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Aims: Hepatocellular carcinoma (HCC) develops even in patients with hepatitis C virus (HCV) eradication by direct-acting antiviral agents. Fatty liver and metabolic dysfunction are becoming major etiologies of HCC. We aimed to evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), a new definition of steatotic liver disease, on the development of HCC after HCV eradication., Methods: We enrolled 1280 elderly patients with HCV eradication and no history of HCC. We evaluated α-fetoprotein (AFP), Fibrosis-4 index and MASLD after 24 weeks of sustained virological response. Decision tree analysis was used to investigate factors associated with HCC development after HCV eradication., Results: A total of 86 patients (6.7%) developed HCC during the follow-up period (35.8 ± 23.7 months). On multivariate analysis, serum AFP level (HR 1.08, CI 1.04-1.11, P = 0.0008), Fibrosis-4 index (HR 1.17, CI 1.08-1.26, P = 0.0007), and MASLD (HR 3.04, CI 1.40-6.58, P = 0.0125) at 24 weeks of sustained virological response were independent factors associated with HCC development. In decision tree analysis, the initial classifier for HCC development was AFP ≥7 ng/mL. However, in patients with AFP <7 ng/mL, MASLD, rather than Fibrosis-4 index, was the classifier for HCC development. No significant difference was observed in the cumulative incidence of HCC between patients with AFP ≥7 ng/mL and patients with AFP <7 ng/mL and MASLD., Conclusion: MASLD at 24 weeks of sustained virological response is a risk factor for HCC development in elderly patients with HCV eradication. Additionally, decision tree analysis revealed that MASLD was associated with HCC development, even in patients with serum AFP levels <7 ng/mL., (© 2023 Japan Society of Hepatology.)

Aim: Metabolic dysfunction is a risk factor for esophageal squamous cell carcinoma (ESCC). We investigated the impact of the recently proposed metabolic dysfunction-associated fatty liver disease (MAFLD) and its subtypes on ESCC recurrence after endoscopic treatment., Methods: This multicenter observational cohort study enrolled consecutive patients newly diagnosed with ESCC after endoscopic treatment. Patients were classified into MAFLD or non-MAFLD groups. The MAFLD group was further classified into non-obese and obese MAFLD groups with a body mass index cutoff value of 25 kg/m 2 . The impact of MAFLD on the recurrence of ESCC was evaluated using a decision tree algorithm and random forest analysis., Results: A total of 147 patients (average age 69 years; male : female, 127:20; observational period, 2.4 years) were enrolled. The 1-, 3-, and 5-year recurrence rates were 2.0%, 21.1%, and 33.7%, respectively. Independent risk factors for the recurrence of ESCC were MAFLD (HR 2.2812; 95% confidence interval 1.0497-4.9571; p = 0.0373), drinking status, and smoking status. Metabolic dysfunction-associated fatty liver disease was identified as the second most important classifier for recurrence, followed by drinking status. The cumulative incidence of ESCC recurrence was higher in the MAFLD group than in the non-MAFLD group. In a subanalysis, the cumulative incidence of recurrence was significantly higher in the non-obese than in the obese MAFLD group among abstainers/non-drinkers. Directed acyclic graphs revealed that MAFLD directly contributes to ESCC recurrence., Conclusions: MAFLD was independently and directly associated with ESCC recurrence after endoscopic treatment; a high recurrence rate was observed in patients with non-obese MAFLD. Metabolic dysfunction-associated fatty liver disease may identify patients at high risk for ESCC recurrence., (© 2023 Japan Society of Hepatology.)

The fifth version of the Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine and partly to the Grading of Recommendations Assessment, Development and Evaluation system, which was published in October 2021 in Japanese. In addition to surveillance-diagnostic and treatment algorithms, a new algorithm for systemic therapy has been created, as multiple drugs for hepatocellular carcinoma can be currently selected. Here, new or revised algorithms and evidence on which the recommendations are based are described., (© 2023 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aim: Lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Metabolic dysfunction-associated fatty liver disease (MAFLD) is becoming a major etiology of HCC. We aimed to evaluate the impact of MAFLD on the efficacy of lenvatinib., Methods: We enrolled 320 patients with HCC who were treated with lenvatinib. All patients were classified into the MAFLD (n = 155) and non-MAFLD (n = 165) groups. Independent factors for overall survival (OS) were analyzed. In the stratification analysis, HCC was categorized as non-viral (n = 115) or viral HCC (n = 205)., Results: The OS rate was significantly higher in the MAFLD group than in the non-MAFLD group (median 21.1 vs. 15.1 months, p = 0.002). Multivariate analysis demonstrated that, in addition to albumin-bilirubin grade and Barcelona Clinic Liver Cancer stage, MAFLD was identified as an independent factor for OS (HR 0.722, 95% CI 0.539-0.966, p = 0.028). In the stratification analysis, the OS rate was significantly higher in the MAFLD group than in the non-MAFLD group among patients with non-viral HCC (median 21.1 vs. 15.1 months, p = 0.002), but not in patients with viral HCC. Furthermore, MAFLD was an independent negative risk factor for OS in patients with non-viral HCC (HR 0.506, 95% CI 0.297-0.864, P < 0.01). However, MAFLD was not an independent factor for OS in patients with viral HCC., Conclusions: MAFLD was a beneficial factor for survival in patients with HCC treated with lenvatinib. Moreover, the better OS of the MAFLD group was more pronounced in patients with non-viral HCC. Lenvatinib may be a suitable agent for patients with non-viral HCC and MAFLD., (© 2022 Japan Society of Hepatology.)

Aim: Reflux esophagitis is associated with metabolic dysfunction. Recently, fatty liver has been redefined as metabolic dysfunction-associated fatty liver disease (MAFLD). We investigated the impact of MAFLD and its subtypes on the incidence of reflux esophagitis., Methods: This multicenter, observational cohort study enrolled 9100 consecutive health-check examinees who underwent esophagogastroduodenoscopy and ultrasonography. All patients were classified into the MAFLD or non-MAFLD group. Based on the Asian cut-off value for body mass index (BMI), the MAFLD group was further classified into the lean/normal-weight (BMI <23 kg/m 2 ) and overweight/obese (BMI ≥23 kg/m 2 ) subgroups. The impact of MAFLD and its subtypes on the cumulative incidence of reflux esophagitis was evaluated using multivariable Cox proportional hazards regression analysis., Results: MAFLD was diagnosed in 26.5% (2416/9100) of patients. Multivariable Cox proportional hazards regression analysis indicated that MAFLD (hazard ratio [HR] 1.2183; 95% confidence interval [CI] 1.0954-1.3550; p = 0.0003), hiatal hernia, and aging were independent risk factors for reflux esophagitis. Stratification analysis indicated that cumulative incidence of reflux esophagitis among patients with MAFLD was significantly higher in the lean/normal-weight than in the overweight/obese group (HR 1.3274; 95% CI 1.0043-1.7547; p = 0.0466). Among various metabolic factors, visceral adiposity was the only independent metabolic risk factor for reflux esophagitis (HR 2.8331; 95% CI 1.0201-7.8691; p = 0.0457) in the lean/normal-weight MAFLD group., Conclusions: MAFLD, in particular lean/normal-weight MAFLD, is independent risk factor for reflux esophagitis. Furthermore, visceral adiposity was identified as the most strong metabolic risk factor for reflux esophagitis in lean/normal-weight patients with MAFLD., (© 2022 Japan Society of Hepatology.)

Recently, international expert panels have proposed a new definition of fatty liver: metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD is not just a simple renaming of non-alcoholic fatty liver disease (NAFLD). The unique feature of MAFLD is the inclusion of metabolic dysfunctions, which are high-risk factors for events. In addition, MAFLD is independent of alcohol intake and the co-existing causes of liver disease. This new concept of MAFLD may have a widespread impact on patients, medical doctors, medical staff, and various stakeholders regarding fatty liver. Thus, MAFLD may renovate clinical practice and disease awareness of fatty liver. In this review, we introduce the definition of and rationale for MAFLD. We further describe representative cases showing how the diagnostic processes differ between MAFLD and NAFLD. We also summarize recent studies comparing MAFLD with NAFLD and discuss the impact of MAFLD on clinical trials, Japanese populations, and disease awareness., (© 2021 Japan Society of Hepatology.)

Introduction: Portopulmonary hypertension (PoPH) is a severe complication of chronic liver disease. We aimed to investigate the etiology of chronic liver disease and the factors associated with the severity of PoPH., Subjects and Methods: Echocardiography was undergone in 833 patients with chronic liver disease during 2005-2019 and 13 patients (1.6%) were diagnosed with PoPH in this observational study. At the diagnosis of PoPH, liver function was evaluated by albumin-bilirubin (ALBI) score. Severe PoPH was defined as (1) mean pulmonary arterial pressure (mPAP) ≥50 mmHg or (2) mPAP: 35-49 mmHg and pulmonary vascular resistance ≥400 dyne/s/cm 5 . Factors associated with severe PoPH were evaluated by decision-tree analysis., Results: In patients with PoPH, the leading etiology of chronic liver disease was hepatitis C virus (HCV) (46.2% [sustained virological response (SVR): 23.1% and non-SVR: 15.4%]). Severe PoPH was observed in 53.8% of patients and the 5-year survival rate was 48.1%. There was a significant correlation of mPAP with ALBI score (r = 0.6456, p = 0.0171). In the decision-tree and random forest analyses, the most impacted classifier for severe PoPH was the ALBI score. In patients with ALBI score ≥-1.45, all patients showed severe PoPH, while the prevalence of severe PoPH was 25.0% in patients with ALBI score <-1.45., Conclusions: We found that HCV including SVR was the major etiology of chronic liver disease in patients with PoPH. Moreover, we revealed that the ALBI score was the most impacted factor associated with severe PoPH. Thus, ALBI score may be useful for the estimation of pulmonary vascular resistance., (© 2021 Japan Society of Hepatology.)

Thrombocytopenia is highly prevalent in patients with chronic liver disease (CLD) and these patients often require invasive procedures that carry a risk of bleeding. To prevent bleeding, guidelines recommend increasing platelet counts in patients with CLD who have thrombocytopenia and are planned to undergo invasive procedures. There are currently two options to increase platelet counts in patients in this setting: platelet transfusion or thrombopoietin receptor agonists (TPORAs). Several treatment algorithms have been developed in the US to help physicians choose the best course of treatment for each patient; however, to date, no such algorithm has been proposed in other countries, where the choice of treatment has been based on each physician's judgment and experience. Here, we discuss the pathogenesis and treatment of thrombocytopenia in patients with CLD, we review and present current evidence of the efficacy of TPORAs for the treatment of thrombocytopenia in patients with CLD, and we present our expert opinion on a Japanese treatment algorithm for thrombocytopenia in patients with CLD who are planned to undergo invasive procedures. This algorithm aims to provide guidance for optimal decision making in the selection of TPORA therapy or platelet transfusion based on the latest evidence and according to actual clinical practice., (© 2021 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Background: Advanced Hepatocarcinoma (HCC) is an important health problem worldwide. Recently, the REFLECT trial demonstrated the non-inferiority of Lenvatinib compared to Sorafenib in I line setting, thus leading to the approval of new first-line standard of care, along with Sorafenib., Aims and Methods: With aim to evaluate the optimal choice between Sorafenib and Lenvatinib as primary treatment in clinical practice, we performed a multicentric analysis with the propensity score matching on 184 HCC patients., Results: The median overall survival (OS) were 15.2 and 10.5 months for Lenvatinib and Sorafenib arm, respectively. The median progression-free survival (PFS) was 7.0 and 4.5 months for Lenvatinib and Sorafenib arm, respectively. Patients treated with Lenvatinib showed a 36% reduction of death risk (p = 0.0156), a 29% reduction of progression risk (p = 0.0446), a higher response rate (p < 0.00001) and a higher disease control rate (p = 0.002). Sorafenib showed to be correlated with more hand-foot skin reaction and Lenvatinib with more hypertension and fatigue. We highlighted the prognostic role of Barcelona Clinic Liver Cancer (BCLC) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), bilirubin, alkaline phosphatase and eosinophils for Sorafenib. Conversely, albumin, aspartate aminotransferase (AST), alkaline phosphatase and Neutrophil-Lymphocyte Ratio (NLR) resulted prognostic in Lenvatinib arm. Finally, we highlighted the positive predictive role of albumin > Normal Value (NV), ECOG > 0, NLR < 3, absence of Hepatitis C Virus positivity, and presence of portal vein thrombosis in favor of Lenvatinib arm. Eosinophil < 50 and ECOG > 0 negatively predicted the response to Sorafenib., Conclusion: SLenvatinib showed to better perform in a real-word setting compared to Sorafenib. More researches are needed to validate the predictor factors of response to Lenvatinib rather than Sorafenib., (© 2021 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aim: Metabolic associated fatty liver disease (MAFLD) partly overlaps with non-alcoholic fatty liver disease (NAFLD). Thus, using a generalized estimating equation (GEE) approach, we aimed to investigate the difference in worsening of atherosclerotic cardiovascular disease (ASCVD) risk between patients with MAFLD and NAFLD. We also investigated factors related to the difference between the two groups., Methods: We enrolled 2306 subjects with fatty liver (MAFLD 80.7%, NAFLD 63.4%). Subjects with MAFLD/NAFLD were sub-classified into three groups: NAFLD with no metabolic dysfunction (non-Met NAFLD), overlapping, and MAFLD with moderate alcohol consumption (mod-Alc MAFLD). ASCVD risk was estimated by non-invasive tests, including the Suita score. An event was defined as worsening of these scores from the low-risk to the high-risk group. Independent factors for the event were analyzed by Cox regression analysis with the GEE., Results: In Cox regression analysis, MAFLD (HR 1.08, 95% CI 1.02-1.15, p = 0.014) and alcohol consumption (20-39 g/day; HR 1.73, 95% CI 1.26-2.36, p = 0.001) were independently associated with worsening of the Suita score. In a subanalysis, the incidence of the event was significantly lower in non-Met NAFLD than in the overlapping group (HR 0.70, 95% CI 0.50-0.98, p = 0.042). However, no significant difference was observed in the incidence between the overlapping and mod-Alc MAFLD group (HR 1.19, 95% CI 0.89-1.58, p = 0.235)., Conclusions: The GEE approach demonstrates that MAFLD better identifies patients with worsening of ASCVD risk than NAFLD. Moreover, the superiority of MAFLD over NAFLD was due to the presence of metabolic dysfunction rather than moderate alcohol consumption., (© 2021 The Japan Society of Hepatology.)

Aims: Exercise is effective for the prevention of liver cancer. Exercise exerts biological effects through the regulation of microRNAs (miRNAs) and cytokines/myokines. We aimed to investigate the effects of low-intensity resistance exercise on serum miRNA and cytokine/myokine expressions in subjects with no exercise habits., Methods: We enrolled seven male subjects with no exercise habits in this prospective before-after study. All subjects performed a low-intensity resistance exercise program (three metabolic equivalents, approximately 20 min/session). Serum miRNA expressions were evaluated using microarrays. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of differentially expressed miRNAs before and after exercise. Serum cytokine/myokine expressions were evaluated using a multiplex panel., Results: All subjects completed the exercise program with no adverse events. In the microarray analysis, seven miRNAs showed a significant change between before and after exercise. Of these, microRNA (miR)-630 and miR-5703 showed a >1.5-fold increase (miR-630: 40.7 vs. 69.3 signal intensity, p = 0.0133; miR-5703: 30.7 vs. 55.9 signal intensity, p = 0.0051). KEGG pathway enrichment analysis showed that miR-630- and miR-5703-related genes were enriched in 37 and 5 pathways, including transforming growth factor-beta and Wnt signaling pathways, respectively. In the multiplex analysis, 12 cytokines/myokines showed significant alteration after exercise compared to before exercise. Of these, fractalkine/CX3CL1 showed the most significant up-regulation by exercise (94.5 vs. 109.1 pg/ml, p = 0.0017)., Conclusions: A low-intensity resistance exercise program was associated with upregulation of serum miR-630, miR-5703, and fractalkine/CX3CL1 expressions in subjects with no exercise habits. Thus, even low-intensity exercise may alter miRNA and cytokine/myokine expressions in humans., (© 2021 The Japan Society of Hepatology.)

This contingency guide was formulated on the premise that delivering standard treatment for hepatocellular carcinoma (HCC) has come under strain due to the coronavirus (COVID-19) pandemic. Measures required are likely to vary largely across regions and individual institutions, depending on the level of the strain imposed by the pandemic (e.g., number of inpatients infected with COVID-19 and the availability of resources, including personal protective equipment and inpatient beds). In addition, models suggest that the second and third waves of COVID-19 will occur before effective vaccines and medicines become widely available in Japan (expected time, 2-3 years). This guide should serve as a good reference for best practices in the management of HCC, which is in light of the possible risk of impending collapse of the healthcare system due to a surge in COVID-19 infections., (© 2020 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aim: Muscle atrophy is a prognostic factor for patients with chronic liver disease (CLD) and hepatocellular carcinoma (HCC). The Liver Frailty Index (LFI) is a simple physical function test; however, an association between LFI and muscle mass remains unclear. We aimed to investigate the utility of LFI for predicting muscle atrophy in CLD patients with HCC., Methods: We enrolled 138 CLD patients with HCC (aged 77 years, female/male 34.8%/65.2%). Muscle mass was assessed by skeletal muscle index, and patients were classified into the muscle atrophy group (n = 109) or the non-muscle atrophy group (n = 29). Physical frailty was assessed by LFI. The optimal cut-off value of LFI for predicting muscle atrophy was identified by receiver operating characteristic analysis., Results: In the muscle atrophy group, the prevalence of pre-frail/frail was significantly higher than the non-muscle atrophy group (87.2% vs. 58.6%, P = 0.0005). In the logistic regression analysis, being female and pre-frail/frail were identified as independent factors associated with muscle atrophy (pre-frail/frail; OR 3.601, 95% CI 1.381-9.400, P = 0.0088). In patients with normal grip strength, 71.1% of patients were pre-frail/frail, in which 82.8% of patients showed muscle atrophy. Receiver operating characteristic statistics provided an area under the curve of 0.74, and an LFI cut-off value of 2.94 for predicting muscle atrophy (sensitivity 88.06%, specificity 52.17%, accuracy 77.91%)., Conclusions: We showed that pre-frail/frail was an independent factor for muscle atrophy in CLD patients with HCC. Furthermore, LFI predicted muscle atrophy with high sensitivity, even in patients with normal grip strength. Thus, LFI might be a useful screening tool for muscle atrophy in CLD patients with HCC., (© 2019 The Japan Society of Hepatology.)

Aim: Advanced hepatic fibrosis is seen in individuals with potential hepatocellular carcinoma and cardiovascular disease. Hepatic fibrosis can be assessed using a combination of the FIB-4 index and imaging modalities, including shear wave elastography. We aimed to investigate the prevalence of advanced fibrosis in the general population and the profiles associated with advanced fibrosis using a data-mining analysis., Methods: We enrolled 1155 health checkup examinees (median age 53 years, 685 women, 470 male). Advanced fibrosis was defined by FIB-4 index ≥1.3 and liver stiffness ≥8.07 kPa using shear wave elastography. Participants were classified as normal-mild fibrosis (n = 1035) or advanced fibrosis (n = 120). Factors associated with advanced fibrosis were analyzed by logistic regression and decision-tree analyses., Results: Advanced fibrosis was observed in 10.4% of participants (120/1155). In the logistic regression analysis, independent factors for advanced fibrosis were age (≥75 years; OR 2.12, 95% CI 1.021-4.415; P = 0.0419) and the presence of metabolic syndrome (OR 2.51, 95% CI 1.416-4.462; P = 0.0017). The decision-tree analysis showed two profiles associated with advanced fibrosis: profile 1 - individuals aged ≥65 years with metabolic syndrome and mild-to-moderate alcohol consumption (prevalence of advanced fibrosis 73.3%); and profile 2 - individuals without metabolic syndrome, aged ≥75 years, with no exercise habit (prevalence of advanced fibrosis 56.3%)., Conclusions: Advanced fibrosis was observed in 10.4% of health checkup examinees. Furthermore, we showed that aging, metabolic syndrome with mild-to-moderate alcohol consumption, and physical inactivity were associated with advanced fibrosis. Thus, prevention of metabolic syndrome and alcohol withdrawal, as well as exercise habits, might inhibit the progression of hepatic fibrosis., (© 2019 The Japan Society of Hepatology.)

Juvenile hemochromatosis (JH) is known as a progressive iron-storage disease, and causes severe organ impairments, including cardiomyopathy and liver cirrhosis. However, JH is a rare genetic disorder, and information for genetic mutations and phenotypes is limited. Here, we report a case of JH with heterozygous p.Y150C and p.V274M mutations in the HJV gene. A 39-year-old Japanese man was referred to Kurume University Hospital, Kurume, Japan, for fatigue and liver injury, which first appeared at the age of 25 years. There was no history of alcohol abuse and medication, and viral hepatitis, autoimmune liver diseases, and Wilson's disease were absent. However, transferrin saturation, serum ferritin, and fasting serum hepcidin levels were 98.4%, 6421 ng/mL, and 7.4 ng/mL, respectively. Furthermore, a marked reduction in signal intensity of the liver in T1/T2-weighted magnetic resonance images was seen and the R2* maps showed hepatic iron overload. Family history of hemochromatosis and severe organ impairment, such as cardiac dysfunction and diabetes mellitus, were negative. In addition, the HFE and HAMP genes did not show any mutation. However, we identified novel heterozygous p.Y150C and p.V274M mutations in the HJV gene in the patient. The p.Y150C and p.V274M mutations were seen in his mother and father, respectively. After phlebotomy, fatigue disappeared and serum transaminase levels were normalized. Furthermore, R2* maps showed a reduction of hepatic iron concentration. We first demonstrated heterozygous p.Y150C and p.V274M mutations in the HJV gene of patients with a mild JH phenotype. Thus, genetic testing should be considered even in patients with a mild phenotype of hemochromatosis., (© 2019 The Japan Society of Hepatology.)

Aim: Walking speed and grip strength are parameters of muscle function; however, evaluating walking speed is not always available in clinical practice. We aimed to investigate the impact of walking speed on the evaluation of muscle dysfunction in chronic liver disease (CLD) patients with hepatocellular carcinoma (HCC)., Methods: We enrolled 107 consecutive CLD patients with HCC in this study (age 76 years [range 60-92 years]; female/male 39/68; body mass index 22.9 [range 20.0-25.3]; chronic hepatitis/liver cirrhosis 25/82). Muscle dysfunction was evaluated using the Asian Working Group for Sarcopenia criteria (grip strength or walking speed) and the Japan Society of Hepatology criteria (grip strength). A correlation between walking speed and skeletal muscle index was evaluated. Independent factors for slow walking speed were evaluated using a logistic regression analysis., Results: There was no significant correlation between walking speed and skeletal muscle index (r = 0.14, P = 0.16). For both the Asian Working Group for Sarcopenia and Japan Society of Hepatology criteria, 33.6% of all patients were classified as having muscle dysfunction. All patients with slow walking speed (4.7% of all patients) also showed low handgrip strength. The logistic regression analysis identified grip strength as an independent factor for slow walking speed (OR 0.65; 95% CI 0.432-0.838; P = 0.008)., Conclusions: No difference was seen in the prevalence of muscle dysfunction between the Asian Working Group for Sarcopenia and Japan Society of Hepatology criteria in CLD patients with HCC. Furthermore, all patients with slow walking speed also showed low handgrip strength. Thus, for the evaluation of muscle dysfunction, grip strength might be a suitable proxy for walking speed in CLD patients with HCC., (© 2019 The Japan Society of Hepatology.)

The fourth version of Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine and partly to the Grading of Recommendations Assessment, Development, and Evaluation system, which was published in October 2017 in Japanese. New or revised recommendations were described, herein, with a special reference to the surveillance, diagnostic, and treatment algorithms., (© 2019 The Japan Society of Hepatology.)

Aims: We aimed to investigate the impact of interleukin (IL)-34 and YKL-40, regulators of hepatic fibrosis and tumor growth, on the prognosis of patients with non-viral hepatocellular carcinoma (HCC)., Methods: We enrolled 159 non-viral HCC patients (age, 70.8 ± 8.5 years; female/male, 43/116). Of these, 86 patients were alive and 73 patients had died at the censor time point. Serum IL-34 and YKL-40 levels were quantified by enzyme-linked immunosorbent assay. Patients were stratified by the median level of serum IL-34 to examine its effect on survival. Multivariate analysis and random forest analysis were used to evaluate the impact of IL-34 and YKL-40 on the prognosis of non-viral HCC patients., Results: Interleukin-34 (hazard ratio [HR] 1.30; 95% confidence interval [CI], 1.13-1.49; P ≤ 0.01), tumor size (HR 1.63; 95% CI, 1.37-1.94; P ≤ 0.01), and tumor number (HR 1.53; 95% CI, 1.25-1.87; P ≤ 0.01) were independent predictive factors for survival. Furthermore, the survival rates were significantly lower in the high IL-34 group than in the low IL-34 group (5-year survival rates, 34.7% vs. 59.8%, respectively; P < 0.05). In the random forest analysis for survival, IL-34 was the third-highest ranking factor, following tumor size and number. In a stratification analysis, serum α-fetoprotein level and Fibrosis-4 index were independent positive risk factors for high serum IL-34 level. YKL-40 was not associated with prognosis in either the multivariate or random forest analysis., Conclusion: Interleukin-34 was an independent factor for survival of non-viral HCC patients. Interleukin-34 might be associated with prognosis through tumor and hepatic fibrosis factors., (© 2019 The Japan Society of Hepatology.)

Aims: The prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE) is still poor. We aimed to evaluate the impact of TACE combined with radiofrequency ablation (TACE+RFA) on the prognosis of HCC patients using decision-tree analysis after propensity score matching., Methods: This was a retrospective study. We enrolled 420 patients with HCC treated with TACE alone (n = 311) or TACE+RFA (n = 109) between 1998 and 2016 (median age, 72 years; male / female, 272/148; Barcelona Clinic Liver Cancer (BCLC) stage A / B, 215/205). The prognosis of patients who underwent TACE+RFA was compared to patients who underwent TACE alone after propensity score matching. Decision-tree analysis was used to investigate the profile for prognosis of the patients., Results: After propensity score matching, there was no significant difference in age, sex, BCLC stage, or albumin-bilirubin (ALBI) score between both groups. The survival rate of the TACE+RFA group was significantly higher than the TACE alone group (median survival time [MST] 57.9 months vs. 33.1 months, P < 0.001). In a stratification analysis according to BCLC stage, the overall survival rate of the TACE+RFA group was significantly higher than the TACE alone group in BCLC stage A and B (MST 57.9 and 50.7 months vs. 39.8 and 24.5 months [P = 0.007 and 0.001], respectively). Decision-tree analysis showed that TACE+RFA was the third distinguishable factor for survival in patients with α-fetoprotein level >7 ng/mL and ALBI <-2.08., Conclusion: Decision-tree analysis after propensity score matching showed that TACE+RFA could prolong the survival of HCC patients compared to TACE alone., (© 2019 The Japan Society of Hepatology.)

Aim: In order to know the present status of drug-induced liver injury (DILI) in Japan, we present the data of prospectively collected DILI cases between 2010 and 2018 from 27 hospitals., Methods: Drug-induced liver injury cases diagnosed by DILI experts from 27 hospitals all over Japan have been prospectively collected since 2010. Alanine aminotransferase level ≥150 U/L and/or alkaline phosphatase ≥2× upper limit of normal were inclusion criteria., Results: In total, data of 307 cases (125 male and 182 female individuals) aged between 17 and 86 years old were collected. The types of liver injury were as follows: 64% hepatocellular type, 20% mixed type, and 16% cholestatic type. A drug-induced lymphocyte stimulation test was carried out in 59% of cases, and was positive in 48% and semipositive in 3% of cases. Eosinophilia ≥6% was observed in 27% of cases. Fifty-three percent of DILI cases occurred within 30 days and 79% of DILI cases occurred within 90 days after starting drug administration. By the diagnostic scale of the Digestive Disease Week (DDW)-Japan 2004 workshop, 93.8% of cases were diagnosed as "highly probable", and 5.9% as "possible"., Conclusions: Japanese DILI patients are somewhat different from those of Europe and North America. The diagnostic scale of the DDW-Japan 2004 workshop has been used in Japan. However, there are many issues to improve the causality assessment of DILI that we must investigate in the future. It is critical to elucidate the mechanisms of drug metabolism and the pathophysiology of liver injury by various drugs to prevent DILI., (© 2018 The Japan Society of Hepatology.)

Background and Aims: Advanced hepatic fibrosis can occur in patients with various diseases, including diabetes mellitus and hypertension. We aimed to investigate the prevalence and risk factors of advanced hepatic fibrosis in patients with various internal diseases., Patients and Methods: We performed a community-based survey in which 1012 patients were enrolled (mean age, 63.1 ± 10.8 years; female/male, 505/507). Hepatic fibrosis was evaluated by Fib-4 index and patients were classified into high and low Fib-4 groups. Independent factors for the high Fib-4 group were analyzed using logistic regression and decision tree analysis., Results: A high prevalence of high Fib-4 index was observed in patients with cardiovascular diseases; 37.1% of patients with hypertension belonged to the high Fib-4 group. Independent factors associated with the high Fib-4 group were BMI (OR 0.95, 95%CI 0.918-0.989, P < 0.01), male sex (OR 1.35, 95%CI 1.03-1.78, P < 0.05), and hypertension (OR 1.41, 95%CI 1.03-1.92, P < 0.05). In patients with hypertension, a decision tree algorithm revealed three profiles for Fib-4 index: 1) creatinine level < 0.76 mg/dL (high Fib-4; 30.0%), 2) creatinine level ≥ 0.76 mg/dL without sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment (high Fib-4; 48.2%), and 3) creatinine level ≥ 0.76 mg/dL with SGLT2i treatment (high Fib-4; 23.5%)., Conclusions: A high prevalence of advanced hepatic fibrosis was observed in patients with hypertension. Hypertension was an independent risk factor, and creatinine level and SGLT2i were divergence variables for advanced hepatic fibrosis. Thus, hypertension with chronic kidney injury may exacerbate hepatic fibrosis, while SGLT2i treatment may ameliorate hepatic fibrosis., (© 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: The risk of malignancies in autoimmune diseases is high and is regarded to be due to immunological abnormalities, the use of immunosuppressive agents, and/or chronic inflammation. The aim of this study was to investigate the incidence and risk of malignancies in patients with autoimmune hepatitis (AIH) type 1 in Japan., Methods: Two hundred and fifty-six patients diagnosed with AIH were enrolled. A person-year calculation was carried out for AIH patients, and the numbers of expected events were clarified using data from "The Monitoring of Cancer Incidence in Japan Project" in order to examine the standard incident rate (SIR) of each type of malignancy. Biochemical data regarding carcinogenesis and its background factors were also examined., Results: Twenty-seven patients (10.5%) developed malignancies; 11 (4.3%) with hepatobiliary cancer and 16 (6.3%) with extrahepatic malignancies. The overall SIR for malignancies in AIH was significantly high at 2.04 (95% confidence interval [CI], 1.34-2.96), and was high among female patients at 2.49 (95% CI, 1.60-3.71). The SIR for hepatobiliary cancer was 14.14 (95% CI, 7.05-25.30), and was markedly high for female patients at 21.83 (95% CI, 10.45-40.16). The SIR for oral/pharyngeal cancer was significantly high for female patients at 14.61 (95% CI, 1.64-52.77). The risk factors for hepatobiliary cancer at the diagnosis of AIH were low levels of alanine aminotransferase (P = 0.0226), low platelet counts (P < 0.0001), and cirrhosis (P = 0.0004). The risk factor for extrahepatic malignancy was relapse of AIH (P = 0.0485)., Conclusion: The risk of malignancies was generally high among AIH patients. Those with the risk factors of malignancies should be carefully followed up., (© 2017 The Japan Society of Hepatology.)

Aim: Covert hepatic encephalopathy is frequently seen in cirrhotic patients. This condition can be diagnosed by a computerized neuropsychological test system (NPT); however, NPT has not been updated for approximately two decades in Japan. The aim of this study is to update the NPT to be more suitable for both the elderly and modern society by resetting of cut-off values., Methods: We enrolled 367 healthy subjects aged between 40 and 79 years old between 2003 and 2010. The NPT consists of the following eight tests: number connection tests (NCT)-A and -B, a figure position test, a digit symbol test, a block design test, and reaction time tests (RTT)-A, -B, and -C. All subjects were classified into eight groups (5-year quartile ranges from 40 to 79 years old), and the cut-off value for each test was compared to the former cut-off value (NPT version 1)., Results: In all eight tests, most of the cut-off values were different from those in NPT version 1. The difference was minimal in RTT-A, RTT-B, and RTT-C. However, the difference was evident in the NCT-A, NCT-B, digit symbol test, and block design test. In particular, a 57.8-s decrease in the cut-off value was seen in the 65-69-year-old group for the NCT-B test (71.3 s vs. 129.1 s)., Conclusions: We updated the NPT by covering subjects aged 40-79 years and resetting the cut-off values. Thus, the updated NPT is an elderly and modern subject-compliant application. This update may improve the diagnostic ability of covert hepatic encephalopathy in contemporary cirrhotic patients., (© 2017 The Japan Society of Hepatology.)

Aims: Sarcopenia and physical disability assessed by a 6-min walking test (6MWT) are associated with poor prognosis of patients with chronic liver disease (CLD). However, CLD patients with hepatocellular carcinoma (HCC) mostly rest in bed during hospitalization. We aimed to investigate the effects of therapeutic exercise on liver function, 6MWT, and skeletal muscle mass during HCC treatment in patients with CLD., Methods: We enrolled 54 CLD patients with HCC (median age, 76 years). During hospitalization, patients performed a combination of stretching, strength training, balance practice, and endurance training (2.5-4 metabolic equivalents/20 min/day). Primary outcomes were changes from admission to discharge in Child-Pugh class, 6MWT, and skeletal muscle mass. Furthermore, factors associated with skeletal muscle atrophy were analyzed by a decision-tree analysis., Results: Exercise did not worsen the Child-Pugh class. On discharge, the 6MWT ambulation distance was maintained, and heart rate variability during the 6MWT was significantly improved compared to that on admission (area under the curve 50.3 vs. 39.0 arbitrary units; P = 0.0027). Although skeletal muscle mass was significantly reduced (20.6 kg vs. 20.0 kg, P = 0.0301), branched-chain amino acid (BCAA) treatment was identified as the most distinguishable factor for minimizing muscle mass atrophy (-1.1 kg vs. -0.5 kg/hospitalization)., Conclusions: Therapeutic exercise improved physical ability without worsening liver function during hospitalization for HCC treatment in CLD patients. Although exercise did not completely prevent skeletal muscle atrophy, BCAA treatment minimized the skeletal muscle atrophy. Thus, exercise with BCAA treatment may be important for the management of CLD patients with HCC., (© 2016 The Japan Society of Hepatology.)

Aim: Various factors are underlying for the onset of non-B, non-C hepatitis virus-related hepatocellular carcinoma (NBNC-HCC). We aimed to investigate the independent risk factors and profiles associated with NBNC-HCC using a data-mining technique., Methods: We conducted a case-control study and enrolled 223 NBNC-HCC patients and 669 controls from a health checkup database (n = 176 886). Multivariate analysis, random forest analysis and a decision-tree algorithm were employed to examine the independent risk factors, factors distinguishing between the case and control groups, and to identify profiles for the incidence of NBNC-HCC, respectively., Results: In multivariate analysis, besides γ-glutamyltransferase (GGT) levels and the Brinkman index, albumin level was an independent negative risk factor for the incidence of NBNC-HCC (odds ratio = 0.67; 95% confidence interval = 0.60-0.70; P < 0.0001). In random forest analysis, serum albumin level was the highest-ranked variable for distinguishing between the case and control groups (98 variable importance). A decision-tree algorithm was created for albumin and GGT levels, the aspartate aminotransferase-to-platelet ratio index (APRI) and the Brinkman index. The serum albumin level was selected as the initial split variable, and 82.5% of the subjects with albumin levels of less than 4.01 g/dL were found to have NBNC-HCC., Conclusion: Data-mining analysis revealed that serum albumin level is an independent risk factor and the most distinguishable factor associated with the incidence of NBNC-HCC. Furthermore, we created an NBNC-HCC profile consisting of albumin and GGT levels, the APRI and the Brinkman index. This profile could be used in the screening strategy for NBNC-HCC., (© 2013 The Japan Society of Hepatology.)

Aim:   Hepatitis C virus (HCV) core protein critically contributes to hepatocarcinogenesis, which is often observed in liver cirrhosis. Since the liver cirrhosis microenvironment is affected by hypoxia, we focused on the possible driving force of HCV core protein on signal relay from hypoxia-inducible factor (HIF)-1α to vascular endothelial growth factor (VEGF)., Methods:   Human hepatocellular carcinoma cells stably overexpressing HCV core (Core cells) and NS5A (NS5A cells) were established; empty vector-transfected (EV) cells were used as controls. Hypoxia was induced by oxygen deprivation or by using cobalt chloride (CoCl(2) ). YC-1 was used to inhibit HIF-1α expression. Protein analyses for cultured cells and liver tissues obtained from CoCl(2) -treated HCV core-transgenic (Core-Tg) mice were performed by western blot and/or immunocytochemistry. Cellular mRNA levels were evaluated by quantitative real-time reverse transcription-polymerase chain reaction., Results:   Under hypoxia, the sustained expression of HIF-1α, but not HIF-2α, was profoundly observed in Core cells but, was faint in EV and NS5A cells. Immunocytochemistry revealed increased HIF-1α in the nucleus. HIF-1α mRNA levels were significantly higher in Core cells than in EV cells under both normoxia and hypoxia. The HIF-1α-targeted VEGF and Bcl-xL expressions were increased in Core cells under hypoxia and abolished by YC-1 treatment. Hypoxic liver samples of Core-Tg mice indicated significant increases in both HIF-1α and VEGF expression compared with the wild type., Conclusions:   Hepatitis C virus core protein has the distinct potential to transcriptionally upregulate and sustain HIF-1α expression under hypoxia, thereby contributing to increased VEGF expression, a key regulator in the hypoxic milieu of liver cirrhosis., (© 2012 The Japan Society of Hepatology.)

Aim:   This study explored recent improvements in the management of hepatocellular carcinoma (HCC) diagnosed during surveillance., Methods:   The subjects were 1074 patients with HCC, subdivided into three groups. Group A comprised 211 patients for whom HCC was detected during periodic follow-up examinations at Kurume University School of Medicine, Group B comprised 544 patients diagnosed with HCC during periodic follow-up examinations at other institutions, and, Group C comprised 319 patients with HCC detected incidentally or because of symptoms., Results:   In 1995-2000 and 2001-2006, 91% and 91% of group A, 68% and 70% of group B, and 27% and 26% of group C patients with HCC, respectively, met the Milan criteria. For groups A and B, the proportions of patients with Child-Pugh class A and use of promising treatment increased in the later periods compared to those diagnosed during the earlier periods (group A, Child-Pugh class A, 72% vs 58% [P = 0.040], receiving treatment, 90% vs 70% [P < 0.0001]; group B, Child-Pugh class A, 71% vs 62% [P = 0.031]; receiving treatment, 72% vs 52% [P < 0.0001], respectively). The cumulative survival rates of the 405 patients with HCC detected in the latter 6 years tended to be better than those for patients diagnosed in the former 6 years (350 patients) (4 years, 58% vs 50% [P = 0.0349])., Conclusion:   The use of promising treatment and prognosis have improved in the last 6 years for patients with HCC diagnosed through surveillance relative to those identified in 1995-2000., (© 2010 The Japan Society of Hepatology.)

Aim:   Interferon (IFN) dramatically reduces the risk of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) to chronic hepatitis C (CH-C). However, HCC still develops in some patients after SVR. To evaluate metabolic factors in patients with HCC occurring after SVR and to determine whether insulin resistance and adipocytokines were involved in this etiology., Methods:   We examined clinical and biochemical features, histological findings and serum levels of adipocytokine prior to IFN therapy and at the detection of HCC in nine patients who were diagnosed with HCC. As controls, 27 patients were included who showed SVR but had not been diagnosed with HCC for at least 5 years after SVR., Results:   Three of four patients who developed HCC within 5 years after SVR showed liver cirrhosis when HCC was diagnosed. Prior to IFN therapy, four of nine HCC patients were diagnosed as having type 2 diabetes mellitus. Serum levels of leptin and insulin, Homeostatic Model of Assessment of Insulin Resistance and body mass index (BMI) were significantly higher and serum adiponectin was significantly lower in HCC patients at the time of HCC detection than in control patients more than 5 years after SVR. Six HCC patients had increased BMI and one HCC patient had a decreased BMI during the observation period., Conclusion:   Hepatic fibrosis may be tightly related to the emergence of HCC after SVR. Insulin resistance and adipocytokine disorders may be implicated in hepatocarcinogenesis after SVR, in part by promoting hepatic fibrosis.