Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: Fibrosis-4 (FIB-4) index and genetic polymorphisms have been used in assessing the risk of liver-related events (LRE) in metabolic dysfunction-associated steatotic liver disease (MASLD). To establish a more efficient prediction strategy for LRE, we investigated a combined approach that uses the FIB-4 index and genetic polymorphisms. METHODS: We enrolled 1304 Japanese patients with biopsy-proven MASLD in this longitudinal multicenter cohort study. PNPLA3, TM6SF2, GCKR and MBOAT7 genotypes were genotyped, and polygenic risk score high fat content (PRS-HFC) were calculated. RESULTS: During the follow-up period of 8.1 year, 96 LRE occurred and 53 patients died. PNPLA3, TM6SF2 and GCKR genotypes were associated with LRE development. We divided patients into three groups based on the FIB-4 index and PNPLA3 and TM6SF2 genotype. The cumulative LRE development rate in each group was 2.1%/28.9%/53.5%, respectively, at 10 years. Multivariate analysis revealed hazard ratios (HRs) for LRE of 10.72 in the high-risk group and 4.80 in the intermediate-risk group. Overall survival in each group was 98.8%/85.2%/72.4%, respectively, at 10 years. HRs for prognosis were 8.74 in the high-risk group and 5.62 in the intermediate-risk group. Patients with FIB-4 index > 2.67 and high PRS-HFC had HR of 6.70 for LRE development and HR of 6.07 for prognosis compared to patients with FIB-4 ≤ 2.67. CONCLUSIONS: The approach of measuring the FIB-4 index first followed by assessment of genetic polymorphisms efficiently detected patients at high risk of developing LRE. Therefore, this two-step strategy could be used as a screening method in large populations of patients with MASLD.

DOI： 10.1111/liv.16124

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

AIMS: The multisociety consensus nomenclature has introduced steatotic liver disease (SLD) with diverse subclassifications, which are metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated steatotic liver disease (MetALD), alcohol-associated liver disease (ALD), specific etiology, and cryptogenic. We investigated their prevalence, as per the new definition, in individuals undergoing health check-ups. Additionally, we analyzed the distribution of Fibrosis-4 (FIB-4) index and vibration-controlled transient elastography (VCTE)-derived liver stiffness measurement (LSM) for MASLD. METHODS: In this cross-sectional study, 6530 subjects undergoing a health check-up in Japan were included. Conventional B-mode ultrasound was carried out on all 6530 subjects, and those with MASLD underwent VCTE. RESULTS: The prevalence of SLD was 39.5%, comprising MASLD 28.7%, MetALD 8.6%, ALD 1.2%, specific etiology SLD 0.3%, and cryptogenic SLD 0.7%. Subjects with VCTE-derived LSM ≥8 kPa constituted 2.1% of MASLD. FIB-4 ≥1.3 showed that the sensitivity, specificity, positive predictive value (PPV), and negative predictive value for diagnosing VCTE-derived LSM ≥8 kPa were 60.6%, 77.0%, 5.3%, and 98.9%, respectively. The referral rate to specialists was 23.8% using FIB-4 ≥1.30. "FIB-4 ≥1.3 in subjects <65 years and FIB-4 ≥2.0 in subjects ≥65 years" showed higher PPV (6.7%) and lower referral rate (17.1%) compared with FIB-4 ≥1.3, but the sensitivity (54.5%) did not show adequate diagnostic capability as a noninvasive test for diagnosing VCTE-derived LSM ≥8 kPa. CONCLUSIONS: Acknowledging the selection bias in hepatology centers, we undertook this prospective health check-up study. Although the FIB-4 index proves to be a convenient marker, it might not perform well as a primary screening tool for liver fibrosis in the general population (UMIN Clinical Trials Registry No. UMIN000035188).

DOI： 10.1111/hepr.14117

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

近年,NAFLDという病名が正しい病態生理を反映していないことから,2020年にmetabolic dysfunction-associated fatty liver disease(MAFLD)という疾患概念が提唱され,また,差別や不利益につながるスティグマに配慮し,2023年にmetabolic dysfunction-associated steatotic liver disease:MASLD(代謝機能障害関連脂肪性肝疾患)という疾患概念が提唱された.MASLDの疾患概念と診断基準は,日本肝臓学会を含め世界中の70以上の組織により支持され国際的なコンセンサスとなっている.本稿ではNAFLDから,MAFLD,MASLD名称変更の変遷に至った歴史的背景,診断法,治療法のパラダイムシフトについて解説する.(著者抄録)

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

近年,NAFLDという病名が正しい病態生理を反映していないことから,2020年にmetabolic dysfunction-associated fatty liver disease(MAFLD)という疾患概念が提唱され,また,差別や不利益につながるスティグマに配慮し,2023年にmetabolic dysfunction-associated steatotic liver disease:MASLD(代謝機能障害関連脂肪性肝疾患)という疾患概念が提唱された.MASLDの疾患概念と診断基準は,日本肝臓学会を含め世界中の70以上の組織により支持され国際的なコンセンサスとなっている.本稿ではNAFLDから,MAFLD,MASLD名称変更の変遷に至った歴史的背景,診断法,治療法のパラダイムシフトについて解説する.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00263&link_issn=&doc_id=20240913020001&doc_link_id=10.2957%2Fkanzo.65.420&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.65.420&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Background and Objectives: The incidence of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) is increasing worldwide, alongside the epidemic of obesity and metabolic syndrome. Based on preliminary reports regarding the potential association of HCC and periodontitis, this study aimed to analyze the involvement of periodontal bacteria as well as the oral and intestinal bacterial flora in MASH-related HCC (MASH-HCC). Materials and Methods: Forty-one patients with MASH and nineteen with MASH-HCC participated in the study, completing survey questionnaires, undergoing periodontal examinations, and providing samples of saliva, mouth-rinsed water, feces, and peripheral blood. The oral and fecal microbiome profiles were analyzed by 16S ribosomal RNA sequencing. Bayesian network analysis was used to analyze the causation between various factors, including MASH-HCC, examinations, and bacteria. Results: The genus Fusobacterium had a significantly higher occupancy rate (p = 0.002) in the intestinal microflora of the MASH-HCC group compared to the MASH group. However, Butyricicoccus (p = 0.022) and Roseburia (p &lt; 0.05) had significantly lower occupancy rates. The Bayesian network analysis revealed the absence of periodontal pathogenic bacteria and enteric bacteria affecting HCC. However, HCC directly affected the periodontal bacterial species Porphyromonas gingivalis, Tannerella forsythia, Fusobacterium nucleatum, and Prevotella intermedia in the saliva, as well as the genera Lactobacillus, Roseburia, Fusobacterium, Prevotella, Clostridium, Ruminococcus, Trabulsiella, and SMB53 in the intestine. Furthermore, P. gingivalis in the oral cavity directly affected the genera Lactobacillus and Streptococcus in the intestine. Conclusions: MASH-HCC directly affects periodontal pathogenic and intestinal bacteria, and P. gingivalis may affect the intestinal bacteria associated with gastrointestinal cancer.

DOI： 10.3390/medicina60071150

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Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞MR elastography(MRE)はMASLDの肝線維化診断において最も正確な非侵襲的検査であり,MRI-PDFFは最も正確な肝脂肪量の測定法である.国内で2,000万人以上と想定されるMASLD患者全例にエラストグラフィ検査を行うことは難しく,適応患者を絞り込む2ステップアルゴリズムが提唱されている.近年ではMREで測定した肝硬度がMASLD患者の予後と相関することが報告された.さらに,肝硬度を複数回測定して,その推移を評価することも重要である.MREは正確性が注目されており,開発治験の選択基準やエンドポイントに採用されつつある.

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Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞MR elastography(MRE)はMASLDの肝線維化診断において最も正確な非侵襲的検査であり,MRI-PDFFは最も正確な肝脂肪量の測定法である.国内で2,000万人以上と想定されるMASLD患者全例にエラストグラフィ検査を行うことは難しく,適応患者を絞り込む2ステップアルゴリズムが提唱されている.近年ではMREで測定した肝硬度がMASLD患者の予後と相関することが報告された.さらに,肝硬度を複数回測定して,その推移を評価することも重要である.MREは正確性が注目されており,開発治験の選択基準やエンドポイントに採用されつつある.

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND & AIMS: PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 have been associated with an increased risk of liver-related events (LRE) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we investigated the combined effects of these variants on LRE. METHODS: The longitudinal multicenter cohort study enrolled 1178 patients with biopsy-proven MASLD. We calculated the genetic risk of hepatic fibrosis and LRE according to the impact of these variants. RESULTS: Patients with genetic fibrosis scores of 2, 3, and 4 or 5 were at greater risk than were patients with scores of 0 or 1, with odds ratios of 2.45 (95% confidence interval [CI] 1.27-4.74), 2.14 (95% CI 1.17-3.94), and 2.54 (95% CI 1.35-4.77), respectively. Multivariate analysis revealed that PNPLA3 and TM6SF2, but not HSD17B13, were significantly associated with LRE development. The hazard ratio (HR) of the genetic high-risk group for LRE was 1.91 (95% CI 1.20-3.04). The higher risk of LRE development in the genetic high-risk group was also seen in patients with F ≥ 3 or FIB-4 index > 2.67. The HRs of the genetic high-risk group for LRE were greater in patients without obesity, without diabetes, and of younger age compared with patients with obesity, with diabetes, or of older age, respectively. CONCLUSIONS: This combination of MASLD-related genetic variants is useful for predicting LRE in Japanese patients with MASLD. The genetic risk according to these variants is useful for LRE risk assessment, especially in patients without metabolic risk factors or in younger patients in Japan.

DOI： 10.1016/j.cgh.2024.02.031

PubMed

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(NPO)日本歯周病学会  

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Language：Japanese   Publisher：(NPO)日本歯周病学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Approved drug therapies for nonalcoholic steatohepatitis (NASH) are lacking, for which various agents are currently being tested in clinical trials. Effective drugs for liver fibrosis, the factor most associated with prognosis in NASH, are important. AREAS COVERED: This study reviewed the treatment of NASH with a focus on the effects of existing drugs and new drugs on liver fibrosis. EXPERT OPINION: Considering the complex pathophysiology of fibrosis in NASH, drug therapy may target multiple pathways. The method of assessing fibrosis is important when considering treatment for liver fibrosis in NASH. The Food and Drug Administration considers an important fibrosis endpoint to be histological improvement in at least one fibrosis stage while preventing worsening of fatty hepatitis. To obtain approval as a drug for NASH, efficacy needs to be demonstrated on endpoints such as liver-related events and myocardial infarction. Among the current therapeutic agents for NASH, thiazolidinedione, sodium-glucose co-transporter 2, and selective peroxisome proliferator-activated receptors α modulator have been reported to be effective against fibrosis, although further evidence is required. The effects of pan-peroxisome proliferator-activated receptors, obeticholic acid, and fibroblast growth factor-21 analogs on liver fibrosis in the development stage therapeutics for NASH are of particular interest.

DOI： 10.1080/14728214.2024.2328036

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND & AIMS: FibroScan® Expert 630 and FibroScan® Mini+430 are novel vibration-controlled transient elastography devices equipped with the same SmartExam software, which allows continuous measurement of controlled attenuation parameter (CAP) during the entire examination. This study aims to compare the CAP variabilities and the quantification for liver fibrosis and steatosis between the conventional FibroScan and the SmartExam-equipped machines in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: This retrospective study included 118 patients with biopsy-proven MASLD who underwent liver biopsy at two tertiary centres between 2021 and 2023. Liver stiffness and steatosis measurements were performed using both FibroScan machines and M and XL probes for each individual. Liver histology was used as the reference standard for liver fibrosis and steatosis staging. RESULTS: Standard deviations of continuous CAP (cCAP) were significantly lower than those of CAP for all probes (p < .0001). CAP variability was significantly associated with body mass index (p < .01), probe selection (p < .001) as well as the random effect of centre. Only the effect of probe selection (p < .001) was significantly associated with cCAP variability. No significant difference was found in the performance of staging liver fibrosis and steatosis between two types of machines at the same cut-offs. CONCLUSIONS: The SmartExam-based VCTE reduces the variability of CAP measurement and achieves a similar accuracy as the FibroScan 502 device for the estimation of both hepatic steatosis and fibrosis. Future studies should determine if cCAP is a better tool to monitor changes in steatosis than the original CAP.

DOI： 10.1111/liv.15862

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Liver fibrosis is a major risk factor for hepatocellular carcinoma (HCC). We have previously reported that differentially methylated regions (DMRs) are correlated with the fibrosis stages of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, the methylation levels of those DMRs in liver fibrosis and subsequent HCC were examined. METHODS: The methylation levels of DMRs were investigated using alcoholic cirrhosis and HCC (GSE60753). The data of hepatitis C virus-infected cirrhosis and HCC (GSE60753), and two datasets (GSE56588 and GSE89852) were used for replication analyses. The transcriptional analyses were performed using GSE114564, GSE94660, and GSE142530. RESULTS: Hypomethylated DMR and increased transcriptional level of zinc finger and BTB domain containing 38 (ZBTB38) were observed in HCC. Hypermethylated DMRs, and increased transcriptional levels of forkhead box K1 (FOXK1) and zinc finger CCCH-type containing 3 (ZC3H3) were observed in HCC. The methylation levels of DMR of kazrin, periplakin interacting protein (KAZN) and its expression levels were gradually decreased as cirrhosis progressed to HCC. CONCLUSIONS: Changes in the methylation and transcriptional levels of ZBTB38, ZC3H3, FOXK1, and KAZN are important for the development of fibrosis and HCC; and are therefore potential therapeutic targets and diagnostic tools for cirrhosis and HCC.

DOI： 10.1186/s12876-024-03149-3

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: Although numerous noninvasive diagnostic methods have been developed to predict liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD), they lack markers for predicting lobular inflammation, hepatocellular ballooning, or changes related to metabolic dysfunction-associated steatohepatitis (MASH). We examined serum cytokeratin 18 fragment (CK18F) as a noninvasive marker for predicting treatment response and "at-risk MASH" and "MASH resolution" in patients with MASLD. METHODS: One-hundred-and-ten patients with MASLD who underwent repeated biopsy were enrolled (age, 4 [0.5-21] years) in this retrospective study. We investigated associations among serum CK18F levels, liver histology, and blood tests and compared them with changes in serum CK18F levels and liver histology and the resolution of MASH. Additionally, 565 biopsy-proven patients were analyzed for associations among serum CK18F levels, liver histology, and blood tests. Moreover, the Fibrosis-4 (FIB-4) index and CK18F were examined for their usefulness in predicting "at-risk MASH." RESULTS: CK18F changes were strongly correlated with changes in lobular inflammation, hepatocellular ballooning, and nonalcoholic fatty liver disease activity score. Multiple regression analysis showed that contributing to "MASH resolution" was associated with changes in CK18F levels as independent factors. Patients diagnosed with MASLD and an FIB-4 index >2.67, or those with an FIB-4 index ≤2.67 and CK18F > 200 U/L, were at high risk of developing MASH and should be referred to a hepatologist. Conversely, those with an FIB-4 index ≤2.67 and CK18F ≤ 200 U/L were effectively managed through regular follow-up appointments. CONCLUSION: CK18F changes are associated with nonalcoholic fatty liver disease activity score changes and are a promising noninvasive diagnostic marker for "at risk MASH" and "MASH resolution."

DOI： 10.1016/j.gastha.2024.08.008

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Language：English   Publishing type：Research paper (scientific journal)  

Chronic intestinal pseudo-obstruction (CIPO) is a rare intractable disease with limited treatment options. Small intestinal bacterial overgrowth (SIBO) often co-occurs with several diseases, including CIPO. While rifaximin (RFX) is effective in treating SIBO, its efficacy for CIPO remains unclear. Here, we aimed to investigate the efficacy and safety of RFX in adult patients with CIPO. Twelve patients were randomly assigned to receive RFX (400 mg three times daily, n=8) or a placebo (PBO, n=4) for 4 weeks. The global symptom score for abdominal bloating (GSS-bloating) and an original whole gastrointestinal symptoms score (O-WGSS) were collected, and a glucose hydrogen breath test (GHBT) and abdominal computed tomography (CT) were performed. No significant differences were observed in the primary endpoint. GSS-bloating improved by 75% and 25% in the PBO and RFX groups, respectively, and O-WGSS improved by 25% in both groups. No significant differences were observed in secondary and other endpoints, including the SIBO eradication rate in the GHBT and small intestinal volume on CT. In a post hoc analysis of SIBO-positive patients with CIPO (4/4 and 4/8 in the PBO and RFX groups), SIBO was eradicated in 25% and 75% of the patients (PBO and RFX groups, respectively) at the end of treatment, indicating a high eradication rate in the RFX group. Furthermore, the small intestinal gas volume decreased in the RFX group, and no severe adverse events occurred. Although no significant improvements were observed in subjective indicators, RFX may be beneficial in alleviating SIBO and reducing the small intestinal gas volume in SIBO-positive patients with CIPO.

DOI： 10.12938/bmfh.2023-080

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: The diagnostic performance of the Fibrosis-4 (FIB-4) index and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is poor in patients with type 2 diabetes mellitus (T2DM). We determined the usefulness of the enhanced liver fibrosis (ELF) test in patients with T2DM. METHODS: A total of 1,228 patients with biopsy-proven NAFLD were enrolled. The diagnostic performance of the ELF test for predicting advanced fibrosis in participants with or without T2DM was evaluated in comparison with the FIB-4 index and NFS. RESULTS: Overall, the area under the curve of the ELF test for predicting advanced fibrosis was greater (0.828) than that of the FIB-4 index (0.727) and NFS (0.733). The diagnostic performance of the ELF test (area under the curve 0.820) was also superior to that of the FIB-4 index (0.698) and NFS (0.700) in patients with T2DM. With the low cutoff values for each non-invasive test, the ELF test provided an acceptable false-negative rate (cutoff value 9.8, 6.7%) in this population, unlike the FIB-4 index (1.30, 14.5%) and NFS (-1.455, 12.4%). After propensity score matching to avoid selection bias including age, sex, body mass index, and the prevalence of advanced fibrosis, the ELF test with a low cutoff value showed a high sensitivity (≥91.4%) and a high negative predictive value (≥96.8%), irrespective of the presence or absence of T2DM. CONCLUSION: The high diagnostic performance of the ELF test for predicting advanced fibrosis in individuals with or without T2DM could address an unmet medical need for accurate assessment of liver fibrosis in patients with diabetes and NAFLD.

DOI： 10.1016/j.cgh.2023.11.022

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(株)診断と治療社  

＜文献概要＞Headline 1 NAFLDにおいて,肝硬度(≒肝線維化の程度)と肝脂肪化の測定を行い,適切なフォローアップをする必要がある.2 NITsでは,肝硬度だけでなく肝脂肪化も測定可能である.3 侵襲的検査である肝生検は,組織学的な評価が可能であるゆえ,ほかの肝疾患の合併が疑われる場合や腫瘍生検など今後も失われることのない技術である.しかし,NITsの進歩に伴い,今後,肝硬度や肝脂肪化測定目的に行われる機会はますます減少する可能性が高い.

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00697&link_issn=&doc_id=20231218110014&doc_link_id=10.34433%2Fdt.0000000514&url=https%3A%2F%2Fdoi.org%2F10.34433%2Fdt.0000000514&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：(株)診断と治療社  

＜文献概要＞Headline 1 NAFLDにおいて,肝硬度(≒肝線維化の程度)と肝脂肪化の測定を行い,適切なフォローアップをする必要がある.2 NITsでは,肝硬度だけでなく肝脂肪化も測定可能である.3 侵襲的検査である肝生検は,組織学的な評価が可能であるゆえ,ほかの肝疾患の合併が疑われる場合や腫瘍生検など今後も失われることのない技術である.しかし,NITsの進歩に伴い,今後,肝硬度や肝脂肪化測定目的に行われる機会はますます減少する可能性が高い.

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00697&link_issn=&doc_id=20231218110014&doc_link_id=10.34433%2Fdt.0000000514&url=https%3A%2F%2Fdoi.org%2F10.34433%2Fdt.0000000514&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Publishing type：Research paper (scientific journal)   Publisher：The Korean Society of Neurogastroenterology and Motility  

DOI： 10.5056/jnm22162

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status. METHODS: Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC). RESULTS: We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model. CONCLUSIONS: Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH.

DOI： 10.1097/HC9.0000000000000285

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Language：English   Publishing type：Research paper (scientific journal)  

Drug-induced liver injury (DILI) is a major cause of acute liver injury, liver failure, and liver transplantation worldwide. In recent years, immune checkpoint inhibitors have become widely used. This has led to an increase in DILI, for which pathophysiology and management methods differ significantly from the past. As the number of cases of acute liver injury and liver transplantation due to DILI is expected to increase, information about a DILI is becoming more valuable. DILI is classified into two types according to its etiology: intrinsic DILI, in which the drug or its metabolites cause liver damage that is dose-dependent and predictable; and idiosyncratic DILI, in which liver damage is also dose-independent but unpredictable. In addition, depending on the course of the disease, chronic DILI or drug-induced autoimmune hepatitis may be present. The number of DILI cases caused by antimicrobial agents is decreasing, whereas that caused by drugs for malignant tumors and health foods is increasing. The Roussel Uclaf Causality Assessment Method is widely used to assess causality in DILI. Liver injury is a type of immune-related adverse event. The pattern of hepatic injury in immune-related adverse events is mostly hepatocellular, but mixed type and bile stasis have also been reported. Sclerosing cholangitis caused by immune checkpoint inhibitors has also been reported as a unique type of injury. Treatment mainly comprises withdrawal of immune checkpoint inhibitors and steroid administration; however, mycophenolate mofetil may be considered if the disease is refractory to steroids.

DOI： 10.14218/JCTH.2022.00067S

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BACKGROUND: The prognosis of metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with liver fibrosis. We aimed to investigate whether liver stiffness measurement (LSM) and changes in LSM (ΔLSM) on magnetic resonance elastography (MRE) can predict clinical events in patients with MASLD. METHODS: We included 405 patients with MASLD who underwent at least two MREs. The patients were divided into five groups corresponding to fibrosis stages (0-4) based on initial LSM and classified as progressors (ΔLSM ≥ 19%) or non-progressors (ΔLSM < 19%) based on the difference between the first and last LSM. RESULTS: The mean follow-up period was 72.6 months, and the mean interval between MREs was 23.5 months. There were 52 (12.8%) progressors and 353 (87.2%) non-progressors. The initial LSM was significantly associated with the cumulative probabilities of decompensated cirrhosis, hepatocellular carcinoma (HCC), liver-related events, extrahepatic malignancies, and overall mortality but not with cardiovascular disease. Progressors had significantly higher hazard ratios (HRs) for decompensated cirrhosis, HCC, and liver-related events but not for extrahepatic malignancies, cardiovascular disease, or overall mortality. Among patients without cirrhosis, the HR for developing cirrhosis among progressors was 60.15. Progressors had a significantly higher risk of liver-related events, even in the low initial LSM (fibrosis stage 0-2) subgroups. CONCLUSIONS: Both initial LSM and ΔLSM can predict liver-related events in patients with MASLD, even for low initial LSM. This integrated assessment can allow more detailed risk stratification compared with single LSM assessments and identify high-risk patients with MASLD among those previously considered as low risk.

DOI： 10.1007/s00535-023-02049-9

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DOI： 10.21037/hbsn-23-342

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

This retrospective cohort study compared the number of newly diagnosed patients, stage at diagnosis, and detection process of gastrointestinal cancers based on hospital-based cancer registry data at two tertiary Japanese hospitals. The pre-COVID-19 period was from January 2017 to February 2020, with phase 1 (midst of COVID-19 pandemic) from March to December 2020 and phase 2 (the transition period to the "new normal") from January to December 2021. Each month, the number of patients diagnosed with esophageal, gastric, colorectal, pancreatic, liver, and biliary tract cancers were aggregated, classified by stage and detection process, and compared, including a total of 6453 patients. The number of colorectal Stage 0-II patients decreased significantly in phase 1 and increased in phase 2. The total number of colorectal cancer patients returned to pre-COVID-19 levels (mean monthly patients [SD]: 41.61 [6.81] vs. 36.00 [6.72] vs. 46.00 [11.32]). The number of patients with gastric cancer Stage I significantly decreased in phase 2 following phase 1. The number of gastric cancer patients decreased significantly from pre-COVID-19 levels (30.63 [6.62] vs. 22.40 [5.85] vs. 24.50 [4.15]). During phase 2, the number of patients diagnosed after screening with colorectal cancer increased significantly, whereas that with gastric cancer remained considerably lower. The number of Stage III colorectal and gastric cancer patients increased significantly from the pre-COVID-19 levels. Thus, gastric cancer may not be optimally screened during phases 1 and 2. There was a significant increase in patients with Stage III colorectal and gastric cancers from the pre-COVID-19 period; hence, the stage at diagnosis may have progressed.

DOI： 10.3390/cancers15174410

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Language：English   Publishing type：Research paper (scientific journal)  

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and there has been a rapid increase in cases worldwide. NAFLD is rapidly becoming the leading cause of hepatocellular carcinoma and is also associated with an increased risk of cardiovascular disease or exacerbation of other organ diseases, thus posing a significant health problem from both a medical and a socioeconomic perspective. NAFLD is a systemic disease and requires the involvement of numerous medical professionals. Multidisciplinary collaboration, in which different professionals within different specialties come together and work together toward a common goal, supports better patient care by integrating perspectives of multiple experts and facilitating the exchange of opinions. Due to the large number of potential patients, gastroenterologists and hepatologists cannot manage the patients alone, and collaboration between specialists in various fields, including family doctors, dentists, nutritionists, and pharmacists is required for treatment of NAFLD. This review will discuss NAFLD from the perspective of various specialties and introduce multidisciplinary collaboration.

DOI： 10.5009/gnl220545

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BACKGROUND AND AIM: Ischemic colitis (IC) is a benign disease associated with acute lower gastrointestinal bleeding and frequent recurrence. While several studies have investigated risk factors for IC onset, few have assessed the risk factors for recurrent IC. This study aimed to identify risk factors for recurrent IC. METHODS: Potential risk factors for recurrence were assessed by examining medical records and laboratory findings in this single-center retrospective study. We extracted the following data from the patients' medical records: patient characteristics, clinical signs and symptoms, laboratory findings, method of treatment, length of hospital stay, disease course, and the frequency of IC morbidities. Patients with IC were selected from a total of 439 312 patients over an 11-year period. Patients were divided into recurrent and nonrecurrent IC groups. RESULTS: In total, 225 patients met the diagnostic criteria for IC during the specified study period; of these, 204 patients (90.7%) and 21 patients (9.3%) were included in the nonrecurrent and recurrent IC groups, respectively. Univariate and multivariate analyses showed a significant association between IC recurrence and both cerebral infarction (P = 0.008, odds ratio [OR] = 6.3) and history of appendectomy (P = 0.0005, OR = 6.2). The median (interquartile range [IQR]) follow-up time for all patients was 1556 (353-2768) days; this was much longer than the median (IQR) time to recurrence of 291 (64-907) days in the recurrent IC group. CONCLUSION: The results of this study suggest that prior cerebral infarction and appendicectomy may be risk factors for IC recurrence.

DOI： 10.1002/jgh3.12948

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/liv.15678

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OBJECTIVE: Liver stiffness measurements (LSMs) and controlled attenuation parameters (CAPs) obtained using vibration-controlled transient elastography (VCTE) are recognized non-invasive methods of assessing liver histology. The usefulness of CAP for predicting liver-related events (LREs: hepatocellular carcinoma, decompensation, bleeding varices) is not well understood worldwide. Our aim was to re-evaluate the cutoff values of LSM/CAP in Japan and to examine whether LSM/CAP can predict LRE. METHODS: Japanese NAFLD patients (n = 403) who underwent both liver biopsy and VCTE were enrolled. We determined optimal cutoff values of LSM/CAP diagnoses for fibrosis stage and steatosis grade and investigated their clinical outcome based on LSM/CAP values. RESULTS: The LSM cutoff values for F1 to F4 are 7.1, 7.9, 10.0 and 20.2 kPa, and the CAP cutoff values for S1 to S3 are 230, 282 and 320 dB/m. During a median follow-up of 2.7 y (range: 0.0-12.5 y), 11 patients developed LREs. The incidence of LREs in the LSM Hi (≥8.7) group was significantly higher than that in the LSM Lo (<8.7) group (p = 0.003), and the incidence in the CAP Lo (<295) group was higher than that in CAP Hi (≥295) group (p = 0.018). Considering LSM and CAP together, the risk of LRE was higher in the LSM Hi CAP Lo group than in the LSM Hi CAP Hi group (p = 0.03). CONCLUSION: We set LSM/CAP cutoff values to diagnose liver fibrosis and steatosis in Japan. Our study determined that NAFLD patients with high LSM and low CAP values are at high risk for LREs.

DOI： 10.1016/j.ultrasmedbio.2023.03.023

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(有)科学評論社  

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AIM: The noninvasive tests (NITs) Agile 3+ and Agile 4 effectively identify patients with nonalcoholic fatty liver disease (NAFLD) complicated with advanced fibrosis (F3-4) and cirrhosis (F4), respectively. Little information is available on associations between Agile scores and intra-/extrahepatic events. The aim of this study was to determine the predictive performance of Agile scores for intra-/extrahepatic events in Asian patients with biopsy-proven NAFLD. METHODS: We undertook a retrospective multicenter cohort study to investigate associations between intra-/extrahepatic events and two Agile scores, Agile 3+ and Agile 4. The scores were obtained by combining clinical parameters and liver stiffness measurement using transient elastography. RESULTS: Among 403 enrolled patients, 11 had liver-related events (LREs), including seven with hepatocellular carcinoma (HCC). The incidence of LREs and HCC showed a stepwise increase in the advanced fibrosis group (F3-4), Agile 3+ rule-in (F3-4, highly suspected), and Agile 4 rule-in (F4, highly suspected) groups, compared to their counterparts. Hazard ratios for LREs in the advanced fibrosis group, Agile 3+ rule-in, and Agile 4 rule-in groups were 4.05 (p = 0.03), 23.5 (p = 0.003), and 45.5 (p < 0.001), respectively. The predictive performance results for Agile 3+ and Agile 4 were 0.780 and 0.866, respectively, which were higher than for fibrosis (0.595). Unlike for LREs, Agile scores failed to identify patients with extrahepatic events, including cardiovascular events and extrahepatic cancer. CONCLUSIONS: Agile 3+ and Agile 4 scores are excellent NITs for predicting LREs in patients with NAFLD, possibly without histological assessment.

DOI： 10.1111/hepr.13938

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DOI： 10.1111/apt.17505

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BACKGROUND: Clinical trials enroll patients with active fibrotic non-alcoholic steatohepatitis (NASH) (NAFLD activity score≥4) and significant fibrosis (F≥2); however, screening failure rates are high following biopsy. We developed new scores to identify active fibrotic NASH using FibroScan and magnetic resonance imaging (MRI). METHODS: We conducted prospective primary (n=176), retrospective validation (n=169) and University of California San Diego (UCSD; n=234) studies of liver biopsy-proven NAFLD. Liver stiffness measurement (LSM) using FibroScan or magnetic resonance elastography (MRE), controlled attenuation parameter (CAP) or proton density fat fraction (PDFF), and AST were combined to develop two-step strategy-FibroScan-based LSM followed by CAP with AST (F-CAST) and MRE-based LSM followed by PDFF with AST (M-PAST)-and compared with FibroScan-AST (FAST) and MRI-AST (MAST) for diagnosing active fibrotic NASH. Each model was categorized using rule-in and rule-out criteria. RESULTS: Areas under receiver operating characteristic curves (AUROCs) of F-CAST (0.826) and M-PAST (0.832) were significantly higher than those of FAST (0.744, p=0.004) and MAST (0.710, p<0.001). Following the rule-in criteria, positive predictive values of F-CAST (81.8%) and M-PAST (81.8%) were higher than those of FAST (73.5%) and MAST (70.0%). Following the rule-out criteria, negative predictive values of F-CAST (90.5%) and M-PAST (90.9%) were higher than those of FAST (84.0%) and MAST (73.9%). In the validation and UCSD cohorts, AUROCs did not differ significantly between F-CAST and FAST, but M-PAST had a higher diagnostic performance than MAST. CONCLUSIONS: The two-step strategy, especially M-PAST, showed reliability of rule-in/-out for active fibrotic NASH, with better predictive performance compared with MAST. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13927

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Aim: Impacts of platelet counts at the time of liver biopsy on hepatocellular carcinoma (HCC) development in patients with nonalcoholic fatty liver disease (NAFLD) remain unknown. The aim of this study was to investigate the prognostic value of platelet counts in patients with biopsy-confirmed NAFLD using data from a multicenter study. Methods: One thousand three hundred ninety-eight patients were included in this subanalysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia study. Liver biopsy specimens were pathologically diagnosed, and histologically scored using the NASH Clinical Research Network system. Demographic, clinical, laboratory, and pathological data were collected. Results: During a median follow-up period of 4.6 years (range, 0.3–21.6 years), which corresponds to 8874 person-years, 37 patients developed HCC. Using a cut-off baseline platelet count of 192 × 109/L, the lower platelet group had a higher HCC rate than the higher platelet group (6.7% vs. 0.4%; p < 0.001). This cut-off value significantly stratified the event-free rate for HCC. Lower platelet counts were associated with an increased risk of HCC development. Relative to patients with platelet counts of 192 × 109/L, patients with platelet counts of 100 × 109/L had an unadjusted hazard ratio (HR) for HCC development of 7.37 (95% confidence interval [CI], 3.81–14.2) and an adjusted HR of 11.2 (95% CI, 3.81–32.7; p < 0.001), adjusting for age, sex, NASH, and diabetes. Conclusions: Baseline platelet counts of 192 × 109/L and lower are associated with a higher risk of developing HCC in patients with biopsy-confirmed NAFLD and require active surveillance.

DOI： 10.1111/hepr.13884

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Language：Japanese   Publisher：産業開発機構(株)  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00116&link_issn=&doc_id=20230519190009&doc_link_id=%2Fan7eizoc%2F2023%2F005506%2F011%2F0056-0061%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fan7eizoc%2F2023%2F005506%2F011%2F0056-0061%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：産業開発機構(株)  

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The relationship between baseline serum albumin level and long-term prognosis of patients with nonalcoholic fatty liver disease (NAFLD) remains unknown. This is a sub-analysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) study. The main outcomes were: death or orthotopic liver transplantation (OLT), liver-related death, and liver-related events (hepatocellular carcinoma [HCC], decompensated cirrhosis, and gastroesophageal varices/bleeding). 1383 Japanese patients with biopsy-confirmed NAFLD were analyzed. They were divided into 3 groups based on serum albumin: high (>4.0 g/dL), intermediate (3.5-4.0 g/dL), and low (<3.5 g/dL). Unadjusted hazard ratio [HR] of the intermediate albumin group, compared with the high albumin group, were 3.6 for death or OLT, 11.2 for liver-related death, 4.6 for HCC, 8.2 for decompensated cirrhosis, and 6.2 for gastroesophageal varices (all risks were statistically significant). After adjusting confounding factors, albumin remained significantly associated with death or OLT (intermediate vs. high albumin group: HR 3.06, 95% confidence interval [CI] 1.59-5.91, p < 0.001; low vs. high albumin group: HR 22.9, 95% CI 8.21-63.9, p < 0.001). Among biopsy-confirmed NAFLD patients, those with intermediate or low serum albumin had a significantly higher risk of death or OLT than those with high serum albumin.

DOI： 10.3390/nu15092014

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12328-023-01789-8

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Other Link： https://link.springer.com/article/10.1007/s12328-023-01789-8/fulltext.html

Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：English   Publishing type：Research paper (scientific journal)  

The increasing incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), along with global lifestyle changes, requires further in-depth research to elucidate the mechanisms and develop new treatment strategies. In addition, the number of patients with periodontal disease has increased recently, suggesting that periodontal disease is sometimes associated with systemic conditions. In this review, we summarize recent studies linking periodontal disease and NAFLD, the concept of the mouth-gut-liver axis, oral and intestinal microbiota, and liver disease. We suggest new research directions toward a detailed mechanistic understanding and novel targets for treatment and prevention. Forty years have passed since the concepts of NAFLD and NASH were first proposed. however, no effective prevention or treatment has been established. We also found that the pathogenesis of NAFLD/NASH is not limited to liver-related diseases but has been reported to be associated with various systemic diseases and an increasing number of causes of death. In addition, changes in the intestinal microbiota have been shown to be a risk factor for periodontal diseases, such as atherosclerosis, diabetes, rheumatoid arthritis, nonalcoholic fatty liver disease, and obesity.

DOI： 10.3390/nu15051269

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Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

SmartExam搭載FibroScan(FS)による肝硬度測定・脂肪化測定が高齢者においても有用かどうか検討した。非アルコール性脂肪性肝疾患(NAFLD)の診断で当院通院中の65歳以上の高齢者69例(男性47.7%、年齢65～89歳)を対象とした後ろ向き観察研究を行った。69例に対して従来型FSとSmartExam搭載FSの両方の機器を用いて肝硬度と肝脂肪化測定を行った。このうち42例にはMagnetic Resonance Elastography(MRE)およびMagnetic Resonance Imaging-Proton Dense Fat Fraction(MRI-PDFF)による肝硬度・肝脂肪化測定も行った。従来型FSで測定した肝硬度とSmartExam搭載FSで測定した肝硬度の相関係数は0.95、従来型FSの肝脂肪化とSmartExam搭載FSの肝脂肪化の相関係数は0.83であった。高齢者の肝線維化と脂肪化評価において、従来型FS/SmartExam搭載FSはともに診断能が高く、いずれの測定結果にも差がないことが示された。SmartExamは従来機器と高い相関を認めること、MRE/MRI-PDFFを基準としたときに高い診断能を有することが利点として挙げられる。SmartExam搭載FSは肝硬度および肝脂肪化の測定において、従来型FS同様に高い診断能を有し、高齢者においてもこれまでと同様に実臨床で使用できるnew computation methodであると推定された。

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/app13063893

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: Agile 3+ and Agile 4 scores, based on liver stiffness measurement (LSM) by transient elastography and clinical parameters, were recently reported to be effective in identifying advanced fibrosis and cirrhosis in nonalcoholic fatty liver disease (NAFLD). This study aimed to validate the utility of these scores in Japanese patients with NAFLD. METHODS: Six hundred forty-one patients with biopsy-proven NAFLD were analyzed. The severity of liver fibrosis was pathologically evaluated by one expert pathologist. LSM, age, sex, diabetes status, platelet count, and aspartate aminotransferase and alanine aminotransferase levels were used to calculate Agile 3+ scores, and the parameters above excluding age were used for Agile 4 scores. The diagnostic performance of the two scores was evaluated using receiver operating characteristic (ROC) curve analysis. Sensitivity, specificity, and predictive values of the original low cut-off (for rule-out) value and high cut-off (for rule-in) value were tested. RESULTS: For diagnosis of fibrosis stage ≥ 3, the area under the ROC (AUROC) was 0.886, and the sensitivity of the low cut-off value and the specificity of the high cut-off value were 95.3% and 73.4%, respectively. For diagnosis of fibrosis stage 4, AUROC, the sensitivity of the low cut-off value, and the specificity of the high cut-off value were 0.930, 100% and 86.5%, respectively. Both scores had higher diagnostic performance than the FIB-4 index and the enhanced liver fibrosis score. CONCLUSIONS: Agile 3+ and Agile 4 are reliable noninvasive tests to identify advanced fibrosis and cirrhosis in Japanese NAFLD patients with adequate diagnostic performance. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13890

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND & AIMS: Noninvasive tests (NITs) have prognostic potential, but whether NITs are comparable with liver biopsy is unclear. This study aimed to examine the prognostic accuracy of NITs for liver-related mortality (LRM) and events (LREs) in patients with biopsy-proven NAFLD. METHODS: We investigated 1,313 patients with NAFLD. Patients were assigned to low-, indeterminate-, and high-risk groups using conventional cutoff values of each FIB-4 and NAFLD fibrosis score (NFS), and to stage 0-2 and stage 3-4 groups using the fibrosis stage. Survival and Cox regression analyses of the prognostic potential of NITs for LRM/LREs were conducted. RESULTS: During a median follow-up of 4.5 years, regarding to FIB-4, the incidence rate (/1000 person-years) in the low-risk was zero for LRM, and 0.5 for LREs. In contrast, the rate in stage 0-2 was 1.3 for LRM, 2.8 for LRE. The adjusted hazard ratios (aHRs) for LREs in the high-risk compared with the low-risk were 32.85 (p<0.01). The aHRs in stage 3-4 compared with stage 0-2 were 2.68 (p=0.02) for LREs, and 2.26 (p=0.582) for LRM. In the same fibrosis stage, the incidence of LRM/LREs was more frequent with a higher risk stratification. The same trend was observed for NFS. CONCLUSIONS: NITs accurately predict LRM and LREs as well as a liver biopsy in Japanese patients with NAFLD. Patients in the low-risk may not require close follow-up for at least 5 years. The simple NITs could be an acceptable alternative method to performing a liver biopsy for the prognosis of NAFLD.

DOI： 10.1111/jgh.16144

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Language：English   Publishing type：Research paper (scientific journal)  

With the increasing incidence of non-alcoholic fatty liver disease (NAFLD) and the aging of the population, sarcopenia is attracting attention as one of the pathological conditions involved in the development and progression of NAFLD. In NAFLD, sarcopenia is closely associated with insulin resistance and results from the atrophy of skeletal muscle, an insulin target organ. In addition, inflammatory cytokines that promote skeletal muscle protein breakdown, low adiponectin levels leading to decreased insulin sensitivity, and hyperleptinemia are also involved in NAFLD pathogenesis. The presence of sarcopenia is a prognostic factor and increases the risk of mortality in patients with cirrhosis and post-treatment liver cancer. Sarcopenia, the presence of which mainly occurs due to decreased muscle mass, combined with increased visceral fat, can lead to sarcopenia-associated obesity, which increases the risk of NASH, liver fibrosis, and cardiovascular disease. In order to treat sarcopenia, it is necessary to properly evaluate sarcopenia status. Patients with high BMI, as in sarcopenic obesity, may improve with caloric restriction. However, inadequate oral intake may lead to further loss of muscle mass. Aerobic and resistance exercise should also be used appropriately.

DOI： 10.3390/nu15040891

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, the prognosis of NAFLD/NASH has been reported to be dependent on liver fibrosis degree. Liver biopsy remains the gold standard, but it has several issues that must be addressed, including its invasiveness, cost, and inter-observer diagnosis variability. To solve these issues, a variety of noninvasive tests (NITs) have been in development for the assessment of NAFLD progression, including blood biomarkers and imaging methods, although the use of NITs varies around the world. The aim of the Japan NASH NIT (JANIT) Forum organized in 2020 is to advance the development of various NITs to assess disease severity and/or response to treatment in NAFLD patients from a scientific perspective through multi-stakeholder dialogue with open innovation, including clinicians with expertise in NAFLD/NASH, companies that develop medical devices and biomarkers, and professionals in the pharmaceutical industry. In addition to conventional NITs, artificial intelligence will soon be deployed in many areas of the NAFLD landscape. To discuss the characteristics of each NIT, we conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis in this study with the 36 JANIT Forum members (16 physicians and 20 company representatives). Based on this SWOT analysis, the JANIT Forum identified currently available NITs able to accurately select NAFLD patients at high risk of NASH for HCC surveillance/therapeutic intervention and evaluate the effectiveness of therapeutic interventions.

DOI： 10.1007/s00535-022-01932-1

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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.

DOI： 10.1016/j.cgh.2022.01.002

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Language：English   Publishing type：Research paper (scientific journal)  

Non-invasive imaging techniques have greatly advanced the assessment of liver fibrosis and steatosis but are not fully evaluated in overweight patients. We evaluated the diagnostic performance of vibration-controlled transient elastography (VCTE) and magnetic resonance elastography (MRE) to assess fibrosis and controlled attenuation parameter (CAP) and MR imaging (MRI)-proton density fat fraction (MRI-PDFF) to assess steatosis in overweight and obese patients with non-alcoholic fatty liver disease (NAFLD). We included 163 biopsy-proven patients with NAFLD who underwent VCTE, MRE/MRI-PDFF, and liver biopsy (years 2014-2020) who were classified according to their body mass index (BMI) as normal (BMI < 25 kg/m2, n = 38), overweight (25 ≤ BMI < 30 kg/m2, n = 68), and obese (BMI ≥ 30 kg/m2, n = 57). VCTE and MRE detected fibrosis of stages ≥ 2, ≥ 3, and 4 with an area under the receiver operating curve (AUROC) of 0.83-0.94 (VCTE) and 0.85-0.95 (MRE) in all groups, without considerable differences. MRI-PDFF detected steatosis of grades ≥ 2 and 3 with high AUROC in all groups (0.81-1.00). CAP's diagnostic ability (0.63-0.95) was lower than that of MRI-PDFF and decreased with increasing BMI compared to MRI-PDFF. VCTE and MRE similarly accurately assess fibrosis, although MRI-PDFF is more accurate than CAP in detecting steatosis in overweight and obese patients with NAFLD.

DOI： 10.1038/s41598-022-25843-6

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: The enhanced liver fibrosis (ELF) test is a noninvasive method for diagnosing hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). This multicenter cohort study aimed to evaluate the accuracy of the ELF test and compare it with other noninvasive tests in Japan. METHODS: We analyzed 371 Japanese patients with biopsy-proven NAFLD. We constructed area under the receiver operator characteristic curves (AUROC) to determine the diagnostic accuracies of the ELF test, the Mac-2-binding protein glycosylation isomer (M2BPGi), the Fibrosis-4 (FIB-4) index, and combinations of these indices. RESULTS: In patients with F0/F1/F2/F3/F4 fibrosis, the median values of the ELF test were 8.98/9.56/10.39/10.92/11.41, respectively. The AUROCs of the ELF test for patients with F0 versus F1-4, F0-1 versus F2-4, F0-2 versus F3-4, and F0-3 versus F4 fibrosis were 0.825/0.817/0.802/0.812, respectively. The AUROCs of the ELF test were greater than those of the FIB-4 index and M2BPGi at each fibrosis stage. Respective low and high cut-off values yielded sensitivities and specificities for predicting advanced fibrosis (≥F3) of 91.1% and 50.8%, and 38.5% and 92.8%, respectively. For F3 or F4 fibrosis, the combined values from the ELF test and FIB-4 index showed a sensitivity of 98.5%, and the combined values from the ELF test and M2BPGi assay showed a specificity of 97.5%. CONCLUSIONS: In Japan, the ELF test predicts NAFLD-related fibrosis from its early stages. The diagnostic ability of the ELF test was not inferior to that of other indices, and the combined values of ELF plus other indices were more accurate.

DOI： 10.1111/hepr.13871

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Language：English   Publishing type：Research paper (scientific journal)  

Non-alcoholic fatty liver disease is currently the most common chronic liver disease, affecting up to 25% of the world's population. Simple fatty liver, in which fat is deposited in the liver without fibrosis, has been regarded as a benign disease in the past, but it is now known to be prognostic. In the future, more emphasis should be placed on the quantification of liver fat. Traditionally, fatty liver has been assessed by histological evaluation, which requires an invasive examination, but technological innovations have made it possible to evaluate fatty liver by noninvasive imaging methods such as ultrasonography, computed tomography, and magnetic resonance imaging. In addition, quantitative as well as qualitative measurements for the detection of fatty liver have become available. In this review, we summarize currently used qualitative evaluations of fatty liver and discuss quantitative evaluations that are expected to further develop in the future.

DOI： 10.3350/cmh.2022.0357

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: Older age, type 2 diabetes mellitus (T2DM), and obesity are known risk factors for liver-related events (LREs). We investigated the impacts of T2DM and obesity on LRE according to age in Japanese patients with non-alcoholic fatty liver disease (NAFLD). METHODS: We performed a subanalysis of a retrospective cohort study (CLIONE in Asia), including 1395 patients with biopsy-proven NAFLD. The median follow-up was 4.6 years. RESULTS: The median age was 57 years, and 36.2% had T2DM. The median body mass index (BMI) was 27.4, and 28.5% were severely obese (BMI ≥ 30). During follow-up, 37 patients developed hepatocellular carcinoma (HCC), and 58 patients developed LRE. In patients younger than 65 years, advanced fibrosis (hazard ratio [HR] 7.69, P < 0.001) and T2DM (HR 3.37, P = 0.017) were HCC risk factors, and advanced fibrosis (HR 9.40, P < 0.001) and T2DM (HR 2.51, P = 0.016) were LRE risk factors. In patients 65 years and older, advanced fibrosis (HR 4.24, P = 0.010) and obesity (HR 4.60, P = 0.006) were HCC risk factors, and advanced fibrosis (HR 4.22, P = 0.002) and obesity (HR 4.22, P = 0.002) were LRE risk factors. CONCLUSION: Type 2 diabetes mellitus and obesity contributed to LRE in younger and older patients, respectively, along with advanced fibrosis. Therefore, controlling T2DM in patients younger than 65 years and controlling weight in patients 65 years and older could prevent LRE. The development of age-dependent screening and management strategies is necessary for patients with NAFLD.

DOI： 10.1111/jgh.16019

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: SmartExam is a novel computational method compatible with FibroScan that uses a software called SmartDepth and continuous controlled attenuation parameter measurements to evaluate liver fibrosis and steatosis. This retrospective study compared the diagnostic accuracy of conventional and SmartExam-equipped FibroScans for liver stiffness measurement (LSM). METHODS: The liver stiffness and the associated controlled attenuation parameters of 167 patients were measured using conventional and SmartExam-Equipped FibroScan as well as reference methods like magnetic resonance elastography (MRE) and magnetic resonance imaging-based proton density fat fraction measurements (MRI-PDFF) to assess its diagnostic performance. M or XL probes were selected based on the probe-to-liver capsule distance for all FibroScan examinations. RESULTS: The liver stiffness and controlled attenuation parameter (CAP) correlation coefficients calculated from conventional and SmartExam-equipped FibroScan were 0.97 and 0.82, respectively. Using MRE/MRI-PDFF as a reference and the DeLong test for analysis, LSM and the area under the receiver operating characteristic curve for CAP measured by conventional and SmartExam-equipped FibroScan showed no significant difference. However, the SmartExam-equipped FibroScan measurement (33.6 seconds) took 1.4 times longer than conventional FibroScan (23.2 seconds). CONCLUSIONS: SmartExam has a high diagnostic performance comparable to that of conventional FibroScan. Since the results of the conventional and SmartExam-equipped FibroScan were strongly correlated, it can be considered useful for assessing the fibrosis stage and steatosis grade of the liver in clinical practice, with less variability but little longer measurement time compared to the conventional FibroScan.

DOI： 10.1111/jgh.16076

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/hepr.13857

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

A 2-step approach, Fibrosis-4 index (FIB-4) followed by vibration-controlled transient elastography (VCTE), has been proposed to predict advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to develop a novel 3-step approach for predicting advanced fibrosis. We enrolled 284 biopsy-confirmed NAFLD patients from two tertiary care centers and developed subgroups (n = 190), including 3.7% of patients with advanced fibrosis, assuming a primary care setting. In the 3-step approach, patients with intermediate-to-high FIB-4 in the first step underwent an enhanced liver fibrosis test or measurement of type IV collagen 7S domain as the second step, and VCTE was performed if the second step value was higher than the cutoff. In 284 cases, a tertiary care cohort with 36.3% advanced fibrosis, the 3-step approach showed significantly higher specificity and positive predictive value than the 2-step approach. In the subgroup with 3.7% advanced fibrosis, the 3-step approach significantly reduced the referral rate to specialists, the number of high-risk patients (i.e., liver biopsy candidates), and healthcare costs by 12.5% to 15.8%. The 3-step approach may improve the diagnostic performance to predict advanced fibrosis in NAFLD, which could lower rates of referrals to specialists, liver biopsies, and medical costs.

DOI： 10.1038/s41598-022-22767-z

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Other Link： https://www.nature.com/articles/s41598-022-22767-z

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UNLABELLED: Leukotriene receptor antagonists (LTRA) are widely used drugs for treating allergic asthma, and they have recently been suggested to have a suppressive effect on carcinogenesis and cancer cell proliferation. Aberrant crypt foci (ACF) are considered a reliable surrogate biomarker of colorectal cancer. This prospective study explored the chemopreventive effect of an LTRA on colonic ACF formation and the safety of the medicine in patients as a pilot trial leading to a colorectal cancer chemoprevention trial. This was a nonrandomized, open-label, controlled trial in patients with colorectal ACFs. The participants were allocated to LTRA or observation groups. Patients in the LTRA group received 10 mg of montelukast orally daily for 8 weeks. After the intervention, colonoscopy was performed to evaluate the changes in the number of ACFs. From November 2017 to March 2020, 40 patients were enrolled. The first 30 were assigned to the LTRA group, and the remaining 10 were assigned to the observation group. In the LTRA group, the mean change in the number of ACFs per patient at 8 weeks from baseline was -2.4 ± 2.2, while the mean change in the observation group was 0.4 ± 2.3 (P = 0.002). There were no severe adverse events. This is the first study to explore the effect of LTRAs against colorectal ACF formation in humans. LTRAs are potential candidates for chemoprevention in colorectal cancer. PREVENTION RELEVANCE: We conducted the first LTRA chemoprevention trial for human rectal ACFs, which is considered a surrogate marker of colorectal carcinogenesis. 8-week treatment with LTRA suppressed ACF formation and cell proliferation in colonic epithelium. LTRAs are possible candidates for chemoprevention in colorectal cancer. See related Spotlight, p. 637.

DOI： 10.1158/1940-6207.CAPR-22-0049

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Global lifestyle changes have led to an increased incidence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), requiring further in-depth research to understand the mechanisms and develop new therapeutic strategies. In particular, high-fat and high-fructose diets have been shown to increase intestinal permeability, which can expose the liver to endotoxins. Indeed, accumulating evidence points to a link between these liver diseases and the intestinal axis, including dysbiosis of the gut microbiome and leaky-gut syndrome. Here, we review the mechanisms contributing to these links between the liver and small intestine in the pathogenesis of NAFLD/NASH, focusing on the roles of intestinal microbiota and their metabolites to influence enzymes essential for proper liver metabolism and function. Advances in next-generation sequencing technology have facilitated analyses of the metagenome, providing new insights into the roles of the intestinal microbiota and their functions in physiological and pathological mechanisms. This review summarizes recent research linking the gut microbiome to liver diseases, offering new research directions to elucidate the detailed mechanisms and novel targets for treatment and prevention.

DOI： 10.3390/ijms231911689

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

非アルコール性脂肪肝疾患(nonalcoholic fatty liver disease:NAFLD)と非アルコール性脂肪性肝炎(nonalcoholic steatohepatitis:NASH)の罹患率は世界中で急激な増加をきたしており,医療および社会経済学の両方の観点から重要な健康問題となっている.NAFLDはメタボリックシンドロームの肝臓の表現型と見なされており,メタボリックシンドロームの危険因子と関連していると報告されている.そのためNAFLD/NASHは肝臓の特異的疾患だけでなく,全身疾患に関与すると認識されるべきと考えられている.肝生検はNASHの診断やNAFLD患者における肝線維症のステージングのためのゴールドスタンダードとして推奨されている.しかしながら,肝生検はコストが高く,合併症リスクも低くなく,医療資源への負荷が大きいため,このように罹患率の高い状況において侵襲的な検査である肝生検のみが正式な評価方法であるという考えが最適とはいえない.よって,NASHから肝硬変へ進行するリスクを評価し,心血管系有害事象のリスクを評価し,HCC早期発見のサーベイランスの必要性を検知し,NAFLD/NASH患者の治療の際の道標となる,肝線維化評価のための信頼性の高い非侵襲的手法の開発が求められている.この総論では,NAFLD患者の肝線維化ステージや脂肪変性度を評価するための超音波エラストグラフィ(Real-time Tissue Elastography,vibration-controlled transient elastography,point shear wave elastography,およびtwo-dimensional shear wave elastography)の原理と近年の臨床応用に焦点を当てる.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00833&link_issn=&doc_id=20220921440003&doc_link_id=%2Fed5choon%2F2022%2F004905%2F005%2F0397-0410%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fed5choon%2F2022%2F004905%2F005%2F0397-0410%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(有)科学評論社  

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/jgh3.12808

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jgh3.12808

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Periodontal disease is associated with non-alcoholic fatty liver disease (NAFLD). We evaluated periodontal treatment efficacy in patients with NAFLD and periodontal disease. METHODS: This multicenter, 2-arm, randomized study recruited adult patients with NAFLD and periodontitis, alanine aminotransferase levels ≥40 U/L, and equivalent steatosis grade ≥1. Forty eligible patients (18 men and 22 women) were randomly assigned to 2 groups (scaling and root planning [SRP; n = 20] and tooth-brushing [n = 20] groups) stratified by age and sex. The primary and secondary endpoints were changes in alanine aminotransferase levels and serum Porphyromonas gingivalis IgG-antibody titers from baseline to 12 weeks, respectively. Efficacy analysis was performed using an intention-to-treat approach (t-test). This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMINXXXXXXX). RESULTS: We observed a significantly higher decrease in absolute alanine aminotransferase levels and P. gingivalis IgG-antibody titers in the SRP group than in the tooth-brushing group (-12 vs 1 U/L; mean difference [δ], -12; 95% confidence interval [CI], -20 to -5; P = 0.002). The decrease in P. gingivalis IgG-antibody titer was significantly higher in the SRP group than in the tooth-brushing group (FDC381, -1.6 [2.5]; δ, -1.6; 95% CI, -2.7 to -0.4; P = 0.0092; SU63, -1.7 [2.0]; δ, -1.7; 95% CI, -2.7 to -0.7). No life-threatening events or treatment-related deaths occurred. CONCLUSION: Periodontal treatment induced significant short- and mid-term reductions in liver enzyme levels and antibody titers. Further research is warranted to clearly define SRP efficacy and tolerability in patients with NAFLD and periodontitis.

DOI： 10.14309/ctg.0000000000000520

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

The risk factors for non-alcoholic fatty liver disease (NAFLD) progression are not completely known. Porphyromonasgingivalis infection is a risk factor for systemic diseases. We investigated the association of P.gingivalis infection with the risk of non-alcoholic steatohepatitis progression. Here, hematological tests, periodontal examination, and saliva collection were performed for 164 patients with NAFLD. P.gingivalis was identified in saliva using polymerase chain reaction. Hepatic steatosis and stiffness were evaluated using vibration-controlled transient elastography (VCTE) and magnetic resonance imaging. In patients with NAFLD, P.gingivalis positivity (P.gingivalis ratio ≥ 0.01%) in saliva correlated with liver stiffness determined using magnetic resonance elastography (MRE; p &lt; 0.0001). A P.gingivalis ratio of 0.01% corresponds to 100,000 cells/mL and indicates the proportion of P.gingivalis in the total number of bacteria in the oral cavity. Patients with NAFLD and advanced fibrosis on MRE showed significantly elevated endotoxin activity; those who had &gt; 10 periodontal pockets with depths ≥ 4 mm had significantly increased hepatic stiffness on both VCTE and MRE.

DOI： 10.1038/s41598-022-17917-2

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Other Link： https://www.nature.com/articles/s41598-022-17917-2

Language：Japanese   Publisher：(NPO)日本歯周病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Background: Approximately 60% of patients with chronic constipation (CC) have a significantly higher rate of loss of defecation desire (LODD). Bile acids are expected to have a restorative effect on defecation desire (DD) because they lower the rectal sensory threshold, which is an objective index of DD. Elobixibat (EXB) specifically inhibits the ileal bile acid transporter/apical sodium-dependent bile acid transporter, which is a transporter involved in the reabsorption of bile acids in the terminal ileum. This study aims to investigate the LODD improvement rate in patients with CC after 4 weeks of EXB treatment. Methods: A total of 40 adult patients with CC who meet the eligibility criteria will be enrolled. Patients will receive oral EXB (10 mg/day) for 4 weeks. A patient diary will be provided daily at 4 weeks after treatment. The primary endpoint will be the percentage LODD improvement at week 4 of the treatment period from week 2 of the observation period using questionnaires. Ethics and dissemination: Ethical approval was obtained from the Yokohama City University Certified Institutional Review Board prior to participant enrolment (approval number: CRB21-008). The results of this study will be submitted for publication in international peer-reviewed journals, and key findings will be presented at international scientific conferences. Participants desiring the results of this study will be directly contacted for data dissemination. Trial registration: This trial was registered at ClinicalTrials.gov (NCT05165199). Protocol version: 1.0, September 21, 2021.

DOI： 10.1016/j.conctc.2022.100958

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Language：Japanese   Publisher：(NPO)日本歯周病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome phenotype in the liver and thus obviously associated with metabolic abnormalities, including insulin resistance-related to hyperglycaemic and hyperlipidaemia. The prevalence of NAFLD is increasing worldwide. However, currently, there is no consensus regarding the efficacy and safety of drugs used to treat patients with NAFLD/non-alcoholic steatohepatitis (NASH). Guanabenz acetate, a selective α2-adrenoceptor stimulator used in the treatment of hypertension, binds at a high-affinity constant to a nuclear transcriptional coregulator, helicase with zinc finger 2 (Helz2) and inhibits Helz2-medaited steatosis in the liver; chronic oral administration of guanabenz acetate produces a dose-dependent inhibition of lipid accumulation by inhibiting lipogenesis and activating fatty acid Β-oxidation in the liver of obese mice, resulting in improvement of insulin resistance and hyperlipidaemia. Taken all together, guanabenz acetate has a potentially effective in improving the development of NAFLD/NASH and metabolic abnormalities. In this randomised, open label, parallel-group, phase IIa study, we made attempts to conduct a proof-of-concept assessment by evaluating the efficacy and safety of guanabenz acetate treatment in patients with NAFLD/NASH. METHODS AND ANALYSIS: A total of 28 adult patients with NAFLD or NASH and hypertension complications meeting the inclusion/exclusion criteria will be enrolled. Patients will be randomised to receive either 4 or 8 mg guanabenz acetate (n=14 per group). Blood tests and MRI will be performed 16 weeks after commencement of treatment. The primary endpoint will be the percentage reduction in hepatic fat content (%) measured using MRI-proton density fat fraction from baseline by at least 3.46% at week 16 after treatment initiation. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment (YCU021001). 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. Participants wishing to know the results of this study will be contacted directly on data publication. TRIAL REGISTRATION NUMBER: This trial is registered with ClinicalTrials.gov (number: NCT05084404). PROTOCOL VERSION: V.1.1, 19 August 2021.

DOI： 10.1136/bmjopen-2021-060335

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Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：(一社)日本動脈硬化学会  

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Language：Japanese   Publisher：(一社)日本動脈硬化学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We previously reported that two differentially methylated region (DMR) networks identified by DMR and co-methylation analyses are strongly correlated with the fibrosis stages of nonalcoholic fatty liver disease (NAFLD). In the current study, we examined these DMR networks in viral hepatitis and hepatocellular carcinoma (HCC). METHODS: We performed co-methylation analysis of DMRs using a normal dataset (GSE48325), two NAFLD datasets (JGAS000059 and GSE31803), and two HCC datasets (GSE89852 and GSE56588). The dataset GSE60753 was used for validation. RESULTS: One DMR network was clearly observed in viral hepatitis and two HCC populations. Methylation levels of genes in this network were higher in viral hepatitis and cirrhosis, and lower in HCC. Fatty acid binding protein 1 (FABP1), serum/glucocorticoid regulated kinase 2 (SGK2), and hepatocyte nuclear factor 4 α (HNF4A) were potential hub genes in this network. Increased methylation levels of the FABP1 gene may be correlated with reduced protection of hepatocytes from oxidative metabolites in NAFLD and viral hepatitis. The decreased methylation levels of SGK2 may facilitate the growth and proliferation of HCC cells. Decreased methylation levels of HNF4A in HCC may be associated with tumorigenesis. The other DMR network was observed in NAFLD, but not in viral hepatitis or HCC. This second network included genes involved in transcriptional regulation, cytoskeleton organization, and cellular proliferation, which are specifically related to fibrosis and/or tumorigenesis in NAFLD. CONCLUSIONS: Our results suggest that one DMR network was associated with fibrosis and tumorigenesis in both NAFLD and viral hepatitis, while the other network was specifically associated with NAFLD progression. Furthermore, FABP1, SGK2, and HNF4A are potential candidate targets for the prevention and treatment of HCC.

DOI： 10.1186/s12876-022-02360-4

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Language：Japanese   Publisher：(有)科学評論社  

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Publishing type：Research paper (scientific journal)   Publisher：AME Publishing Company  

DOI： 10.21037/hbsn-21-579

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(株)医学出版  

NASH/NAFLD診断のゴールデンスタンダードは肝生検であるが、その侵襲性や診断における病理医内や病理医間の一致率が低いこと、サンプリングエラーが看過できないことから、非侵襲的診断方法が精力的に開発されている。画像診断では脂肪蓄積の定性的評価方法として腹部超音波診断、CTなどが用いられ、定量的評価ではCAPに代表される深部減衰の原理を用いた定量方法が開発されている。もっとも正確かつ全肝臓を評価できる点でMRI-PDFFが有用である。線維化の評価に関しては、肝硬度の測定を行い評価するエラストグラフィーが各種開発され実臨床で利用できるようになった。疾患活動性はmultiparametric MRIによるcT1値で把握することができる。現在ハイリスク患者の選別には、rule-out strategyとFASTやMEFIBといったrule-in strategyが提唱されValidationが行われている。(著者抄録)

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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.

DOI： 10.1007/s10620-021-07342-2

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BACKGROUND AND AIM: Liver stiffness measurement (LSM) and spleen stiffness measurement (SSM@50 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 (SSM@100 Hz) has been developed. We evaluated the diagnostic performance of SSM@100 Hz, SSM@50 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. SSM@100 Hz, SSM@50 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 SSM@50 Hz. SSM@100 Hz was most accurate (area under the receiver operating characteristic [AUROC] = 0.944) for the diagnosis of GEV compared to SSM@50 Hz, LSM, and scoring systems. AUROC of SSM@100 Hz for diagnosis of high-bleeding risk varices (HRV) was 0.941, which was significantly higher than that of SSM@50 Hz (AUROC = 0.842, P = 0.002). SSM@100 Hz showed higher specificity (82.0%) for diagnosis of HRV than SSM@50 Hz (specificity = 67.1%). SSM@100 Hz was significantly correlated with HVPG (r = 0.71, P < 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.

DOI： 10.1002/jgh3.12689

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1002/hep.32302

PubMed

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Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞▼画期的な治療薬の開発によりB型肝炎,C型肝炎を代表とするウイルス性肝疾患は制御されている.▼現在,生活習慣病に密接した肝疾患である非アルコール性脂肪性肝疾患(NAFLD)患者が増加し,その罹患率は成人の約25%に達する.▼2020年,アルコール飲酒の有無は問わず,肥満,2型糖尿病,代謝異常などを病因とした脂肪肝をmetabolic dysfunction associated fatty liver disease(MAFLD)とする新しい疾患概念が提唱された.▼肝臓病変の進行度,とくに線維化の進展程度を客観的に評価するための手法として肝生検がgold standardとされてきたが,近年,肝生検にかわる非侵襲的診断方法(NITs)の開発・臨床応用が進んでいる.

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00974&link_issn=&doc_id=20211203160010&doc_link_id=issn%3D0022-1961%26volume%3D128%26issue%3D6%26spage%3D1159&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0022-1961%26volume%3D128%26issue%3D6%26spage%3D1159&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：(一社)日本アルコール・アディクション医学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1016/j.freeradbiomed.2021.10.017

PubMed

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Language：Japanese   Publisher：梵天書房  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：John Wiley and Sons Inc  

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.

DOI： 10.1111/apt.16596

Scopus

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1007/s00535-021-01796-x

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1007/s00535-021-01828-6

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1111/hepr.13681

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1016/j.jphs.2021.07.002

PubMed

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Language：Japanese   Publisher：医学図書出版(株)  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J06599&link_issn=&doc_id=20211101360016&doc_link_id=%2Faa6kancd%2F2021%2F000701%2F017%2F0096-0100%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa6kancd%2F2021%2F000701%2F017%2F0096-0100%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1111/hepr.13688

PubMed

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Publishing type：Research paper (scientific journal)   Publisher：American Medical Association (AMA)  

DOI： 10.1001/jamanetworkopen.2021.26334

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：医歯薬出版(株)  

＜Key Point＞・NAFLDは、肥満人口や2型糖尿病罹患率の増加にともない世界中で増加している生活習慣病と密接にかかわる肝疾患である。・NAFLDとサルコペニアの発症にはインスリン抵抗性のほか、炎症性サイトカイン、アディポサイトカイン、ヘパトカインなどが関与し、双方向性の増悪因子となっている。・サルコペニア肥満を合併するNAFLD症例の場合、食事療法による減量のみならず適切な運動療法(有酸素運動、無酸素運動)の併用が必要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publishing type：Research paper (scientific journal)  

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/m2 ) and 51 obese patients with non-alcoholic fatty liver disease (body mass index ≥30 kg/m2 ) 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).

DOI： 10.1111/jgh.15487

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1097/MEG.0000000000002176

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.3390/ijms22158161

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(株)アークメディア  

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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.

DOI： 10.1007/s40265-021-01545-7

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Language：Japanese   Publisher：(株)アークメディア  

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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-1 . In addition, R2* mapped AUROC of HIB for grades ≥3 was 0.799 with cutoff value of 58.5 s-1 . When R2* was <62.5 s-1 , 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-1 , 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-1 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.

DOI： 10.1002/jmri.27810

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/hep4.1696

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/hep4.1696

Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞日米欧の診療ガイドラインにおいてNASHの診断,進行度の判定に肝生検はGold standardであるが,侵襲的な検査である肝生検はサンプリングエラーや合併症,コストの問題などがあり,すべてのNAFLD患者に施行することは不可能である.NAFLD/NASHの診療にとって肝脂肪量,線維化程度を評価することは診断のみならず治療方針の決定や治療効果の判定の際に最も重要な評価項目である.肝線維化評価のための超音波エラストグラフィやMRエラストグラフィ,肝脂肪を評価するMRIのPDFF法,フィブロスキャンのCAP法などを活用して肝生検を行うべきNAFLD患者を拾い上げ,また臨床経過に応じ適時フォローアップを行うことが望まれる.

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞日米欧の診療ガイドラインにおいてNASHの診断,進行度の判定に肝生検はGold standardであるが,侵襲的な検査である肝生検はサンプリングエラーや合併症,コストの問題などがあり,すべてのNAFLD患者に施行することは不可能である.NAFLD/NASHの診療にとって肝脂肪量,線維化程度を評価することは診断のみならず治療方針の決定や治療効果の判定の際に最も重要な評価項目である.肝線維化評価のための超音波エラストグラフィやMRエラストグラフィ,肝脂肪を評価するMRIのPDFF法,フィブロスキャンのCAP法などを活用して肝生検を行うべきNAFLD患者を拾い上げ,また臨床経過に応じ適時フォローアップを行うことが望まれる.

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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.

DOI： 10.1111/1346-8138.15963

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: We aimed to develop a novel noninvasive test using an artificial intelligence (AI)/neural network (NN) system (named nonalcoholic steatohepatitis [NASH]-Scope) to screen nonalcoholic fatty liver disease (NAFLD) and NASH. METHODS: We enrolled 324 and 74 patients histologically diagnosed with NAFLD for training and validation studies, respectively. Two independent pathologists histologically diagnosed patients with NAFLD for validation study. Additionally, 48 subjects who underwent a medical health checkup and did not show fatty liver ultrasonographically and had normal serum aminotransferase levels were categorized as the non-NAFLD group. NASH-Scope was based on 11 clinical values: age, sex, height, weight, waist circumference, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, cholesterol, triglyceride, and platelet count. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operator characteristic curve of NASH-Scope for distinguishing NAFLD from non-NAFLD in the training study and validation study were 99.7% versus 97.2%, 97.8% versus 97.8%, 99.7% versus 98.6%, 97.8% versus 95.7%, and 0.999 versus 0.950, respectively. Those for distinguishing NASH with fibrosis from NAFLD without fibrosis were 99.5% versus 90.7%, 84.3% versus 93.3%, 94.2% versus 98.0%, 98.6% versus 73.7%, and 0.960 versus 0.950. These results were excellent, even when the output data were divided into two categories without any gray zone. CONCLUSIONS: The AI/NN system, termed as NASH-Scope, is practical and can accurately differentially diagnose between NAFLD and non-NAFLD and between NAFLD without fibrosis and NASH with fibrosis. Thus, NASH-Scope is useful for screening nonalcoholic fatty liver and NASH.

DOI： 10.1111/hepr.13628

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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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. Conclusion: COL4-7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.

DOI： 10.1002/hep4.1637

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>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 <italic>Cre</italic> 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 <italic>Kras</italic> and <italic>Trp53</italic> loss generated in vitro by lentiviral <italic>Cre</italic> 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.

DOI： 10.1038/s41389-021-00322-1

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Other Link： http://www.nature.com/articles/s41389-021-00322-1

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Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare intrahepatic tumor. There are usually no specific physical findings, and the tumors are often diagnosed incidentally and are frequently large-sized at diagnosis. The imaging findings of LELCC resemble those of hepatocellular carcinoma (HCC). Tumors are often found in large-sized and advanced at diagnosis, and the main treatment of the disease is surgical resection. Herein, we report treating a patient with early stage LELCC by radiofrequency ablation (RFA). We diagnosed this tumor in a 27-year-old Chinese female with a history of chronic hepatitis B (CHB). Based on the findings of blood examination, abdominal ultrasonography, and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), this tumor was diagnosed as suspected HCC. Ultrasound-guided percutaneous tumor biopsy and RFA were performed at the same time. The histopathological findings finally revealed the diagnosis of LELCC. To the best of our knowledge, this is the first report, in the English-language literature, of the treatment of LELCC by RFA; we suggest that RFA might be a candidate treatment for small-sized early stage LELCC.

DOI： 10.1007/s12328-020-01303-4

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Language：Japanese   Publisher：(株)自然科学社  

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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, p = 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, p<0.001) despite no significant changes in body mass index, even in those not taking vitamin E (n = 17, 18.8 ± 6.9 to 16.7 ± 7.3, p = 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.

DOI： 10.3164/jcbn.20-142

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BACKGROUND: Non-invasive assessment of non-alcoholic steatohepatitis (NASH) is increasing in desirability due to the invasive nature and costs associated with the current form of assessment; liver biopsy. Quantitative multiparametric magnetic resonance imaging (mpMRI) to measure liver fat (proton density fat fraction) and fibroinflammatory disease [iron-corrected T1 (cT1)], as well as elastography techniques [vibration-controlled transient elastography (VCTE) liver stiffness measure], magnetic resonance elastography (MRE) and 2D Shear-Wave elastography (SWE) to measure stiffness and fat (controlled attenuated parameter, CAP) are emerging alternatives which could be utilised as safe surrogates to liver biopsy. AIM: To evaluate the agreement of non-invasive imaging modalities with liver biopsy, and their subsequent diagnostic accuracy for identifying NASH patients. METHODS: From January 2019 to February 2020, Japanese patients suspected of NASH were recruited onto a prospective, observational study and were screened using non-invasive imaging techniques; mpMRI with LiverMultiScan ®, VCTE, MRE and 2D-SWE. Patients were subsequently biopsied, and samples were scored by three independent pathologists. The diagnostic performances of the non-invasive imaging modalities were assessed using area under receiver operating characteristic curve (AUC) with the median of the histology scores as the gold standard diagnoses. Concordance between all three independent pathologists was further explored using Krippendorff's alpha (a) from weighted kappa statistics. RESULTS: N = 145 patients with mean age of 60 (SD: 13 years.), 39% females, and 40% with body mass index ≥ 30 kg/m2 were included in the analysis. For identifying patients with NASH, MR liver fat and cT1 were the strongest performing individual measures (AUC: 0.80 and 0.75 respectively), and the mpMRI metrics combined (cT1 and MR liver fat) were the overall best non-invasive test (AUC: 0.83). For identifying fibrosis ≥ 1, MRE performed best (AUC: 0.97), compared to VCTE-liver stiffness measure (AUC: 0.94) and 2D-SWE (AUC: 0.94). For assessment of steatosis ≥ 1, MR liver fat was the best performing non-invasive test (AUC: 0.92), compared to controlled attenuated parameter (AUC: 0.75). Assessment of the agreement between pathologists showed that concordance was best for steatosis (a = 0.58), moderate for ballooning (a = 0.40) and fibrosis (a = 0.40), and worst for lobular inflammation (a = 0.11). CONCLUSION: Quantitative mpMRI is an effective alternative to liver biopsy for diagnosing NASH and non-alcoholic fatty liver, and thus may offer clinical utility in patient management.

DOI： 10.3748/wjg.v27.i7.609

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The prevalence of obesity or metabolic syndrome is increasing worldwide (globally metabodemic). Approximately 25% of the adult general population is suffering from nonalcoholic fatty liver disease (NAFLD), which has become a serious health problem. In 2020, global experts suggested that the nomenclature of NAFLD should be updated to metabolic-dysfunction-associated fatty liver disease (MAFLD). Hepatic fibrosis is the most significant determinant of all cause- and liver -related mortality in MAFLD. The non-invasive test (NIT) is urgently required to evaluate hepatic fibrosis in MAFLD. The fibrosis-4 (FIB-4) index is the first triaging tool for excluding advanced fibrosis because of its accuracy, simplicity, and cheapness, especially for general physicians or endocrinologists, although the FIB-4 index has several drawbacks. Accumulating evidence has suggested that vibration-controlled transient elastography (VCTE) and the enhanced liver fibrosis (ELF) test may become useful as the second step after triaging by the FIB-4 index. The leading cause of mortality in MAFLD is cardiovascular disease (CVD), extrahepatic malignancy, and liver-related diseases. MAFLD often complicates chronic kidney disease (CKD), resulting in increased simultaneous liver kidney transplantation. The FIB-4 index could be a predictor of not only liver-related mortality and incident hepatocellular carcinoma, but also prevalent and incident CKD, CVD, and extrahepatic malignancy. Although NITs as milestones for evaluating treatment efficacy have never been established, the FIB-4 index is expected to reflect histological hepatic fibrosis after treatment in several longitudinal studies. We here review the role of the FIB-4 index in the management of MAFLD.

DOI： 10.3390/life11020143

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Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: The treatment of diabetes has a significant impact on the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We compared the effectiveness of tofogliflozin, a selective sodium-glucose cotransporter 2 inhibitor, and pioglitazone for the treatment of NAFLD patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: This open-label, prospective, single-center, randomized clinical trial recruited NAFLD patients with type 2 diabetes mellitus and a hepatic fat fraction of at least 10% as assessed based on the MRI-proton density fat fraction (MRI-PDFF). Eligible patients were stratified according to hemoglobin A1c (HbA1c), alanine transaminase, and MRI-PDFF levels and randomly assigned (1:1) to receive either 20 mg tofogliflozin or 15-30 mg pioglitazone, orally, once daily for 24 weeks. The primary endpoint was an absolute change in MRI-PDFF at 24 weeks. Efficacy and safety was assessed in all treated patients. This trial was registered in the Japan Registry of Clinical Trials. RESULTS: Overall, 40 eligible patients were randomly assigned to receive tofogliflozin (n=21) or pioglitazone (n=19). Changes in hepatic steatosis after 24 weeks of treatment were evaluated by MRI-PDFF, which showed a significant decrease in both groups (-7.54% (p<0.0001) and -4.12% (p=0.0042) in the pioglitazone and tofogliflozin groups, respectively). Compared with baseline, the body weight decreased by 2.83±2.86 kg (-3.6%, p=0.0443) in the tofogliflozin group and increased by 1.39±2.62 kg (1.7%, p=0.0002) in the pioglitazone group after 24 weeks. No life-threatening events or treatment-related deaths occurred. CONCLUSIONS: Tofogliflozin was well tolerated, and it reduced the MRI-PDFF levels in NAFLD patients with type 2 diabetes mellitus. TRIAL REGISTRATION NUMBER: jRCTs031180159.

DOI： 10.1136/bmjdrc-2020-001990

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ Publishing Group  

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/m2
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 (&lt
1.3
≥2.67) followed by LSM-VCTE cut-offs (&lt
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 (&lt
1.3
≥3.48) followed by LSM cut-offs (&lt
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.

DOI： 10.1136/gutjnl-2021-324243

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Ltd.  

DOI： 10.1080/14656566.2021.1912014

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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 Bifidobacterium bifidum 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, Sarcina and Sarcina maxima 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.

DOI： 10.12938/bmfh.2020-073

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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.

DOI： 10.3389/fendo.2021.770986

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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.

DOI： 10.1016/j.cgh.2020.12.016

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Non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common chronic liver disease worldwide, along with the concurrent epidemics of metabolic syndrome and obesity. Patients with NAFLD have increased risks of end-stage liver disease, hepatocellular carcinoma, and liver-related mortality. However, the largest cause of death among patients with NAFLD is cardiovascular disease followed by extrahepatic malignancies, whereas liver-related mortality is only the third cause of death. Extrahepatic complications of NAFLD include chronic kidney disease, extrahepatic malignancies (such as colorectal cancer), psychological dysfunction, gastroesophageal reflux disease, obstructive sleep apnea syndrome, periodontitis, hypothyroidism, growth hormone deficiency, and polycystic ovarian syndrome. The objective of this narrative review was to summarize recent evidences about extrahepatic complications of NAFLD, with focus on the prevalent/incident risk of such diseases in patients with NAFLD. To date, an appropriate screening method for extrahepatic complications has not yet been determined. Collaborative care with respective experts seems to be necessary for patient management because extrahepatic complications can occur across multiple organs. Further studies are needed to reveal risk profiles at baseline and to determine an appropriate screening method for extrahepatic diseases.

DOI： 10.3390/diagnostics10110912

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Hepatology  

DOI： 10.2957/kanzo.61.504

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The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased rapidly worldwide, making NAFLD/NASH an important global health problem from both a medical and socioeconomic standpoint. NAFLD is also regarded as a liver component of metabolic syndrome and is reported to be associated with the risk factors for metabolic syndrome. It has been suggested that NAFLD/NASH be recognized both as a liver-specific disease and as an early mediator of systemic diseases. Liver biopsy is recommended as the gold standard method for the diagnosis of NASH and for the staging of liver fibrosis in patients with NAFLD. However, because of its high cost, high risk, and high weightage as a healthcare resource, invasive liver biopsy is a poorly suited diagnostic test for such a highly prevalent condition. Therefore, the development of reliable noninvasive methods for the assessment of liver fibrosis has been sought to estimate the risk of progression of NASH to cirrhosis, estimate the risk of cardiovascular events, aid in the surveillance for HCC, and guide therapy in patients with NAFLD/NASH. In this review, we highlight the principles and recent advances in ultrasound elastography techniques (Real-time Tissue Elastography®, vibration-controlled transient elastography, point shear wave elastography, and two-dimensional shear wave elastography) used to evaluate the liver fibrosis stage and steatosis grade in patients with NAFLD.

DOI： 10.1007/s10396-020-01040-8

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Language：Japanese   Publisher：(一社)日本肝臓学会  

症例は45歳女性。急性骨髄性白血病に対して同種骨髄移植が行われ、移植後はタクロリムス、ステロイドによる免疫抑制療法を18ヵ月継続した。移植前はHBV既往感染の状態であったが、移植から38ヵ月後に肝機能障害、HBs抗原陽転化、HBV-DNA量上昇を認め、HBV再活性化と診断した。同種骨髄移植前後に赤血球濃厚液の頻回の輸血によりヘモクロマトーシスを合併していた影響もあり、血清フェリチン値は著明高値であった。肝生検では過剰な鉄沈着と急性肝炎の所見を認めた。ラミブジンにより治療を開始し、その後テノホビルアラフェナミドへ切り替えた。HBV再活性化とヘモクロマトーシスの関連性は不明であったが、HBV治療と鉄キレート剤により血清フェリチン値も漸減した。HBV既往感染状態での同種骨髄移植では、長期間にわたりHBV再活性化への注意が必要である。(著者抄録)

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

DOI： 10.3389/fonc.2020.555963

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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.

DOI： 10.1136/bmjopen-2020-037961

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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.

DOI： 10.1016/S2468-1253(20)30216-8

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Language：Japanese   Publisher：(一社)日本動脈硬化学会  

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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.

DOI： 10.1186/s13063-020-04385-0

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Background: Liver biopsy has been the standard procedure for diagnosing and evaluating the severity of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, interobserver discordance remains a critical issue in its pathological diagnosis. Methods and Results: We examined the concordance rates of pathological scoring and diagnosis between pathologists at individual institutions (local diagnosis) and two central pathologists specialized in liver pathology (central diagnosis). A total of 150 patients with NAFLD underwent prospective liver biopsies. NAFLD activity score (NAS) and fibrosis stage were evaluated, and NASH was determined according to Matteoni's classification. NAS, scores for all NAS components, and fibrosis stage were diagnosed at a lower degree by central compared with local diagnosis. NASH was diagnosed in 34% of the patients according to central pathologists compared with 54% according to local pathologists (P < 0.001). The concordance rates for NAS, steatosis, inflammation, ballooning, fibrosis, and NASH diagnosis were 26.7, 62.7, 51.3, 48.7, 43.3, and 50.7%, respectively. The correlation coefficient between local and central diagnoses was the lowest for the scoring of ballooning (ρ = 0.218). Conclusion: Concordance rates among pathologists for the evaluation of NAFLD are currently poor, and simple and reliable diagnostic and evaluation criteria are urgently needed to improve the clinical management of NAFLD patients.

DOI： 10.1002/jgh3.12289

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AIM: The Enhanced Liver Fibrosis (ELF) test comprises a logarithmic algorithm combining three serum markers of hepatic extracellular matrix metabolism. We aimed to evaluate the performance of ELF for the diagnosis of liver fibrosis and to compare it with that of liver stiffness measurement (LSM) by FibroScan in non-alcoholic fatty liver disease. METHODS: ELF cut-off values for the diagnosis of advanced fibrosis were obtained using receiver operating characteristic analysis in patients with biopsy-confirmed non-alcoholic fatty liver disease (training set; n = 200). Diagnostic performance was analyzed in the training set and in a validation set (n = 166), and compared with that of LSM in the FibroScan cohort (n = 224). RESULTS: The area under receiver operating characteristic curve was 0.81 for the diagnosis of advanced fibrosis, and the ELF cut-off values were 9.34 with 90.4% sensitivity and 10.83 with 90.6% specificity in the training set, and 89.8% sensitivity and 85.5% specificity in the validation set. There was no significant difference in the area under the receiver operating characteristic curve between ELF and LSM (0.812 and 0.839). A combination of ELF (cut-off 10.83) and LSM (cut-off 11.45) increased the specificity to 97.9% and the positive predictive value, versus ELF alone. Sequential use of the Fibrosis-4 index (cut-off 2.67) and ELF (cut-off 9.34) increased the sensitivity to 95.9%. CONCLUSIONS: ELF can identify advanced liver fibrosis in non-alcoholic fatty liver disease, and its diagnostic accuracy is comparable to that of FibroScan. According to the clinical setting, combinations or sequential procedures using other non-invasive tests complement the diagnostic performance of ELF for the identification of advanced fibrosis.

DOI： 10.1111/hepr.13495

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AIM: Liver biopsy is still required for the diagnosis of hepatocellular ballooning and inflammation, which are important histological feature of nonalcoholic steatohepatitis (NASH). We conducted this multicenter, cross-sectional study to identify novel blood markers for the diagnosis of hepatocellular ballooning. METHODS: We enrolled 176 patients, and 132 patients proven by liver biopsy as having NAFLD were classified as non-ballooning (ballooning grade 0) (n = 83) or ballooning (ballooning grade 1 and 2) (n = 49) by a central pathology review. We performed gas chromatography-mass spectrometry, hydrophilic interaction liquid chromatography tandem mass spectrometry, and lipidomics with plasma. RESULTS: As correlates of hepatocellular ballooning, among the clinical parameters, serum type IV collagen 7S correlated the most significantly with the ballooning grade (correlation coefficient [CC] = 0.463; P < 0.001). Among the metabolic-/lipidomic-markers, phosphatidylcholine (PC)(aa-44:8) correlated the most significantly with the ballooning grade (CC = 0.394; P < 0.001). The area under the receiver operating characteristic curve of type IV collagen 7S, choline, and lysophosphatidylethanolamine (LPE) (e-18:2), was 0.846 (95% confidence interval: 0.772-0.919). CONCLUSIONS: Plasma levels of PC were positively correlated, and those of lysophosphatidylcholine and LPE were negatively correlated with hepatocellular ballooning in NAFLD patients. These noninvasive metabolic-/lipidomic-based plasma tests might be useful to distinguish between cases of NAFLD with and without hepatocellular ballooning.

DOI： 10.1111/hepr.13528

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Few studies have evaluated both liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD) using both FibroScan® M and XL probes. This study was performed to investigate the accuracy of both FibroScan® probes to diagnose liver fibrosis and steatosis in patients with NAFLD. METHODS: We prospectively enrolled 137 consecutive patients with clinically suspected NAFLD in our joint-research facilities. Liver biopsies, liver stiffness measurements (LSMs), and controlled attenuation parameter (CAP) measurements were performed, and 122 patients with NAFLD diagnosed pathologically by central pathologists were included in the final analysis. RESULTS: Reliable LSM results were obtained in 85.2% (M) and 89.3% (XL) of patients, and CAP was reliable in 90.2% (M) and 90.2% (XL). The median LSM was significantly lower with the XL than M probe, and CAP was significantly higher with the XL than M probe. The optimal cut-off values for diagnosing the fibrosis stage were lower for LSM with the XL than M probe (stage ≥ 2, 6.7 vs. 7.0; stage ≥ 3, 8.2 vs. 10.8; stage 4, 14.3 vs. 16.8, respectively), whereas those of CAP were higher for the XL than M probe (score of ≥ 2, 273 vs. 267; score of 3, 302 vs. 286, respectively). There were no significant differences in accuracy of the LSM and CAP between the probes. CONCLUSIONS: Liver fibrosis and steatosis could be equally evaluated with FibroScan® M and XL probes in patients with NAFLD. There was no significant difference in diagnostic accuracy between the two probes using probe-specific cut-off values.

DOI： 10.1007/s00535-019-01635-0

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BACKGROUND: We report the first protocol for a multicenter, randomized comparison study to compare the efficacies of periodontal scaling and root-planing treatment against that of tooth-brushing treatment for nonalcoholic fatty liver disease (NAFLD) (PERION: PERIOdontal treatment for NAFLD). Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD, which can progress to cirrhosis and hepatocellular carcinoma. Increased endotoxemia is associated with the progression of NAFLD. Periodontal bacteria possess endotoxins; Porphyromonas gingivalis is well-known as a major pathogenic bacterium in periodontitis, and serum antibody levels for P. gingivalis are high in patients with periodontitis. Several reports have indicated that P. gingivalis is related to NAFLD. This study aims to investigate the effect of periodontal treatment for liver damage, P. gingivalis infection, and endotoxemia on patients with NAFLD. METHODS: We will include adult patients (20-85 years old) with NAFLD, alanine aminotransferase (ALT) ≥ 40 IU/L, and equivalent steatosis grade ≥ 1 (target sample size, n = 40 patients; planned number of patients with outcome data, n = 32). Participants will be randomly assigned to one of two groups: a scaling and root-planing group or tooth-brushing as the usual group. The primary outcome will be the change in ALT levels from baseline to 12 weeks; the key secondary outcome will be the change in the serum immunoglobulin G (IgG) antibody titer for P. gingivalis at 12 weeks. DISCUSSION: This study should determine whether periodontal treatment decreases liver damage, P. gingivalis infection, and endotoxemia in patients with NAFLD. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, ID: UMIN000022079.

DOI： 10.1186/s13063-020-4201-y

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Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D.

DOI： 10.3390/ijms21061907

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Publishing type：Research paper (scientific journal)   Publisher：Asploro Open Access Publications  

A fourth of the adult population is now suffering from nonalcoholic fatty liver disease (NAFLD) worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to liver-related mortality. NAFLD/NASH is closely associated with type 2 diabetes. Although pioglitazone is now recommended as the 1st line therapy for NASH with type 2 diabetes, pioglitazone has several safety concerns such as body weight gain, heart failure, fluid retention, and bone fracture in women. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have a variety of functions such as glycemic control, bodyweight reduction, and decreased body pressure. Accumulating evidence has shown that this agent has also cardioprotective and renoprotective effects in patients with or without type 2 diabetes. Recent studies that SGLT2 inhibitor can also reduce in transaminase activities or hepatic fat content in NAFLD. NAFLD patients with type 2 diabetes can be indicated for SGLT2 inhibitor, because they are obese, have insulin resistance, and at high risk of cardiovascular events. The phase 3 study of dapagliflozin for NAFLD (DEAN study) is now ongoing. It remains unknown whether this agent can ameliorate hepatic fibrosis in NASH, leading to improved over-all or liver-related survival. Since the leading cause of NAFLD mortality is cardiovascular events, SGLT2 inhibitors will become the 1st line treatment for NAFLD/NASH.

DOI： 10.36502/2020/droa.6159

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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.

DOI： 10.1016/j.conctc.2019.100516

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Language：Japanese   Publisher：(一社)広島県歯科医師会  

以下について概説した。1)NAFLD/NASHの歴史的背景、2)NAFLD/NASHの疾患概念、3)疫学から見たNAFLD/NASHと口腔疾患との関連、4)病態から見たNAFLD/NASHと歯周病(歯周病原細菌Porphyromonas gingivalis)との関連、5)NAFLD/NASH発症に関与する因子、歯周病を介した口腸肝軸、6)NAFLD治療における歯周病治療の可能性、7)NAFLD/NASHの予後、について述べた。

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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.

DOI： 10.3390/diagnostics10030129

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：(株)じほう  

＜Key Points＞・腸管壁のバリア機能が低下し、各種疾患の増悪因子となることを腸管透過性亢進(Leaky Gut)という。・長期にわたり微量エンドトキシンに曝露し、病態が悪化することをmetabolic endotoxemia(メタボリックエンドトキセミア)という。・脂肪細胞から分泌されるレプチンはエンドトキシンの感度を高め、ごくごく微量のエンドトキシンでも炎症が起こりやすくなる。・腸管と肝臓の相互作用(Gut-Liver Axis)は病気の発症が起きる機序で腸管側の異常のみでは不十分で、肝臓側の異常も必要である。(著者抄録)

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Background: 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. Case presentation: 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. Conclusion: 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.

DOI： 10.3389/fonc.2020.555963

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BACKGROUND: Since pancreatic steatosis is reported as a possible risk factor for pancreatic cancer, the development of a non-invasive method to quantify pancreatic steatosis is needed. Proton density fat fraction (PDFF) measurement is a magnetic resonance imaging (MRI) based method for quantitatively assessing the steatosis of a region of interest (ROI). Although it is commonly used for quantification of hepatic steatosis, pancreatic PDFF can greatly vary depending on the ROI's location because of the patchy nature of pancreatic fat accumulation. In this study, we attempted to quantify pancreatic steatosis by fat-water MRI with improved reproducibility. METHODS: Using the MRI images of 159 patients with nonalcoholic fatty liver disease, we attempted to calculate the average PDFF of whole pancreas. We set ROIs covering the entire area of the pancreas appearing in every slice and calculated the average PDFF from all the voxels included in the pancreas. We named this average value as whole-pancreatic PDFF and evaluated the reproducibility of the measured values. In addition to whole-pancreatic PDFF, we measured the average PDFF of the pancreatic head (head-PDFF) and that of the pancreatic body plus tail separately and analyzed their correlation with the clinical characteristics of the patients. RESULTS: The mean inter-examiner coefficient of variation of the whole-pancreatic PDFF was 11.39%. The whole-pancreatic PDFF was correlated with age (p = 0.039), body mass index (p = 0.0093) and presence/absence of diabetes (p = 0.0055). The serum level of low-density lipoprotein cholesterol was inversely correlated with the head-PDFF. CONCLUSION: We developed a new measurement method of the pancreatic PDFF with greater reproducibility. Using this method, we characterized pancreatic steatosis in detail. This novel measurement method allows accurate estimation of the severity of pancreatic steatosis and is therefore useful for the detailed characterization of pancreatic steatosis.

DOI： 10.1371/journal.pone.0224921

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2169/internalmedicine.2894-19

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Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

DOI： 10.1159/000502815

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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AIM: Although liver biopsy is the gold standard for the diagnosis and staging of non-alcoholic fatty liver disease (NAFLD), repeated assessment of patients' liver tissue conditions are impractical. We assessed the 10-year changes in liver stiffness measurements (LSM) utilizing vibration-controlled transient elastography in NAFLD patients. METHODS: From January 2006 to September 2007, LSM was carried out for 97 biopsy-proven NAFLD patients. Of these, 34 patients underwent 10-year LSM reassessments (14 of them with paired biopsies). RESULTS: We evaluated the changes in the fibrosis stage as estimated using LSM (FS-LSM). Over a 10-year period, 32.4% had FS-LSM progression, 50% had static disease, and 17.6% had FS-LSM improvement. From among the initially diagnosed non-alcoholic steatohepatitis patients, 18% had progressed to considerable stage 4 (cirrhosis) 10 years later. In this cohort, none of the patients who had been initially diagnosed as FS-LSM stage 0 had progressed to cirrhosis 10 years later. The changes in LSM were correlated with the change in the histological fibrosis stage, the NAFLD activity score, and the change in the sum of the steatosis, activity, and fibrosis score. Improving more than 1 body mass index (kg/m2 ) and having a higher initial aspartate aminotransferase, alanine aminotransferase (ALT), or ALT responder (>30% improvement or reduction to less than 40 IU/L) were factors contributing to LSM improvements (≥2 kPa). CONCLUSIONS: Vibration-controlled transient elastography is likely to become a more clinically important tool for the long-term monitoring of NAFLD patients.

DOI： 10.1111/hepr.13349

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Pruritus is a common pathogenesis in liver diseases, including chronic hepatitis B (CHB). The phases of hepatitis B virus (HBV) infection are defined in the American Association for the Study of Liver Diseases guidelines. However, it still remains unclear whether the phase independently affects pruritus. The aim of this study was to clarify the effect of HBV infection phase on pruritus in patients with HBV. Of the 1,631 patients that attended the joint research facilities and were interviewed regarding their pruritus between January and June 2016, 196 patients with HBV infection were selected for the present analysis. One-to-one propensity score-matching using 13 variables was performed between participants in the hepatitis B e antigen (HBe-Ag)-positive/negative immune-active phase group and the inactive CHB phase group. Data from 47 patients per group were included in the final analysis. The prevalence of pruritus in the inactive CHB phase was significantly lower than in the HBe-Ag-positive/negative immune-active phase (23 vs. 47%; P=0.031). Being in the inactive CHB phase was determined to be an independent risk factor for pruritus (odds ratio, 0.35; 95% confidence interval, 0.143-0.842; P=0.019). The progression to inactive CHB phase may contribute to the amelioration of pruritus in patients with HBV infection.

DOI： 10.3892/br.2019.1224

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BACKGROUND AND AIM: In the condition of high prevalence of non-alcoholic fatty liver disease (NAFLD), a new diagnostic algorithm to efficiently identify NAFLD patients with significant fibrosis is urgently required. We evaluated the predictive ability of the fibrosis-4 index (FIB-4 index) for significant liver fibrosis (F ≥ 2) in a cohort of Japanese patients with NAFLD. METHODS: We prospectively calculated the FIB-4 index in patients who were incidentally diagnosed as fatty liver in medical checkups and then conducted liver stiffness measurement by vibration-controlled transient elastography (VCTE) only in patients in whom the FIB-4 index was more than the low cut-off index (> 1.45). RESULTS: Of the 5929 people who underwent medical checkups, a total of 1374 people were identified as having fatty liver. Among these, we performed VCTE in 106 patients in whom the FIB-4 index was higher than 1.45. The distribution of the fibrosis stage as estimated by VCTE in the patients was as follows: F0, 52.8%; F1, 10.3%; F2, 21.6%; F3, 11.3%; and F4, 3.7%. The positive predictive value of the FIB-4 index for detecting NAFLD with significant fibrosis was 36.6%. The minimum value of the FIB-4 index was constant for each estimated fibrosis stage. CONCLUSIONS: This is the first prospective study to evaluate the usefulness of the FIB-4 index as the first step to screen NAFLD patients with significant fibrosis. In Japan, addition of one further step that combined with the FIB-4 index is necessary to meaningfully reduce the number of patients needing liver stiffness measurement or liver biopsy.

DOI： 10.1111/jgh.14559

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Background and Aim Although non-alcoholic fatty liver disease (NAFLD) is common in the general population, identifying patients with advanced fibrosis remains a challenge. We investigated whether the homeostasis model assessment parameter of insulin resistance (HOMA-IR), an index of IR and one of the most important metabolic factors, is an independent predictive factor for advanced fibrosis in nondiabetic patients with NAFLD. Methods This was a retrospective, cross-sectional multicenter study. We included 361 patients with biopsy-proven NAFLD who had not been diagnosed with type 2 diabetes mellitus: 175 (48%) were women and 48 (13%) had advanced fibrosis. We used simple random sampling; the sampling ratio of the estimation and validation groups was 7:3. A logistic model was constructed for both the estimation and validation groups. The explanatory variables were age &gt;= 49 years, sex (women), body mass index &gt;= 26.7 kg/m(2), the presence of hypertension, presence of dyslipidemia, fasting plasma glucose level &gt;= 98 mg/dL, fasting immune reactive insulin level &gt;= 12.0 mu U/mL, and HOMA-IR &gt;= 2.90. The median HOMA-IR of the patients was 2.88 (interquartile range: 2.1-4.8). Results In t

DOI： 10.1111/jgh.14595

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Language：Japanese   Publisher：(株)ライフメディコム  

非アルコール性脂肪性肝疾患(nonalcoholic fatty liver disease:NAFLD)は今日最も重要な慢性肝疾患とされているが、その治療において保険適用のある薬剤は存在しない。さまざまな糖尿病治療薬が開発、発売されているなか、糖尿病を合併しているNAFLDの治療において有力視されているのがGLP-1受容体作動薬である。ピオグリタゾンに次いで肝脂肪化や炎症など肝組織所見の改善効果を認めた薬剤であり、米国では食欲低下による体重減少により肥満症に対する適用ももつ薬剤でもある。糖尿病や肥満を合併したNAFLDにおいても、その治療効果は大いに期待されている。本稿では、糖尿病を合併したNAFLDに焦点を当てて概説する。(著者抄録)

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Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

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Language：Japanese   Publisher：(株)日本臨床社  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01205&link_issn=&doc_id=20190423250009&doc_link_id=%2Fag6niria%2F2019%2F007705%2F009%2F0792-0798%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2019%2F007705%2F009%2F0792-0798%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(有)科学評論社  

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AIM: We investigated the characteristics of serum autotaxin (ATX) and its diagnostic performance for liver fibrosis in a large cohort of patients with non-alcoholic fatty liver disease (NAFLD). METHODS: We compared the usefulness of ATX and other fibrosis markers in 307 biopsy-confirmed NAFLD patients. In addition, in 145 participants with NAFLD, we compared the diagnostic performance of ATX with that of non-invasive imaging methods (vibration-controlled transient elastography and magnetic resonance elastography [MRE]). RESULTS: Serum ATX concentration was significantly correlated with fibrosis stage in male and female NAFLD patients. In male patients, the area under the receiver operating characteristic (AUROC) curve values of ATX for the diagnosis of ≥stage 1, ≥stage 2, ≥stage 3, and ≥stage 4 fibrosis were 0.65, 0.75, 0.81, and 0.95, respectively. In female NAFLD participants, the AUROC values were all >0.81. The sensitivity of ATX was highest for the diagnosis of ≥stage 2 and ≥stage 3 fibrosis in both men and women with NAFLD. In the comparison between ATX and non-invasive imaging methods, the AUROC for MRE was the highest at every stage of fibrosis. CONCLUSIONS: Serum ATX concentration is significantly correlated with fibrosis stage in NAFLD patients. The diagnostic accuracy of ATX for liver fibrosis is lower than that of MRE, but the sensitivities of ATX for the diagnosis of ≥stage 2 and ≥stage 3 were highest. We conclude that ATX is useful for the selection of patients requiring further evaluation for liver fibrosis.

DOI： 10.1111/hepr.13382

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：(一社)日本臨床内科医会  

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Language：Japanese   Publisher：(株)アークメディア  

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INTRODUCTION: Multiple parallel factors are implicated in the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). Currently recommended therapies for NASH include vitamin E and pioglitazone, besides dietary and lifestyle changes. AREAS COVERED: This review focuses on the clinical development of several emerging drugs for the treatment of NASH and the impact of these drugs on current treatment standards. EXPERT OPINION: Four drug classes (FXR agonists, CCR2/CCR5 antagonists, ASK1 inhibitors, and PPARα/δ agonists) have moved into phase 3 trials for their investigation as NASH treatments. Results from phase 2 trials of other therapeutic agents with other pharmacological actions are also expected. The importance of combinational therapies with synergistic benefits engaging different targets, is now understood. Furthermore, studies have determined that the Mediterranean diet is beneficial for patients with NAFLD, while the traditional Okinawan diet is also considered useful. In the future, it will be important to establish new biomarkers to assess NAFLD activity, furthermore non-invasive diagnostic methods will promote the development of new drugs for NASH.

DOI： 10.1080/14656566.2018.1543403

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Language：Japanese   Publisher：(株)響文社  

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Language：Japanese   Publisher：(株)響文社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

Background and Aim: In the condition of high prevalence of non-alcoholic fatty liver disease (NAFLD), a new diagnostic algorithm to efficiently identify NAFLD patients with significant fibrosis is urgently required. We evaluated the predictive ability of the fibrosis-4 index (FIB-4 index) for significant liver fibrosis (F ≥ 2) in a cohort of Japanese patients with NAFLD. Methods: We prospectively calculated the FIB-4 index in patients who were incidentally diagnosed as fatty liver in medical checkups and then conducted liver stiffness measurement by vibration-controlled transient elastography (VCTE) only in patients in whom the FIB-4 index was more than the low cut-off index (&gt
 1.45). Results: Of the 5929 people who underwent medical checkups, a total of 1374 people were identified as having fatty liver. Among these, we performed VCTE in 106 patients in whom the FIB-4 index was higher than 1.45. The distribution of the fibrosis stage as estimated by VCTE in the patients was as follows: F0, 52.8%
F1, 10.3%
F2, 21.6%
F3, 11.3%
and F4, 3.7%. The positive predictive value of the FIB-4 index for detecting NAFLD with significant fibrosis was 36.6%. The minimum value of the FIB-4 index was constant for each estimated fibrosis stage. Conclusions: This is the first prospective study to evaluate the usefulness of the FIB-4 index as the first step to screen NAFLD patients with significant fibrosis. In Japan, addition of one further step that combined with the FIB-4 index is necessary to meaningfully reduce the number of patients needing liver stiffness measurement or liver biopsy.

DOI： 10.1111/jgh.14559

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: The Baveno VI criteria enable non-invasive screening for esophageal varices. However, these criteria were established based on studies examining a large proportion of patients with viral hepatitis and relatively few patients with non-alcoholic fatty liver disease (NAFLD). Furthermore, because vibration-controlled transient elastography (VCTE) has a high incidence of measurement error, improved criteria are needed. We aimed to develop criteria based on magnetic resonance elastography (MRE) even among patients with NAFLD. METHODS: We performed a cross-sectional analysis of patients who had undergone MRE and/or VCTE as well as an esophagogastroduodenoscopy. The patients were classified as having either a low risk or a high risk of varices. The optimal cut-offs for ruling out esophageal varices were calculated for the MRE and VCTE liver stiffness measurement (LSM), the platelet count in an estimation cohort, and the cut-offs were then evaluated using validation cohorts composed of patients who had undergone only MRE or VCTE. RESULTS: The study included 627 patients (39% with NAFLD). The optimal cut-off values for the MRE-LSM and the platelet count were 4.2 kPa and 18.0 × 104 /μL, respectively. An MRE-LSM of 4.2 kPa plus a platelet count of 18.0 × 104 /μL had a negative predictive value of 1.00 for both low-risk plus high-risk varices as well as for high-risk varices in a validation cohort, enabling the presence of varices to be ruled out. CONCLUSIONS: Magnetic resonance elastography might enable a safer avoidance of screening endoscopy, with a smaller measurement error, among patient populations with a high prevalence of NAFLD.

DOI： 10.1111/jgh.14298

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Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞近年,NAFLD診療において肝臓の線維化を非侵襲的に定量するエラストグラフィの普及が進んでいる.MRIベースのMRエラストグラフィ(MRE)は超音波ベースのFibroScan(VCTE)に比べ線維化診断能の感度・特異度が高いが汎用性ではVCTEが勝っている.実臨床では各種エラストグラフィの長所短所,さらには肝硬度と病理学的線維化との対応などを熟知したうえでの使用が望まれる.

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(NPO)日本歯周病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: The fibrosis stage of liver is associated with the long-term outcomes in patients with non-alcoholic fatty liver disease (NAFLD). However, significant fibrosis, defined as fibrosis stages 2-4, is associated with an elevated risk of progression to severe liver disease; there have been scant reports about diagnosing significant fibrosis. We compare the noninvasive method and aim to identify appropriate liver fibrosis markers for detecting significant fibrosis in NAFLD patients. METHODS: We compared the usefulness of liver fibrosis markers (Wisteria floribunda agglutinin-positive Mac-2-binding protein [WFA+ -M2BP], type 4 collagen 7S, etc.), clinical scoring systems, and liver stiffness measurement obtained using vibration-controlled transient elastography and magnetic resonance imaging-based magnetic resonance elastography in the same individuals and identified the most appropriate noninvasive method for detecting significant fibrosis in 165 patients with liver biopsy-diagnosed NAFLD. RESULTS: The area under the receiver operating characteristic curve based on the serum cutoff index values of WFA+ -M2BP/the serum levels of type IV collagen 7S for the diagnosis of significant fibrosis was 0.832 (95% confidence interval: 0.771-0.894)/0.837 (95% confidence interval: 0.778-0.898). "WFA+ -M2BP (cutoff index) ≥ 0.83 or type IV collagen 7S ≥ 5.2 ng/mL" showed a high sensitivity (91.4%) and negative predictive value (87.9%) for the diagnosis of significant fibrosis. CONCLUSIONS: We showed that serum WFA+ -M2BP or type IV collagen 7S levels serve as useful independent markers for detecting significant fibrosis and that use of both WFA+ -M2BP and type IV collagen 7S together increased the sensitivity and negative predictive value for the diagnosis of liver fibrosis. These results need to be validated in larger populations from multiple clinical centers.

DOI： 10.1111/jgh.14156

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Language：Japanese   Publisher：(公社)日本薬理学会  

肥満・メタボリックシンドロームの増加に伴い非アルコール性脂肪性肝疾患(nonalcoholic fatty liver disease:NAFLD)はわが国に2,000万人程度と患者数が多い。NAFLDのうち1〜2割が非アルコール性脂肪肝炎(nonalcoholic steatohepatitis:NASH)へ、さらに肝硬変や肝蔵がんに至るとされておりその対策は非常に重要である。患者数は増加の一途を辿っているが、その病態は多岐にわたり有効な治療はいまだ食事・運動療法が中心である。NASHの組織像は、好中球浸潤が主体であり、その病態進展にはグラム陰性桿菌由来のエンドトキシンの関与が推察されてきた。NASH進展におけるエンドトキシンを介した腸肝連関における肝臓側の要因として肥満を呈する高レプチン血症がNASH患者のエンドトキシンに対する過剰応答は重要なファクターである。さらに腸管側の要因として腸管バリアー機能の低下による腸管透過性の亢進が問題となっており、これらによって門脈中のエンドトキシンの増加をきたす。次世代シークエンサーの登場により、NAFLD/NASHにおける腸内細菌叢が解明されつつある。腸内細菌の乱れが引き起こす腸管透過性亢進による血中エンドトキシン上昇はNASH病態に重要であり、腸管透過性亢進の制御はNAFLD/NASH治療に新たな可能性を秘めているとわれわれは考えている。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01200&link_issn=&doc_id=20181009400004&doc_link_id=1390564238031540224&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390564238031540224&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

Language：Japanese   Publisher：(一社)日本肥満学会  

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The progression of nonalcoholic fatty liver disease (NAFLD) is affected by epigenetics. We performed differentially methylated region (DMR) and co-methylation analyses to identify DMR networks associated with the progression of NAFLD. DMRs displaying differences in multiple consecutive differentially methylated CpGs between mild and advanced NAFLD were extracted. The average values of topological overlap measures for the CpG matrix combining two different DMRs were calculated and two DMR networks that strongly correlated with the stages of fibrosis were identified. The annotated genes of one network included genes involved in transcriptional regulation, cytoskeleton organization, and cellular proliferation. The annotated genes of the second network were primarily associated with metabolic pathways. The CpG methylation levels in these networks were strongly affected by age and fasting plasma glucose levels, which may be important co-regulatory factors. The methylation status of five DMRs in the second network was reversible following weight loss. Our results suggest that CpG methylation in DMR networks is regulated concomitantly via aging and hyperglycemia and plays important roles in hepatic metabolic dysfunction, fibrosis, and potential tumorigenesis, which occur during the progression of NAFLD. By controlling weight and blood glucose levels, the methylation of DMRs in the second network may be reduced.

DOI： 10.1038/s41598-018-31886-5

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Language：Japanese   Publisher：(一社)日本臨床内科医会  

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Although previous studies have indicated important roles of palmitate, a saturated fatty acid, in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), it remains unclear how palmitate contributes to inflammation and fibrosis in the liver. Administration of palmitate in high fat diet (HFD)-fed but not basal diet (BD)-fed mice resulted in an increase in serum alanine aminotransferase (ALT) levels. Surprisingly, combined administration of very low dose lipopolysaccharide in palmitate-treated mice led to a marked increase in serum ALT levels despite BD-fed conditions. Administration of palmitate alone in BD-fed mice caused inflammatory cell infiltration and liver fibrosis mediated by the toll-like receptor 4 pathway without ALT elevation. In addition, a significant correlation between serum free fatty acid levels and liver fibrosis stage was observed in patients with NAFLD. These results indicate that palmitate may play crucial roles in the pathogenesis of NAFLD in the presence of gut-derived endotoxin.

DOI： 10.1038/s41598-018-29735-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The prognosis of patients with nonalcoholic fatty liver disease-related hepatocellular carcinoma (NAFLD-HCC) is intricately associated with various factors. We aimed to investigate the prognostic algorithm of NAFLD-HCC patients using a data-mining analysis. A total of 247 NAFLD-HCC patients diagnosed from 2000 to 2014 were registered from 17 medical institutions in Japan. Of these, 136 patients remained alive (Alive group) and 111 patients had died at the censor time point (Deceased group). The random forest analysis demonstrated that treatment for HCC and the serum albumin level were the first and second distinguishing factors between the Alive and Deceased groups. A decision-tree algorithm revealed that the best profile comprised treatment with hepatectomy or radiofrequency ablation and a serum albumin level &gt;= 3.7 g/dL (Group 1). The second-best profile comprised treatment with hepatectomy or radiofrequency ablation and serum albumin levels &lt;3.7 g/dL (Group 2). The 5-year overall survival rate was significantly higher in the Group 1 than in the Group 2. Thus, we demonstrated that curative treatment for HCC and serum albumin level &gt;3.7 g/dL was the best prognostic profile for NAF

DOI： 10.1038/s41598-018-28650-0

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Aims: The purpose of this study was to clarify the predictive clinical characteristics of therapy switching from sitagliptin to dulaglutide in patients with type 2 diabetes mellitus. Methods: This single-center, open-label, investigator-initiated pilot study was conducted in 40 patients with type 2 diabetes mellitus. The patients, who had been treated with 50 mg sitagliptin daily for at least 6 months were switched to 0.75 mg dulaglutide weekly. Results: A total of 36 patients could be followed for 24 weeks of treatment with dulaglutide. They were assessed for several clinical parameters before the start of and 24 weeks after the study. Multiple linear regression analysis was used to search for independent predictors of reduction of hemoglobin A1c (HbA1c) levels after 24 weeks of treatment switching from sitagliptin to dulaglutide. Dulaglutide administration for 24 weeks resulted in significant reductions in fasting plasma glucose (FPG), HbA1c, and low-density lipoprotein cholesterol (LDL-C) levels. In addition, baseline HbA1c, FPG, body mass index (BMI), and age were significantly correlated with the change in HbA1c levels (ΔHbA1c). Furthermore, multiple linear regression analysis revealed that BMI and age significantly correlated with ΔHbA1c. Conclusion: In summary, our prospective 24-week study showed that baseline low BMI and old age are significantly useful in predicting the HbA1c-lowering effect of switching from sitagliptin to dulaglutide. Trial Registration: UMIN Clinical Trials Registry (UMIN000023245).

DOI： 10.1007/s13340-018-0348-0

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BACKGROUND: This paper reports the protocol of a randomised, double-blind, placebo-controlled study to test the efficacy, safety, and tolerability of lubiprostone (LUB) vs. placebo on suppressing gut permeability in non-alcoholic fatty liver disease (NAFLD) patients with constipation. NAFLD, including non-alcoholic steatohepatitis (NASH), is a common chronic liver disorder. Progression is associated with increased gut permeability and gut-derived endotoxins. Most NAFLD/NASH clinical trial drugs aim to improve liver function or systemic metabolism. LUB is a type 2 chloride channel activator used as a laxative for the treatment of patients with constipation. LUB suppresses gut permeability induced by non-steroidal anti-inflammatory drugs in healthy volunteers and lowers blood endotoxin levels. There have been no clinical studies of LUB for NAFLD/NASH patients. METHODS: The study plans to enrol adult patients (20-85 years, planned enrolment, n = 150; planned sample size, n = 120) with NAFLD and constipation, alanine aminotransferase ≥40 IU/L, equivalent steatosis grade ≥1, and equivalent fibrosis stage <4 measured using non-invasive vibration-controlled transient elastography and magnetic resonance imaging. Participants will be randomly allocated into three groups: LUB 12 μg, LUB 24 μg, and a placebo group. RESULTS: The primary endpoint will be changes in alanine aminotransferase from baseline at 12 weeks. The main secondary endpoint will be changes in intestinal permeability from baseline at 12 weeks using the lactulose mannitol ratio. CONCLUSIONS: This study will determine whether LUB improves gut permeability in NAFLD patients with constipation. TRIAL REGISTRATION: This trial is registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000026635).

DOI： 10.1016/j.cct.2018.04.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

The coauthor Masashi Yoneda’s affiliation has been incorrectly published in the original publication of the article. The correct affiliation is provided in this correction.

DOI： 10.1007/s00535-018-1478-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

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

DOI： 10.1007/s00535-018-1474-y

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BACKGROUND AND AIM: The aim of this study was to assess the efficacy of a new microwave ablation (MWA) system, the Emprint Ablation System, for the ablation of unresectable large liver tumors (≥ 30 mm). METHODS: Twenty-one hepatic tumors (mean diameter, 34.7 mm) from 21 patients who underwent percutaneous MWA were included in this cross-sectional study. A volume analyzer based on computed tomography imaging was used for all patients within the month before and month after the procedure to evaluate the shape and volume of ablation zones. In addition, computed tomography imaging was performed again 3 months after the procedure to evaluate the presence of residual tumors and local recurrence. RESULTS: Mean ablation time was 11.3 min, and mean overall procedure time was 33.4 min. An ablated adrenal gland-induced Takotsubo (stress) cardiomyopathy occurred immediately after MWA as a major complication in one patient. Roundness index A, B, and C presented a mean value of 0.94, 0.94, and 1.01, respectively (all values near 1 is a perfect sphere), indicating that a spherical ablation zone was achieved. The mean ablation volume was larger than the volume of tumors (24.5 vs 41.7 cm3 ). Residual tumors were confirmed in only 4.8% of tumors after a single ablation session. There was no local recurrence. CONCLUSIONS: In our experience, the new MWA system provides an effective treatment option for unresectable large liver tumors. However, to ablate the liver tumors safely, it is necessary to consider the surrounding organs, such as the adrenal glands.

DOI： 10.1111/jgh.14294

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Language：Japanese   Publisher：(株)響文社  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(株)響文社  

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Language：Japanese   Publisher：(株)響文社  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Aim: The progression of non-alcoholic fatty liver disease (NAFLD) is affected by epigenetics. We undertook co-methylation and differentially methylated region (DMR) analyses to identify the genomic region that is under epigenetic regulation during NAFLD progression. Methods: We collected liver biopsy specimens from 60 Japanese patients with NAFLD and classified these into mild (fibrosis stages 0–2) or advanced (fibrosis stages 3–4) NAFLD. We carried out a genome-wide DNA methylation analysis and identified the differentially methylated CpGs between mild and advanced NAFLD. Differentially methylated regions with multiple consecutive differentially methylated CpGs between mild and advanced NAFLD were extracted. Results: Co-methylation analysis showed that individual differentially methylated CpG sites were clustered into three modules. The CpG sites clustered in one module were hypomethylated in advanced NAFLD and their annotated genes were enriched for “immune system” function. The CpG sites in another module were hypermethylated and their annotated genes were enriched for “mitochondria” or “lipid particle”, and “lipid metabolism” or “oxidoreductase activity”. Hypomethylated DMRs included tumorigenesis-related genes (FGFR2, PTGFRN, and ZBTB38), the expressions of which are upregulated in advanced NAFLD. Tumor suppressor MGMT had two DMRs and was downregulated. Conversely, FBLIM1 and CYR61, encoding proteins that reduce cell proliferation, showed hypomethylated DMRs and were upregulated. Expression of the antioxidant gene NQO1 was upregulated, with a hypomethylated DMR. The DMR containing cancer-related MIR21 was hypomethylated in advanced NAFLD. Conclusions: Co-methylation and DMR analyses suggest that the NAFLD liver undergoes mitochondrial dysfunction, decreased lipid metabolism, and impaired oxidoreductase activity, and acquires tumorigenic potential at the epigenetic level.

DOI： 10.1111/hepr.12992

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

Nonalcoholic fatty liver disease (NAFLD) is an important cause of chronic liver injury in many countries. The incidence of NAFLD is rising rapidly in both adults and children, because of the currently ongoing epidemics of obesity and type 2 diabetes. Notably, histological liver fibrosis is recognized as the main predictive factor for the overall long-term outcome of NAFLD, including cardiovascular disease and liver-related mortality. Thus, staging of liver fibrosis is essential in determining the prognosis and optimal treatment for patients with NAFLD and in guiding surveillance for the development of hepatocellular carcinoma (HCC). Whereas liver biopsy remains the gold standard for staging liver fibrosis, it is impossible to enforce liver biopsy in all patients with NAFLD. Noninvasive biological markers, scoring systems and noninvasive modalities are increasingly being developed and investigated to evaluate fibrosis stage of NAFLD patients. This review will highlight recent studies on the diagnosis and staging of NAFLD based on invasive (liver biopsy) or noninvasive (biomarker, scoring systems, US-based elastography and MR elastography) methods.

DOI： 10.1007/s00535-017-1414-2

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Language：Japanese   Publisher：(有)科学評論社  

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AIM: Pruritus is a common comorbidity in chronic liver disease. The aim of this study was to clarify the prevalence of pruritus and its characteristics in patients with chronic liver disease. METHODS: A total of 1631 patients with chronic liver disease who attended one of nine joint-research facilities from January to June 2016 were enrolled. We investigated the prevalence of pruritus, itch location, itch duration, daily itch fluctuation, seasonal itch exacerbation, treatment drugs, and therapeutic effects using a medical interview questionnaire. RESULTS: The median age was 66 years and 890 (54.6%) patients were women. The prevalence of pruritus was 40.3% (658/1631), and it differed according to the underlying liver disease. The most frequent body location for pruritus was on the back (63.1%). Pruritus duration was more than 6 months in 252 (38.3%) patients. The severity of pruritus, assessed using a visual analog scale, was higher during the day than at night (median, 4 vs. 3, P < 0.001). Seasonal exacerbation was observed in 296 (45.0%) patients. Although 301 (45.7%) patients were treated with antipruritic agents, 57.8% (174/301) patients reported an insufficient effect. Active hepatitis B virus infection (odds ratio [OR], 2.51; P = 0.043), primary biliary cholangitis (OR, 3.69; P = 0.018), diabetes (OR, 1.57; P = 0.010), and aspartate aminotransferase ≥60 U/L (OR, 2.06; P = 0.011) were independent factors associated with pruritus. CONCLUSION: The prevalence of pruritus varies according to the chronic liver disease etiology. Underlying liver disease, aspartate aminotransferase ≥60 U/L, and comorbid diabetes are factors associated with pruritus in patients with chronic liver disease.

DOI： 10.1111/hepr.12978

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), is a disease that may lead to liver cirrhosis or hepatocellular carcinoma. The number of patients is increasing steadily and the pathology is diverse. Effective treatment is still mainly focused on diet and exercise therapy. With the advent of the next-generation sequencer, the intestinal flora in NAFLD/NASH is being elucidated. We believe that elevation of endotoxin in the blood caused by intestinal bacterial dysbiosis caused by intestinal permeability enhancement is important for NASH pathology and control of intestinal permeability enhancement has a new possibility for treatment of NAFLD/NASH.

DOI： 10.1254/fpj.152.187

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

AimNon-alcoholic fatty liver disease (NAFLD) progresses because of the interaction between numerous genes. Thus, we carried out a weighted gene coexpression network analysis to identify core gene networks and key genes associated with NAFLD progression.
MethodsWe enrolled 39 patients with mild NAFLD (fibrosis stages 0-2) and 21 with advanced NAFLD (fibrosis stages 3-4). Total RNA was extracted from frozen liver biopsies, and sequenced to capture a large dynamic range of expression levels.
ResultsA total of 1777 genes differentially expressed between mild and advanced NAFLD (q-value &lt;0.05) clustered into four modules. One module was enriched for genes that encode cell surface or extracellular matrix proteins, and are involved in cell adhesion, proliferation, and signaling. This module formed a scale-free network containing four hub genes (PAPLN, LBH, DPYSL3, and JAG1) overexpressed in advanced NAFLD. PAPLN is a component of the extracellular matrix, LBH and DPYSL3 are reported to be tumor suppressors, and JAG1 is tumorigenic. Another module formed a random network, and was enriched for genes that accumulate in the mitochondria. These genes were downregulated in advanced NAFLD, reflecting impaired mitochondrial function. However, the other two modules did not form unambiguous networks. KEGG analysis indicated that 71 differentially expressed genes were involved in pathways in cancer. Strikingly, expression of half of all differentially expressed genes was inversely correlated with methylation of CpG sites (q-value &lt;0.05). Among clinical parameters, serum type IV collagen 7s was most strongly associated with the epigenetic status in NAFLD.
ConclusionsNewly identified core gene networks suggest that the NAFLD liver undergoes mitochondrial dysfunction and fibrosis, and acquires tumorigenic potential epigenetically. Our data provide novel insights into the pathology and etiology of NAFLD progression, and identify potential targets for diagnosis and treatment.

DOI： 10.1111/hepr.12877

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：医歯薬出版(株)  

近年、メタボリック症候群の増加に伴い、非アルコール性脂肪性肝疾患(NAFLD)が増加している。そのうち、肝硬変や肝細胞癌に至る非アルコール性脂肪肝炎(nonalcoholic steatohepatitis;NASH)の病態進展因子として、腸内フローラ(microbiome)の関与が示唆される。NAFLD/NASHの病態進展を腸内細菌を軸にして考えると、腸管側因子として腸内細菌の異常(dysbiosisや異常増殖)、腸管透過性亢進が考えられ、肝臓側の要因として肥満に伴うエンドトキシン感受性亢進が病態進展に関与することが推察される。以上3つの要因が複雑に関与して本疾患の病態進展に深くかかわっているものと考えられる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本アルコール・アディクション医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Glutathione plays crucial roles in the detoxification and antioxidant systems of cells and has been used to treat acute poisoning and chronic liver diseases by intravenous injection. This is a first study examining the therapeutic effects of oral administration of glutathione in patients with nonalcoholic fatty liver disease (NAFLD).
Methods: The study was an open label, single arm, multicenter, pilot trial. Thirty-four NAFLD patients diagnosed using ultrasonography were prospectively evaluated. All patients first underwent intervention to improve their lifestyle habits (diet and exercise) for 3 months, followed by treatment with glutathione (300 mg/day) for 4 months. We evaluated their clinical parameters before and after glutathione treatment. We also quantified liver fat and fibrosis using vibration-controlled transient elastography. The primary outcome of the study was the change in alanine aminotransferase (ALT) levels.
Results: Twenty-nine patients finished the protocol. ALT levels significantly decreased following treatment with glutathione for 4 months. In addition, triglycerides, non-esterified fatty acids, and ferritin levels also decreased with glutathione treatment. Following dichotomization of ALT responders based on a median 12.9% decrease from baseline, we found that ALT responders were younger in age and did not have severe diabetes compared with ALT non-responders. The controlled attenuation parameter also decreased in ALT responders.
Conclusions: This pilot study demonstrates the potential therapeutic effects of oral administration of glutathione in practical dose for patients with NAFLD. Large-scale clinical trials are needed to verify its efficacy.

DOI： 10.1186/s12876-017-0652-3

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

非アルコール性脂肪性肝疾患(nonalcoholic steatohepatitis:NAFLD)はわが国に2,000万人程度と患者数が多い。NAFLDのうち1〜2割が非アルコール性脂肪肝炎(Nonalcoholic Steatohepatitis:NASH)へ、さらに肝硬変や肝蔵癌に至るとされておりその対策は重要である。NASH進展における腸内細菌の役割は、腸管側の要因と肝臓側の要因に分けると考えやすい。腸管側の要因としては、腸管バリアー機能の低下をきたす一連の症候群(leaky gut症候群)による腸管透過性亢進や内因性エタノール産生菌の増加が問題となっている。一方、肝蔵側の要因として、高レプチン血症がNASH患者のエンドトキシンに対する過剰応答によって肝内炎症や線維化が進展することが示唆されてきた。(著者抄録)

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Language：Japanese   Publisher：(株)響文社  

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Language：Japanese   Publisher：(株)響文社  

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Language：Japanese   Publisher：(株)響文社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The efficacy of peroxisome proliferator-activated receptor alpha-agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptor a modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH.

DOI： 10.1038/srep42477

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Aim: There are a considerable number of patients with non-obese non-alcoholic fatty liver disease (NAFLD). However, the clinical characteristics of non-obese NAFLD is not fully understood. We investigated genetic and other clinical parameters in non-obese and obese NAFLD. Methods: The single nucleotide polymorphism rs738409 in the patatin-like phospholipase 3 gene (PNPLA3) was genotyped by the Invader assay in 540 NAFLD patients (134 non-obese and 406 obese) and 1012 control subjects (782 non-obese and 230 obese). All NAFLD patients underwent liver biopsy. Odds ratios were calculated by multiple logistic regression analysis using age, sex, body mass index (BMI), type 2 diabetes mellitus (T2DM) and rs738409 genotype as explanatory variables. Results: Non-obese NAFLD subjects had a higher rs738409 GG genotype than obese NAFLD. Multiple logistic regression analysis indicated that the odds ratios of T2DM and rs738409 GG genotype for NAFLD were higher in non-obese than in obese groups. In non-obese NAFLD, rs738409 GG genotype was associated with lobular inflammation, hepatocyte ballooning and NAFLD activity score. In obese NAFLD, BMI and T2DM but not rs738409 GG genotype were associated with severity of histology. Conclusion: We demonstrated that the risk factors for the development and progression of NAFLD were different between non-obese and obese patients and that PNPLA3 rs738409 was strongly associated with the development and progression of non-obese NAFLD.

DOI： 10.1111/hepr.12648

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Cell-intrinsic innate immunity provides a rapid first line of defense to thwart invading viral pathogens through the production of antiviral and inflammatory genes. However, the presence of many of these signaling pathways in the liver and their role in hepatitis B virus (HBV) pathogenesis is unknown. Recent identification of intracellular DNA-sensing pathways and involvement in numerous diverse disease processes including viral pathogenesis and carcinogenesis suggest a role for these processes in HBV infection. To characterize HBV-intrinsic innate immune responses and the role of DNA-and RNA-sensing pathways in the liver, we used in vivo and in vitro models including analysis of gene expression in liver biopsies from HBV-infected patients. In addition, mRNA and protein expression were measured in HBV-stimulated and DNA-treated hepatoma cell lines and primary human hepatocytes. In this article, we report that HBV and foreign DNA stimulation results in innate immune responses characterized by the production of inflammatory chemokines in hepatocytes. Analysis of liver biopsies from HBV-infected patients supported a correlation among hepatic expression of specific chemokines. In addition, HBV elicits a much broader range of gene expression alterations. The induction of chemokines, including CXCL10, is mediated by melanoma differentiation-associated gene 5 and NF-kappa B-dependent pathways after HBV stimulation. In conclusion, HBV-stimulated pathways predominantly activate an inflammatory response that would promote the development of hepatitis. Understanding the mechanism underlying these virus-host interactions may provide new strategies to trigger noncytopathic clearance of covalently closed circular DNA to ultimately cure patients with HBV infection.

DOI： 10.4049/jimmunol.1502677

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Language：Japanese   Publisher：(株)響文社  

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Language：Japanese   Publisher：(株)響文社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W.B. Saunders  

Background &amp
Aims Noninvasive methods have been evaluated for the assessment of liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD). We compared the ability of transient elastography (TE) with the M-probe, and magnetic resonance elastography (MRE) to assess liver fibrosis. Findings from magnetic resonance imaging (MRI)-based proton density fat fraction (PDFF) measurements were compared with those from TE-based controlled attenuation parameter (CAP) measurements to assess steatosis. Methods We performed a cross-sectional study of 142 patients with NAFLD (identified by liver biopsy
mean body mass index, 28.1 kg/m2) in Japan from July 2013 through April 2015. Our study also included 10 comparable subjects without NAFLD (controls). All study subjects were evaluated by TE (including CAP measurements), MRI using the MRE and PDFF techniques. Results TE identified patients with fibrosis stage ≥2 with an area under the receiver operating characteristic (AUROC) curve value of 0.82 (95% confidence interval [CI]: 0.74-0.89), whereas MRE identified these patients with an AUROC curve value of 0.91 (95% CI: 0.86-0.96
P =.001). TE-based CAP measurements identified patients with hepatic steatosis grade ≥2 with an AUROC curve value of 0.73 (95% CI: 0.64-0.81) and PDFF methods identified them with an AUROC curve value of 0.90 (95% CI: 0.82-0.97
P &lt
.001). Measurement of serum keratin 18 fragments or alanine aminotransferase did not add value to TE or MRI for identifying nonalcoholic steatohepatitis. Conclusions MRE and PDFF methods have higher diagnostic performance in noninvasive detection of liver fibrosis and steatosis in patients with NAFLD than TE and CAP methods. MRI-based noninvasive assessment of liver fibrosis and steatosis is a potential alternative to liver biopsy in clinical practice. UMIN Clinical Trials Registry No. UMIN000012757.

DOI： 10.1053/j.gastro.2015.11.048

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

Aims: Our purpose was to clarify the predictive clinical characteristics of add-on therapy using dapagliflozin in patients with type 2 diabetes mellitus. Methods: This single-center, open-label, pilot study was conducted in 50 patients with type 2 diabetes mellitus. They were treated with 50 mg dapagliflozin, once daily. A total of 46 patients were successfully followed over 12 weeks of treatment with dapagliflozin. They were assessed for several clinical parameters before the start of the study and at 12 weeks. Multiple linear regression analysis was used to search for independent predictors of reduction of hemoglobin A1c (HbA1c) levels after 12 weeks of dapagliflozin add-on treatment (ΔHbA1c). Results: Dapagliflozin administration for 12 weeks resulted in significant reductions in baseline body mass index, systolic blood pressure, fasting plasma glucose, HbA1c, alanine aminotransferase, and uric acid. We were also able to show that HbA1c levels and low-density lipoprotein cholesterol (LDL-C) significantly correlated with ΔHbA1c. Furthermore, multiple linear regression analysis showed that baseline HbA1c and LDL-C significantly correlated with ΔHbA1c. Conclusion: Our prospective 12-week study showed that baseline HbA1c and LDL-C significantly contribute to the HbA1c-lowering effect of dapagliflozin. Trial registration: UMIN Clinical Trials Registry (UMIN000014922).

DOI： 10.1007/s13340-015-0215-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The natural polyphenol compound resveratrol (RSV) is considered to have a broad spectrum of beneficial biological activities upon human health. However, the exact effect of RSV on steatosis (a phenotype of non-alcoholic fatty liver [NAFL]) or fibrosis and inflammation (major phenotypes of non-alcoholic steatohepatitis [NASH]) is not known. Our data showed that administration of RSV (2 or 20 mg/kg/day) did not suppress steatosis in a high-fat diet-induced model of NAFL in mice. In contrast, identical concentrations of RSV dramatically inhibited inflammation and fibrosis in a low-dose lipopolysaccharide-induced model of NASH. These data suggested that RSV administration-mediated improvement of inflammation and fibrosis was due to the inhibition of LPS reactivity controlled by CD14 expression in Kupffer cells. These findings suggest that RSV could be a candidate agent for the treatment of NASH.

DOI： 10.1038/srep22251

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background & Aims
In recent years, nonalcoholic steatohepatitis (NASH) has become a considerable healthcare burden worldwide. Pathogenesis of NASH is associated with type 2 diabetes mellitus (T2DM) and insulin resistance. However, a specific drug to treat NASH is lacking. We investigated the effect of the selective sodium glucose cotransporter 2 inhibitor (SGLT2I) ipragliflozin on NASH in mice.
Methods
We used the Amylin liver NASH model (AMLN), which is a diet-induced model of NASH that results in obesity and T2DM. AMLN mice were fed an AMLN diet for 20 weeks. SGLT2I mice were fed an AMLN diet for 12 weeks and an AMLN diet with 40 mg ipragliflozin/kg for 8 weeks. Results AMLN mice showed steatosis, inflammation, and fibrosis in the liver as well as obesity and insulin resistance, features that are recognized in human NASH. Ipragliflozin improved insulin resistance and liver injury. Ipragliflozin decreased serum levels of free fatty acids, hepatic lipid content, the number of apoptotic cells, and areas of fibrosis; it also increased lipid outflow from the liver.
Conclusions
Ipragliflozin improved the pathogenesis of NASH by reducing insulin resistance and lipotoxicity in NASH-model mice. Our results suggest that ipragliflozin has a therapeutic effect on NASH with T2DM.

DOI： 10.1371/journal.pone.0146337

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ATHEROSCLEROSIS SOC  

Aim: Visceral fat accumulation contributes to the development of metabolic syndrome. As visceral fat accumulation increases, adiponectin levels decrease; therefore, adiponectin provides a link between visceral fat accumulation and metabolic disorders. Genome-wide association studies (GWASs) have identified genetic variations in the cadherin 13 (CDH13) gene that are associated with adiponectin levels.
Methods: We investigated whether single nucleotide polymorphisms (SNPs) in CDH13 was associated with adiponectin levels and metabolic syndrome traits independent of the visceral fat area (VFA), as measured using computed tomography (CT) in 945 Japanese individuals.
Results: We found that three CDH13 SNPs reported by recent GWASs (i.e., rs3865188, rs4783244, and rs12051272) were significantly associated with higher adiponectin levels (P &lt; 1 x 10(-14)), even after adjustment for VFA. However, these adiponectin-inducing alleles of CDH13 SNPs were significantly associated with traits consistent with deteriorating metabolic symptoms, such as higher fasting insulin, homeostasis model assessment-insulin resistance (HOMA-IR) scores, and triglycerides and lower highdensity lipoprotein (HDL)-cholesterol levels, similar to increasing VFA and decreasing adiponectin levels.
Conclusion: These results suggested that CDH13 SNPs cause an adiponectin-resistant status to compensate for increasing adiponectin levels and could result in the deterioration of metabolic syndrome traits.

DOI： 10.5551/jat.31567

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: Although many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We therefore investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet. Methods: eNOS-knockout and wild-type mice were fed a basal diet or a high-fat diet for 12 weeks. Lipid accumulation and inflammation were evaluated in the liver, and various factors that are closely associated with NAFLD/NASH and hepatic tissue blood flow were analyzed. Results: Lipid accumulation and inflammation were more extensive in the liver and lipid accumulation was less extensive in the visceral fat tissue in eNOS-knockout mice, compared with wild-type mice, after 12 weeks of being fed a high-fat diet. While systemic insulin resistance was comparable between the eNOS-knockout and wild-type mice fed a high-fat diet, hepatic tissue blood flow was significantly suppressed in the eNOS-knockout mice, compared with the wild-type mice, in mice fed a high-fat diet. The microsomal triglyceride transfer protein activity was down-regulated in eNOS-knockout mice, compared with wild-type mice, in mice fed a high-fat diet. Conclusions: A deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.

DOI： 10.1186/s12876-015-0409-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

BACKGROUND & AIMS: Assessment of the severity of liver fibrosis is an important step in evaluating patients with chronic liver disease and determining their prognosis. We compared liver stiffness measurements (LSMs) made by supersonic shear imaging (SSI) with those of transient elastography (TE)-XL for their ability to determine the degree of liver fibrosis in overweight or obese patients with chronic liver disease.
METHODS: We performed a prospective study of 258 patients with chronic hepatitis of different etiologies and a body mass index greater than 25, evaluated at the University of Miami from October 2013 to December 2014. Liver stiffness was measured using the TE-XL probe and SSI of the right and left lobes during the same clinic visit, and comparisons were made for fibrosis stage in 124 biopsy-proven patients. In addition, further analysis was performed on a subgroup of 102 chronic hepatitis C virus (HCV)-positive patients for whom biopsy data were available.
RESULTS: Reliable LSMs were obtained from 96.1%, 94.6%, and 72.1% of patients using the TE-XL probe, SSI of the right lobe, and SSI of the left lobe, respectively. TE-XL, SSI of the right lobe, and SSI of the left lobe detected severe fibrosis (fibrosis stages 3-4), with area under the receiver operating characteristic curve (AUROC) values of 0.955, 0.954, and 0.910, respectively, compared with results from histologic analysis for the 124 biopsy-proven patients included in the study; these values were 0.952, 0.949, and 0.917, respectively, for the 102 biopsy-proven patients with HCV infection. TE-XL, SSI of the right lobe, and SSI of the left lobe detected fibrosis stage 4 with AUROC values of 0.920, 0.930, and 0.910, respectively, compared with histologic analysis, in all 124-biopsy proven patients, and with AUROC values of 0.907, 0.914, and 0.887, respectively, in the 102 biopsy-proven patients with chronic HCV infection
. CONCLUSIONS: SSI and the TE-XL probe each accurately quantify liver fibrosis in overweight or obese patients with chronic liver disease, including those with HCV infection, when compared with data obtained from histologic analysis. SSI data obtained from the right lobe and the TE-XL probe can be used to evaluate fibrosis with similar accuracy.

DOI： 10.1016/j.cgh.2015.03.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Background and AimMajor depressive disorder (MDD) is an important public health problem, and it is often comorbid with many chronic diseases. The purpose of this study was to identify the clinical features of non-alcoholic fatty liver disease (NAFLD) patients comorbid with MDD and to investigate the influence of MDD on the effect of treatment in patients with NAFLD.
MethodsA total of 258 patients with biopsy-proven NAFLD were included. MDD was diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision. The patients were followed up for 48 weeks under standard care for NAFLD, which consisted mainly of lifestyle modification.
ResultsThere were 32 patients comorbid with MDD. They were characterized by more severe histological steatosis and higher NAFLD activity score, and also significantly higher levels of serum aminotransferase, -glutamyl transpeptidase and ferritin, than age-and-sex-matched NAFLD patients without MDD. Moreover, NAFLD patients with MDD showed poor response to the standard care for NAFLD, in body weight loss and in other parameters. Particularly, NAFLD patients with unstable MDD (not in full/partial remission) showed severe resistance to the treatment.
ConclusionThis is the first study to demonstrate the clinical features and response to therapy of NAFLD patients comorbid with MDD. The comorbid state of MDD was associated with more severe histological liver steatosis and worse treatment outcomes in patients with NAFLD. Further investigations are required to develop new lifestyle modification programs that enable NAFLD patients with MDD to achieve the treatment goal.

DOI： 10.1111/jgh.12897

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Language：English   Publisher：KOWSAR PUBL  

DOI： 10.5812/hepatmon.15(5)2015.28957

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Language：English   Publisher：Springer-Verlag Tokyo  

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various noninvasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise
however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 to January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.

DOI： 10.1007/s00535-015-1050-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral dose of a proton pump inhibitor, esomeprazole 20 mg and omeprazole 20 mg. Methodology: A total of 14 Helicobacter pylori-negative male subjects participated in this study. Intragastric pH was monitored continuously for 6 hours after a single oral dose of omeprazole 20 mg and a single oral dose of esomeprazole 20 mg. Each administration was separated by a 7-day washout period. Results: During the 6-hour study period, the average pH after administration of esomeprazole was higher than that after the administration of omeprazole. Also during the 6-hour study period, each of pH &gt; 2, 3, 3.5, 4, and 5 was maintained for a longer duration after administration of esomeprazole 20 mg than after administration of omeprazole 20 mg (median: 75.4% vs. 53.8%, p = 0.0138; 52.1% vs. 33.4%, p = 0.0188; 45.8% vs. 28.2%, p = 0.0262; 42.5% vs. 20.7%, p = 0.0414; 35.8% vs. 11.6%, p = 0.0262; respectively). Conclusions: In Helicobacter pylori-negative healthy male subjects, single oral administration of esomeprazole 20 mg increased the intragastric pH more rapidly than single oral administration of omeprazole 20 mg.

DOI： 10.5754/hge13850

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/MCG.0000000000000186

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT  

Viral hepatitis is a significant disease afflicting hundreds of millions of people. Hepatitis-causing viruses initiate significant morbidity and mortality by establishing both acute and chronic infections, and several of these viruses are specifically associated with the development of hepatocellular carcinoma (HCC). Consequently, intense research efforts are focused on increasing our understanding of virus biology and on improving antiviral therapy. Even though viral hepatitis can be caused by several viruses from a range of virus families, the discovery of components of the hepatitis B virus (HBV) became a catalyst for the development of diagnostic assays that differentiate between these viruses as well as strategies for novel methods of vaccine development. Improvements in both the treatment and prevention of viral hepatitis are advancing rapidly. However, HBV, along with the associated infection by the hepatitis D virus, is still among the most common pathogens afflicting humans.

DOI： 10.1101/cshperspect.a021345

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Language：English   Publisher：SPRINGER WIEN  

DOI： 10.1007/s00508-014-0621-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Background &amp
Aims: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is affected by epigenetic factors as well as by genetic variation. Methods:We performed targeted-bisulfite sequencing to determine the levels of DNA methylation of 4 CpG islands (CpG99, CpG71, CpG26, and CpG101) in the regulatory regions of PNPLA3, SAMM50, PARVB variant 1, and PARVB variant 2, respectively. We compared the levels of methylation of DNA in the livers of the first and second sets of patients with mild (fibrosis stages 0 and 1) or advanced (fibrosis stages 2 to 4) NAFLD and in those of patients with mild (F0 to F2) or advanced (F3 and F4) chronic hepatitis C infection. The hepatic mRNA levels of PNPLA3, SAMM50, and PARVB were measured using qPCR. Results: CpG26, which resides in the regulatory region of PARVB variant 1, was markedly hypomethylated in the livers of patients with advanced NAFLD. Conversely, CpG99 in the regulatory region of PNPLA3 was substantially hypermethylated in these patients. These differences in DNA methylation were replicated in a second set of patients with NAFLD or chronic hepatitis C. PNPLA3 mRNA levels in the liver of the same section of a biopsy specimen used for genomic DNA preparation were lower in patients with advanced NAFLD compared with those with mild NAFLD and correlated inversely with CpG99 methylation in liver DNA. Moreover, the levels of CpG99 methylation and PNPLA3 mRNA were affected by the rs738409 genotype. Conclusions: Hypomethylation of CpG26 and hypermethylation of CpG99 may contribute to the severity of fibrosis in patients with NAFLD or chronic hepatitis C infection.

DOI： 10.1016/j.jhep.2015.02.049

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Visceral fat accumulation contributes to the development of insulin resistance, leading to metabolic syndrome. Adiponectin provides a link between visceral fat accumulation and insulin resistance. In addition to environmental factors, genetic factors play important roles in visceral fat accumulation and circulating adiponectin levels. Genome-wide association studies (GWASs) have identified genetic variations in the adiponectin, C1Q and collagen domain containing (ADIPOQ) gene that are associated with adiponectin levels. In this study, we investigated whether ADIPOQ single nucleotide polymorphisms (SNPs) were associated with visceral fat accumulation and insulin resistance. We measured the visceral fat area (VFA) by computed tomography (CT) and examined the presence of the insulin resistance-related phenotype (fasting plasma glucose, fasting insulin, and homeostasis model assessment-insulin resistance [HOMA-IR]) in a set of Japanese individuals (731 men and 864 women) who were genotyped for seven ADIPOQ SNPs reported by recent GWASs (namely, rs6810075, rs10937273, rs1648707, rs864265, rs182052, rs17366568, and rs6773957). SNPs associated with the phenotype (P < 0.05) were then evaluated by association analysis using a second set of the study participants (383 men and 510 women). None of the SNPs was associated with body mass index (BMI) or VFA in men or women. However, the adiponectin-decreasing alleles of rs10937273 and rs1648707 were significantly associated with HOMA-IR (P = 0.0030 and P = 0.00074, respectively) in women, independently of BMI. These SNPs were significantly associated with decreased adiponectin levels in women. Our results suggested that rs10937273 and rs1648707 may affect insulin sensitivity by regulating adiponectin production by adipose tissue in women.

DOI： 10.1507/endocrj.EJ14-0574

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science  

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with increased risks of atherosclerotic diseases, including cardiovascular disease. However, the difference in risk between patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) has not yet been determined. Accumulating evidence has shown that high amounts of small dense low-density lipoprotein (sdLDL) are closely associated with atherosclerotic diseases. This study investigated differences in risk factors for atherosclerotic diseases, especially LDL-migration index (LDL-MI), an indicator of sdLDL, between patients with NAFL and NASH. Methods: LDL-MI was analyzed in a primary cohort of 156 patients with NAFLD, including 53 with NAFL and 103 with NASH, and a validation cohort of 69 patients with NAFLD, including 25 with NAFL and 44 with NASH. Results: In the primary cohort, NASH was associated with elevated LDL-MI (p=0.039). Multiple regression analysis showed that NASH and the non-use of lipid lowering medications were independently correlated with higher LDL-MI in all patients with NAFLD. Among patients not on lipid lowering medications, those with NASH had significantly higher LDL-MI than those with NAFL (p=0.001). These findings were confirmed in a validation cohort, in that LDL-MI was significantly higher in patients with NASH than with NAFL (p=0.043). Conclusion: This study is the first to show that LDL-MI, an indicator of sdLDL, was higher in patients with NASH than with NAFL, suggesting that the risk of atherosclerotic diseases may be higher in NASH than NAFL. Patients with NASH should be followed closely, especially for the progression of liver pathology and atherosclerotic diseases. Trial Registration: UMIN000009614.

DOI： 10.1371/journal.pone.0115403

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Serum ferritin was recently reported to have low diagnostic accuracy for the detection of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). To corroborate these findings, we investigated the diagnostic accuracy of serum ferritin levels for detecting liver fibrosis in NAFLD patients utilizing a large Japanese cohort database. A total 1201 biopsy-proven NAFLD patients, seen between 2001 and 2013, were enrolled into the Japan Study Group of NAFLD. Analysis was performed on data from this cohort comparing between serum ferritin levels and hepatic histology. Serum ferritin increased with increasing histological grade of steatosis, lobular inflammation and ballooning. Multivariate analyses revealed that sex differences, steatotic grade and fibrotic stage were independently associated with serum ferritin levels (P&lt;0.0001, &lt;0.0001, 0.0248, respectively). However, statistical analyses performed using serum ferritin levels demonstrated that the area under the receiver-operator curve for detecting fibrosis was not adequate for rigorous prediction. Several factors including sex differences, steatosis and fibrosis were found to correlate with serum ferritin levels. Therefore, serum ferritin may have low diagnostic accuracy for specifically detecting liver fibrosis in NAFLD patients due to the involvement of multiple hepatocellular processes.

DOI： 10.1111/hepr.12327

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DOI： 10.5152/tjg.2014.5262

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

Background The prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome have been increasing worldwide. The associations between metabolic factors and the histologic severity of NAFLD have not yet been clarified. Therefore, we studied the relationships between relevant metabolic factors and the histological severity of NAFLD. Methods In a cross-sectional multicenter study conducted in Japan, we examined 1,365 biopsy-proven NAFLD patients. The frequencies of underlying lifestyle-related diseases and their relationships to the NAFLD histology were investigated. Results The hepatic fibrosis stages (Stage 0/1/2/3/4) were 22.6/34.1/26.7/14.5/2.1 (%) in the male patients, and 16.2/ 31.7/23.9/21.6/6.6 (%) in the female patients. Dyslipidemia was present in 65.7 % (hypertriglyceridemia, 45.3 %
increased low-density lipoprotein cholesterol, 37.5 %
decreased high density lipoprotein cholesterol, 19.5 %) of patients. Hypertension was present in 30.2 %, and diabetes mellitus (DM) in 47.3 %. The fibrosis stage increased with age, especially in postmenopausal females. The body mass index was positively correlated with the fibrosis stage. Deterioration of glucose control was positively correlated with the fibrosis stage, this correlation being more prominent in females. Multivariate analysis identified age and DM as significant risk factors for advanced fibrosis. No significant correlation of the fibrosis stage was observed with hypertension. There was a negative correlation between the serum triglyceride levels and the fibrosis stage. Conclusions DM appeared to be a significant risk factor for advanced fibrosis in patients with NAFLD, and would therefore need to be properly managed to prevent the progression of NAFLD.

DOI： 10.1007/s00535-013-0911-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Aim: Serum alanine aminotransferase (ALT) is important for screening, diagnosis and management of chronic liver diseases. The incidence of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), which is considered a hepatic manifestation of lifestyle-related diseases, is increasing worldwide. However, the upper limit of the normal ALT level has not yet been established because of not excluding many lifestyle-related diseases. The aim of this study was to evaluate the upper limit of normal serum ALT levels in Japanese subjects. Methods: We analyzed the serum ALT levels of 11 404 Japanese subjects negative for hepatitis B surface antigen and hepatitis C virus antibody, and who received health checkups. Lifestyle factors related to ALT levels were determined by multivariate analysis. Subjects with all factors identified by multivariate analysis within the normal range were defined as "healthy" subjects. The 90th percentile of ALT levels in healthy subjects was defined as the upper limit of normal ALT. Results: Whereas alcohol intake was not a significant factor, the following were independently associated with ALT concentration by multivariate analysis: sex
age
body mass index
waist circumference
concentrations of total cholesterol, high-density lipoprotein cholesterol, triglycerides and fasting blood glucose
and fatty liver on ultrasonography. Healthy subjects consisted of 1462 (21.2%) men and 2046 (45.4%) women, and the 90th percentiles of the ALT levels in the two groups were 29 and 23 IU/L, respectively. Conclusion: The upper limits of normal ALT when considering lifestyle factors in Japanese subjects were 29 IU/L in men and 23 IU/L in women.

DOI： 10.1111/hepr.12293

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

DOI： 10.1002/hep.27097

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Language：English   Publisher：OMICS International  

DOI： 10.4172/2161-069X.1000221

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WJG Press  

AIM: To investigate a simple noninvasive scoring system for predicting liver cirrhosis in nonalcoholic fatty liver disease (NAFLD) patients. METHODS: A total of 1048 patients with liver-biopsy-confirmed NAFLD were enrolled from nine hepatology centers in Japan (stage 0, 216
stage 1, 334
stage 2, 270
stage 3, 190
stage 4, 38). The weight and height of the patients were measured using a calibrated scale after requesting the patients to remove their shoes and any heavy clothing. Venous blood samples were obtained in the morning after the patients had fasted overnight for 12 h. Laboratory evaluation was performed in all patients. Statistical analysis was conducted using SPSS version 12.0. Continuous variables were expressed as mean ± SD. RESULTS: The optimal cutoff value of platelet count, serum albumin, and aminotransferase/alanine aminotransferase ratio (AAR) was set at &lt
15.3 10&lt
sup&gt
4&lt
/sup&gt
/μL, &lt
4.0 g/dL, and &gt
0.9, respectively, by the receiver operating characteristic curve. These three variables were combined in an unweighted sum (platelet count = 1 point, serum albumin = 1 point, AAR = 1 point) to form an easily calculated composite score for predicting cirrhosis in NAFLD patients, called the PLALA (platelet, albumin, AAR) score. The diagnosis of PLALA ≥ 2 had sufficient accuracy for detecting liver cirrhosis in NAFLD patients. CONCLUSION: The PLALA score may be an ideal scoring system for detecting cirrhosis in NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use.

DOI： 10.3748/wjg.v20.i29.10108

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

DOI： 10.1016/j.clinbiochem.2014.04.026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Ramosetron is a new selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist that reportedly has more potent antiemetic effects than other 5-HT3 receptor antagonists. The aim of this study was to determine the effect of ramosetron pretreatment on gastric emptying using the 13c-acetic acid breath test. Methodology: Ten healthy male and female volunteers participated in this randomized, twoway crossover study. After they had fasted overnight, the subjects were randomly assigned to receive 0.1 mg ramosetron 1 hour before ingestion of a test meal (200 kcal per 200 mL, containing 100 mg 13(c) acetate) or to receive the test meal alone. Under both conditions, breath samples were collected for 150 min following ingestion of the meal. Statistical com arison of the parameters tetween e two test conditions was formed. Results: No significant differences in the lated parameters, including T 1/2, T lag, GEC or beta and kappa, were observed between the two test conditions. Conclusions: The present study revealed that 0.1 mg mosetron had no significant effect on the rate of gastric emptying. Thus, our results suggest that ramosetron can be administered safely, without gastrointestinal adverse effects, even to terminal cancer patients with delayed or accelerated gastric emptying abnormality.

DOI： 10.5754/hge13057

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ENDOCRINE SOC  

In several genome-wide association studies, nonalcoholic fatty liver disease and alanine aminotransferase susceptibility variants have been identified in several genes, including LYPLAL1, ZP4, GCKR, HSD17B13, PALLD, PPP1R3B, FDFT1, TRIB1, COL13A1, CPNI, ERLIN1, CWF19L1, EFCAB4B, PZP, and NCAN. To investigate the relationship between these genes and nonalcoholic fatty liver disease in the Japanese population, we genotyped 540 patients and 1012 control subjects for 18 variations. We performed logistic regression analyses to characterize the association between the tested variations and nonalcoholic fatty liver disease. Metabolic syndrome and histological traits were also analyzed by linear regression. We also examined GCKR rs780094, TRIB1 rs2954021, and PNPLA3 rs738409 for epistatic effects. The A-allele of rs780094 in GCKR (P = 0.0024) and the A-allele of rs2954021 TRIB1 (P = 4.5x10(-5)) were significantly associated with nonalcoholic fatty liver disease. GCKR rs780094 was also associated with decreased plasma glucose, and increased triglycerides in the patient and control groups. GCKR rs780094 was also associated with an increased ratio of visceral to subcutaneous fat area in the patients with nonalcoholic fatty liver disease. Variations in GCKR, TRIB1, and PNPLA3 independently influenced nonalcoholic fatty liver disease and had no epistatic effects. Our data suggest variations in GCKR and TRIB1 are involved in the development of nonalcoholic fatty liver disease.

DOI： 10.1507/endocrj.EJ14-0052

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The genomic regions containing PNPLA3, SAMM50 and PARVB are susceptibility loci for the development and progression of nonalcoholic fatty liver disease (NAFLD). In order to search for all common variations in this region, we amplified the genomic DNA of 28 NAFLD patients by long-range PCR, covering the entire susceptibility region and sequenced the DNA using indexed multiplex next-generation sequencing. We found 329 variations, including four novel variations. Fine mapping of variations including insertion/deletions was performed for 540 NAFLD patients (488 with nonalcoholic steatohepatitis (NASH) and 52 with simple steatosis) and 1012 control subjects. HaploView analysis showed that linkage disequilibrium (LD) block 1 and 2 occurred in PNPLA3, block 3 in SAMM50 and block 4 in PARVB. Variations in LD blocks 1-4 were significantly associated with NAFLD as compared with control subjects (P&lt;1 x 10(-8)). Variations in LD block 2 were significantly associated with the NAFLD activity score (NAS), aspartate aminotransferase and alanine aminotransferase. Variations in LD block 1 were significantly associated with the fibrosis stage. The strongest associations were observed for variations in LD block 4, with NASH as compared with simple steatosis (P = 7.1 x 10(-6)) and NAS (P = 3.4 x 10(-6)). Our results suggested that variations, including insertion/deletions, in PARVB, as well as those in PNPLA3, are important in the progression of NAFLD.

DOI： 10.1038/jhg.2014.17

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Although therapeutic intervention for nonalcoholic steatohepatitis (NASH) at an early stage is important owing to the progressive nature of the disease, diagnosis using noninvasive methods remains difficult. We previously demonstrated NASH specific impairment of choline metabolism and the use of fasting plasma free choline (fCh) levels for NASH diagnosis. Here, we investigated the utility of an oral choline tolerance test (OCTT), based on disordered choline metabolism, as a novel noninvasive method for NASH diagnosis.
Sixty-five patients with biopsy proven nonalcoholic fatty liver disease (NAFLD) and 17 healthy controls were enrolled. Blood samples were obtained from all subjects five times during the OCTT (before and 1, 2, 3, and 4 h after oral loading with 260 mg choline).
Four-hour fCh levels after oral loading choline were markedly increased in NASH patients, compared with non-NASH subjects. For detecting NASH, compared with non-NASH subjects, the area under the curve for 4-h fCh levels was 0.829 on receiver operating characteristic (ROC) analysis. The cut-off level for NASH diagnosis was a parts per thousand yen0.16 mg/dL, and the sensitivity, specificity, positive predictive value, and negative predictive value were 80.1, 82.6, 78.4, and 84.4 %, respectively. Moreover, 4-h fCh levels were significantly associated with the disease activity based on NAFLD activity score in patients with NAFLD.
Four-hour fCh levels obtained by an OCTT reflect a NASH specific disorder of choline metabolism, suggesting that the OCTT is a novel and useful noninvasive method for diagnosing NASH at an early stage with sufficient accuracy for clinical practice.

DOI： 10.1007/s00535-013-0776-3

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Language：English   Publisher：SPRINGER HEIDELBERG  

The recent rise in obesity-related diseases, such as nonalcoholic fatty liver disease and its strong association with microbiota, has elicited interest in the underlying mechanisms of these pathologies. Experimental models have highlighted several mechanisms connecting microbiota to the development of liver dysfunction in nonalcoholic steatohepatitis (NASH) such as increased energy harvesting from the diet, small intestine bacterial overgrowth, modulation of the intestinal barrier by glucagon-like peptide-2 secretions, activation of innate immunity through the lipopolysaccharide-CD14 axis caused by obesity-induced leptin, periodontitis, and sterile inflammation. The manipulation of microbiota through probiotics, prebiotics, antibiotics, and periodontitis treatment yields encouraging results for the treatment of obesity, diabetes, and NASH, but data in humans is scarce.

DOI： 10.1007/s00281-013-0404-6

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Language：Japanese   Publisher：The Japanese Society of Gastroenterology  

DOI： 10.11405/nisshoshi.111.14

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Other Link： http://search.jamas.or.jp/link/ui/2014080150

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag Tokyo  

Background: It is suggested that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), can be associated with insomnia and gastro-esophageal reflux disease (GERD). The relationship between GERD and insomnia in subjects with biopsy-proven NAFLD was investigated. Methods: This study enrolled 123 patients with biopsy-proven NAFLD. Insomnia was assessed by the Athens Insomnia Scale (AIS), a self-assessment psychometric instrument designed to quantify sleep difficulty based on ICD-10 criteria
AIS scores ≥ 6 were considered positive for insomnia. GERD symptoms were evaluated using a frequency scale for the symptoms of GERD (FSSG)
FSSG scores ≥ 8 were considered positive. Logistic regression models were used to evaluate the association of insomnia with GERD, after adjusting for potential confounders. Thirteen patients with GERD were treated with the proton pump inhibitor rabeprazole (RPZ
10 mg/day), for 12 weeks. Results: Of the 123 patients, 76 (62 %) were female and 87 (71 %) were obese, with 34 (28 %) having AIS scores ≥ 6 and 31 (25 %) having FSSG scores ≥ 8. Liver biopsy revealed that 40 patients (33 %) had NAFL and 83 (67 %) had NASH. FSSG and AIS scores were similar in the two groups. HOMA-IR, FSSG scores and γGT (GGT) concentrations were significantly higher in insomniacs than in non-insomniacs. Logistic regression analysis demonstrated that FSSG score and GGT concentration were independently associated with insomnia. RPZ treatment resulted in significantly reductions in both AIS and FSSG scores. Conclusions: Nearly 30 % of patients with biopsy-proven NAFLD had insomnia, which was related to GGT and GERD and could be relieved by RPZ treatment. © 2013 Springer.

DOI： 10.1007/s00535-013-0871-5

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Language：English  

Research in nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), has been limited by the availability of suitable models for this disease. A number of rodent models have been described in which the relevant liver pathology develops in an appropriate metabolic context. These models are promising tools for researchers investigating one of the key issues of NASH: not so much why steatosis occurs, but what causes the transition from simple steatosis to the inflammatory, progressive fibrosing condition of steatohepatitis. The different rodent models can be classified into two large groups. The first includes models in which the disease is acquired after dietary or pharmacological manipulation, and the second, genetically modified models in which liver disease develops spontaneously. To date, no single rodent model has encompassed the full spectrum of human disease progression, but individual models can imitate particular characteristics of human disease. Therefore, it is important that researchers choose the appropriate rodent models. The purpose of the present review is to discuss the metabolic abnormalities present in the currently available rodent models of NAFLD, summarizing the strengths and weaknesses of the established models and the key findings that have furthered our understanding of the disease's pathogenesis. © 2013 by the authors
licensee MDPI, Basel, Switzerland.

DOI： 10.3390/ijms141121833

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Language：English   Publishing type：Research paper (scientific journal)  

Aims/Introduction: We reinvestigated the clinical usefulness of the modified NAFIC scoring system, modified by changing the weightage assigned to the fasting serum insulin level based on the importance of hyperinsulinemia in the pathogenesis of non-alcoholic steatohepatitis (NASH), in Japanese patients with non-alcoholic fatty liver disease (NAFLD) who had undergone liver biopsy. Materials and Methods: The NAFIC score is conventionally calculated as follows: serum ferritin ≥200 ng/mL (female) or ≥300 ng/mL (male), 1 point
serum fasting insulin ≥10 μU/mL, 1 point
and serum type IV collagen 7 s ≥5.0 ng/mL, 2 points. A total of 147 patients with NAFLD who had undergone liver biopsies were included in the estimation group. To validate the modified scoring system, 355 patients from nine hepatology centers in Japan were also enrolled. Results: In the estimation group, 74 (50.3%) patients were histologically diagnosed as having NASH, whereas the remaining 73 (49.7%) were diagnosed as not having NASH. As the percentage of NASH patients increased not only among participants with serum insulin levels greater than 10 μU/mL, but also in those with serum levels greater than 15 μU/mL, we advocated use of the modified NAFIC score, as follows: serum fasting insulin 10-15 μU/mL, 1 point and ≥15 μU/mL, 2 points. The modified NAFIC score showed improved sensitivity and negative predictive value for the diagnosis of NASH. This finding was also confirmed in the validation group. Conclusions: The modified NAFIC scoring system could be a clinically useful diagnostic screening tool for NASH. © 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.

DOI： 10.1111/jdi.12101

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Language：English   Publishing type：Research paper (scientific journal)  

Aim: Recently, several studies have shown the existence of associations between lipoprotein profiles and hepatitis C virus (HCV), although only a limited amount of information is available about the mechanisms underlying the changes in the lipoprotein profiles associated with HCV. In this study, we investigated the association between lipoprotein profile, classified according to the particle size, and lipoprotein metabolism. Methods: We used four kinds of cells for this experiment
full-length genome HCV RNA replicon cells (OR6), sub-genomic HCV RNA replicon cells (sO), and OR6c cells and sOc cells, which were the same cell lines treated with interferon-α. The triglyceride (TG) levels in the lipoprotein subclasses of the culture medium were measured by high-performance liquid chromatography. The mRNA expression levels of several molecules associated with lipoprotein metabolism were measured in the OR6, OR6c, sO and sOc cells. To confirm some of the results obtained using the in vitro system, liver biopsy samples obtained from the patients were also examined. Results: The content of TG in the large low-density lipoprotein (LDL) and medium LDL in the culture medium was increased only in the OR6 cells. The hepatic triglyceride lipase (HTGL) mRNA expression levels were lower in the OR6 cells than in the OR6c cells (P&lt
0.01). Examination of the HTGL expression levels in the patients' livers revealed a decrease in HTGL expression in the chronic hepatitis C liver as compared with that in the chronic hepatitis B or non-alcoholic steatohepatitis liver (P&lt
0.01). Conclusion: We showed that HCV inhibits HTGL production in hepatocytes, inducing a change of the lipoprotein profile. © 2013 The Japan Society of Hepatology.

DOI： 10.1111/hepr.12072

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

The severity of liver fibrosis must be estimated to determine the prognosis, for surveillance, and for optimal treatment of nonalcoholic fatty liver disease (NAFLD). However, the severity of hepatic fibrosis tends to be underestimated in patients with normal ALT.
We investigated histological data and scoring systems (FIB-4 index, NAFLD fibrosis score, BARD score, and AST/ALT ratio) of 1,102 liver-biopsy-confirmed NAFLD patients.
A total of 235 NAFLD patients with normal ALT were estimated to exist. The ratio of advanced fibrosis (stage 3-4) was seen in 16.1 % of subjects with normal ALT. Scoring systems, especially the FIB-4 index and NAFLD fibrosis score, were clinically very useful (AUROC &gt; 0.8), even in patients with normal ALT. Furthermore, with resetting of the cutoff values, the FIB-4 index (&gt; 1.659) and NAFLD fibrosis score (&gt; 0.735) were found to have a higher sensitivity and higher specificity for the prediction of advanced fibrosis, and all of these scoring systems (FIB-4 index, NAFLD fibrosis score, BARD score, and AST/ALT ratio) had higher negative predictive values (&gt; 90.3 %). By using the resetting cutoff value, liver biopsy could have been avoided in 60.4 % (FIB-4), 66.4 % (NAFLD fibrosis score), 51.9 % (BARD score), and 62.1 % (AST/ALT ratio).
We reset the cutoff values of numerous non-invasive scoring systems to improve their clinical usefulness in the prediction of liver fibrosis in NAFLD patients with normal ALT, and these non-invasive scoring systems with the reset cutoff values could be of substantial benefit to reduce the number of liver biopsies performed.

DOI： 10.1007/s00535-012-0704-y

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Language：English   Publishing type：Research paper (scientific journal)  

Aim: There have been some reports on the use of paired biopsies for monitoring disease progression in non-alcoholic fatty liver disease (NAFLD) patients. Recently, transient elastography has been developed as a non-invasive method for predicting the severity of liver fibrosis. We investigated 4-year disease progression in NAFLD patients by evaluating liver stiffness measurements (LSM) obtained using transient elastography. Methods: Of 97 biopsy-proven NAFLD patients whose LSM were obtained 4 years prior, we revaluated 36 who were available for follow up and compared their current stage of fibrosis with that at initial assessment. Fibrosis stage was diagnosed according to the cut-off values previously reported by our institution. We also investigated correlations between changes in LSM and changes in non-invasive fibrosis markers obtained by performing biochemical tests and clinical data. Results: A total of nine (25%) patients had fibrosis progression, 17 (47.2%) had static disease and 10 (27.8%) had fibrosis remission. Among patients with stage 0 fibrosis as per initial LSM (n=16), 11 had static disease and five had fibrosis progression according to LSM obtained 4 years later. Changes in LSM correlated with changes in the FIB4 index (R=0.519, P=0.0011) and aspartate aminotransferase-to-platelet ratio index (R=0.346, P=0.0412), but not with changes in other non-invasive markers. Conclusion: Transient elastography is non-invasive and easy to use
therefore, it can be a useful tool for monitoring the severity of hepatic fibrosis in NAFLD patients. © 2013 The Japan Society of Hepatology.

DOI： 10.1111/hepr.12039

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