Comparison of Efficacy and Safety of Atezolizumab Plus Bevacizumab and Lenvatinib as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

BACKGROUND: A comparison between atezolizumab plus bevacizumab (ATEZO/BEVA) and lenvatinib (LEN) for the treatment of hepatocellular carcinoma (HCC) remains unclear. OBJECTIVE: This study aimed to compare the therapeutic effects and safety of ATEZO/BEVA and LEN as first-line therapies for HCC. PATIENTS AND METHODS: This study was a retrospective analysis of 810 patients with HCC who underwent ATEZO/BEVA (n = 186) or LEN (n = 624) as first-line systemic therapy between March 2018 to March 2022 at 14 facilities. After propensity score matching, 304 patients (ATEZO/BEVA group: n = 152; LEN group: n = 152) were analyzed. RESULTS: After propensity score matching, although there was no significant difference in objective response rates (ORRs) between the ATEZO/BEVA and LEN groups (ORR 44.8% vs. 46.7%, p = 0.644), the median progression-free survival (PFS) and median overall survival (OS) in the ATEZO/BEVA group were significantly higher than those in the LEN group (median PFS: 8.3 months vs. 6.0 months, p = 0.005; median OS: not reached vs. 20.2 months, p = 0.039). The rates of appetite loss, fatigue, and proteinuria of grade 3 or higher in the ATEZO/BEVA group were lower than those in the LEN group. However, the rate of bleeding of grade 3 or higher in the ATEZO/BEVA group was higher than that in the LEN group. The conversion rate was higher in the ATEZO/BEVA group than that in the LEN group (8.6% vs. 1.9%, p = 0.007). CONCLUSIONS: ATEZO/BEVA showed superiority to LEN in terms of prognosis and conversion rate as first-line therapy. Moreover, ATEZO/BEVA had a lower rate of severe adverse events, except for bleeding, than LEN.

HSPA8 Single-Nucleotide Polymorphism Is Associated with Serum HSC70 Concentration and Carotid Artery Atherosclerosis in Nonalcoholic Fatty Liver Disease.

There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 NAFLD patients who had been diagnosed using a liver biopsy, and the NAFLD phenotype including the maximum intima-media thickness (Max-IMT) of the carotid artery was investigated. Patients with the minor allele (A/G or G/G) of rs2236659 showed a lower serum heat shock cognate 71 kDa protein concentration than those with the major A/A allele. Compared with the patients with the major allele, those with the minor allele showed a higher prevalence of hypertension and higher Max-IMT in men. No significant associations between the HSPA8 genotype and hepatic pathological findings were identified. In decision-tree analysis, age, sex, liver fibrosis, and HSPA8 genotype were individually associated with severe carotid artery atherosclerosis (Max-IMT ≥ 1.5 mm). Noncirrhotic men aged ≥ 65 years were most significantly affected by the minor allele of HSPA8. To predict the risk of atherosclerosis and cardiovascular disease, HSPA8 SNP genotyping might be useful, particularly for older male NAFLD patients.

Effect of skin-capsular distance on controlled attenuation parameter for diagnosing liver steatosis in patients with nonalcoholic fatty liver disease.

The effect of the skin-capsular distance (SCD) on the controlled attenuation parameter (CAP) for diagnosis of liver steatosis in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. The SCD was measured using B-mode ultrasound, and the CAP was measured using the M probe of FibroScan®. According to the indications of the M probe, 113 patients with an SCD of ≤ 25 mm were included in the present study. The association between the SCD and CAP was investigated, and the diagnostic performance of the SCD-adjusted CAP was tested. The SCD showed the most significant positive correlation with the CAP (ρ = 0.329, p < 0.001). In the multiple regression analysis, the SCD and serum albumin concentration were associated with the CAP, independent of pathological liver steatosis. According to the multivariate analysis, two different formulas were developed to obtain the adjusted CAP using the SCD and serum albumin concentration as follows: adjusted CAP (dB/m) = CAP - (5.26 × SCD) and adjusted CAP (dB/m) = CAP - (5.35 × SCD) - (25.77 × serum albumin concentration). The area under the receiver operating characteristic curve for diagnosis of a steatosis score ≥ 2 of adjusted CAP was 0.678 and 0.684 respectively, which were significantly greater than the original CAP (0.621: p = 0.030 and p = 0.024). The SCD is associated with the CAP independent of liver steatosis. Adjustment of the CAP using the SCD improves the diagnostic performance of the CAP in NAFLD.

Prediction of Nonalcoholic Fatty Liver Disease Using Noninvasive and Non-Imaging Procedures in Japanese Health Checkup Examinees.

Access to imaging is limited for diagnosing nonalcoholic fatty liver disease (NAFLD) in general populations. This study evaluated the diagnostic performance of noninvasive and nonimaging indexes to predict NAFLD in the general Japanese population. Health checkup examinees without hepatitis virus infection or habitual alcohol drinking were included. Fatty liver was diagnosed by ultrasonography. The hepatic steatosis index (HSI), Zhejiang University (ZJU) index, and fatty liver index (FLI) were determined, and risk of advanced liver fibrosis was evaluated by the fibrosis-4 index. NAFLD was diagnosed in 1935 (28.0%) of the 6927 subjects. The area under the receiver operating characteristic (AUROC) curve of the HSI, ZJU index, and FLI was 0.874, 0.886, and 0.884, respectively. The AUROC of the ZJU index (p < 0.001) and FLI (p = 0.002) was significantly greater than that for the HSI. In subjects with a high risk of advanced fibrosis, the sensitivity of the HSI, ZJU index, and FLI were 88.8%, 94.4%, and 83.3% with a low cut-off value and the specificity was 98.5%, 100%, and 100% with a high cut-off value. In conclusion, all indexes were useful to diagnose NAFLD in the general Japanese population and in subjects with potentially advanced liver fibrosis.

Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis.

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive ß-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.

Discordant pathological diagnosis of non-alcoholic fatty liver disease: A prospective multicenter study.

BACKGROUND: Liver biopsy has been the standard procedure for diagnosing and evaluating the severity of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, interobserver discordance remains a critical issue in its pathological diagnosis. METHODS AND RESULTS: We examined the concordance rates of pathological scoring and diagnosis between pathologists at individual institutions (local diagnosis) and two central pathologists specialized in liver pathology (central diagnosis). A total of 150 patients with NAFLD underwent prospective liver biopsies. NAFLD activity score (NAS) and fibrosis stage were evaluated, and NASH was determined according to Matteoni's classification. NAS, scores for all NAS components, and fibrosis stage were diagnosed at a lower degree by central compared with local diagnosis. NASH was diagnosed in 34% of the patients according to central pathologists compared with 54% according to local pathologists (P < 0.001). The concordance rates for NAS, steatosis, inflammation, ballooning, fibrosis, and NASH diagnosis were 26.7, 62.7, 51.3, 48.7, 43.3, and 50.7%, respectively. The correlation coefficient between local and central diagnoses was the lowest for the scoring of ballooning (ρ = 0.218). CONCLUSION: Concordance rates among pathologists for the evaluation of NAFLD are currently poor, and simple and reliable diagnostic and evaluation criteria are urgently needed to improve the clinical management of NAFLD patients.

Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells.

Hypoxia-inducible factor 1 (HIF-1) plays important roles in cancer cell biology. HIF-1α is reportedly activated by several factors, including protein kinase C (PKC), in addition to hypoxia. We investigated the role of PKC isoforms and the effects of vitamin K2 (VK2) in the activation process of HIF-1α. Human hepatocellular carcinoma (HCC)-derived Huh7 cells were cultured under normoxic and hypoxic (1% O2) conditions with or without the PKC stimulator TPA. The expression, transcriptional activity and nuclear translocation of HIF-1α were examined under treatment with PKC inhibitors, siRNAs against each PKC isoform and VK2. Hypoxia increased the expression and activity of HIF-1α. TPA increased the HIF-1α activity several times under both normoxic and hypoxic conditions. PKC-δ siRNA-mediated knockdown, PKC-δ inhibitor (rottlerin) and pan-PKC inhibitor (Ro-31-8425) suppressed the expression and transcriptional activity of HIF-1α. VK2 significantly inhibited the TPA-induced HIF-1α transcriptional activity and suppressed the expression and nuclear translocation of HIF-1α induced by TPA without altering the HIF-1α mRNA levels. These data indicate that PKC-δ enhances the HIF-1α transcriptional activity by increasing the nuclear translocation, and that VK2 might suppress the HIF-1α activation through the inhibition of PKC in HCC cells.

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.

Supplementation with branched-chain amino acids ameliorates hypoalbuminemia, prevents sarcopenia, and reduces fat accumulation in the skeletal muscles of patients with liver cirrhosis.

BACKGROUND: Liver cirrhosis induces marked metabolic disorders, protein-energy malnutrition, and sarcopenia. The objective of the study reported here was to investigate the effects of dietary branched-chain amino acids (BCAAs) on systemic glucose metabolism, skeletal muscle, and prognosis of patients with liver cirrhosis. METHODS: Japanese patients with liver cirrhosis (n = 21) were enrolled into a longitudinal study in which their diets were supplemented with BCAAs. We evaluated glucose metabolism and analyzed the skeletal muscle area index (SAI) and intramuscular adipose tissue content (IMAC) using computed tomography. RESULTS: After 48 weeks of supplementation with BCAAs, there were no changes in glucose metabolism and skeletal muscle findings. In patients with ameliorated hypoalbuminemia, IMAC was significantly decreased and SAI was preserved concomitant with decreasing 90- and 120-min post-challenge plasma glucose levels (P < 0.01 each). In patients without increased albumin levels, IMAC was significantly increased and the SAI was significantly decreased (P < 0.01 each). Liver-related event-free survival rates for 72 months were 63.6% in patients with decreased IMAC and 20.0% in patients with increased IMAC. CONCLUSIONS: Amelioration of hypoalbuminemia associated with BCAA supplementation correlated with decreased fat accumulation in skeletal muscle, maintenance of skeletal muscle mass, and improved glucose sensitivity, all factors which may contribute to improving the survival of patients with liver cirrhosis.

PDCD4 Knockdown Induces Senescence in Hepatoma Cells by Up-Regulating the p21 Expression.

While the over-expression of tumor suppressor programmed cell death 4 (PDCD4) induces apoptosis, it was recently shown that PDCD4 knockdown also induced apoptosis. In this study, we examined the cell cycle regulators whose activation is affected by PDCD4 knockdown to investigate the contribution of PDCD4 to cell cycle regulation in three types of hepatoma cells: HepG2, Huh7 (mutant p53 and p16-deficient), and Hep3B (p53- and Rb-deficient). PDCD4 knockdown suppressed cell growth in all three cell lines by inhibiting Rb phosphorylation via down-regulating the expression of Rb itself and CDKs, which phosphorylate Rb, and up-regulating the expression of the CDK inhibitor p21 through a p53-independent pathway. We also found that apoptosis was induced in a p53-dependent manner in PDCD4 knockdown HepG2 cells (p53+), although the mechanism of cell death in PDCD4 knockdown Hep3B cells (p53-) was different. Furthermore, PDCD4 knockdown induced cellular senescence characterized by ß-galactosidase staining, and p21 knockdown rescued the senescence and cell death as well as the inhibition of Rb phosphorylation induced by PDCD4 knockdown. Thus, PDCD4 is an important cell cycle regulator of hepatoma cells and may be a promising therapeutic target for the treatment of hepatocellular carcinoma.

Impact of Body Weight Reduction via Diet and Exercise on the Anti-Viral Effects of Pegylated Interferon Plus Ribavirin in Chronic Hepatitis C Patients with Insulin Resistance: A Randomized Controlled Pilot Trial.

OBJECTIVE: Insulin resistance (IR) modifies the anti-viral effects of interferon (IFN) therapy in patients with chronic hepatitis C (CHC). This prospective study evaluated whether lifestyle interventions improve the anti-viral response to treatment with pegylated (PEG)-IFN plus ribavirin (RBV) in patients with CHC. METHODS: The study cohort consisted of 60 patients chronically infected with a high viral load of hepatitis C virus genotype 1b and a homeostasis model assessment of IR (HOMA-IR) value above 2. The patients were divided into two groups, an intervention group (n=26) and a control group (n=34). The patients in the intervention group were prescribed diet and exercise treatment for 3-6 months to reduce their body weight by ≥5% before starting treatment with PEG-IFN plus RBV. RESULTS: Diet and exercise significantly reduced the HOMA-IR values in the intervention group, from 3.4 to 2.5 (p=0.0009), especially among the 15 patients who achieved a body weight reduction of ≥5%. The viral disappearance rate at 12 weeks was significantly higher in the intervention group among the patients with a ≥5% weight reduction than in the control group (53.3% vs. 23.5%, p=0.01). However, the sustained viral response (SVR) rates were similar. CONCLUSION: Improvements in IR achieved through weight reduction via lifestyle interventions may enhance the early viral response to PEG-IFN plus RBV in patients with CHC. However, this intervention program has no effect on the SVR rate.

Efficacy of ezetimibe for reducing serum low-density lipoprotein cholesterol levels resistant to lifestyle intervention in patients with non-alcoholic fatty liver disease.

AIM: To investigate the efficacy of ezetimibe and lifestyle intervention for treating patients with non-alcoholic fatty liver disease (NAFLD) and residual dyslipidemia via a combination of ezetimibe and lifestyle intervention. METHODS: Patients with NAFLD with residual dyslipidemia after a 6-month lifestyle intervention program were included. After completion of the 6-month program, the patients received p.o. administration of ezetimibe at 10 mg/day, in addition to lifestyle intervention, for 6 months. RESULTS: Of the 59 patients with NAFLD who had participated in the 6-month lifestyle intervention program between 2007 and 2012, 21 with residual dyslipidemia (10 males and 11 females) were enrolled. Median age was 58 years (range, 27-75), median bodyweight was 63.0 kg (range, 39.4-109.0), median body mass index was 25.4 kg/m2 (range, 18.2-37.1), median alanine aminotransferase was 23 IU/L (14-73), median high-density lipoprotein (HDL) was 58 mg/dL (range, 37-93), median triglycerides (TG) was 105 mg/dL (range, 42-216) and median low-density lipoprotein (LDL) was 153 (66-209) mg/dL. After 6 months of treatment with ezetimibe, serum LDL levels were improved in 15 of 20 (75%) patients (P = 0.0015), while no improvements were observed in the remaining five patient (25%). Ezetimibe was discontinued in one patient who developed skin rash. CONCLUSION: Ezetimibe is effective for treating residual dyslipidemia after lifestyle intervention in patients with NAFLD.

Impairment of health-related quality of life in patients with chronic hepatitis C is associated with insulin resistance.

BACKGROUND: Although it has been reported that hepatitis C virus (HCV) infection is associated with a significant decline in health-related quality of life (HRQOL), the underlying causes and mechanisms are still unknown. Insulin resistance (IR) is recognized as a distinct aspect of chronic HCV infection. Therefore, we attempted to identify the factors including IR indices that are related to the HRQOL of patients with chronic hepatitis C (CHC). METHODS: One hundred and seventy-five CHC patients (91 female, 84 male, mean age, 56.4 years) not using antidiabetic agents were included and underwent a 75-g oral glucose tolerance test (OGTT) and completed a self-administered HRQOL questionnaire, the Short Form 36 (SF-36), which is a well-validated questionnaire for assessing general QOL. Scale scores were standardized and summarized into physical and mental component summary (PCS and MCS). We investigated which clinical parameters, including homeostasis model assessment of insulin resistance (HOMA-IR), were associated with decline in PCS and MCS scores in CHC patients. RESULTS: There were no significant differences in clinical parameters between high and low MCS, but there were significant differences in age, sex, hemoglobin, liver fibrosis, OGTT pattern, and HOMA-IR between high and low PCS. Multivariate analysis showed that HOMA-IR >2 was independently associated with lower PCS (OR 2.92, p < 0.01). CONCLUSIONS: Our results suggest that impairment of HRQOL, especially physical domains, in CHC patients is associated with IR.

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.

Severity of non-alcoholic steatohepatitis is associated with substitution of adipose tissue in skeletal muscle.

BACKGROUND AND AIMS: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is now focusing on its organ cross-talk with not only adipose tissue but also systemic skeletal muscle. Cross-sectional and longitudinal studies were conducted to determine the role of intramuscular adipose tissue content (IMAC) measured by computed tomography on the severity of NAFLD/non-alcoholic steatohepatitis (NASH). METHODS: Two hundred eight Japanese patients with NAFLD/NASH diagnosed by liver biopsy were enrolled into a cross-sectional study. Twenty-one patients were enrolled in a longitudinal study and received a programmed diet and exercise intervention, in some cases the combination of pharmacotherapy. We measured IMAC in the multifidus muscle and biochemical parameters, and conducted liver histology to assess NAFLD/NASH status. RESULTS: Histopathological stage in terms of simple steatosis and Brunt's classification was significantly correlated with IMAC (P < 0.01). Multivariate logistic regression analysis indicated that risk factors associated with the severity of NASH were IMAC and aging (IMAC: odds ratio = 2.444, P < 0.05; Age: odds ratio = 2.355, P < 0.05). The interventions improved histopathological changes in 11 patients with NASH as well as IMAC. CONCLUSION: These results suggest that skeletal muscle fat accumulation may have been linked to the pathogenesis and severity of NASH.

Efficacy of pegylated interferon plus ribavirin in combination with corticosteroid for two cases of combined hepatitis C and autoimmune hepatitis.

The treatment strategy for cases of combined autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) has not yet been established. A 47-year-old woman and a 53-year-old-woman were hospitalized for treatment of CHC. Ultrasonography and histological findings revealed that their liver was not cirrhotic but did have chronic damage. The histological findings of both patients were suggestive of AIH. The patients were systematically treated with pegylated interferon-alpha 2b plus ribavirin which was preceded by and combined with corticosteroid (CS), and showed sustained virological responses and normal liver function. Although these two patients with combined AIH and CHC were successfully treated with this regimen, careful attention to exacerbation of hepatic inflammation is needed because hepatitis C viral load was increased due to immunosuppression during CS treatment.

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.

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.

The pathological role of visceral fat accumulation in steatosis, inflammation, and progression of nonalcoholic fatty liver disease.

BACKGROUND: Our previous studies have indicated a close association between visceral fat accumulation and hepatic steatosis in nonalcoholic fatty liver disease (NAFLD). This study investigated whether visceral fat accumulation was related to the pathogenesis and disease progression of nonalcoholic steatohepatitis (NASH)/NAFLD. METHODS: First, a total of 550 subjects who underwent a health checkup and measurement of visceral fat accumulation, done with a bioelectrical impedance analyzer (X-SCAN; Owa Medical, Fukuoka, Japan), were included. The relationship between visceral fat accumulation and biochemical parameters was examined. Second, a total of 74 patients with NASH/NAFLD who underwent liver biopsy were reviewed. Visceral fat accumulation was determined by abdominal computed tomography. The association between visceral fat accumulation and the histopathological grade/stage determined by the NAFLD activity score and Brunt's classification was evaluated. RESULTS: There was a significant relationship between visceral fat accumulation and glucose, triglyceride, and alanine aminotransferase (ALT; r = 0.423, P < 0.01). In stepwise regression analysis, visceral fat area (VFA), serum triglyceride level, and serum low-density lipoprotein (LDL)-cholesterol level were selected as predictor variables for serum ALT level, in a continuous manner (serum ALT level = -1.359 + 0.143 × VFA + 0.046 × triglyceride + 0.059 × LDL, R(2) = 0.217, P < 0.001). In patients with NASH, there was no correlation between histological grade and the visceral fat volume. Visceral fat accumulation in patients with stage 3/4 advanced NASH was greater than that in patients with stage 1/2 early NASH (P < 0.05). CONCLUSIONS: These results suggest that visceral fat accumulation plays a role in steatosis and fibrosis in the pathogenesis and prognosis of NAFLD.