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The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

Background/Aims Endoscopic resection (ER) for superficial non-ampullary duodenal epithelial tumors (SNADETs) is challenging. Conventional endoscopic mucosal resection (CEMR) is also problematic due to the anatomical features of the duodenum. We compared the safety and efficacy of underwater endoscopic mucosal resection (UEMR) with those of CEMR through a retrospective analysis. Methods Altogether, 44 consecutive patients with 46 SNADETs underwent ER (18 CEMR cases and 28 UEMR cases) between January 2016 and October 2019. We investigated the proportions of en bloc resection, R0 resection, complications, resection time, and total procedure time and compared the outcomes of patients from the CEMR group with those of patients from the UEMR group. Results The median tumor size was 8.0 mm (range, 2.0–20.0 mm). The UEMR group showed a higher proportion of en bloc resection (96.4% vs. 72.2%, p

AIM Although some relationships between gut microbiota and liver diseases have been reported, it remains uncertain whether changes in gut microbiota owing to differences in race, food and living environment have similar effects. Response to ursodeoxycholic acid (UDCA) may predict the long-term prognosis of patients with primary biliary cholangitis (PBC); however, little is known about the significance of the gut microbiome in patients with PBC. We elucidated the relationships among clinical profiles, biochemical response to UDCA and gut microbiome composition in patients with PBC. METHODS Fecal samples from 76 patients with PBC treated at our hospital were collected; patients whose UDCA intake period was

Background and Aim Hypothyroidism might play a crucial role in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD). The association of subclinical hypothyroidism with NAFLD has been inconsistent. The relationship of NAFLD with thyroid function parameters and subclinical hypothyroidism was determined. Methods This cross‐sectional study included 70 patients with subclinical hypothyroidism and 70 controls with euthyroidism matched according to gender, age, and body mass index (BMI). NAFLD was diagnosed via abdominal ultrasonography. The association between NAFLD and subclinical hypothyroidism was analyzed. Results The prevalence of NAFLD was significantly higher in patients with subclinical hypothyroidism than in those with euthyroidism. Multivariate analysis showed that subclinical hypothyroidism was an independent risk factor of NAFLD adjusted by metabolic‐related factors, such as BMI, triglyceride, high‐density lipoprotein‐cholesterol, hypertension, and diabetes. Thyroid‐stimulating hormone (TSH) was an independent risk factor of NAFLD adjusted by the same metabolic‐related factors, but free thyroxine (FT4) was not a risk factor. The FIB‐4 index, a noninvasive marker of liver fibrosis was significantly higher in patients with subclinical hypothyroidism than in those with euthyroidism. Compared with patients with euthyroidism, the proportion of the FIB‐4 index ≥2.67 was significantly higher, and the proportion of the FIB‐4 index, Thyroid‐stimulating hormone elevation, even within the euthyroid range, is an independent risk factor of non‐alcoholic fatty liver disease and may have an influence on the progression of liver fibrosis, even with a normal free T4 level.

Chronic hepatitis B (CHB) virus continues to be a leading cause of morbidity and mortality worldwide. The diagnosis of liver fibrosis has a key role in selecting patients with CHB for antiviral treatment. However, serum biomarkers demonstrate limited diagnostic utility. The present study aimed to compare the performances of fibrosis biomarkers for diagnosing significant liver fibrosis that indicates the need for antiviral therapy in patients with CHB and to identify the most appropriate biomarker for these patients. The current study included 96 antiviral-naive patients with CHB who underwent liver biopsy. METAVIR scoring system was used to assess liver fibrosis and necroinflammation. The diagnostic performances were evaluated of the platelet (PLT) count; the levels of hyaluronan, serum 7S domain of type 4 collagen, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer (M2BPGi) and N-terminal type III collagen propeptide (Pro-C3); the fibrosis index based on four factors; the aspartate aminotransferase-to-platelet ratio index; and enhanced liver fibrosis score for identifying significant liver fibrosis [≥fibrosis stage 2 (F2)]. All fibrosis biomarkers, except the Pro-C3 level, correlated with the fibrosis stage. M2BPGi was better than other biomarkers for diagnosing ≥F2, with the highest area under the curve of 0.902. M2BPGi demonstrated a higher diagnostic accuracy for significant fibrosis than mild/severe fibrosis or cirrhosis. However, no significant correlation was observed between the M2BPGi level and fibrosis stage in patients with CHB having significant liver necroinflammation defined as ≥ necroinflammatory activity 2. The M2BPGi level and PLT count were exclusively correlated with the fibrosis stage in 73 patients without significant liver necroinflammation. M2BPGi demonstrated the highest diagnostic performance for significant fibrosis in patients having significant liver fibrosis with no significant liver necroinflammation. In conclusion, the M2BPGi level can accurately diagnose significant liver fibrosis that indicates the need for antiviral therapy in patients with CHB.

Mortality and recurrence rates of hepatocellular carcinoma (HCC) are high. Recent studies show that for patients with HCC beyond up-to-seven criteria, treatment with molecular-targeted agents (MTAs) is recommended because the treatment efficiency of transcatheter arterial chemoembolization (TACE) is poor, further, TACE increases decline in liver function. However, the relationship between TACE and liver function decline in patients with HCC within up-to-seven criteria has not been clarified. Hence, we aimed to investigate this relationship. This retrospective observational study included 189 HCC tumors within up-to-seven criteria in 114 Child–Pugh class A patients. Twenty-four (12.7%) tumors were changed from Child–Pugh class A to B after TACE, and 116 (61.4%) tumors exhibited recurrence within 6 months after TACE. Prothrombin time (PT) and albumin–bilirubin (ALBI) score before TACE were significantly associated with liver dysfunction from Child–Pugh class A to B. The combination of PT and ALBI score before TACE had high predictive ability for liver dysfunction from Child–Pugh class A to B after TACE (specificity = 100%, sensitivity = 91.7%). The combined use of pre-TACE PT and ALBI score has a high predictive ability for liver dysfunction after TACE for Child–Pugh class A patients with HCC within up-to-seven criteria.

We aimed to prospectively identify the risk factors of sarcopenia in patients with cirrhosis. Patients (n = 193) included in a discovery cohort (January 2011 and December 2014) were categorized into alcoholic (A1; n = 55) and non-alcoholic cirrhosis (NA; n = 138) groups, and those (n = 235) in a validation cohort (January 2015 to December 2019) were categorized into alcoholic (n = 92), non-alcoholic steatohepatitis-related (n = 27), and hepatitis C virus-related cirrhosis groups (n = 116). Skeletal muscle mass index (SMI) was determined using computed tomography (SMI-CT) and bioelectrical impedance analysis (SMI-BIA). Endotoxin activity (EA) was measured with an EA assay. SMI-CT correlated with grip strength in all the groups but significantly correlated with SMI-BIA of the men in group A1 (R = 0.64, P

Background/Aims: We previously reported the comparable efficacy of bi-monthly hepatic arterial infusion chemotherapy (B-HAIC) to that of sorafenib chemotherapy for the treatment of advanced hepatocellular carcinoma (aHCC) in patients with compensated cirrhosis. In this study, we demonstrate the efficacy of B-HAIC in patients with decompensated cirrhosis. Methods: Forty-five patients with aHCC refractory to transcatheter arterial chemo-embolization (TACE) were treated with B-HAIC and were divided into two groups according to hepatic functional reserve (Child-Pugh grade). Overall survival period, treatment response, and adverse events in each group were analyzed. Results: Efficacy and disease control rates in the Child-Pugh B group (n=24; 21% and 71%, respectively) were not significantly impaired compared the Child-Pugh A group (n=21; 38% and 67%, respectively). Median survival time and survival rate at 12 months in the Child-Pugh B group were 422 days and 58.3%, respectively, whereas those in the Child- Pugh A group were 567 days and 70.8%, respectively. Importantly, the hepatic functional reserve of patients did not worsen in either group during the treatment period. Furthermore, the occurrence rate of adverse events leading to discontinuation of anti-tumor treatment was not significantly increased in the Child-Pugh B group. Conclusions: Given the preservation of hepatic functional reserve afforded by B-HAIC chemotherapy in patients with decompensated cirrhosis, B-HAIC might be an acceptable alternative strategy for aHCC patients who do not respond to TACE. (Clin Mol Hepatol 2019;25:381-389)

Aims: Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). To increase platelet counts, lusutrombopag, a small-molecule, second-generation thrombopoietin receptor agonist, was developed in September 2015. Lusutrombopag is mainly used in patients with platelet counts Methods: We evaluated 36 patients who received lusutrombopag for CLD. Changes in platelet counts were evaluated. A treatment response was defined as an increasing platelet count ≥20,000/µL from baseline after drug administration. The differences related to these changes between platelet counts ≥50,000 and Results: Of the patients, 25 had platelet counts ≥50,000/µL. The increase in platelet count and the date in which it reached a maximum did not significantly differ between the groups. The effectiveness of lusutrombopag did not significantly differ between the groups. In both groups, no adverse reaction was observed during lusutrombopag administration. Conclusion: In this study, we showed the effectiveness of lusutrombopag, which had no complications. This study is the first to report that the effectiveness of lusutrombopag was the same for patients with platelet counts ≥50,000/µL and

AIM To identify laboratory predictors of histological progression (HP) of primary biliary cholangitis (PBC). METHODS Sequential biopsies were carried out on 35 (11.4%) of 308 patients with PBC treated with ursodeoxycholic acid (UDCA). Patients were divided into high γ-glutamyl transpeptidase (GGT) (n = 18) and low GGT (n = 17) groups, based on the median value of GGT at baseline. Patients were then categorized as showing HP (progressive group, PG) or lacking HP (non-progressive group, NPG) according to the Scheuer and Nakanuma classifications, with the latter grading liver fibrosis (fibrosis score) and bile duct loss (BDL score). RESULTS According to the Scheuer definition, 12 patients had HP and 23 did not. According to the Nakanuma definition, 8 and 27 patients were in the PG and NPG groups, respectively. The fibrosis and BDL scores progressed in 13 and 8 patients, respectively, whereas 22 and 25 patients did not show HP, respectively. Fisher's exact probability test analysis revealed that the rate of HP using the Nakanuma fibrosis score was significantly higher in the high GGT group compared to the low GGT group (P

ObjectivesThis study aimed to evaluate and compare the outcomes of palliative endoscopic biliary stenting (EBS) and complete stone removal among elderly patients with choledocholithiasis using propensity score matching.MethodsFrom April 2012 to October 2017, 161 patients aged 75 years and older with choledocholithiasis underwent endoscopic retrograde cholangiopancreatography at our institution. Among them, 136 (84.5%) had complete stone removal, and 25 (15.5%) underwent palliative EBS without further intervention until symptom occurrence. The median age of the EBS group was significantly higher than that of the complete stone removal group. The proportion of patients with dementia, cerebral infarction, preserved gallbladder with gallstones, and surgically altered anatomy was higher in the EBS group than in the complete stone removal group. Propensity score matching was used to adjust for different factors. In total, 50 matched patients (n = 25 in each group) were analyzed.ResultsThe median duration of cholangitis-free periods was significantly shorter in the EBS group (596 days) than in the complete stone removal group. About half of patients in the EBS group required retreatment and rehospitalization for cholangitis during the observation period. Cholangitis was mainly caused by stent migration. There was no significant difference in terms of mortality rate and procedure-related adverse events between the two groups. Death was commonly attributed to underlying diseases. However, one patient in the EBS group died due to severe cholangitis.ConclusionsPalliative EBS should be indicated only to patients with choledocholithiasis who have a poor prognosis.

Background: This study aimed to compare the diagnostic performance of carbohydrate-deficient transferrin (CDT) and gamma-glutamyltranspeptidase (γ-GTP) to assess the single and combined benefits of these biological markers for the detection of chronic excessive alcohol consumption in patients with alcoholic cirrhosis. Methods: Biological markers were determined in blood samples from patients with alcoholic cirrhosis (drinking group, n = 35, nondrinking group, n = 81). The prediction accuracy of %CDT alone, γ-GTP alone, and their combination for the detection of excessive alcohol consumption was determined in patients with alcoholic cirrhosis. Results: Serum total bilirubin, alanine aminotransferase, aspartate aminotransferase, γ-GTP, and alkaline phosphatase levels and %CDT were significantly higher and serum albumin levels were significantly lower in the drinking group than in the nondrinking group. The combination of %CDT and γ-GTP compared with %CDT or γ-GTP alone showed a higher prediction accuracy. The combination of %CDT and γ-GTP exhibited a higher specificity than γ-GTP alone. However, in terms of sensitivity, no significant difference was found between single or combined markers. Conclusions: The combination of %CDT and γ-GTP is considered a useful biomarker of chronic excessive alcohol consumption in patients with alcoholic cirrhosis.

Aim: The aim of the present study is to investigate the effect of long-term zinc supplementation, which is important for the activation of various enzymes that contribute to antioxidant and antifibrotic activities, on the improvement of serum fibrotic markers in patients with autoimmune hepatitis (AIH). Methods: A total of 38 patients with AIH under regular treatment at our hospital who provided their consent for being treated with polaprezinc (75 mg twice daily) were included and classified into 2 groups: the patients with zinc elevation (n = 27) and the patients without zinc elevation (n = 11). Serum biomarker of fibrosis, protein expression levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were evaluated. Results: A significant difference was found between the variability of serum procollagen type Ⅲ and collagen type Ⅳ-7S between the 2 groups before and after zinc administration for more than 24 months (p = 0.043 and p = 0.049). In the patients with zinc elevation, no significant changes were found in collagenase (MMP-1 and MMP-13) before and after zinc administration, whereas a significant increase in the expression of gelatinase (MMP-2 and MMP-9) was found after administration (p = 0.021 and p = 0.005). As for the relative ratio of MMPs to TIMPs, only MMP-9 to TIMP-1 showed a significant increase (p = 0.004). Conclusions: Long-term treatment with polaprezinc has been demonstrated to safely improve serum fibrosis indices through increases in MMP-2/-9 and MMP-9/TIMP-1 and is expected to be well combined with direct antifibrotic therapies such as molecularly targeted agents.

A potential restriction of the Baveno VI consensus, which helps to avoid unnecessary endoscopies, is the limited availability of FibroScan. We aimed to identify serum fibrosis indices that might aid in ruling out the presence of high-risk varices in cirrhotic patients. This retrospective study included 541 consecutive patients with cirrhosis who underwent endoscopy and had data available for nine serum fibrosis indices, including platelet count, hyaluronic acid, 7S fragment of type 4 collagen, procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer, fibrosis index based on four factors (FIB-4), aspartate transaminase/platelet ratio index and enhanced liver fibrosis score. Optimal index cutoffs for predicting high-risk varices were calculated in an estimation cohort (n = 127) and evaluated in a validation cohort (n = 351). The diagnostic performance of the indices was assessed by receiver operating characteristic curve analysis. In the estimation cohort, a FIB-4 cutoff of 2.78 provided the greatest diagnostic accuracy in predicting both all-grade and high-risk varices. FIB-4 had a negative predictive value of 1.00 for high-risk varices in both cohorts, and 21.3% (27/127) and 14.8% (52/351) of the estimation and validation cohorts, respectively, avoided esophagogastroduodenoscopy, no high-risk varices were missed in either cohort. FIB-4 correctly identifies the absence of high-risk varices in patients with cirrhosis. Therefore, those with a FIB-4 of &ge, 2.78 should undergo esophagogastroduodenoscopy, and FIB-4 determination should be recommended every 6&ndash, 12 months concurrently with the other blood tests until the index value reaches 2.78 in those with a FIB-4 of &lt, 2.78.

Background/Aims: L-carnitine not only alleviates hyperammonemia and reduces muscle cramps in patients with liver cirrhosis, but also improves anemia in patients with chronic hepatitis and renal dysfunction. This study prospectively evaluated the preventative efficacy of L-carnitine supplementation against hemolytic anemia during antiviral treatment using ribavirin in patients with hepatitis C virus (HCV)-related chronic liver disease. Methods: A total of 41 patients with chronic hepatitis were consecutively enrolled in this study. Group A (n=22) received sofosbuvir plus ribavirin for 3 months, whereas group B (n=19) was treated with sofosbuvir, ribavirin, and L-carnitine. Hemoglobin concentration changes, the effects of antiviral treatment, and the health status of patients were analyzed using short form-8 questionnaires. Results: A significantly smaller decrease in hemoglobin concentration was observed in group B compared to group A at every time point. Moreover, the prescribed dose intensity of ribavirin in group B was higher than that of group A, resulting in a higher ratio of sustained virological response (SVR) 24 in group B compared with group A. The physical function of patients in group B was also significantly improved compared to group A at the end of antiviral treatment. Conclusions: L-carnitine supplementation alleviates ribavirin-induced hemolytic anemia in patients with HCV and helps relieve the physical burden of treatment with ribavirin-containing regimens. These advantages significantly increase the likelihood of achieving SVR.

Acute-on-chronic liver failure (ACLF) leads to systematic inflammatory response syndrome and multiple organ failure. This study investigated the relationship between endotoxin (Et) and ACLF with the aim of determining whether Et activity (EA) is useful as a predictive biomarker of ACLF development and whether rifaximin treatment decreased the risk of ACLF development. Two hundred forty-nine patients with liver cirrhosis were enrolled in this study. Et concentration was determined in the whole blood by a semiquantitative EA assay. Predictive factors of ACLF development and the risk of ACLF development with and without rifaximin treatment were identified by univariate and multivariate analysis using Fine and Gray&rsquo, s proportional subhazards model. EA level was higher in Child&ndash, Pugh class B than in class A patients, and class B patients had an increased risk of ACLF development compared with class A patients. Multivariate analysis showed that EA level was a predictive factor independently associated with ACLF development. Rifaximin decreased EA level and the risk of ACLF development in Child&ndash, Pugh class B patients. Et levels were associated with functional liver capacity and were predictive of ACLF development in cirrhotic patients. Rifaximin decreased Et level and the risk of ACLF development in advanced cirrhotic patients.

Rifaximin is a poorly absorbable antibiotic against hepatic encephalopathy (HE). This observational study aimed to elucidate the effect of rifaximin on intestinal permeability and gut microbiota in patients with decompensated cirrhosis. Thirty patients with decompensated cirrhosis were assessed by ammonia level, neuropsychological testing, endotoxin activity (EA), and serum proinflammatory cytokines at baseline and after four weeks of rifaximin treatment (1200 mg/day). Intestinal permeability was indicated by serum soluble CD163 (sCD163), mannose receptor (sMR), and zonulin levels. To evaluate the gut microbiome, 16S ribosomal RNA gene sequencing was applied. Rifaximin ameliorated hyperammonemia and cognitive dysfunction, although it did not change the serum proinflammatory cytokine levels. It decreased EA levels as well as serum levels of sCD163 and sMR, but not zonulin, and both decreases in sCD163 and sMR showed positive correlations with EA decrease (&Delta, sCD163: Correlation coefficient (R) = 0.680, p = 0.023, &Delta, sMR: R = 0.613, p = 0.014, vs. &Delta, EA). Gut microbial analysis revealed that the richness and complexity of species were unchanged while the abundance of the Streptococcus genus was reduced after treatment with rifaximin. Collectively, rifaximin alleviated HE and endotoxemia with improved intestinal hyperpermeability in patients with decompensated cirrhosis, and this effect is partially involved in a gut microbial change.

We aimed to elucidate the effect of chronic alcohol consumption on fatty liver. We assessed the consumption of alcohol in 2429 Japanese males (mean age: 54.2 &plusmn, 9 years), they were classified according to average consumption into non-drinkers (ND), light drinkers (LD), moderate drinkers (MD), and heavy drinkers (HD). The prevalence of fatty liver was the lowest in the MD and highest in the ND group (p &lt, 0.001), while obesity was not significantly different among the groups (p = 0.133). Elevated levels of alanine aminotransferase (ALT) were the lowest in the MD group (p = 0.011) along with resistance to insulin (homeostasis model assessment-insulin resistance (HOMA-IR)), which was highest in the ND group (p = 0.001). Chronic consumption of alcohol was independently and inversely associated with fatty liver and insulin resistance after adjusting for obesity, hypertension, fasting hyperglycemia, habit of drinking sweet beverages, physical activity, and age (odds ratios are as follows: ND, 1, LD, 0.682, MD, 0.771, HD, 0.840 and ND, 1, LD, 0.724, MD, 0.701, HD, 0.800, respectively). We found that regardless of the type of alcoholic beverage, chronic consumption of alcohol is inversely associated with insulin resistance and fatty liver in Japanese males. This study had limitations, most notably the lack of investigation into diet and nutrition.

Aim Proton pump inhibitors (PPIs) are frequently prescribed in patients with cirrhosis, but this therapy entails potential complications. We aimed to investigate the influence of PPI use on intestinal permeability in patients with cirrhosis. Methods We recruited 228 patients with cirrhosis and divided them into four groups. Group (Gp)1 comprised patients receiving a PPI with concurrent neomycin (NEO) (PPI-NEO group, n = 14 [6.1%]), Gp2 and Gp3 comprised those receiving either PPI or NEO (PPI group, n = 91 [39.9%]; and NEO group, n = 11 [4.4%]), and Gp4 comprised those receiving neither of these medications (control group; n = 112 [49.1%]). We assessed the intestinal permeability by measuring endotoxin activity (EA) using a luminol chemiluminescence method. Results Endotoxin activity levels were significantly higher in patients with Child B cirrhosis than in those with Child A cirrhosis, but we found no significant differences in EA levels between patients with Child C cirrhosis and those with either Child A or B cirrhosis. We observed no significant differences in EA levels among groups 1-4. Patients without antibiotic exposure (n = 203), comprising 91 patients on PPI therapy (Gp2) and 112 no-PPI-therapy controls (Gp4), were subdivided according to Child-Pugh (CP) classification. We found no significant differences in EA levels between Gp2 and Gp4 in either CP class. Conclusion Our results suggest that PPI usage does not have a significant impact on serum levels of gut-derived endotoxins, which are already elevated because of the increased intestinal permeability in patients with cirrhosis.

Even though the Barcelona Clinic Liver Cancer (BCLC) staging system is widely accepted, controversies on the management of hepatocellular carcinoma (HCC) still exist. We evaluated the efficacy of an approach with repeated hepatic arterial infusion chemotherapy (HAIC) given at eight-week intervals for the treatment of advanced HCC.Of the 66 compensated cirrhotic patients with advanced HCC refractory to transcatheter arterial chemo-embolization (TACE) enrolled in our study, 21 were treated by bi-monthly hepatic arterial infusion chemotherapy (B-HAIC) and the rest by sorafenib. The overall survival periods, curative responses, and adverse events in each group were retrospectively analyzed.The efficacy rate was significantly higher in the B-HAIC group (38%, 11%, P0.05). The median survival time and the survival rate at 12 months in the B-HAIC group were 567 days and 70.8%, and those in the sorafenib group were 366 days and 47.6%, respectively. Thus, our data suggests that the B-HAIC treatment is not inferior to sorafenib for the treatment of advanced HCC in compensated cirrhotic patients. Furthermore, the occurrence of serious adverse events leading to discontinuation of treatment was less frequent in the B-HAIC group.Given the hepatic function reserve preservation afforded by the B-HAIC treatment in our experience, we suggest that B-HAIC should be considered an alternative strategy for advanced HCC patients who do not respond to TACE.

Equol is a metabolite of daidzein, a major soybean isoflavone with estrogenic and antioxidant activities. As the production of equol depends on the presence of certain members of the intestinal microflora, not all individuals can produce equol. We examined the relationship between NASH histological features and equol production. In an animal model, obese OLETF rats were intraperitoneally injected with a porcine serum to augment liver fibrogenesis. Equol-rich soy product, SE5-OH was orally administered during the experimental period. Treatment with SE5-OH markedly attenuated the development of liver fibrosis and expression of alpha-smooth muscle actin. In clinical research, 38 NAFLD patients (13 men and 25 women) were included. The degree of fibrosis and ballooning in equol-nonproducers was significantly higher than in equol-producers in women. The percentage of nonproducers with NAFLD activity score (NAS) ≥ 5 was significantly higher than that of producers. None of the histological features were significantly different between nonproducers and producers in men. Decision tree analysis identified predictors for NAS ≥ 5 in women. The status of equol production was the strongest predictor, followed by fasting glucose. Since equol can be noninvasively detected in urine, it can be applied as a screening tool for the progression of NASH in women.

SCOPE This study investigated the combined effect of the angiotensin II (AT-II) receptor blocker losartan and branched-chain amino acids (BCAAs) on skeletal muscle atrophy in rats with cirrhosis and steatohepatitis. METHOD AND RESULTS Fischer 344 rats are fed a choline-deficient l-amino acid-defined (CDAA) diet for 12 weeks and treated with oral losartan (30 mg kg-1 day-1 ) and/or BCAAs (Aminoleban EN, 2500 mg kg-1 day-1 ). Treatment with losartan and BCAAs attenuated hepatic inflammation and fibrosis and improved skeletal muscle atrophy and strength in CDAA-fed rats. Both agents reduced intramuscular myostatin and pro-inflammatory cytokine levels, resulting in inhibition of the ubiquitin-proteasome system (UPS) through interference with the SMAD and nuclear factor-kappa B pathways, respectively. Losartan also augmented the BCAA-mediated increase of skeletal muscle mass by promoting insulin growth factor-I production and mitochondrial biogenesis. Moreover, losartan decreased the intramuscular expression of transcription factor EB (TFEB), a transcriptional inducer of E3 ubiquitin ligase regulated by AT-II. In vitro assays illustrated that losartan promoted mitochondrial biogenesis and reduced TFEB expression in AT-II-stimulated rat myocytes, thereby potentiating the inhibitory effects of BCAAs on the UPS and caspase-3 cleavage. CONCLUSION These results indicate that this regimen could serve as a novel treatment for patients with sarcopenia and liver cirrhosis.

The presence of bridging fibrosis predicts survival of primary biliary cholangitis (PBC). This study aimed to compare serum parameters for the estimation of liver fibrosis and prediction of clinical outcomes in PBC. Out of 392 patients with PBC, 102 who underwent liver biopsy and in whom fibrosis indices, platelet count, hyaluronic acid, type IV collagen 7 second domain, procollagen type III amino-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer, N-terminal type III collagen propeptide levels; fibrosis index based on 4 factors, aspartate aminotransferase-to-platelet ratio index, and enhanced liver fibrosis (ELF) score were determined, were included. The correlation of histological stages based on both Scheuer and Nakanuma classifications with fibrosis indices was investigated. The Nakanuma system comprises grading for liver fibrosis and bile duct loss. Diagnostic performances of 10 fibrosis indices were evaluated to identify patients with poor prognosis. Moreover, correlations of those with PBC clinical manifestation and survival were also investigated. Enhances liver fibrosis (ELF) score had the highest correlation coefficient for liver fibrosis evaluated according to either the Scheuer or Nakanuma classification among 10 serum fibrosis indices. It also had the highest diagnostic performance in estimating Scheuer stage III and Nakanuma fibrosis score 2, both of which represent portal-bridging fibrosis. Patients with an ELF score of ≥10.0 had shorter survival and presented more frequently clinical complications than those with an ELF score of

AIM To determine the efficacy of rifaximin for hepatic encephalopathy (HE) with the linkage of gut microbiome in decompensated cirrhotic patients. METHODS Twenty patients (12 men and 8 women; median age, 66.8 years; range, 46-81 years) with decompensated cirrhosis (Child-pugh score > 7) underwent cognitive neuropsychological testing, endotoxin analysis, and fecal microbiome assessment at baseline and after 4 wk of treatment with rifaximin 400 mg thrice a day. HE was determined by serum ammonia level and number connection test (NCT)-A. Changes in whole blood endotoxin activity (EA) was analyzed by endotoxin activity assay. Fecal microbiome was assessed by 16S ribosome RNA (rRNA) gene sequencing. RESULTS Treatment with rifaximin for 4 wk improved hyperammonemia (from 90.6 ± 23.9 μg/dL to 73.1 ± 33.1 μg/dL; P < 0.05) and time required for NCT (from 68.2 ± 17.4 s to 54.9 ± 20.3 s; P < 0.05) in patients who had higher levels at baseline. Endotoxin activity was reduced (from 0.43 ± 0.03 to 0.32 ± 0.09; P < 0.05) in direct correlation with decrease in serum ammonia levels (r = 0.5886, P < 0.05). No statistically significant differences were observed in the diversity estimator (Shannon diversity index) and major components of the gut microbiome between the baseline and after treatment groups (3.948 ± 0.548 at baseline vs 3.980 ± 0.968 after treatment; P = 0.544), but the relative abundances of genus Veillonella and Streptococcus were lowered. CONCLUSION Rifaximin significantly improved cognition and reduced endotoxin activity without significantly affecting the composition of the gut microbiome in patients with decompensated cirrhosis.

Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). Lusutrombopag, an oral thrombopoietin receptor agonist, is used to reduce the risk of hemorrhage in patients with thrombocytopenia who are undergoing invasive procedures. Platelet transfusion was the standard treatment for thrombocytopenia; however, multiple platelet transfusions lead to the production of antiplatelet antibody. The effect of giving lusutrombopag three times or more has not been previously reported. In this study, we investigated the effect of lusutrombopag readministration in patients with thrombocytopenia.This study included 14 patients (total, 24 readministrations) who received lusutrombopag two times or more. Changes in platelet counts were evaluated. Treatment response was defined as an increased platelet count of ≥20 000/μL after lusutrombopag treatment.Lusutrombopag was given twice in nine patients, three times in three patients, five times in one patient, and six times in one patient. An elevated platelet count of20 000/μL was noted in only one of the 24 readministrations. There were no postoperative hemorrhagic complications, and no patient had an increased platelet count of200 000/μL. One patient had a portal venous mural thrombus; however, he was asymptomatic, and the thrombus resolved after anticoagulant treatment, without recurrence. The comparison between the first, second, and third or more treatments showed there was no significant difference in platelet increase.Repeated treatment of lusutrombopag is effective for CLD patients with thrombocytopenia. Moreover, three or more treatments with lusutrombopag showed equal effect compared with one and two treatments with the medication.

BackgroundTo investigate the von Willebrand factor to ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma (HCC) in cirrhosis.MethodsSerum levels of alpha-fetoprotein, des-γ-carboxy prothrombin,Lens culinarisagglutinin-reactive fraction of alpha-fetoprotein (alpha-fetoprotein-L3%), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2, as well as the plasma levels of von Willebrand factor antigen (von Willebrand factor: Ag) and ADAMTS13 activity (ADAMTS13:AC), were evaluated in 41 cirrhotic patients with HCC undergoing radiofrequency ablation and in 20 cirrhotic patients without HCC. The diagnostic accuracy of each biomarker was evaluated using the receiver operating characteristic curve analysis.ResultsThe von Willebrand factor: Ag and von Willebrand factor: Ag/ADAMTS13:AC ratios were significantly higher in cirrhotic patients with HCC than in those without HCC (p p ConclusionsThe von Willebrand factor: Ag/ADAMTS13:AC ratio can potentially serve as a novel biomarker for early diagnosis of HCC in cirrhotic patients.

Patients with liver cirrhosis frequently experience non-specific symptoms and report severe reductions in their quality of life (QOL). The underlying mechanisms of the disease are multifactorial that may be specific to the disease or directly related to the liver. The major concern of liver cirrhosis with ascites, however, is the decreased QOL. Therefore, in the present study, the Ascites Symptom Inventory-7 (ASI-7) questionnaire was applied to subjectively evaluate the symptoms in patients with cirrhotic ascites following tolvaptan administration. In total, 69 patients with liver cirrhosis with ascites hospitalized to Nara Medical University were evaluated after being treated with tolvaptan (3.75-7.5 mg/day) and conventional diuretics between December 2013 and April 2018. A follow-up assessment was conducted 7 days after tolvaptan treatment, whilst ASI-7 was used on days 1 and 8 of the study. After an uneventful 7-day tolvaptan treatment regimens, 49 patients (71.0%) lost >1.5 kg of their body weight, who were referred to as responders, with the change in the ASI-7 score being found to correlate with the body weight change. By contrast, changes in urine volume did not correlate with those in the ASI-7 score. The responders experienced a greater reduction in the ASI-7 score after 7 days compared with those in the non-responders (P

Background and aim Patients with cirrhosis usually experience muscle cramps of varying severity. Although diuretics have been reported to cause muscle cramps, clinical evidence is limited. Also, it has been pointed out that the use of diuretics is associated with the progression of sarcopenia in patients with cirrhosis. We conducted a questionnaire survey to clarify the effects of diuretics and skeletal muscle loss on muscle cramps. Methods Overall, we enrolled 152 adults with cirrhosis in this study. Cramp questionnaires were obtained after informed consent. Study variables (demographics, physical findings, serum metabolic panel, and drugs taken that affect muscle cramps) were extracted from medical records. Body composition, including muscle volume, was analyzed using a bioelectrical impedance analysis method, and muscle strength (handgrip) was evaluated at enrollment. Cross-sectional skeletal muscle area was evaluated on computed tomography imaging at the L3 vertebral level to investigate the relationship between muscle cramps and sarcopenia. Results The proportion of furosemide administration was higher in patients with cramping compared with those without. On a multivariate logistic regression analysis, furosemide use was a significant factor in the presence of muscle cramps. Furthermore, regarding factors contributing to muscle cramp severity, furosemide use was extracted by multivariate logistic regression analysis. In the presence or severity of muscle cramps, skeletal muscles did not show any significant difference. Conclusions Furosemide use for patients with cirrhosis was considered a risk factor for occurrence and severity of muscle cramps. On the other hand, skeletal muscle mass loss was not associated with muscle cramps.

Despite the availability of molecularly targeted agents for advanced hepatocellular carcinoma (aHCC), these are limited to compensated cirrhotic patients, and concerns about decreased hepatic functional reserve (HFR) and unknown adverse events, which may affect long-term survival, remain unaddressed. In this study, we enrolled 96 aHCC patients treated with bimonthly hepatic arterial infusion chemotherapy (B-HAIC) with cisplatin or sorafenib monotherapy (oral sorafenib 400 mg twice daily) not only to demonstrate its efficacy and significance but also to indicate preferable candidates by setting a response-related biomarker. Differences in treatment had no significant effect on overall survival (OS). The response rate in patients treated with B-HAIC was relatively higher than those treated with sorafenib. HFR was well maintained over the treatment course with B-HAIC, while it was significantly impaired with sorafenib. By employing multivariate analysis, we found negative trends between progression-free survival (PFS) periods and serum levels of alpha fetoprotein as well as des-gamma-carboxy prothrombin (DCP). In addition, a logistic regression analysis of the relationship between serum DCP levels and PFS periods over 420 days (14 months) showed that the PFS periods of patients with higher DCP was significantly shorter than those of patients with lower DCP (p = 0.02). Subsequently, the present study demonstrated the efficacy and safety of B-HAIC and identified a predictor of unpreferable patients. Based on these results, B-HAIC might be an alternative treatment after the implementation of new molecularly targeted therapies.

L-carnitine (4-N-trimethylammonium-3-hydroxybutyric acid) is the physiologically active form of carnitine and is a natural compound that has been shown to exhibit antioxidant activity. L-carnitine is used as a supplementary treatment in patients with cirrhosis with hepatic encephalopathy, hyperammonemia or muscle cramps. In the present study, the effect of L-carnitine supplementation on health-related quality of life in 30 patients with cirrhosis was prospectively examined. L-carnitine (1,800 mg/day) was administered orally for 6 months. To assess the effects of L-carnitine on chronic fatigue, patients filled out a self-report questionnaire regarding their physical and mental health. The levels of total and free carnitine, and acylcarnitine were found to be significantly higher 1, 3 and 6 months after therapy initiation compared with before treatment. Serum albumin levels were significantly increased 3 and 6 months after initiation of therapy. L-carnitine supplementation significantly increased the BAP/d-ROM ratio, a marker of antioxidant status in patients with cirrhosis. Changes in serum carnitine concentrations were positively correlated with changes in serum albumin levels (R2=0.369; P=0.012), but not with changes in serum ammonia levels (R2= 0.005; P=0.78). Total and mental health scores improved significantly, and physical scores improved marginally 3 and 6 months after initiation of L-carnitine. These findings may be attributed to the enhanced serum albumin levels and oxidative stress rather than the reduced serum ammonia levels. Based on these results, it is suggested that L-carnitine can potentially alleviate chronic fatigue, along with the increased BAP/d-ROM ratio, which were involved in increased oxidative stress in patients with cirrhosis. The specific mechanisms by which L-carnitine ameliorates chronic fatigue is not fully understood and requires further investigation.

It is unclear whether the link between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) is mediated by common risk factors. We aimed to elucidate the association between NAFLD and CKD using propensity score (PS)-matched analysis. We assessed 3725 Japanese individuals, excluding those with hepatitis B or C infection and men and women who consumed &gt, 30 and &gt, 20 g/day of alcohol, respectively. Of these, we enrolled 1097 Japanese subjects with NAFLD diagnosed by ultrasonography and 1097 PS-matched subjects without NAFLD. The prevalence of CKD was higher in subjects with NAFLD than in those without NAFLD before PS matching, but there was no significant difference between these groups in terms of CKD prevalence after PS matching. There was no difference in the prevalence of CKD between those with and without NAFLD in the subgroup analyses. Logistic regression analysis demonstrated that obesity, hypertension, and hyperuricemia were independent predictors of CKD, but NAFLD was not independently associated with CKD. In subjects with NAFLD, obesity, hypertension, and hyperuricemia were independent predictors of CKD. Thus, the link between NAFLD and CKD may be mediated by common risk factors. We recommend screening for CKD when patients with NAFLD have the aforementioned comorbidities.

BACKGROUND Many advanced hepatocellular carcinoma (HCC) patients are receiving sorafenib treatment. Sorafenib reportedly improves overall survival (OS) significantly in patients with HCC. Prediction of sorafenib response and prognosis in patients with HCC receiving sorafenib treatment are important due to the potentially serious side effects of sorafenib. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) and von Willebrand factor (VWF) are associated with the pathophysiology of liver cirrhosis and HCC through their roles in hypercoagulability; they are also associated with angiogenesis via vascular endothelial growth factor (VEGF). The imbalance between ADAMTS13 and VWF was associated with prognosis of various cancers in patients undergoing chemotherapy. AIM To investigate ADAMTS13 and VWF as potential biomarkers for sorafenib response and prognosis in patients with HCC receiving sorafenib treatment. METHODS Forty-one patients with HCC receiving sorafenib treatment were included in this study. The initial daily sorafenib dose was 400 mg in all patients. ADAMTS13 activity (ADAMTS13:AC), VWF antigen (VWF:Ag), VEGF levels were determined by enzyme-linked immunosorbent assay. Univariate and multivariate analyses were used to determine predictive factors for sorafenib response and prognosis in patients with HCC receiving sorafenib treatment. RESULTS ADAMTS13:AC was significantly higher in patients with stable disease (SD), partial response (PR), and complete response (CR) than in those with progressive disease (PD) (P < 0.05). In contrast, VWF:Ag and the VWF:Ag/ADAMTS13:AC ratio were significantly lower in patients with SD, PR, and CR than in those with PD (P < 0.05 for both). Multivariate analysis showed that the VWF:Ag/ADAMTS13:AC ratio was the only predictive factor for sorafenib response and ADAMTS13:AC was the only prognostic factor in patients with HCC receiving sorafenib treatment. The patients with a low ADAMTS13:AC (< 78.0) had significantly higher VEGF levels than those with a high ADAMTS13:AC (≥ 78.0) (P < 0.05). CONCLUSION The VWF:Ag/ADAMTS13:AC ratio and ADAMTS13:AC are potentially useful biomarkers for sorafenib response and prognosis, respectively, in patients with HCC receiving sorafenib treatment.

Depression is a major reason for interferon (IFN) therapy cessation. IFN-free direct-acting antiviral (DAA) therapy for depression is not well-documented. Thus, four different IFN-free regimens were assessed in genotype-1 hepatitis C virus (HCV) patients with depression. Overall, 287 HCV genotype-1 patients who received combination therapies with IFN-free DAAs of daclatasvir/asunaprevir (DCV/ASV) (n=84), sofosbuvir/ledipasvir (SOF/LDV) (n=95), ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) (n=74), and elbasvir/grazoprevir (EBR/GZR) (n=34) were included. Treatment-induced depression as a complication of HCV therapy in IFN-free DAA regimens was assessed. The severity of depression was evaluated using the Beck Depression Inventory-II (BDI-II) questionnaire. It was demonstrated that all four DAA regimens achieved similar high efficacy in Japanese patients with HCV genotype-1 infection. Moreover, in seven patients with depression who received the 24-week DCV/ASV treatment regimen, the BDI-II scores significantly increased at week 4 as compared with pretreatment values; furthermore, they decreased below baseline at week 12 despite the rapid decline of serum HCV levels after the initiation of DCV/ASV therapy. The BDI-II scores gradually decreased during therapy in the remaining 77 DCV/ASV-treated patients without depression. The BDI-II scores showed a significant decrease from baseline to the end of treatment with 12-week regimens, including SOF/LDV and EBR/GZR. The 12-week DAA regimen of SOF/LDV and EBR/GZR can be safely used with high efficacy in patients with genotype-1 HCV infection, including those with depression.

Several noninvasive biomarkers are available for diagnosing liver fibrosis stage and predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis and liver cirrhosis. However, these biomarkers are not sufficiently accurate. Recently, von Willebrand factor (VWF) has been related to angiogenesis and apoptosis. Furthermore, VWF is associated with hepatic spare ability and HCC.We aimed to determine whether VWF is a potential biomarker for liver fibrosis and HCC development.Two hundred and twelve patients with chronic hepatitis B and C were recruited. VWF antigen (VWF: Ag) levels in each patient were determined via enzyme-linked immunosorbent assay. Univariable and multivariable analyses were used to determine the risk factor of HCC.The VWF: Ag levels were higher in patients with severe liver fibrosis stage and/or HCC development than in those without. The area under the curve of VWF: Ag for diagnosis of severe liver fibrosis stage was 0.721. Multivariable analysis showed that only VWF: Ag was a predictive biomarker for HCC development.VWF: Ag is related to liver fibrosis and may be useful for predicting HCC development. VWF is a potentially useful biomarker to diagnose severe liver fibrosis and predict HCC development.

Background We present the first description of en bloc endoscopic submucosal dissection (ESD) for total circumferential Barrett’s adenocarcinoma, predominantly of the long-segment Barrett’s esophagus (LSBE), with a 2-year follow-up and management strategies for esophageal stricture prevention. Case presentation A 59-year-old man was diagnosed with LSBE and Barrett’s adenocarcinoma by esophagogastroduodenoscopy (EGD). A 55-mm-long circumferential tumor was completely resected by ESD. Histopathology revealed a well-differentiated adenocarcinoma within the LSBE superficial muscularis mucosa. For post-ESD stricture prevention, the patient underwent an endoscopic triamcinolone injection administration, oral prednisolone administration, and preemptive endoscopic balloon dilatation. Two years later, there is no evidence of esophageal stricture or recurrence. Conclusions ESD appears to be a safe, effective option for total circumferential Barrett’s adenocarcinoma in LSBE.

The farnesoid X receptor (FXR) agonist, a bile acid-activated nuclear receptor, has been shown to improve the histologic features of nonalcoholic steatohepatitis (NASH); however, a satisfactory effect on hepatic fibrosis has not been achieved. We aimed to investigate the combined effect of FXR agonist and angiotensin II type 1 receptor blocker on hepatic fibrogenesis in rat models of NASH. For 8 weeks, two rat models of NASH were developed. Otsuka Long-Evans Tokushima Fatty (OLETF) rats were administered intraperitoneal injections of 1 mL/kg pig serum (PS) twice a week, whereas Fischer-344 rats were fed a choline-deficient, L-amino acid-defined diet (CDAA). The in vitro and in vivo effects of an FXR agonist (INT747) and an angiotensin II type 1 receptor blocker (losartan) on hepatic fibrogenesis were evaluated. In PS-administered OLETF rats, INT747 and losartan had potent inhibitory effects on hepatic fibrogenesis with suppression of hepatic stellate cell (HSC) activation and expression of transforming growth factor β1 and toll-like receptor 4. INT747 decreased intestinal permeability by ameliorating zonula occuludens-1 disruption, whereas losartan directly suppressed activated-HSC (Ac-HSC) regulation. The in vitro inhibitory effects of INT747 and losartan on messenger RNA expressions of transforming growth factor β1, toll-like receptor 4, and myeloid differentiation factor 88 and phosphorylation of nuclear factor-κB and mothers against decapentaplegic homolog 3 in Ac-HSC were almost in parallel. Losartan directly inhibited the regulation of Ac-HSC. Likewise, INT747 in combination with losartan was beneficial on hepatic fibrogenesis in rats fed with CDAA diet. The therapeutic effects of these agents were almost comparable between PS-administered OLETF and CDAA-treated rats. Conclusion: INT747 and losartan synergistically suppressed hepatic fibrogenesis by reversing gut barrier dysfunction and inhibiting Ac-HSC proliferation. Combined therapy may represent a promising novel approach for NASH. (Hepatology Communications 2017;1:928-945).

Cirrhosis patients often have abnormal glucose metabolism. We investigated the effects of a late-evening snack (LES) with branched-chain amino acid-enriched nutrients (BCAA-EN) on glucose metabolism in cirrhosis patients. LES with BCAA-EN was administered for 1 week in 13 patients with cirrhosis and hypoalbuminemia. Blood glucose (BG) levels were measured every 15 min. The patients were divided into two groups based on BG levels: group 1 (G1, n = 11): nocturnal BG levels n = 2): nocturnal BG levels ≥200 mg/dL. G1 had nocturnal BG levels p < 0.01). The glycated albumin level (16.6 ± 0.9% vs. 16.2 ± 2.1%), fasting immunoreactive insulin (F-IRI) level (53.9 ± 34.0 μU/mL vs. 16.5 ± 11.0 μU/mL), and homeostasis model assessment of insulin resistance (HOMA-IR) score (17.85 ± 10.58 vs. 4.02 ± 2.59) were significantly higher in G2 than in G1 (p < 0.05, p < 0.05, and p < 0.01, respectively). The quantitative insulin sensitivity check indices (0.32 ± 0.03 vs. 0.27 ± 0.02) were significantly higher in G1 than in G2 (p < 0.01). One patient in G2 was obese and had type 2 diabetes. The other patient was obese and had a high HOMA-IR score and F-IRI level. A LES with BCAA-EN does not inhibit overt diabetes in most cirrhosis patients. However, close attention should be paid to fluctuations in BG levels in cirrhosis patients who present with obesity and severe insulin resistance.

To examine predictive factors for abdominal obesity or metabolic syndrome, we investigated the association of plasma fatty acid composition, estimated desaturase activity, and nutrient intakes, with abdominal obesity or metabolic syndrome in Japanese males. Clinical characteristics, the fatty acid composition of plasma cholesteryl esters, and energy and nutrient intakes were analyzed in 3 groups: metabolic syndrome (MS, n=24), abdominal obesity (OB, n=43), and control (n=27). The estimated desaturase activities were calculated by the ratio of 16:1n-7/16:0, 18:3n-6/18:2n-6, and 20:4n-6/20:3n-6 in plasma cholesteryl esters as surrogates of the measure of the delta 9, delta 6, delta 5 desaturase (D9-16D, D6D and D5D) activities, respectively. Plasma fatty acid composition did not differ significantly between the OB group and the control group. The MS group had higher levels of palmitoleic, oleic, and gamma-linolenic acids, but a lower level of linoleic acid than the control. Stronger D6D activity and weaker D5D activity were observed in the OB group. A higher level of D9-16D activity as well as a higher level of D6D activity and a lower level of D5D activity was observed in the MS group. A logistic regression analysis showed that the low D5D activity and high D9-16D activity were predictive of the development of abdominal obesity from controls (odds ratio=0.39, p0.05) and metabolic syndrome from abdominal obesity (odds ratio=2.44, p0.05), respectively. In the multiple linear regression analysis, D5D activity positively correlated with the intake of eicosapentaenoic acid (EPA). In conclusion, the estimated D5D activity was a predictive factor for abdominal obesity and the estimated D9-16D activity was a predictive factor for developing metabolic syndrome from abdominal obesity in Japanese male subjects. Dietary intake of EPA would play an important role in preventing abdominal obesity and the development of metabolic syndrome.