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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.

Introoduction: Primary sclerosing cholangitis (PSC) is a rare disease, especially in Asian countries. PSC often develops during ulcerative colitis (UC). Little is known about the severity of PSC in patients with UC. Thus, this study aimed to investigate the impact of concomitant UC on the clinical course of patients with PSC using a nationwide database in Japan. Methods: We collected data on patients who were admitted for PSC using a nationwide database and divided eligible admissions according to concomitant UC (PSC-UC group vs. PSC-alone group). We conducted propensity score matching and compared the rates of liver transplantation, biliary drainage, and other clinical events between the two groups. We also conducted a multivariate analysis to identify the clinical factors that affect biliary drainage, cholangiocarcinoma, and liver transplantation. Results: We enrolled 672 patients after propensity score matching. The rate of liver transplantation in the PSC-UC group was lower than that in the PSC-alone group (2.2 vs. 5.4%, p = 0.002), whereas the rate of biliary drainage did not differ between the two groups (38.1 vs. 33.8%, p = 0.10). On multivariate analysis, concomitant UC was identified as a clinical factor that decreased the risk of liver transplantation (odds ratio = 0.40, 95% confidence interval: 0.23–0.68, p = 0.0007). Discussion: Concomitant UC in patients with PSC may decrease the risk of liver transplantation. The milder disease activity of PSC with UC is more likely compared to that of PSC without UC.

Aims Primary sclerosing cholangitis (PSC) is a relatively common complication of ulcerative colitis (UC). Only a few studies have investigated the impact of PSC on the clinical course of UC, and their conclusions are contradictory. Therefore, we aimed to compare the disease activity of UC with and without PSC. Methods and Results We collected UC patient data using the Diagnosis Procedure Combination database system in Japan and classified eligible admissions into two groups based on their diagnosis of either UC alone or UC associated with PSC. We then compared therapeutic details (medical treatment and surgery) between the two groups. Multivariable logistic regression analysis and propensity score matching was also performed. The rates of systemic steroid injection and infliximab administration in patients with PSC were lower than those in patients without PSC (21% vs. 28%, P = 0.012, 9.6% vs. 16%, P = 0.01, respectively). The rates of surgery, colorectal cancer, duration of hospital stay, and in‐hospital mortality did not differ between the two groups. Multivariable analysis revealed that concomitant PSC was a clinical factor that reduced the odds of systemic steroid injection (odds ratio [OR] = 0.66, 95% confidence interval [CI]: 0.49–0.90, P = 0.008) and infliximab (OR = 0.48, 95% CI: 0.32–0.74, P = 0.0008) administration. Conclusion UC patients with PSC might have less UC disease activity than those with UC alone., We compared ulcerative colitis alone (UC) and UC‐associated primary sclerosing cholangitis (UC‐PSC) using a nationwide database in Japan. The propensity score‐matched analysis revealed that the rates of administration of systemic steroid and infliximab in the UC‐PSC group were lower than that of the UC group. Our results indicate that UC‐PSC patients might have lesser disease activity compared to UC patients.

BACKGROUND AND AIM Although colonic diverticular bleeding (CDB) is considered to have good prognosis with conservative therapy, some cases are severe. The efficacy of urgent colonoscopy for CDB and clinical factors affecting CDB prognosis are unclear. This study aimed to evaluate the efficacy of urgent colonoscopy for CDB and identify risk factors for unfavorable events, including in-hospital death during admission, owing to CDB. METHODS We collected CDB patients' data using the Diagnosis Procedure Combination database system. We divided eligible patients into urgent and elective colonoscopy groups using propensity score matching and compared endoscopic hemostasis and in-hospital death rates and length of hospital stay. We also conducted logistic regression analysis to identify clinical factors affecting CBD clinical events, including in-hospital death, a relatively rare CDB complication. RESULTS Urgent colonoscopy reduced the in-hospital death rate (0.35% vs 0.58%, P = 0.033) and increased the endoscopic hemostasis rate (3.0% vs 1.7%, P

We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient l-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis.

Background & aims PNPLA3 rs738409 has been associated with increased risks of fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Recently, carriage of the rs6834314 G allele, which is in high linkage with rs72613567 of 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13), was reported to be associated with a reduced risk of liver injury in NAFLD patients. We estimated the impact of these genetic variants on hepatic fibrosis in Japanese patients with NAFLD. Methods We analysed the associations of these genetic variants with liver histology in 290 Japanese patients with biopsy-proven NAFLD diagnosed during 2002-2019. During follow-up, 14 patients (4.8%) developed hepatocellular carcinoma. Results Prevalences of the PNPLA3 rs738409 genotypes were 0.17 for CC, 0.41 for CG, 0.42 for GG, and those for HSD17B13 rs6834314 were 0.54 for AA, 0.39 for AG and 0.07 for GG. There was no significant interaction between the PNPLA3 and HSD17B13 genotypes. Prevalences of advanced fibrosis according to PNPLA3/HSD17B13 genotypes were 0.16 for CC,CG/AG,GG, 0.20 for CC,CG/AA, 0.30 for GG/AG,GG and 0.37 for GG/AA. Multivariate analysis identified PNPLA3 GG as a predictor of advanced fibrosis (stage 3/4) in carriers of HSD17B13 AA (odds ratio 2.4, P = .041), but not HSD17B13 AG/GG (P = .776). The HSD17B13 genotype G was significantly associated with lower prevalences of severe inflammation and ballooning and tended to be associated with a higher prevalence of advanced steatosis. Conclusions In Japanese patients with NAFLD, carriage of the HSD17B13 rs6834314 G allele attenuated the effect of the PNPLA3 rs738409 GG genotype on advanced hepatic fibrosis.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.

Background: weight loss as a result of lifestyle intervention is effective when treating non-alcoholic fatty liver disease (NAFLD). We estimated the effects of PNPLA3 rs738409 and HSD17B13 rs6834314 variants in response to diet therapy in Japanese patients with NAFLD. Methods: we analyzed the correlation between the change in liver stiffness and change in body weight in 140 patients administered diet therapy for 1-year, according to PNPLA3 and HSD17B13 genotypes. Results: the bodyweight (BW) reduction rate was greater in patients with the PNPLA3 genotype CC than CG and GG (p = 0.035). Change in liver stiffness measurement (LSM) was significantly associated with a change in BW in PNPLA3 CG/GG (r = 0.279/0.381), but not in PNPLA3 CC (p = 0.187). Change in LSM was correlated with change in BW only in patients with HSD17B13 AG/GG (r = 0.425), but not the AA genotype (p = 0.069). A multivariate analysis identified that a change in LSM was correlated with a change in BW in carriers of HSD17B13 AG/GG (B = 3.043, p = 0.032), but not HSD17B13 AA. The change in LSM of patients with a BW reduction of more than 7% (0.50) was significantly greater than that of patients with a BW reduction of less than 7% (0.83) (p = 0.038). Conclusions: in Japanese patients with NAFLD, HSD17B13 rs6834314 polymorphism is associated with the change in LSM by lifestyle intervention. The approach, including genetic assessments, may contribute to the establishment of appropriate therapeutic strategies to treat NAFLD.

Background and Aim The number of elderly patients with ulcerative colitis (UC) is increasing worldwide. The clinical practice of associated treatment is still unclear. Therefore, we aimed to analyze clinical treatment realities and mortality in elderly and non‐elderly patients with UC. Methods We collected UC patients' data using the diagnosis procedure combination (DPC) database system and divided eligible patients into elderly (≥65 years) and non‐elderly (≤64 years) groups. We investigated and compared their therapeutic histories (medical treatments vs. surgery). Logistic regression analysis was conducted to identify clinical factors affecting surgery and in‐hospital death in each group. Results The rates of systemic steroid injection, molecular targeting drug usage, and surgery were not different between the two age groups. Meanwhile, the rate of in‐hospital death in elderly patients was higher than that in non‐elderly patients (2.7% vs. 0.19%, P, The clinical practice of treating elderly patients with ulcerative colitis (UC) is overall not different from treating non‐elderly patients with UC. Although the form of medical treatment and surgery rate for elderly patients with UC may not be significantly different from non‐elderly patients, the rate of in‐hospital death for elderly patients is higher.

In patients with nonalcoholic fatty liver disease (NAFLD), liver fibrosis is the predictive factor for liver-related events and prognosis. This retrospective study aimed to evaluate longitudinal changes in the FIB-4 index and to determine a strategy for diagnosing and following patients with NAFLD using this index. We analyzed the FIB-4 index at baseline and after 1 and 5 years in 272 consecutive patients with biopsy-proven NAFLD. Of these, 52 patients underwent serial biopsies. The change in the FIB-4 index was correlated with changes in the fibrosis stage among these patients (p = 0.048). The median FIB-4 index was 1.64 at baseline, 1.45 at 1 year, and 1.74 at 5 years. The negative predictive value for advanced fibrosis at a low cutoff point was 90.4/90.1 at baseline/1 year. Its specificity at a high cutoff point increased from 65.0% at baseline to 82.3% at 1 year. Multivariate analysis identified the FIB-4 index at 1 year as a predictive factor for a FIB-4 index &gt, 2.67 at 5 years. A FIB-4 index &lt, 1.30 was acceptable for excluding advanced fibrosis at baseline. In contrast, to evaluate and predict advanced liver fibrosis with the FIB-4 index at a high cutoff point, we should use the index at 1 year after appropriate therapy.

Aim Dyslipidemia (DL) is commonly associated with non-alcoholic fatty liver disease (NAFLD). Pemafibrate, a selective peroxisome proliferator activated receptor α modulator (SPPARMα), has been shown to improve liver function among patients with DL. The aim of this single-arm prospective study is to evaluate the efficacy of pemafibrate in NAFLD patients with DL. Methods Twenty NAFLD patients with DL who received pemafibrate (0.1 mg) twice a day for 12 weeks were prospectively enrolled in this study. The primary end-point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12. Results Serum ALT levels decreased from 75.1 IU/L at baseline to 43.6 IU/L at week 12 (P = 0.001). Significant improvements in triglyceride, high-density lipoprotein cholesterol, total fatty acid, saturated fatty acid (SFA), and unsaturated fatty acid were also noted. The serum level of remnant-like protein cholesterol, SFA, and polyunsaturated / saturated fatty acid ratio (PUFA / SFA ratio) at baseline were correlated with change in ALT level (r = -0.53, r = -0.57, and r = 0.46, respectively). Change in PUFA and change in PUFA / SFA ratio were negatively correlated with change in ALT level (r = -0.49 and r = -0.53). No hepatic or renal adverse events were reported. Conclusions Selective peroxisome proliferator activated receptor α could be a promising novel agent for treatment of NAFLD patients with DL by regulating fatty acid composition. A further long-term large-scale trial is warranted to confirm the efficacy of SPPARMα on NAFLD with DL.

Sodium-glucose cotransporter-2 inhibitors (SGLT2I) have been reported to have renal-protective effects in patients with type 2 diabetes (T2DM). This a retrospective study aimed to evaluate the effect of SGLT2I on renal function in patients with nonalcoholic fatty liver disease (NAFLD) and T2DM. We analyzed 69 consecutive patients with a biopsy-proven NAFLD and T2DM with an estimated glomerular filtration rate (eGFR) &gt, 60 mL/min. Of these 69 patients, 22 received SGLT2I and 47 were treated without SGLT2I. Liver function and eGFR were analyzed at baseline and after three years. Body mass index, liver function and HbA1c improved significantly in both groups. In the total population, the median eGFR declined from 80.7 mL/min at the baseline to 74.9 mL/min at the end of follow-up. The median eGFR at the baseline/end of follow-up was 81.2/80.4 mL/min in patients treated with SGLT2I and 80.2/70.8 mL/min in patients treated without SGLT2I. Multivariate analysis identified an increased FIB-4 index with an odds ratio (OR) of 4.721, (p = 0.045) and SGLT2I treatment (OR 0.263, p = 0.033) as predictive factors for decreased eGFR. SGLT2I treatment has a protective effect on the renal function for NAFLD with T2DM. A long-term, randomized, controlled trial is warranted to confirm the renal protective effect of SGLT2I in NAFLD patients with T2DM.

An 85-year-old woman underwent endoscopic retrograde cholangiopancreatography (ERCP) for obstructive jaundice. Selective bile duct cannulation was unsuccessful because of periampullary diverticula (PAD). A pancreatic spontaneous dislodgement stent (PSDS) (5F diameter, 3 cm, straight type) was inserted to prevent post-ERCP pancreatitis. Three days after ERCP, she complained of abdominal pain, and computed tomography revealed retroperitoneal perforation because of PSDS migration to the PAD. If the papillary orifice is observed at the diverticular rim or in the diverticula, a pigtailed PSDS on the duodenal side or flanged stent on the pancreatic ductal side should be inserted in order to prevent this rare adverse event.

Since the introduction of direct-acting antiviral (DAA)-based combination therapies in September 2014 for patients with chronic hepatitis-C (CH-C), numerous patients have been diagnosed with hepatitis-C virus (HCV)-associated hepatocellular carcinomas (HCCs) during the screening performed prior to DAA therapy. The present study was conducted on the antiviral therapy for CH-C in two phases:i) the interferon (IFN) phase between January 2011 and August 2014 and ii) the DAA phase between September 2014 and September 2016. During the DAA phase, HCCs were detected in eight patients who were referred to our hospital for anti-HCV therapy. In contrast, HCCs were detected in only two patients during the IFN phase. The number of patients with newly detected HCC in the DAA phase (20.5%) who were referred for the anti-HCV therapy was significantly higher than that in the IFN phase (1.7%). Owing to the high efficacy and safety of the DAA therapy, the number of patients referred to our hospital for anti-HCV therapy increased from 40.5 persons/year in the IFN phase to 80.3 persons/year in the DAA phase. The average ages of patients in the DAA and IFN phases were 68 and 61 years, respectively. The increase in the number of patients with newly detected HCC referred for the anti-HCV therapy in the DAA phase could be attributed to the increase in the number of referred patients for anti-HCV therapy and the aging of these patients in the DAA phase. All the eight patients with newly detected HCC who were referred for anti-HCV therapy in the DAA phase received curative treatments. The median age, rate of liver cirrhosis, and median tumor size of the patients were 69 years, 13%, and 16mm. Therefore, the findings of this study indicate that DAA therapies not only eradicate HCV infection but also contribute to the early diagnosis of HCC by encouraging the HCV-infected patients to visit hospitals and by promoting active network between hepatologists and family physicians.