bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic hepatitis C: Interferon retreatment of relapsers. A meta-analysis of individual patient data
Authors: Cammà Calogero , Giunta Marco , Chemello Liliana , Alberti Alfredo , Toyoda Hidenori , Trepo Christian , Marcellin Patrick , Zahm Friederike , Schalm Solko , Craxì Antonio
Published: July 2004

Relapse after interferon (IFN) therapy for chronic hepatitis C virus (HCV) infection occurs in 50% of patients after the initial response. The benefit of retreatment with IFN alone has not been assessed in large controlled studies. To assess the effectiveness and the tolerability of IFN retreatment and to identify the optimal second course regimen, we performed a meta-analysis of individual patient's data on a set of 549 patients (mean age 43.8 years; 12.2 SD, men: 65%) who had an end-of-treatment biochemical response to a first IFN course and then relapsed. Retreatment was started within 24 months after the end of the first course. Biochemical end-of-treatment responses (ETR) and sustained responses (SR) were observed in 405 of 549 (73.8%; 95% confidence interval [CI] 70.1-77.5) and in 124 of 549 (22.6%; CI 19.1-26.1) patients, respectively. One hundred seventy-five of 404 patients (43.3%; CI 38.6-48.2) developed an end-of-treatment, biochemical, and virological response when retreated. A biochemical and virological SR to retreatment occurred in 73 of 494 (14.8%; CI 11.7-18) patients. Thirty-two patients (5.8%; CI 3.5-7.8) stopped retreatment for adverse effects. Biochemical and virological SR was predicted independently by logistic regression analysis using a negative HCV RNA at the end of the first cycle of IFN (P= .01) and by retreatment with a high IFN dose (P= .03). Age, cirrhosis, genotype, and γ-glutamyl transferase levels before retreatment were not significant by multivariate analysis. The excellent tolerability of IFN monotherapy retreatment makes it an option for patients who transiently cleared HCV-RNA during their first IFN course. Patients should be retreated with a high IFN dose regardless of the strength of the dose received during the previous course of treatment.
Prognosis of biliary atresia in the era of liver transplantation: French national study from 1986 to 1996
Authors: Chardot Christophe , Carton Matthieu , Spire-Bendelac Nathalie , Le Pommelet Christophe , Golmard Jean-Louis , Auvert Bertran
Published: July 2004

Since the sequential treatment of Kasai operation with or without liver transplantation became available, the overall prognosis of biliary atresia remains unclear. This study examined the prognostic factors from diagnosis. All patients with biliary atresia living in France and born in the years 1986 to 1996 were reviewed. Actuarial survival rates were calculated for survival with native liver, survival after liver transplantation, and overall survival. Potential prognostic factors were analyzed using the logrank test and the Cox model. A total of 472 patients were identified. Ten-year overall survival was 68%. Independent prognostic factors for overall survival were (S = 10-year rates) performance of Kasai operation (performed: S = 69%; not performed: S = 50%), age at Kasai operation (≤45 days: S = 80%; >45 days: S = 66%), anatomical pattern of extrahepatic bile ducts, polysplenia syndrome, experience of the center (≤2 new biliary atresia [BA] patients/year [24 centers]: S = 54%; 3 to 5 [2 centers]: S = 60%; ≥20 [1 center]: S = 78%). Survival with native liver depended on the same independent prognostic factors. In conclusion (1) Kasai operation remains the first line treatment of BA, and (2) early performance of Kasai operation and treatment in an experienced center reduces the need for liver transplantation in infancy and childhood and provides children with the best chance of survival.
Clinical manifestations of gallstone disease: Evidence from the multicenter Italian study on cholelithiasis (MICOL)
Authors: Festi Davide , Sottili Sandra , Colecchia Antonio , Attili Adolfo , Mazzella Giuseppe , Roda Enrico , Romano Ferdinando
Published: July 2004

Despite the many efforts to delineate the clinical manifestations of gallbladder disease, the precise symptom complex associated with gallstones is still a matter of debate, and even the existence of gallstone-specific symptoms has been questioned. We carried out a large population-based cross-sectional study (MICOL) to identify symptoms significantly related to gallstones. Fourteen centers throughout Italy enrolled 29,504 subjects aged 30 to 69 years. All subjects were administered an ultrasonographic examination of the upper abdomen and a precoded questionnaire. All subjects were divided into 4 groups: 25,374 (86.0%) gallstone-free subjects (GF), 1,832 (6.2%) patients with gallstones not previously diagnosed (GNPD), 638 (2.2%) patients with gallstones previously diagnosed (GPD), 1,660 (5.6%) patients with a history of cholecystectomy for gallstones (CC). In logistic regression analysis, pain at epigastrium and, even more, pain at right hypocondrium were significantly associated with gallstones. For pain at right hypocondrium, this association progressively increased from GNPD (OR = 1.60, 95% CI = 0.97-2.65) to GPD (OR = 8.77, 95% CI = 5.27-14.61) to CC (OR = 59.40, 95% CI = 43.87-80.42). Absence of heartburn combined with right hypocondrium or epigastrium pain and intolerance to fried or fatty food were also significantly related to gallstones. We also found some pain characteristics significantly associated with gallstones, i.e., pain radiated to the right shoulder, forcing the patient to rest, occurring soon after meals or unrelated to meals, not relieved by bowel movements, and frequently accompanied by gallstone-related morbidities. We developed a probability tree reporting the cumulative probability of having gallstones for each combination of those symptoms and characteristics of pain significantly associated with gallstones. In conclusion, we have identified symptoms and signs significantly associated with gallstones. We have shown that there is an increase in frequency and severity of these symptoms and signs across the different stages of gallstone disease. We have proposed a complex of symptoms and signs significantly associated with gallstones that might help physicians in clinical decision making.
Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus
Authors: Christie John M. , Chapel Helen , Chapman Roger W. , Rosenberg William M.
Published: July 2004

How Hepatitis C Virus (HCV) causes persistent infection is unknown. One hypothesis is that HCV evades the host immune response through mutation in immune epitopes. We have investigated mutations in the HCV genome to see if they cluster within immune epitopes; and we have studied the effect of antibody deficiency on mutation rates. We studied patients with chronic hepatitis C, 3 with antibody deficiency and 3 with normal immunity. Regions of the core and envelope genes of HCV, encoding cytotoxic (CTL), and B cell epitopes were sequenced at 2 time points, 2 years apart. The diversity of quasispecies increased with time. The HCV genetic mutation rate was higher than previously predicted. The cryptic nucleotide mutation rate in core was similar to that observed in envelope, suggesting that the error rate of the HCV RNA polymerase is similar in both regions. In contrast, the coding mutation rate was decreased in core and increased in envelope. No genetic mutation was seen in any of the core CTL epitopes despite detectable cellular responses. All patients had mutations within a previously described envelope CTL epitope but did not exhibit immune responses to either index or mutated peptides. There was no difference in mutation rates in any cellular or humoral epitopes between patients with antibody deficiency and normal immunity. Thus we have found no evidence that mutations were selected by T-lymphocytes or antibodies. These findings implicate alternative virus-host interactions in the selection of HCV mutations.
Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients
Authors: Benhamou Yves , Bochet Marie , Di Martino Vincent , Charlotte Frederic , Azria Felipe , Coutellier Anne , Vidaud Michel , Bricaire François , Opolon Pierre , Katlama Christine , Poynard Thierry
Published: July 2004

The natural history of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients has never been studied according to the concept of liver fibrosis progression. The aim of this work was to assess the fibrosis progression rate in HIV-HCV coinfected patients and in patients infected by HCV only. A cohort of 122 HIV-HCV coinfected patients was compared with a control group of 122 HIV-negative HCV-infected patients. Groups were matched according to age, sex, daily alcohol consumption, age at HCV infection, and duration and route of HCV infection. The fibrosis progression rate was defined as the ratio between fibrosis stage (METAVIR scoring system) and the HCV duration. The prevalence of extensive liver fibrosis (METAVIR fibrosis scores 2, 3, and 4) and moderate or severe activity were higher in HIV-infected patients (60% and 54%, respectively) than in control patients (47% and 30%, respectively; P < .05 and P < .001, respectively). The median fibrosis progression rate in coinfected patients and in control patients was 0.153 (95% confidence interval [CI], 0.117-0.181) and 0.106 (95% CI, 0.084-0.125) fibrosis units per year, respectively (P < .0001). HIV seropositivity (P < .0001), alcohol consumption (>50 g/d, P = .0002), age at HCV infection (<25 years old,P< .0001), and severe immunosuppression (CD4 count ≤200 cells/μL,P< .0001) were associated with an increase in the fibrosis progression rate. In coinfected patients, alcohol consumption (>50 g/d), CD4 count (≤200 cells/μL), and age at HCV infection (<25 years old) (P< .0001, respectively) were associated with a higher fibrosis progression rate. HIV seropositivity accelerates HCV-related liver fibrosis progression. In coinfected patients, a low CD4 count, alcohol consumption rate, and age at HCV infection are associated with a higher liver fibrosis progression rate.
Accurate preoperative evaluation of liver mass lesions without fine-needle biopsy
Authors: Torzilli Guido , Minagawa Masami , Takayama Tadatoshi , Inoue Kazuto , Hui Ai-Min , Kubota Keiichi , Ohtomo Kuni , Makuuchi Masatoshi
Published: July 2004

Fine-needle biopsy (FNB) is associated with problems, such as tumor seeding, which are probably underestimated. The aim of this study was to validate prospectively the accuracy of our diagnostic work-up without FNB, for defining indications for surgery in a cohort of patients with focal liver lesions (FLLs). Between January 1997 and December 1998, 160 consecutive patients carrying 225 FLLs admitted to our department were evaluated prospectively. Preoperative diagnoses were established by means of clinical histories, serum tumor marker levels, ultrasonography, and spiral computed tomography (CT). Angiography, magnetic resonance imaging (MRI), and Lipiodol-CT were performed when it was considered necessary to plan the surgical strategy. All the patients underwent surgery and results of pathological examinations were obtained for all of them. The preoperative diagnoses of 221 of the 225 lesions (98.2%) were confirmed, and the indications for liver resection in 156 of the 160 patients (97.5%) were correct. The respective accuracy, sensitivity, specificity, and positive and negative predictive values were 99.6%, 100%, 98.9%, 99.3%, and 100% for diagnosis of hepatocellular carcinoma (HCC); 99.1%, 100%, 98.8%, 96.9%, and 100% for metastases; 99.6%, 100%, 99.5%, 91%, and 100% for cholangiocellular carcinomas (CCCs); all 100% for mixed HCC-CCCs; and 98.7%, 57.1%, 100%, 100%, and 98.6% for benign tumors. In view of these results, the fact that the real risks of FNB have yet to be established and the possibility that tumor seeding has a major impact on patient prognosis, the use of FNB should be drastically limited.
Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis
Authors: Cookson Sharon , Constantini Patrizia K. , Clare Michael , Underhill James A. , Bernal Will , Czaja Albert J. , Donaldson Peter T.
Published: July 2004

Genetic involvement in type 1 autoimmune hepatitis (AIH) is indicated by a marked female preponderance and strong, well-established, human leukocyte antigen (HLA) associations. These associations, however, are not universal and a number of genes outside the major histocompatibility complex may also play a role in susceptibility to type 1 AIH. Prime candidates at present are those polymorphic genes encoding the proinflammatory and immunoregulatory cytokines. The aim of this study was to investigate, for the first time, 2 members of the interleukin-1 (IL-1) family (IL-1B and IL-1RN), 3 polymorphic sites in the interleukin-10 (IL-10) gene promoter (positions −1082, −819, and −592), and 2 polymorphisms in the tumor necrosis factor-α (TNF-α) promoter (positions −308 and −238) in type 1 AIH. The study was performed on 2 independently collected DNA banks, each with appropriate controls, and throughout the analysis associations described in the first set were confirmed in the second set. Standard polymerase chain reaction (PCR)-based genotyping techniques were used. Overall there were no significant differences in the distributions of the IL-1B and IL-10 alleles, genotypes, or haplotypes in either study set. In contrast we report a significant association between type 1 AIH and TNF*2 (first set: 34% of controls vs. 49% of patients, Pc = .014 and second set: 26% vs. 56%, P = .00008). However, TNF2 is found in strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype and stratification analysis indicates that the association with TNF*2 is interdependent with HLA DRB10301 This is an indication that there is more than one susceptibility allele for type 1 AIH on chromosome 6p21.3.
Induction of cytochrome P450 enzymes and generation of protein-aldehyde adducts are associated with sex-dependent sensitivity to alcohol-induced liver disease in micropigs
Authors: Niemelä Onni , Parkkila Seppo , Pasanen Markku , Viitala Katja , Villanueva Jesus A. , Halsted Charles H.
Published: July 2004

To assess possible links between ethanol-induced oxidant stress, expression of hepatic cytochrome P450 (CYP) enzymes, and sex steroid status, we used immunohistochemical methods to compare the generation of protein adducts of acetaldehyde (AA), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) with the amounts of CYP2E1, CYP2A, and CYP3A in the livers of castrated and noncastrated male micropigs fed ethanol for 12 months. In castrated micropigs, ethanol feeding resulted in accumulation of fat, hepatocellular necrosis, inflammation, and centrilobular fibrosis, whereas only minimal histopathology was observed in their noncastrated counterparts. CYP2A and CYP3A were more prominent in the castrated animals than in the noncastrated micropigs. Ethanol feeding increased the hepatic content of all CYP forms. The most significant increases occurred in CYP2E1 and CYP3A in the noncastrated animals and in CYP2E1 and CYP2A in the castrated animals. Ethanol-fed castrated animals also showed the greatest abundance of perivenular adducts of AA, MDA, and HNE. In the noncastrated ethanol-fed micropigs a low expression of each CYP form was associated with scant evidence of aldehyde-protein adducts. Significant correlations emerged between the levels of different CYP forms, protein adducts, and plasma levels of sex steroids. The present findings indicate that the generation of protein-aldehyde adducts is associated with the induction of several cytochrome enzymes in a sex steroid-dependent manner. It appears that the premature, juvenile, metabolic phenotype, as induced by castration, favors liver damage. The present findings should be implicated in studies on the gender differences on the adverse effects of ethanol in the liver.
Participation of platelet-activating factor in the lipopolysaccharide-induced liver injury in partially hepatectomized rats
Authors: Sakaguchi Takanori , Nakamura Satoshi , Suzuki Shohachi , Oda Toshiaki , Ichiyama Arata , Baba Satoshi , Okamoto Takashi
Published: July 2004

Platelet-activating factor (PAF) has been shown to be an important mediator in the pathogenesis of lipopolysaccharide (LPS)-induced liver injury in regenerating rat livers. Both LPS and PAF activate nuclear factor-kappa B (NF-κB), a key transcription factor for tumor necrosis factor-α (TNF-α) and cytokine-induced neutrophil chemoattractant (CINC). The aim of this study is to investigate how PAF participates in the LPS-induced and NF-κB-mediated regulation of TNF-α and CINC in regenerating rat livers. LPS (1.5 mg/kg) was intravenously administered into 70% hepatectomized rats and sham-operated rats 48 hours postoperatively. LPS administration caused a high mortality rate, scattered necrosis in the liver with infiltration of CINC-positive neutrophils, and a continuous CINC messenger RNA up-regulation and activation of NF-κB in the liver only in hepatectomized rats. These phenomena were all effectively prevented by pretreatment and posttreatment with a PAF receptor antagonist, TCV-309. Hepatectomized rats showed NF-κB staining in hepatocytes, Kupffer cells, and neutrophils around necrosis 4 hours after the LPS injection, representing the activation of this factor in these cells. Based on these results, we propose that PAF contributes to continuous CINC up-regulation and NF-κB activationviaaccumulation and activation of neutrophils, and thereby is involved in LPS-induced liver injury in regenerating rat livers.
Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection
Authors: Caronia Simona , Taylor Kevin , Pagliaro Luigi , Carr Colin , Palazzo Ugo , Petrik Juraj , O'Rahilly Stephen , Shore Sarah , Tom Brian D. , Alexander Graeme J. M.
Published: July 2004

Non-insulin-dependent diabetes mellitus (NIDDM) may be associated with chronic hepatitis C virus (HCV) infection. This was studied further in two parts. First, 1,151 patients with HCV-related cirrhosis and 181 patients with hepatitis B virus (HBV)-related cirrhosis, well matched for age, sex, and severity of cirrhosis, were reviewed retrospectively. The prevalence of diabetes mellitus was higher in HCV-related cirrhosis (23.6%) than in HBV-related cirrhosis (9.4%; odds ratio [OR], 2.78; 95% confidence interval [CI], 1.6-4.79; P = .0002). The prevalence of diabetes mellitus was associated closely with the Child-Pugh score (OR, 3.83; 95% CI, 2.38-6.17; P < .0001) and increasing age (OR, 1.02; 95% CI, 1.00-1.03;P= .0117). Second, 235 patients with biopsy confirmed chronic HBV or HCV underwent an oral glucose tolerance test. Only 1 of 70 patients with chronic viral hepatitis without cirrhosis was diabetic. However, 31 of 127 patients with HCV-related cirrhosis (24.4%) were diabetic compared with 3 of 38 patients with HBV-related cirrhosis (7.9%,P= .0477). The major variables associated with NIDDM were cirrhosis (OR, 14.39; 95% CI, 1.91-108;P= .0096) and male sex (OR, 4.64; 95% CI, 1.32-16.18;P= .0161). Fasting insulin levels in 30 patients with HCV-related cirrhosis and diabetes mellitus were elevated significantly, which was consistent with insulin resistance. However, acute insulin responsiveness was reduced in all patients with HCV infection and diabetes suggesting concomitant B-cell dysfunction. This study confirms an association between HCV and NIDDM.
Cycloprodigiosin hydrochloride, a new H+/Cl− symporter, induces apoptosis in human and rat hepatocellular cancer cell lines in vitro and inhibits the growth of hepatocellular carcinoma xenografts in nude mice
Authors: Yamamoto Chizuko , Takemoto Hiroto , Kuno Kenji , Yamamoto Daigo , Tsubura Airo , Kamata Keiko , Hirata Hajime , Yamamoto Akitsugu , Kano Haruhiko , Seki Toshihito , Inoue Kyoichi
Published: July 2004

The effects of cycloprodigiosin hydrochloride (cPrG-HCl), a new H+/Cl− symporter, were examined in liver cancer cell lines in vitro and in vivo. In the in vitro MTT assay, cPrG-HCl inhibited the growth of 6 liver cancer cell lines (Huh-7, HCC-M, HCC-T, dRLh-84, and H-35, hepatocellular carcinoma; HepG2, hepatoblastoma) in a dose- and time-dependent manner. The 50% inhibitory concentrations (IC50) at 72 hours' treatment for liver cancer cell lines were 276 to 592 nmol/L, while that for isolated normal rat hepatocyte was 8.4 μmol/L. The cPrG-HCl treatment of Huh-7 cells induced apoptosis as confirmed by the appearance of a subG1 population, intranucleosomal DNA fragmentation, and chromatin condensation. cPrG-HCl raised the pH of acidic organelles and lowered pHi (below pH 6.8). In addition, the apoptosis in Huh-7 cells induced by cPrG-HCl was strongly suppressed when the cells were cultured with imidazole, a cell-permeable base. In thein vivoassay, nude mice bearing subcutaneous xenografted Huh-7 cells received 2 weeks of treatment with cPrG-HCl (1 or 10 mg/kg/d) subcutaneously. This treatment significantly inhibited tumor growth compared with the control after 8 days. The control mice were treated with 1% dimethylsulfoxide (DMSO) in saline (vehicle). A histopathological examination using the terminal deoxynucleotidyl transferase mediated dUTP biotin nick end labeling (TUNEL) method showed apoptosis in the treated tumor cells. No pathological changes were observed in any organs, and the serum alanine transaminase levels remained within normal limits. These results suggest that cPrG-HCl may be useful for the treatment of hepatocellular carcinoma.
Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes
Authors: Oren Ran , Dabeva Mariana D. , Karnezis Anthony N. , Petkov Petko M. , Rosencrantz Richard , Sandhu Jaswinder P. , Moss Steven F. , Wang Shaobai , Hurston Ethel , Laconi Ezio , Holt Peter R. , Thung Swan N. , Zhu Liang , Shafritz David A.
Published: July 2004

Recently, we reported near-complete repopulation of the rat liver by transplanted hepatocytes using retrorsine (RS), a pyrrolizidine alkaloid that alkylates cellular DNA and blocks proliferation of resident hepatocytes, followed by transplantation of normal hepatocytes in conjunction with two-thirds partial hepatectomy (PH). Because two-thirds PH is not feasible for use in humans, in the present study, we evaluated the ability of thyroid hormone (triiodothyronine [T3]), a known hepatic mitogen, to stimulate liver repopulation in the retrorsine model. Because T3initiates morphogenesis in amphibians through a process involving both cell proliferation and apoptosis, we also determined whether apoptosis might play a role in the mechanism of hepatocyte proliferation induced by T3. Following hepatocyte transplantation and repeated injections of T3, the number of transplanted hepatocytes in the liver of RS-pretreated animals increased progressively to repopulate 60% to 80% of parenchymal cell mass in 60 days. We show further that T3treatment augments proliferation of normal hepatocytes, as evidenced by increased histone 3 mRNA and cyclin-dependent kinase 2 (cdk2) expression, and this is followed by apoptosis. These combined effects of T3lead to selective proliferation of transplanted hepatocytes in RS-pretreated rats, while endogenous hepatocytes, which are blocked in their proliferative capacity by RS, mainly undergo apoptosis. Thus, T3can replace PH in the RS-based rat liver repopulation model and therefore represents a significant advance in developing methods for hepatocyte transplantation.
In situ nucleic acid detection of human telomerase in intrahepatic cholangiocarcinoma and its preneoplastic lesion
Authors: Ozaki Satoru , Harada Kenichi , Sanzen Takahiro , Watanabe Kishichiro , Tsui Wilson , Nakanuma Yasuni
Published: July 2004

Human telomerase, an enzyme associated with cellular immortality and tumorigenesis, is expressed by most malignant tumor cells. Human telomerase consists of human telomerase RNA (hTR) and telomerase protein components. One of the latter has been cloned and was termed telomerase-associated protein 1 (TP1). Using anin situ hybridization method, expression of hTR and TP1 mRNA was surveyed in 20 cases of intrahepatic cholangiocarcinoma (ICC) (5 of them were associated with hepatolithiasis), 5 cases of hepatolithiasis alone and 6 normal livers. Biliary dysplasia, which is suspected as a preneoplastic lesion of ICC, was found in the biliary tree in all 5 ICC cases with hepatolithiasis and in 1 of 5 cases of hepatolithiasis alone. Normal colonic mucosa was used as positive control. In 17 (85%) of 20 ICC cases, hTR and TP1 mRNA were detected in carcinoma cells. There was no correlation between histological subtype of ICC and expression of hTR and TP1 mRNA. Biliary dysplasia was also positive for both RNA. These signals were mainly located in the cytoplasm of carcinoma and dysplastic cells, especially around their nuclei. The signals were homogeneously detected in the carcinoma, while their distribution was more or less heterogeneous in the dysplastic foci. These signals were not detected in nondysplastic biliary epithelia in hepatolithiasis and normal livers. It seems likely that almost all ICC acquired telomerase activities irrespective of histological subtype and more importantly that cellular immortalization has already occurred in biliary dysplasia and this lesion is already involved in the malignant progression of ICC.
Cost-effectiveness analysis of hepatitis A vaccination strategies for adults
Authors: O'Connor Barry J. , Imperiale Thomas F. , Singer Mendel E.
Published: July 2004

Our objective in this study was to determine the cost-effectiveness of hepatitis A vaccination strategies in healthy adults in the United States. We constructed a decision model simulating costs and health consequences for otherwise healthy adults with respect to hepatitis A prevention. Three strategies were compared: (1) no intervention, (2) vaccination against hepatitis A, and (3) testing for antibodies to hepatitis A and vaccinating those without antibodies. Costs and probabilities were obtained from the published literature. One- and two- way sensitivity analyses were performed. Under baseline conditions, the “test” strategy cost $230,100 per life-year saved compared with the “no intervention” strategy. The incremental cost-effectiveness of the “vaccination” strategy compared with the “test” strategy was $20.1 million per life-year saved. The “test” strategy was cost-effective when the hepatitis A case fatality rate exceeded 17% (baseline 2.7%). The “vaccination” strategy was cost-effective when 1 dose of vaccine cost $7 or less (baseline $57). Under baseline conditions, neither the “test” nor the “vaccination” strategies are considered cost-effective according to current standards. Large changes in hepatitis A incidence, mortality rates, or vaccine cost are required for either of the intervention strategies to approach potentially cost-effectiveness. Such conditions may occur in areas in which hepatitis A is endemic, and/or under mass-vaccination scenarios.
Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy
Authors: Dienstag Jules L. , Schiff Eugene R. , Mitchell Mack , Casey Donald E. , Gitlin Norman , Lissoos Trevor , Gelb Lawrence D. , Condreay Lynn , Crowther Lynn , Rubin Marc , Brown Nathaniel
Published: July 2004

In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (HBeAg) despite 1 to 3 months of prior therapy. Therapy was to be stopped after HBeAg loss or seroconversion (acquisition of antibody to HBeAg); posttreatment monitoring continued for 6 months. During therapy, which was well tolerated, HBV DNA became undetectable in all evaluable patients, accompanied by reduced alanine transaminase (ALT) activity. The cumulative 18-month confirmed loss of HBeAg during therapy was 9 of 24 (38%) and seroconversion was 5 of 24 (21%). Therapy was discontinued after HBeAg loss/seroconversion in 7 patients, and HBeAg status was maintained in all. Four of the patients with HBeAg responses lost HBsAg at least once. In 10 (43%) of 23 patients tested, we identified HBV polymerase YMDD mutations, 3 with detectable HBV DNA (2 with ALT elevations) and 7 without virological/biochemical breakthrough. In conclusion, up to 18 months of lamivudine therapy was well tolerated, suppressed HBV replication consistently, and tripled the frequency of HBeAg losses observed during brief-duration therapy; HBeAg loss/seroconversion remained durable posttreatment. The emergence of YMDD-variant HBV was relatively common but occurred typically without reappearance of detectable HBV DNA or ALT elevation. Our observations suggest that lamivudine can be stopped after confirmed HBeAg loss or seroconversion.
Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis
Authors: Master Sonali , Gottstein Jeanne , Blei Andres T.
Published: July 2004

Two mechanisms may account for brain edema in fulminant hepatic failure: the osmotic effects of brain glutamine, a product of ammonia detoxification, and a change of cerebral blood flow (CBF). We have shown brain edema, a marked increase in brain glutamine, and a selective rise in CBF in rats after portacaval anastomosis receiving an ammonia infusion. In this study, we inhibited the activity of glutamine synthetase with methionine-sulfoximine (MSO) and examined ammonia levels, brain water and CBF. Four groups received either a continuous ammonium acetate or control infusion; half of the animals had been pretreated with MSO or vehicle. The ammonia group exhibited brain edema (79.97 ± 0.04 vs. 81.11 ± 0.13% water), an increase in cerebrospinal fluid (CSF) glutamine (1.29 ± 0.21 vs. 2.84 ± 0.39 mmol/L) and CBF (63 ± 11 vs. 266 ± 45 mL/min/100 g brain). When MSO was added to the ammonia infusion, ammonia levels rose further (928 ± 51 vs. 1,293 ± 145 mmol/L, P < .05) but CSF glutamine decreased (2.84 ± 0.39 vs. 1.61 ± 0.2 mmol/L, P < .01). Brain edema (80.48 ± 0.11%) and cerebral hyperemia (140 ± 25 mL/min/100 g brain) were significantly ameliorated in the ammonia plus MSO group. Brain output of circulating nitric oxide (NOx) was increased in the ammonia-infused group but normalized in the ammonia plus MSO group. In this model, the rise of CBF reflects intracranial events that occur after glutamine synthesis. Activation of nitric oxide synthase in the brain could account for these findings.
Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine
Authors: Gülberg Veit , Bilzer Manfred , Gerbes Alexander L.
Published: July 2004

Peripheral vasodilation is considered an important factor in the pathophysiology of the hepatorenal syndrome (HRS). Therefore, the aim of this study was to evaluate the therapeutic potential of the vasoconstrictor ornipressin plus dopamine in the treatment of the most severe form of HRS, namely HRS type 1. Seven cirrhotic patients (creatinine clearance 15 ± 1 mL/min, UNaV 7 ± 2 mmol/24 h) with HRS type 1 were included in the study after normalization of central venous pressure with intravenous albumin and low-dose dopamine had failed to prevent further deterioration of renal function. Ornipressin was given continuously (intravenous 6 IU/h) in combination with dopamine (2-3 μg/kg/min) until creatinine clearance had increased to above 40 mL/min or adverse events prevented further treatment. HRS was reverted in 4 of 7 patients after 5 to 27 days (creatinine clearance 51 ± 4 mL/min, UNaV 47 ± 11 mmol/24 h) of treatment. Withdrawal was necessary in 1 patient after 15 days because of intestinal ischemia. Treatment failure was observed in 2 of 7 patients (creatinine clearance 19 ± 10 mL/min, UNaV 8 ± 3 mmol/24 h). Two of 4 responders had recidivant HRS 2 and 8 months after initial therapy, respectively. HRS in 1 of these patients was reverted with 18 days of ornipressin retreatment. The other patient had to be withdrawn from ornipressin after 2 hours because of ventricular tachyarrhythmia. Altogether, 3 of 7 patients survived HRS type 1, 1 after successful ornipressin therapy and liver transplantation, 1 with 2 successful courses of ornipressin, and 1 with liver transplantation after ornipressin treatment had failed. Thus, ornipressin plus dopamine can be a useful therapeutic option in patients with HRS type 1, especially as bridge to liver transplantation.
Matrix metalloproteinase-2 activation in human hepatic fibrosis regulation by cell-matrix interactions
Authors: Préaux Anne-Marie , Mallat Ariane , Van Nhieu Jeanne Tran , d'Ortho Marie-Pia , Hembry Rosalind M. , Mavier Philippe
Published: July 2004

Matrix metalloproteinase-2 (MMP-2) is involved in extracellular matrix remodeling. It is secreted as a proenzyme and activated by membrane type-MMPs (MT-MMP), such as MT1-MMP. In liver fibrosis, MMP-2 is highly expressed in myofibroblasts and may have a profibrogenic role. The mechanisms of its activation in the liver are still unclear. The aim of this work was to show that pro-MMP-2 is efficiently activated in human fibrotic liver and to investigate the role of cell-matrix interactions in this process. Liver specimens obtained from patients with active cirrhosis were compared to normal liver specimens. Human hepatic myofibroblasts were cultured either on plastic, fibronectin, laminin, or on collagen I gels. MMP-2 activity was visualized by gelatin zymography. MMP-2 active form (59 kd) was detected in active cirrhosis but not in normal liver. Myofibroblasts cultured on plastic, fibronectin, or laminin predominantly expressed inactive pro-MMP-2 (66 kd). In contrast, myofibroblasts cultured on collagen I markedly activated the enzyme. Similar results were obtained using membrane fractions from cells previously cultured on collagen or plastic. Activation was inhibited by the tissue inhibitor of metalloproteinases-2 but not by tissue inhibitor of metalloproteinases-1, implicating a MT-MMP-mediated process. Culture on collagen I up-regulated MT1-MMP protein detected by Western blotting, but decreased MT1-MMP mRNA. This study shows that MMP-2 is activated in fibrotic liver. It suggests that interactions between collagen I and myofibroblasts promote this process through a post-translational increase of MT1-MMP expression in these cells.
CYP2E1-mediated oxidative stress induces collagen type I expression in rat hepatic stellate cells
Authors: Nieto Natalia , Friedman Scott L. , Greenwel Patricia , Cederbaum Arthur I.
Published: July 2004

Hepatic stellate cells (HSCs) are a major source of extracellular matrix, which, during fibrogenesis, undergo a process of “activation” characterized by increased proliferation and collagen synthesis. Oxidative stress can stimulate HSC proliferation and collagen synthesis in vitro. Cytochrome P4502E1 (CYP2E1) is an effective producer of reactive oxygen species. To study how intracellular oxidative stress modulates alpha 2 collagen type I (COL1A2) gene induction, a rat HSC line (HSC-T6) was transfected with human CYP2E1 complementary DNA in the sense and antisense orientation and with empty vector, and stable cell lines were generated. The cells expressing CYP2E1 displayed elevated production of reactive oxygen species and showed a 4-fold increase in COL1A2 messenger RNA (mRNA) levels; expression of this mRNA among different clones appeared to correlate with the level of CYP2E1. COL1A2 expression was decreased by vitamin E treatment or transfection with manganese superoxide dismutase, and was further increased after treatment with l-buthionine sulfoximine (BSO) to lower GSH levels. Thus, CYP2E1-dependent oxidative stress plays a major role in the elevation of COL1A2 mRNA levels in this system. Nuclear run-on assay showed a 3-and-a-half-fold increase in COL1A2 transcription in the cells expressing CYP2E1; stabilization of COL1A2 mRNA was also observed. These results indicate that under oxidative stress conditions, COL1A2 mRNA expression is regulated both transcriptionally and through mRNA stabilization. The CYP2E1-expressing HSC appear to be a valuable model for the sustained generation of reactive oxygen species and may allow the elucidation of signaling pathways responsible for oxidant stress-mediated collagen gene induction.
Changing blood into liver: Adding further intrigue to the hepatic stem cell story
Authors: Strain Alastair J.
Published: July 2004

Bone marrow stem cells develop into hematopoietic and mesenchymal lineages but have not been known to participate in production of hepatocytes, biliary cells, or oval cells during liver regeneration. Cross-sex or cross-stain bone marrow and whole liver transplantation were used to trace the origin of the repopulating liver cells. Transplanted rats were treated with 2-acetylaminofluorene, to block hepatocyte proliferation, and then hepatic injury, to induce oval cell proliferation. Markers for Y chromosome, dipeptidyl peptidase IV enzyme, and L21-6 antigen were used to identify liver cells of bone marrow origin. From these cells, a proportion of the regenerated hepatic cells were shown to be donor-derived. Thus, a stem cell associated with the bone marrow has epithelial cell lineage capability.
Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis
Authors: Graziadei Ivo W. , Wiesner Russell H. , Marotta Paul J. , Porayko Michael K. , Hay Eileen J. , Charlton Michael R. , Poterucha John J. , Rosen Charles B. , Gores Gregory J. , LaRusso Nicholas F. , Krom Ruud A. F.
Published: July 2004

Liver transplantation is the only effective therapeutic option for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC). In this study, we analyzed a single center's experience with 150 consecutive PSC patients who received 174 liver allografts. Mean follow-up was 55 months. Actuarial patient survival at 1, 2, 5, and 10 years was 93.7%, 92.2%, 86.4%, and 69.8%, respectively, whereas graft survival was 83.4%, 83.4%, 79.0%, and 60.5%, respectively. The main indication for retransplantation was hepatic artery thrombosis, and the major cause of death was severe infection. Patients with PSC had a higher incidence of acute cellular and chronic ductopenic rejection compared to a non-PSC control group. Chronic ductopenic rejection adversely affected patient and graft survival. Biliary strictures, both anastomotic and nonanastomotic, were frequent and occurred in 16.2% and 27.2% of patients, respectively. The incidence of recurrent PSC was 20%. A negative impact on patient survival was not seen in patients with either postoperative biliary strictures or recurrence of PSC. Six patients (4%) had cholangiocarcinoma and 1 patient died related to recurrence of malignant disease. Seventy-eight percent of PSC patients had associated inflammatory bowel disease, most commonly chronic ulcerative colitis, which did not adversely impact patient outcome posttransplantation. Nine patients required proctocolectomy after liver transplantation; 5 because of intractable symptoms related to inflammatory bowel disease and 4 due to the development of colorectal carcinoma/high-grade dysplasia. Our data show that liver transplantation provides excellent long-term patient and graft survival for patients with end-stage PSC.
Activation of caspase-8 in transforming growth factor-β-induced apoptosis of human hepatoma cells
Authors: Shima Yuka , Nakao Kazuhiko , Nakashima Tomoki , Kawakami Atsushi , Nakata Keisuke , Hamasaki Keisuke , Kato Yuji , Eguchi Katsumi , Ishii Nobuko
Published: July 2004

Transforming growth factor-β1 (TGF-β1) has been shown to induce apoptosis in normal or transformed hepatocytes. To elucidate the biochemical pathways leading to apoptosis induced by TGF-β1 in human hepatoma cells (HuH-7), we examined the expression of Bcl-2-related proteins and X-chromosome-linked inhibitor of apoptosis (XIAP), and activation of the caspase cascade following TGF-β1 treatment. Bcl-xL expression began to decline at 12 hours after TGF-β1 treatment and progressively decreased to very low levels in a time-dependent manner. Bax expression showed a little change throughout the experiment. On the other hand, activation of caspase-8 was clearly observed at 36 hours after TGF-β1 treatment, followed by activation of caspase-9, and caspase-3 was activated at 48 hours after treatment at which time apoptosis of HuH-7 cells was observed. TGF-β1 significantly decreased XIAP expression in HuH-7 cells. Addition of an inhibitor of caspase-8 or caspase-3 (IETD-FMK or DEVD-CHO) markedly inhibited TGF-β1-induced apoptosis of HuH-7 cells. Fas/Fas ligand (FasL) interactions in HuH-7 cells were not involved in the apoptotic process. Furthermore, epidermal growth factor (EGF) also completely inhibited TGF-β1-induced apoptosis of HuH-7 cells by inhibiting activation of the caspase cascade. Our results suggested that activation of caspase-3 initiated through caspase-8 activation is involved in the apoptotic process induced by TGF-β1 in HuH-7 cells. Our results also showed that down-regulation of the expression of Bcl-xL and XIAP by TGF-β1 may facilitate activation of caspase-3 in these cells.
The impact of diagnosis of hepatitis C virus on quality of life
Authors: Rodger Alison J. , Jolley Damien , Thompson Sandra C. , Lanigan Anna , Crofts Nick
Published: July 2004

The aim of this study was to examine the effects of diagnosis of hepatitis C virus (HCV) infection on quality of life in a cohort admitted to Fairfield Infectious Diseases Hospital with acute hepatitis from 1971 to 1975. Sera stored from the original admission were tested for antibody to HCV. Systematic approaches were used to locate anti-HCV-positive individuals and outcomes assessed by the Short Form 36 (SF-36) scale and a study-specific questionnaire as well as clinical review. Study subjects' SF-36 scores were compared with Australian population norms. Anti-HCV and HCV-RNA positive individuals (n = 15) aware of their serostatus rated significantly worse on 7 of 8 SF-36 scales compared with population norms. However, HCV-seropositive and RNA-positive individuals unaware of their HCV serostatus (n = 19) scored significantly worse in only 3 scales. Those aware of their serostatus did not differ sociodemographically, clinically, virologically, or serologically from those who were unaware, nor was there a link between quality of life (QOL) scores and objective measures of ill health. All subjects had injected drugs in the past. In conclusion, HCV-RNA and anti-HCV-positive individuals in our study have significantly poorer subjective health status 26 years after original infection compared with population norms. QOL measures were significantly worse for HCV-seropositive individuals aware of their serostatus compared with those unaware. We feel that the reduced QOL in the diagnosed group may be partially an effect of labeling and that the impact of the diagnostic processper seon QOL in individuals with HCV requires further evaluation.
Decreased p27Kip1 expression and cyclin D1 overexpression, alone and in combination, influence recurrence and survival of patients with resectable extrahepatic bile duct carcinoma
Authors: Hui Ai-Min , Cui Xing , Makuuchi Masatoshi , Li Xin , Shi Ya-Zhou , Takayama Tadatoshi
Published: July 2004

This study was undertaken to identify potential abnormalities of p27Kip1 and cyclin D1 expression in extrahepatic bile duct carcinomas and to assess the prognostic significance of p27Kip1 and cyclin D1 levels for patients with this disease. Decreased p27Kip1 expression (<50% nuclei staining) and cyclin D1 overexpression (>5% nuclei staining) was observed immunohistochemically in 19 (56%) and 23 (68%) of the 34 tumors examined, respectively. Both decreased p27Kip1 and cyclin D1 overexpression were associated with relapse (P = .0005 for p27Kip1 and P = .0004 for cyclin D1). Kaplan-Meier curves showed that both decreased p27Kip1 and cyclin D1 overexpression correlate significantly with shortened survival rates (for p27Kip1, P = .0419 andP= .002 for overall and disease-free survival; for cyclin D1, P = .0392 andP= .0021 for overall and disease-free survival). Cox regression model analyses identified decreased p27Kip1 and cyclin D1 overexpression as independent markers predicting death from relapse (P = .0371, risk ratio: 3.891 for p27Kip1; P = .0429, risk ratio: 8.31 for cyclin D1). Decreased p27Kip1 was associated with cyclin D1 overexpression (P = .0202), and coincident abnormalities of the 2 proteins occurred in 16 of the 34 (47%) tumors, indicating that extrahepatic bile duct carcinoma progression may require synchronous dysfunction of p27Kip1 and cyclin D1 in about half of patients. Patients with tumors showing coincident abnormalities of p27Kip1 and cyclin D1 showed even more frequent recurrence than patients with an alteration in only 1 of the 2 proteins. In conclusion, decreased p27Kip1 expression and cyclin D1 overexpression, alone and in combination, predict poor prognosis in patients with resectable extrahepatic bile duct carcinoma
Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in taiwan
Authors: Hsu Hong-Yuan , Chang Mei-Hwei , Liaw Shwu-Huey , Ni Yen-Hsuan , Chen Huey-Ling
Published: July 2004

Mutants ofadeterminant of hepatitis B surface antigen (HBsAg) identified in vaccinated children pose a potential threat to long-term success of vaccination programs. We examined the mutants of adeterminant (residues 110-160) of HBsAg in hepatitis B virus (HBV) DNA-positive children identified during previous serosurveys in Taipei undertaken just before (1984), 5 years after (1989), and 10 years after (1994) universal vaccination began. In HBV DNA-positive children from 3 surveys, the prevalence of adeterminant mutants increased from 8 of 103 (7.8%) in 1984 to 10 of 51(19.6%) in 1989 and 9 of 32 (28.1%) in 1994 and was higher in those fully-vaccinated than unvaccinated (12/33 vs. 15/153,P= .0003). Most amino acid changes of the variants clustered in residues 125-129 and 140-149. In all 27 children with detectable mutants, the mean age of those vaccinated was younger than those unvaccinated (4.8 ± 3.8 vs. 7.9 ± 2.3 yrs,P< .05); and mutations occurred in a region with greatest local hydrophilicity (residues 140-149) more frequently in those vaccinated than in those unvaccinated (10/12 vs. 6/15,P= .0253). More mutated residues and more mutations at neutralizing epitopes, such as N146, C147, T148, and C149, were found in the 1994 survey. Vaccinated children may contract variant infections through vertical or horizontal transmission. Universal vaccination has accelerated an accumulation of HBsAgadeterminant mutants with amino acid changes critical for immune escape in vaccinated children who became carriers, suggesting that new vaccination strategies should be considered.