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Background: While the proportion of hepatocellular carcinoma (HCC) cases with non-viral etiology continues to increase in Japan, the epidemiological trends in the sex and age distribution of new HCC cases remain unclear. This study examines the epidemiological trends, including the distribution of sex, age, and disease etiology, in HCC incidence over 24 years.Methods: Data of 20,547 newly diagnosed HCC patients in 1996–2019 at 19 institutions participating in the Liver Cancer Study Group of Kyushu were analyzed in this prospective study. We divided the study period into four 6-year quarters. HCC etiology was categorized as hepatitis B virus (HBV) infection, HBV+hepatitis C virus (HCV) infection, HCV infection, and both negative (non-BC). Results: The incidences of HCC per quarter of the study period were 4,311 (21.0%), 5,505 (26.8%), 5,776 (28.1%), and 4,955 (24.1%) cases, sequentially. Overall, 14,020 (68.2%) patients were male. The number of HCC cases in patients ≤50 years, 60–69 years, 70–79 years, and ≥80 years were 3,711 (18.1%), 6,652 (32.4%), 7,448 (36.2%), and 2,736 (13.3%), respectively. The average age of newly diagnosed patients increased in each quarter. HCC was associated with HBV, HBV+HCV, and HCV infections and non-BC in 2,997 (14.6%), 187 (0.9%), and 12,019 (58.5%), and 5,344 (26.0%) cases, respectively. The number of HCV-associated cases decreased in each quarter, while that of non-BC-associated cases increased.Conclusions: HCC incidence tends to increase in the elderly and in non-BC patients; in contrast, HCC incidence due to HCV tends to decrease. In countries where HCV infection is likely the predominant cause of HCC, similar trends in HCC incidence are anticipated in the future.

Background: Lenvatinib (LEN) has been approved for patients with unresectable hepatocellular carcinoma (u-HCC) since March 2018 in Japan. We performed a retrospective nationwide multicenter study to clarify the clinical characteristics of LEN in real-world practice. Methods: A total of 343 u-HCC patients who received LEN from March 2018 to May 2020 at 23 sites in Japan were registered. Results: During the median observation period of 10.5 months, 143 patients died. In Child-Pugh A (n = 276) and Child-Pugh B (n = 67) patients, the median overall survival (OS) was 21.0 and 9.0 months. The median progression-free survival (PFS) was 8.8 months in Child-Pugh A patients. The objective response rate (ORR) and disease control rate (DCR) according to modified response evaluation criteria in solid tumors (RECIST criteria) were 42.1% and 82.1%. The independent pretreatment factors associated with mortality in all patients were AFP ≥ 400 ng/mL (hazard ratio (HR) 2.00, 95% confidential interval (95% CI) 1.08–2.09, p &lt, 0.0001), modified albumin-bilirubin (ALBI) grade 2b or 3 (HR 1.56, 95% CI 1.09–2.17, p = 0.012), major vascular invasion (HR 1.91, 95% CI 1.26–2.89, p = 0.0022), PS &gt, 0 (HR 1.50, 95% CI 1.09–2.08, p = 0.014), and MTT (molecular targeted therapy) experience (HR 2.22, 95% CI 1.56–3.13, p = 0.00038). In the MTT naïve patients with ALBI grade 1 or modified ALBI 2a and BCLC stage B (n = 68), median OS and PFS were 25.3 and 12.3 months. Liver-related adverse events during LEN were the only significant adverse event associated with OS (HR 2.74, 95% CI 1.93–3.88, p &lt, 0.0001). Among the Child-Pugh A patients with extrahepatic metastasis and no major vascular invasion, median PFS in the patients with bone metastasis was significantly shorter than those with lung or adrenal grand metastasis (6.3 vs. 12.5 months, p = 0.0025). Conclusion: LEN showed a high response rate in real-world practice. Pretreatment factors, including ALBI score, AFP, and major vascular invasion are important in making a treatment strategy for patients with u-HCC. The patients with bone metastasis would be candidates for new therapeutic approaches.

Aim Rescue therapy for patients with genotype 2 (GT2) chronic hepatitis C who failed prior sofosbuvir (SOF) plus ribavirin (RBV) awaits establishment. This study aims to investigate the efficacy and safety of the fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) (GLE/PIB) for patients with GT2 chronic hepatitis C. Methods In this nationwide observational study undertaken by the Japanese Red Cross Liver Study Group, 28 GT2 patients with prior failure of SOF + RBV were retreated with GLE/PIB for 12 weeks. We evaluated the rate of sustained virologic response (SVR) and adverse events. Results After 4 weeks of therapy, serum hepatitis C virus RNA was below the limit of quantification in all patients. The SVR after 4 and 12 weeks of the end of treatment was validated in 100% (28/28) and 100% (28/28), respectively. The adverse events comprised pruritus (eight patients), fatigue (four patients), and appetite loss (four patients), all of which were mild in severity. Conclusions This study establishes the efficacy of GLE/PIB as retreatment in Japanese patients with GT2 chronic hepatitis C not responding to SOF + RBV.

Aim To evaluate the virologic responses and clinical course of daclatasvir plus asunaprevir treatment in non-hemodialysis (non-HD) and hemodialysis (HD) patients infected with genotype 1 hepatitis C virus (HCV). Methods A total of 1113 non-HD patients and 67 HD patients were assessed. To evaluate pretreatment factors contributing to sustained virological response at 12 weeks (SVR12), univariate and multivariate analyses were carried out. To adjust for differences in patient background, propensity score matching was undertaken. Results The overall SVR12 rates were 91.6% in non-HD patients and 95.5% in HD patients. Compared with non-HD patients, HD patients were younger, were more likely to be male, were less likely to have received interferon-based pretreatment, had a lower viral load, and had lower levels of alanine transaminase, hemoglobin, and α-fetoprotein. Multivariate analysis revealed that viral load, α-fetoprotein, L31 substitution negative, and Y93 substitution negative were independent predictive factors for SVR12 in non-HD patients. The proportion of patients with undetectable HCV-RNA during the initial 4 weeks was significantly higher in HD patients than in non-HD patients. The SVR12 rate was clearly higher in HD patients than in non-HD patients, although the difference was not statistically significant. After propensity score matching to adjust for viral load, α-fetoprotein, L31 substitution, and Y93 substitution, these trends disappeared. Conclusions For treatment of HCV genotype 1 infection, daclatasvir plus asunaprevir is useful not only in non-HD patients but also in HD patients. Viral load, α-fetoprotein levels, L31 substitution, and Y93 substitution influence treatment course and outcome.

BACKGROUND Direct-acting antivirals (DAAs) rapidly clear hepatitis C virus (HCV), but the lipid dynamics after DAA treatment remain unknown. Low-density lipoprotein (LDL) cholesterolemia is the predicting factor for the onset and death of atherosclerotic cardiovascular diseases. Thus, in this study, we examined the frequency and risk of hyper-LDL cholesterolemia in HCV patients who achieved sustained virologic response (SVR) with DAA treatment. METHODS A total of 121 patients with HCV genotype 1b, who achieved SVR with DAA treatment, were examined for serum levels of total cholesterol, LDL-cholesterol (LDL-C), high-density lipoprotein, and triglycerides from the start of treatment until 2 years after SVR (SVR-2y). ΔLDL-C was defined as the change in LDL-C levels from treatment initiation to SVR-2y. Hyper-LDL cholesterolemia was defined as ≥ 140 mg/dL LDL-C at SVR-2y. Stepwise multiple regression analysis was performed to determine whether ΔLDL-C and hyper-LDL cholesterolemia are associated with other factors, including viral kinetics. RESULTS A total of 63, 3, and 55 patients were administered daclatasvir + asunaprevir, ombitasvir + paritaprevir + ritonavir, and ledipasvir + sofosbuvir, respectively. ΔLDL-C in patients with the IL28B (rs8099917) TG/GG genotype was significantly higher than in those with IL28B TT (27.3 ± 27.0 and 9.6 ± 27.3 mg/dL; P

AIM The present study aimed to determine the real-world efficacy and safety of the non-structural protein (NS)5A inhibitor elbasvir (EBR) combined with the NS3/4A protease inhibitor grazoprevir (GZR) in patients with hepatitis C virus (HCV) genotype 1 (GT1) infection. METHODS This study retrospectively evaluated the rate of sustained virologic response at 12 weeks post-treatment (SVR12) and the safety of EBR/GZR treatment in 159 men and 194 women with a median age of 72 years, and it assessed factors associated with the SVR12 rate. The attending physicians were responsible for selecting candidate patients for EBR/GZR in this retrospective study. RESULTS Treatment outcomes for EBR/GZR were good in direct-acting antiviral (DAA)-naive patients, of whom 99.4% achieved SVR. Of 353 patients, 10 (2.9%) had treatment failure. Of these patients, eight previously underwent DAA therapy, and the remaining two had NS5A-L31/Y93 double mutation. The SVR rate was 50% (8/16 patients) in patients who previously underwent DAA therapy, and 18.2% (2/11 patients) in patients with NS5A-L31/Y93 double mutation. On multivariate logistic regression analysis, NS5A-Y31/Y93 double mutation (odds ratio 356.3; 95% confidence interval, 23.91-16 940; P

AIM This study aimed to describe the real-world efficacy and safety of sofosbuvir (SOF) + ribavirin (RBV) for chronic hepatitis C, genotype 2. METHODS This was a retrospective analysis of a nationwide, multicenter registry including 914 hepatitis C genotype 2 Japanese patients treated with SOF + RBV for 12 weeks. The rate of sustained virologic response at 12 weeks after treatment (SVR12), incidence of adverse events, and changes in serological parameters were analyzed. RESULTS Treatment was completed in 98.9% of patients. Ribavirin dose reduction was required in 29.7% of patients. The SVR12 rate was 96.8% in the intention-to-treat population and 97.6% in the per-protocol population. Factors associated with SVR12 were absence of advanced fibrosis (odds ratio, 5.76, P = 0.003) and interferon-treatment-naive status (odds ratio, 4.79, P = 0.017). Dose reduction or total adherence of RBV was not associated with SVR. The resistance-associated substitution S282 T in NS5B was not detected in any patient at virologic failure. Serum albumin levels significantly increased, and the degree of increase was greater in patients with advanced fibrosis than in those without (0.21 ± 0.32 vs. 0.05 ± 0.29, P

We aimed to describe the real-world efficacy and safety of combination therapy with ledipasvir and sofosbuvir (LDV/SOF) for chronic hepatitis C virus (HCV) genotype 1 (GT1) infection. This retrospective analysis of a prospective, nationwide, multicenter registry included GT1-infected patients treated with LDV/SOF for 12 weeks. We assessed the rate of sustained virological response at 12 weeks post-treatment (SVR12), incidence of adverse events, and serum markers of hepatocellular carcinoma (HCC). Among the 1461 patients included (mean age, 69 years; 29.5% aged > 75 years; cirrhosis, 23.8%; history of treatment for HCC, 10.9%), the overall SVR12 rate was 98.4% (1438/1461). Factors associated with treatment failure were cirrhosis (odds ratio, 4.19; p = 0.014) and resistance-associated substitutions (RASs) in NS5A at baseline (odds ratio, 7.78; p = 0.0004). The SVR12 rate in patients with cirrhosis and NS5A RASs was 93.0% compared to 100% in patients without cirrhosis or NS5A RASs. In patients with SVR, the levels of alpha-fetoprotein (AFP), AFP-L3, and Mac-2 binding protein glycosylation isomer (M2BPGi) decreased from baseline to end of treatment (from 13.4 ± 37.6 to 6.0 ± 10.6 ng/mL, p

Background and aim This study aimed to elucidate whether interferon (IFN)-free direct-acting antiviral (DAA) therapy for hepatitis C after curative treatment of hepatocellular carcinoma (HCC) promotes HCC recurrence in a real-world large-scale cohort. Methods This multicenter study was conducted by the Japanese Red Cross Hospital Liver Study Group. This retrospective study analyzed 516 patients who underwent antiviral treatment for hepatitis C with either IFN (n = 148) or IFN-free DAA (n = 368) after curative HCC treatment; 78 IFN-treated patients and 347 IFN-free DAA-treated patients achieved sustained virological response (SVR). The recurrence rate of HCC was compared between the antiviral therapies. Logistic analysis and Cox proportional hazards analysis identified factors associated with early recurrence of HCC within 24 weeks of antiviral therapy and recurrence throughout the observation period, respectively. Results AFP at the completion of antiviral therapy, clinical stage of HCC, and non-SVR were independent factors associated with early recurrence of HCC. Among patients who had achieved SVR, the clinical stage of HCC and the level of AFP at completion of antiviral therapy were independent factors associated with early recurrence of HCC. For recurrence throughout the observation period in SVR patients, AFP at completion of antiviral therapy, duration between last HCC treatment to antiviral therapy, and the number of treatments were independent factors. There was no significant difference in the rate of early recurrence of HCC or recurrence throughout the observation period between IFN and IFN-free DAA treated patients. Conclusions There were no differences in the early recurrence rate of HCC between patients who underwent IFN and those who underwent IFN-free DAA as antiviral therapies.

A 73-year-old female with hepatocellular carcinoma (HCC) received percutaneous transhepatic portal vein embolization (PTPE) before extensive right lobe hepatectomy. Serum levels of des-gamma-carboxy-prothrombin (DCP) were increased and remained at a high level until hepatectomy. Immunohistochemical examination revealed that an increased expression of DCP was demonstrated not only in HCC tissues, but also in the non-cancerous liver of the right lobe, where portal blood flow was blocked off as a result of PTPE. The serum level of DCP is known to be greatly increased in patients with HCC accompanied by portal vein invasion. We speculate that this increased DCP level is caused by both increased DCP production in HCC tissue and the surrounding non-cancerous liver, where portal flow is blocked off as a result of portal invasion by HCC.

Balloon-occluded retrograde transvenous obliteration (BRTO) is a highly effective therapy for gastric varices with liver cirrhosis. We have investigated the incidence of hepatocellular carcinoma (HCC) after BRTO. We enrolled 71 patients with viral hepatitis in which HCC had not appeared with liver imaging findings at the time of BRTO. The overall survival rate after BRTO was 86.8%, 76.1%, and 50.5% at 1, 3, and 5 years. The occurrence rate of HCC after BRTO was 20.9%, 41.1%, and 60.7% at 1, 3, and 5 years, especially showing a higher occurrence of HCC at one year. Meanwhile, the occurrence rate of HCC after treatment which excluded BRTO for esophagogastric varices in patients was 6.3%, 19.2%, and 42.5% at 1, 3, and 5 years. The log-rank test revealed that the occurrence rate of HCC after treatment was significantly higher in the BRTO group compared with that in the non-BRTO group (P=0.0447). The recurrence rate of HCC after BRTO was 35.8% and 80.0% at 1 and 3 years. The present study demonstrated a high incidence of HCC after BRTO in liver cirrhosis patients with viral hepatitis infection. We have suggested the potential for BRTO to accelerate hepatocarcinogenesis.

AIM In primary biliary cirrhosis (PBC), damaged hepatocytes resulting from chronic cholestasis follow a compensatory mechanism that alters hepatobiliary transporter expression to reduce the accumulation of potentially toxic compounds such as bile acid. Organic anion transporter peptide 1B3 (OATP1B3), which transports agents such as gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), has reduced expression in the late stages of PBC. Therefore, we investigated the use of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) as a useful detection method for the advanced staging of PBC. METHODS Stage I-III PBC (non-liver cirrhosis [LC]-PBC, n = 12), stage IV (LC-PBC, n = 6), and non-PBC patients (control group, n = 4) were included in this study. We obtained liver tissue samples by percutaneous liver biopsy. Hepatic OATP1B3 expression was determined immunohistochemically, and OATP1B3 mRNA levels were assessed using real-time reverse transcription polymerase chain reaction. The relative enhancement (RE) in the hepatobiliary phase was calculated using the signal intensity of Gd-EOB-DTPA-enhanced MRI. RESULTS Immunohistochemistry revealed markedly reduced expression of OATP1B3 in hepatocytes around the central vein in LC-PBC patients. Hepatic OATP1B3 mRNA expression in LC-PBC patients was significantly lower than that in non-LC-PBC patients (P

Telaprevir (TVR) plays a major role in renal damage and anemia associated with TVR/pegylated interferon/ribavirin therapy for chronic hepatitis C. Adjusting the TVR starting dose may reduce these adverse effects. We aimed to determine whether adjusting the starting dose according to renal function reduces TVR-associated renal damage and anemia and affects the sustained virological response (SVR).Our study included 112 patients infected with hepatitis C genotype 1 treated with pegylated interferon/ribavirin/TVR triple therapy. The TVR starting dose adjusted according to renal function was calculated as TVR/unadjusted estimated glomerular filtration rate (eGFR) ratio=TVR/(eGFR×body surface area/1.73).A TVR/unadjusted eGFR ratio of 32 or greater was a predictor of renal impairment and anemia in multivariate analysis (odds ratio 12.09, P0.001, and OR 4.14, P0.001, respectively). Patients with a TVR/unadjusted eGFR ratio of 32 or greater developed significant renal impairment and anemia (P0.001 and P=0.002, respectively). SVR was significantly reduced in patients with a TVR/unadjusted eGFR ratio less than 23 versus 23 or greater (66.7 and 87.2%, respectively, P=0.045). SVR tended to increase stepwise [23.0 (66.7%), ≥23 to32 (84.8%), and ≥32 (89.6%), respectively]. The TVR/unadjusted eGFR ratio was correlated significantly with the serum TVR concentration (r=0.541, P0.001).Adjusting the TVR starting dose according to the TVR/unadjusted eGFR ratio decreased adverse effects and affected the SVR rate. The TVR starting dose should be adjusted by a TVR/unadjusted eGFR ratio of 23 or greater to less than 32 to safely achieve SVR.

Reticuloendothelial iron overload is associated with secondary hemochromatosis including repeated transfusions and iron over-supplementation. Ferroportin disease B is a severe subtype of hereditary iron overload syndrome with an activated reticuloendothelial system. The iron exporter ferroportin may be insensitive to hepcidin 25 in this subtype. However, the interactions between the hepcidin-ferroportin system and modifiers of reticuloendothelial iron overload have not yet been elucidated. We describe two patients with iron overload conditions that were compatible with ferroportin disease B, but their genetic backgrounds and habitual states differed. Both patients had diabetes, periportal fibrosis with severe iron deposits in their hepatocytes and Kupffer cells, and adequate levels of circulating hepcidin 25. However, the first patient was heterozygous for a mutation in the FP gene and free from the acquired factors of iron overload, while the second patient was a heavy drinker with a heterozygous mutation in the TFR2 gene and no mutations in the FP gene. The first patient was the second reported case of ferroportin disease B in Japan. Our study on these 2 patients suggests that liver fibrosis associated with compound iron overload of reticuloendothelial cells and hepatocytes may occur via multi-etiological backgrounds.

Background and Aim: Percutaneous radiofrequency ablation (RFA) has been shown to be a highly effective treatment for hepatocellular carcinoma (HCC). We investigated the controllability of HCC and explored the algorithm of therapeutic strategy for HCC in patients who met the RFA criteria. Methods: We enrolled 472 patients with HCC who met the RFA criteria (≤ 3 nodules, ≤ 3 cm) and underwent RFA for initial therapy. Patients who underwent repeated RFA were evaluated retrospectively when HCC exceeded the RFA criteria, or the functional hepatic reserve progressed to Child–Pugh grade C. Results: Overall survival rates were: 1 year, 96%; 3 years, 79%; and 5 years, 56%. In 5 years, 14% of patients progressed to Child–Pugh grade C. Meanwhile, 47% of patients exceeded the RFA criteria. Annually, 8% of patients deviated from the RFA criteria. The percentage of patients who were able to receive RFA significantly decreased at the fourth session compared with up to the third session. The survival rates decreased at the rate of 7% annually until the third year after the initial RFA. Afterwards, it shifted to a decrease at the rate of 12% annually. In a multivariate analysis, the presence of hepatitis C virus infection and the existence of a single tumor were identified as significant independent factors contributing to probabilities exceeding the RFA criteria. Conclusions: HCC was controlled by RFA up to three RFA treatments and 3 years from the initial therapy. On this basis, we propose a “three (times) × 3 (years) index” for considering a shift from RFA to other treatment modalities.

症例1は30歳代の男性．出生時の合併症によるてんかん発作を繰り返すため，抗てんかん薬を内服中であった．てんかん治療のため近医入院中に肝障害と意識障害を認め，当院紹介入院となった．高トランスアミナーゼ血症，プロトロンビン（PT）活性38％，肝性脳症II度，C型肝炎ウイルス（HCV）抗体低力価陽性，血清HCV RNA陽性より，HCVによる急性肝不全昏睡型と診断した．感染経路は不明であった．症例2は30歳代の男性．医師．HCV抗体陽性患者からの血液汚染事故によりC型急性肝炎（AHC）を発症した．入院後，低PT活性が持続し黄疸が遷延した．2症例ともに早期に集学的治療を行ない，インターフェロン（IFN）治療も併用した．IFN併用集学的治療により，肝機能は改善した．急性期を脱した後にもIFNを継続することでHCVの持続感染を阻止できた．HCVによる急性肝不全やAHCにIFNが有用である可能性が示唆された．

Ectopic hepatocellular carcinoma (HCC) is a very rare clinical entity that is defined as HCC arising from extrahepatic liver tissue. This report presents a case of ectopic multiple HCC arising in the abdominal cavity. A 42-year-old otherwise healthy male presented with liver dysfunction at a general health checkup. Both HCV antibody and hepatitis B surface antigen were negative. Laboratory examination showed elevations in serum alpha-fetoprotein and PIVKA-II. Ultrasonography and computed tomography revealed multiple nodular lesions in the abdominal cavity with ascites without a possible primary tumor. Exploratory laparoscopy was performed, which revealed bloody ascites and multiple brown nodular tumors measuring approximately 10 mm in size that were disseminated on the perineum and mesentery. A postoperative PET-CT scan was performed but it did not reveal any evidence of a tumor in the liver. The tumors resected from the peritoneum were diagnosed as HCC. The present case of HCC was thought to have possibly developed from ectopic liver on the peritoneum or mesentery.

Aim: The diagnosis of Wilson disease is based on the results of several clinical and biochemical tests. This study aimed to clarify the clinical features and spectrum of Wilson disease, including severe Wilson disease. Methods: Between 1985 and 2009, 10 patients with clinical, biochemical or histological evidence of Wilson disease were either diagnosed or had a previously established diagnosis confirmed at Fukuoka University Hospital. Severe Wilson disease was defined by a serum prothrombin time ratio of more than 1.5 or serum prothrombin activity of less than 50%. The 10 Wilson disease patients were divided into two groups, one containing three non-severe patients and the other containing seven severe patients, and the biochemical features of the patients in these two groups were compared. Results: The mean age at diagnosis was 21.5 ± 11.7 years (range, 7–39). Decreased serum ceruloplasmin, enhanced 24-h urinary copper excretion, presence of Kayser–Fleischer rings and histological signs of chronic liver damage were confirmed in 100%, 100%, 66.7% and 100% of patients, respectively. Severe Wilson disease patients had higher levels of serum ceruloplasmin and serum copper (P

We report two cases of Budd-Chiari syndrome. Case 1: A 57-year-old man presented with leg edema and esophageal varices. Cavography showed obstruction of the inferior vena cava with antiphospholipid syndrome. Further, the patient showed positive serology for hepatitis C virus and consumed large quantities of alcohol. Percutaneous transluminal angioplasty was performed on this patient and anticoagulants administered; leg edema and esophageal varices were ameliorated although liver biopsy showed cirrhosis without evident congestion. More than 9 months since the diagnosis, restenosis of the inferior vena cava has not occurred. Case 2: A 73-year-old woman presented abdominal pain but no edema or varices. Cavography showed membranous obstruction of the inferior vena cava which required no therapy. Manifestation of portal hypertension was not present and liver function was maintained although liver biopsy showed obvious congestion. These cases showed untypical features against histopathology, and careful observation will be required for emergence of hepatocellular carcinoma.

Purpose This study aimed to clarify the long-term efficacy of the lamivudine treatment in Japanese patients with chronic hepatitis B either with or without lamivudine resistance or with or without adefovir add-on treatment. Methods We followed 110 patients who received lamivudine for more than 12 months, including 67 hepatitis B e antigen (HBeAg)-positive and 43 HBeAg-negative patients. Results The median follow-up after the onset of lamivudine was 48 (range = 12–86) months. In all the patients with or without lamivudine resistance, the level of alanine aminotransferase (ALT) normalization decreased from 70.0% at 1 year to 36.4% at 5 years and the loss of serum HBV DNA level decreased from 72.7% at 1 year to 31.8% at 5 years. Sixty patients (54.6%) developed a lamivudine-resistant mutation, and this occurrence was more frequently observed in those who were HBeAg-positive (P

C型慢性肝炎の抗ウイルス療法は，ペグインターフェロンとリバビリン併用療法が主流であるが，リバビリンの副作用のため併用療法困難な症例ではペグインターフェロンα-2a（PEG-IFN）単独療法も考慮される．今回我々は，PEG-IFN単独療法の治療効果とSustained virological response（SVR）予測因子について検討を行った．PEG-IFN単独療法を行った84例のうち，SVRは56例（ITT解析，66.7%）であった．治療前のSVR予測因子は，若年例（p=0.0464），肝線維化が軽度の症例であり（p=0.0002），治療後の因子は，治療開始後4週以内のHCV RNA定性陰性化を来たすRapid virological response（RVR）（p

A 54-year-old woman was admitted to our hospital because of acute liver injury. Since she had a history of having used a diet product, drug-induced liver injury (DILI) was initially considered. However, the patient was subsequently diagnosed as suffering from primary biliary cirrhosis (PBC) based on the findings of liver histology and serum anti-mitochondrial antibody positivity. Overlap syndrome between PBC and autoimmune hepatitis (AIH) was also suspected, however, serum levels of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase became normal three months later, after treatment with combination therapy comprising ursodeoxycholic acid plus bezafibrate. We therefore concluded that the liver disease in this patient was actually PBC, but that it resembled overlap syndrome or DILI. In cases of PBC, a rapid onset, as frequently seen in the case of DILI, viral hepatitis or AIH, is not common. We herein report a rare case of PBC which resembled DILI.

A 24-year-old man was admitted to our hospital because of liver dysfunction. He had been diagnosed as having psoriasis vulgaris at 18 years of age. Physical examination demonstrated obesity, general erythema, and hepatomegaly. Laboratory data revealed elevated serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and glucose. A histological examination of the liver revealed macrovesicular fatty change and infiltration of inflammatory cells, including lymphocytes and polymorphonuclear cells, within the liver lobules. Pericentral fibrosis and pericellular fibrosis were also recognized. He was diagnosed as having nonalcoholic steatohepatitis (NASH), based on the fact that he had no habit of drinking alcohol, as well as psoriasis vulgaris and diabetes mellitus. We herein report a very rare case of NASH associated with psoriasis vulgaris.

A 70-year-old woman was admitted to our hospital because of a liver tumor. Laboratory data revealed mild liver dysfunction. Neither serum anti-HCV antibody nor HCV-RNA was detected. Computed tomography revealed a tumor lesion measuring 2 cm in diameter within the liver. Histological examination of the tumor revealed moderately differentiated hepatocellular carcinoma while the non-tumorous liver tissue demonstrated liver cirrhosis. By the RT-PCR method, HCV-RNA was detected from the non-tumorous liver tissue. We herein report a very rare case of hepatocellular carcinoma in a patient with liver cirrhosis associated with negative serum HCV findings, but positive finding for liver tissue HCV RNA.

This case of hepatocellular carcinoma (HCC) with alcoholic liver fibrosis, which was not associated with hepatitis viruses, was accompanied by hypoglycaemia. The immunoreactive insulin level was low and other hormonal examinations were almost normal. Immunohistochemical studies showed a high level of insulin-like growth factor II (IGF2) peptide in the HCC section and the size heterogeneity of serum IGF2 investigated by western blot revealed a large form at approximately 15 kDa. These results suggest that the HCC with alcoholic liver fibrosis produced IGF2 and that the hypoglycaemia was caused by tumour-associated IGF2.

A 67-year-old man was admitted to our hospital because of a large liver tumor revealed by ultrasonography. Laboratory data showed increased serum levels of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), which are tumor markers for hepatocellular carcinoma. In addition, the serum cholesterol level was extremely high. Endoscopic examination revealed advanced gastric cancer. Histological findings of the stomach and liver tumor showed they were both hepatoid adenocarcinomas and were both positive for antibodies against AFP as well as DCP, suggesting that the tumors were gastric cancer with liver metastasis. Moreover, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme for regulation of cholesterol synthesis, was upregulated in the tumor tissues. Accordingly, we diagnosed this patient with AFP- and DCP-producing gastric cancer accompanied by paraneoplastic hypercholesterolemia. Paraneoplastic hypercholesterolemia is sometimes seen in hepatocellular carcinoma, but never in gastric cancer. This case is interesting because of the feature of hepatoid adenocarcinoma.

BACKGROUND/AIMS We have evaluated the effectiveness of systemic chemotherapy for patients with extrahepatic metastasis from hepatocellular carcinoma. METHODOLOGY We examined the background, survival rates, median survival time and side effects of 15 cases in which systemic chemotherapy using carboplatin and 5-fluorouracil was done (chemotherapy group) and 59 cases in which chemotherapy was not done (non-chemotherapy group) out of a total of 74 cases of patients with extrahepatic metastasis from hepatocellular carcinoma. RESULTS The prognoses of the 15 chemotherapy cases and the 59 non-chemotherapy cases were as follows: 66.0%, 33.3%, 20.0% at 6 months, 12 months, 18 months respectively for the chemotherapy cases and 44.0%, 18.2%, 7.1% respectively for the non-chemotherapy cases. Median survival periods were 10.7 months for the chemotherapy group and 5.1 months for the non-chemotherapy group. A significantly better prognosis of survival (p=0.037) was identified in the chemotherapy group and no serious side effects were observed. CONCLUSIONS The present research preceded the approval of sorafenib. This systemic combination chemotherapy will provide an extended survival prognosis and is thus considered to be comparatively safe and effective in those patients.

A 54-year-old male was treated for chronic hepatitis C with pegylated interferon (PEG-IFN) α-2a administered for 24 weeks. HCV-RNA was negative at 24 weeks after treatment, showing sustained virological response (SVR). Abdominal distention and diarrhea were observed 28 weeks after commencing the treatment, i.e., 4 weeks after completing treatment. The elevation of eosinophil count was observed in blood tests and ascites, and because eosinophilic infiltration was also observed on gastrointestinal histopathology, the patient was diagnosed with eosinophilic enteritis. As the eosinophil count spontaneously improved and abdominal symptoms disappeared, the patient was not treated with steroids. The onset of eosinophilic enteritis during interferon therapy is comparatively rare. In this case, PEG-IFN was considered to be the causative factor. Furthermore, we suggested that subserosal eosinophilic enteritis may have characteristic symptoms in patients having hepatic diseases treated with interferon.

This study was designed to investigate whether different vascular endothelial growth factor (VEGF) genotypes are associated with ascites formation in cirrhotic patients. Seventy cirrhotic patients were included in the study: 25 cirrhotic patients with ascites and 45 cirrhotic patients without ascites. Patient characteristics were investigated and compared between the two groups. With regard to VEGF genotype, 42 patients were C/C and 28 patients were T/T or C/T. The genotypes T/T or C/T were observed in 23 cases (51%) among the non-ascites group, but in only five cases (20%) among the ascites group. Serum levels of albumin and creatinine, and the VEGF genotypes were significantly different between the two groups. Multiple regression analysis showed that serum levels of creatinine and the VEGF genotypes were significantly correlated with ascites formation. Thus, it can be concluded that VEGF genotyping might be a valuable susceptibility marker for ascites formation in cirrhotic patients.

Background and Aim: Hepatocellular carcinoma (HCC) is frequently associated with paraneoplastic hypercholesterolemia. In familial hypercholesterolemia, genetic mutation of the low-density lipoprotein (LDL) receptor gene has been recognized as being a pathogenesis of the disease. We investigate the expression of a LDL receptor protein and gene abnormalities of a LDL receptor in HCC cells in cases with paraneoplastic hypercholesterolemia. Methods: Eleven patients with HCC associated with paraneoplastic hypercholesterolemia and seven patients with HCC who did not have hypercholesterolemia were studied. Paraffin-embedded tissues were obtained at operative resection, autopsy, or biopsy. Immunohistochemistry was performed using a monoclonal antibody against human LDL receptors. Confocal laser–scanning microscopy was used to observe the FITC-labeled LDL receptor. DNA samples were extracted from paraffin-embedded tissues. Since a LDL receptor gene is located on chromosome 19p13.2, a microsatellite marker, D19S413, was used to analyze the chromosomes. Results: Immunoreactive LDL receptors were observed all over the surface of non-tumorous hepatocytes. However, expression of the LDL receptor was significantly decreased in all HCC cells derived from the 11 patients with hypercholesterolemia. In contrast, the expression was retained in the HCC cells of all patients without hypercholesterolemia. In two patients with hypercholesterolemia, DNA analysis revealed a loss of heterozygosity on chromosome 19p13.2. Conclusion: We demonstrated reduced expression of the LDL receptor in HCC cases with paraneoplastic hypercholesterolemia. LDL receptor genes with genomic disorders may cause decreased expression of the LDL receptor protein, leading to feed-back failure of the cholesterol regulation system, as seen in familial hypercholesterolemia. This is the first report considering the mechanism behind the development of paraneoplastic hypercholesterolemia in HCC.

Background and Aim: Fulminant hepatitis is still a fatal liver disease, and no specific treatment for it has been available. Vascular endothelial growth factor (VEGF) is the focus of attention because of its various actions. We investigated the effect of vascular endothelial growth factor (VEGF) on Fas-induced fulminant hepatic failure (FHF). Method: Male Balb/c mice were treated with an intraperitoneal injection of an anti-Fas antibody (Jo-2 Ab) with or without premedication with intraperitoneally administered human recombinant VEGF. Results: The serum level of alanine aminotransferase (ALT) was up to 300 times higher that of normal mice following the Jo-2 Ab injection, and histological analysis revealed hepatic injury and massive hepatocyte apoptosis. The VEGF significantly suppressed an elevation in serum ALT levels and hepatocyte apoptosis. Immunohistochemically, VEGF-treated mice showed that Bcl-xL in hepatocytes was strongly expressed. Conclusions: Since hepatocytes do not express VEGF receptors, we speculated that VEGF acts on sinusoidal endothelial cells (SECs) and promotes production of cytokines such as hepatocyte growth factor in SECs, resulting in reducing apoptosis through an increase expression of Bcl-xL in hepatocytes. We suggest that VEGF has a potent antiapoptotic effect on hepatocytes through cell–cell interaction between SECs and hepatocytes.

A 45-year-old man was admitted to our hospital because of chronic hepatitis C and a large liver tumor accompanied by increased serum levels of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), the tumor markers for hepatocellular carcinoma. Endoscopic examination revealed advanced gastric cancer. Biopsy specimens of the stomach and liver showed gastric adenocarcinoma and its metastasis to the liver. Immunohistochemical studies demonstrated that adenocarcinoma cells both of the stomach and liver, were positive for the antibodies against AFP as well as DCP. Expression of AFP mRNA was shown in the cancer cells of the stomach. Accordingly, we diagnosed this patient with AFP- and DCP-producing adenocarcinoma of the stomach together with liver metastasis.

A case of hemochromatosis associated with HFE gene mutation has never been previously reported in a Japanese patient. A 65-yr-old Japanese woman presenting with primary hemochromatosis underwent HFE mutation analyses, which demonstrated a C282Y mutation, this being the definitive gene mutation of Caucasian hemochromatosis.

An 80-year-old man was admitted to our hospital because of the rupture of the liver. Laboratory data showed iron-deficiency anemia, although there was no liver dysfunction. A computed tomography scan showed large liver tumor with intraperitoneal hemorrhage, and since a serum level of α-fetoprotein (AFP) was extremely high, we initially suspected a rupture of hepatocellular carcinoma (HCC). Transarterial embolization was performed to stop bleeding from the tumor, followed by an endoscopic examination that revealed advanced gastric cancer. Histological analysis revealed that both the gastric and the hepatic tumors were moderately to poorly differentiated adenocarcinoma, as well as that both tumors were immunohistochemically positive for AFP. Finally, we diagnosed AFP-producing gastric cancer associated with liver metastasis. Rupture of metastatic liver cancer is rare, and accordingly, distinction from HCC is important, particularly for the cases of AFP-producing gastric cancer.