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Aim: This study aimed to establish the shear wave measurement (SWM) cut-off value for each fibrosis stage using magnetic resonance (MR) elastography values as a reference standard., Methods: We prospectively analyzed 594 patients with chronic liver disease who underwent SWM and MR elastography. Correlation coefficients (were analyzed, and the diagnostic value was evaluated by the area under the receiver operating characteristic curve. Liver stiffness was categorized by MR elastography as F0 (<2.61 kPa), F1 (≥2.61 kPa, <2.97 kPa, any fibrosis), F2 (≥2.97 kPa, <3.62 kPa, significant fibrosis), F3 (≥3.62 kPa, <4.62 kPa, advanced fibrosis), or F4 (≥4.62 kPa, cirrhosis)., Results: The median SWM values increased significantly with increasing fibrosis stage (p < 0.001). The correlation coefficient between SWM and MR elastography values was 0.793 (95% confidence interval 0.761-0.821). The correlation coefficients between SWM and MR elastography values significantly decreased with increasing body mass index and skin-capsular distance; skin-capsular distance values were associated with significant differences in sensitivity, specificity, accuracy, or positive predictive value, whereas body mass index values were not. The best cut-off values for any fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis were 6.18, 7.09, 8.05, and 10.89 kPa, respectively., Conclusions: This multicenter study in a large number of patients established SWM cut-off values for different degrees of fibrosis in chronic liver diseases using MR elastography as a reference standard. It is expected that these cut-off values will be applied to liver diseases in the future., (© 2024 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Background and Aims: Because the accuracy of the Fibrosis-4 (FIB-4) index for predicting liver fibrosis changes with age, the need for different cut-offs in various age groups has frequently been discussed. We developed the age-independent score, the Fibrosis-3 (FIB-3) index, and have shown its usefulness in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB-3 index to predict fibrosis progression using a large new patient cohort., Methods: The ability of the FIB-3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB-4 index using data from 1398 patients with MASLD enrolled in the Asia-based clinical outcome NAFLD study., Results: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB-3 and FIB-4 indices in the entire cohort. Using the single ideal cut-offs of the indices (3.41 for FIB-3 index and 2.01 for FIB-4 index), the predictive accuracy of the FIB-3 index was not significantly different from that of the FIB-4 index among patients aged <60 years; however, the accuracy of the FIB-3 index was significantly higher than that of the FIB-4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001)., Conclusion: The high ability of the FIB-3 index with a single cut-off to predict liver fibrosis in patients with MASLD was confirmed. The FIB-3 index could serve as a useful tool for assessing liver fibrosis regardless of age., (© 2024 The Japan Society of Hepatology.)

Aim: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. The aim of this study was to determine the recent prevalence and clinical characteristics of NAFLD in Japan., Methods: This study initially included 410 061 retrospectively enrolled adults from the medical health checkup registry for metabolic syndrome, chronic kidney disease, and fatty liver in Japan (MIRACLE-J; UMIN-CTR no. UMIN000049419), who were evaluated between 2014 and 2018 at 13 health centers in Japan. Individuals consuming >20 g of alcohol/day or with chronic liver disease were excluded. Fatty liver was diagnosed by ultrasonography. The probability of NAFLD with advanced fibrosis was estimated based on the fibrosis-4 index and NAFLD fibrosis score., Results: A total of 71 254 participants were included in the final analysis. The overall prevalence of NAFLD was 25.8%. There was a significant, twofold difference in NAFLD prevalence between men (37.4%) and women (18.1%). Nonalcoholic fatty liver disease prevalence increased linearly with body mass index, triglycerides, and low-density lipoprotein cholesterol regardless of threshold values, even in the absence of obesity. Among patients with NAFLD, 14% had diabetes mellitus, 31% had hypertension, and 48% had dyslipidemia. The estimated prevalence of NAFLD with advanced fibrosis was 1.7% and 1.0% according to the fibrosis-4 index and NAFLD fibrosis score, respectively., Conclusions: The prevalence of NAFLD was approximately one-quarter of the general population in Japan. There was a linear relationship between NAFLD prevalence and various metabolic parameters, even in nonobese participants. The prevalence of NAFLD with advanced fibrosis was estimated to be 1%-2%., (© 2023 The Japan Society of Hepatology.)

Aim: The noninvasive tests (NITs) Agile 3+ and Agile 4 effectively identify patients with nonalcoholic fatty liver disease (NAFLD) complicated with advanced fibrosis (F3-4) and cirrhosis (F4), respectively. Little information is available on associations between Agile scores and intra-/extrahepatic events. The aim of this study was to determine the predictive performance of Agile scores for intra-/extrahepatic events in Asian patients with biopsy-proven NAFLD., Methods: We undertook a retrospective multicenter cohort study to investigate associations between intra-/extrahepatic events and two Agile scores, Agile 3+ and Agile 4. The scores were obtained by combining clinical parameters and liver stiffness measurement using transient elastography., Results: Among 403 enrolled patients, 11 had liver-related events (LREs), including seven with hepatocellular carcinoma (HCC). The incidence of LREs and HCC showed a stepwise increase in the advanced fibrosis group (F3-4), Agile 3+ rule-in (F3-4, highly suspected), and Agile 4 rule-in (F4, highly suspected) groups, compared to their counterparts. Hazard ratios for LREs in the advanced fibrosis group, Agile 3+ rule-in, and Agile 4 rule-in groups were 4.05 (p = 0.03), 23.5 (p = 0.003), and 45.5 (p < 0.001), respectively. The predictive performance results for Agile 3+ and Agile 4 were 0.780 and 0.866, respectively, which were higher than for fibrosis (0.595). Unlike for LREs, Agile scores failed to identify patients with extrahepatic events, including cardiovascular events and extrahepatic cancer., Conclusions: Agile 3+ and Agile 4 scores are excellent NITs for predicting LREs in patients with NAFLD, possibly without histological assessment., (© 2023 Japan Society of Hepatology.)

Aim: Agile 3+ and Agile 4 scores, based on liver stiffness measurement (LSM) by transient elastography and clinical parameters, were recently reported to be effective in identifying advanced fibrosis and cirrhosis in nonalcoholic fatty liver disease (NAFLD). This study aimed to validate the utility of these scores in Japanese patients with NAFLD., Methods: Six hundred forty-one patients with biopsy-proven NAFLD were analyzed. The severity of liver fibrosis was pathologically evaluated by one expert pathologist. The LSM, age, sex, diabetes status, platelet count, and aspartate aminotransferase and alanine aminotransferase levels were used to calculate Agile 3+ scores, and the parameters above excluding age were used for Agile 4 scores. The diagnostic performance of the two scores was evaluated using receiver operating characteristic (ROC) curve analysis. Sensitivity, specificity, and predictive values of the original low cut-off (for rule-out) value and high cut-off (for rule-in) value were tested., Results: For diagnosis of fibrosis stage ≥3, the area under the ROC (AUROC) was 0.886, and the sensitivity of the low cut-off value and the specificity of the high cut-off value were 95.3% and 73.4%, respectively. For diagnosis of fibrosis stage 4, AUROC, the sensitivity of the low cut-off value, and the specificity of the high cut-off value were 0.930, 100%, and 86.5%, respectively. Both scores had higher diagnostic performance than the FIB-4 index and the enhanced liver fibrosis score., Conclusions: Agile 3+ and Agile 4 are reliable noninvasive tests to identify advanced fibrosis and cirrhosis in Japanese NAFLD patients with adequate diagnostic performance., (© 2023 Japan Society of Hepatology.)

Aim: Impacts of platelet counts at the time of liver biopsy on hepatocellular carcinoma (HCC) development in patients with nonalcoholic fatty liver disease (NAFLD) remain unknown. The aim of this study was to investigate the prognostic value of platelet counts in patients with biopsy-confirmed NAFLD using data from a multicenter study., Methods: One thousand three hundred ninety-eight patients were included in this subanalysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia study. Liver biopsy specimens were pathologically diagnosed, and histologically scored using the NASH Clinical Research Network system. Demographic, clinical, laboratory, and pathological data were collected., Results: During a median follow-up period of 4.6 years (range, 0.3-21.6 years), which corresponds to 8874 person-years, 37 patients developed HCC. Using a cut-off baseline platelet count of 192 × 109/L, the lower platelet group had a higher HCC rate than the higher platelet group (6.7% vs. 0.4%; p < 0.001). This cut-off value significantly stratified the event-free rate for HCC. Lower platelet counts were associated with an increased risk of HCC development. Relative to patients with platelet counts of 192 × 109/L, patients with platelet counts of 100 × 109/L had an unadjusted hazard ratio (HR) for HCC development of 7.37 (95% confidence interval [CI], 3.81-14.2) and an adjusted HR of 11.2 (95% CI, 3.81-32.7; p < 0.001), adjusting for age, sex, NASH, and diabetes., Conclusions: Baseline platelet counts of 192 × 109/L and lower are associated with a higher risk of developing HCC in patients with biopsy-confirmed NAFLD and require active surveillance., (© 2023 Japan Society of Hepatology.)

Aim: The enhanced liver fibrosis (ELF) test is a noninvasive method for diagnosing hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). This multicenter cohort study aimed to evaluate the accuracy of the ELF test and compare it with other noninvasive tests in Japan., Methods: We analyzed 371 Japanese patients with biopsy-proven NAFLD. We constructed area under the receiver operator characteristic curves (AUROC) to determine the diagnostic accuracies of the ELF test, the Mac-2-binding protein glycosylation isomer (M2BPGi), the Fibrosis-4 (FIB-4) index, and combinations of these indices., Results: In patients with F0/F1/F2/F3/F4 fibrosis, the median values of the ELF test were 8.98/9.56/10.39/10.92/11.41, respectively. The AUROCs of the ELF test for patients with F0 versus F1-4, F0-1 versus F2-4, F0-2 versus F3-4, and F0-3 versus F4 fibrosis were 0.825/0.817/0.802/0.812, respectively. The AUROCs of the ELF test were greater than those of the FIB-4 index and M2BPGi at each fibrosis stage. Respective low and high cut-off values yielded sensitivities and specificities for predicting advanced fibrosis (≥F3) of 91.1% and 50.8%, and 38.5% and 92.8%, respectively. For F3 or F4 fibrosis, the combined values from the ELF test and FIB-4 index showed a sensitivity of 98.5%, and the combined values from the ELF test and M2BPGi assay showed a specificity of 97.5%., Conclusions: In Japan, the ELF test predicts NAFLD-related fibrosis from its early stages. The diagnostic ability of the ELF test was not inferior to that of other indices, and the combined values of ELF plus other indices were more accurate., (© 2022 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aim: Elastography is an established, noninvasive method for measuring liver stiffness using to 2-D shear-wave elastography (2D-SWE) or magnetic resonance elastography (MRE). The aim of this study was to determine the usefulness of combined measurement using 2D-SWE and MRE to stratify the risk of developing hepatocellular carcinoma (HCC) in patients who achieved hepatitis C virus eradication., Methods: Five hundred and twenty-five patients who underwent 2D-SWE and MRE before antiviral therapy and who achieved eradication were enrolled. The optimal 2D-SWE and MRE cutoff values were determined using time-dependent receiver operating characteristic (ROC) curves for predicting HCC development. Inverse probability of treatment weighting (IPTW) and a Cox proportional hazards model were used to adjust the cumulative incidence rate of HCC development for potential imbalances., Results: Time-dependent ROC analysis showed that the optimal cut-off values of 2D-SWE and MRE for predicting HCC development were 11.7 and 4.5 kPa, respectively. The IPTW-adjusted cumulative incidence rate of HCC development in patients with both an 2D-SWE value ≥ 11.7 kPa and an MRE value ≥ 4.5 kPa had a higher hazard ratio (28.080; 95% confidence interval, 5.527-132.600; p < 0.001) than those with either an 2D-SWE value < 11.7 kPa or an MRE value < 4.5 kPa., Conclusions: The combined measurement of 2D-SWE and MRE was very effective for identifying patients at high risk of HCC development. US-based elastography should be performed first, and if the 2D-SWE value is high, MRE should then be carried out to confirm the degree of liver stiffness., (© 2022 Japan Society of Hepatology.)

Aims: Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality in Japan. As the treatment of viral hepatitis improves, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are rapidly becoming leading causes of HCC in Japan. This structured review aims to characterize the morbidity and mortality of HCC and other malignant and non-malignant complications among Japanese NAFLD and NASH patients., Methods: An English and Japanese structured search of published works was undertaken in PubMed, Embase, and Ichushi Web databases, identifying 6553 studies, 34 of which met predefined inclusion criteria., Results: Hepatocellular carcinoma was the most common incident malignancy among NAFLD/NASH patients, with higher incidence in patients with advanced/severe fibrosis (F3/F4) of 10.5%-20.0%. Although NASH results in a lower HCC cumulative incidence than hepatitis C virus (HCV) (11.3% vs. 30.5%), they have similar impacts on health outcomes, including overall mortality. Among Japanese NASH patients, HCC was found to be the main driver of mortality (40.0% in 2.7 years in NASH-HCC). With longer follow-up, higher mortality rates are observed in F3/4 patients: 25.0% in NASH F3/F4 versus 0.0% in NASH F0/2 over 7.7 years. The NASH-HCC patients also have a higher post-operative mortality than HCV-HCC patients. Additionally, NAFLD/NASH patients had higher rates of cardiovascular disease than non-NAFLD/NASH controls, and slightly higher rates of gastric cancer than HCV patients., Conclusion: Hepatocellular carcinoma is the most common malignancy and cause of death among NAFLD/NASH patients in Japan, with higher mortality observed among those with advanced disease and complications. Early identification and effective treatments are needed., (© 2020 The Japan Society of Hepatology.)

Despite the invasive nature of liver biopsy, it remains the current standard for diagnosing non-alcoholic steatohepatitis (NASH) and fibrosis staging. Given the rising prevalence of non-alcoholic fatty liver disease (NAFLD) in Japan, there is a need for reliable non-invasive tests to accurately and efficiently identify NASH and advanced (F3/F4) fibrosis. A review of published works from English and Japanese sources was undertaken in PubMed, Embase, and Ichushi Web to identify studies reporting diagnostic characteristics of NITs in biopsy-proven Japanese NAFLD/NASH patients including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve. The performance of non-invasive tests for two diagnostic questions were assessed, namely: (i) identifying NASH cases among NAFLD; and (ii) distinguishing advanced fibrosis (F3-4) from milder fibrosis (F0-2). Twenty-five studies reported outcomes for serum biomarkers, imaging, scoring systems, and novel complex techniques (based on multivariable regression models) for both diagnostic questions. Serum biomarkers were the most commonly assessed method for NASH identification, whereas scoring systems and imaging techniques were most commonly studied for fibrosis staging. In general, tests for NASH identification showed higher PPVs than NPVs, suggesting their usefulness in identifying probable NASH cases. The reverse was observed for fibrosis staging, with higher NPVs than PPVs, suggesting their use in excluding patients at low risk of F3/F4 disease rather than identifying definite F3/F4 fibrosis. In Japanese studies, simple scoring systems and imaging techniques showed particular usefulness in prediction of fibrosis staging, and combinations of serum biomarkers showed diagnostic potential for NASH screening., (© 2020 The Japan Society of Hepatology.)

Non-alcoholic steatohepatitis (NASH), which is a more severe form of non-alcoholic fatty liver disease, can at least partly lead to cirrhosis, hepatocellular carcinoma, and hepatic failure. Liver transplantation is the only option for NASH cirrhosis at this time. By 2020, NASH is projected to overtake hepatitis C as the leading cause of liver transplants in the USA. There are still no approved drugs for treating NASH. Although there are approximately 196 agents of investigational NASH therapies in various stages of development, we here mainly review phase 3 drug candidates in the pipeline for NASH. The NASH space across the seven major markets of the USA, France, Germany, Italy, Spain, the UK, and Japan, is set to rise from $618 million in 2016 to approximately $25.3 billion by 2026. However, the fact that the race to develop an effective drug against NASH has reached the home stretch, with five drug candidates (obeticholic acid, elafibranor, selonsertib, cenicriviroc, and resmetirom) in phase 3 stage of the trial, is welcome news for patients. The very earliest a NASH drug could hit the market is 2021, assuming all goes well as planned., (© 2019 The Japan Society of Hepatology.)

Aims: No pharmacological therapies are approved for non-alcoholic fatty liver disease (NAFLD). Luseogliflozin, a sodium glucose cotransporter 2 inhibitor, has been developed for the treatment of adults with type 2 diabetes (T2DM). The aim of this prospective, single-arm study is to evaluate the efficacy of luseogliflozin on hepatic fat content and glycated hemoglobin (HbA1c) in T2DM patients with NAFLD., Methods: Forty T2DM patients with NAFLD were treated with luseogliflozin 2.5 mg/day for 24 weeks. Primary end-points were changes in HbA1c and hepatic steatosis evaluated by magnetic resonance imaging-hepatic fat fraction from baseline. Secondary end-points were changes in metabolic and hepatic function-related parameters, including hepatic fibrosis markers (Fibrosis-4 index, NAFLD fibrosis score, type IV collagen 7S. and Wisteria floribunda agglutinin-positive Mac-2 binding protein)., Results: Not only HbA1c and transaminase activities but also hepatic fat content were significantly decreased after 24 weeks of therapy with luseogliflozin. The reduction of hepatic fat content was significantly correlated with the reduction of alanine aminotransferase. Although hepatic fibrosis markers were unchanged, serum ferritin levels reduced and serum albumin significantly increased after the treatment., Conclusion: Luseogliflozin can be a novel promising agent for the treatment of T2DM patients with NAFLD. Prospective randomized controlled trials are warranted to confirm this impact of luseogliflozin onT2DM with NAFLD., (© 2018 The Japan Society of Hepatology.)

Aim: Pruritus is a common comorbidity in chronic liver disease. The aim of this study was to clarify the prevalence of pruritus and its characteristics in patients with chronic liver disease., Methods: A total of 1631 patients with chronic liver disease who attended one of nine joint-research facilities from January to June 2016 were enrolled. We investigated the prevalence of pruritus, itch location, itch duration, daily itch fluctuation, seasonal itch exacerbation, treatment drugs, and therapeutic effects using a medical interview questionnaire., Results: The median age was 66 years and 890 (54.6%) patients were women. The prevalence of pruritus was 40.3% (658/1631), and it differed according to the underlying liver disease. The most frequent body location for pruritus was on the back (63.1%). Pruritus duration was more than 6 months in 252 (38.3%) patients. The severity of pruritus, assessed using a visual analog scale, was higher during the day than at night (median, 4 vs. 3, P < 0.001). Seasonal exacerbation was observed in 296 (45.0%) patients. Although 301 (45.7%) patients were treated with antipruritic agents, 57.8% (174/301) patients reported an insufficient effect. Active hepatitis B virus infection (odds ratio [OR], 2.51; P = 0.043), primary biliary cholangitis (OR, 3.69; P = 0.018), diabetes (OR, 1.57; P = 0.010), and aspartate aminotransferase ≥60 U/L (OR, 2.06; P = 0.011) were independent factors associated with pruritus., Conclusion: The prevalence of pruritus varies according to the chronic liver disease etiology. Underlying liver disease, aspartate aminotransferase ≥60 U/L, and comorbid diabetes are factors associated with pruritus in patients with chronic liver disease., (© 2017 The Japan Society of Hepatology.)

Aim: Type 2 diabetes mellitus (T2DM) is a major complication of patients with non-alcoholic fatty liver disease (NAFLD). The aim of this retrospective study is to determine the risk factors for development of T2DM in patients with biopsy-proven NAFLD., Methods: One hundred and sixty two consecutive patients with biopsy-proven NAFLD who received a 75-g oral glucose tolerance test were enrolled as the total cohort. Among them, we analyzed 89 patients without T2DM diagnosed by oral glucose tolerance test to estimate the cumulative rate for development of T2DM as the follow-up cohort., Results: Of 162 patients, the glucose tolerance pattern were DM in 45 patients (27.8%), impaired glucose tolerance in 68 (42.0%), and normal glucose tolerance in 49 (30.2%). Patients with NAFL tended to be more likely to have normal glucose tolerance than those with non-alcoholic steatohepatitis (NASH). The serum levels of pre- and post-load insulin were significantly higher in the NASH group. Of 89 patients without T2DM, 13 patients newly developed T2DM during a follow-up period of 5.2 years. The cumulative rate of T2DM incidence was 8.8% at the end of the 5th year and 23.4% at the end of the 10th year. Multivariate analysis identified homeostasis model of assessment - insulin resistance (≥3.85, hazard ratio 40.1, P = 0.033) as an independent risk factor for development of T2DM., Conclusions: Patients with NASH have an underlying potential of glucose intolerance. In NAFLD patients, insulin resistance is the most important risk factor for the incidence of T2DM. Appropriate therapy against insulin resistance could be needed for patients with NAFLD to prevent development of T2DM., (© 2017 The Japan Society of Hepatology.)

Aims: No pharmacological therapies have been established for non-alcoholic fatty liver disease (NAFLD) with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy and safety of dulaglutide, a novel glucagon-like peptidase-1 receptor agonist, in Japanese NAFLD patients with T2DM., Methods: Fifteen biopsy-proven NAFLD patients with T2DM refractory to diet intervention who received once weekly dulaglutide 0.75 mg for 12 weeks were retrospectively enrolled after exclusion of two patients by 12 weeks. In five patients, transient elastography and body composition were also evaluated before and after the treatment., Results: Not only body weight and hemoglobin A1c but also transaminase activities were significantly decreased after the 12-week therapy with dulaglutide. Total body fat mass and liver stiffness measurement also decreased after the treatment., Conclusion: Dulaglutide, a new glucagon-like peptidase-1 receptor agonist, could be a novel promising agent for the treatment for NAFLD patients with T2DM due to its efficacy in body weight reduction, the nature of weekly injection, and patient preference. Prospective randomized controlled trials are warranted to confirm this impact of dulaglutide on NAFLD with T2DM., (© 2016 The Japan Society of Hepatology.)

Aim: Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC). Patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (encoding the I148M variant) has been associated with advanced fibrosis and HCC. We determined the risk factors for HCC, including the PNPLA3 rs738409 polymorphism, in Japanese patients with biopsy-proven NAFLD., Methods: In this retrospective cohort study, we analyzed hepatocarcinogenesis in 238 patients. PNPLA3 rs738409 genotype was determined by allelic discrimination in 130 patients. Among them, 86 patients who were followed up for >5 years and without liver cirrhosis were analyzed to clarify the relationship between PNPLA3 genotype and long-term changes in biomarkers., Results: Of 238 patients, PNPLA3 genotype frequencies were: CC, 0.14; CG, 0.46; and GG, 0.40. During a follow-up period of 6.1 years, 10 patients (4.2%) with non-alcoholic steatohepatitis developed HCC. The cumulative rate of HCC was 1.9% at the end of the 5th year and 8.3% at the end of the 10th year. Multivariate analysis identified PNPLA3 genotype GG (hazard ratio, 6.36; P = 0.019) and fibrosis stage (fibrosis stage 3/4; hazard ratio, 24.4; P = 0.011) as predictors of HCC development. In the long follow-up cohort, a larger reduction in platelet count was found in the GG group (P = 0.032) despite a larger reduction in alanine aminotransferase (P = 0.023) compared to that in the CC/CG group., Conclusions: In Japanese patients with NAFLD, severe fibrosis and PNPLA3 GG genotype were predictors of HCC development, independent of other known risk factors. Patients with the PNPLA3 GG genotype have the potential for a decreased platelet count, even when alanine aminotransferase levels are well controlled., (© 2016 The Japan Society of Hepatology.)

Aim: No pharmacological therapies have been established for non-alcoholic fatty liver disease (NAFLD). Sodium glucose cotransporter 2 inhibitor (SGLT2I) was developed for the treatment of adults with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM., Methods: Twenty-four biopsy-proven NAFLD patients with T2DM who received SGLT2I for 24 weeks were retrospectively enrolled as the SGLT2I group. Another 21 NAFLD patients with T2DM treated with dipeptidyl peptidase-4 inhibitor (DPP4I) for 24 weeks were selected as the DPP4I group. Clinical data were evaluated at baseline and at 4, 12, and 24 weeks. Seventeen patients in the SGLT2I group were evaluated by body composition before and after therapy., Results: Not only body weight and hemoglobin A1c but also transaminase activities were significantly decreased in the SGLT2I group. Reductions in transaminase activities were similar between SGLT2I and DPP4I groups. In the SGLT2I group, body mass index and fasting plasma glucose also decreased after the treatment., Conclusion: Sodium glucose cotransporter 2 inhibitor can be a novel promising agent for the treatment for NAFLD patients with T2DM. Prospective randomized controlled trials are warranted to confirm this efficacy of SGLT2I on NAFLD with T2DM., (© 2016 The Japan Society of Hepatology.)

Aim: Platelet count and liver stiffness measurement (LSM) using transient elastography could identify significant fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). We constructed a novel index combining LSM with platelet count for staging fibrosis in Japanese patients with NAFLD., Methods: We recruited 173 Japanese patients with liver biopsy-proven NAFLD. The areas under the receiver operating characteristic curves were calculated and compared with established parameters and scoring systems for staging liver fibrosis., Results: After excluding 10 patients in whom LSM failed, 163 patients with NAFLD were enrolled. The areas under the receiver operating characteristic curves of the LSM/platelet ratio (LPR) index for detecting fibrosis ≥stage 1, ≥stage 2, and ≥stage 3 were the greatest (0.835, 0.913, and 0.936, respectively) compared with those for various other parameters and established scoring systems, such as LSM, type IV collagen 7 s domain, platelet count, NAFIC score, fibrosis-4 index, NAFLD fibrosis score, aspartate aminotransferase/alanine aminotransferase ratio, and aspartate aminotransferase to platelet ratio index. The optimal cut-off, positive predictive, and negative predictive values of the LPR index for detecting ≥stage 3 fibrosis were 0.60, 48.9%, and 99.2%, whereas those of LSM were 10.0 kPa, 35.0%, and 99.0%, respectively. The novel LPR index helps avoid biopsies in a larger percentage of patients with NAFLD compared with that LSM alone., Conclusions: The LPR index was the best predictor for staging fibrosis in patients with NAFLD. It represents a simple and non-invasive alternative to liver biopsy in clinical practice., (© 2016 The Japan Society of Hepatology.)

Liver-related diseases are the leading causes of death in patients with type 2 diabetes mellitus (T2DM) in Japan. Type 2 diabetes mellitus is closely associated with non-alcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma and hepatic failure. Non-alcoholic steatohepatitis can be called "diabetic hepatopathy". There are no established pharmacotherapies for NAFLD/NASH patients with T2DM. Although metformin is established as the first-line therapy for T2DM, given its relative safety and beneficial effects on glycosylated hemoglobin, weight, and cardiovascular mortality, this agent is not recommended as specific therapy for NASH/NAFLD due to lack of clinical evidence. The effects of pioglitazone on NASH histology with T2DM have been extensively proved, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. In recent years, novel antidiabetic medications have been approved for T2DM, such as glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and sodium/glucose cotransporter 2 inhibitors. A key clinical question for hepatologists is what kinds of antidiabetic medications are the most appropriate for the treatment of NAFLD accompanied by T2DM, to prevent progression of hepatic fibrosis resulting in HCC/liver-related mortality without increased risk of cardiovascular events. This review focuses on novel antidiabetic agents and future perspectives on the treatment of NAFLD/NASH with T2DM., (© 2017 The Japan Society of Hepatology.)

Aims: Cardiovascular events are the leading cause of death among patients with non-alcoholic fatty liver disease (NAFLD), but their relationship remains unclear. This study examined the association between coronary atherosclerosis and liver fibrosis, represented by the coronary artery calcification (CAC) score and non-invasive fibrosis markers, respectively., Methods: Among 698 patients with chest pain or electrocardiographic abnormalities who underwent coronary computed tomography (CT) between April 2006 and March 2010, those with known liver disorders or history of emergency coronary angioplasty were excluded, leaving 366 patients for this study. Diagnosis of NAFLD was based on abdominal CT and history of alcohol consumption. Subjects with CAC of 100 AU or more were categorized into the high-risk group for cardiovascular events. Patient records were examined for clinical parameters including CAC score and non-invasive fibrosis marker FIB-4 index., Results: Ninety-four patients (25.7%) had NAFLD. In this group, univariate analysis identified old age, high diastolic blood pressure, high liver to spleen ratio and high FIB-4 index as risk factors for cardiovascular events and multivariate analysis identified age of 66 years or older and FIB-4 index of 2.09 or more as the significant risk factors. For the observation period until August 2014, the cumulative proportion of PCI performance was significantly higher in patients with FIB-4 of 2.09 or more than those with FIB-4 of less than 2.09., Conclusion: The progression of arteriosclerosis and that of liver fibrosis may be associated in NAFLD patients. The FIB-4 index can be easily determined and thus can be a useful marker for predicting cardiovascular events in NAFLD patients., (© 2016 The Japan Society of Hepatology.)

Aim: Some cases with non-alcoholic fatty liver disease (NAFLD), particularly non-alcoholic steatohepatitis (NASH), can ultimately progress to liver cirrhosis. However, studies to clarify factors predictive of histological change in patients with NASH remain scarce. Our aim is to determine predictors of histological progression in Japanese patients with biopsy-proven NASH., Methods: This retrospective cohort study enrolled 52 patients with NASH who underwent serial liver biopsies. Histological evaluation included NAFLD activity score (NAS) and liver fibrosis. The median interval between initial and second liver biopsies was 968 days. An alanine aminotransferase (ALT) response was defined as a decrease of 30% or more from baseline., Results: Of 52 patients, NAS was ameliorated in 30.8%, deteriorated in 30.8% and remained unchanged in 38.4%. Liver fibrosis was improved in 25.0% of patients, progressed in 25.0% and remained stable in 50.0%. Multivariate analysis identified ALT non-response as a predictor of deterioration of NAS (hazard ratio [HR], 5.85; P = 0.031) and progression of liver fibrosis (HR, 4.50; P = 0.029). The mean annual rate of fibrosis was 0.002 stages/year overall, increasing to 0.15 stages/year in ALT non-responders., Conclusion: A lack of reduction in serum ALT level by at least 30% from baseline was a predictor for histological progression in patients with NASH. Serum ALT level is a better predictor of histological change than insulin resistance or bodyweight and can be a valid index in treatment. Serum ALT should be strictly controlled to prevent liver histological progression in patients with NASH., (© 2014 The Japan Society of Hepatology.)

A 56-year-old male patient with chronic hepatitis C was treated with pegylated interferon (PEG IFN)-α-2b and ribavirin (RBV) for 72 weeks in 2006. The patient achieved an early virological response (EVR); however, hepatitis C relapsed 12 weeks after discontinuation of PEG IFN and RBV. In 2012, the patient was treated with a PEG IFN/RBV/telaprevir combination therapy. After 5 days of treatment, he suffered from a telaprevir-associated skin rash on his body and four limbs. He chose to be treated with PEG IFN and RBV until 60 weeks. He again achieved EVR but no sustained virological response. In 2014, he was treated with PEG IFN/RBV/simeprevir combination therapy. He achieved rapid virological response, but after 6 weeks of therapy, a striking elevation of serum aminotransferase level was recorded with no accompanying skin rash; he was admitted to our hospital. PEG IFN/RBV/simeprevir was stopped, but sodium valproate (400 mg/day), which had been administrated for more than 10 years to prevent epilepsy was continued. Liver biopsy revealed typical features of drug-induced liver injury. After stopping PEG IFN/RBV/simeprevir, serum aminotransferase levels soon returned to the normal range. We diagnosed this case to be simeprevir-induced hepatitis clinically and histologically. Physicians need to stay alert to the possibility of drug-induced liver injury in using simeprevir., (© 2015 The Japan Society of Hepatology.)

Aim: No pharmacological therapies have been established for non-alcoholic steatohepatitis (NASH), which can lead to liver-related mortality. Human placental extract (HPE), which has anti-inflammatory effects, has been expected to be a promising treatment for chronic liver disease. This pilot study was conducted to evaluate the efficacy of HPE for biopsy-diagnosed NASH., Methods: After a lifestyle intervention for 12 weeks, 10 subjects with abnormal alanine aminotransferase (≥30 IU/L) and biopsy-proven NASH (Non-Alcoholic Fatty Liver Disease Activity Score [NAS], ≥4) received i.m. injections of HPE (Laennec) at a dose of 4 mL/day twice per week for 24 weeks, and seven of them underwent a second liver biopsy after the treatment. Liver biopsies were scored for NAS and fibrosis. Histological response was defined as a decrease of 2 points or more in NAS and no increase in fibrosis., Results: Serum transaminase activities were significantly lower at 8 weeks compared with pretreatment levels in nine patients who continued treatment for 24 weeks. One patient refused to continue the treatment soon after starting therapies. In seven patients undergoing post-treatment biopsies, NAS (mean [standard deviation]) mildly decreased from 5.29 (0.95) to 4.00 (1.83) without reaching statistical significance (P = 0.078). Histological response was observed in all three obese patients and in only one of four non-obese ones. No significant changes were observed in body mass index, lipid profiles and diabetic control/insulin resistance., Conclusion: In NASH patients who received HPE treatment, significant reductions in serum liver enzymes were obtained after 8 weeks. Histological efficacy may be better in obese patients than in non-obese ones., (© 2014 The Japan Society of Hepatology.)

Aim: Some patients with non-alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC) and have higher mortality than others. The evidence causally linking NAFLD to extrahepatic malignancies is scarce. Our aim was to determine the incidence of and risk factors for HCC, extrahepatic cancer and mortality in Japanese patients with biopsy-proven NAFLD., Methods: This retrospective cohort study analyzed outcomes including onset of malignant tumors and death in 312 patients with NAFLD diagnosed by liver biopsy., Results: Of 312 patients, 176 (56.4%) were diagnosed with non-alcoholic steatohepatitis. During a median follow-up period of 4.8 years (range, 0.3-15.8), six patients (1.9%) developed HCC, and 20 (6.4%) developed extrahepatic cancer. Multivariate analysis identified fibrosis stage (≥3; hazard ratio [HR], 12.3; 95% confidence interval [CI], 1.11-136.0; P = 0.041) as a predictor for HCC and type IV collagen 7s (>5 ng/mL; HR, 1.74; 95% CI, 1.08-2.79; P = 0.022) as a predictor for extrahepatic cancer. Eight patients (2.6%) died during the follow-up period. The most common cause of death was extrahepatic malignancy. None died of cardiovascular disease. Multivariate analysis identified type IV collagen 7s (>5 ng/mL; HR, 3.38; 95% CI, 1.17-9.76; P = 0.024) as a predictor for mortality., Conclusion: The incidence of extrahepatic cancer was higher than that of HCC. Severe fibrosis was a predictor for HCC. Patients with NAFLD and elevated type IV collagen 7s levels are at increased risk for extrahepatic cancer and overall mortality., (© 2014 The Japan Society of Hepatology.)

Aim: Growth hormone (GH) deficiency may be associated with histological progression of non-alcoholic fatty liver disease (NAFLD) which includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Insulin-like growth factor 1 (IGF-1) is mainly produced by hepatocytes and its secretion is stimulated by GH. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of IGF-1 in Japanese patients., Methods: Serum samples were obtained in 199 Japanese patients with biopsy-proven NAFLD and in 2911 sex- and age-matched healthy people undergoing health checkups. The serum levels of IGF-1 were measured using a commercially available immunoradiometric assay. The standard deviation scores (SDS) of IGF-1 according to age and sex were also calculated in NAFLD patients., Results: The serum IGF-1 levels in NAFLD patients were significantly lower (median, 112 ng/mL) compared with the control population (median, 121 ng/mL, P < 0.0001). IGF-1 SDS less than -2.0 SD from median were found in 11.6% of 199 patients. NASH patients exhibited significantly lower levels of IGF-1 SDS (n = 130; median, -0.7) compared with NAFL patients (n = 69; median, -0.3; P = 0.026). The IGF-1 SDS values decreased significantly with increasing lobular inflammation (P < 0.001) and fibrosis (P < 0.001). In multiple regressions, the association between the IGF-1 SDS values and the severity of NAFLD persisted after adjusting for age, sex and insulin resistance., Conclusion: Low levels of circulating IGF-1 may have a role in the development of advanced NAFLD, independent of insulin resistance. Supplementation with GH/IGF-1 may be a candidate for the treatment of NASH., (© 2014 The Japan Society of Hepatology.)

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various non-invasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 through January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan., (© 2015 The Japan Society of Hepatology.)

Serum ferritin was recently reported to have low diagnostic accuracy for the detection of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). To corroborate these findings, we investigated the diagnostic accuracy of serum ferritin levels for detecting liver fibrosis in NAFLD patients utilizing a large Japanese cohort database. A total 1201 biopsy-proven NAFLD patients, seen between 2001 and 2013, were enrolled into the Japan Study Group of NAFLD. Analysis was performed on data from this cohort comparing between serum ferritin levels and hepatic histology. Serum ferritin increased with increasing histological grade of steatosis, lobular inflammation and ballooning. Multivariate analyses revealed that sex differences, steatotic grade and fibrotic stage were independently associated with serum ferritin levels (P < 0.0001, <0.0001, 0.0248, respectively). However, statistical analyses performed using serum ferritin levels demonstrated that the area under the receiver-operator curve for detecting fibrosis was not adequate for rigorous prediction. Several factors including sex differences, steatosis and fibrosis were found to correlate with serum ferritin levels. Therefore, serum ferritin may have low diagnostic accuracy for specifically detecting liver fibrosis in NAFLD patients due to the involvement of multiple hepatocellular processes., (© 2014 The Japan Society of Hepatology.)

Aim: Sorafenib is the standard systemic therapy for patients with advanced hepatocellular carcinoma (HCC). We aimed to assess the efficacy and safety of sorafenib therapy in very elderly patients aged 80 years and older with advanced HCC., Methods: In a retrospective multicenter study in Japan, we reviewed 185 patients (median age, 71 years; 82% male; 95% Child-Pugh class A) with advanced HCC who received sorafenib therapy. Data were compared between 24 (13%) patients aged 80 years and older and 161 (87%) patients aged less than 80 years. We used propensity score matching to adjust for differences between the two groups., Results: Median overall survival was 10.6 months in all patients: 11.7 months in patients aged 80 years and older and 10.5 months in those aged less than 80 years. There were no significant differences in overall survival, tumor response, and frequency and severity of drug-related adverse events between patients aged 80 years and older and those aged less than 80 years in both the entire study cohort and the propensity-matched cohort., Conclusion: Sorafenib may be effective and well tolerated, even in patients with advanced HCC who are aged 80 years and older, as well as those aged less than 80 years., (© 2014 The Japan Society of Hepatology.)

Aim: This study examined serum alanine aminotransferase (ALT) levels at first visit and their relationship with long-term normal serum ALT levels in hepatitis C virus (HCV) carriers with persistently normal ALT (PNALT)., Methods: HCV carriers with PNALT were identified as those patients with positivity of serum HCV RNA, ALT levels of 30 IU/L or less over a 12-month period on at least three different occasions, platelet count of more than 15 × 10(4)  μl/mL and body mass index of 30 kg/m(2) or less. Outcome was retrospectively studied in 49 HCV carriers with PNALT, who were followed up for more than 10 years., Results: During the mean follow-up period of 14.7 ± 2.5 years, ALT levels of 30 IU/L or less were preserved in only eight patients (8/49; 16.3%). Among the 17 patients with initial ALT levels of 19 IU/L or less, nine patients remained with ALT levels of 30 IU/L or less after 10 years (9/17; 52.9%). The probability of ALT levels in PNALT being maintained at 30 IU/L or less was significantly higher (P = 0.001) in these patients than in those with initial ALT levels of 20 IU/L or more (n = 32). Abnormal ALT levels were more common in female PNALT patients aged 45-55 years, which is usually the time of menopause onset., Conclusion: Because antiviral therapy in the treatment of chronic hepatitis C is rapidly advancing, waiting for more effective and safer treatments may be an option. The results of this study provide an important insight into this issue., (© 2012 The Japan Society of Hepatology.)

Aim:   Choline is a dietary component that is crucial for normal cellular function. Choline is predominantly absorbed from the small intestine and completely metabolized in the liver. We recently demonstrated that free choline (fCh) levels in blood reflect the level of phosphatidylcholine synthesis in the liver and is correlated with the onset of non-alcoholic steatohepatitis (NASH). Our aim here was to validate the utility of this biomarker for NASH diagnosis., Methods:   Our cohort consisted of 110 patients with biopsy proven non-alcoholic fatty liver disease (NAFLD) from four centers across Japan and 25 age-matched healthy controls. Plasma fCh levels were measured using high-performance liquid chromatography., Results:   Patients with diagnosed or borderline NASH had significantly increased plasma fCh levels when compared with control subjects, or patients not diagnosed with NASH. Interestingly, an association between plasma fCh levels and expression of microsomal triglyceride transfer protein, which catalyzes the transfer of triglyceride, was reflected in the markedly negative correlation between these two variables in patients with NAFLD. Moreover, the grade of liver steatosis and fibrosis stage increased with increasing plasma fCh levels (P < 0.05). The area under the receiver-operating characteristic (ROC) curves for NASH, including borderline diagnosis, was 0.811. Additionally, the areas under the ROC for fibrosis stage were 0.816 for >stage 1, 0.805 for >stage 2, 0.809 for >stage 3 and 0.818 for >stage 4., Conclusion:   Plasma fCh levels are closely related to the grade of liver steatosis and fibrosis, and predict NASH severity. Plasma fCh levels are therefore a potential diagnostic marker for early-stage NASH in clinical practice., (© 2012 The Japan Society of Hepatology.)

Aim:   Hepatic steatosis is one of the factors limiting the virological response to interferon-based antiviral therapy for chronic hepatitis C (CH-C) patients infected with genotype 1, while contradictory results have been reported for genotype 2. We aimed to clarify the effect of hepatic steatosis on therapeutic outcome and cumulative positivity of serum HCV RNA in CH-C patients infected with genotype 2 treated by peginterferon (PEG-IFN)α2b and ribavirin (RBV) combination therapy., Methods:   A total of 74 treatment-naïve non-cirrhotic CH-C patients infected with genotype 2 who received PEG-IFNα2b and RBV according to the standard regimen were divided into hepatic steatosis 0-10% and >10% groups. The clinical backgrounds, sustained virological response (SVR) rates and cumulative positivity of serum HCV RNA were compared between the two groups., Results:   Among the 74 patients, 61 (82.4%) had hepatic steatosis 0-10% and 13 (17.6%) had hepatic steatosis >10%. Scores of homeostasis model assessment-insulin resistance and hepatic fibrosis were higher in patients with hepatic steatosis >10% than hepatic steatosis 0-10% (P = 0.040 and 0.042, respectively). Non-SVR was more frequent in patients with hepatic steatosis >10% than hepatic steatosis 0-10% (P = 0.003). Cumulative positivity of serum HCV RNA was significantly higher in patients with hepatic steatosis >10% than hepatic steatosis 0-10% (P = 0.004)., Conclusions:   In CH-C patients infected with genotype 2 treated by PEG-IFNα2b and RBV combination therapy, hepatic steatosis >10% was associated with increased insulin resistance, advanced hepatic fibrosis and higher cumulative positivity of serum HCV RNA, which lead to a higher risk of non-SVR., (© 2011 The Japan Society of Hepatology.)

Aim:   The biological basis of variability in histological progression of non-alcoholic fatty liver disease (NAFLD) remains unknown. Dehydroepiandrosterone (DHEA), the most abundant steroid hormone, has been shown to influence sensitivity to reactive oxygen species, insulin sensitivity and expression of peroxisome proliferator-activated receptor-α. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA in Japanese patients., Methods:   Serum samples were obtained in 133 Japanese patients with biopsy-proven NAFLD and in 399 sex- and age-matched healthy people undergoing health checkups. Serum levels of sulfated DHEA (DHEA-S) were measured by chemiluminescent enzyme immunoassay., Results:   Serum DHEA-S levels in NAFLD patients were similar to those in the control group. Of 133 patients, 90 patients were diagnosed as non-alcoholic steatohepatitis (NASH): 73 patients had stage 0-2, and 17 had stage 3 or 4. Patients with advanced NAFLD (NASH with fibrosis stage 3 or 4) had lower plasma levels of DHEA-S than patients with mild NAFLD (simple steatosis or NASH with fibrosis stage 0-2). The area under the receiver operating characteristic curve for DHEA in separating patients with and without advanced fibrosis was 0.788. A "dose effect" of lower DHEA-S and incremental fibrosis stage was observed with a mean DHEA-S of 170.4 ± 129.2, 137.6 ± 110.5, 96.2 ± 79.3, 61.2 ± 46.3 and 30.0 ± 32.0 µg/dL for fibrosis stages 0, 1, 2, 3, and 4, respectively. The association between DHEA-S and severity of NAFLD persisted after adjusting for age, sex and insulin resistance., Conclusion:   Low circulating DHEA-S might have a role in the development of advanced NASH.

Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of clinical entities ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) with possible evolution to cirrhosis and hepatocellular carcinoma. Iron is considered a putative element that interacts with oxygen radicals in inducing liver damage and fibrosis. The role of hepatic iron in the progression of NASH remains controversial, but in some patients, iron may have a role in the pathogenesis of NASH. Though genetic factors, insulin resistance, dysregulation of iron-regulatory molecules, erythrophagocytosis by Kupffer cells may be responsible for hepatic iron accumulation in NASH, exact mechanisms involved in iron overload remain to be clarified. Iron reduction therapy such as phlebotomy or dietary iron restriction may be promising in patients with NASH/NAFLD to reduce insulin resistance as well as serum transaminase activities.

Aim: The mechanisms by which metabolic disorders develop in patients with chronic hepatitis C are unknown. Our study aimed to test whether oxidative stress contributes to these mechanisms., Methods: The index of homeostasis model assessment-insulin resistance (HOMA-IR) and serum and hepatic levels of thioredoxin (Trx), which are markers of oxidative stress, were evaluated in 203 biopsy-proven chronic hepatitis C patients with hepatitis C virus (HCV) genotype 1 or 2 infection. HOMA-IR and Trx levels were compared with baseline values after phlebotomy in 23 patients., Results: HOMA-IR and serum Trx levels were significantly correlated with disease stage (HOMA-IR, P < 0.00001; Trx, P < 0.0001) and independently predicted fibrosis scores (HOMA-IR, P < 0.05; Trx, P < 0.005). Steatosis (%) was significantly correlated with HOMA-IR (P < 0.00005) and Trx (P < 0.001) stage (P < 0.00001). Serum Trx levels were significantly correlated with HOMA-IR (P < 0.05), even after adjustment for body mass index (P < 0.05). Furthermore, the mRNA levels of hepatic Trx were significantly correlated with HOMA-IR (P < 0.05) and independently-predicted HOMA-IR (P < 0.05). The alanine aminotransferase (P < 0.00001), Trx (P < 0.05), and HOMA-IR (P < 0.05) serum levels decreased significantly after phlebotomy; these effects were similar even in non-responders to interferon., Conclusion: Oxidative stress contributed to the development of IR irrespective of obesity in patients with HCV genotype 1 or 2 infection. This study could contribute to our understanding of how metabolic disorders develop and how they should be treated in chronic hepatitis C patients.

Background/aim: Insulin resistance and hepatic iron overload are frequently demonstrated in hepatitis C virus (HCV)-related liver diseases. We investigated the relationship between insulin resistance and hepatic iron deposition in patients with chronic HCV infection., Methods: Insulin resistance was evaluated using the homeostasis model assessments for insulin resistance (HOMA-IR) in 56 non-diabetic non-obese patients with biopsy proven chronic hepatitis C. The relationship between insulin resistance and serum ferritin levels or the grade of hepatic iron deposition was assessed., Results: The levels of plasma immunoreactive insulin (IRI) and HOMA-IR were significantly correlated with serum ferritin levels and the grade of hepatic iron deposition (P = 0.003).Although IRI and HOMA-IR increased in parallel with the development of hepatic fibrosis, insulin resistance (HOMA-IR > 2) was observed in 11 (26.2%) of 42 patients even without severe fibrosis (F0-2). Among patients without severe fibrosis, IRI and HOMA-IR were significantly higher in patients with iron deposits than in those without iron deposits., Conclusion: Hepatic iron overload may be associated with insulin resistance in patients with chronic hepatitis C, especially in patients with mild to moderate fibrosis.

Aims: The present study was aimed at determining the predictors of hepatic steatosis and fibrosis in Japanese patients with chronic hepatitis C., Methods: The relationship between the degrees of hepatic steatosis or fibrosis and several clinical parameters was evaluated using univariate and multivariate analyses., Results: Steatosis was observed in 117 out of 184 patients (64%), including 45 patients (25%) with grade 1 (<10% of hepatocytes affected), 56 patients (30%) with grade 2 (10-30%), 12 patients (7%) with grade 3 (30-50%), and four patients (2%) with grade 4 (>50%). In the multivariate analysis, body mass index (BMI) (P = 0.0038) and serum ferritin (P < 0.0001) were selected as independent predictors of hepatic steatosis. Six of the 184 patients (3%) had stage 0 fibrosis (no fibrosis), 87 patients (47%) had stage 1, 55 patients (30%) had stage 2 and 36 patients (20%) had stage 3. In the multivariate analysis, platelet count (P = 0.0012), aspartate aminotransferase (AST) (P = 0.0219), hyaluronic acid (P < 0.0001) and the grade of steatosis (P = 0.0008) were selected as independent predictors of hepatic fibrosis., Conclusion: Obesity and iron storage, as evaluated by BMI and serum ferritin level, respectively, have important roles in the pathogenesis of hepatic steatosis, which is a factor responsible for the development of hepatic fibrosis in Japanese patients with chronic hepatitis C.

Increased hepatic iron deposition may play a role in the pathogenesis of nonalcoholic steatohepatitis (NASH). This study aimed to test whether iron removal by phlebotomy improves serum transaminase activities in patients with NASH. Eleven patients (six males and five females) with biopsy-proven NASH underwent phlebotomy biweekly until they reached near-iron deficiency (NID) (serum ferritin concentration lower than or equal to 30ng/ml). Nine patients completed this study. Serum ferritin levels in these patients fell from 563+/-322 to 18+/-9ng/ml (p=0.001). The treatment reduced mean serum alanine aminotransferase (ALT) activity from 126+/-47 to 56+/-17IU/l (p=0.002). Their weight did not change significantly throughout the study period. Although two patients withdrew from the study, none was affected by any side effects of repeated phlebotomy that required discontinuing the treatment. In conclusion, this pilot study suggests that iron reduction therapy by phlebotomy will be one of the promising therapies for NASH.

Thioredoxin (TRX) is induced by many oxidative stresses. Serum TRX levels were significantly elevated in nonalcoholic steatohepatitis (NASH) patients, as compared to simple fatty liver (FL) patients or healthy controls. Serum TRX levels in NASH patients were significantly correlated with serum ferritin levels, but not with other variables. Removal of hepatic excess iron by phlebotomy significantly decreased the serum levels of TRX and ALT in NASH patient. Therefore, the pathogenesis of NASH may be associated with iron-related oxidative stress. The serum TRX level is a parameter for discriminating NASH from FL.

Nitroxide radicals (nitroxides) are reduced to the corresponding hydroxylamines and lose their electron spin resonance (ESR) signals, but these hydroxylamines are easily reoxidized to nitroxides and regain the ESR signals. In the present study the effects of nitric oxide (NO) on the reduction/oxidation (redox) status of hepatic microsomes were investigated by ESR spectroscopy using nitroxide probes. Rat hepatic microsomes were treated with an NO donor, NOR3 or NOC7, and then labeled with a water-soluble nitroxide, 2,2,6,6-tetramethyl-4-hydroxy-1-piperidinyloxy (Tempol), or a lipid-soluble nitroxide, 5-doxyl stearic acid (5-DSA). The reduction of Tempol was facilitated under hypoxic conditions in control microsomes. In NOR3 or NOC7-treated microsomes, the reduction of Tempol and the reoxidation of the corresponding hydroxylamine hardly occurred under both normoxic and hypoxic conditions. The ESR signals of 5-DSA changed just as those of Tempol did in control and NO-treated microsomes. The concentrations of total thiol and cytochrome P-450, and the activity of mixed function amine oxidase were reduced in NOR3 or NOC7-treated microsomes. In conclusion, NO affects not only the reduction of nitroxides but also the oxidation of hydroxylamines in hepatic microsomes, suggesting that the microsomal capability of redox regulation was lost by NO.