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A 69-year-old Japanese woman was transferred to our hospital due to pancytopenia with a fever. She had Murphy's sign, and computed tomography showed pleural effusion and a swollen gallbladder without gallstones. We diagnosed her with systemic lupus erythematosus (SLE)-associated acute acalculous cholecystitis (AAC). Partly because her clinical and laboratory findings were not serious enough to warrant immediate surgical intervention, and partly because her poor general condition made her ineligible for surgery, surgical therapy was not selected. Corticosteroid therapy was performed with azathioprine, and the swelling in her gallbladder improved. As a conservative therapy for SLE-associated AAC, corticosteroid therapy combined with azathioprine might be beneficial.

ObjectivesThe aims were to determine the incidence rate, predictive factors and severity of liver injury that develops during MTX treatment for RA and to evaluate the role of pretreatment hepatic fat deposition.MethodsWe used an ongoing real-life registry containing RA patients who had started MTX between August 2007 and April 2018 at participating institutions. The liver-to-spleen attenuation ratio on CT scans at enrolment was used to evaluate pretreatment fat deposition quantitatively. Patients were followed until persistent transaminitis developed or until the end of the study. Liver biopsy was performed for patients who presented with persistent transaminitis.ResultsWe followed 289 new MTX users without pretreatment elevations of transaminases (mean follow-up time, 58.3 months). Hepatic fat deposition was detected in half of the patients at enrolment. During follow-up, persistent transaminitis occurred at a crude incidence rate of 3.13 per 100 person-years, and the cumulative incidence at 5 years was estimated to be 13%. A multivariate Fine–Gray regression analysis showed that the most important predictive factors were pre-existing moderate to severe fat deposition (adjusted hazard ratio, 7.69; 95% CI: 3.10, 19.10) and obesity (adjusted hazard ratio, 2.68; 95% CI: 1.37, 5.25). Non-alcoholic steatohepatitis (NASH) was the most predominant pattern in liver biopsy samples. Hepatic fibrosis was found in 90% of samples, but most cases were not advanced.ConclusionAggravation of underlying fatty liver to NASH with fibrosis seems to be an important mechanism of liver injury that occurs in MTX-treated RA patients.

In the UNITY-3 study, 96% sustained virologic response (SVR12) rate was observed in Japanese patients with hepatitis C virus (HCV) genotype (GT)-1 infection treated for 12 weeks with fixed-dose daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO). As HCV clearance may improve liver outcomes, we assessed hepatic fibrosis and alpha-fetoprotein (AFP), a hepatocellular carcinoma risk marker, pre- and post-treatment in UNITY-3. Treatment-naive or interferon-experienced UNITY-3 patients with HCV GT-1 who received twice-daily DCV-TRIO were assessed for fibrosis [FibroTest; FibroScan; fibrosis-4 index (FIB-4), aspartate-aminotransferase-to-platelet-ratio index] and AFP at baseline and Weeks 4 (FIB-4 only), 12 or 24 post-treatment. Of 217 patients, 99% had GT-1b infection, 46% were aged > 65 years, 21% had compensated cirrhosis, and 26% baseline HCV-RNA > 107 IU/mL. All GT-1b patients treated ≥ 4 weeks achieved SVR12 with (n = 54) or without (n = 144) baseline NS5A polymorphisms associated with DCV resistance (positions 28/30/31/93). Statistically significant post-treatment reductions from baseline were observed for all fibrosis measures and AFP, with numerically greater reductions in cirrhotic patients. FibroTest category improved in 44%, remained stable in 50%, and worsened in 6% of patients; 98% with baseline AFP

Aim The assessment of liver fibrosis in patients with hepatitis C is important to predict carcinogenesis. In this study, we evaluated the usefulness of virtual touch quantification (VTQ) for staging liver fibrosis, and investigated factors causing discrepancies between the estimated fibrosis stage using VTQ and the pathological fibrosis stage. Methods Patients with hepatitis C (n = 302) were assessed using VTQ and underwent pathological liver investigation within 1 week before and after VTQ. A receiver operator characteristic (ROC) curve was obtained for VTQ, fibrosis-4 (FIB-4) index, and aspartate aminotransferase-to-platelet ratio index (APRI), and each area under the ROC curve (AUROC) was compared to predict fibrosis stage. We used univariate and multivariate analyses to investigate the factors related to the discrepancy between the estimated fibrosis stage using VTQ and the pathological fibrosis stage. Results At any stage, VTQ was the most accurate for staging liver fibrosis. The VTQ cut-off values were 1.33 m/s (AUROC = 0.822) for ≥F2, 1.51 m/s (AUROC = 0.836) for ≥F3, and 1.92 m/s (AUROC = 0.890) for F4. Skin liver capsule distance (SCD) was the most relevant factor for the discrepancy between the estimated fibrosis stage using VTQ and the pathological fibrosis stage. The SCD cut-off value was 17.5 mm. Conclusions Virtual touch quantification is a non-invasive, simple method that is more accurate for staging liver fibrosis than the FIB-4 index and APRI. However, when the SCD is longer than 17.5 mm, there may be measurement failures.

Tamibarotene is a synthetic retinoid expected to inhibit tumor-cell proliferation and to induce apoptosis by selective interaction with retinoic acid receptor α/β. We conducted an open-label phase I/II study to determine the maximum tolerated dose (MTD) and recommended dose (RD), and to evaluate the pharmacokinetics, efficacy, and safety profiles for advanced hepatocellular carcinoma (HCC).Patients with histologically confirmed, measurable, unresectable HCC of Child-Pugh classification A or B and with no effective systemic or local therapies were eligible. In phase I, patients were assigned based on the 3 + 3 dose escalation criteria to receive tamibarotene at 8, 12, and 16 mg/day. The RD determined in phase I was employed for phase II. The planned sample size in phase II was 25, including the RD-treated patients in phase I.Thirty-six patients were enrolled. No patients experienced dose-limiting toxicity (DLT) at 8 mg/day. However, two out of six patients experienced the DLTs at 12 mg/day: one experienced thrombosis in a limb vein and pulmonary artery, and the other experienced an increase of γ-GTP. The MTD and RD were determined as 12 and 8 mg/day, respectively. In phase II, one patient achieved partial response, and seven achieved stable disease. The disease control rate was 32 % (95 % CI: 15.0-53.5). The following drug-related serious adverse events were reported: thrombosis in a limb vein, pulmonary artery, and portal vein; interstitial lung disease; and vomiting.Tamibarotene demonstrated the inhibition of tumor cell growth in advanced HCC with acceptable tolerance.

Aim There have been only a few trials demonstrating additional effects of human serum albumin (HSA) on diuretic therapy in patients with cirrhotic ascites. We aimed to evaluate the safety and efficacy of recombinant HSA, KD-294, treatment in patients with cirrhotic ascites. Methods The inclusion criteria were patients 20–75 years of age, with cirrhotic ascites and a serum albumin concentration of less than 3.0 g/dL. Eighty-five patients were registered and 71 patients underwent randomization. Enrolled patients received oral spironolactone at 50 mg/day and i.v. furosemide at 20 mg/day in addition to low-sodium diet. They were divided randomly into a KD-294 treatment group (n = 35) or non-treatment control group (n = 36). Patients in the KD-294 group received KD-294 at 25 g/day for up to 5 days and those in the control group continued the diuretic therapy. They were followed up for 5 weeks. Results KD-294 was well tolerated. A correlation between the increases in serum albumin and decreases in bodyweight was not shown. However, changes of plasma renin concentration (PRC) showed a significant decrease in the KD-294 group compared with the control group. As a result of this exploratory analysis, patients with high PRC showed a significant correlation between increases in serum albumin and decreases in bodyweight. Conclusion The present data do not show efficacy in all patients with cirrhotic ascites, however, they suggest that additional effects of HSA on diuretic therapy are expected in high PRC patients.

Background Eltrombopag is an oral thrombopoietin receptor agonist that stimulates thrombopoiesis and shows higher exposure in East Asian patients than in non-Asian patients. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with thrombocytopenia associated with chronic liver disease (CLD). Methods Thirty-eight patients with CLD and thrombocytopenia (platelets

Objective The mechanism of liver injury with low-dose methotrexate (MTX) is incompletely understood. This study was designed to evaluate the association between non-alcoholic fatty liver disease (NAFLD) and liver injury during MTX treatment for rheumatoid arthritis (RA). Methods Between October 2014 and May 2015, we enrolled all MTX users for RA and monitored participant serum hepatic transaminase levels for 1 year. All patients had normal transaminase levels before the first MTX prescription. Using diagnostic criteria for non-alcoholic steatohepatitis (NASH), we performed histological analyses for patients presenting persistent transaminitis, defined as elevations of hepatic transaminases in four of six determinations during the follow-up period. Possible risk factors for persistent transaminitis were also examined. Results We followed 846 RA patients with a mean cumulative MTX dose of 2.48 g and identified 51 patients presenting persistent transaminitis. According to multivariate logistic regression analysis, obesity (odds ratio [OR] 3.23, p < 0.001), type 2 diabetes (OR 3.52, p = 0.001), hypercholesterolemia (OR 2.56, p = 0.004), and hyperuricemia (OR 3.52, p = 0.019), which are recognized as risk factors for NAFLD, were independently associated with a risk of persistent transaminitis. Among patients with persistent transaminitis, 42 showed fatty liver at ultrasonography. These patients had no evidence of alcoholic fatty liver, chronic viral hepatitis, autoimmune liver diseases, or hereditary liver diseases. Biopsy specimens were obtained from 32 patients, and we found that a NASH-like pattern was the most prevalent histological abnormality. There was no significant impact of MTX dose and duration on the histological severity. Conclusion Risk factors and histological findings are similar between NAFLD/NASH and liver injury during low-dose MTX treatment for RA, which suggests a strong association between both entities. NAFLD/NASH may be an underlying condition causing persistent transaminitis in MTX-treated RA patients. The results of this study illustrate the need for monitoring liver injury in RA patients with NAFLD risk factors during MTX treatment.

Background and aim: There has so far been no questionnaire report on patients who were treated with peginterferon plus ribavirin (PEG IFN+RBV) therapy. The purpose of this study was to investigate the problems of this therapy by a questionnaire survey. Patients and methods: A survey of 681 patients with chronic hepatitis C who received treatment with PEG IFN+RBV was conducted in the Kyushu region of Japan. Using an original questionnaire, the survey was conducted prior to the treatment, during the third month of treatment, at the completion of treatment or the discontinuation of treatment, and at 6 months after the completion of treatment. Results: It was indicated that the patients had a high level of comprehension and understanding of chronic hepatitis C and PEG IFN+RBV treatment. However, the results also indicated that patients had a high level of anxiety. Side effects were adequately dealt with by physicians. However, dermatological symptoms were not adequately explained to the patients, although they were the second most severe side-effect. It was also revealed that side-effects were most distressing during the first and second months after the start of treatment. Conclusion: The questionnaire survey provided new information that has never been reported. It is believed that understanding this information is important for future treatment.

Background/Aims Transcatheter arterial chemoembolization (TACE) is a combination of transarterial infusion chemotherapy (TAI) and embolization, and has been widely used to treat patients with hepatocellular carcinoma (HCC). However, since the impact of adding embolization on the survival of patients treated with TAI had never been evaluated in a phase III study, we conducted a multi-center, open-label trial comparing TACE and TAI to assess the effect of adding embolization on survival. Methods Patients with newly diagnosed unresectable HCC were randomly assigned to either a TACE group or a TAI group. Zinostatin stimalamer was injected into the hepatic artery, together with gelatin sponge in the TACE group and without gelatin sponge in the TAI group. Treatment was repeated when follow-up computed tomography showed the appearance of new lesions in the liver or re-growth of previously treated tumors. Results Seventy-nine patients were assigned to the TACE group, and 82 were assigned to the TAI group. The two groups were comparable with respect to their baseline characteristics. At the time of the analysis, 51 patients in the TACE group and 58 in the TAI group had died. The median overall survival time was 646days in the TACE group and 679days in the TAI group ( p =0.383). Conclusions The results of this study suggest that treatment intensification by adding embolization did not increase survival over TAI with zinostatin stimalamer alone in patients with HCC.

Objective. To assess retrospectively whether continuously high serum alanine aminotransferase (ALAT) levels (80 IU) in the first three successive years after the diagnosis of liver cirrhosis (LC) are predictive of a subsequent high incidence of hepatocellular carcinoma (HCC) in patients with Child Stage A hepatitis C virus (HCV)-LC. Material and methods. The study comprised 132 HCV-LC (Child Stage A) patients who had not received interferon therapy but had been treated with anti-inflammatory agents. At the end of a 3-year follow-up after the diagnosis of LC, the patients were subdivided into three groups according to their serum ALAT levels and the subsequent incidence of HCC was assessed. Results. The cumulative incidence of HCC starting from 3 years after the diagnosis of LC in the continuously high ALAT group (annual average over 3 years alwaysor =80 IU; n=41; Group A) was markedly higher than that in the continuously low ALAT group (always80 IU; n=48; Group B) (p0.005) during an observation period of 7.9+/-3.7 years. The incidence of HCC in Group A was 11.8%/year. The odds ratios of developing HCC in Group A and Group C (mixed high and low ALAT levels; n=43) were 5.1-fold and 1.5-fold that of Group B, respectively. A multivariate analysis revealed that the ALAT group was independently associated with HCC development. Conclusions. Continuously high ALAT levels for three successive years following the diagnosis of LC can be predictive of a very high incidence of HCC in Child A HCV-LC patients. Prospective trials using therapeutic approaches aimed at decreasing ALAT levels are necessary in order to confirm a positive impact of ALAT reduction on the incidence of HCC in patients with HCV-LC.

Background and Aim Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b. Methods Treatment-naive patients (20–70 years; baseline viral load, ≥100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks or telaprevir 750 mg (3 × 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20–75 years; baseline viral load, ≥100,000 IU/mL) received daclatasvir plus asunaprevir. Results In treatment-naive patients, sustained virologic response at post-treatment week 12 in daclatasvir plus asunaprevir recipients was non-inferior (treatment difference, +25.8% in favor of daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% (n = 21/22) of relapsers. Numerically, fewer patients receiving daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% vs. 5.4%), adverse events leading to discontinuation of any drug (5.0% vs. 62.2%), grade 3/4 treatment-related adverse events (14.3% vs. 72.1%), rash-related events (0% vs. 13.5%), or anemia (0% vs. 47.7%). Conclusion Marked differences were observed in the efficacy and safety profile of daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin.

Objective: This study compared the antitumor effect, adverse effects and survival between transcatheter arterial embolization (TAE) and transcatheter arterial infusion chemotherapy (TAI) in patients with hepatocellular carcinoma (HCC). Methods: The study population consisted of 168 consecutive patients with advanced HCC treated with transcatheter arterial treatments using cisplatin suspended in lipiodol. Among these, 74 patients were treated with TAE, and the remaining 94 patients were treated with TAI. Results: There were no significant differences in any baseline characteristics except hemoglobin, platelets, albumin, and glutamic pyruvic transaminase. Complete or partial tumor response was achieved in 54 patients (73%) in the TAE group and in 48 patients (51%) in the TAI group (p < 0.01). There were two treatment-related deaths caused by acute hepatic failure and acute renal failure in the TAE group. Nausea and deterioration of serum transaminase after TAE were significantly more severe than after TAI. Median survival time and survival rates at 5 years were 3.1 years and 25% in the TAE group, and 2.5 years and 18% in the TAI group (p = 0.37). Conclusion: TAE has a higher antitumor effect than TAI, but does not significantly improve the survival of patients with HCC.

内視鏡的経鼻胆管ドレナージ (endoscopic naso-biliary drainage: ENBD) による胆管クーリング下経皮的マイクロ波凝固療法 (PMCT) を試行した. 症例は60歳の女性. 後区域グリソン鞘に近接した20×17mm の高分化型肝細胞癌を認めた. C型肝硬変を合併しており, 臨床病期はII期であった.ENBD チューブから冷却した生理食塩水の注入と吸引を繰り返すことにより胆管をクーリングした.1.6mmの深部針で60W, 30秒凝固の条件で5回のPMCT を試行した. 術後に一過性の高アミラーゼ血症を認めたが, 保存的に治癒した. 治療後の造影CTでは血管損傷を認めることなく, 腫瘍は周囲肝組織を含めて直径30mmの造影効果のない低吸収域となった. 胆管についてはMRCPで経過観察を行っているが, 狭窄や拡張を認めていない. 術後半年の現在, 無再発生存中である.本法は肝内グリソン鞘に近接した肝細胞癌治療における新しい選択肢となりうる.

The number of available studies on the role of human serum albumin (HSA) in the treatment of cirrhotic ascites is currently limited. In this study, we aimed to investigated the parameters associated with diuretic therapy with HSA in patients with advanced cirrhotic ascites. The patient inclusion criteria were cirrhotic ascites and a serum albumin (Alb) concentration of

Although hepatitis C virus (HCV) has now been classified into several subtypes, the clinical significance of HCV subtypes is not well known. Typing of HCV is now routinely performed in Japan. In the present study, HCV subtypes in hepatocellular carcinoma (HCC) patients were analysed from nationwide data collected in Japan using a standard questionnaire. Answers to the questionnaire concerning HCV subtypes in patients with chronic hepatitis (CH), liver cirrhosis (LC) and HCC were obtained from 14 hospitals. The prevalence of the 1b-related subtype, which includes the mixed subtype of 1b and 2a or 2b, in patients with LC and HCC in each hospital was higher than in patients with CH, with few exceptions. However, the differences were not statistically significant because of the small number of patients in each hospital. In summarized data from all 14 hospitals, the 1b-related subtype was found in 1370 of 1922 patients with CH (71.2%). In 356 LC and 426 HCC patients, the prevalence of the 1b-related subtype was 79.8 and 80.5%, respectively. The prevalence of the 1b-related subtype in patients with LC and HCC was significantly higher than in patients with CH. There was no significant difference between the prevalence of the 1b-related subtype in patients with HCC and LC. These results indicate that the oncogenic activity of subtype 1b, although not yet clearly characterized, may be stronger than subtypes 2a and 2b.

The overall prevalence of anti-hepatitis A virus antibodies was 49.6% in 385 inhabitants in Honda City, Japan in 1991. An approximately 50% prevalence rate occurred between 40 and 49 years of age. The prevalence of anti-HAV antibodies was significantly lower in 1991 than in 1982 in the age groups 20 to 29 years and 30 to 39 years (p0.01), suggesting there has been no significant HAV infection since 1982. In addition, anti-HAV antibody titers of sera from convalescent hepatitis. A patients were compared with those from seropositive healthy subjects and from healthy subjects following administration of a lyophilized inactivated hepatitis A vaccine or immune serum globulin. Titers after vaccine administration were considerably higher than after immune serum globulin and, although lower than those obtained after natural infection, should be sufficient for protection against hepatitis A virus.

A cDNA clone, C8-2, derived from nonstructural (NS) protein 5 region of hepatitis C virus (HCV) genome hasbeen isolated and was expressed in Escherichia coli as a fusion protein with β -galactosidase ( β -Gal). The recombinant protein, β -Gal/C8-2, was partially purified and used for detection of anti-HCV antibody by enzyme-linked immunosorbent assay (ELISA). Anti-C8-2 antibody was detected in 47% of patients with post-transfusion non-A, non-B (NANB) acute hepatitis and in 55% of patients with NANB chronic liver diseases. Of 1491 normal blood donors, ten (0.7%) were positive for anti-C8-2 antibody, and three of these ten samples were negative for anti-C100-3 antibody. HCV RNA was detected in one of these three samples. These results suggest that the recombinant protein containing C8-2 peptide may be useful as another nonstructural protein epitope for diagnosis of hepatitis C and screening of blood donors.

We measured antibodies to hepatitis C virus (HCV) in 380 patients with various liver diseases by three enzyme-linked immunosorbent assays (ELISAs): HCV antibody ELISA test (C100), KCL-163 (KCL) corresponding to the nonstructural protein of HCV, and JCC based on the translation product of the presumptive HCV core gene. Of 233 cases of non-A, non-B (NANB) liver disease, 63.9% were anti-C100 positive, 69.1% were anti-KCL positive, and 79.8% were anti-JCC positive. Detection of serum HCV-RNA in 213 cases of chronic NANB liver disease revealed that the concordance was 80.3% for C100, 86.4% for KCL, 94.8% for JCC, and 95.3% for all three ELISAs. Overall, 85.4% of chronic NANB cases were considered to have type C disease with HCV infection. The most reliable assays for diagnosing chronic NANB liver disease as type C appeared to be the KCL and JCC ELISAs.

Twelve patients with primary biliary cirrhosis (PBC), stages I to III, received long-term therapy with a combination of 600 mg ursodeoxycholic acid (UDCA) and 1 mg colchicine given daily for more than 2 years. Drug toxicity was mild; one patient experienced diarrhoea that was probably due to colchicine. Serum levels of bilirubin, alkaline phosphatase (ALPase), gamma-glutamyl transpeptidase and alanine aminotransferase decreased by more than 50% of the initial values. Serum albumin and cholesterol levels also improved, but immunoglobulins and anti-mitochondrial antibody titre did not change. Histologic features in the eight patients who received serial liver biopsies before and 2 years after the beginning of treatment were evaluated. Piecemeal necrosis and portal inflammation were improved, but there was no change in portal fibrosis. Patients were divided into two groups; the first received both drugs from the outset, and the second group were started on UDCA for 3 months followed by the addition of colchicine. After 3 months, the improvement in serum bilirubin and ALPase in the first group was greater than in the second. However, in the second group, the ALPase levels had decreased significantly when measured at 6 and 9 months after the treatment compared with the levels at 3 months. These findings suggest that UDCA and colchicine may have a synergistic effect. This combination therapy appears to be safe and effective, both clinically and histologically, for treating PBC.

インターフェロン(IFN)治療中に精神症状を呈したC型慢性活動性肝炎の2例を報告した.症例1は44歳,男性.トランスアミナーゼの異常,HCV抗体陽性を認めたためHLBIを投与した.開始当初,発熱,食欲不振が出現,遅れて13日目より不眠,抑鬱症状が出現し,さらに自殺企図,被害妄想も認めた.それ故,投与を中止し,抗精神薬で徐々に改善した.症例2は34歳,女性.トランスアミナーゼの異常,HCV-RNA陽性を認めたため,IFN-α投与を関始した.当初,発熱,悪寒,倦怠感,食思不振が出現し,4日目から不眠,焦燥感も出現した.精神安定剤を併用したところ,症状は改善し,IFN投与を終了しえた.IFNは,慢性肝炎に対する通常量でも,稀ながら精神症状を呈する例もあるため,IFN治療中は充分な注意が必要である.

The safety and immunogenicity of a lyophilized inactivated hepatitis A vaccine was tested in healthy adult male volunteers. Thirty-six volunteers, all of whom were negative for antibody to HAV (anti-HAV), were divided into three dosage groups, 1.0, 0.5 and 0.25 micrograms of viral protein, respectively. Each group received a total course of three intramuscular injections at months 0, 1 and 6. Slight side effects were noted after 16 of 99 injections and the occurrence and degree were almost identical to those of other commercial vaccines. On the other hand, all subjects had measurable titres of serum anti-HAV neutralizing antibodies as early as 2 months after the first injection. The mean values of serum anti-HAV neutralizing antibodies at 7 months in the 1.0, 0.5 and 0.25 micrograms dose groups were 64-, 12-, and 9-fold higher, respectively, than those observed at 5 days in five recipients given 7.5 mg kg-1 body weight of immune serum globulin (ISG).

Des-γ-carboxy prothrombin (DCP) was evaluated as a serological marker for hepatocellular carcinoma (HCC), particularly in patients with early HCC. In 1192 patients with various diseases, plasma DCP levels were measured by a newly developed enzyme immunoassay method using an anti-DCP monoclonal antibody. Of the 254 patients with HCC, 143 (56%) had abnormal DCP levels of greater than 0.1 AU/ml. In contrast, elevated DCP levels were rarely observed in patients with chronic hepatitis, liver cirrhosis, metastatic liver cancer, and other malignant tumors. Because no correlation was observed between DCP and α-fetoprotein (AFP), the combined measurement of these two complementary markers appears to be useful in the diagnosis of HCC. Since normal levels were observed in 29 of 30 patients (97%) with small liver tumors measuring 2 cm or less in diameter, the diagnostic application of the DCP assay to small liver tumors is limited. However, in patients with tumors larger than 2 cm, the plasma DCP assay may even be more useful than AFP. Among 46 patients with liver cirrhosis or chronic hepatitis who subsequently developed HCC, significantly increased DCP and AFP levels were observed in nine patients (20%) and 14 patients (30%), respectively, when a tumor was detected. When the results of both assays were combined, 19 patients (41%) had elevated levels of one or both markers. Although the plasma DCP assay alone is not sensitive enough to detect early small liver cancers, it could be applied as a complementary tumor marker together with AFP. The use of both these markers together with imaging modalities in the regular follow-up of patients with chronic liver disease who are at high risk for HCC might be of great benefit.

Accompanying the increased use of biological and non-biological antirheumatic drugs, a greater number of cases of hepatitis B virus (HBV) reactivation have been reported in inactive hepatitis B surface antigen (HBsAg) carriers and also in HBsAg-negative patients who have resolved HBV infection. The prevalence of resolved infection varies in rheumatic disease patients, ranging from 7.3% to 66%. Through an electronic search of the PubMed database, we found that among 712 patients with resolved infection in 17 observational cohort studies, 12 experienced HBV reactivation (1.7%) during biological antirheumatic therapy. Reactivation rates were 2.4% for etanercept therapy, 0.6% for adalimumab, 0% for infliximab, 8.6% for tocilizumab, and 3.3% for rituximab. Regarding non-biological antirheumatic drugs, HBV reactivation was observed in 10 out of 327 patients with resolved infection from five cohort studies (3.2%). Most of these patients received steroids concomitantly. Outcomes were favorable in rheumatic disease patients. A number of recommendations have been established, but most of the supporting evidence was derived from the oncology and transplantation fields. Compared with patients in these fields, rheumatic disease patients continue treatment with multiple immunosuppressants for longer periods. Optimal frequency and duration of HBV-DNA monitoring and reliable markers for discontinuation of nucleoside analogues should be clarified for rheumatic disease patients with resolved HBV infection.

Background and Aim: This study investigated the clinical features of hepatocellular carcinoma in patients with sustained virological response to interferon for hepatitis C viral (HCV) infection. Methods: A total of 7715 patients with HCV infection were treated with interferon and followed up for more than 1 year after withdrawal of interferon in 64 Japanese hospitals and clinics between July 1988 and August 2001. Sustained virological response was obtained in 2515 (32.6%) patients. Of these 2515 patients, clinical data were collected for 38 patients in whom hepatocellular carcinoma developed. Sustained virological response was defined as HCV RNA negativity more than 6 months after the termination of interferon. Results: All patients were HCV RNA negative at the time of diagnosis of hepatocellular carcinoma. The median period until the detection of hepatocellular carcinoma was 4.7 years (range 1.4–9.0 years). There were significant improvements in hepatic function including serum albumin, aspartate aminotransferase, alanine aminotransferase, indocyanine green test, platelet count and histological activity grade in comparison with those before interferon therapy and at the onset of hepatocellular carcinoma. The maximum tumor size in patients without medical follow-up for 1 year or more (median: 60 mm) was significantly larger than in patients who were periodically followed up for 6 months or less (median: 25 mm) (P = 0.002). Conclusions: The present findings emphasize the importance of regular medical follow up of patients with HCV infection, as even patients showing a sustained virological response to interferon and in whom hepatic function has improved have the potential to develop hepatocellular carcinoma.

Summary: Ribavirin has recently been demonstrated to be efficacious in combination with interferon (IFN) α -2b for the treatment of relapsed hepatitis C infections. The aim of this study was to evaluate the relationship between the pharmacokinetics and adverse reactions of ribavirin when ribavirin plus IFN α -2b were administered to patients affected with chronic hepatitis C. Nineteen patients received intramuscular IFN α -2b at a dose of 6 or 10 million units and oral ribavirin at 600 mg or 800 mg daily for 24 weeks. The pharmacokinetic profiles of ribavirin were assessed by the measurement of plasma concentrations. Twelve patients were continuously given both ribavirin and IFN α -2b, whereas in 7 patients the therapy was discontinued due to severe adverse drug reactions such as skin eruption, anemia and depression. There were no significant differences in ribavirin dose, Hb, ALT and AST values between the continued and the discontinued therapy groups. In contrast, the pretreatment platelet level and patient age of the discontinued therapy group were significantly different to the continued group. The trough plasma concentration of ribavirin in the discontinued therapy group was significantly higher than that in the continued group at week 1. These results suggest that the monitoring of plasma ribavirin concentrations may be valid for predicting the early phase of adverse drug reactions, thereby providing useful information for the adjustment of the ribavirin dosing for each patient.

SM-11355, a lipophilic platinum derivative, is a novel intra-arterial chemotherapeutic agent for hepatocellular carcinoma (HCC). A phase II study of SM-11355 was conducted to evaluate the antitumor activities and the toxicity in chemotherapy-naive patients with HCC. Sixteen patients were treated with transcatheter arterial injection of SM-11355-lipiodol emulsion (20-120 mg/body). The responses were evaluated by computed tomography 3 months after treatment. Complete response (CR) was defined as disappearance or 100% necrosis of all tumors, and lipiodol accumulation in tumors was regarded as indicating necrosis. Nine patients achieved CR (56%; 95% confidence interval, 29.9-80.2%). The grade 3 toxicities were neutropenia (19%), total bilirubin elevation (19%), AST elevation (44%), and ALT elevation (19%). None of the patients showed grade 4 toxicities or episodes of renal dysfunction. Other common adverse effects were eosinophilia (100%) and pyrexia (94%). Intra-arterial chemotherapy with SM-11355, which was well tolerated, showed promising antitumor activity in patients with HCC.

SM-11355 is a platinum complex developed to treat hepatocellular carcinoma (HCC). It is administered via the hepatic artery, using a carrier, lipiodol, that consists of ethyl esters of iodized poppy seed oil. We have performed a phase I clinical trial of an SM-11355-lipiodol formulation in 11 HCC patients, in order to investigate the maximum allowable dose and to maximize the efficacy and safety of the drug in the treatment of HCC. The SM-11355 arterial infusion suspension was administered at doses of 6, 12 and 20 mg ml(-1) in a maximum lipiodol volume of 6 ml. An antitumour efficacy rating of complete response was achieved for one patient and a partial response rating was achieved for a second patient, giving an overall response rate of 18.2%. Anorexia, nausea and vomiting, pyrexia, thrombocytopenia and increases in AST, ALT and total bilirubin were observed as adverse effects, but each was transient and each patient had recovered completely by 4 weeks after drug administration. Hence, we concluded that the maximum allowable dose was not reached in this study. Overall, our results suggest that SM-11355 is effective in treating HCC and we suggest that the dose for early phase II trials should be 20 mg ml(-1).

Granulomas are characterized histologically by a nodular collection of macrophages with occasional admixture of epithelioid cells, multinucleate giant cells, and other immunocompetent cells. Chemokines are considered to play an important role in the recruitment of these constituent cells of granulomas. The present study has examined the effect of a deficiency of C–C chemokine receptor-2 (CCR2) on hepatic granuloma formation induced by a single injection of Zymosan A. In CCR2+/+ mice, the number and the size of granulomas gradually increased until they reached peak values at 10 days after the injection. In contrast, both the number and the size of granulomas were smaller in CCR2−/− mice than in CCR2+/+ mice from days 5 to 21. They showed low peaks at day 5, after which the number and the size of the granulomas gradually decreased. Immunohistochemical analysis of the constituent granuloma cells using cell type-specific monoclonal antibodies revealed rapid accumulation of blood monocytes, with subsequent differentiation to macrophages, in CCR2+/+ mice during days 2–10. This process was greatly impaired in CCR2−/− mice and granulomas remained small. At all time points, the percentage of polymorphonuclear cells in granulomas was higher in CCR2−/− mice than in CCR2+/+ mice. Interestingly, multinucleate giant cells were frequently observed in granulomas in CCR2−/− mice, whereas they rarely appeared in CCR2+/+ mice. Profiles of liver cytokine RNA levels as well as serum cytokine levels revealed reduced expression of the Th1 cytokine IFN-γ in CCR2−/− mice. These data clearly indicate that signalling through CCR2 has many effects on the normal growth and development of hepatic granulomas. Copyright © 2003 John Wiley & Sons, Ltd.

With the global pandemic of hepatitis B and C infections, the incidence of Hepatocellular carcinoma (HCC) is rapidly increasing world wide. We identified glypican-3 (GPC3), a novel oncofetal gene over-expressed specifically in human HCC, as based on data of cDNA microarrays. As GPC3 is a GPI-anchored membrane protein and could be secreted, we attempted to detect secreted GPC3 protein in sera from HCC patients using Western blotting and ELISA. GPC3 protein was positive in sera of 40.0% (16/40) of HCC patients, and negative in sera from subjects with liver cirrhosis (LC) (0/13), chronic hepatitis (CH) (0/34), and healthy donors (0/60). All subjects were Japanese. Although 12 of 40 HCC patients were negative for both alpha-fetoprotein (AFP) and PIVKA-II well known tumor markers of HCC, four of these were GPC3-positive in the sera. We also observed vanishing GPC3 protein in the sera of three patients after the surgical treatment for HCC. On the other hand, immunohistochemical analysis revealed that HCC expressed GPC3 protein in all 14 HCC patients tested. In conclusion, GPC3, as defined in this study was shown to be a useful tumor marker for cancer-diagnosis for large numbers of patients with HCC.

Background & Aims: The effects of interferon therapy in chronic hepatitis C patients on survival are unclear. Our objective was to analyze survival among a large cohort of chronic hepatitis C patients. Methods: We used a retrospective cohort study design in the setting of 7 university hospitals and 1 regional core hospital in Japan. Our study included 2889 patients with histological-proven chronic hepatitis C: 2430 patients received interferon therapy, and 459 patients were untreated. For intervention, the median dose and duration of interferon administration was 480 million units and 137 days, respectively. For measurements, survival status was confirmed by medical records or direct questionnaires. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality among the Japanese general population and by risk ratio calculated by proportional hazards regression. Results: Thirty of 459 untreated patients, 7 of 817 virologic sustained responders, and 49 of 1613 nonresponders died in 5.4-years follow-up. Fifty-eight (67%) of 86 patient deaths were due to liver diseases (39 to hepatocellular carcinoma). Compared with the general population, overall mortality was high among untreated patients (SMR: 1.9; CI: 1.3–2.8) but not among interferon-treated patients (SMR: 0.9; CI: 0.7–1.1). The risk of death was reduced, compared with untreated patients, among interferon-treated patients (risk ratio for overall death: 0.367; CI: 0.236–0.596; for liver-related death: 0.284; CI: 0.164–0.494) and among sustained responders (risk ratios: 0.148; CI: 0.064–0.343 and 0.050; CI: 0.012–0.216). The risk of liver-unrelated deaths remained unchanged. Conclusions: Interferon therapy improved survival of chronic hepatitis C patients by preventing liver-related deaths. GASTROENTEROLOGY 2002;123:483-491

The factors contributing to local recurrence and survival rates of patients with hepatocellular carcinoma (HCC) were analyzed by univariate and multivariate analysis using the Cox proportional hazard model in 356 patients treated by transcatheter arterial chemoembolization (TAE) or transcatheter arterial chemolipiodolization (TAI). Potential predictors of recurrence and survival analyzed included: patient characteristics (gender and age), basal liver disease, tumor characteristics (number of tumors, size of tumor nodule and presence of vascular invasion), Child classification, serum albumin and total bilirubin level, prothrombin time, treatment modality (TAE or TAI) and serum levels of the tumor markers [alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (PIVKA-II)]. In 259 patients (72.5%) with confirmed complete necrosis of the primary lesion, the local recurrence rate in the TAE group was significantly lower than that of the TAI group (P

The mainstay for the diagnosis for hepatocellular carcinoma (HCC) includes serological tumor markers, such as alpha-fetoprotein, the L3 fraction thereof and PIVKA-II, in addition to imaging modalities. They do not correlate, but complement each other. Hence, a combination of them designed on the basis of their characteristics needs to be worked out. First, it is necessary to identify the patients at high risk for developing HCC, such as those with chronic hepatitis or liver cirrhosis, and in the follow-up conduct regular check-ups for serological tumor markers. Those testing positive for any marker are at the highest risk for developing HCC, even when imaging fails to disclose any space-occupying lesions. Following high-risk patients for serological tumor markers, in concert with imaging, makes accurate evaluation of the efficacy of therapies for HCC possible. Since serological tumor markers can signal the development of HCC earlier than any other laboratory tests, they offer excellent means of identifying relapsing HCC. Equally important in the management of patients with HCC are biological indicators for malignancy, the selection of therapeutic interventions and the prediction of the outcome.

Short-term histologic improvement in hepatitis C-related hepatic fibrosis has been noted in studies with more than 2 years of follow-up, but the long-term effects of interferon therapy on hepatic fibrosis remain unclear.To assess changes in hepatic fibrosis after interferon therapy in patients with chronic hepatitis C.Retrospective cohort study.7 university hospitals and 1 national hospital in Japan.593 patients with chronic hepatitis C who underwent a paired liver biopsy from 1987 to 1997. Of these, 487 patients received interferon therapy and 106 patients were untreated.Patients in the treatment group received a 2- to 6-month course of interferon within 6 months after the initial biopsy.Fibrosis and inflammatory activity in paired biopsy samples obtained a median of 3.7 years apart (range, 1 to 10 years) were graded by using the criteria of Desmet and colleagues (F0 to F4) and those of the French METAVIR Cooperative Study Group (A0 to A3), respectively. Changes in fibrosis staging and activity scores and yearly rates of fibrosis progression and regression were calculated.183 of the 487 interferon-treated patients showed a sustained virologic response. Activity grade was unchanged in most of the untreated patients and improved in 89% (CI, 83% to 93%) of patients with a sustained virologic response. A sustained response to interferon was associated with a mean (+/-SE) reduction in fibrosis score of -0.60+/-0.07 at less than 3 years of follow-up and -0.88+/-0.08 at 3 years or more of follow-up. The rate of fibrosis progression was -0.28+/-0.03 unit/y (regression) in patients with sustained response, 0.02+/-0.02 unit/y in patients with nonsustained response (P0.001), and 0.10+/-0.02 unit/y in untreated patients.Although the time between biopsies partly affected the patient's clinical course, the differences observed here suggest that in patients with chronic hepatitis C, regression of fibrosis is associated with sustained virologic response to interferon therapy.

To evaluate the long-term efficacy and the timing of booster injection of a lyophilized, inactivated hepatitis A vaccine (HAV), we studied the acquired anti-hepatitis A virus titres in 45 subjects who received either two or three doses of the vaccine. With three doses > or = 0.5 microgram administered at 0, 1 and 6 months, antibody titres increased to approximately half those seen in people with a history of natural hepatitis A infection. Although the titres decreased gradually, all subjects remained anti-HAV positive at least 5 years after the third injection. The geometric mean titre exceeded 100 mIU/mL, which approximated the highest titre obtainable by the inoculation of immune serum globulin. A prompt antibody reaction was seen with two doses administered 2 weeks apart, with the titres achieved being 5.6-fold the peak titres obtained by the inoculation of immune serum globulin. All 33 subjects were antibody positive 18 months after the first injection, but some became seronegative by 30 months, suggesting that a third booster dose would be desirable at 18 months.

Interferon (IFN) is now commonly used for the treatment of type C hepatitis ; however, its effects differ depending upon the subtype of hepatitis C virus (HCV) being treated. It has been recently confirmed in many studies in Japan that the effectiveness of IFN treatment is poor in patients having type 1b and better in patients having type 2a HCV. However, the effects of IFN treatment on other subtypes of HCV were not clear because of the small number of patients in each hospital. In the present study, the effects of IFN treatment in patients with other HCV subtypes were analysed from nationwide data collected in Japan using a standard questionnaire. From this questionnaire, local differences in the distribution of HCV subtypes in Japan were also analysed. A standard questionnaire, consisting of questions about the number of patients with chronic type C hepatitis with different HCV subtypes and the number of patients showing different responses to IFN treatment, was sent to over 40 study groups in Japan. Answers to the questionnaire concerning HCV subtyes and the effects of IFN treatment were obtained from 26 and 22 hospitals, respectively, throughout Japan. The incidence of HCV type 1b was highest in the Kinki area (south-central Japan). The incidence of type 1b HCV decreased in parallel with distance from this area. The mortality rates of hepatic cancer in different areas were significantly correlated with the incidence of HCV type 1b. The efficacy of IFN treatment was significantly better for both types 2a and 2b HCV than for type 1b HCV ; the efficacy of IFN treatment was poor in the mixed type of 1b and 2a and tended to be better in type la. The efficacy of IFN treatment for other types of HCV was also better. These results indicate that there are local differences in the distribution of HCV subtypes in Japan and that these differences may be closely associated with the clinical features of HCV-related liver disease. The efficacy of IFN treatment was significantly poorer in patients with the 1b-related type HCV than in patients with other types of HCV.

Immunoglobulin A class antibody to hepatitis C virus core antigen (IgA anti-HCc) was measured in the serum of 128 patients with type C chronic liver disease. Fifty-eight patients (45.3%) were seropositive. IgA anti-HCc was detected in only one of 20 patients with chronic persistent hepatitis; however, 52.3% (46/88) of patients with chronic active hepatitis and 55% (11/20) of patients with liver cirrhosis were seropositive. Histological examination revealed that 22 (71.0%) of 31 patients with severe disease activity were seropositive compared to 35 (44.9%) of 78 patients with moderate (P

Antibody subclasses directed against the core protein (HCc) of hepatitis C virus (HCV) were measured in 27 patients with acute non-A, non-B (NANB) hepatitis, and 99 patients with chronic HCV-associated liver disease. IgM, IgA, and IgG anti-HCc responses were observed in 11 (40.7%), 7 (25.9%), and 18 (67%) patients with acute NANB hepatitis, respectively. Twenty-four (24.2%) and 40 (40.4%) patients with chronic HCV infection also had detectable IgM and IgA, respectively. IgM anti-HCc inconsistently detected acute infection, and HCV ribonucleic acid (RNA) could be detected preceding the rise in anti-HCc antibodies in five consecutive patients with acute hepatitis. IgM anti-HCc also could not distinguish acute from chronic infection and did not correlate with histologic progression. However, the form of IgA present (polymeric vs monomeric) did discriminate acute from chronic infection and the IgA anti-HCc titer correlated with histologic evidence of liver disease in patients with chronic HCV infection.

Enzyme-linked immunosorbent assays for detecting antibodies against hepatitis C virus and the polymerase chain reaction were tested in 82 chronic hepatitis B surface antigen carriers for their accuracy in diagnosing patients coinfected with hepatitis B and C viruses. To clarify the role of each virus in chronic hepatitis, serologic assays against hepatitis B virus were also tested. Thirteen (14.9%), 14 (17.1%) and 15 (18.3%) patients were anti-HCV positive using C100 (HCV1), JCC, and a second generation test (HCV2), respectively. HCV RNA was detected by polymerase chain reaction in 9 of 18 anti-HCV-positive cases. Although HCV1 assays were not sufficient, either the JCC or HCV2 assay detected all polymerase chain reaction-positive cases. Fifteen of 18 specimens that were positive in at least one of the three ELISA were seronegative for the hepatitis B e antigen. As judged by HBV DNA polymerase activity, titers of hepatitis B surface antigen and immunoglobulin A antibody against hepatitis B core antigen (IgA anti-HBc), activity of hepatitis B virus replication and immune response against hepatitis B virus in patients with coinfection was decreased to the level of hepatitis B virus asymptomatic carriers. These results show that hepatitis C virus appears to be the primary cause of active hepatitis in most patients with hepatitis B and hepatitis C virus coinfection.

This study evaluates the immune response of 20 haemodialysis (HD) patients vaccinated with hepatitis A (HA) vaccine and eight patients vaccinated with hepatitis B (HB) vaccine. Twenty patients and 22 healthy adults were immunized three times (months 0, 1 and 6) intramuscularly with a 0.5 microgram dose. All members of both groups were positive for the antibody to hepatitis A virus (anti-HAV) after three vaccinations. The geometric mean titres at 7 months were similar in both groups. No serious side effects were observed. Eight of the HD patients with HA vaccination were injected with yeast-derived hepatitis B vaccine. The three doses of 10 micrograms were administered intramuscularly at 0, 1 and 6 months. The occurrence of antibody to hepatitis B surface antigen (anti-HBs) was late in HD patients and the anti-HBs level in HD patients was lower than that in healthy subjects. These results indicate that this HA vaccine has good immunogenicity compared with the HB vaccine and that the standard three doses of HA vaccine given at 0, 1 and 6 months are safe and effective even in HD patients.

The clinical utility of a new JCC-2 enzyme-linked immunosorbent assay kit that detects and quantitates anti-hepatitis C virus (anti-HCV) core antibodies (anti-HCc) was investigated. Serum samples were obtained from 102 patients with various non-A, non-B liver diseases, including 19 cases of chronic hepatitis type C who had been treated with interferon (IFN). The results of the anti-JCC-2 assay were significantly correlated with serum HCV-RNA positivity. Patients who were HCV-RNA positive exhibited a high rate of positivity for anti-JCC-2 (72.2% in acute hepatitis, > 90% in chronic liver diseases). The geometric mean of the anti-JCC-2 titre was not significantly different among different stages of chronic liver disease (among CPH, CAH and LC). The anti-JCC-2 titre decreased gradually in cases that became HCV-RNA negative after IFN therapy. If HCV-RNA positivity recurred, the anti-JCC-2 titre increased, indicating that serial measurements of the anti-JCC-2 titre are useful for monitoring the antiviral effect of IFN treatment. These results suggest that quantification of anti-HCc by the anti-JCC-2 assay is superior to the semi-quantification of circulating HCV-RNA provided by monitoring of IFN therapy. Monitoring of HCV-RNA status using reverse transcription-nested polymerase chain reaction (RT-nested PCR) is possible, but it is technically demanding and too expensive for routine clinical use.

The intrafamilial transmission pattern of hepatitis C virus (HCV) was examined in 118 family members of 61 index patients with type C chronic liver disease using anti-HCV antibodies and HCV RNA assay. The study subjects consisted of eight parents, 49 spouses, 50 children, eight siblings and three other relatives. The positivity rates of anti-C100, anti-JCC, second-generation anti-HCV and HCV RNA were 6.8, 12.7, 12.7 and 11.0%, respectively. Positivity in one or more anti-HCV antibody assay was detected in 3/24 (12.5%) father-child pairs, 3/17 (17.6%) mother-child pairs, 2/8 (25%) sibling pairs, 6/38 (15.8%) husband-wife pairs and 2/13 (15.4%) wife-husband pairs. In spouses, positivity for anti-HCV antibody or HCV RNA was observed after 40 years of age. None of 11 spouses married 50 years and duration of marriage was > 25 years, anti-HCV or HCV RNA was frequently detected (32.0%). However, when seven pairs involving four spouses, one mother-daughter pair and two sibling pairs were subtyped, the same HCV subtypes were found in only four pairs (type II in three pairs and type III in one pair). Further, the agreement rate between anti-HCV and HCV RNA was > 90%. These results suggest that intrafamilial transmission of HCV, revealed by the subtyping method, is considered lower than the percentage of positivity for anti-HCV antibodies or HCV RNA in family members of patients with type C chronic liver disease. Thus, the intrafamilial transmission of HCV seems to be quite rare and much less common than that of HBV.

Optimum cutoff levels for plasma des-gamma-carboxy (abnormal) prothrombin (DCP) and serum alpha-fetoprotein (AFP) were determined by analyzing receiver operating characteristic (ROC) curves to discriminate between hepatocellular carcinoma (HCC) and benign hepatic conditions. Plasma DCP levels in 200 patients with HCC and 197 control patients with benign liver diseases were measured by an enzyme immunoassay with anti-DCP monoclonal antibodies, while serum AFP levels for both groups were measured by radioimmunoassay. From ROC curves and tangential lines with a slope of 1.0, the cutoff levels of DCP and AFP were determined to be 0.11 AU/ml and 150 ng/ml, respectively. Lowered cutoff levels of DCP did not improve the sensitivity, in contrast to the increased sensitivity obtained by lowering the specificity of AFP. The sensitivities and specificities determined in this study were close to the currently used values of 0.1 AU/ml for DCP and 200 ng/ml for AFP, justifying these cutoff levels for the differentiation of benign and malignant liver diseases.

In 1989, the Chiron group developed an enzyme immunoassay system (C100) for detecting antibodies to hepatitis C virus (anti-HCV). In our examinations, the postivie rate was 65.3% of the total number of patients (199) with non-A, non-B (NANB) liver disease. Additionally, a specific ELISA system (KCL-163) was developed by Kaketsuken (Kumamoto, Japan) based on synthetic peptides corresponding to an HCV genome of a Japanese isolate. In this study, we measured antibodies to HCV by KCL-163, and compaired the results of KCL-163 with that of C100 in patients with various liver diseases. Our emphasis was on the discrepancies between the results of the two types of ELISA. We concluded that it was not sufficient to diagnose hepatitis C only by assay systems based on the C100-3 region of an HCV genome, and that KCL-163 was superior to C100 in its specificity and sensitivity in the diagnosis of hepatitis C.

Endoscopic injection sclerotherapy (EIS) for rupture of esophageal varices was carried out in 13 patients of liver cirrhosis with hepatocellular carcinoma (HCC). Sclerotherapy was performed by intravariceal injections of 5% ethanolamine oleate. According to the manual for the staging of cancer, these HCCs were classified as Stage I in 1 case, II in 1 case, III in 2 cases, and IV in 9 cases. There was no difference between post EIS prognosis and stage. Child’s classification of these patients were class A in 1 case, B in 5 cases, and C in the remaining 7 cases. Only in 1 case of Child’s A and 1 case of Child’s B who were less advanced clinically and were free from icterus and ascites did EIS produce favorable results, it arresting esophageal variceal hemorrhage and led to a relatively good outcome. We suggest that emergency EIS for rupture of esophageal varices should be performed in patients with relatively good general conditions, irrespective of the stage of HCC.

To clarify the involvement of atrial natriuretic peptide (ANP) in the pathogenesis of liver cirrhosis, we measured plasma ANP in patients with various stages of cirrhosis and in age-matched normal subjects. Urinary cyclic guanosine monophosphate (cGMP) was also measured as a marker of active biological ANP. In addition, effects of exogenous synthetic human ANP (0.5 micrograms/kg) on renal functions were examined in normal subjects and in cirrhotics without ascites or with mild ascites. Plasma ANP levels were not significantly different among these 3 groups. Urinary cGMP concentrations were significantly higher in both cirrhotics without ascites and cirrhotics with mild ascites, (340 pmol/ml, P less than 0.05 and 496 pmol/ml, P less than 0.01 respectively) than normal subjects (95 pmol/ml). In normal subjects, marked increases in urinary volume (UV), sodium excretion (UNaV), fraction excretion of sodium (FENa) and free water clearance (CH2O) were induced after ANP infusion, and significant recoveries were subsequently observed in these parameters. However, in cirrhotics, the responses to ANP infusion of UV, FENa and CH2O were far less dramatic. The response of UV, UNaV and FENa in cirrhotics with mild ascites was delayed compared to cirrhotics without ascites. These results suggest that the blunted natriuretic responsiveness to ANP is contributory to the pathogenesis of initial sodium retention in cirrhotics.

To evaluate the effect of hepatitis B vaccine on the persistence of anti-HBs and its efficacy in preventing hepatitis type B, anti-HBs and anti-HBc levels were studied over a period of 5.5 years. Plasma-derived hepatitis B vaccine, containing 20 micrograms of HBsAg protein, was injected subcutaneously in 122 healthy medical staff members, followed by two identical injections 1 and 6 months later. Anti-HBs and anti-HBc levels were then measured by radio-immunoassay. The anti-HBs titres were expressed as the sample/negative (S/N) ratios, and an S/N ratio of more than 2.1 was considered positive. The mean (and s.d.) anti-HBs titre peaked 7 months after the first vaccination with an S/N ratio of 153.6 +/- 149.8, after which it decreased with time. The mean anti-HBs titre dropped to an S/N ratio of 8.0 +/- 5.1 5.5 years after the first vaccination. The percentage of vaccinees who were anti-HBs positive also gradually decreased with time after a peak of 84.2% at 7 months following the first vaccination. The percentage of vaccinees who were anti-HBs positive was 38.9% 5.5 years after the first vaccination. The anti-HBc level was not positive in all subjects during the observation period. Five vaccinated volunteers who had developed anti-HBs after the basic vaccination, but whose acquired antibody level became negative within 4.5 years following the first vaccination, were administered a booster dose of 20 micrograms of HBsAg 4.5 years after the first vaccination. Only one of these subjects did not respond to the booster vaccination.(ABSTRACT TRUNCATED AT 250 WORDS)