Entecavir administration to pregnant Japanese woman with chronic hepatitis B and hepatocellular carcinoma: A case report.

Women taking entecavir hydrate (ETV) may not need to consider abortion in the event of an unexpected pregnancy. If a woman with renal dysfunction and taking ETV for chronic hepatitis B becomes pregnant, continuous use of ETV may also be tolerated.

FIB-4 index-based surveillance for advanced liver fibrosis in diabetes patients.

Liver fibrosis is associated with lifestyle-related diseases, including diabetes. The identification of diabetic patients with severe liver fibrosis is important, but a simple and reliable diagnostic procedure remains to be determined. We conducted an observational study to evaluate the performance of a FIB-4 index-based screening strategy for the diagnosis of advanced liver fibrosis in patients with diabetes or prediabetes. Two hundred and forty-two patients underwent abdominal imaging in our Study. According to the abdominal imaging findings, fatty liver, liver cirrhosis, and hepatocellular carcinoma were defined, and their association with FIB-4 index evaluated. The prevalences of liver cirrhosis and hepatocellular carcinoma in patients with a high (≥ 2.67; liver cirrhosis: 42.9%, hepatocellular carcinoma: 14.3%) FIB-4 index were significantly higher than in those with an intermediate (1.3 ≤ FIB-4 < 2.67; liver cirrhosis: 1.6%, hepatocellular carcinoma: 0.8%) or low FIB-4 index (< 1.3; liver cirrhosis: 1.2%, hepatocellular carcinoma: 0%). The diagnostic accuracy, specificity, and sensitivity of the FIB-4 index for the diagnosis of liver cirrhosis or hepatocellular carcinoma were 84.3%, 85.5%, and 89.3%, respectively, with an optimized cut-off value of 2.96 (sensitivity = 0.86, specificity = 0.98). Using an optimized cut-off value, FIB-4 index might be useful to identify liver cirrhosis or hepatocellular carcinoma in diabetes patients with high diagnostic accuracy.

Recommendations from primary care physicians, family, friends and work colleagues influence patients' decisions related to hepatitis screening, medical examinations and antiviral treatment.

Identification and screening of patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) is important to prevent liver cancer. Comprehensive antiviral treatments should follow three sequential steps: Hepatitis screening (step 1; examination of HB surface antigen and HCV antibody), medical examination (step 2; examination of HBV-DNA and/or HCV-RNA and performance of abdominal ultrasonography) and antiviral treatment (step 3). Patients who underwent these three steps were studied to determine effective information sources (factors) for raising awareness of comprehensive treatments. A total of 182 patients from 11 medical institutions were who were undergoing antiviral treatment were investigated. The number of patients who accessed each of the 18 information sources in each of the three steps and the percentage of these information sources that directly influenced the participants to make treatment-related decisions were calculated. 'Recommendation from a primary care physician' was the most common information source (64.3, 77.5, and 75.8% at steps 1, 2, and 3, respectively). 'Recommendation from a public health nurse (PHN),' 'recommendation from friends or family,' and 'recommendation from work colleagues' were the next most common human factors (3.3-19.8%). 'Recommendation from a primary care physician' had the greatest influence (76.9, 73.0, and 77.5% at steps 1, 2, and 3, respectively). 'Recommendation from a PHN' (50.0, 26.3 and 64.3%), 'recommendations from friends and family' (58.3, 38.9 and 58.3%), and 'recommendations from work colleagues' (33.3, 33.3 and 42.9%) were highly influential factors. Media such as TV commercial messages and programs also had high recognition, but were not directly influential. The findings of the present study indicated that recommendations from primary care physicians, friends, family and work colleagues influenced patients' decision-making regarding hepatitis screening, examination and treatment.

Generation Gap for Screening and Treatment of Hepatitis C Virus in Saga Prefecture, Japan: An Administrative Database Study of 35,625 Subjects.

Objective Despite recent advances in hepatitis C virus (HCV) treatment, some HCV-positive individuals are unaware of their infection. The present study aimed to assess the rate and age distribution in Saga Prefecture regarding i) HCV infection and HCV screening and ii) direct acting anti-viral (DAA) treatment. Methods HCV screening data collected at a medical institution or in the workplace were obtained from the administrative database in Saga Prefecture between April 1, 2008 and March 31, 2014. DAA treatment data from Saga Prefecture were obtained from the DAA treatment reimbursement recipient database between October 2014 and March 2017. Results There were 35,625 individuals who underwent HCV screening, and the HCV positive rate was 1.18% (421 individuals), which increased in an age-related manner. The screening rate in the screened populations peaked at 45-74 years of age (approximately 6%) and decreased in the younger and older generations. The estimated percentage of DAA treatment peaked at 65-74 years old (65.8%) and significantly decreased inversely with age in the younger generations; only 9.4% of HCV carriers received DAA treatment in the 20- to 34-year age group. The proportion of subjects who received a complete physical examination for DAA treatment was higher in the subjects who were screened at a medical institution than in those screened at the workplace. Conclusion The rate of subjects who underwent HCV screening and DAA treatment was not high, especially in the younger generation, in Saga Prefecture. This group should be targeted for HCV screening and treatment.

Real-World Effectiveness From the Asia Pacific Rim Liver Consortium for HBV Risk Score for the Prediction of Hepatocellular Carcinoma in Chronic Hepatitis B Patients Treated With Oral Antiviral Therapy.

BACKGROUND: Patients on oral antiviral (OAV) therapy remain at hepatocellular carcinoma (HCC) risk. Risk prediction tools distinguishing treated patients with residual HCC risk are limited. The aim of this study was to develop an accurate, precise, simple-to-use HCC risk score using routine clinical variables among a treated Asian cohort. METHODS: Adult Asian chronic hepatitis B (CHB) patients on OAV were recruited from 25 centers in the United States and the Asia-Pacific region. Excluded persons were coinfected with hepatitis C, D, or human immunodeficiency virus, had HCC before or within 1 year of study entry, or their follow-up was <1 year. Patients were randomized to derivation and validation cohorts on a 2:1 ratio. Statistically significant predictors from multivariate modeling formed the Real-world Effectiveness from the Asia Pacific Rim Liver Consortium for HBV (REAL-B) score. RESULTS: A total of 8048 patients were randomized to the derivation (n = 5365) or validation group (n = 2683). The REAL-B model included 7 variables (male gender, age, alcohol use, diabetes, baseline cirrhosis, platelet count, and alpha fetoprotein), and scores were categorized as follows: 0-3 low risk, 4-7 moderate risk, and 8-13 high risk. Area under receiver operating characteristics were >0.80 for HCC risk at 3, 5, and 10 years, and these were significantly higher than other risk models (p < .001). CONCLUSIONS: The REAL-B score provides 3 distinct risk categories for HCC development in Asian CHB patients on OAV guiding HCC surveillance strategy.

Hepatitis C Virus Cure Rates Are Reduced in Patients With Active but Not Inactive Hepatocellular Carcinoma: A Practice Implication.

BACKGROUND: Cure rates of hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) for patients with active and inactive hepatocellular carcinoma (HCC) may differ, but well-controlled studies are limited. We aimed to evaluate DAA outcomes in a large East Asian HCV/HCC population compared with HCV/non-HCC patients. METHODS: Using data from the Real-World Evidence from the Asia Liver Consortium (REAL-C) registry (Hong Kong, Japan, South Korea, and Taiwan), we used propensity score matching (PSM) to match HCC and non-HCC (1:1) groups for age, sex, cirrhosis, prior treatment, HCV genotype, treatment regimen, baseline platelet count, HCV RNA, total bilirubin, alanine aminotransferase, and albumin levels to evaluate DAA treatment outcomes in a large population of HCV/HCC compared with HCV/non-HCC patients. RESULTS: We included 6081 patients (HCC, n = 465; non-HCC, n = 5 616) treated with interferon-free DAAs. PSM of the entire study population yielded 436 matched pairs with similar baseline characteristics. There was no statistically significant difference in the overall SVR rate of HCC (92.7%) and non-HCC (95.0%) groups. Rates of treatment discontinuation, adverse effects, and death were also similar between HCC and non-HCC groups. Among patients with HCC, those with active HCC had a lower SVR than inactive HCC cases (85.5% vs 93.7%; P = .03). On multivariable analysis, active HCC, but not inactive HCC, was significantly associated with lower SVR (OR, 0.28; P = .01) when compared with non-HCC. CONCLUSIONS: Active HCC but not inactive HCC was independently associated with lower SVR compared with non-HCC patients undergoing DAA therapy, although cure rate was still relatively high (85%) in active HCC patients.

Direct-acting antivirals in East Asian hepatitis C patients: real-world experience from the REAL-C Consortium.

BACKGROUND AND AIMS: One-third of the global hepatitis C virus (HCV) burden is found in Asia. Real-world data from diverse East Asian cohorts remain limited. This study addressed the real-world status of direct-acting antiviral (DAA) therapy among patients from East Asia. METHODS: Chronic hepatitis C (CHC) patients from clinical sites in Japan, Taiwan, South Korea, and Hong Kong were recruited in the REAL-C registry, an observational chart review registry. The primary outcome was sustained virologic response (SVR12, HCV RNA PCR < 25 IU/mL 12 week post-therapy). RESULTS: A total of 6287 CHC patients were enrolled. Compared to other East Asian patients, patients from Japan were older (66.3 vs. 61.5 years, p < 0.0001), had lower body mass indices (22.9 kg/m2 vs. 24.6 kg/m2, p < 0.001), and were more likely to have non-liver malignancy history (12.2% vs. 5.0%, p < 0.001).The overall SVR12 rate was 96.4%, similar to patients both inside and outside Japan (96.6% vs. 96%, p = 0.21). The SVR12 rate ranged from 91.1 to 99.4% except treatment-experienced cirrhotic HCV genotype-1 patients who received daclatasvir/asunaprevir (85.9%) and the treatment-experienced cirrhotic HCV genotype-2 patients treated with sofosbuvir/ribavirin (87%). The overall rate of drug discontinuation was 1.9%, also similar across regions. On multivariate regression analyses, there was no significant association between geographic region and SVR outcomes. CONCLUSIONS: In this large multinational CHC cohort from the East Asia, oral DAAs were highly effective and well tolerated across the region. Policies should encourage treatment for all CHC patients with DAAs in Asia with its heavy burden of HCV.

Regulation of interferon signaling and HCV­RNA replication by extracellular matrix.

Although interferon (IFN)­based treatment of patients with chronic hepatitis C virus (HCV) infection is widely applied, treatment resistance is often observed in patients with advanced liver fibrosis. Given that the molecular mechanisms of IFN resistance in liver fibrosis remain elusive, the present study investigated the effects of extracellular matrix (ECM) on IFN signaling in hepatic cells. The native HuH­7 human hepatoma cell line and HuH­7 cells were stably transfected with full­length HCV­RNA fused with Renilla luciferase (OR6 cells) were cultured on ECM­coated dishes or non­coated plastic dishes (NDs), and treated with human IFN­α. In Huh­7 cells cultured on coated dishes, the IFN­stimulated response element (ISRE) luciferase activity was measured following ISRE plasmid transfection and the expression of IFN­stimulated genes (ISG) were significantly lower than those in cells cultured on NDs. In addition, after IFN­α treatment, the amount of HCV­RNA and viral protein produced by OR6 cells cultured on coated dishes was higher than that produced by cells cultured on NDs. When cells were treated with ß1­integrin­blocking antibody to disrupt the cell­matrix interaction, the ISRE luciferase activity was restored, and the protein expression of ISG was increased, while that of HCV proteins was suppressed. Treatment of cells with integrin­linked kinase (ILK) inhibitor or focal adhesion kinase (FAK) inhibitor restored the ISRE luciferase activity and expression of ISG proteins. These results suggested that ß1­integrin­mediated signals affected the IFN signaling and promoted HCV replication. Therefore, the accumulation of ECM in liver fibrosis may impair IFN signaling through ß1­integrin­mediated signaling involving ILK and FAK.

Reducing the mortality rate of hepatitis and liver cancer in Japan.

The Basic Act on Hepatitis Countermeasures issued in 2009 states the comprehensive measures that can be taken against viral hepatitis as well as the responsibility that the national government, local governments, health insurance provides, physicians, and citizens should take in these measures, thereby organically facilitating the construction of a hepatitis management system in Japan. In addition, the Committee for the Clinical Management of Hepatitis has established branches in each prefecture to create a hepatitis management network for public hepatitis screening facilities, primary care physicians, medical institutions specializing in hepatitis, and primary hospitals for cooperative medical care of liver diseases to address regional hepatitis-related issues.

"Weariness" and "unpleasantness" reduce adherence to branched-chain amino acid granules among Japanese patients with liver cirrhosis: results of a single-center cross-sectional survey.

AIM: Branched-chain amino acids (BCAA) are valuable in the treatment of liver cirrhosis because they increase serum albumin levels. Poor adherence to BCAA may adversely affect prognosis, but little is known about factors predicting adherence. We undertook a survey of patients prescribed BCAA for the treatment of cirrhosis. METHODS: Pharmacists carried out face-to-face interviews with patients (or their representatives) prescribed any of nine BCAA formulations. Question categories included patient characteristics, prescription of BCAA granules, and perceptions of BCAA administration, including adherence and possible factors that might impact adherence. "Poor adherence" was defined as "not taking the medication appropriately" or "forgetting to take the medication". RESULTS: Overall, 253 patients (or representatives) completed the survey, of whom 135 were men, 114 were women, and 148 were ≥70 years old. Most patients (163) were prescribed BCAA for ≥2 years and were using three packs per day. Thirty-two patients did not take their medication appropriately and 69 sometimes forgot to administer it. Weariness of taking the medication (P < 0.001) and the perceived unpleasantness (P = 0.023) of the medication in terms of its taste and volume were significantly associated with poor adherence. The patients reported that the most influential educators were general practitioners, followed by certified hepatologists, then pharmacists. CONCLUSION: Most patients had good adherence to BCAA in clinical practice. Poor adherence was associated with weariness with taking medication, and the unpleasantness of the medication itself. Patient education from general practitioners and hepatologists combined with adherence counseling from pharmacists may help improve adherence.

Optimal Follow-up of Patients with Viral Hepatitis Improves the Detection of Early-stage Hepatocellular Carcinoma and the Prognosis of Survival.

Objective To manage patients with viral hepatitis, it is important to screen for hepatitis, conduct a comprehensive examination if such screening is positive, administer antiviral treatment, and conduct surveillance for hepatocellular carcinoma (HCC). The proper execution of this strategy is expected to effectively reduce the number of deaths from viral hepatitis. Such an "optimal" follow-up for HCC surveillance is therefore important. This study aimed to determine the benefits of performing an optimal follow-up of patients with viral hepatitis. Methods The subjects were infected with the hepatitis virus and were initially diagnosed with or treated for HCC from 2004-2012. We retrospectively analyzed the history of a patient's current illness using the hospital discharge summary. To minimize any lead-time bias, we calculated the corrected survival for patients who received an optimal follow-up. Results Of 333 patients, 107 (32.1%) did not receive an optimal follow-up and thus had low cumulative survival rates in comparison to those who did. The median corrected survival was 51.5 months for patients with an optimal follow-up compared with 31.4 months for those without (p=0.011). A multivariate analysis revealed that AFP <35 [odds ratio (OR), 2.054], Child-Pugh A (OR, 2.488), and an optimal follow-up (OR, 4.539) were independent factors associated with the detection of early-stage HCC. Age (OR, 0.939), tumor stage I/II (OR, 6.918), and an optimal follow-up (OR, 3.213) were found to be independent factors associated with receiving curative treatment. Conclusion An optimal follow-up of patients with viral hepatitis independently increased the detection of early-stage HCC and the administration of curative treatment. Patients with an optimal follow-up survived longer than those without.

Clinical course of hepatitis B surface antigen positive subjects following screening: A retrospective observational study from April 2008 to January 2013.

AIM: Determination of the percentage of hepatitis B surface antigen (HBsAg) positive participants who undergo screening and treatment may reduce the development of hepatocellular carcinoma. This study assessed the percentages of HBsAg positive participants detected by free screening at medical institutions in Saga Prefecture who underwent detailed examinations and antiviral treatment. METHODS: Participants were screened for HBsAg positivity at medical institutions in Saga Prefecture from April 2008 to January 2013, with some visiting physicians for detailed examinations and applying for reimbursement. Participants in the database of the Health Promotion Division of Saga Prefecture and results of detailed examinations were analyzed retrospectively. RESULTS: Screening revealed 193 eligible participants, 105 men (54%) and 88 women (46%), of a mean age of 55.5 ± 14.9 years. Of these 193 participants, 147 (76%) visited physicians for detailed examinations, 24 (16%) were regarded as needing treatment and seven (3.6%) were reimbursed for antiviral treatments. The 46 participants who did not undergo detailed examinations were significantly younger than the 147 examined participants (50.9 ± 13.2 vs 56.9 ± 15.2 years, P = 0.018). Of the 110 participants thought to require observation, 68 (62%) were assigned to this group without determination of alanine aminotransferase or hepatitis B virus DNA concentration, and 15 (14%) had indications for antiviral treatment according to the 2014 guidelines of the Japanese Society of Hepatology. CONCLUSION: The proportion of HBsAg positive participants receiving antiviral treatment was lower than that of participants undergoing detailed examinations.

Granulomatous reaction in hepatic inflammatory angiomyolipoma after chemoembolization and spontaneous rupture.

A 77-year-old Japanese woman was transported to a nearby hospital due to sudden abdominal pain and transient loss of consciousness. Abdominal computed tomography (CT) suggested hemoperitoneum and hepatic nodule. She was conservatively treated. Contrast-enhanced CT two months later revealed an increased mass size, and the enhancement pattern suggested the possibility of hepatocellular carcinoma (HCC). Under a clinical diagnosis of HCC, transcatheter arterial chemoembolization (TACE) was performed. A subsequent imaging study revealed that most of the lipiodol used for the embolization was washed out. Therefore, surgical resection was performed. Histologically, the nodule contained numerous inflammatory cells including small lymphocytes, plasma cells and macrophages. Notably, epithelioid granulomatous features with multinucleated giant cells were observed in both the nodule and background liver. Some of the multinucleated giant cells contained oil lipid. Among the infiltrating inflammatory cells, spindle-shaped, histiocytoid or myoid tumor cells with eosinophilic cytoplasm were found. The tumor cells were positive for Melan A and HMB45. The nodule contained many IgG4-positive plasma cells; these were counted and found to number 72.6 cells/HPF (range: 61-80). The calculated IgG4:IgG ratio was 33.2%. The nodule was finally diagnosed as previously ruptured inflammatory angiomyolipoma modified by granulomatous reaction after TACE.

Whole-body insulin resistance is associated with elevated serum α-fetoprotein levels in patients with chronic hepatitis C.

OBJECTIVE: Little is known about the relationship between elevated serum α-fetoprotein (AFP) levels and insulin resistance, which adversely influence the clinical course of chronic hepatitis C (CHC). Therefore, we investigated the association between serum AFP and insulin resistance in patients with CHC. METHODS: We retrospectively investigated 300 patients with CHC without hepatoma who underwent liver biopsies and oral glucose tolerance tests. Patients taking antidiabetic drugs were excluded. We analyzed factors associated with elevated AFP levels (≥ 10.0 ng/mL) in 265 eligible patients. Twenty patients with a homeostasis model assessment for insulin resistance value of ≥ 2.0 and a whole-body insulin sensitivity index of <5.0 received prospective lifestyle intervention. RESULTS: A univariate analysis showed that the body mass index, platelet count, levels of albumin, aspartate aminotransferase, alanine aminotransferase and γ-glutamyl transpeptidase, glucose metabolism, hepatic inflammation, fibrosis and steatosis were associated with elevated AFP levels. In a multivariate analysis, a platelet count of < 15 × 10(4) /µL, aspartate aminotransferase level of ≥ 50 IU/L, γ-glutamyl transpeptidase level of ≥ 35 IU/L, whole-body insulin sensitivity index of <5.0 and stage 3-4 fibrosis were independently associated with an elevated AFP level. A Bayesian Network analysis showed that the aspartate aminotransferase level, whole-body insulin sensitivity index and hepatic fibrosis were directly associated with an elevated AFP level. The lifestyle intervention significantly improved the serum AFP level, homeostasis model assessment for insulin resistance and whole-body insulin sensitivity index. CONCLUSION: Whole-body insulin resistance is associated with an elevated serum AFP level in patients with CHC. Lifestyle interventions targeting insulin resistance can reduce the serum AFP level and may ameliorate the clinical course of CHC.

Survival advantage of radiofrequency ablation for hepatocellular carcinoma: comparison with ethanol injection.

BACKGROUND/AIMS: The aims of this study were to compare long-term prognosis of patients with hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI). METHODOLOGY: Two hundred and thirteen patients with HCC were initially treated with PEI or RFA at Saga University Hospital between 1990 and 2004. The present study included 190 patients: 98 treated with PEI from 1990 to 1999, and 92 with RFA from 2000 to 2004. The association of treatment method with survival prognosis was evaluated by multivariate analysis. RESULTS: There were no significant differences in gender, etiology, and tumor stage between the two groups. Five-year survival rate in the PEI group was 40% and 51% in the RFA group. According to tumor stage, there were no differences in 5-year survival rate between the two groups for tumor stage I and III. For stage II patients, RFA had better survival than PEI (48% vs. 28%, p = 0.03). Multivariate analysis indicated that RFA was more effective for long-term survival than PEI in patients with tumor stage II (p = 0.04). CONCLUSIONS: Compared to PEI, RFA improved survival in patients with stage II HCC, indicating a therapeutic advantage of RFA.

A case of unclassified multicystic biliary tumor with biliary adenofibroma features.

A 40-year-old Japanese man was admitted to our hospital for evaluation of upper abdominal pain. Abdominal computed tomography (CT) revealed a well-circumscribed multicystic mass measuring approximately 7 × 6 cm. The mass contained a solid lesion measuring 3 × 2 cm. Biopsy of a swollen cervical lymph node led to a diagnosis of diffuse large B-cell lymphoma. After initial chemotherapy for lymphoma, the multicystic mass was surgically resected. The tumor was composed of a multicystic lesion and a solid lesion. Histopathologic examination of the multicystic lesion revealed that the locules were lined by biliary epithelium, demonstrating various degrees of cytological atypia. The stroma was fibrous, and the tumor showed marked apocrine snouts. Part of the tumor showed papillary growth with strong cytological atypia. The solid lesion showed tubulocystic proliferation of tumor cells, with prominent apocrine snouts, embedded in dense and partially hyalinized fibrous stroma. The morphology of the solid part was quite similar to that of reported biliary adenofibroma. Despite lengthy discussion, an appropriate pathological diagnosis could not be found among the current classifications of biliary tumor. The tumor was finally diagnosed as unclassified multicystic biliary tumor with adenofibroma features.

The role of PKC isoforms in the inhibition of NF-κB activation by vitamin K2 in human hepatocellular carcinoma cells.

Vitamin K (VK) has diverse protective effects against osteoporosis, atherosclerosis and carcinogenesis. We recently reported that menatetrenone, a VK2 analogue, suppressed nuclear factor (NF)-κB activation in human hepatoma cells. Although NF-κB is regulated by isoforms of protein kinase C (PKC), the involvement of PKCs in VK2-mediated NF-κB inhibition remains unknown. Therefore, the effects of VK2 on the activation and the kinase activity of each PKC isoform were investigated. The human hepatoma Huh7 cells were treated with PKC isoform-specific inhibitors and/or siRNAs against each PKC isoform with or without 12-O-tetradecanoylphorbol-13-acetate (TPA). VK2 inhibited the TPA-induced NF-κB activation in Huh7 cells. NF-κB activity was inhibited by the pan-PKC inhibitor Ro-31-8425, but not by the PKCα-specific inhibitor Gö6976. The knockdown of individual PKC isoforms including PKCα, δ and ɛ showed only marginal effects on the NF-κB activity. However, the knockdown of both PKCδ and PKCɛ, together with treatment with a PKCα-specific inhibitor, depressed the NF-κB activity. VK2 suppressed the PKCα kinase activity and the phosphorylation of PKCɛ after TPA treatment, but neither the activation nor the enzyme activity of PKCδ was affected. The knockdown of PKCɛ abolished the TPA-induced phosphorylation of PKD1, and the effects of PKD1 knockdown on NF-κB activation were similar to those of PKCɛ knockdown. Collectively, all of the PKCs, including α, δ and ɛ, and PKD1 are involved in the TPA-mediated activation of NF-κB. VK2 inhibited the NF-κB activation through the inhibition of PKCα and ɛ kinase activities, as well as subsequent inhibition of PKD1 activation.

Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C.

BACKGROUND: Several epidemiological studies have reported that diabetes mellitus is a risk factor for hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-positive patients. However, it is unclear whether or not post-challenge hyperglycemia is a risk factor. The purpose of this study was to determine the association between post-challenge hyperglycemia and hepatocarcinogenesis in HCV-positive patients. METHODS: A total of 203 HCV-RNA-positive subjects (108 males, mean age 54.3 ± 10.8 years; 95 females, mean age 56.6 ± 10.3 years; genotype 1b/2a/2b/3a: 152/38/12/1) who underwent liver biopsy and a 75-g oral glucose tolerance test, and who were treated with interferon (IFN) were enrolled in this study. None of the subjects had been treated with antidiabetic drugs. The subjects underwent ultrasonography and/or computed tomography every 6 months after the end of the IFN therapy. RESULTS: Thirteen patients, including one patient who achieved a sustained viral response (SVR) with IFN, developed HCC. On multivariate analysis, male sex, age >65 years, excessive alcohol consumption, non-SVR, liver steatosis area >5% in liver specimens, and 120-min post-challenge hyperglycemia were risk factors for the development of HCC. After matching subjects for sex, age, alcohol intake, and response to the IFN therapy, advanced fibrosis stages [hazard ratio (HR) 2.8], liver steatosis (HR 5.4), and 120-min post-challenge hyperglycemia (HR 4.9) were significant risk factors for the development of HCC. Furthermore, after matching for the fibrosis stage, liver steatosis (HR 5.7) and 120-min post-challenge hyperglycemia (HR 6.9) remained as significant factors for HCC development. CONCLUSION: Post-challenge hyperglycemia is an independent risk factor for HCC in HCV-positive patients.

Vitamin K2 augments 5-fluorouracil-induced growth inhibition of human hepatocellular carcinoma cells by inhibiting NF-κB activation.

Although 5-fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in various cancer including hepatocellular carcinoma (HCC), chemoresistance has precluded single use of 5-FU in clinical settings. Since menatetrenone, an analogue of vitamin K2 (VK2), inhibits growth of cancer cells including HCC cells in vitro and in vivo, we examined VK2 modulation of HCC cell response to 5-FU. VK2 pretreatment dose-dependently enhanced growth-inhibition by 5-FU through a G1 cell cycle arrest. VK2 inhibited 5-FU-induced NF-κB activation and cyclin D1 expression. Therefore, combination of VK2 and 5-FU might represent a new therapeutic strategy for patients with HCC.

Metabolic factors are associated with serum alanine aminotransferase levels in patients with chronic hepatitis C.

BACKGROUND: Although serum alanine aminotransferase (ALT) activity is an important marker for the management of chronic hepatitis C (CHC), the factors associated with serum ALT levels remain to be fully understood. This study aimed to clarify the association between serum ALT levels and clinical, histological, and virological factors in patients with CHC. METHODS: We retrospectively analyzed 256 patients with CHC who underwent liver biopsy, and classified them into three groups according to serum ALT levels: normal to minimal (<40 IU/L), mild (40-80 IU/L), and moderate to severe elevation (≥80 IU/L). All demographic and laboratory data were collected at the time of liver biopsy. All biopsies were evaluated for fibrosis, inflammation, and steatosis. Glucose metabolism was assessed by various indices derived from oral glucose tolerance tests, including the homeostasis model assessment for insulin resistance (HOMA-IR). In 180 patients, visceral fat area was measured at the umbilical level by abdominal computed tomography. RESULTS: Ordered logistic regression analysis showed that higher serum ALT levels were significantly associated with male sex, lower high-density lipoprotein cholesterol (HDL-C), higher HOMA-IR, and higher grades of histological inflammation and steatosis. HOMA-IR, HDL-C, and hepatic steatosis were associated with visceral fat accumulation. CONCLUSIONS: Metabolic factors, as well as sex and hepatic inflammation, are independent risk factors for serum ALT elevation in hepatitis C virus (HCV)-infected patients. Metabolic factors may offer targets to decrease serum ALT levels.