Publications by authors named "Masato Yoneda"

317 Publications

Combination of tofogliflozin and pioglitazone for NAFLD: Extension to the ToPiND randomized controlled trial.

Hepatol Commun 2022 May 16. Epub 2022 May 16.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

The incidence of nonalcoholic fatty liver disease (NAFLD) has recently increased and is related to obesity and the associated surge in type 2 diabetes mellitus (T2DM) and metabolic syndromes. This trial follows up on our previous work and forms part of the ToPiND study. We aimed to combine tofogliflozin and pioglitazone treatment for hepatic steatosis in patients with NAFLD and T2DM. In this open-label, prospective, single-center, randomized clinical trial, patients with NAFLD with T2DM and a hepatic fat fraction of ≥10% were assessed based on magnetic resonance imaging proton density fat fraction. Eligible patients received either 20 mg tofogliflozin or 15-30 mg pioglitazone orally, once daily for 24 weeks, followed by combination therapy with both medicines for an additional 24 weeks. The effects on diabetes mellitus and hepatic steatosis were examined at baseline and after the completion of monotherapy and combination therapy. Thirty-two eligible patients received the combination therapy of tofogliflozin and pioglitazone. The combination therapy showed additional improvement in glycated hemoglobin compared with each monotherapy group and showed improvement in steatosis, hepatic stiffness, and alanine aminotransferase levels compared with the tofogliflozin monotherapy group. Pioglitazone monotherapy-mediated increase in body weight decreased following concomitant use of tofogliflozin. The combination therapy resulted in lower triglyceride, higher high-density lipoprotein cholesterol, higher adiponectin, and higher ketone body levels. Conclusion: In addition to the additive effects of tofogliflozin and pioglitazone in patients with T2DM and NAFLD, combination therapy was suggested to reduce weight gain and induce cardioprotective effect. Further studies with more patients are needed to investigate the combination therapy of various drugs.
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http://dx.doi.org/10.1002/hep4.1993DOI Listing
May 2022

Effectiveness of Naldemedine Compared with Magnesium Oxide in Preventing Opioid-Induced Constipation: A Randomized Controlled Trial.

Cancers (Basel) 2022 Apr 24;14(9). Epub 2022 Apr 24.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.

Opioid-induced constipation (OIC) may occur in patients receiving opioid treatment, decreasing their quality of life (QOL). We compared the effectiveness of magnesium oxide (MgO) with that of naldemedine (NAL) in preventing OIC. This proof-of-concept, randomized controlled trial (registration number UMIN000031891) involved 120 patients with cancer scheduled to receive opioid therapy. The patients were randomly assigned and stratified by age and sex to receive MgO (500 mg, thrice daily) or NAL (0.2 mg, once daily) for 12 weeks. The change in the average Japanese version of Patient Assessment of Constipation QOL (JPAC-QOL) from baseline to 2 weeks was assessed as the primary endpoint. The other endpoints were spontaneous bowel movements (SBMs) and complete SBMs (CSBMs). Deterioration in the mean JPAC-QOL was significantly lower in the NAL group than in the MgO group after 2 weeks. There were fewer adverse events in the NAL group than in the MgO group. Neither significant differences in the change in SBMs between the groups nor serious adverse events/deaths were observed. The CSBM rate was higher in the NAL group than in the MgO group at 2 and 12 weeks. In conclusion, NAL significantly prevented deterioration in constipation-specific QOL and CSBM rate compared with MgO.
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http://dx.doi.org/10.3390/cancers14092112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102438PMC
April 2022

Two-Step Strategy, FIB-4 Followed by Magnetic Resonance Elastography, for Detecting Advanced Fibrosis in NAFLD.

Clin Gastroenterol Hepatol 2022 Feb 2. Epub 2022 Feb 2.

NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, California; Division of Epidemiology, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California. Electronic address:

Background & Aims: A two-step strategy combining a serum marker and magnetic resonance elastography (MRE) for detecting advanced fibrosis (stage 3-4) among patients with nonalcoholic fatty liver disease (NAFLD) has been proposed, but its diagnostic accuracy has not been evaluated. In this multicenter study, we aimed to investigate the diagnostic accuracy of a two-step strategy including Fibrosis-4 (FIB-4) followed by MRE.

Methods: In this multicenter study, 806 patients with biopsy-proven NAFLD who underwent contemporaneous MRE were enrolled and randomly assigned to training and validation cohorts. As a first step, patients with FIB-4 <1.3 were defined as test negative regardless of MRE. As a second step, among patients with FIB-4 ≥1.3, MRE <3.6 and ≥3.6 kPa were defined as test negative and positive. The primary outcome was the diagnostic accuracy for advanced fibrosis comparing MRE alone versus the two-step strategy.

Results: Area under the receiver characteristic curves of MRE alone and the two-step strategy were 0.840 and 0.853 in the training cohort (P = .4) and 0.867 and 0.834 in the validation cohort (P = .2), respectively, and the diagnostic accuracy was comparable between the 2 methods. In the entire cohort, negative predictive value (NPV) and positive predictive value (PPV) of MRE for advanced fibrosis were 92.2% and 73.7%, respectively, whereas NPV at the first and second step and PPV at the second step were 90.9%, 84.4%, and 77.0%, respectively.

Conclusions: The diagnostic accuracy of the two-step strategy was comparable to MRE and could reduce cost by reducing excessive MRE. Therefore, the two-step strategy could be used as a screening method in a large population.
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http://dx.doi.org/10.1016/j.cgh.2022.01.023DOI Listing
February 2022

Gastroesophageal varices evaluation using spleen-dedicated stiffness measurement by vibration-controlled transient elastography.

JGH Open 2022 Jan 14;6(1):11-19. Epub 2021 Dec 14.

Department of Gastroenterology and Hepatology Yokohama City University Graduate School of Medicine Yokohama Japan.

Background And Aim: Liver stiffness measurement (LSM) and spleen stiffness measurement ([email protected] Hz) using standard vibration-controlled transient elastography (VCTE) have been studied as a noninvasive test for screening of gastroesophageal varices (GEV) in chronic liver disease (CLD). Recently, a novel spleen-dedicated VCTE ([email protected] Hz) has been developed. We evaluated the diagnostic performance of [email protected] Hz, [email protected] Hz, LSM, and other noninvasive tests using esophagogastroduodenoscopy (EGD) as the reference as well as the correlation with hepatic venous pressure gradient (HVPG).

Methods: A total of 123 patients with CLD enrolled in this cross-sectional study. [email protected] Hz, [email protected] Hz, and LSM were determined by VCTE. EGD and HVPG were performed within 12 weeks before or after VCTE.

Results: GEV were present in 60 patients. Failure or suboptimal SSM were fewer at 100 Hz (4.0%) than at 50 Hz (17.7%). All SSM values obtained at 100 Hz were lower than the 100 kPa ceiling threshold, but 10 patients reached the 75 kPa ceiling threshold for [email protected] Hz. [email protected] Hz was most accurate (area under the receiver operating characteristic [AUROC] = 0.944) for the diagnosis of GEV compared to [email protected] Hz, LSM, and scoring systems. AUROC of [email protected] Hz for diagnosis of high-bleeding risk varices (HRV) was 0.941, which was significantly higher than that of [email protected] Hz (AUROC = 0.842,  = 0.002). [email protected] Hz showed higher specificity (82.0%) for diagnosis of HRV than [email protected] Hz (specificity = 67.1%). [email protected] Hz was significantly correlated with HVPG ( = 0.71,  < 0.001).

Conclusions: The novel spleen-dedicated VCTE examination can be used for noninvasive assessment of GEV and HVPG in CLD. Japan Registry of Clinical Trials Registry No. jRCTs032200119.
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http://dx.doi.org/10.1002/jgh3.12689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762624PMC
January 2022

Clinical Outcomes in Biopsy-Proven Nonalcoholic Fatty Liver Disease Patients: A Multicenter Registry-based Cohort Study.

Clin Gastroenterol Hepatol 2022 Jan 17. Epub 2022 Jan 17.

Department of Clinical Pharmacology and Therapeutics, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Background & Aims: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage.

Methods: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients.

Results: The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality.

Conclusions: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.
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http://dx.doi.org/10.1016/j.cgh.2022.01.002DOI Listing
January 2022

Learning Curve of Endoscopic Retrograde Cholangiopancreatography Using Single-Balloon Enteroscopy.

Dig Dis Sci 2022 Jan 1. Epub 2022 Jan 1.

Division of Gastroenterology and Hepatology, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama, 2360004, Japan.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) in patients with surgically altered anatomy is technically difficult. Extensive training is required to develop the ability to perform this procedure.

Aims: To investigate the learning curve of single-balloon-assisted enteroscopy ERCP (SBE-ERCP).

Methods: We conducted a retrospective, observational case series at a single center. We evaluated the SBE-ERCP procedures between April 2011 and February 2021. The main outcomes were the rate of reaching the target site and the success rate of the entire procedure. These parameters were additionally expressed as a learning curve.

Results: A total of 687 SBE-ERCP procedures were analyzed. The learning curve was analyzed in blocks of 10 cases. In this study, seven endoscopists, experts in conventional ERCP, were included. The overall SBE-ERCP procedural success rate was 92.2% (634/687 cases). Combining all data from individual endoscopists' evaluation periods, the insertion and success rates of the SBE-ERCP procedures gradually increased with increased experience performing SBE-ERCP. The insertion success rates for the number of SBE-ERCP cases (< 20, 21-30, > 30) were 82.9%, 92.9%, and 94.3%, respectively; the procedure success rates were 74.3%, 81.4%, and 92.9%, respectively. The endoscopists who had performed > 30 SBE-ERCP cases had a success rate of ≥ 90%.

Conclusions: Our results suggest that performing > 30 cases is one of the targets for conventional ERCP experts to become competent in performing SBE-ERCP in patients with a surgically altered anatomy.
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http://dx.doi.org/10.1007/s10620-021-07342-2DOI Listing
January 2022

Influence of liver stiffness heterogeneity on staging fibrosis in patients with nonalcoholic fatty liver disease.

Hepatology 2021 Dec 24. Epub 2021 Dec 24.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Background And Aims: Despite that hepatic fibrosis often affects the liver globally, spatial distribution can be heterogeneous. This study aimed to investigate the effect of liver stiffness (LS) heterogeneity on concordance between MR elastography (MRE)-based fibrosis staging and biopsy staging in patients with NAFLD.

Approach And Results: We retrospectively evaluated data from 155 NAFLD patients who underwent liver biopsy and 3 Tesla MRE and undertook a retrospective validation study of 169 NAFLD patients at three hepatology centers. Heterogeneity of stiffness was assessed by measuring the range between minimum and maximum MRE-based LS measurement (LSM). Variability of LSM was defined as the stiffness range divided by the maximum stiffness value. The cohort was divided into two groups (homogenous or heterogeneous), according to whether variability was below or above the average for the training cohort. Based on histopathology and receiver operating characteristic (ROC) analysis, optimum LSM thresholds were determined for MRE-based fibrosis staging of stage 4 (4.43, kPa; AUROC, 0.89) and stage ≥3 (3.93, kPa; AUROC, 0.89). In total, 53 had LSM above the threshold for stage 4. Within this group, 30 had a biopsy stage of <4. In 86.7% of these discordant cases, variability of LSM was classified as heterogeneous. In MRE-based LSM stage ≥3, 88.9% of discordant cases were classified as heterogeneous. Results of the validation cohort were similar to those of the training cohort.

Conclusions: Discordance between biopsy- and MRE-based fibrosis staging is associated with heterogeneity in LSM, as depicted with MRE.
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http://dx.doi.org/10.1002/hep.32302DOI Listing
December 2021

Endotoxins and Non-Alcoholic Fatty Liver Disease.

Front Endocrinol (Lausanne) 2021 29;12:770986. Epub 2021 Oct 29.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. It occurs with a prevalence of up to 25%, of which 10-20% cases progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. The histopathology of NASH is characterized by neutrophilic infiltration, and endotoxins from gram-negative rods have been postulated as a contributing factor. Elevations in endotoxin levels in the blood can be classified as intestinal and hepatic factors. In recent years, leaky gut syndrome, which is characterized by impaired intestinal barrier function, has become a significant issue. A leaky gut may prompt intestinal bacteria dysbiosis and increase the amount of endotoxin that enters the liver from the portal vein. These contribute to persistent chronic inflammation and progressive liver damage. In addition, hepatic factors suggest that liver damage can be induced by low-dose endotoxins, which does not occur in healthy individuals. In particular, increased expression of CD14, an endotoxin co-receptor in the liver, may result in leptin-induced endotoxin hyper-responsiveness in obese individuals. Thus, elevated blood endotoxin levels contribute to the progression of NASH. The current therapeutic targets for NASH treat steatosis and liver inflammation and fibrosis. While many clinical trials are underway, no studies have been performed on therapeutic agents that target the intestinal barrier. Recently, a randomized placebo-controlled trial examined the role of the intestinal barrier in patients with NAFLD. To our knowledge, this study was the first of its kind and study suggested that the intestinal barrier may be a novel target in the future treatment of NAFLD.
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http://dx.doi.org/10.3389/fendo.2021.770986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586459PMC
February 2022

Role of vitamin E in the treatment of non-alcoholic steatohepatitis.

Free Radic Biol Med 2021 12 29;177:391-403. Epub 2021 Oct 29.

Hepatology Center, Saiseikai Suita Hospital, Osaka, Japan. Electronic address:

Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD), can progress to cirrhosis, hepatocellular carcinoma (HCC), and hepatic failure/liver transplantation. Indeed, NASH will soon be the leading cause of HCC and liver transplantation. Lifestyle intervention represents the cornerstone of NASH treatment, but it is difficult to sustain. However, no pharmacotherapies for NASH have been approved. Oxidative stress has been implicated as one of the key factors in the pathogenesis of NASH. Systematic reviews with meta-analyses have confirmed that vitamin E reduces transaminase activities and may resolve NASH histopathology without improving hepatic fibrosis. However, vitamin E is not recommended for the treatment of NASH in diabetes, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. Nevertheless, vitamin E supplementation may improve clinical outcomes in patients with NASH and bridging fibrosis or cirrhosis. Further studies are warranted to confirm such effects of vitamin E and that it would reduce overall mortality/morbidity without increasing the incidence of cardiovascular events. Future clinical trials of the use of vitamin E in combination with other anti-fibrotic agents may demonstrate an additive or synergistic therapeutic effect. Vitamin E is the first-line pharmacotherapy for NASH, according to the consensus of global academic societies.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.10.017DOI Listing
December 2021

Risk of cardiovascular disease in patients with fatty liver disease as defined from the metabolic dysfunction associated fatty liver disease or nonalcoholic fatty liver disease point of view: a retrospective nationwide claims database study in Japan.

J Gastroenterol 2021 11 3;56(11):1022-1032. Epub 2021 Oct 3.

Department of Gastroenterology and Hepatology, Yokohama City University Hospital, 3-9 Fukuura, Kanazawaku, Yokohama, 236-0004, Japan.

Background: Nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction associated fatty liver disease (MAFLD) have important associations with cardiovascular disease (CVD). The main objective of this study was to compare the frequency of incidence rate of CVD in the NAFLD or MAFLD patients utilizing a large claims database.

Methods: Using the JMDC database from April 2013 to March 2019, we retrospectively analyzed data for 1,542,688 and 2,452,949 people to estimate the relationship between CVD and NAFLD, MAFLD, respectively.

Results: The incidence rates of CVD were 0.97 (95% CI 0.94-1.01) and 2.82 (95% CI 2.64-3.01) per 1000 person-years in the non-NAFLD and NAFLD groups, respectively, and 1.01 (95% CI 0.98-1.03) and 2.69 (95% CI 2.55-2.83) per 1000 person-years in the non-MAFLD and MAFLD groups, respectively. The overall prevalence of hypertriglyceridemia and diabetes mellitus (DM) was 13.1, and 4.2%, respectively, in the non-NAFLD group and 63.6, and 20.2%, respectively, in the NAFLD group. The overall prevalenceof hypertriglyceridemia and DM was 13.6 and 4.3%, respectively, in the non-MAFLD group and 64.1, and 20.6%, respectively, in the MAFLD group. HRs for CVD increased with hypertriglyceridemia and DM.

Conclusions: Results indicated that incident rate of CVD increased with NAFLD/MAFLD; the complication rate of DM and hypertriglyceridemia among NAFLD/MAFLD patients is high and may affect the development of CVD.
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http://dx.doi.org/10.1007/s00535-021-01828-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531127PMC
November 2021

Ipragliflozin Improves the Hepatic Outcomes of Patients With Diabetes with NAFLD.

Hepatol Commun 2022 01 17;6(1):120-132. Epub 2021 Jun 17.

Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.

Sodium glucose cotransporter-2 inhibitors (SGLT2is) are now widely used to treat diabetes, but their effects on nonalcoholic fatty liver disease (NAFLD) remain to be determined. We aimed to evaluate the effects of SGLT2is on the pathogenesis of NAFLD. A multicenter, randomized, controlled trial was conducted in patients with type 2 diabetes with NAFLD. The changes in glycemic control, obesity, and liver pathology were compared between participants taking ipragliflozin (50 mg/day for 72 weeks; IPR group) and participants being managed without SGLT2is, pioglitazone, glucagon-like peptide-1 analogs, or insulin (CTR group). In the IPR group (n = 25), there were significant decreases in hemoglobin A1c (HbA1c) and body mass index (BMI) during the study (HbA1c, -0.41%, P < 0.01; BMI, -1.06 kg/m , P < 0.01), whereas these did not change in the CTR group (n = 26). Liver pathology was evaluated in 21/25 participants in the IPR/CTR groups, and hepatic fibrosis was found in 17 (81%) and 18 (72%) participants in the IPR and CTR groups at baseline. This was ameliorated in 70.6% (12 of 17) of participants in the IPR group and 22.2 % (4 of 18) of those in the CTR group (P < 0.01). Nonalcoholic steatohepatitis (NASH) resolved in 66.7% of IPR-treated participants and 27.3% of CTR participants. None of the participants in the IPR group developed NASH, whereas 33.3% of the CTR group developed NASH. Conclusion: Long-term ipragliflozin treatment ameliorates hepatic fibrosis in patients with NAFLD. Thus, ipragliflozin might be effective for the treatment and prevention of NASH in patients with diabetes, as well as improving glycemic control and obesity. Therefore, SGLT2is may represent a therapeutic choice for patients with diabetes with NAFLD, but further larger studies are required to confirm these effects.
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http://dx.doi.org/10.1002/hep4.1696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710792PMC
January 2022

Gastrointestinal Cancer Stage at Diagnosis Before and During the COVID-19 Pandemic in Japan.

JAMA Netw Open 2021 09 1;4(9):e2126334. Epub 2021 Sep 1.

Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama, Japan.

Importance: The COVID-19 pandemic has delayed medical consultations, possibly leading to the diagnosis of gastrointestinal cancer at advanced stages.

Objective: To evaluate stage at diagnosis among patients with gastrointestinal cancer in Japan before and during the COVID-19 pandemic.

Design, Setting, And Participants: This retrospective cohort study included patients in a hospital-based cancer registry who were diagnosed with gastrointestinal cancer (ie, esophageal, gastric, colorectal, pancreatic, liver, and biliary tract cancers) between January 2016 and December 2020 at 2 tertiary Japanese hospitals.

Exposures: The pre-COVID-19 period was defined as January 2017 to February 2020, and the COVID-19 period was defined as March 2020 to December 2020.

Main Outcome And Measure: Monthly numbers of patients with newly diagnosed cancer were aggregated, classified by stage, and compared.

Results: The study evaluated 5167 patients, including 4218 patients (2825 [67.0%] men; mean [SD] age, 71.3 [10.9] years) in the pre-COVID-19 period and 949 patients (607 [64.0%] men; mean [SD] age, 71.8 [10.7] years) in the COVID-19 period. Comparing the pre-COVID-19 period with the COVID-19 period, significant decreases were observed in the mean (SD) number of patients with newly diagnosed gastric cancer (30.63 [6.62] patients/month vs 22.40 [5.85] patients/month; -26.87% change; P < .001) and colorectal cancer (41.61 [6.81] patients/month vs 36.00 [6.72] patients/month; -13.47% change; P = .03). Significant decreases were also observed in the mean (SD) number of cases of stage I gastric cancer (21.55 [5.66] cases/month vs 13.90 [5.99] cases/month; -35.51% change; P < .001), stage 0 colorectal cancer (10.58 [3.36] cases/month vs 7.10 [4.10] cases/month; -32.89% change; P = .008), and stage I colorectal cancer (10.16 [3.14] cases/month vs 6.70 [2.91] cases/month; -34.04% change; P = .003). No significant increases were observed for esophageal, gastric, pancreatic, liver, or biliary tract cancers. A significant decrease was observed in the mean (SD) number of cases per month of stage II colorectal cancer (7.42 [3.06] cases/month vs 4.80 [1.75] cases/month; -35.32% change; P = .01); a significant increase was observed for the mean (SD) number of cases per month of stage III colorectal cancer (7.18 [2.85] cases/month vs 12.10 [2.42] cases/month; 68.42% change; P < .001).

Conclusions And Relevance: In this cohort study of patients in a hospital-based cancer registry form Japan, significantly fewer patients were diagnosed with stage I gastric and colorectal cancers during the COVID-19 pandemic. Thus, the number of screening-detected cancers might have decreased, and colorectal cancer may have been diagnosed at more advanced stages.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.26334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456386PMC
September 2021

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020.

J Gastroenterol 2021 11 17;56(11):951-963. Epub 2021 Sep 17.

Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis'', The Japanese Society of Gastroenterology / The Japan Society of Hepatology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.

Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease (CVD) event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary provides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.
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http://dx.doi.org/10.1007/s00535-021-01796-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531062PMC
November 2021

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020.

Hepatol Res 2021 Oct 17;51(10):1013-1025. Epub 2021 Sep 17.

Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis", The Japanese Society of Gastroenterology, The Japan Society of Hepatology, Tokyo, Japan.

Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary pro- vides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.
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http://dx.doi.org/10.1111/hepr.13688DOI Listing
October 2021

Randomised clinical trial: Pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), versus placebo in patients with non-alcoholic fatty liver disease.

Aliment Pharmacol Ther 2021 11 16;54(10):1263-1277. Epub 2021 Sep 16.

NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California, USA.

Background: Pemafibrate is a novel, selective peroxisome proliferator-activated receptor α modulator (SPPARMα). In mice, Pemafibrate improved the histological features of non-alcoholic steatohepatitis (NASH). In patients with dyslipidaemia, it improved serum alanine aminotransferase (ALT).

Aims: To evaluate the efficacy and safety of Pemafibrate in patients with high-risk, non-alcoholic fatty liver disease (NAFLD).

Methods: This double-blind, placebo-controlled, randomised multicentre, phase 2 trial randomised 118 patients (1:1) to either 0.2 mg Pemafibrate or placebo, orally, twice daily for 72 weeks. The key inclusion criteria included liver fat content of ≥10% by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF); liver stiffness of ≥2.5 kPa, by magnetic resonance elastography (MRE); and elevated ALT levels. The primary endpoint was the percentage change in MRI-PDFF from baseline to week 24. The secondary endpoints included MRE-based liver stiffness, ALT, serum liver fibrosis markers and lipid parameters.

Results: There was no significant difference between the groups in the primary endpoint (-5.3% vs -4.2%; treatment difference -1.0%, P = 0.85). However, MRE-based liver stiffness significantly decreased compared to placebo at week 48 (treatment difference -5.7%, P = 0.036), and was maintained at week 72 (treatment difference -6.2%, P = 0.024), with significant reduction in ALT and LDL-C. Adverse events were comparable between the treatment groups and therapy was well tolerated.

Conclusions: Pemafibrate did not decrease liver fat content but had significant reduction in MRE-based liver stiffness. Pemafibrate may be a promising therapeutic agent for NAFLD/NASH, and also be a candidate for combination therapy with agents that reduce liver fat content. ClinicalTrials.gov, number: NCT03350165.
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http://dx.doi.org/10.1111/apt.16596DOI Listing
November 2021

Magnetic resonance elastography plus Fibrosis-4 versus FibroScan-aspartate aminotransferase in detection of candidates for pharmacological treatment of NASH-related fibrosis.

Hepatology 2022 03 15;75(3):661-672. Epub 2021 Dec 15.

NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, California, USA.

Background And Aims: Patients with NAFLD with significant hepatic fibrosis (Stage ≥ 2) are at increased risk of liver-related morbidity and are candidates for pharmacologic therapies. In this study, we compared the diagnostic accuracy of MEFIB (the combination of magnetic resonance elastography [MRE] and Fibrosis-4 [FIB-4]) and FAST (FibroScan-aspartate aminotransferase; combined liver stiffness measurement by vibration-controlled transient elastography, controlled attenuation parameter, and aspartate aminotransferase) for detecting significant fibrosis.

Approach And Results: This prospective cohort study included 234 consecutive patients with NAFLD who underwent liver biopsy, MRE, and FibroScan at the University of California San Diego (UCSD cohort) and an independent cohort (N = 314) from Yokohama City University, Japan. The primary outcome was diagnostic accuracy for significant fibrosis (Stage ≥ 2). The proportions of significant fibrosis in the UCSD and Yokohama cohorts were 29.5% and 66.2%, respectively. Area under the receiver operating characteristic curve (95% CI) of MEFIB (0.860 [0.81-0.91]) was significantly higher than that of FAST (0.757 [0.69-0.82]) in the UCSD cohort (p = 0.005), with consistent results in the Yokohama cohort (AUROC, 0.899 [MEFIB] versus 0.724 [FAST]; p < 0.001). When used as the rule-in criteria (MEFIB, MRE ≥ 3.3 kPa and FIB-4 ≥ 1.6; FAST ≥ 0.67), the positive predictive value for significant fibrosis was 91.2%-96.0% for MEFIB and 74.2%-89.2% for FAST. When used as the rule-out criteria (MEFIB, MRE < 3.3 kPa and FIB-4 < 1.6; FAST ≤ 0.35), the negative predictive value for significant fibrosis was 85.6%-92.8% for MEFIB and 57.8%-88.3% for FAST.

Conclusions: MEFIB has higher diagnostic accuracy than FAST for significant fibrosis in NAFLD, and our results support the utility of a two-step strategy for detecting significant fibrosis in NAFLD.
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http://dx.doi.org/10.1002/hep.32145DOI Listing
March 2022

Protective effect of SGL5213, a potent intestinal sodium-glucose cotransporter 1 inhibitor, in nonalcoholic fatty liver disease in mice.

J Pharmacol Sci 2021 Oct 8;147(2):176-183. Epub 2021 Jul 8.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic disease. SGL5213, which is minimally absorbed and is restricted to the intestinal tract, is a potent intestinal sodium-glucose cotransporter 1 (SGLT1) inhibitor. In this study, we investigated the protective effect of SGL5213 in a rodent model of NAFLD.

Methods: Using a rodent model of NAFLD, we compared SGL5213 efficacy with miglitol, which is an α-glucosidase inhibitor. We used a high-fat and high-sucrose diet-induced NAFLD model.

Results: SGL5213 and miglitol improved obesity, liver dysfunction, insulin resistance, and the NAFLD severity. To further investigate the effects of SGL5213, we analyzed the mRNA expression of genes involved in lipid metabolism, inflammation, and liver fibrosis, and cecal pH levels. SGL5213 and miglitol treatment significantly decreased mRNA expression of factors involved in inflammation and liver fibrosis. SGL5213 treatment significantly decreased cecal pH levels, which did not occur with miglitol.

Conclusions: SGL5213 had a protective effect on the pathogenesis of NAFLD in a rodent model. We considered that inhibiting glucose absorption and increasing glucose content in the gastrointestinal tract with SGL5213 might have contributed to the protective effect in NAFLD. SGL5213 is a promising therapeutic agent for NAFLD with obesity and insulin resistance.
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http://dx.doi.org/10.1016/j.jphs.2021.07.002DOI Listing
October 2021

The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target.

Int J Mol Sci 2021 Jul 29;22(15). Epub 2021 Jul 29.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.

The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10-20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut-liver axis in NAFLD pathogenesis and progression.
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http://dx.doi.org/10.3390/ijms22158161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347478PMC
July 2021

Predictive value of cytokeratin-18 fragment levels for diagnosing steatohepatitis in patients with nonalcoholic fatty liver disease.

Eur J Gastroenterol Hepatol 2021 11;33(11):1451-1458

Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Aichi, Japan.

Objective: Several noninvasive markers have been developed to predict nonalcoholic steatohepatitis (NASH). We investigated the predictive value of the cytokeratin-18 fragment (CK18-F) level and FIB-4 index for diagnosing NASH in patients with nonalcoholic fatty liver disease (NAFLD).

Methods: A total of 246 patients histologically diagnosed with NASH (n = 185) or nonalcoholic fatty liver (n = 61) were enrolled. We analyzed weighted receiver operating characteristic (ROC) curves for the prediction of NASH and determined the relationship between the CK18-F level and the histological features of NASH. In addition, we investigated the predictive value of the combination of the CK18-F level and FIB-4 index for diagnosing NASH.

Results: The area under the ROC curve (AUROC) value of the CK18-F level was 0.77. With a CK18-F cutoff level of 260 U/L, the sensitivity and specificity for diagnosing NASH were 82.7 and 57.4%, respectively. Multiple comparisons showed that the CK18-F level did not differ among fibrosis stages but did significantly differ among hepatocyte ballooning grades. Overall, 95.7% (66/69) of patients with a FIB-4 index of ≥2.67 had NASH. In patients with a FIB-4 index of <2.67, the AUROC value of the CK18-F level for predicting NASH was 0.77 and a CK18-F cutoff level of 260 U/L resulted in a sensitivity and specificity of 82.4 and 56.9%.

Conclusions: The CK18-F level had a good predictive ability for diagnosing NASH in patients with NAFLD. Additionally, the combination of the CK18-F level and FIB-4 index accurately and noninvasively predicted NASH, even those with a low FIB-4 index.
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http://dx.doi.org/10.1097/MEG.0000000000002176DOI Listing
November 2021

MRI-Based Quantitative R2 Mapping at 3 Tesla Reflects Hepatic Iron Overload and Pathogenesis in Nonalcoholic Fatty Liver Disease Patients.

J Magn Reson Imaging 2022 01 28;55(1):111-125. Epub 2021 Jun 28.

Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Background: The role of hepatic iron overload (HIO) in nonalcoholic fatty liver disease (NAFLD) pathogenesis has not been fully elucidated.

Purpose: This study aimed to investigate the effect of HIO and examine the diagnostic usefulness of magnetic resonance imaging (MRI)-based R2 quantification in evaluating hepatic iron content (HIC) and pathological findings in NAFLD.

Study Type: Prospective and retrospective.

Population: A prospective study of 168 patients (age, 57.2 ± 15.0; male/female, 80/88) and a retrospective validation study of 202 patients (age, 57.0 ± 14.4; male/female, 113/89) with liver-biopsy-confirmed NAFLD were performed.

Field Strength/sequence: 3 T; chemical-shift encoded multi-echo gradient echo.

Assessment: Using liver tissues obtained by liver biopsy, HIC was prospectively evaluated in 168 patients by atomic absorption spectrometry. Diagnostic accuracies of HIC and R2 for grading hepatic inflammation plus ballooning (HIB) as an indicator of NAFLD activity were assessed.

Statistical Tests: Student's t-test and analysis of variance (ANOVA) with Scheffe's multiple testing correction for univariate comparisons; multivariate logistic analysis. P-value less than 0.05 is statistically significant.

Results: HIC was significantly correlated with HIB grades (r = 0.407). R2 was significantly correlated with HIC (r = 0.557) and HIB grades (r = 0.569). R2 mapped an area under the receiver operating characteristic (AUROC; 0.774) for HIC ≥808 ng/mL (median value) with cutoff value of 62.5 s . In addition, R2 mapped AUROC of HIB for grades ≥3 was 0.799 with cutoff value of 58.5 s . When R2 was <62.5 s , R2 correlated weakly with HIC (r = 0.372) as it was affected by fat deposition and did not correlate with HIB grades (P = 0.052). Conversely, when R2 was ≥62.5 s , a significant correlation of R2 with HIC (r = 0.556) and with HIB grades was observed (P < 0.0001) with being less affected by fat deposition.

Data Conclusion: R2  ≥ 62.5 s is a promising modality for non-invasive diagnosis of clinically important high grades (≥3) of HIB associated with increased HIC.

Level Of Evidence: 1 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27810DOI Listing
January 2022

Cholestatic Liver Disease: Current Treatment Strategies and New Therapeutic Agents.

Drugs 2021 Jul 17;81(10):1181-1192. Epub 2021 Jun 17.

Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Cholestatic liver disease is a disease that causes liver damage and fibrosis owing to bile stasis. It is represented by primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), but the pathophysiological pathways that cause bile stasis in both diseases are different. The pathogenesis of the disease is still unclear, although autoimmune mechanisms have been postulated and partially elucidated. Although the disease may progress slowly with only mild liver dysfunction, it may progress to liver cirrhosis or liver failure, which require liver transplantation. As a medical treatment, ursodeoxycholic acid is widely used for PBC and has proved to be very effective against disease progression in cases of PBC. On the other hand, its efficacy is limited in cases of PSC, and the research and development of various drugs are underway. Furthermore, the clinical course of both diseases is quite variable, making the design of clinical trials fairly difficult. In this review, we present the general natural history of PBC and PSC, and provide information on the latest drug therapies currently available and those that are under investigation.
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http://dx.doi.org/10.1007/s40265-021-01545-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282588PMC
July 2021

Novel artificial intelligent/neural network system for staging of nonalcoholic steatohepatitis.

Hepatol Res 2021 Oct 30;51(10):1044-1057. Epub 2021 Jun 30.

Department of Human Pathology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.

Aim: To develop a novel noninvasive test using an artificial intelligence (AI)/neural network (NN) system (named Fibro-Scope) to determine the fibrosis stage in nonalcoholic steatohepatitis (NASH).

Methods: Three hundred twenty-four and 110 patients with histologically diagnosed nonalcoholic fatty liver disease (NAFLD) were enrolled for training and validation studies, respectively. Two independent pathologists histologically diagnosed patients with NAFLD for the validation study. Fibro-Scope was undertaken using 12 items: age, sex, height, weight, waist circumference, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, cholesterol, triglyceride, platelet count, and type 4 collagen 7s.

Results: Differentiation of F0 versus F1-4 using the Fibro-Scope revealed 99.5% sensitivity, 90.9% specificity, 97.4% positive predictive value, and 98.0% negative predictive value in a training study with gray zone analysis, which was also effective in the analysis without gray zone. Discrimination was also excellent when comparing F0-1 versus F2-4 and F0-2 versus F3-4. In a validation study with gray zone analysis, differentiation of F0 from F1-4 using Fibro-Scope was also excellent. The discrimination of F0-1 from F2-4 using Fibro-Scope with gray zone analysis showed over 80% sensitivity and specificity in the histological diagnosis of both pathologists, but was lower without the gray zone analysis. The discrimination of F0-2 from F3-4 was effective in the analysis with gray zone; however, their sensitivity and specificity were slightly inferior in the analysis without gray zone.

Conclusions: Artificial intelligence/neural network algorithms termed Fibro-Scope are easy to use and can accurately differentially diagnose minimal, moderate, and advanced fibrosis. Fibro-Scope will promote rapid NASH diagnosis and facilitate diagnosing the fibrosis stage in NASH.
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http://dx.doi.org/10.1111/hepr.13681DOI Listing
October 2021

A pediatric case of Stevens-Johnson syndrome with acute liver failure, resulting in liver transplantation.

J Dermatol 2021 Sep 21;48(9):1423-1427. Epub 2021 May 21.

Department of Dermatology, Yokohama City University School of Medicine, Yokohama, Japan.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are fatal adverse skin reactions characterized by high fever, epidermal detachment, and mucositis. It is well known that SJS/TEN occasionally affects various organs, leading to permanent damage and death in some patients. Although acute liver dysfunction is a relatively common complication of SJS/TEN, severe acute liver dysfunction requiring liver transplantation is rare. We present the case of a 14-year-old girl with SJS complicated by severe and rapidly progressive liver dysfunction, specifically, acute liver failure (ALF) requiring liver transplantation. A lymphocyte transformation test showed positive results for acetaminophen and cefdinir. Furthermore, human leukocyte antigen (HLA) genotyping revealed the presence of the HLA-A*02:06 genotype, which is reported to be strongly associated with acetaminophen-related SJS/TEN with severe ocular complications. These results suggested that our patient may have presented with acetaminophen-induced SJS complicated by ALF, but no ocular complications. This is the first report of a pediatric patient with SJS who required liver transplantation. In rare instances, severe liver dysfunction requiring liver transplantation should be considered as a possible complication of SJS/TEN.
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http://dx.doi.org/10.1111/1346-8138.15963DOI Listing
September 2021

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis.

Gut 2022 05 17;71(5):1006-1019. Epub 2021 May 17.

Department of Internal Medicine I, University Medical Centre of the Johannes Gutenberg-University Mainz, Mainz, Rhineland-Palatinate, Germany.

Objective: Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies.

Design: Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations.

Results: Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63-68) and 86% (84-87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37-39) and specificity of 90% (89-91) with 19% needing biopsy.

Conclusion: Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.
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http://dx.doi.org/10.1136/gutjnl-2021-324243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995830PMC
May 2022

Efficacy of G9-1 in improving quality of life in patients with chronic constipation: a prospective intervention study.

Biosci Microbiota Food Health 2021 19;40(2):105-114. Epub 2021 Jan 19.

Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.

Chronic constipation is a functional disorder that decreases a patient's quality of life (QOL). Because dysbiosis has been associated with constipation, we aimed to investigate the efficacy of G9-1 (BBG9-1) in improving QOL in patients with constipation. This was a prospective, single-center, non-blinded, single-arm feasibility trial. A total of 31 patients with constipation and decreased QOL received BBG9-1 treatment for 8 weeks, followed by a 2-week washout period. The primary endpoint was change in the overall Japanese version of the patient assessment of constipation of QOL (JPAC-QOL) score after probiotic administration relative to that at baseline. Secondary endpoints included changes in gut microbiota, stool consistency, frequency of bowel movement, degree of straining, sensation of incomplete evacuation, and frequency of rescue drug use. The overall JPAC-QOL scores and frequency of bowel movement significantly improved after BBG9-1 administration from those at baseline (p<0.01 and p<0.01, respectively). There were no statistically significant changes in other clinical symptoms. Subset analysis revealed that patients with initial Bristol Stool Form Scale stool types of <4 had improvements in stool consistency, a significant increase in the frequency of bowel movements, and a significant alleviation in the degree of straining, following BBG9-1 administration. At the genus and species levels, and were significantly increased. Functional analysis showed that butanoate metabolism increased significantly, whereas methane metabolism decreased significantly. We concluded that BBG9-1 is safe and improves QOL in patients with constipation. The underlying improvements may be due to changes in stool consistency.
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http://dx.doi.org/10.12938/bmfh.2020-073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099630PMC
January 2021

What considerations are there for the pharmacotherapeutic management of nonalcoholic steatohepatitis?

Expert Opin Pharmacother 2021 Jul 21;22(10):1217-1220. Epub 2021 Apr 21.

Department of Gastroenterology and Hepatology, Yokohama City University Hospital, Yokohama, Japan.

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http://dx.doi.org/10.1080/14656566.2021.1912014DOI Listing
July 2021

Vitamin B6 efficacy in the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, single-center trial.

J Clin Biochem Nutr 2021 Mar 16;68(2):181-186. Epub 2021 Jan 16.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.

Vitamin B6 is an important cofactor in fat metabolism and its deficiency has been correlated with nonalcoholic fatty liver disease. However, no study has investigated the efficacy of vitamin B6 supplementation in these patients. The aim of this open-label, single-arm, single-center study was to examine the therapeutic effect of vitamin B6 in patients with nonalcoholic fatty liver disease. Twenty-two patients with nonalcoholic fatty liver disease received vitamin B6 (90 mg/day) orally for 12 weeks. Clinical parameters were evaluated, and liver fat and fibrosis were quantified before and after treatment using magnetic resonance imaging-based proton density fat fraction and magnetic resonance elastography. Serum alanine aminotransferase levels, the primary endpoint, did not change significantly after vitamin B6 treatment (93.6 ± 46.9 to 93.9 ± 46.6,  = 0.976). On the other hand, magnetic resonance imaging-based proton density fat fraction, a parameter of hepatic lipid accumulation, was significantly reduced (18.7 ± 6.1 to 16.4 ± 6.4, <0.001) despite no significant changes in body mass index, even in those not taking vitamin E ( = 17, 18.8 ± 6.9 to 16.7 ± 7.3,  = 0.0012). Vitamin B6 administration significantly ameliorated hepatic fat accumulation. As an inexpensive agent with few side effects, vitamin B6 could be a novel therapeutic agent for the treatment of nonalcoholic fatty liver disease.
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http://dx.doi.org/10.3164/jcbn.20-142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046002PMC
March 2021

Precision modeling of gall bladder cancer patients in mice based on orthotopic implantation of organoid-derived tumor buds.

Oncogenesis 2021 Apr 17;10(4):33. Epub 2021 Apr 17.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Kanagawa, 236-0004, Japan.

Genetically engineered mice (GEM) are the gold standard for cancer modeling. However, strict recapitulation of stepwise carcinogenesis from a single tumor-initiating epithelial cell among genetically intact cells in adults is not feasible with the currently available techniques using GEM. In previous studies, we partially overcame this challenge by physically isolating organs from adult animals, followed by genetic engineering in organoids and subcutaneous inoculation in nude mice. Despite the establishment of suitable ex vivo carcinogenesis models for diverse tissues, tumor development remained ectopic and occurred under immunodeficient conditions. Further refinement was, therefore, necessary to establish ideal models. Given the poor prognosis and few models owing to the lack of gall bladder (GB)-specific Cre strain, we assumed that the development of authentic models would considerably benefit GB cancer research. Here, we established a novel model using GB organoids with mutant Kras and Trp53 loss generated in vitro by lentiviral Cre transduction and CRISPR/Cas9 gene editing, respectively. Organoid-derived subcutaneous tumor fragments were sutured to the outer surface of the GB in syngeneic mice, which developed orthotopic tumors that resembled human GB cancer in histological and transcriptional features. This model revealed the infiltration of similar subsets of immune cells in both subcutaneous and orthotopic tumors, confirming the appropriate immune environment during carcinogenesis. In addition, we accurately validated the in vivo efficacy of gemcitabine, a common therapeutic agent for GB cancer, in large cohorts. Taken together, this model may serve as a promising avatar of patients with GB cancer in drug discovery and precision medicine.
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http://dx.doi.org/10.1038/s41389-021-00322-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053198PMC
April 2021

Type IV Collagen 7S Is the Most Accurate Test For Identifying Advanced Fibrosis in NAFLD With Type 2 Diabetes.

Hepatol Commun 2021 04 16;5(4):559-572. Epub 2020 Nov 16.

Department of Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Kyoto Japan.

This study aimed to examine whether the diagnostic accuracy of four noninvasive tests (NITs) for detecting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is maintained or is inferior to with or without the presence of type 2 diabetes. Overall, 874 patients with biopsy-proven NAFLD were enrolled. After propensity-score matching by age, sex, and the prevalence of dyslipidemia, 311 patients were enrolled in each group of with or without diabetes. To evaluate the effect of diabetes, we compared the diagnostic accuracy of the fibrosis-4 (FIB-4) index, the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen 7S (COL4-7S) in patients with NAFLD with and without diabetes. The areas under the receiver operating characteristic curve (AUROC) for identifying advanced fibrosis in patients without diabetes were 0.879 for the FIB-4 index, 0.851 for the NFS, 0.862 for the APRI, and 0.883 for COL4-7S. The AUROCs in patients with diabetes were 0.790 for the FIB-4 index, 0.784 for the NFS, 0.771 for the APRI, and 0.872 for COL4-7S. The AUROC of COL4-7S was significantly larger than that of the other NITs in patients with NAFLD with diabetes than in those without diabetes. The optimal high and low cutoff points of COL4-7S were 5.9 ng/mL and 4.8 ng/mL, respectively. At the low cutoff point, the accuracy of COL4-7S was better than that of the other NITs, especially in patients with diabetes. COL4-7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.
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http://dx.doi.org/10.1002/hep4.1637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034577PMC
April 2021

Gut microbiota composition associated with hepatic fibrosis in non-obese patients with non-alcoholic fatty liver disease.

J Gastroenterol Hepatol 2021 Aug 29;36(8):2275-2284. Epub 2021 Mar 29.

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Background And Aim: Gut microbiota composition is associated with the pathogenesis of non-alcoholic fatty liver disease. However, the association between gut microbiota composition and non-alcoholic fatty liver disease in non-obese patients remains unclear. We compared clinical parameters and gut microbiota profiles of healthy controls and non-obese and obese patients with non-alcoholic fatty liver disease.

Methods: We examined the clinical parameters and gut microbiota profiles by 16S rRNA sequences and short-chain fatty acid levels in fecal samples from 51 non-obese patients with non-alcoholic fatty liver disease (body mass index <25 kg/m ) and 51 obese patients with non-alcoholic fatty liver disease (body mass index ≥30 kg/m ) who underwent pathological examination and 87 controls at five hospitals in Japan.

Results: Although no significant differences between the non-obese and other groups were observed in alpha diversity, a significant difference was found in beta diversity. We observed a significant decrease in serum alanine aminotransferase levels, Eubacterium population, and butyric acid levels in non-obese patients with non-alcoholic fatty liver disease compared with those in obese patients with non-alcoholic fatty liver disease. A significant negative correlation was found between the stage of hepatic fibrosis and Eubacterium abundance in non-obese patients with non-alcoholic fatty liver disease.

Conclusions: The decrease in the abundance of Eubacterium that produces butyric acid may play an important role in the development of non-alcoholic fatty liver disease in non-obese individuals. This study was registered at the University Hospital Medical Information Network clinical trial registration system (UMIN000020917).
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http://dx.doi.org/10.1111/jgh.15487DOI Listing
August 2021
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