Explore the vast range of titles available.

Patients with nonalcoholic steatohepatitis were randomly assigned to receive subcutaneous semaglutide or placebo. The incidence of NASH resolution was significantly higher with semaglutide than with placebo, but the between-group difference in the incidence of an improvement in fibrosis stage was not significant.

BackgroundWe previously reported that the incidence of hepatocellular carcinoma (HCC) with non-viral etiologies increased rapidly between 1991 and 2010 in Japan.MethodsTo update this investigation, we enrolled patients who were initially diagnosed as having non-B, non-C HCC at participating hospitals between 2011 and 2015. In addition to the patient characteristics investigated in the previous report, we also investigated the duration of alcohol consumption. The overall survival rate was analyzed using the Kaplan–Meier method, and the hazard function against the body mass index (BMI) was plotted using cubic splines.ResultsA total of 2087 patients were enrolled. The proportion of patients with non-viral etiologies has continued to increase from 10.0% in 1991 to 32.5% in 2015. Patients were also older (median ages, 70–73 years) and more obese (median BMIs, 23.9–24.2 kg/m2), and the proportions of patients with diabetes mellitus (46.1% to 51.6%), hypertension (42.7% to 58.6%), dyslipidemia (14.6% to 22.9%), and fatty liver (24.0% to 28.8%) had all increased significantly. There was a significant inverse relationship between the duration and the amount of daily alcohol consumption. The improvement in the overall survival was relatively small, with a decreased proportion of patients under surveillance (41.3% to 31.6%). A hazard function plot showed a curve similar to that in our previous report, with a lowest hazard of ~ 26 kg/m2.ConclusionsThe proportion of HCC patients with non-viral etiologies continues to increase in Japan. Lifetime total amount of alcohol consumption may be a risk factor.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases worldwide, including in Japan. The Japanese Society of Gastroenterology (JSGE) and the Japanese Society of Hepatology (JSH) have established the Japanese NAFLD/NASH guidelines in 2014 and revised these guidelines in 2020. As described in these guidelines, weight reduction by diet and/or exercise therapy is important for the treatment of NAFLD patients. The I148M single nucleotide polymorphism (rs738409 C > G) of PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is widely known to be associated with the occurrence and progression of NAFLD. In the Japanese, the ratio of PNPLA3 gene polymorphisms found is approximately 20%, which is higher than that found in Westerners. In addition, the ratio of lean NAFLD patients is also higher in Japan than in Western countries. Therefore, the method for lifestyle guidance for the NAFLD patients in Japan would be different from that for the people in Western countries. The problems in the treatment of NAFLD patients include alcohol consumption and sarcopenia. Therefore, guidelines that can help clinicians treat Japanese patients with NAFLD are needed. In this expert review, we summarize evidence-based interventions for lifestyle modification (diet, exercise, alcohol, and sarcopenia) for the treatment of patients with NAFLD, especially from Japan and Asian countries.

Fibroblast growth factor (FGF) 21 is an endocrine growth factor mainly secreted by the liver in response to a ketogenic diet and alcohol consumption. FGF21 signaling requires co-receptor β-klotho (KLB) co-acting with FGF receptors, which has pleiotropic metabolic effects, including induced hepatic fatty acid oxidation and ketogenesis, in human and animal models of obesity. We examined the hepatocyte-specific enhancer/promoter of FGF21 expression plasmids in high-fat diet-fed mice for 12 weeks. Hydrodynamic injection for FGF21 delivery every 6 weeks sustained high circulating levels of FGF21, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and liver steatosis. FGF21-induced lipolysis in the adipose tissue enabled the liver to be flooded with fat-derived FFAs. The hepatic expression of Glut2 and Bdh1 was upregulated, whereas that of gluconeogenesis-related genes, G6p and Pepck, and lipogenesis-related genes, Srebp-1 and Srebp-2, was significantly suppressed. FGF21 induced the phosphorylation of AMPK at Thr172 and Raptor at ser792 and suppressed that of mTOR at ser2448, which downregulated mTORC1 signaling and reduced IRS-1 phosphorylation at ser1101. Finally, in the skeletal muscle, FGF21 increased Glut4 and Mct2, a membrane protein that acts as a carrier for ketone bodies. Enzymes for ketone body catabolism (Scot) and citrate cycle (Cs, Idh3a), and a marker of regenerating muscle (myogenin) were also upregulated via increased KLB expression. Thus, FGF21-induced lipolysis was continuously induced by a high-fat diet and fat-derived FFAs might cause liver damage. Hepatic fatty acid oxidation and ketone body synthesis may act as hepatic FFAs' disposal mechanisms and contribute to improved liver steatosis. Liver-derived ketone bodies might be used for energy in the skeletal muscle. The potential FGF21-related crosstalk between the liver and extraliver organs is a promising strategy to prevent and treat metabolic syndrome-related nonalcoholic steatohepatitis. Sustained high circulating levels of fibroblast growth factor (FGF) 21 improve obesity/systemic insulin resistance and promote ketone body production as a second hepatic disposal system for excess free fatty acids. Liver-derived ketone bodies may be utilized for energy in skeletal muscle. The potential FGF21-related crosstalk between the liver and extrahepatic organs is a promising strategy against nonalcoholic fatty liver disease.

Background The number of hepatocellular carcinoma (HCC) patients with non-viral etiologies is increasing in Japan. We conducted a nation-wide survey to examine the characteristics of those patients. Methods After we assessed the trend of patients who were first diagnosed with HCC at 53 tertiary care centers in Japan from 1991 to 2010, we collected detailed data of 5326 patients with non-viral etiology. The etiologies were categorized as autoimmune hepatitis, primary biliary cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), unclassified, and other. Baseline characteristics at initial diagnosis, the modality of the initial treatment, and survival status were collected via a website. Survival of the patients was assessed by the Kaplan–Meier method and Cox proportional hazard regression. Results The proportion of patients with non-viral etiologies increased from 10.0 % in 1991 to 24.1 % in 2010. Of the patients, 92 % were categorized as ALD, NAFLD, or unclassified. Body mass index (BMI) was ≥ 25 kg/m 2 in 39 %. Diabetes was most prevalent in NAFLD (63 %), followed by unclassified etiology (46 %) and ALD (45 %). Approximately 80 % of patients underwent radical therapy, including resection, ablation, or transarterial chemoembolization. Survival rates at 3, 5, 10, 15, and 20 years were 58.2, 42.6, 21.5, 15.2, and 15.2 %, respectively. Multivariate analysis revealed that patients with BMI > 22 and ≤ 25 kg/m 2 showed the best prognosis versus other BMI categories, after adjusting by age, gender, tumor-related factors, and Child-Pugh score. Conclusions Most cases of non-B, non-C HCC are related to lifestyle factors, including obesity and diabetes. Slightly overweight patients showed the best prognosis.

BackgroundThe FIB4 index is clinically useful, but because its formula includes age, the appropriate cutoff point may differ by age group. Here, new FIB4 index cutoff points were validated using cohort data from 14 hepatology centers in Japan.MethodsThe FIB4 index was determined in biopsy-confirmed NAFLD patients (n = 1050) who were divided into four groups: ≤ 49, 50–59, 60–69, and ≥ 70 years. ROC analysis predicted advanced fibrosis in each age group; low and high cutoff points were defined by a sensitivity and specificity of 90%. The new and conventional cutoffs were compared for detecting advanced fibrosis.ResultsThe modified low and high cutoff points were 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50–59 years, 1.88 and 3.24 in 60–69 years, and 1.95 and 4.56 in ≥ 70 years. In ≥ 60 years, the false-negative rate was increased using the modified high cutoff point, and the high cutoff point was better with the conventional cutoff point. The new proposed low and high cutoff points are 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50–59 years, 1.88 and 2.67 in 60–69 years, and 1.95 and 2.67 in ≥ 70 years; these cutoff points improved the accuracy of advanced fibrosis diagnosis.ConclusionsFIB4 index cutoff points for predicting advanced fibrosis in NAFLD increased with age. Cutoff points modified by age improved the diagnostic accuracy of estimations of advanced liver fibrosis using the FIB4 index.

Management of nonalcoholic steatohepatitis (NASH) is a currently unmet clinical need. Digital therapeutics (DTx) is an emerging class of medicine that delivers evidence-based therapeutic interventions. This study was aimed at investigating the efficacy of DTx in patients with NASH. We conducted a multicenter, single-arm, 48-week trial in 19 patients with biopsy-confirmed NASH. All patients received a DTx intervention with a newly developed smartphone application. The primary endpoint was change in the nonalcoholic fatty liver disease activity score (NAS) without worsening of liver fibrosis. The secondary endpoints included improvement of the NAS by ≥2 points without worsening of liver fibrosis, change in the body weight, and regression of fibrosis. After the 48-week DTx intervention, improvement of the NAS was observed in 68.4% (13/19) of patients. The mean change in the NAS from baseline to the end of the intervention was -2.05 ± 1.96 ( P < 0.001 when compared with the threshold of -0.7). A decrease in the NAS by ≥ 2 points was achieved in 11 (57.9%). The average weight loss at the end of the intervention was 8.3% ( P < 0.001). Reduction of the fibrosis stage was observed in 58.3% when the analysis was limited to patients with stage F2/3 fibrosis. There were no serious adverse events that could be considered as being related to the DTx intervention. DTx for NASH was found to be highly efficacious and well-tolerated. Further evaluation of the DTx intervention for NASH in a phase 3 trial is warranted.

Background Liver histology is the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH). Noninvasive, simple, reproducible, and reliable biomarkers are greatly needed to differentiate NASH from nonalcoholic fatty liver disease (NAFLD). Methods To construct a scoring system for predicting NASH, 177 Japanese patients with biopsy-proven NAFLD were enrolled. To validate the scoring system, 442 biopsy-proven NAFLD patients from eight hepatology centers in Japan were also enrolled. Results In the estimation group, 98 (55%) patients had NASH. Serum ferritin [≥200 ng/ml (female) or ≥300 ng/ml (male)], fasting insulin (≥10 μU/ml), and type IV collagen 7S (≥5.0 ng/ml) were selected as independent variables associated with NASH, by multilogistic regression analysis. These three variables were combined in a weighted sum [serum ferritin ≥200 ng/ml (female) or ≥300 ng/ml (male) = 1 point, fasting insulin ≥10 μU/ml = 1 point, and type IV collagen 7S ≥5.0 ng/ml = 2 points] to form an easily calculated composite score for predicting NASH, called the NAFIC score. The area under the receiver operating characteristic (AUROC) curve for predicting NASH was 0.851 in the estimation group and 0.782 in the validation group. The NAFIC AUROC was the greatest among several previously established scoring systems for detecting NASH, but also for predicting severe fibrosis. Conclusions NAFIC score can predict NASH in Japanese NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use.

BackgroundNumerous biomarkers have been developed for assessing the presence and severity of liver fibrosis associated with non-alcoholic fatty liver disease (NAFLD). Fibrosis can be assessed by liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE). Here we examined whether diagnostic accuracy and applicability can be further improved by combining various biomarker measurements with LSM.MethodsA total of 278 patients with biopsy-confirmed Japanese NAFLD patients were enrolled. Area under the receiver operator characteristic curve (AUROC) was evaluated for obtaining the optimum interpretation criteria for LSM by VCTE and comparing various biomarkers alone and in combination with LSM.ResultsLiver stiffness measurements including cases with interquartile range (IQR)/median (M) < 30% or LSM ≤ 7.1 kPa demonstrated high applicability (90% of patients with NAFLD) and accuracy (AUROC: 0.891) for predicting stage ≥ 3 fibrosis. For all biomarkers tested, the AUROC values for predicting stage ≥ 3 fibrosis were increased when combined with LSM [platelet count, 0.734 vs. 0.912; type-4 collagen 7s (T4C7s), 0.894 vs. 0.921; aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), 0.774 vs. 0.906; AST to platelet ratio index, 0.789 vs. 0.902; FIB-4 index, 0.828 vs. 0.922; NAFLD fibrosis score, 0.800 vs. 0.906; CA index-fibrosis, 0.884 vs. 0.913; FM-fibro index, 0.920 vs. 0.943; FIB-4 index + T4C7s, 0.901 vs. 0.930], demonstrating the advantage of concurrent LSM.ConclusionsWhile VCTE has slightly limited applicability (90%) for patients with NAFLD, concurrent measurement with certain biomarkers (especially FM-fibro, T4C7s, and FIB-4) greatly improves the diagnostic accuracy.

Background Elbasvir (EBR) in combination with grazoprevir (GZR) has demonstrated efficacy in patients with hepatitis C virus (HCV) infections in trials primarily conducted in the USA and Europe. We investigated the safety and efficacy of EBR in combination with GZR in Japanese patients with chronic HCV infection, with or without cirrhosis. Methods The study was conducted in two parts. In part 1, noncirrhotic patients were randomized 1:1 to receive EBR (50 mg) in combination with GZR (50 or 100 mg) once daily for 12 weeks. In part 2, noncirrhotic patients were randomized 3:1 to receive immediate or deferred treatment with EBR (50 mg) and GZR (100 mg, determined in part 1) for 12 weeks; cirrhotic patients received open-label immediate treatment. The primary efficacy end point was the rate of sustained virologic response 12 weeks after completion of the study treatment. Results In part 1, 63 patients were randomized to receive EBR in combination with GZR at a dose of 50 mg ( n  = 31) or 100 mg ( n  = 32). The SVR12 rates were 100% with GZR at a dose of 50 mg and 96.8% with GZR at a dose of 100 mg. Tolerability was similar in both arms. In part 2, 301 noncirrhotic patients were randomized to receive immediate treatment ( n  = 227) or deferred treatment ( n  = 74), and 35 cirrhotic patients were enrolled. The SVR12 rates were 96.5% and 97.1% after immediate treatment in noncirrhotic and cirrhotic patients respectively. Safety was generally similar between immediate and deferred treatment. Conclusion Treatment with EBR in combination with GZR for 12 weeks is effective and well tolerated in Japanese patients with chronic HCV infection. ClinicalTrials.gov identifier NCT02203149.