Development Of Chronic Hepatitis Research Articles

Early treatment of acute hepatitis C infection with monotherapy interferon alfa is effective to prevent development of chronic hepatitis

Early treatment of acute hepatitis C infection with monotherapy interferon alfa is effective to prevent development of chronic hepatitis

FACTORS CONTRIBUTING TO THE EVOLUTION AND OUTCOME OF CIRRHOSIS IN HEPATITIS C

A number of factors are important in the evolution of chronic hepatitis C to cirrhosis. These include the length of time that the patient has been infected, the age at exposure, dual infection with other viruses, alcohol use, and genotypes, especially in liver transplant recipients. The diagnosis of cirrhosis is made by clinical assessment of the patient, the use of imaging studies, a thoughtful laboratory evaluation, and histologic examination of liver tissue.

The mouse interferon-gamma transgene chronic hepatitis model (Review).

Acute hepatitis models are widely used for the evaluation of drugs for liver disease or for basic research on hepatitis. However, it is difficult to produce similar liver conditions to human chronic hepatitis with an acute hepatitis model. The interferon-gamma (IFN-gamma) transgenic mouse, which carries the mouse IFN-gamma gene, strongly expresses the IFN-gamma gene in the liver and develops chronic hepatitis from the age of 6-10 weeks. We found that the hepatitis in this mouse reflects human chronic hepatitis at least in the following points, i) infiltration by lymphoid cells into the portal areas and necroinflammation in the lobules, and ii) expression of Fas antigen and Fas ligand mRNAs in the liver. Furthermore, the induction of CPP32-like protease activity in the transgenic mouse liver suggests the involvement of this protease activity in the development of chronic hepatitis.

Influence of the transmission route and disease duration in the histopathology of chronic hepatitis C: a study of 101 patients.

Different studies have demonstrated that factors such as transmission route, disease duration and age at the time of infection can influence the histological evolution of chronic hepatitis by the hepatitis C virus (HCV). The aim of this study was to determine if epidemiological factors such as disease duration and transmission route influence the severity of the histological lesions of patients with chronic hepatitis by HCV. A prospective study. The hepatic biopsies of 101 patients diagnosed with chronic hepatitis by HCV were studied. The patients were divided into three groups according to transmission mode: (1) post-transfusional (n = 28), (2) associated with the use of drugs by parenteral route or intravenous drug use (n = 28), and (3) sporadic hepatitis (n = 45). We found more severe forms of hepatopathy in post-transfusional hepatitis and sporadic groups than in the intravenous drug user group of patients. The disease evolution time was significantly higher in patients diagnosed as having chronic active hepatitis with or without cirrhosis (13.8 +/- 9 years) than in patients with chronic persistent hepatitis (8 +/- 4 years), P < 0.01. We found a significant correlation between the evolution time of the infection by HCV and the Histology Activity Index (P < 0.01). The multivariate analysis showed that only the transmission route and the disease evolution time are predictive variables of Histology Activity Index in chronic hepatitis C. These results suggest that the post-transfusional and sporadic transmission routes and a greater evolution time of the disease are epidemiological variables that are associated with the presence of more severe histological lesions in chronic hepatitis C.

HLA-DRB1 is related to the pathological changes of the liver in chronic hepatitis C

We examined the association between the HLA-DRB1 allele and the development of pathological changes in the liver in patients chronically infected with the hepatitis C virus (HCV) to determine the role of the immune system in the development of chronic hepatitis C. We examined 124 patients positive for HCV-RNA, who had undergone a liver biopsy and allele typing of the HLA-DRB1. Pathological changes in the liver were assessed by the histology activity index (HAI) score and HLA-DRB1 was typed by the polymerase chain reaction-sequence specific olygonucleotide probe (PCR-SSOP) method using DNA extracted from the peripheral blood of patients. HAI scores in category 1, 3 and 4 but not in category 2 were related with the HLA-DRB1 allele. Patients positive for DRB1*1101, 0802 and 1302 had a lower HAI score than those positive for other alleles. Although the HAI score was related to the age of patients chronically infected with HCV, the mean age of subjects positive for DRB1*1101, 0802 or 1302 was not lower than those positive for other alleles. Neither the serum level nor the serotype of the virus was associated with histological damage to the liver. These findings suggest that the HLA-DRB1 allele is associated with the severity of histological damage of the liver mediated by the immune system in chronic hepatitis C.

Posttransplantation chronic hepatitis in fulminant hepatic failure.

Non-A, non-B or seronegative hepatitis is the leading indication for liver transplantation in patients with fulminant hepatic failure (FHF). We examined protocol annual review liver allograft biopsy specimens in consecutive adult patients transplanted for FHF in an attempt to determine the extent of the histological changes. One hundred eleven biopsy specimens from 41 patients transplanted for fulminant seronegative hepatitis and 34 from a comparison group of 16 patients transplanted for other causes of FHF (11 paracetamol overdose, 2 idiosyncratic drug reaction, 3 Wilson's disease) were available. Specimens were analyzed using standard proforma without knowledge of the original diagnosis. Chronic hepatitis was present in 29 patients (71%) transplanted for fulminant seronegative hepatitis (23 mild, 3 moderate, and 3 severe) compared with 5 patients (31%, all mild) transplanted for other causes of FHF. Twenty-five patients (61%) grafted for seronegative FHF had fibrosis (13 mild, 9 moderate, and 3 severe) in contrast to 4 fibrosis (25%) (all mild) in the comparison group. Excluding early allograft failure because of primary graft nonfunction or vascular complications, six patients with seronegative FHF required retransplantation (2 = chronic rejection; 1 = severe hepatitis with panacinar necrosis, resembling original liver; and 3 = chronic hepatitis with precirrhotic fibrosis and prominent cholestasis of unknown cause). One patient in the comparison group had a second graft (chronic rejection). Posttransplantation chronic hepatitis is more frequent and severe in patients transplanted for seronegative hepatitis. Graft survival may be adversely influenced by the development of chronic hepatitis, which may represent persistent or recurrent disease.

Outcome of liver disease and response to interferon treatment are not influenced by hepatitis B virus core gene variability in children with chronic type B hepatitis

Background/Aims: Hepatitis B virus (HBV) core gene heterogeneity may influence the outcome of liver disease and the response to interferon (IFN) therapy in adult HBV carriers. The aim of this study was to evaluate the possible association between HBV core gene variability and evolution of chronic hepatitis in children. Methods: We examined serum samples from 25 children with HBV chronic hepatitis and HBe antigen (HBeAg) positivity who were followed-up for a mean of 7.4 years. Seven cases spontaneously seroconverted to anti-HBe, becoming HBV healthy carriers; nine cases were successfully treated with IFN; nine cases were non-responders to IFN therapy. HBV-DNA was extracted from one serum sample (“I”) collected during the HBeAg positive phase, and from a second sample (“II”) collected after the anti-HBe seroconversion or, in non-responders, after stopping therapy. The entire core gene of the HBV isolates was amplified and sequenced. Results: Each isolate showed single or no missense mutation independent of the clinical behavior of the patients. HBe-Ag-defective viruses were detected in one cases in both samples and in two cases only in sample “II”. Conclusions: Core gene variability does not seem to be involved either in the outcome of infection or in the responses to IFN treatment in children with HBV chronic hepatitis. Considering that most of the HBV carriers in our area acquire the infection in childhood, out data suggest that core gene heterogeneity is not a major cause of progression to chronicity.

Hepatitis B virus variants with core gene deletions in the evolution of chronic hepatitis B infection

BACKGROUND & AIMS: Genomic variants of the hepatitis B virus (HBV) with core gene deletions have been identified in patients with chronic active hepatitis B, but the significance of these mutations in the course of chronic HBV infection remains unknown. The aim of this study was to longitudinally analyze the changes of HBV core gene deletion variants under the enhanced immune pressure of interferon alfa treatment and hepatitis B e antigen (HBeAg) to antibody to hepatitis B e antigen (anti-HBe) seroconversion. METHODS: HBV precore/core gene was amplified in 358 serum samples from 67 chronic HBV carriers (all HBeAg- positive) followed up for a period of 2-11 years. The core gene deletions were analyzed by gel electrophoresis, cloning, and DNA sequencing. RESULTS: HBV mutants with core gene deletions (37-250 base pairs) were detected in patients with long-standing HBV replication and ongoing hepatic inflammation, always together with the wild-type strain. They were associated with a significantly lower level of viremia and a high rate of seroconversion to anti-HBe. Core gene deletion mutants were preferentially eliminated after seroconversion, in contrast to the accumulation of HBV strains with a precore stop codon. CONCLUSIONS: These data indicate that HBV variants with core gene deletions may inhibit HBV replication, do not persist in preference of the wild-type HBV under enhanced immune pressure, and do not confer resistance to interferon alfa treatment. (Gastroenterology 1996 Jul;111(1):183-92)

Independent and additive effect modification of hepatitis C and B viruses infection on the development of chronic hepatitis

Background/Aims: This study aimed to assess the effects and interaction between hepatitis B virus and hepatitis C virus infection on the development of chronic hepatitis. Methods: Anti-HCV and HBsAg were detected in 125 histology-proven chronic hepatitis and 250 sex-matched and age-matched healthy controls. Results: The prevalances of anti-HCV (24.8%) and HBsAg (68.0%) in patients were higher than in controls (2.4% and 18.0%, respectively; each p<0.0001). Univariate analysis showed that anti-HCV and HBsAg were strongly associated with the development of chronic hepatitis. Calculation of synergy index and Mantel extension test for trend indicated that there was additive effect modification between HCV and HBV. Multivariate analysis inidicated that anti-HCV (odds ratio, 46.1; 95% confidence interval, 9.1–233.2) and HBsAg (odds ratio, 25.8; 95% confidence interval (9.3–67.2) were independent risk factors of chronic hepatitis. The population-attributable risk was estimated as 15.6% for anti-HCV alone, 52.4% for HBsAg alone and 6.8% for both anti-HCV and HBsAg. The frequency of chronic active hepatitis in patients with anti-HCV alone (100%) was higher than in patients with HBsAg alone (75%, p<0.001). Conclusion: HCV and HBV infections are risk factors of chronic hepatitis. The act independently and probably with additive effect modification.

Activated Cellular Immunity in Chronic Hepatitis C.

The importance of local immune mechanisms in the development of chronic hepatitis C and its relation with systemic immune disorders is becoming clear and suggests a more generalized involvement of the immune response in this disease. For this reason, we have investigated the serum concentrations of the soluble immune activation markers neopterin, β2-microglobulin and interferon-γ in 28 patients with hepatitis C virus related chronic active hepatitis (n=20) or chronic persistent hepatitis (n=8). Increased levels of neopterin, β2-microglobulin and interferon-γ were found in a subgroup of the patients. Serum β2-microglobulin and neopterin concentrations were strongly related. Patients with chronic active hepatitis had higher β2-microglobulin levels than those with chronic persistent hepatitis. There were no significant differences in neopterin and interferon-γ levels between chronic active hepatitis and chronic persistent hepatitis. A strong association was found between older age and higher β2-microglobulin levels. Because patients with chronic active hepatitis were older than patients with chronic persistent hepatitis, older age may have at least partly contributed to the difference in β2-microglobulin. Because of the known association between cell-mediated immune activation and the production of interferon-γ, neopterin and β32-microglobulin, our results imply that a Th1-type immune response is stimulated in chronic hepatitis C.

Hepatic Expression of Hepatitis B Virus Genome in Chronic Hepatitis B Virus Infection

The expression of hepatitis B virus (HBV) DNA in the liver was studied by nonisotopic in situ hybridization and correlated with liver histology, different phases in the natural evolution of chronic hepatitis B, and hepatic expression of HBV antigens in 251 Chinese patients with chronic HBV infection. A good correlation was found between the detection of HBV-DNA by in situ hybridization and serum HBV-DNA (P < .01). Chronic active hepatitis had the highest HBV-DNA detected in cytoplasm and nuclei, compared with livers showing minimal change, chronic persistent hepatitis, cirrhosis, and hepatocellular carcinoma. HBV-DNA in cytoplasm exceeded HBV-DNA in nucleus in all patients except in livers with hepatocellular carcinoma. Hepatic HBV-DNA correlated with disease activity (P < .02) and the correlation was highly significant with intralobular activity (P < .001). Patients in the early viral replicative phase of infection had higher levels of cytoplasmic and nuclear HBV-DNA compared with the late viral nonreplicative phase. Cytoplasmic and nuclear HBV-DNA correlated with hepatic expression of HBcAg and HBsAg (P < .05 in both cases), but not with HBeAg. These data indicate that hepatic expression of HBV-DNA follows the natural history of chronic HBV infection and is associated with active liver disease.

Risks and benefits of interferon-alpha in the treatment of hepatitis.

The high worldwide prevalence of chronic viral hepatitis, as well as its progressive course, have led to the performance of multiple clinical studies. The natural history of the disease is different depending on the infecting virus; thus, the evolution to liver cirrhosis and/or hepatocellular carcinoma for the hepatitis B, C and delta (D) viruses in chronic hepatitis is 15, 20 and 75%, respectively. Different therapeutic agents have been used in attempts to modify the natural course of these diseases, interferon-alpha (IFN alpha) having proved to be the most effective. In 30 to 50% of patients, treatment with IFN alpha has achieved inhibition of viral replication, as well as normalisation of aminotransferase levels. Moreover, in a majority of patients, histological improvement is observed, principally in piece-meal necrosis and portal inflammation. The dosage currently recommended for treatment of chronic hepatitis B is 30 to 35MU weekly for a minimum of 4 months; when there is a co-existing delta virus infection, the total dosage employed should be greater. For hepatitis C, the minimum effective dosage is 9MU weekly, and a treatment duration of 12 months is recommended. The administration of IFN alpha produces a series of dose-dependent adverse effects, which are reversible on suspension of the medication. The most frequent of these adverse reactions is the 'flu-like' syndrome, which is self-limited and generally well tolerated. Secondary haematological alterations (leucopenia and thrombocytopenia) are the most frequent cause of reduction in dosage or suspension of treatment, although the latter is not normally necessary. The proportion of patients requiring dosage modification or suspension of treatment fluctuates between 5 and 15%. Taking the evolution of chronic hepatitis into account, there can be no doubt that all patients with this disease should be offered treatment. At present, the drug of choice is IFN alpha, as it slows disease progression and it is generally well tolerated.

Evolution of chronic hepatitis C into hepatocellular carcinoma in an elderly man after IFN treatment

Evolution of chronic hepatitis C into hepatocellular carcinoma in an elderly man after IFN treatment

Allotype distribution of human T cell receptor beta and gamma chain genes in Caucasians, Asians and Australian aborigines: relevance to chronic hepatitis B.

RFLPs of TCR beta and gamma genes have been analyzed in chronic HBV carriers of three different ethnic populations to determine if there is an association of TCR allotypes with the development of chronic hepatitis B. The RFLPs of TCR beta and gamma genes were defined respectively by BglII and PvuII genomic fragments on Southern blots. These methods allow allotype assignment. The distribution of TCR beta alleles showed ethnic variation, with one allele significantly decreased in Australian Aborigines, but there was no association with chronic hepatitis B. The distribution of TCR gamma alleles did not show ethnic variation. However, a significant frequency decrease of one allele occurred in Aboriginal HBV carriers, suggesting the possibility of involvement of TCR gamma allotypes in the development of the chronic HBV carrier state in Australian Aborigines.

Seroconversion to hepatitis C virus antibodies in patients with acute posttransfusion non-A, non-B hepatitis in Sweden with a second generation test.

28 patients with posttransfusion non-A, non-B (NANB) hepatitis in Stockholm, Sweden, were studied for seroconversion to hepatitis C virus antibodies (anti-HCV) and time lag to seroconversion by first and second generation tests. 15/28 patients (54%) seroconverted to anti-HCV with a first generation anti-HCV ELISA using C100-3 from the nonstructural (NS) region 4 of the HCV genome and 23 (82%) with a second generation anti-HCV ELISA including also antigens from the core and NS3 regions of the HCV genome. The mean time from onset of hepatitis to seroconversion was 6.1 weeks (0-18 weeks) with the first generation test and 2.3 weeks (0-7 weeks) with the second generation test. Development of chronic hepatitis was noticed in 14/23 (61%) patients who seroconverted to anti-HCV with the second generation ELISA and in none of 5 patients with posttransfusion NANB hepatitis who did not seroconvert. The inclusion of antigens from the core and NS3 regions of the HCV genome has increased the sensitivity of the second generation anti-HCV ELISA as compared to the first generation ELISA and also shortened the time lag to seroconversion in patients with posttransfusion hepatitis C. Patients with posttransfusion NANB hepatitis seroconverting seem more prone to develop chronic disease than patients not seroconverting.

Antibody to hepatitis C virus in patients with chronic schistosomiasis.

To clarify the effect of hepatitis C virus (HCV) infection in patients with chronic schistosomiasis, 96 patients with schistosomiasis and 137 patients with chronic liver disease without schistosomal infection were analysed by domination of antibody to HCV (anti-HCV). In 45 of 96 schistosomiasis patients, the serum alanine aminotransferase (ALT) level was continuously elevated, and the positive rate of anti-HCV was 52.9%, which is almost the same prevalence rate as in patients with chronic liver disease (48.9%). In contrast, in the remaining 51 schistosomiasis patients, serum ALT level was continuously within the normal range and the positive rate of anti-HCV was 0%. Histological investigation showed that the positive rate of anti-HCV in HBsAg-negative schistosomiasis patients was 14% for hepatic fibrosis, 71% for chronic hepatitis, 80% for liver cirrhosis and 56% for hepatocellular carcinoma. In all anti-HCV-positive patients, serum ALT level was continuously elevated. The serum transaminase levels in anti-HCV-positive patients were higher than those in anti-HCV-negative patients. These data suggest that in patients with chronic schistosomiasis, HCV infection accelerates the derangement of liver function, and may be a major aetiological factor in the development of chronic hepatitis and liver cirrhosis, supporting a causative association between HCV infection and hepatocellular carcinoma.

Export of intracellular HBsAg in chronic hepatitis B virus infection is related to viral replication

Serum and liver HBsAg bear an inverse relation to each other during the evolution of chronic hepatitis B virus infection and the quantity of HBsAg in tissue rises gradually with time. In this study, intracellular and extracellular levels of HBsAg were measured by radioimmunoassay in primary culture of hepatocytes from 30 patients with chronic hepatitis B virus infection to determine a possible relationship with hepatitis B virus replication. Serum levels of HBsAg correlated with markers of active viral replication (serum hepatitis B virus DNA, p less than 0.005, and tissue HBcAg, p less than 0.02) but inversely with tissue HBsAg (p less than 0.05). In similar fashion, in vitro export of HBsAg was also related to the presence of active viral replication markers (serum hepatitis B virus DNA, p less than 0.02, and tissue HBcAg, p less than 0.05) and negatively with tissue HBsAg (p less than 0.001). Export of HBeAg also correlated positively with markers of active viral replication (serum hepatitis B virus DNA, p less than 0.05 and tissue HBcAg, p less than 0.05). Further experiments indicated that intrahepatic pre-S1 and pre-S2 correlated closely with intrahepatic HBsAg, indicating that a failure to export HBsAg was unlikely to be attributable to deficient intracellular expression of pre-S1 or pre-S2. These data indicate that in vitro primary hepatocyte culture of hepatitis B virus-infected cells provides an accurate reflection of in vivo export of HBsAg and that this is closely related to the presence of active viral replication.

Export of intracellular HBsAg in chronic hepatitis B virus infection is related to viral replication

Serum and liver HBsAg bear an inverse relation to each other during the evolution of chronic hepatitis B virus infection and the quantity of HBsAg in tissue rises gradually with time. In this study, intracellular and extracellular levels of HBsAg were measured by radioimmunoassay in primary culture of hepatocytes from 30 patients with chronic hepatitis B virus infection to determine a possible relationship with hepatitis B virus replication. Serum levels of HBsAg correlated with markers of active viral replication (serum hepatitis B virus DNA, p < 0.005, and tissue HBcAg, p < 0.02) but inversely with tissue HBsAg (p < 0.05). In similar fashion, in vitro export of HBsAg was also related to the presence of active viral replication markers (serum hepatitis B virus DNA, p < 0.02, and tissue HBcAg, p < 0.05) and negatively with tissue HBsAg (p < 0.001). Export of HBeAg also correlated positively with markers of active viral replication (serum hepatitis B virus DNA, p < 0.05 and tissue HBcAg, p < 0.05). Further experiments indicated that intrahepatic pre-S1 and pre-S2 correlated closely with intrahepatic HBsAg, indicating that a failure to export HBsAg was unlikely to be attributable to deficient intracellular expression of pre-S1 or pre-S2. These data indicate that in vitro primary hepatocyte culture of hepatitis B virus—infected cells provides an accurate reflection of in vivo export of HBsAg and that this is closely related to the presence of active viral replication.

Breed, sex and age distribution in dogs with chronic liver disease: a demographic study

ABSTRACTBreed, sex and age distribution were studied in dogs with histopathologically diagnosed chronic (active or progressive) hepatitis and liver cirrhosis in Sweden. The study was based on clinical and histopathological records obtained during three years from a histopathological laboratory and during six years from an animal hospital. Some breeds were significantly (P&lt;0–001) over‐represented: American and English cocker spaniels, labrador retrievers and West Highland white terriers. In both spaniel breeds the males were most frequent whereas in the labrador retriever, the females were over represented. In the West Highland white terrier there was no sex difference. The average age at presentation was approximately five years in spaniels and West Highland white terriers and seven years in labrador retrievers. The high incidence of chronic liver disease and liver cirrhosis in certain breeds indicate that hereditary factors may be of importance in the development of chronic hepatitis and liver cirrhosis.

The Effects of Recombinant Interleukin 2 on HBe Antigen Positive Chronic Hepatitis B.

Recombinant interleukin (IL-2) was administered to 16 patients with HBe antigen-positive chronic active hepatitis in which the diagnosis was ascertained histologically. In 7 of the 16 patients, a decrement of the serum HBe antigen value was observed (Group A). In group A, the findings showed an increment of peripheral Leu 11-positive cells and NK and LAK cell activity, an acute exacerbation during and after IL-2 administration, disappearance of HBc antigen observed in liver biopsy histology, and decrement of serum DNA-p activity. However, seroconversion of HBs antigen was not observed and no case showed the elimination status of continuous HB virus infection. On the other hand, in the other 9 patients (Group B), these changes were not observed and the existence of a HLA type difference between Group A and B was shown by HLA analysis. These results indicated that the immune responses mediated by IL-2 may play an important role in the development of chronic hepatitis B, and these results may be regulated genetically.