterminada, emagrecimento inexplicado, hepatomegalia ou anormalidades na bioquímica hepática. O fragmento de tecido hepático foi submetido a histopatologia por métodos habituais e cultura para micobacteria e fungo. RESULTADOS: padrão reacional, hepatite granulomatosa e hepatite crônica ativa foram encontrados em 28 (54 por cento), 11 (21 por cento) e 8 (15 por cento) dos pacientes respectivamente. Infecções oportunistas foram diagnosticadas em 18 (36 por cento) dos pacientes: micobacteria em 12 (24 por cento), Cryptococcus neoformans em 5 (10 por cento) pacientes e micobacteria e fungo foram isolados no mesmo fragmento em um paciente. CONCLUSÕES: micobacteriose foi a infecção oportunista mais comum e a cultura de tecido hepático foi um importante método para detecção de infecções, mesmo na ausência de lesões histológicas.

Relationship between Serum HBV DNA Levels and Liver Histology in Chronic Hepatitis B / 대한소화기학회지

BACKGROUND/AIMS: Serum HBV DNA levels are correlated with hepatic histologic activity in chronic HBV infection based on HBeAg. Liver injury may persist, even though HBV DNA are not detected by hybridization assay. This study was to investigate whether serum HBV DNA levels determined by more sensitive quantitative method are correlated with histologic activities in chronic HBV infections. METHODS: This study included 66 chronic HBV infected patients. HBV DNA level was quantified by Cobas Amplicor HBV Monitor(TM). RESULTS: Serum HBV DNA levels in HBeAg-positive patients were significantly higher than HBeAg-negative patients. In HBeAg-positive patients, serum HBV DNA levels showed a significant negative correlation with portal-periportal activity and fibrosis (r=-0.451, -0.446 respectively). AST levels were correlated with lobular, portal-periportal activity and fibrosis (r=0.432, 0.365, 0.301 respectively), whereas ALT levels were related to lobular activity (r=0.294). Elevated AST levels predicted lobular activity, portal-periportal activity, and fibrosis with moderate to severe degree (OR 1.733, 95% CI 1.083-2.775; OR 1.518, 95% 1.028-2.243, p=0.336; OR 17.897, 95% CI 1.517-211.208, p=0.022, respectively). CONCLUSIONS: In HBeAg-positive patients, serum HBV DNA level correlates inversely with histologic activity. On the other hands AST level correlates with histologic activity and the stage of moderate or severe degree.

Liver biopsies on renal transplant recipients with hepatitis virus infection: significance and complication / 解放军医学杂志

Objective The study was performed to determined the significance and safety of liver biopsies in these patients as a pre-transplantation screening test. Methods From January 1999 to August 2002, seventy-four renal transplant recipients with hepatitis B or C virus infection were received the percutaneous liver biopsy. The severity of liver inflammation(G) and fibrosis(S) were evaluated by semi-quantity technique. The patients whose liver histological diagnosis was G 0-2 S 0-2 received renal transplantation(n=31). Patients with hepatitis B or C virus infection who received renal transplantation in the period of January 1995 to December 1998 were selected as historic controls. Normal level of serum transaminase was considered as a indication for the received renal transplantation during this period. The incidence of liver dysfunction after transplantation was compared between the two groups. Results It showed among thirty-one patients received renal transplantation from 1999-2002, only 1 patient (3.2%) developed liver failure after transplantation. However, among 60 patients of historic control, 17 (23.8%) suffered from liver dysfunction (P

Peritoneoscopic liver biopsy findings in asymptomatic chronic HBsAg carriers with normal liver function tests and no hepatomegaly

Asymptomatic chronic HBsAg carriers with normal liver function tests are, in general regarded as having no liver pathology. Most of the histologic findings in asymptomatic chronic carriers have been reported from areas with low incidence of Hepatitis B virus (HBV) infection, such as North America and Western Europe. It is well known that there are many differences in HBV infection between low and high endemic areas, but there have been few reports on the histologic findings of asymptomatic chronic HBsAg carriers from endemic areas. The present study was undertaken in Korea which is one of the endemic areas for HBV infection and was designed to assess the prevalence of chronic liver disease by peritoneoscopic liver biopsy among asymptomatic chronic HBsAg carriers and to make a basis for the follow-up of asymptomatic chronic HBsAg carriers according to the results obtained. One hundred and ten asymptomatic HBsAg-positive carriers with normal liver function tests and no hepatomegaly were included in the study. Final diagnosis by peritoneoscopic liver biopsy revealed that of the 110 asymptomatic carriers only 27 (24.5%) had a histologically normal liver, while 51 (46.4%) had chronic liver diseases, and the remaining 32 (29.1%) had nonspecific histologic abnormalities (nonspecific reactive changes in 18 cases, cholestasis in 6 cases, and fatty change in 8 cases). Of the 51 patients with chronic liver diseases, 3 had liver cirrhosis, 4 chronic active hepatitis with cirrhosis, 11 chronic active hepatitis and 33 chronic persistent hepatitis. The frequency of liver cirrhosis and chronic active hepatitis with cirrhosis was significantly high in the over 30 years of age group (12.1%) than in the under 30 years of age group (0%; p = 0.011 by Fisher's exact test). In conclusion, 46.4% of the Korean asymptomatic chronic HBsAg carriers with normal liver function tests and no hepatomegaly had chronic liver disease. This finding contrasted with reports from low incidence areas of HBV infection. Our results suggest that in endemic areas, a liver biopsy should be considered to assess the status of liver disease in asymptomatic chronic HBsAg carriers even if liver function tests are normal and hepatomegaly is absent, and the result can be used as a basis for the follow-up of each asymptomatic chronic HBsAg carriers.