摘要:

AbstractThe efficacy of recombinant interferon‐alfa therapy in children with chronic hepatitis C has been evaluated in a randomized, controlled pilot study including 27 patients, aged 2 to 14 years, without underlying systemic diseases. On entry, all patients had abnormal alanine transaminase (ALT) levels, 22 were hepatitis C virus (HCV) RNA positive, 19 had mild chronic active hepatitis, and 8 had chronic persistent hepatitis on liver biopsy. Fourteen children received 5 MU/m2of recombinant interferon‐alfa2b thrice weekly for 4 months. If at this time ALT had been reduced to at least 50% the baseline level, treatment was continued up to 12 months. The other 13 children remained untreated. The whole follow‐up period lasted 24 months. Interferon was stopped at 4 months in 4 children because of an ALT increase (2 cases), unchanged ALT and febrile convulsions (1 case), and slight ALT decrease (1 case). This latter patient, however, had normal ALT at 6 months and throughout further follow‐up, and cleared HCV RNA, thus behaving as a sustained responder. All 10 children treated for 12 months had normal levels of ALT, and 9 were HCV RNA negative at the end of treatment. Of the 9 children who could be followed to 24 months, 4 relapsed soon after therapy withdrawal and 5 maintained a sustained biochemical and virologic response. Overall, 6 (43%) of 14 treated children had a sustained ALT normalization associated with HCV RNA clearance as compared with only 1 (7.5%) untreated child who had a sustained ALT normalization but did not clear HCV RNA. These results suggest that recombinant interferon therapy, at the regimen used in this study, may induce sustained ALT normalization and HCV clearance in a significant proportion of children with chronic hepatitis C. (Hepatology 1995;22:162

ISSN:0270-9139    

DOI:10.1002/hep.1840220602

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractThe precore stop‐codon variant of hepatitis B virus (HBV) has been implicated in fulminant hepatitis. The precore/core regions of such variants from two sets of patients with interpartner transmission resulting in fulminant hepatitis in the contact, were sequenced to establish whether further sequence variations in the core region are specifically associated with the fulminant disease. In both sets of patients, there was sequence diversity of the precore/core region from the wild type, leading to numerous amino acid substitutions in the core region. Between the infecting source and the contact, there was only one amino acid change in one set of patients and none in the other. In addition, in the second set of patients, serum samples from four different time points were investigated. Sequence data showed no variation in each patient at the nucleotide level in the core region, even in the case of the source, who was followed for 3 years. In this same pair of subjects, the remainder of the genome was sequenced and was identical at the nucleotide level. Therefore, it appears that, at least in some cases of fulminant hepatitis caused by infection with the precore variant, the nucleotide sequence of the patient with fulminant hepatitis is identical to that observed in the asymptomatic source of infection. These data indicate that the severity and outcome of infection in such cases are unrelated to any additional variation in the entire HBV genome, and that the changed clinical picture is dependent on host factors, possibly the HLA environment. HLA typing of both the contact and source in the two sets of patients revealed that the contacts with fulminant hepatitis had one or more alleles at the HLA class II locus, previously shown to be associated with an acute hepatitis sufficient to clear the virus. (Hepatology 1995; 22:1628‐16

ISSN:0270-9139    

DOI:10.1002/hep.1840220603

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractImmunoglobulin M (IgM) antibody to hepatitis C core antigen (anti‐HCV‐core) was tested by enzyme immunoassay against a synthetic peptide representing amino acids 1 to 62 of the core protein. Of 214 patients with different categories of histological activity, 193 (90%) showed positive results for IgM anti‐HCV‐core, and 207 (97%) had HCV RNA; most cases (186, 87%) had both markers detectable simultaneously. No differences in the frequency of IgM anti‐HCV‐core were observed with respect to epidemiological, biochemical, or histological parameters. In 175 interferon alfa (IFN‐α) recipients, and in 39 untreated controls, pretreatment IgM anti‐HCV‐core frequencies were similar: 28 of 32 (88%) in sustained responders; 55 of 61 (90%) in responders with relapse; 72 of 82 (88%) in nonresponders; and 38 of 39 (97%) in untreated controls. After IFN‐α therapy, IgM anti‐HCV‐core levels became undetectable with significantly greater frequency in sustained responders (P= .014); a similar trend was observed for HCV RNA (P<.0001). IgM anti‐HCV‐core levels decreased after therapy in responders (P<.001) but increased in nonresponders. Fifty‐one cases were longitudinally tested in relation to long‐term disease outcome. Both markers remained detectable in most nonresponders with persistent liver disease, in most responders before relapse, and in all but one case at the time of biochemical relapse. IgM anti‐HCV‐core and HCV RNA became undetectable in most sustained responders, but reappeared despite a long‐lasting transaminase normalization, behaving as asymptomatic HCV carriers; the possibility that disease reactivation may take place years afterwards cannot be excluded. These data indicate that IgM anti‐HCV‐core may be useful in the assessment of HCV replication and in monitoring biochemical and virological responses to IFN

ISSN:0270-9139    

DOI:10.1002/hep.1840220604

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractThe precore‐core gene of hepatitis B virus (HBV) was directly sequenced from serum samples of 42 patients with chronic B hepatitis (19 hepatitis B e antigen [HBeAg]+ and 23 anti‐HBe+). Viral genotypes were determined by comparison with 11 reference sequences and by restriction analysis. Genotype A was identified in 16 cases, genotype D in 24 cases, and other genotypes in 2 cases. Precore mutations, mainly M1 (stop at codon 28), were differently distributed among the viral genotypes: 3 cases (18.8%) with genotype A and 18 cases (75%) with genotype D. In sequences with precore mutants, the encapsidation signal was more stable (negative stabilization energy) than in sequences without precore mutants. In genotype A, the M1 mutation coexisted with a second mutation (C → T at position 1858 in codon 15), and both mutations were paired in the secondary structure of the RNA encapsidation signal, which justified the rare presence of precore mutants in this genotype. The analysis showed different distribution of mutations depending on the viral genotype; patients with genotype D were more likely to have persistent HBV infection by selection of precore mutants. Multiple amino acid substitutions were detected in the core region, mainly in two subsequences that have been previously described as epitopes (flanked by codons 11 to 27 and 74 to 83); the presence of these mutations was significantly related to the presence of precore variants which abolished the expression of HBeAg. The study of viral genotypes in chronic HBV infection may be valuable in predicting the persistence of viral replication after seroconversion to anti‐HBe and suggest that the outcome of chronic infection may be affected by the HBV variability. (Hepatology 1995; 22:164

ISSN:0270-9139    

DOI:10.1002/hep.1840220605

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractThe serine proteinase of hepatitis C virus (HCV) nonstructural protein NS3 was efficiently expressed in an active form as a fused protein with oligohistidine inEscherichia coli. The recombinant fusion protein was purified to near homogeneity by affinity chromatography on a metal chelation column.Trans‐cleavage activity of this protein was investigated by using the substrate NS5 protein expressed in insect cells. The purified serine proteinasetrans‐cleaved the partially purified NS5 protein. In contrast, the NS3 proteins with mutations at the proposed catalytic site, Ser1165or His1083, lost thetrans‐cleavage activity. Analysis of the authentic enzyme and variants with site‐directed mutations provides a useful tool for understanding the structure‐function relationship of the NS3 serine proteinase. We then developed anin vivo trans‐cleavage assay system by coexpression of the NS3 proteinase and the NS5 substrate inE coli, and examined the effect of known inhibitors of serine proteinase. Inhibition of its proteolytic activity byN‐p‐tosyl‐L‐lysine chloromethyl ketone (TLCK) was observed, but only at high concentrations. Thein vitroandin vivo trans‐cleavage assays for NS3 serine proteinase will facilitate efficient testing for inhibitors of the replication of HCV and specific treatment for hepatitis C. (Hepatolog

ISSN:0270-9139    

DOI:10.1002/hep.1840220606

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractTo study sexual transmission of hepatitis D virus (HDV), 52 spouses of 56 index patients were observed and HDV genomes from antibody to HDV (anti‐HDV)‐positive couples were sequenced. Of the spouses, 11 (21%) were serum HBsAg positive, 3 (27%) of whom were also anti‐HDV positive. The HDV sequences between spouses were found to be nearly identical (98% to 98.8%) in the region analyzed (nt 911 to nt 1260). Only one couple showed an identity>90% with the genotype I HDV strains. The HDV sequences of the remaining two couples showed>95% identity with each other and>91% homology with genotype II, but they shared only a 73.1% to 73.7% homology with those of the first couple. The regions corresponding to the autocatalytic cleavage sites, the junction between the middle and the carboxyl terminal one‐third domains, and the middle domain of the open reading frame for delta antigen on the antigenomic HDV RNA were more conserved with<19% divergence among the three couples. Interestingly, there was a 56% divergence in the region corresponding to the carboxyl end of the open reading frame for the large delta antigen on the antigenomic HDV RNA. In summary, this study provides a direct nucleotide evidence of a common source of HDV infection in each couple. Despite divergence in the viral nucleotide sequence, both genotypes I and II were found in Taiwan and were transmitted from patients with a history of prostitute contact to spouses through sexual contact. (Hepatology 1995; 22:165

ISSN:0270-9139    

DOI:10.1002/hep.1840220607

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractWe recently observed that more than one third of pediatric patients who presented with non‐A, non‐B fulminant liver failure (FLF) also developed aplastic anemia (AA) either before or shortly after liver transplantation. Factors involved in the suppression of bone marrow could be the same as those causing hepatic failure. We considered parvovirus B19 a candidate etiologic agent because of the known tropism of B19 for erythroid precursors. Archived liver and serum from six patients undergoing liver transplantation for non‐A, non‐B, non‐C FLF with associated AA were analyzed for the presence of B19 DNA and anti‐B19 serology. An age‐ and gendermatched control group (N = 44) was analyzed in parallel. B19 DNA studies and anti‐B19 serology were performed in a blinded fashion. B19 serologies were performed by antibody capture enzyme‐linked immunosorbent assay (ELISA). B19 DNA was detected after polymerase chain reaction (PCR) amplification of target B19 DNA sequences in liver and serum. Liver tissue showed evidence of B19 DNA in four of six (66%) patients with FLF and associated AA. Two of 4 patients with cryptogenic FLF but without AA had B19 DNA detected in the liver tissue. Of the 34 remaining controls, only 5 (15%) showed evidence of B19 DNA in liver tissue (66% vs. 15%,P= .016). B19 DNA was not detected in any of the test or control sera. This study provides evidence to support the role of parvovirus B19 in the development of FLF and associated AA. (Hepatology 19

ISSN:0270-9139    

DOI:10.1002/hep.1840220608

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractAn increased release of nitric oxide (NO), a powerful vasodilating agent, has been proposed to play a role in the pathogenesis of vasodilation and hyperdynamic circulation associated with advanced cirrhosis. We evaluated NO synthase (NOS) activity in peripheral leukocytes of 12 cirrhotic patients and 9 healthy subjects together with plasma endotoxin levels and systemic hemodynamic (by a noninvasive echocardiographic method). NOS activity was evaluated by (1) measuring the capacity of isolated polymorphonuclear cells (PMNs) and monocytes to convert [3H]arginine to [3H]citrulline; (2) measuring the ability of neutrophils and monocytes to inhibit thrombin‐induced platelet aggregation and to increase guanosine 3′‐5′‐cyclic monophosphate content in coincubated platelets, an expression of NO release from these cells. Both neutrophils and monocytes from cirrhotic patients produced significantly higher amounts of [3H]citrulline than cells obtained from healthy subjects (P<.001 andP<.02 for neutrophils and monocytes, respectively) and were more effective than control cells in inhibiting platelet aggregation (P<.05 andP<.001, respectively for 2 × 106cells) and in increasing guanosine 3′‐5′‐cyclic monophosphate content in coincubated platelets (P<.05 andP<.001, respectively). The anti‐aggregating activity expressed by leukocytes has a pharmacological profile similar to that described for NO, because it increased after addition of superoxide dismutase, a superoxide anion scavenger, and markedly decreased after inhibition of nitric oxide synthesis withNG‐monomethyl‐L‐arginine (L‐NMMA) andNG‐nitro‐L‐arginine‐methyl ester (L‐NAME). Cirrhotic patients had significantly higher plasma endotoxin levels (P<.001) and cardiac index (P<.01) when compared with controls. These data support the contention that the NO synthetic pathway is activated in cirrhotic patients with ascites, hyperdynamic circulation, and endoto

ISSN:0270-9139    

DOI:10.1002/hep.1840220609

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractPreoperative distinction between focal nodular hyperplasia (FNH) that should be managed conservatively and hepatocellular adenoma (HA) that should be resected remains difficult. The result is controversial management of these patients. The aims of this study were to report the value of modern imaging procedures for noninvasive diagnosis of these lesions, to assess the value of intraoperative frozen section studies, and to propose a management strategy in those patients. Fortyone consecutive women with FNH (35 cases) or HA (6 cases) treated at our institution between 1985 and 1992 were studied. New imaging techniques, including enhanced magnetic resonance imaging (MRI) and color Doppler ultrasonography (US), were prospectively appraised in addition to usual techniques. Histological examination of surgical specimens was obtained in all cases. A sixfold increase in the number of patients with FNH was observed during this study, whereas the number of patients with HA did not change. FNHs were incidental US findings in 74% of the cases. The best imaging procedure in the diagnosis of FNH was enhanced MRI with a sensitivity of 70% and a specificity of 98%. Color Doppler US was a useful adjunct. Intraoperative frozen section studies were performed in 16 patients with 19 tumors with a sensitivity of 89% and a specificity of 100%. From this study, we have come to the following conclusions: (1) in women, FNH is now much more often detected than HA; (2) using enhanced MRI, a preoperative diagnosis of FNH is possible in 70% of the cases, avoiding unnecessary surgery; (3) when clinical, biochemical, or imaging data are not typical of FNH, histological diagnosis is mandatory and can be safely and consistently made on large surgical biopsy specimens; (4) during surgery, a decision to resect or not resect a lesion can be efficiently assisted by frozen‐section studies. (Hepatology 1995; 22:1674‐16

ISSN:0270-9139    

DOI:10.1002/hep.1840220610

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY

摘要:

AbstractWe performed a partial splenic arterial embolization in 22 patients with cirrhosis associated with thrombocy‐topenia and then evaluated the changes in platelet kinetics after undergoing the procedure using111In‐tropolone–labeled platelets. The controls consisted of eight chronic hepatitis patients who showed a normal platelet count and normal spleen size. The mean splenic infarction ratio after the procedure was 54.9%. A platelet kinetics study was performed before and 2 months after the procedure. Before the procedure, the cirrhotic patients showed increases in the splenic volume and the spleen/liver uptake ratio of the111In‐labeled platelets on both the third and seventh days, and a decrease in the platelet recovery compared with the controls, which suggested an increased platelet pool in the spleen. In addition, the platelet survival time in cirrhotic patients was shortened, whereas the platelet‐associated immuno‐globulin G (PA‐IgG) was higher than that of the controls, which suggested the involvement of immunologic mechanisms in the thrombocytopenia. With an increase of the platelet count after a partial splenic arterial embolization, the spleen/liver uptake ratio of the111In‐labeled platelets decreased, whereas the platelet recovery increased. Furthermore, the platelet survival time was prolonged, whereas the PA‐IgG decreased. The platelet count showed a positive correlation with the platelet survival time and a negative correlation with PA‐IgG before and after the procedure. These results suggest that a transcatheter splenic arterial embolization not only may reduce the increased platelet pool in the spleen but also may improve the thrombocytopenia induced by immunologic mechanisms in patients with cirrhosis. (Hepatology

ISSN:0270-9139    

DOI:10.1002/hep.1840220611

出版商:W.B. Saunders    

年代:1995

数据来源: WILEY