摘要:

AbstractWe investigated amino acid heterogeneity in the variable regions of the E2/NS1 viral protein in interferon‐responsive and interferon‐nonresponsive patients with chronic hepatitis C virus infection. The study assessed whether any particular heterogeneity pattern(s) could be useful in predicting responsiveness to interferon treatment. The nucleic acid sequences of the hepatitis C virus genome were analyzed from six patients with chronic hepatitis treated with an interferon‐β, three of whom did not respond to the therapy and another three who showed remarkable improvement in the serum levels of liver enzymes and hepatitis C virus RNA after 6 mo. The complementary DNA clones propagated from each of the nonresponders showed significant diversity of both nucleotide and amino acid sequence, especially at the hypervariable region 1 within the putative E2/NS1 gene of the virus, suggesting that these patients were infected with a large heterogeneous pool of hepatitis C virus variants. In contrast, the responders showed little or no diversity in the sequence of the complementary DNA clones, suggesting that they were infected with one or a small population of viral genotypes containing significantly less variability in the E2/NS1 hypervariable region 1. These results suggested that a large variable population of hepatitis C virus genotypes is implicated in patients who are nonresponders to interferon treatment. In addition, a significant change in the hepatitis C virus genotype population was observed in nonresponders after interferon treatment. This may reflect a differential viral sensitivity to interferon, selective immune pressure by the host or both. (HEPATOLOGY1992;16:61

ISSN:0270-9139    

DOI:10.1002/hep.1840160302

出版商:W.B. Saunders    

年代:1992

数据来源: WILEY

摘要:

AbstractForty‐six patients with chronic hepatitis delta virus infection were followed between 6 and 116 mo (mean = 32.8 mo; median = 24 mo). Nineteen patients (41%) demonstrated clinical courses with episodes of biochemical reactivation (ALT levels ≥ 10 times baseline values [group A]). Twenty‐seven patients (59%) had stable clinical courses without biochemical reactivation (group B). Patients in group A were younger than those in group B (30.5 vs. 35.3 yr; p = 0.03), were less likely to be intravenous drug abusers (16% vs. 52%; p = 0.01) and were more likely to be homosexual (58% vs. 22%; p = 0.01). Serum hepatitis B virus DNA, hepatitis delta virus RNA, IgM antibody to HBc, HBeAg, antibody to HBe and IgG and IgM antibody to hepatitis delta virus were measured in all patients. In group A, these markers were studied before and during reactivation and during remission. In group B, these parameters were studied in a random fashion at 7‐ to 10‐mo intervals. The presence of antibodies to human immunodeficiency virus and hepatitis C virus was assessed in all patients. A total of 38 biochemical reactivation episodes was noted among the 19 patients in group A. Eleven had sequential changes in hepatitis delta virus markers, suggesting that the exacerbations were due to hepatitis delta virus. In three, the sequential changes of viral markers were consistent with the exacerbations due to hepatitis B virus. In five other patients, no sequential changes in viral markers could be demonstrated to correlate with the biochemical exacerbations. Hepatitis C virus markers were found in 2 of the 19 patients; these two patients were in the group of 11 who had evidence of sequential changes of hepatitis delta virus markers with biochemical exacerbations. Of the patients in the control group (group B) who had stable biochemical courses, 10 had replication of hepatitis delta virus alone, four demonstrated replication of both hepatitis delta virus and hepatitis B virus and two demonstrated replication of hepatitis B virus alone. The viral markers did not reveal sequential or significant fluctuations in this group. In conclusion, the overall prevalence of biochemical reactivation episodes among our subjects with chronic hepatitis delta virus infection was 41%. In 58% of these patients, the episodes were related to hepatitis delta virus activity, whereas in 16% they were related to hepatitis B virus activity. Hepatitis C virus coinfection was rare in this study group. (HEPATOLOGY1992;16

ISSN:0270-9139    

DOI:10.1002/hep.1840160303

出版商:W.B. Saunders    

年代:1992

数据来源: WILEY

摘要:

AbstractRecent studies have shown that hepatitis C virus antibodies are present in a large proportion of patients with autoimmune hepatitis type 2. We have studied 83 patients with liver/kidney microsome antibody‐positive type 1 hepatitis. Hepatitis C virus antibodies were sought in every case by second‐generation tests (hepatitis C virus enzyme‐linked immunosorbent assay and recombinant immunoblot assay). Hepatitis C virus RNA sequences were sought in 22 patients (12 with recombinant immunoblot assay‐positive results and 10 with recombinant immunoblot assay‐negative results) by means of polymerase chain reaction and by use of primers located in the 5′ noncoding region. Sixty‐four patients (77%) had positive results for hepatitis C virus antibodies in the enzyme‐linked immunosorbent assay test, and 41 (49.3%) were confirmed by recombinant immunoblot assay. Hepatitis C virus RNA sequences were found in all the recombinant immunoblot assaypositive patients but in none of the 10 who were recombinant immunoblot assay‐negative. The recombinant immunoblot assay‐negative patients were younger than those who were positive (13 ± 11 vs. 50 ± 11 years) and had higher γ‐globulin levels and liver/kidney microsome antibody‐positive type 1 titers (61% had a titer of 1:1,000 or more, vs. only 17% of the recombinant immunoblot assay‐positive patients). On the basis of these results, chronic hepatitis with liver/kidney microsome antibody‐positive type 1 can be divided into two subgroups: (a) true autoimmune hepatitis type 2 (mainly observed in young women), with high titers of liver/kidney microsome antibody‐positive type 1, and in which direct autoimmune mechanisms appear to be prominent; and (b) hepatitis C virus‐associated hepatitis with liver/kidney microsome antibody‐positive type 1 (generally affecting older patients, especially men), with low titers of liver/kidney microsome antibody‐positive type 1, and in which the autoimmune process could be a consequence of hepatitis C virus

ISSN:0270-9139    

DOI:10.1002/hep.1840160304

出版商:W.B. Saunders    

年代:1992

数据来源: WILEY

摘要:

AbstractThe prevalence of hepatitis B and C virus infections was studied in 70 patients diagnosed as having hepatocellular carcinoma. In addition to viral serological markers, serum hepatitis B virus DNA and hepatitis C virus RNA were determined with a nested polymerase chain reaction assay. Twelve patients (17%) were HBsAg positive, 26 (37%) had antibodies to HBs, HBc or both and 32 (46%) were negative for all hepatitis B virus serological markers. Prevalence of the antibody to hepatitis C virus was 63% (44 patients). Hepatitis B virus DNA was detected in 24 of the 66 tested patients (36%). Twelve of these hepatitis B virus DNA‐positive patients were HBsAg negative (seven were positive for antibody to HBs, antibody to HBc or both and five were negative for all hepatitis B virus serological markers). Hepatitis C virus RNA was found in 42 of 68 patients (62%): A high correlation (95%) existed between hepatitis C virus RNA and hepatitis C virus antibodies. Nevertheless, two patients without antibody to hepatitis C virus had serum hepatitis C virus RNA sequences. Coinfection by the two viruses was detected in nine subjects (14%), but no clinical differences were found between these and the rest of the patients. We conclude that nearly 90% (62 of the 70 patients studied) of cases of hepatocellular carcinoma in our geographical area are related to hepatitis virus infections (detected by serological or molecular studies). Hepatitis C is more prevalent than hepatitis B virus in patients with hepatocellular carcinoma, and the infection is still active when the tumor is diagnosed. This fact is probably important in the contribution of hepatitis C virus to the development of hepatocellular carcinoma. (HEPATOLOGY1992;16:637–6

ISSN:0270-9139    

DOI:10.1002/hep.1840160305

出版商:W.B. Saunders    

年代:1992

数据来源: WILEY

摘要:

AbstractAnin situhybridization method using radiolabeled oligonucleotide probes was developed to study primary sites of hepatitis A virus replication in an experimental animal model of infection. Hepatitis A genomic sequences were demonstrated in hepatocytes of four marmosets with acute hepatitis A by use of antisense probes. In two of these animals, staining was also found when a sense probe was used, which is consistent with active replication in the hepatocytes. The specificity of the hybridization signal was confirmed by neutralization with “cold” (i.e., unlabeled) probes and by absence of hybridization with non‐A hepatitis and reverse antisense probes. The hepatocyte appeared to be the only cell type showing staining. No hybridization was found in other organs, including the intestine (n = 4) and, in one animal, the kidney and spleen. (HEPATOLOGY1992;16:642

ISSN:0270-9139    

DOI:10.1002/hep.1840160306

出版商:W.B. Saunders    

年代:1992

数据来源: WILEY

摘要:

AbstractInterferon‐α therapy is of proven efficacy in chronic hepatitis C, but it is not universally effective and may be associated with intolerable side effects. Ribavirin is a nucleoside analog with a broad spectrum of antiviral action. We conducted an uncontrolled pilot study of ribavirin therapy in 13 patients with chronic hepatitis C. Ribavirin was given for 6 mo, in a dose that was increased, at 2‐mo intervals, from 600 mg to 1,000 mg to 1,200 mg/day. Serum ALT levels gradually decreased in all 13 treated patients; the mean percentage of decrease was 67% (from 210 U/L [range = 109 to 593] to 63 U/L [range = 22 to 108 U/L]; p = 0.0006) after 6 mo of treatment. Serum aminotransferase levels fell to the normal range in four patients (31%). In the 3 to 6 mo after cessation of ribavirin therapy, serum aminotransferase activities gradually rose to near pretreatment levels in all but one patient. Therapy was associated with a significant decrease in the geometric mean titer of hepatitis C virus RNA in serum (1:1,981 vs. 1:199; p<0.02) although no patients lost hepatitis C virus RNA from serum during therapy. No significant improvement was seen in liver histological appearance. Ribavirin therapy resulted in mild, reversible hemolysis; no patient exhibited symptomatic anemia. These findings suggest that ribavirin has a beneficial effect in patients with chronic hepatitis C, although further studies are needed to determine how ribavirin is best used. (HEPATOLOGY1992;16:649

ISSN:0270-9139    

DOI:10.1002/hep.1840160307

出版商:W.B. Saunders    

年代:1992

数据来源: WILEY

摘要:

AbstractThe role that inflammatory cytokines may play in the life cycle of the hepatitis B virus and in the pathogenesis of its associated liver disease has not been carefully delineated. In this report, we demonstrate that bacterial lipopolysaccharide, a potent inducer of inflammatory cytokinesin vivo, causes a severe acute liver disease in transgenic mice whose hepatocytes produce the hepatitis B virus large envelope polypeptide and retain HBsAg within the endoplasmic reticulum. In contrast, 100‐fold higher doses of bacterial lipopolysaccharide do not induce liver cell injury in nontransgenic littermate controls or in transgenic mice whose hepatocytes secrete HBsAg rather than retain it. Coincident with the hepatocellular injury and the influx of inflammatory cells into the liver, a marked reduction occurs in the intrahepatic content of hepatitis B virus steady‐state messenger RNA, thereby confirming the selectivity of this process for the HBsAg‐positive hepatocyte. Bacterial lipopolysaccharide‐induced hepatocellular injury appears to be principally mediated by interferon‐γ because it can be markedly reduced by the prior administration of neutralizing interferon‐γ–specific monoclonal antibodies and because recombinant interferon‐γ is also selectively cytotoxic for the HBsAg‐positive transgenic hepatocytein vivo.Tumor necrosis factor–α is also involved in this process because bacterial lipopolysaccharide‐induced liver cell injury is significantly reduced by tumor necrosis factor–α specific monoclonal antibodies. The role of tumor necrosis factor–α in bacterial lipopolysaccharide–induced liver cell injury is less clear than interferon‐γ, however, because unlike interferon‐γ it is also toxic for nontransgenic hepatocytes. These results demonstrate that the HBsAg‐positive transgenic mouse hepatocyte is selectively sensitive to destruction by interferon‐γin vivo.Because this cytokine has been shown to be produced by intrahepatic lymphocytes during viral hepatitis in humans, these results raise the possibility that a similar pathway may contribute to the clearance of HBsAg‐positive hepatocytes and to the pathogenesis of liver cell injury in human HBV

ISSN:0270-9139    

DOI:10.1002/hep.1840160308

出版商:W.B. Saunders    

年代:1992

数据来源: WILEY

摘要:

AbstractImmunoglobulin secretion by B lymphocytes is a complex process in which lymphokines secreted by T lymphocytes play an important regulatory role. Increased serum levels of IgA and IgG have been characteristically detected in patients with alcoholic cirrhosis. We have studied the functional alterations of T and B lymphocytes implicated in the physiopathology of this common immunoglobulin abnormality. After activation with phytohemagglutinin, purified T cells from alcoholic cirrhotic patients showed significantly enhanced secretion of B‐cell differentiation factors for IgG and IgA with respect to those secreted by T cells from healthy controls (p<0.05). Simultaneously, normal secretion of B‐cell differentiation factor for IgM was demonstrated in T lymphocytes from these patients. The pattern of secretion of the lymphokines involved in the regulation of the B‐cell differentiation pathway found in alcoholic cirrhotic patients was different from that of the primary biliary cirrhotic patients studied. Purified B cells from patients with alcoholic cirrhosis secreted significantly higher amounts of IgA and IgG than did those found in healthy controls, both spontaneously (p<0.05) and after sequential activation with immunoglobulin ligands (Staphylococcus aureusCowan I) and a standard B‐cell differentiation factor preparation (p<0.05). By contrast, the IgM secretion and regulatory pathway were normal in alcoholic cirrhotic patients. These results support a physiopathological explanation for the characteristic hyperimmunoglobulinemia found in patients with alcoholic cirrhosis. (HEPATOLOGY1992;16:6

ISSN:0270-9139    

DOI:10.1002/hep.1840160309

出版商:W.B. Saunders    

年代:1992

数据来源: WILEY

摘要:

AbstractTwenty‐six adult patients with preformed IgG donor lymphocytotoxic antibodies received primary liver allografts under FK 506 immunosuppression. The effect of the crossmatch‐positive state on early graft function and on the immunopathological and histopathological findings was compared with that of 52 crossmatch‐negative control recipients. The presensitized (crossmatch‐positive) patients had prolongation of early graft dysfunction, underwent more clinically indicated biopsies and had a higher incidence of cellular rejection, both overall (p<0.05) and within 10 days of transplantation (p<0.01). They also had a higher incidence of graft failure in the first 180 days (p<0.01). Hyperacute rejection with necrotizing or neutrophilic arteritis was not seen in the crossmatchpositive grafts. However, histological findings associated with presensitization included platelet margination in central veins and sinusoids in biopsy specimens 60 to 90 min after graft revascularization. Later biopsy specimens had neutrophilic portal venulitis followed by cholangiolar proliferation, acute cholangiolitis and centrilobular hepatocyte swelling that mimicked preservation injury, endothelial activation of arteries with medial changes and relapsing episodes of acute cellular rejection. These clinicopathological observations suggest that lymphocytotoxic antibodies can have a deleterious effect on liver allograft function and survival, even if they do not precipitate immediate or hyperacute rejection. (HEPATOLOGY1992;16:6

ISSN:0270-9139    

DOI:10.1002/hep.1840160310

出版商:W.B. Saunders    

年代:1992

数据来源: WILEY

摘要:

AbstractThe localization of the expression of several cytochrome P‐450 genes in normal and diseased human liver was investigated byin situhybridization of formalin‐fixed, paraffin wax–embedded archival tissue samples with35S‐labeled antisense RNA probes. The results demonstrated that genes coding for members of the cytochrome P‐450 3A subfamily (CYP3A) were preferentially expressed in hepatocytes in acinar zone 3 (the centrilobular region), whereas genes coding for CYP1A2, CYP2A, 2B and 2C were expressed uniformly throughout the liver acinus. In cirrhotic livers, CYP2A and 2B genes (and to a lesser extent, CYP3A genes) were highly expressed in isolated hepatocytes located at the junction of parenchyma with fibrous septa. The cause and significance of the position‐dependent expression of specific cytochrome P‐450 genes in normal and diseased human liver are discussed. (HEPATOLOGY199

ISSN:0270-9139    

DOI:10.1002/hep.1840160311

出版商:W.B. Saunders    

年代:1992

数据来源: WILEY