摘要:

AbstractAutoimmune hepatitis (AIH) runs a variable clinical course. Slow disease progression or even spontaneous remissions can be observed and suggest that the autoimmune process can, at least to a certain extent, be controlled by regulatory elements of the patient's own immune system. In experimental autoimmune hepatitis (EAH) spontaneous recovery is regularly observed and associated with antigen‐specific and antigen‐nonspecific suppression. The aim of the current study was to search for similar immunoregulatory phenomena in patients with AIH. We examined T‐cell reactivity to soluble human liver antigens in 11 patients with active autoimmune hepatitis and 30 patients with other liver diseases (chronic viral hepatitis, primary biliary cirrhosis, fatty liver). T‐cell reactivity to liver antigens was almost exclusively confined to the AIH patients. In 9 of these 11 patients we were able to compare the T‐cell response in active untreated disease, directly after initiation of immunosuppressive therapy and in remission, at which point T‐cell reactivity was found to be markedly reduced. Addition of irradiated peripheral blood cells from the active disease phase or the remission phase to the responding cells taken before treatment showed that in eight of the nine patients there was marked suppression of the liver‐specific T‐cell response by cells from the remission phase. Study of the in vivo immune responsiveness by giving a tetanus toxoid booster immunization to nine patients with active untreated AIH as well as healthy controls and patients with other liver diseases showed that none of the patients with AIH showed a response to the tetanus immunization, whereas almost all the other patients showed marked responses. Taken together these results show the presence of active suppression of T‐cell autoreactivityin vitroin AIH and marked nonresponsiveness to in vivo challenge with an unrelated antigen, suggesting generalized spontaneous immunosuppression that is more pronounced in vivo than what can be measuredin vitro. Spontaneous immunosuppression, however, is not sufficient to effectively suppress the disease process. Immunosuppressive therapy is required for remission induction, but is apparently helped by the patient's own immunoregulatory activity. These observations support the concept of peripheral control mechanisms being operative in patients with AIH, and these could be the basis for a more effective and specific immunotherapy of this condition in the future. (Hepatology

ISSN:0270-9139    

DOI:10.1002/hep.1840220202

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractIntrahepatic lymphocytic aggregates are observed in chronic hepatitis C as well as in autoimmune chronic hepatitis. Autoantibodies and autoimmune manifestations may occur in hepatitis C. It has been suggested that the lymphocytic aggregates play a role in the liver injury of chronic hepatitis C by an immune‐mediated mechanism. We studied the occurrence of intrahepatic lymphocytic aggregates and of autoantibodies in a consecutive series of 128 patients with chronic hepatitis C. For the phenotypic characterization of the lymphocytic aggregates cryostat sections and microwaved paraffin embedded sections were immunostained with monoclonal antibodies directed against T cell subsets, B cells, killer/natural killer cells, follicular dendritic cells, and macrophages. Autoantibodies were tested by immunofluorescence (antinuclear, anti‐smooth muscle, antimitochondrial) and by enzyme‐linked immunosorbent assay (anti‐soluble liver antigen, anti‐liver/kidney microsome, anti‐human receptor for asialoglycoprotein). Focal lymphocytic aggregates in portal tracts were observed in 76 of 128 (59%) patients. The cellular composition of the aggregates was constant: a core of B cells mixed with many T helper/inducer lymphocytes, and an outer ring was prominently formed by T suppressor/cytotoxic lymphocytes. A germinal center was rarely identifiable. The presence of lymphocytic aggregates was inversely correlated with the degree of fibrosis. Lymphocytic aggregates appeared more frequently in chronic persistent and chronic active hepatitis in comparison with cirrhosis and in the presence of bile duct damage. No correlation was found between lymphocytic aggregates and autoantibodies or other markers of autoimmunity. The lymphocytic aggregates are frequent in chronic hepatitis C. Their cellular composition is similar to that of primary lymphoid follicles in lymph nodes. Their presence does not seem to be correlated with features of autoimmunity. (Hepatology 1995;

ISSN:0270-9139    

DOI:10.1002/hep.1840220203

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractFenestrations of hepatic endothelial cells play an active role as a sieving barrier allowing extensive exchange between the blood and liver parenchyma. Alteraction of these structures may be induced in the course of various pathological events and provoke important perturbations of liver function. We demonstrate here that sinusoidal endothelial cells are permissive for mouse hepatitis virus 3 (MHV3)in vivoandin vitroand that this infection leads to a striking decrease in the number of fenestrae. The disappearance of these structures observed under scanning electron microscopy or in cryofracture preparationsin vivoandin vitrocannot be reversed by the action of cytochalasin B on the microfilament network. The decrease in the porosity seems to be related directly to the productive infection of the endothelial cells, because it was not observed in A/J mice resistant to the virus and in susceptible BALB/c mice immunized with a thermosensitive mutant in which no viral replication occurs. In conclusion, a viral infection of liver endothelial cells may cause extensive loss of the fenestrations and thus lead to important functional pertubations. (Hepatology 1995; 22:395–401

ISSN:0270-9139    

DOI:10.1002/hep.1840220204

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractThe significance of immunoglobulin (Ig) M antibody to hepatitis C virus core protein (IgM anti‐HCVcore) was studied in 41 patients with chronic hepatitis C virus (HCV) infection diagnosed by the polymerase chain reaction (PCR). IgM anti‐HCVcore was tested with a solid‐phase enzyme‐linked immunoassay. The results were correlated with clinical features, liver histology findings evaluated by the histological activity index, and virological features such as genotypes and viremic levels assessed by a branched DNA assay. IgM anti‐HCVcore was found in 29 (71%) patients, and its occurrence was only related to viremic levels. A significant relationship was observed between viremic levels and IgM anti‐HCVcore cut‐off index (rs= .42,P<.01). Of the eight low viremic (branched DNA‐negative) patients, only two (25%) tested positive for IgM anti‐HCVcore with a low cut‐off index of<3, whereas 27 (82%) of the 33 highly viremic (branched DNA‐positive) patients had IgM anti‐HCVcore (P3 compared with 11 (44%) of the 25 patients with that<3 (P<.05). IgM anti‐HCVcore cut‐off index decreased after therapy in patients who cleared the virus in sera but increased again after reappearance of viremia. These findings suggest that IgM anti‐HCVcore may serve as a simple serological indicator of active virus replication and have relevance to the outcome of antivir

ISSN:0270-9139    

DOI:10.1002/hep.1840220205

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractHepatitis C virus (HCV) has been reported to conform to a quasispecies nature, which is most evident in hypervariable regions of the putative envelope 2 domain. The aim of this study was to determine the relationship between the nucleotide complexity and diversity of hypervariable region 1 and various stages of the carrier states. The subjects studied were 20 HCV carriers with normal alanine aminotransferase (ALT) levels, 50 patients with chronic hepatitis who showed elevated ALT levels, 22 with cirrhosis, and 24 with hepatocellular carcinoma. The quasispecies complexity was analyzed by means of polymerase chain reaction‐mediated single strand conformation polymorphism (PCR‐SSCP). The value of nucleotide diversity was calculated by PCR cloning and sequencing. The number of SSCP bands ranged from 1 to 7, with no significant differences in the mean numbers among the stages of HCV infection. There was no correlation between the amounts of serum HCV RNA and the numbers of SSCP bands. No significant difference was found in the values of nucleotide diversity between carriers with normal ALT levels (mean, 6.6 × 10−2per site) and patients with chronic hepatitis (7.7 × 10−2). These findings suggest that the quasispecies complexity of hypervariable region 1 is independent of the stage of chronic HCV infection. (Hepatology 1995; 22

ISSN:0270-9139    

DOI:10.1002/hep.1840220206

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractTo determine whether the presence of hepatitis C virus (HCV) viremia correlates with the severity of liver disease in anti‐HCV‐positive apparently healthy blood donors, we studied 98 blood donors found positive for anti‐HCV using enzyme‐linked immunosorbent assay (ELISA). Each subject underwent a liver biopsy, a test for HCV RNA in the serum by polymerase chain reaction (PCR), and a panel of liver injury tests. As a result, 97% of the anti‐HCV‐positive blood donors had some type of histological abnormality: 22 (22%) had minimal changes, 1 (1%) had chronic lobular hepatitis, 40 (41%) had chronic persistent hepatitis (CPH), and 32 (33%) had chronic active hepatitis (CAH). Only 3 subjects had a normal liver histology. HCV RNA was detectable in the serum in 65% of the anti‐HCV‐positive donors. HCV RNA in serum was detectable in none of the donors with a normal liver histology, in 36% (confidence interval [CI], 17% to 59%) of those with minimal changes, in 70% (CI, 53% to 83%) of those with CPH, and in 87% (CI, 71% to 96%) of those with CAH (P= .00001). HCV RNA was detectable in 75% of the donors with elevated (>45 U/L) alanine transaminase (ALT) values and in 59% of those with normal ALT levels (P= not significant). The incidence of chronic hepatitis was higher in HCV RNA‐positive than in HCV RNA‐negative donors (88% vs. 50%;P= .00005). By stepwise logistic regression, age older than 50 years (odds ratio = 17.5), an elevated ALT level (odds ratio = 74.4), and serum HCV RNA (odds ratio = 18.9) were independently associated with the presence of chronic hepatitis. In summary, in anti‐HCV‐positive blood donors the prevalence of HCV RNA in serum appears to correlate with the severity of liver injury and is greatest in CAH. The detection of serum HCV RNA in 36% of the donors with minimal changes on biopsy, all of them with normal ALT levels, suggests that a healthy HCV carrier state may exist. (Hepat

ISSN:0270-9139    

DOI:10.1002/hep.1840220207

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractWe investigated anti‐hepatitis C virus (HCV) titers, HCV RNA levels in liver and serum, genetic variability in the hypervariable region of the genome, the form of the virus in the circulation, and liver histology in 21 anti‐HCV‐positive subjects with sustained normal liver biochemical values. Titer of anti‐HCV was determined by second generation anti‐HCV‐passive hemagglutination assay, and HCV RNA levels were semiquantitated by reverse transcriptase polymerase chain reaction (PCR). In 19 (90%) of the 21 subjects who had a higher titer of anti‐HCV (⩾214), HCV RNA was detected in both serum and liver, and histological examination showed minimal or mild chronic hepatitis in all. In the remaining 2 patients who had a lower titer of anti‐HCV, HCV RNA was not detected in serum and liver, and liver histology was normal. Anti‐HCV titers and HCV RNA levels in serum and liver in the 19 HCV RNA‐positive subjects were compared with those levels in the 41 patients with biopsy‐proven chronic hepatitis C and elevated serum aminotransferase levels as a control group. There were no significant differences in viral levels in serum and liver between the two groups. To further investigate virological differences between the two groups with regard to degree of genetic variability and the form in the circulation, we performed the PCR‐single strand conformation polymorphism (PCR‐SSCP) of the hypervariable region 1 and the immunoprecipitation analyses. PCR‐SSCP showed that the anti‐HCV‐positive subjects with normal liver biochemical values had quasispecies nature of the HCV genome similar to the patients with chronic hepatitis C, and the immunoprecipitation analysis showed that the virus circulated both in immune complexes and in the free form in both groups. These findings indicated that both groups had similar virological characteristics but showed different patterns of serum aminotransferase levels and histological findings, suggesting that the two groups may have different immune responses to the viru

ISSN:0270-9139    

DOI:10.1002/hep.1840220208

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractTo evaluate the effect of interferon alfa (IFN‐α) on the hepatic extracellular matrix, we investigated the changes in serum N‐terminal propeptide of type III procollagen during and after 4 months of INF‐α treatment in 178 treated and 45 nontreated patients with chronic hepatitis C. Serum pretreatment levels in nonresponders were significantly higher than those in long‐term and short‐term responders, but those levels were not different in the latter two groups. Serum propeptide levels decreased significantly during and after IFN‐α therapy in the treated patients, although those levels were unchanged in the nontreated patients. This decrease was sustained for 12 months after IFN‐α was completed not only in long‐ but also in short‐term responders and nonresponders. Serum propeptide levels decreased in those with elevated pretreatment levels, but not in those with normal initial levels, whereas serum transaminase levels decreased similarly in both groups. The changes in serum propeptide levels during and after treatment were more closely correlated with the initial levels compared with those in serum transaminase levels. These results suggested that IFN‐α treatment induces the long‐term suppression of active fibrogenesis in chronic hepatitis C independent of antiviral and anti‐necroinflammatory effects, thus preventing progression to cirrhosis. (

ISSN:0270-9139    

DOI:10.1002/hep.1840220209

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractObjective: To prospectively determine the prevalence and annual incidence of hepatocellular carcinoma in hepatitis B carriers in a heterogeneous urban North American population and to assess the diagnostic accuracy of tests used for screening for this cancer. Design: Prospective cohort study of 1,069 chronic carriers of hepatitis B virus using screening with α‐fetoprotein alone or in combination with ultrasonography every 6 months. Results: The mean age of the cohort was 39 ± 12 years (± SD), 65% were men, 71% were Asians. At the first screening visit, serum α‐fetoprotein was ⩾ 20 μg/L in 4%. In those subjects who were also screened by ultrasonography during the first visit, 9% were found to have focal lesions. Only 3 subjects were found to have hepatocellular carcinoma at the first screening, giving a prevalence of 281/100,000 chronic carriers of hepatitis B virus. The cohort was followed for 2,340 person‐years (mean, 26 months follow‐up, with a range from 6 to 60 months). During this period, 11 more subjects, 10 men and 1 woman, were diagnosed to have hepatocellular carcinoma (annual incidence, 470/100,000). In men only, the annual incidence was 657/100,000. During the study, 5 subjects died from hepatocellular carcinoma (annual mortality rate, 214/100,000). Sensitivity and specificity of serum α‐fetoprotein>20 μg/L were 64.3% and 91.4%, respectively. For ultrasonography, sensitivity was 78.8% and specificity 93.8%. Conclusions: These data suggest that the incidence and prevalence of hepatocellular carcinoma in hepatitis B carriers in our area, an urban North American setting, are as high as in countries where hepatitis B is endemic. Current screening tests have significant false‐positive and false‐negative rates, raising questions about the cost‐benefit of screening for hepatocellular carcinoma in our study population. (Hep

ISSN:0270-9139    

DOI:10.1002/hep.1840220210

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractRoutine screening of blood donors for anti‐hepatitis C virus (HCV) has been implemented in most developed countries. However, the independent efficacy of such screening has not been established in a controlled, prospective study. We tracked 478 patients transfused with anti‐HCV‐negative blood by first‐generation enzyme‐linked immunoassay (EIA) between July 1989 and May 1990 and compared the incidence of transfusion‐associated hepatitis and HCV infections with that found among 280 patients transfused with blood unscreened for anti‐HCV during the immediately preceding year. Of the 280 patients who had received transfusions before donors were screened for anti‐HCV, 27 (9.6%) developed posttransfusion hepatitis and 1 additional patient sero‐converted to anti‐HCV without evidence of hepatitis, for a risk of posttransfusion HCV infection of 10.7% (28 of 262 recipients seronegative for anti‐HCV before transfusion). Of the 478 patients transfused after July 1989 with blood screened for anti‐HCV, only 9 (1.9%) developed posttransfusion hepatitis for a risk reduction of 80%. Seven of the 9 residual cases of hepatitis were caused by HCV (7 of 456 recipients seronegative before transfusion or 1.5%) for a risk reduction of transfusion‐associated HCV infection of 86%. In retrospect, an anti‐HCV positive donor was detected by second‐generation immunoassay in 4 (57%) of the 7 HCV cases from the study cohort and in 19 of the 23 (83%) cases from whom all donor samples were available for testing in the historical cohort. No additional infectious donors were detected by third‐generation immunoassay or serum HCV‐RNA by polymerase chain reaction. Implementation of donor screening for anti‐HCV with a first‐generation immunoassay appeared to be independently associated with an 80% and 86% reduction in the risks of transfusion‐associated hepatitis and HCV infection, respectively. Screening of donors with second‐generation immunoassays might have further reduced the risk by 57%. An additional 0.4% may be at risk of developing non‐A, non‐B,

ISSN:0270-9139    

DOI:10.1002/hep.1840220211

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY