Publications by authors named "Michihiro Iwaki"

21 Publications

  • Page 1 of 1

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

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

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

A prospective interventional trial on the effect of periodontal treatment on Fusobacterium nucleatum abundance in patients with colorectal tumours.

Sci Rep 2021 12 9;11(1):23719. Epub 2021 Dec 9.

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

Fusobacterium nucleatum is associated with the progression of colorectal cancer. Thus, the possibility of preventing colorectal cancer or its progression by targeting F. nucleatum has been explored. As F. nucleatum is associated with periodontitis, we analysed whether treating periodontitis could influence F. nucleatum abundance in the colon. Patients with colorectal tumours who underwent colonoscopy were recruited. Patients diagnosed with periodontitis by a dentist were treated for approximately 3 months. Endoscopic resection of colorectal tumours was performed after periodontitis treatment, and resected tumours were pathologically classified as high-(HGD) or low-grade dysplasia (LGD). Saliva and stool samples were collected before and after the treatment. Of the 58 patients with colorectal tumours, 31 were included in the study, 16 showed improvement in periodontitis, and 11 showed no improvement. Stool F. nucleatum levels before treatment were significantly lower in the LGD group than in the HGD group. A significant decrease in faecal F. nucleatum levels was observed in patients who underwent successful treatment but not in those whose treatment failed. Salivary F. nucleatum levels were not altered in patients despite periodontal treatment. Thus, successful periodontitis treatment reduces stool F. nucleatum levels and may aid research on periodontitis and suppression of colorectal cancer development.
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http://dx.doi.org/10.1038/s41598-021-03083-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8660914PMC
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

Tapentadol Safety and Patient Characteristics Associated with Treatment Discontinuation in Cancer Therapy: A Retrospective Multicentre Study in Japan.

Pain Ther 2021 Dec 28;10(2):1635-1648. Epub 2021 Sep 28.

Department of Palliative Medicine, National Cancer Center Hospital, Tokyo, Japan.

Introduction: Tapentadol has analgesic effects comparable to those of conventional opioids and is associated with fewer side effects, including gastrointestinal symptoms, drowsiness, and dizziness, than other opioids. However, the safety of tapentadol in the Japanese population remains unclear; the present multicentre study aimed to examine the safety of tapentadol and the characteristics of patients likely to discontinue this treatment owing to adverse events.

Methods: The safety of tapentadol was assessed retrospectively in patients with any type of cancer treated between August 18, 2014 and October 31, 2019 across nine institutions in Japan. Patients were examined at baseline and at the time of opioid discontinuation. Multivariate analysis was performed to identify factors associated with tapentadol discontinuation owing to adverse events.

Results: A total of 906 patients were included in this study, and 685 (75.6%) cases were followed up until tapentadol cessation for any reason. Among patients who discontinued treatment, 119 (17.4%) did so because of adverse events. Among adverse events associated with difficulty in taking medication, nausea was the most common cause of treatment discontinuation (4.7%), followed by drowsiness (1.8%). Multivariate analysis showed that those who were prescribed tapentadol by a palliative care physician (odds ratio [OR] 2.60, 95% confidence interval [CI] 1.36-4.99, p = 0.004), patients switching to tapentadol due to side effects from previous opioids (OR 2.19, 95% CI 1.05-4.56, p = 0.037), and patients who did not use naldemedine (OR 5.06, 95% CI 2.47-10.37, p < 0.0001) had an increased risk of treatment discontinuation owing to adverse events.

Conclusions: This study presents the safety profile of tapentadol and the characteristics of patients likely to discontinue this treatment owing to adverse events in the Japanese population. Prospective controlled trials are required to evaluate the safety of tapentadol and validate the present findings.

Trial Registration Number: UMIN 000044282 (University Hospital Medical Information Network).
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http://dx.doi.org/10.1007/s40122-021-00327-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586125PMC
December 2021

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

Elobixibat Effectively Relieves Chronic Constipation in Patients with Cancer Regardless of the Amount of Food Intake.

Oncologist 2021 10 16;26(10):e1862-e1869. Epub 2021 Jul 16.

Department of Oncology, Yokohama City University, Yokohama, Japan.

Background: Constipation is a common, distressing complication in patients with cancer receiving palliative care. Elobixibat is a novel inhibitor of the ileal bile acid transporter that is used to treat chronic constipation by stimulating bowel function. However, its efficacy in patients with cancer has not been examined. This study investigated the drug's effectiveness in patients with cancer with chronic constipation.

Patients And Methods: This prospective-sampling, single-center, observational study included hospitalized patients with cancer diagnosed, using the Rome IV criteria, with chronic constipation. Within 2 weeks of hospitalization, each participant was administered elobixibat (5-15 mg) daily until discharge. Spontaneous bowel movements (SBMs), complete spontaneous bowel movements (CSBMs), Bristol stool form scale (BSFS) scores, and the Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL) scores were assessed before and after elobixibat administration. We also evaluated the relationship between the amount of food consumed and the SBM frequency.

Results: Among the 83 participants, the mean pre- and post-treatment frequencies of daily SBMs were 0.3 and 1.2 (p < .0001) and those of CSBMs were 0.1 and 0.6 (p < .0001), respectively. The mean pretreatment BSFS score was 1.6, whereas the post-treatment value was 3.5 (p < .0001); the mean PAC-QOL score (overall) improved from 1.01 to 0.74 (p = .01). There was no significant change in the daily SBM frequency between fasting and feeding states (1.2 vs. 1.3; p = .8), and there was no correlation between the amount of food intake and the SBM frequency after elobixibat administration (r = .03). Serious adverse events were not observed.

Conclusion: This study showed that elobixibat is safe and effective for patients with cancer with chronic constipation, regardless of the food intake amount.

Implications For Practice: Elobixibat was effective at relieving chronic constipation in patients with various cancers. Serious adverse events were not observed, and the relief of constipation was independent of variation in food intake.
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http://dx.doi.org/10.1002/onco.13879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488789PMC
October 2021

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

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

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

Direct Comparison of US and MR Elastography for Staging Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

Clin Gastroenterol Hepatol 2022 04 17;20(4):908-917.e11. Epub 2020 Dec 17.

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

Background & Aims: As alternatives to the expensive liver biopsy for assessing liver fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD), we directly compared the diagnostic abilities of magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE), and two-dimensional shear wave elastography (2D-SWE).

Methods: Overall, 231 patients with biopsy-proven NAFLD were included. Intra- and inter-observer reproducibility was analyzed using intraclass correlation coefficient in a sub-group of 70 participants, in whom liver stiffness measurement (LSM) was performed by an elastography expert and an ultrasound expert who was an elastography trainee on the same day.

Results: Valid LSMs were obtained for 227, 220, 204, and 201 patients using MRE, VCTE, 2D-SWE, and all three modalities combined, respectively. Although the area under the curve did not differ between the modalities for detecting stage ≥1, ≥2, and ≥3 liver fibrosis, it was higher for MRE than VCTE and 2D-SWE for stage 4. Sex was a significant predictor of discordance between VCTE and liver fibrosis stage. Skin-capsule distance and the ratio of the interquartile range of liver stiffness to the median were significantly associated with discordance between 2D-SWE and liver fibrosis stage. However, no factors were associated with discordance between MRE and liver fibrosis stage. Intra- and inter-observer reproducibility in detecting liver fibrosis was higher for MRE than VCTE and 2D-SWE.

Conclusions: MRE, VCTE, and 2D-SWE demonstrated excellent diagnostic accuracy in detecting liver fibrosis in patients with NAFLD. MRE demonstrated the highest diagnostic accuracy for stage 4 detection and intra- and inter-observer reproducibility. UMIN Clinical Trials Registry No. UMIN000031491.
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http://dx.doi.org/10.1016/j.cgh.2020.12.016DOI Listing
April 2022

Case Reports: Transformation of End-Stage Neuroendocrine Tumors With Uncontrollable Liver Metastasis Into a Novel or Additional Functional Phenotype.

Front Oncol 2020 25;10:555963. Epub 2020 Sep 25.

Department of Oncology, Yokohama City University Hospital, Yokohama, Japan.

Neuroendocrine tumors (NETs) are rare, but their worldwide incidence is gradually increasing. NETs are generally heterogeneous; however, in rare cases, they have been shown to change their phenotype (i.e., nonfunctional to functional or one functional phenotype to the addition of another functional phenotype). Here, we present two cases of liver metastatic NETs with phenotype transformation at the advanced stage that led to life-threatening events. A 73-year-old woman had a small intestinal nonfunctional NET with liver metastasis. After uncontrollable liver metastasis at the advanced stage, she developed duodenal perforation with hypergastremia. The patient was treated with octreotide and proton pump inhibitors and underwent endoscopic closure for duodenal perforation, but her general condition gradually deteriorated, and she died 2 weeks after duodenal perforation. Another patient, a 50-year-old man, had a functional NET (gastrinoma) with liver metastasis and duodenal ulcer. After uncontrollable liver metastasis at the advanced stage, he developed hypoglycemia. Although octoreotide and diazoxide were administrated for hyperalimentation, his hypoglycemia was uncontrollable, and he died after 4 months owing to general deterioration. The present cases show that advanced NETs with treatment-uncontrollable liver metastasis can transform their phenotype, specifically from a nonfunctional NET into a functional NET, and from one functional NET into the addition of another functional NET. These experiences suggest that the presence of treatment-resistant liver metastasis might be a hallmark of the potential to gain novel functions.
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http://dx.doi.org/10.3389/fonc.2020.555963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544986PMC
September 2020

Rationale and design of a randomised, double-blind, placebo-controlled, parallel-group, investigator-initiated phase 2a study to investigate the efficacy and safety of elobixibat in combination with cholestyramine for non-alcoholic fatty liver disease.

BMJ Open 2020 09 9;10(9):e037961. Epub 2020 Sep 9.

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

Introduction: Non-alcoholic fatty liver disease (NAFLD) pathogenesis involves abnormal metabolism of cholesterol and hepatic accumulation of toxic free-cholesterol. Elobixibat (EXB) inhibits the ileal bile acid (BA) transporter. EXB and cholestyramine (CTM) facilitate the removal of free cholesterol from the liver by decreasing BA recirculation to the liver, thereby stimulating novel BA synthesis from cholesterol. In this randomised, double-blind, placebo-controlled, parallel-group, phase IIa study, we aim to provide a proof-of-concept assessment by evaluating the efficacy and safety of EXB in combination with CTM in patients with NAFLD.

Methods And Analysis: A total of 100 adult patients with NAFLD, diagnosed based on low-density lipoprotein cholesterol (LDL-C) level of >120 mg/dL and liver fat content of ≥8% by MRI-based proton density fat fraction (MRI-PDFF), who meet the inclusion/exclusion criteria will be enrolled. The patients will be randomly assigned to receive the combination therapy of 10 mg EXB and 9 g CTM powder (4 g CTM), 10 mg EXB monotherapy, 9 g CTM powder monotherapy or a placebo treatment (n=25 per group). Blood tests and MRIs will be performed 16 weeks following treatment initiation. The primary study endpoint will be the absolute LDL-C level change at week 16 after treatment initiation. The exploratory endpoint will include absolute changes in the liver fat fraction as measured by MRI-PDFF. This proof-of-concept study will determine whether the combination therapy of EXB and CTM is effective and safe for patients with NAFLD.

Ethics And Dissemination: Ethics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences.

Trial Registration Number: NCT04235205.
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http://dx.doi.org/10.1136/bmjopen-2020-037961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482497PMC
September 2020

Lubiprostone in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled, phase 2a trial.

Lancet Gastroenterol Hepatol 2020 11 15;5(11):996-1007. Epub 2020 Aug 15.

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

Background: The laxative drug lubiprostone improves intestinal permeability in healthy volunteers. We aimed to assess efficacy and safety of lubiprostone in patients with non-alcoholic fatty liver disease (NAFLD) with constipation via attenuation of intestinal permeability.

Methods: This randomised, double-blind, placebo-controlled, phase 2a study in Yokohama City University Hospital, Japan, recruited patients (aged 20-85 years) with NAFLD and constipation, alanine aminotransferase (ALT) at least 40 U/L, liver stiffness (≤6·7 kPa), and hepatic fat fraction at least 5·2% when assessed by MRI-proton density fat fraction. Eligible patients were randomly assigned (11:10:9) by a computer-based system and stratified by age and sex to receive 24 μg lubiprostone, 12 μg lubiprostone, or placebo, orally, once per day for 12 weeks. The primary endpoint was the absolute changes in ALT at 12 weeks. Efficacy analysis was done by intention to treat. Safety was assessed in all treated patients. This trial was registered with University Hospital Medical Information Network Clinical Trials Registry (UMIN000026635).

Findings: Between March 24, 2017, and April 3, 2018, we screened 288 patients, of whom 150 (52%) were randomly assigned to treatment: 55 patients were assigned to receive 24 μg lubiprostone, 50 to receive 12 μg lubiprostone, and 45 to receive placebo. A greater decrease in the absolute ALT levels from baseline to 12 weeks was seen in the 24 μg lubiprostone group (mean -13 U/L [SD 19]) than in the placebo group (1 U/L [24]; mean difference -15 U/L [95% CI -23 to -6], p=0·0007) and in the 12 μg lubiprostone group (-12 U/L [21]) than in the placebo group (mean difference -13 U/L [-22 to -5], p=0·0023). 18 (33%) of 55 patients in the 24 μg group had at least one adverse event, as did three (6%) of 47 patients in the 12 μg group and three (7%) of 43 in the placebo group. The most common adverse event was diarrhoea (17 [31%] of patients in the 24 μg group, three [6%] in the 12 μg group, none in the placebo group). No life-threatening events or treatment-related deaths occurred.

Interpretation: Lubiprostone was well tolerated and reduced the levels of liver enzymes in patients with NAFLD and constipation. Further studies are necessary to better define the efficacy and tolerability of lubiprostone in patients with NAFLD without constipation.

Funding: Mylan EPD G.K.
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http://dx.doi.org/10.1016/S2468-1253(20)30216-8DOI Listing
November 2020

The benefit of elobixibat in chronic constipation is associated with faecal deoxycholic acid but not effects of altered microbiota.

Aliment Pharmacol Ther 2020 09 20;52(5):821-828. Epub 2020 Jul 20.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Background: Elobixibat, a novel inhibitor of apical sodium-dependent bile acid transporter for treating chronic constipation, increases colonic bile acid concentrations, stimulating bowel function. However, it is not clear which bile acids are altered, or whether altered gut microbiota are associated with functional effects that may alter bowel function.

Aims: To investigate the effects of elobixibat on changes in the faecal concentrations of total and individual bile acids and in faecal microbiota.

Methods: This was a prospective, single-centre study. After baseline period, patients received 10 mg daily of elobixibat for 2 weeks. We evaluated the effects on bowel function, changes in faecal bile acid concentrations and composition of gut bacteria, before and after elobixibat administration.

Results: In the 30 patients analysed, the frequency of pre- and post-treatment bowel movements per fortnight was 7 and 10 (P < 0.001), respectively. The pre-treatment faecal bile acid concentration increased significantly from 10.9 to 15.0 µg/g stool post-treatment (P = 0.030), with a significant increase in faecal deoxycholic acid (pre-treatment 3.94 µg/g stool to post-treatment 5.02 µg/g stool, P = 0.036) and in glycine-conjugated deoxycholic and chenodeoxycholic acids. Shannon index was significantly decreased, but there were no significant changes at the genus and phylum levels.

Conclusions: Short term treatment with elobixibat increased the concentrations of total bile acids and deoxycholic acid and decreased the diversity of faecal microbiota. The biological effects of elobixibat are associated with its effects on secretory bile acids, rather than the structural changes of an altered faecal microbiota.
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http://dx.doi.org/10.1111/apt.15950DOI Listing
September 2020

Comparing the effectiveness of magnesium oxide and naldemedine in preventing opioid-induced constipation: a proof of concept, single institutional, two arm, open-label, phase II, randomized controlled trial: the MAGNET study.

Trials 2020 Jun 1;21(1):453. Epub 2020 Jun 1.

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

Background: Patients taking opioids are known to develop opioid-induced constipation (OIC), which reduces their quality of life. The aim of this study is to compare magnesium oxide with naldemedine and determine which is more effective in preventing OIC.

Methods: This proof-of-concept, prospective, randomized controlled trial commenced in Japan in March 2018. Initially, a questionnaire-based survey will be conducted targeting adult patients with cancer who concomitantly commenced opioid treatment and OIC prevention treatment. Patients will then be randomly allocated to a magnesium oxide group (500 mg thrice daily) or a naldemedine group (0.2 mg once daily). Each drug will be orally administered for 12 weeks. The primary endpoint is defined as any improvement in scores on the Japanese version of Patient Assessment of Constipation Quality of Life questionnaire (JPAC-QOL) from baseline to 2 weeks of treatment.

Discussion: The primary endpoint is change in JPAC-QOL score from baseline to 2 weeks of intervention. The key secondary endpoint will be change in spontaneous bowel movements at 2 and 12 weeks of intervention. This study will determine whether magnesium oxide or naldemedine is more effective for the prevention of OIC.

Trial Registration: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000031891. Registered March 25, 2018.
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http://dx.doi.org/10.1186/s13063-020-04385-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268242PMC
June 2020

Coronary Artery Disease is More Severe in Patients with Non-Alcoholic Steatohepatitis than Fatty Liver.

Diagnostics (Basel) 2020 Feb 26;10(3). Epub 2020 Feb 26.

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

Non-alcoholic fatty liver disease (NAFLD) is associated with a higher risk of atherosclerotic disease. However, the relationships between the severity of coronary atherosclerosis and pathologic findings in patients with NAFLD remain unknown. We aimed to characterize the coronary artery lesions in patients with NAFLD using coronary computed tomography angiography (CCTA). Overall, 101 patients with liver biopsy-proven NAFLD who had chest pain or electrocardiographic abnormalities underwent CCTA. Coronary artery lesions, including coronary artery stenosis (CAS), calcium score (CACS, Agatston score), and coronary artery non-calcified plaque were assessed using multi-slice CT. Multivariate analysis showed that age, smoking status, prevalence of dyslipidemia (DLP) and non-alcoholic steatohepatitis (NASH), and stage of fibrosis were independent risk factors for CAS. Age, and the prevalence of DM and DLP, were independent risk factors for CACS, and the prevalence of NASH tended to be an independent risk factor. In addition, the prevalence of DLP and NASH were independent risk factors for non-calcified plaques. Coronary artery lesions are more common in patients with NASH than in those with non-alcoholic fatty liver, suggesting a higher risk in patients with NASH. Therefore, patients with NASH should be closely followed, with particular vigilance for coronary artery diseases.
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http://dx.doi.org/10.3390/diagnostics10030129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151007PMC
February 2020

Effect of tofogliflozin and pioglitazone on hepatic steatosis in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: A randomized, open-label pilot study (ToPiND study).

Contemp Clin Trials Commun 2020 Mar 31;17:100516. Epub 2019 Dec 31.

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

Background: The incidence of nonalcoholic fatty liver disease (NAFLD) has increased recently and is related to obesity and the associated surge in type 2 diabetes mellitus (DM) and metabolic syndrome diagnoses. We aim to compare the effectiveness of tofogliflozin and pioglitazone treatment on hepatic steatosis in patients with NAFLD with type 2 DM.

Methods: This is an open label, prospective, randomized exploratory study. Patients who meet the inclusion criteria and do not meet any exclusion criteria will undergo magnetic resonance imaging (MRI)-based proton density fat fraction (MRI-PDFF). Patients with ≥10% liver fat content on MRI-PDFF will be randomly assigned to receive tofogliflozin 20 mg per day (n = 20) or pioglitazone 15-30 mg per day (n = 20). MRI will be performed after 24 weeks following initiation of medication therapy. Then, patients will take tofogliflozin and pioglitazone in combination in both groups for 24 weeks. MRI will be performed again at 48 weeks (24 weeks after initiation medication in combination).

Results: Our study's primary endpoint will be change in hepatic steatosis measured by MRI-PDFF at 24 weeks after medication therapy. The secondary endpoint will be change in alanine aminotransferase at 24 weeks of medication therapy and the main exploratory endpoint will be changes in liver fat content and liver sclerosis at 48 weeks of medication.

Conclusions: We will compare the effectiveness of tofogliflozin and pioglitazone treatment using MRI for improving hepatic steatosis in patients with NAFLD complicated by DM and investigate if the combination of these two medications is effective for treating NAFLD.

Trial Registration: This trial is registered in the Japan Registry of Clinical Trials (jRCTs031180159).

Protocol Version: 1.2, 14 December 2018.
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http://dx.doi.org/10.1016/j.conctc.2019.100516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956674PMC
March 2020
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