記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Hilar cholangiocarcinoma often results in repeated early stent dysfunction and difficult-to-control cholangitis after drainage using endoscopic retrograde cholangiopancreatography (ERCP). In this study, we evaluated the effectiveness of additional drainage using endoscopic ultrasound-guided biliary drainage (EUS-BD) in patients with hilar cholangiocarcinoma who had difficult-to-control cholangitis after transpapillary drainage with ERCP alone. METHODS: We retrospectively evaluated 20 patients with hilar cholangiocarcinoma who had difficult-to-control cholangitis after transpapillary drainage with ERCP at our hospital between 2017 and 2025 and therefore underwent additional drainage using EUS-BD. We evaluated the time to recurrent biliary obstruction (TRBO) just before and after combined ERCP and EUS-BD in these patients. RESULTS: The Bismuth classification of stenosis was II in four cases (20.0%), IIIa in five cases (25.0%), IIIb in one case (5.0%), and IV in 10 cases (50.0%). The median (95% confidence interval) TRBO biliary obstruction just before and just after additional drainage with EUS-BD was 16.5 days (7.0-27.0) and 91.0 days (53.0-NR), respectively, and additional drainage with EUS-BD significantly prolonged stent patency. CONCLUSIONS: Combining ERCP with EUS-BD for drainage was effective in patients with hilar cholangiocarcinoma who had stent dysfunction due to cholangitis that was difficult to control using transpapillary drainage with ERCP alone.

DOI： 10.1002/deo2.70210

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Conventional antispasmodics used during endoscopic retrograde cholangiopancreatography (ERCP), such as hyoscine butylbromide and glucagon, are often contraindicated in elderly patients with comorbidities. This trial aimed to assess the efficacy of lidocaine for inhibiting duodenal peristalsis during ERCP. METHODS: This multicenter randomized controlled trial enrolled 40 elderly patients (aged 65-89 years) who were scheduled to undergo ERCP. Patients were randomly assigned to the lidocaine group or the control group using a computer-generated sequence with stratification by age and sex. The lidocaine group (n = 19) received 2% lidocaine jelly mixed with saline, while the control group (n = 21) received a placebo jelly mixed with saline. The primary endpoint was inhibition of duodenal peristalsis. Secondary endpoints included the required time from drug spraying to cessation of duodenal peristalsis, stop duration time (DT) from cessation of peristalsis until peristalsis recovery, and adverse events. RESULTS: Eighteen patients from the lidocaine group and 19 patients from the control group were analyzed for the primary outcome. The inhibition rate of duodenal peristalsis was significantly higher in the lidocaine group (94.4%) than in the control group (52.6%) (p = 0.008). The required time was significantly shorter in the lidocaine group than in the control group (p < 0.001). No significant difference was observed in the stop DT (p = 0.862); no adverse events occurred in either group. CONCLUSIONS: In our limited cohort, lidocaine inhibited duodenal peristalsis during ERCP without adverse events, suggesting its potential as a safe and practical option (jRCT No. 031190059).

DOI： 10.1002/deo2.70252

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The impact of each factor and the number of positive criteria on pathogenesis and the diagnostic performance of non-invasive tests (NITs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to investigate the association between the cardiometabolic criteria and the clinical features. METHODS: This retrospective study investigated clinicopathological characteristics and the diagnostic performance of the Enhanced Liver Fibrosis (ELF) test, fibrosis-4 (FIB-4) index, and nonalcoholic fatty liver disease fibrosis score (NFS) according to the factors and the number of positive cardiometabolic criteria in 1,038 patients with biopsy-proven MASLD. RESULTS: Hypertension is a significant risk factor for progression to advanced fibrosis and at-risk metabolic dysfunction-associated steatohepatitis (MASH) in male patients. In contrast, no significant risk factor was identified in female patients. The incidence of advanced fibrosis increased significantly in patients with three or more positive criteria. Similarly, the incidence of at-risk MASH increased significantly in a stepwise manner with the number of positive cardiometabolic criteria. The diagnostic performance of the ELF test for advanced fibrosis exceeded that of the FIB-4 index and NFS for all factors except hypertension. Regardless of the number of positive cardiometabolic criteria, the ELF test demonstrated a superior diagnostic performance for advanced fibrosis. CONCLUSIONS: MASLD with hypertension in male patients or a higher number of positive cardiometabolic criteria constitutes a significant risk for advanced fibrosis or at-risk MASH. The ELF test is a valuable tool for diagnosing advanced fibrosis progression regardless of individual factors or the number of positive cardiometabolic criteria.

DOI： 10.1007/s00535-026-02393-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Objectives: Endoscopic retrograde cholangiopancreatography (ERCP) is commonly performed for cholangiocarcinoma and often involves multiple procedures, potentially increasing the risk of post-ERCP pancreatitis (PEP). However, PEP characteristics in cholangiocarcinoma patients remain unclear. This study aimed to assess the incidence and diagnostic procedure-specific risk factors for PEP in patients with cholangiocarcinoma. Methods: We retrospectively reviewed 218 ERCP procedures for cholangiocarcinoma performed at our hospital between January 2017 and March 2022. The incidence of PEP, severe PEP, and fatal PEP was recorded. Risk factors for PEP were analyzed using multivariate analysis, and severe cases were further evaluated. Results: Among the 218 patients, 15 (6.9%) developed PEP, 4 (1.8%) had severe PEP, and 2 (0.9%) died. Multivariate analysis identified the pancreatic guidewire technique (PGW) (OR: 8.18; 95% CI: 2.52-26.53, p < 0.001) and intraductal ultrasonography (IDUS) (OR: 6.53; 95% CI: 2.01-21.25, p = 0.002) as significant risk factors. Both fatal cases involved naïve papilla and PGW and IDUS, with no pancreatic duct stent placement. Conclusions: ERCP for cholangiocarcinoma carries a clinically relevant risk of severe or fatal PEP. In particular, ERCP-specific diagnostic procedures required for cholangiocarcinoma may confer a disease-specific risk profile distinct from that of general ERCP. PGW and IDUS were identified as major risk factors, especially in patients with a naïve papilla, in whom prophylactic pancreatic duct stenting should be considered to reduce the risk of severe or fatal outcomes.

DOI： 10.3390/diagnostics16060900

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To assess whether non-invasive test cutoffs recommended in Western guidelines appropriately identify treatment-eligible fibrosis (F2-3) in Japanese patients with MASLD. METHODS: We analyzed Japanese patients with biopsy-proven MASLD who underwent FIB-4 screening, followed by VCTE or ELF testing. Patients with FIB-4 < 1.3 at age < 65 years or < 2.0 at age ≥ 65 years were excluded, leaving 838 patients in the VCTE cohort and 657 in the ELF cohort. Receiver operating characteristic (ROC) analyses were used to derive cohort-specific cutoffs. RESULTS: For predicting F2-4, a VCTE cutoff of 8 kPa yielded sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) of 83.7%/61.2%/80.2%/66.7%. For predicting F4, a VCTE cutoff of 15 kPa yielded 88.1%/76.8%/22.3%/98.8%. For ELF, a cutoff of 9.2 for predicting F2-4 yielded 94.7%/23.1%/66.5%/73.1%. For predicting F4, a ELF cutoff of 10.5 yielded 80.0%/58.4%/9.9%/98.1%. Using ROC-derived cutoffs (VCTE 9.5 and 15 kPa; ELF 10.3 and 10.8), the performance for predicting F2-4 was 74.0%/75.6%/85.1%/60.8% for VCTE and 66.2%/73.9%/80.6%/57.1% for ELF, whereas the performance for predicting F4 was 88.1%/76.8%/22.3%/98.8% for VCTE and 77.1%/69.8%/12.6%/98.2% for ELF. Among test-positive patients, the distribution of F0-1/F2-3/F4 was 28.7%/69.2%/2.1% for VCTE 8-15 kPa and 47.8%/49.8%/2.4% for ELF 9.2-10.5. CONCLUSIONS: Western guideline-recommended VCTE and ELF cutoffs showed high sensitivity in Japanese patients and can be used to exclude cirrhosis. Because the likelihood of cirrhosis increases with VCTE > 15 kPa or ELF > 10.5, treatment eligibility should be determined in conjunction with other clinical information, and confirmatory assessment should be considered when appropriate.

DOI： 10.1111/hepr.70155

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background Autoimmune pancreatitis (AIP) is a distinct type of chronic pancreatitis that responds well to glucocorticoid therapy. However, some patients experience frequent relapses or become glucocorticoid-dependent. In Western countries, immunosuppressive agents such as azathioprine are widely used to maintain remission. In contrast, evidence for the use of immunosuppressive agents for AIP is limited in Japan and other Asian countries. Therefore, this study aimed to evaluate the efficacy and safety of immunosuppressive agents in patients with refractory AIP. Methods We retrospectively analyzed 12 Japanese patients with type 1 AIP who experienced two or more documented relapses and received immunosuppressive therapy. Clinical remission, adverse events, and the incidence of malignancy were assessed. Results Among 199 patients with AIP treated between 2006 and 2024, 12 (6.0%) with multiple relapses were administered immunosuppressive agents, including azathioprine (n=9), tacrolimus (n=2), and methotrexate (n=1). Nine patients continued therapy for at least two months; of these, eight (88.9%) maintained clinical remission without relapse during treatment. One patient relapsed. However, three patients (25.0%) were unable to continue therapy due to adverse events. Two patients developed malignancies during the long-term follow-up: one with malignant lymphoma and the other with small cell lung cancer. Conclusion Immunosuppressive therapy may contribute to the maintenance of remission in some AIP patients with glucocorticoid-dependent or repeated relapses, even among Japanese patients. However, adverse events led to treatment discontinuation in 25% of patients, and two developed malignancies during follow-up. These findings underscore the need for careful patient selection, individualized risk-benefit evaluation, and ongoing monitoring.

DOI： 10.2169/internalmedicine.6646-25

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/a-2794-7734

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & AIMS: Fibrosis-4 Index (FIB-4) is a noninvasive tool for assessing liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). However, its role of dynamic FIB-4 for assessing fibrosis progression and predicting clinical outcomes remains unclear. The aim of this study was to examine the association between changes in FIB-4 and changes in liver stiffness, fibrosis progression, and outcomes in MASLD. METHODS: Three cohorts were analyzed: VCTE-Prognosis cohort (n = 10,203) for stiffness progression, Paired Liver Biopsy cohort (n = 1,145) for fibrosis progression, and Wenzhou Real-World (WRW) cohort (n = 41,105) for clinical outcomes. Stiffness progression was defined as an increase in liver stiffness measurement, and fibrosis progression by a 1-stage increase. Outcomes included all-cause mortality, cardiovascular events, and liver-related events (LREs). FIB-4 was dichotomized into low (<1.3) and high (≥1.3). Increases were defined as ≥20% rise and to ≥1.3 in the low FIB-4 group, and ≥20% rise in the high FIB-4 group. RESULTS: In the VCTE-Prognosis cohort, stiffness progression was more likely with increasing vs stable FIB-4 (adjusted odds ratio [OR], 2.36; P < .001) in those with low baseline FIB-4. In the high FIB-4 group, stiffness progression rates increased from stable to increasing FIB-4 (adjusted OR, 3.42; P < .001). In the Paired Liver Biopsy cohort, fibrosis progression was more frequent with increasing FIB-4 (adjusted OR, 2.20; P = .004 in low FIB-4; adjusted OR, 3.68; P < .001 in high FIB-4). In the WRW cohort, an increase in dynamic FIB-4 was linked to higher risks for all-cause mortality, cardiovascular events, and LREs (all P < .001). CONCLUSIONS: Dynamic FIB-4 monitoring tracks fibrosis and stiffness progression and predicts clinical outcomes in MASLD.

DOI： 10.1016/j.cgh.2025.07.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & AIMS: Hypertension is common in metabolic dysfunction-associated steatotic liver disease (MASLD), but its impact on long-term clinical outcomes and disease progression remains unclear. This study investigated the association of hypertension with the risk of adverse clinical outcomes and progression of liver stiffness/fibrosis in MASLD. METHODS: Three multicenter large cohorts were analyzed: the UK Biobank (UKBB) cohort to assess the risk of adverse clinical outcomes, the VCTE-Prognosis cohort to assess liver stiffness/fibrosis progression, and the Paired Liver Biopsy cohort to assess histologic liver fibrosis progression. Adverse clinical outcomes were defined as all-cause mortality, cardiovascular events, and/or liver-related events. Liver stiffness progression was defined as an increase in liver stiffness measurement from <10 kPa to ≥10 kPa or an increase of ≥20% for baseline liver stiffness measurement ≥10 kPa. Liver fibrosis progression was defined as a 1-stage fibrosis stage increase. Cox regression and Kaplan-Meier analyses were used to evaluate the impact of baseline hypertension on outcomes. RESULTS: A total of 107,316 adults from the UKBB cohort, 8,169 from the VCTE-Prognosis cohort, and 1,670 from the Paired Liver Biopsy cohort were included. The prevalence of hypertension was 37.1%, 33.4%, and 48.9%, respectively. In the UKBB cohort, hypertension was associated with long-term adverse clinical outcomes (adjusted hazard ratio [HR] 1.30, 95% CI 1.26-1.33, p <0.001). In the VCTE-Prognosis cohort, hypertension was associated with a higher risk of liver stiffness progression (adjusted HR 1.57, 95% CI 1.30-1.90, p <0.001), while in the Paired Liver Biopsy cohort, hypertension was associated with a greater risk of histologic liver fibrosis progression (adjusted HR 1.41, 95% CI 1.12-1.78, p = 0.004). Subgroup and sensitivity analyses supported these findings. CONCLUSIONS: Hypertension is a modifiable risk factor that increases the risk of adverse clinical outcomes and progression of liver stiffness and fibrosis in MASLD. IMPACT AND IMPLICATIONS: This study provides robust evidence from three large multicenter cohorts demonstrating that hypertension is independently associated with increased risks of adverse clinical outcomes and liver fibrosis progression in individuals with MASLD. These findings reveal that hypertension, traditionally managed from a cardiovascular perspective, also plays a critical and underrecognized role in liver disease progression, making them highly relevant for hepatologists, cardiologists, and primary care providers. Incorporating non-invasive fibrosis assessments into routine care for patients with MASLD and hypertension may facilitate early risk stratification and support targeted interventions to reduce both hepatic and cardiovascular complications.

DOI： 10.1016/j.jhep.2025.08.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To establish practical, evidence-based strategies for noninvasive assessment and referral of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) in Japan, we must address the urgent clinical need for accurate risk stratification and timely specialist intervention. A panel of 11 Japanese hepatology experts conducted a modified Delphi process to evaluate consensus recommendations regarding the use of noninvasive tests (NITs), including the fibrosis-4 index, enhanced liver fibrosis test, Mac-2-binding protein glycosylation isomer, type IV collagen 7S, cytokeratin-18 fragments, and imaging modalities such as ultrasound elastography and magnetic resonance elastography, for MASLD assessment and clinical referral. Practical algorithms were developed based on current Japanese data and panel consensus. The expert panel validated the utility of NITs as reliable tools for identifying patients with MASLD at risk for advanced fibrosis. Sequential use of NITs improved diagnostic accuracy and referral appropriateness while minimizing unnecessary specialist consultations. The proposed algorithms offer stepwise guidance for primary care physicians, supporting efficient, evidence-based decision-making. However, prospective longitudinal studies remain necessary for full prognostic validation of NITs in MASLD management. Noninvasive testing algorithms enable effective risk stratification and referral for MASLD in real-world Japanese practice with anticipated benefit for patient outcomes and healthcare systems. Broader adoption and further validation are warranted.

DOI： 10.3748/wjg.v32.i2.114097

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: The utility of the Mac-2 binding protein glycosylation isomer (M2BPGi) as a noninvasive biomarker for advanced liver fibrosis in metabolic dysfunction3associated steatotic liver disease (MASLD) is unclear. The aim of this study is to evaluate M2BPGi levels in relation to the histopathological features of MASLD and assess its diagnostic performance individually and in combination with the fibrosis-4 (FIB-4) index. METHODS: A total of 992 patients with biopsy-confirmed MASLD were analyzed. Associations between the M2BPGi levels and histological features were also evaluated. RESULTS: M2BPGi levels were significantly correlated with steatosis, lobular inflammation, ballooning, and fibrosis stages. Patients with mild steatosis (S0-1) had significantly lower M2BPGi levels than those with severe steatosis (S2-3) (P < .001). Patients with severe inflammation (A2-3) had higher M2BPGi levels than those with mild inflammation (A0-1) (P < .001), and those with advanced ballooning (B2) had significantly higher M2BPGi levels than those with lower grades (B0-1) (P < .001). Advanced fibrosis (F3-4) was associated with higher M2BPGi levels than early-stage fibrosis (F0-2) (P < .001), with a cutoff value of 0.99 (area under the curve [AUC]: 0.774). M2BPGi outperformed the FIB-4 index (AUC: 0.719) and aspartate aminotransferase-to-platelet-ratio index (AUC: 0.665) for the diagnosis of advanced fibrosis (P < .001). A 2-step algorithm combining FIB-4 with M2BPGi reduced the need for further testing by 31.5%, while maintaining a false-negative rate of 13.9%. CONCLUSION: M2BPGi is a robust biomarker for advanced liver fibrosis in patients with MASLD. Its integration with FIB-4 in screening algorithms enhances diagnostic accuracy while minimizing unnecessary liver biopsies and specialist referrals.

DOI： 10.1016/j.gastha.2026.100901

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/a-2616-8452

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掲載種別：研究論文（学術雑誌）   出版者・発行元：AME Publishing Company  

DOI： 10.21037/hbsn-2025-439

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記述言語：日本語   出版者・発行元：(一社)日本消化器内視鏡学会-関東支部  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Noninvasive tests (NITs) are vital for the early diagnosis of the stage of metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigates relationships between altmetric scores, traditional Web of Science metrics (citations and impact factor), and the clinical impact as assessed by multiple experts. METHODS: Articles evaluating NITs for MASLD/MASH published in 2022 were evaluated without language/article-type restrictions by five expert hepatologists based on three subtopics: immediate usefulness in daily clinical practice (practicality), potential influence on future guidelines (impact), and new viewpoints and/or topics (innovation). Eligible articles were ranked 1-10 by physicians and scored by rank (10 points to rank 1, 9 points to rank 2, and so on), which were summed across all physicians by subtopic. The physicians' total score was derived from the sum of the subtopic scores. Altmetric scores were manually retrieved using Altmetric Explorer and compared with the summed physician scores and traditional metrics (Clarivate) using Pearson's correlation analysis. RESULTS: Moderate positive correlations existed between the altmetric attention score (AAS) and physician total score (r = 0.52), and between the AAS and innovation subtopic (r = 0.56). Weaker positive correlations existed between the AAS and practicality (r = 0.20) and impact (r = 0.14) subtopics. Among the high-ranking articles, the innovation subtopic demonstrated greater concordance across the five experts than the practicality and impact subtopics. CONCLUSION: The use of altmetrics alongside traditional metrics may contribute to physicians involved in MASLD care obtaining innovative research information on NIT more quickly.

DOI： 10.1111/hepr.14229

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Diagnosing pancreatic tumors ≤ 10 mm is challenging due to limited visualization and low sampling sensitivity. This study aimed to evaluate the cumulative diagnostic performance of repeated endoscopic ultrasound-guided tissue acquisition (EUS-TA) and surrogate repeated endoscopic retrograde pancreatography (ERP). METHODS: This study analyzed 40 patients with suspected pancreatic tumors ≤ 10 mm who underwent EUS-TA and/or ERP retrospectively. When a diagnosis could not be determined based on the initial EUS-TA or ERP procedure, EUS-TA or ERP was repeated as necessary. The cumulative diagnostic performance of EUS-TA and ERP for pancreatic tumors was evaluated. RESULTS: EUS-TA was performed once for 35 cases, twice for seven cases, and three times for one case. ERP was performed for 15 cases, and the median number of ERP attempts was two (range, 1-8). The cumulative sensitivity of EUS-TA increased from 56.7% to 70.0% after three attempts, while ERP sensitivity increased from 54.5% to 72.7% after two attempts. The cumulative diagnostic performance of repeated EUS-TA and ERP combined by case included sensitivity and accuracy rates of 87.9% and 90.0%. When limited to pancreatic cancer, the sensitivity and accuracy rates were 95.8% and 96.8%, respectively. No severe adverse events occurred. CONCLUSION: Repeated EUS-TA and ERP showed good diagnostic sensitivity for small pancreatic cancers ≤ 10 mm. When malignancy is suspected but not confirmed by a single procedure, repeating both may be an option in selected cases. Performing EUS-TA and ERP at least twice may be reasonable when small pancreatic cancer is suspected.

DOI： 10.1007/s10620-025-09373-5

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Many patients develop Fontan-associated liver disease (FALD) after undergoing the Fontan procedure-a surgical treatment for congenital heart disease such as single ventricle-owing to changes in venous pressure and cardiac output. Liver biopsy is the gold standard for diagnosing FALD, but has limitations. Magnetic resonance elastography (MRE) is a popular non-invasive method for evaluating liver stiffness and fibrosis in FALD; however, no unified view exists. This study aimed to assess the usefulness of MRE in evaluating the pathophysiology of FALD, including its correlation with cardiovascular parameters and histological findings. METHODS AND RESULTS: This retrospective cohort study included 22 patients with FALD who underwent MRE at Yokohama City University Hospital. Patients with other liver diseases or a history of heavy alcohol consumption were excluded. Liver biopsies were assigned a congestive hepatic fibrosis score (CHFS). Liver stiffness was measured using MRE, and hemodynamic data were obtained using cardiac catheterization. The correlation between MRE-based liver stiffness and clinical, laboratory, and pathological findings was analyzed.Patients' median age was 21.5 years, and the Fontan procedure was performed 16.3 years (mean) ago. Biochemical findings showed elevated gamma-glutamyl transpeptidase (GGT) levels. Mean liver stiffness measured using MRE was high (5.3 kPa), which significantly correlated with CHFS stage of liver fibrosis, and also correlated with GGT levels, fibrosis 4 index, and central venous pressure. CONCLUSION: MRE seems a promising non-invasive tool for liver fibrosis evaluation in FALD. However, it may also reflect hepatic congestion. Further studies are needed to establish its clinical utility and standard cutoff values.

DOI： 10.1002/jgh3.70274

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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記述言語：日本語   出版者・発行元：医学図書出版(株)  

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記述言語：日本語   出版者・発行元：医学図書出版(株)  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Informa UK Limited  

DOI： 10.1080/17474124.2025.2502549

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

ABSTRACT

Aims

In March 2024, the American Society of Clinical Oncology recommended the combination of tremelimumab plus durvalumab as a treatment for advanced hepatocellular carcinoma (HCC). Although safety data for first‐line treatments are available, information on adverse events related to late‐line treatments is limited. This study aimed to identify risk factors for adverse events in patients who received this combination.

Methods and Results

We conducted a retrospective cohort study from March 2023 to January 2025 at Yokohama City University Hospital, involving 24 patients aged 18 years or older with unresectable HCC. All 24 patients experienced at least one adverse event during treatment. Of these, the incidence of treatment‐related adverse events leading to treatment discontinuation after tremelimumab plus durvalumab therapy was 50.0% (12/24). In the discontinuation group, prior atezolizumab plus bevacizumab therapy (66.7% vs. 16.7%, p = 0.036) was more frequent than in the continuation group.

Conclusion

In patients with unresectable HCC who received tremelimumab plus durvalumab, the risk of treatment‐related adverse events was associated with prior atezolizumab plus bevacizumab therapy. These factors may increase the likelihood of developing treatment‐related adverse events.

DOI： 10.1002/jgh3.70163

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

There are limited studies on the improvement of leaky gut with minor inflammation associated with various diseases. To explore the therapeutic potential of Lactiplantibacillus plantarum 22 A-3, a member of the Lactobacillus species, in addressing a leaky gut. Lactiplantibacillus plantarum 22 A-3 was administered to a leaky gut mice model with low dextran sulfate sodium concentrations. The Lactiplantibacillus plantarum 22 A-3-treated group exhibited amelioration of increased intestinal permeability, as indicated by lower blood fluorescein isothiocyanate-dextran levels compared with that of the control group. Furthermore, the messenger RNA expression of interleukin-10, an anti-inflammatory cytokine, was upregulated in the small intestine of Lactiplantibacillus plantarum 22 A-3-treated mice. Moreover, forkhead box P3 was upregulated in the small intestine and colon following Lactiplantibacillus plantarum 22 A-3 administration. Flow cytometry showed that forkhead box P3-positive regulatory T cells tended to increase in the small intestine and colon; however, this was not significant. Messenger RNA levels for the pro-inflammatory cytokines, interleukin-1 beta, and tumor necrosis factor-alpha showed no significant changes in the small intestine; however, their expressions significantly decreased in the colon. Blood fluorescein isothiocyanate-dextran levels showed that intestinal permeability also decreased in Lactiplantibacillus plantarum 22 A-3-dead bacteria. The bacterial component of Lactiplantibacillus plantarum 22 A-3 ameliorates increased intestinal permeability through its anti-inflammatory effect in the intestinal tract and may be a novel treatment for leaky gut.

DOI： 10.1038/s41598-025-87428-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Various noninvasive tests can be used to identify high-risk groups of patients with metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD). In this study, we compared the diagnostic performance of serum type 4 collagen 7S (COL4-7S) and the Enhanced Liver Fibrosis (ELF) score for detecting fibrosis in patients with MASLD. METHODS: Among 1368 patients with MASLD who underwent liver biopsy, 794 with values for both serum COL4-7S and the ELF score were enrolled in this multicenter study. The diagnostic performance of COL4-7S and ELF for detecting fibrosis stage ≥2, fibrosis stage ≥3, and at-risk metabolic dysfunction-associated steatohepatitis were evaluated using ROC curve, continuous net reclassification improvement, and integrated discrimination improvement analyses. RESULTS: Both COL4-7S and ELF scores increased significantly with increasing fibrosis. The AUROC for each outcome was higher for COL4-7S than ELF, but not significantly. The diagnostic performance for detecting fibrosis stage ≥2 was significantly better for COL4-7S than for the ELF score (s net reclassification improvement=16.7%, p=0.018; integrated discrimination improvement=3.9%, p<0.01). In patients without diabetes, the diagnostic performance for each outcome did not differ significantly between COL4-7S and ELF score, but in patients with diabetes, the diagnostic performance for fibrosis stage ≥2 was higher for COL4-7S than for the ELF score (AUROC=0.817 vs. 0.773, p=0.04; s net reclassification improvement=32.7%, p<0.01; integrated discrimination improvement=5.6%, p<0.01). CONCLUSIONS: The diagnostic performance of serum COL4-7S (a single marker) for identifying more advanced disease in patients with MASLD was at least equivalent to that of the ELF score (a combined marker).

DOI： 10.1097/HC9.0000000000000563

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Immune-mediated colitis (IMC) is a common and potentially severe immune-related adverse event of immune checkpoint inhibitors (ICIs). Although corticosteroids and biologics are standard treatments, some cases remain refractory. Tofacitinib, a Janus kinase inhibitor, has shown promise in refractory IMC; however, evidence regarding its treatment effects remains limited. CASE PRESENTATION: Here, we present a case of pembrolizumab-induced IMC and duodenitis refractory to corticosteroids, infliximab, and vedolizumab. The patient was successfully treated after receiving a 30-day course of tofacitinib, which resulted in rapid symptom resolution and mucosal healing. No recurrence of colitis was observed 3 months after treatment cessation. CONCLUSION: As ICIs are increasingly used, the incidence of refractory IMC and other immune-related toxicities is expected to rise. This case highlights the need for further studies to establish the optimal use of tofacitinib in refractory IMC and duodenitis.

DOI： 10.1159/000547424

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a case of Budd-Chiari syndrome successfully treated with endovascular recanalization of an inferior vena cava occlusion using a modified sharp recanalization technique. A 45-year-old man presented with hepatic dysfunction, and contrast-enhanced computed tomography revealed a 1.5 cm chronic inferior vena cava occlusion. Standard sharp recanalization using the conventional end of a guidewire failed to cross the lesion. Therefore, we reshaped the end of a 0.035-inch guidewire into a sharper form, enabling successful penetration without the use of specialized devices. This modified technique, adapted from peripheral artery interventions, may offer a safer and more cost-effective option for treating fibrotic venous occlusions. Stepwise balloon dilation was subsequently performed to minimize complications. This report highlights the potential utility of a reshaped guidewire end as a practical alternative when the conventional technique fails.

DOI： 10.22575/interventionalradiology.2025-0011

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: New scores were developed to identify at-risk metabolic dysfunction-associated steatohepatitis (MASH) using multiparametric MRI (mpMRI). MATERIALS AND METHODS: A prospective study was conducted on 176 patients with suspected or diagnosed metabolic dysfunction-associated steatotic liver disease (MASLD) paired with an MR scan, vibration-controlled transient elastography (VCTE), and liver biopsy. Liver stiffness measurement (LSM) using magnetic resonance elastography (MRE), proton density fat fraction (PDFF), and mpMRI-based corrected T1 (cT1) were combined to develop a one-step strategy, named MPcT (MRE + PDFF + cT1, combined score), and a two-step strategy-MRE-based LSM followed by PDFF with cT1 (M-PcT, paired score) for diagnosing at-risk MASH. Each model was categorized using rule-in and rule-out criteria (three categorized analyses). To avoid overfitting, the diagnostic accuracies were evaluated based on 5-fold cross-validation. RESULTS: PDFF + cT1 (PcT) had the highest diagnostic performance for severe activity (hepatic inflammation plus ballooning grade ≥ 3) and for NAS ≥ 4 (active MASH). Areas under receiver operating characteristic curves (AUROCs) of M-PcT (0.832) for detecting at-risk MASH were significantly higher than those of Fibroscan-AST (FAST) (0.744, p = 0.017), MRI-AST (MAST) (0.710, p = 0.002), and MPcT (0.695, p < 0.001) in three categorized analysis. Following the rule-in criteria, positive predictive values of M-PcT (84.5%) were higher than those of FAST (73.5%), MAST (70.0%), and MPcT (66.7%). Following the rule-out criteria, negative predictive values of M-PcT (88.7%) were higher than those of FAST (84.0%), MAST (73.9%), and MPcT (84.9%). CONCLUSIONS: The two-step strategy, M-PcT (paired score), showed the reliability of rule-in/-out for at-risk MASH, with better predictive performance compared with FAST and MAST (combined score). CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov (number, UMIN000012757). KEY POINTS: Question There is no mpMRI-based method for detecting as-risk MASH (NAFLD activity score ≥ 4 with fibrosis stage ≥ 2) like FAST and MAST scores. Findings MRE-based LSMs followed by PDFF with cT1 (M-PcT) were more useful in detecting at-risk MASH than the combined score (FAST and MAST). Clinical relevance By combining MRE and PDFF with cT1, it becomes possible to evaluate the pathology of MASH without the need for a liver biopsy, assisting in prognosis prediction and decision-making for treatment options.

DOI： 10.1007/s00330-024-11215-3

PubMed

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記述言語：日本語   出版者・発行元：梵天書房  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated steatotic liver disease (MASLD), is a phenotype of the metabolic syndrome in the liver and is clearly associated with metabolic abnormalities such as hyperglycaemia and dyslipidaemia. Although the prevalence of MASLD is increasing worldwide, there is currently no consensus on the efficacy and safety of the drugs used to treat MASLD/metabolic dysfunction-associated steatohepatitis (MASH). Pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was designed to have higher peroxisome proliferator-activated receptor alfa (PPARα) agonist activity and selectivity than existing PPARα agonists, and in development trials, without increasing creatinine levels, lipid parameters and alanine aminotransferase (ALT) were significantly improved. Thus, pemafibrate may effectively ameliorate the pathogenesis and metabolic abnormalities in MASLD/MASH. In this trial, we evaluated the efficacy and safety of pemafibrate in patients with MASLD/MASH. METHODS AND ANALYSIS: This trial was designed as an open-label, three-arm, randomised controlled study. After obtaining informed consent, patients aged 20-80 years who met the selection criteria were enrolled. Patients were randomised to receive pemafibrate 0.4 mg/day, 0.2 mg/day or fenofibrate (n=120 per group). The duration of treatment was 48 weeks. The primary endpoint was a change in ALT levels after 24 weeks of administration. Secondary endpoints included changes from baseline in liver fibrosis markers (fibrosis-4 index, type IV collagen 7s, enhanced liver fibrosis and Mac-2 binding protein glycosylation isomer) at 48 weeks as well as changes in liver fat mass and liver stiffness measured by MRI and ultrasound (US) at centres equipped with MRI and US capabilities. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Yokohama City University Certified Institutional Review Board before participant enrolment (CRB20-014). 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 understand the results of this study will be contacted directly on data publication. TRIAL REGISTRATION NUMBER: This trial was registered in the Japan Registry of Clinical Trials (number: jRCTs031200280). PROTOCOL VERSION: V.1.9, 23 November 2023.

DOI： 10.1136/bmjopen-2024-088862

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective Myosteatosis affects the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and may be a potential therapeutic target. This study aimed to examine the effects of ipragliflozin on myosteatosis in patients with type 2 diabetes mellitus (T2D) and MASLD. Methods Patients were treated with ipragliflozin (IPR group) or a control (CTR group) for 72 weeks in a randomized trial. Changes in myosteatosis of the lumbar skeletal muscles were evaluated using computed tomography (CT). The response of myosteatosis to treatment and the baseline characteristics of the patients were analyzed. Patients 44 participants (IPR group, 23; CTR group, 21) with MASLD complicated by T2D Results Myosteatosis increased in the CTR group (n=23) but remained unchanged in the IPR group (n=21). The changes were apparent at 24 weeks (P=0.004), but were not significant after 24 weeks. A hierarchical cluster analysis was performed to identify clusters with and without improvement in myosteatosis. The clusters with decreasing intramuscular adipose tissue content (IMAC) at 48 and 72 weeks were not treated, but they had lower visceral fat area and severe liver steatosis at baseline. Improvements in glycemic control and resistance to decreasing abdominal skeletal muscle area from baseline to 24 weeks affected the decrease in IMAC at 48 and 72 weeks. Conclusion Ipragliflozin had a limited effect on skeletal muscle adiposity in patients with T2D and MASLD. Regardless of the treatment, a specific phenotype of adiposity and hepatic steatosis before treatment is associated with the long-term outcomes of myosteatosis. Maintaining skeletal muscle mass and better glycemic control during treatment are essential for the future improvement of myosteatosis.

DOI： 10.2169/internalmedicine.4456-24

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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その他リンク： 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

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：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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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Abstract

Aim

This study aims to evaluate the efficacy and safety of lenvatinib radiofrequency ablation (RFA) sequential therapy for certain hepatocellular carcinoma (HCC) patients.

Methods

One hundred and nineteen patients with unresectable HCC in the intermediate stage with Child–Pugh A were retrospectively recruited in a multicenter setting. Those in the lenvatinib RFA sequential therapy group received lenvatinib initially, followed by RFA and the retreatment with lenvatinib. The study compared overall survival (OS), progression‐free survival (PFS), tumor response, and adverse events (AEs) between patients undergoing sequential therapy and lenvatinib monotherapy.

Results

After propensity score matching, 25 patients on sequential therapy and 50 on monotherapy were evaluated. Independent factors influencing OS were identified as sequential therapy, modified albumin–bilirubin (mALBI) grade, and relative dose intensity (%) with hazard ratios (HRs) of 0.381 (95% confidence interval [CI], 0.186–0.782), 2.220 (95% CI, 1.410–3.493), and 0.982 (95% CI, 0.966–0.999), respectively. Stratified analysis based on mALBI grades confirmed the independent influence of treatment strategy across all mALBI grades for OS (HR, 0.376; 95% CI, 0.176–0.804). Furthermore, sequential therapy was identified as an independent factor of PFS (HR, 0.382; 95% CI, 0.215–0.678). Sequential therapy significantly outperformed monotherapy on survival benefits (OS: 38.27 vs. 18.96 months for sequential therapy and monotherapy, respectively, p = 0.004; PFS: 13.80 vs. 5.32 months for sequential therapy and monotherapy, respectively, p &lt; 0.001). Sequential therapy was significantly associated with complete response by modified Response Evaluation Criteria in Solid Tumors (odds ratio, 63.089). Ten of 119 patients experienced grade 3 AEs, with no AE beyond grade 3 observed.

Conclusion

Lenvatinib RFA sequential therapy might offer favorable tolerability and potential prognostic improvement compared to lenvatinib monotherapy.

DOI： 10.1111/hepr.14089

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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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記述言語：日本語   出版者・発行元：(株)日本メディカルセンター  

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記述言語：日本語   出版者・発行元：(株)日本メディカルセンター  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Because the accuracy of the Fibrosis-4 (FIB-4) index for predicting liver fibrosis changes with age, the need for different cut-offs in various age groups has frequently been discussed. We developed the age-independent score, the Fibrosis-3 (FIB-3) index, and have shown its usefulness in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB-3 index to predict fibrosis progression using a large new patient cohort. METHODS: The ability of the FIB-3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB-4 index using data from 1398 patients with MASLD enrolled in the Asia-based clinical outcome NAFLD study. RESULTS: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB-3 and FIB-4 indices in the entire cohort. Using the single ideal cut-offs of the indices (3.41 for FIB-3 index and 2.01 for FIB-4 index), the predictive accuracy of the FIB-3 index was not significantly different from that of the FIB-4 index among patients aged <60 years; however, the accuracy of the FIB-3 index was significantly higher than that of the FIB-4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001). CONCLUSION: The high ability of the FIB-3 index with a single cut-off to predict liver fibrosis in patients with MASLD was confirmed. The FIB-3 index could serve as a useful tool for assessing liver fibrosis regardless of age.

DOI： 10.1111/hepr.14039

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: A multi-stakeholder consensus has proposed MASLD (metabolic dysfunction-associated steatotic liver disease). We aimed to investigate the pathological findings related to the mid-term mortality of patients with biopsy-proven MASLD in Japan. METHODS: We enrolled 1349 patients with biopsy-proven MASLD. The observational period was 8010 person years. We evaluated independent factors associated with mortality in patients with MASLD by Cox regression analysis. We also investigated pathological profiles related to mortality in patients with MASLD using data-mining analysis. RESULTS: The prevalence of MASH and stage 3/4 fibrosis was observed in 65.6% and 17.4%, respectively. Forty-five patients with MASLD died. Of these, liver-related events were the most common cause at 40% (n = 18), followed by extrahepatic malignancies at 26.7% (n = 12). Grade 2/3 lobular inflammation and stage 3/4 fibrosis had a 1.9-fold and 1.8-fold risk of mortality, respectively. In the decision-tree analysis, the profiles with the worst prognosis were characterised by Grade 2/3 hepatic inflammation, along with advanced ballooning (grade 1/2) and fibrosis (stage 3/4). This profile showed a mortality at 8.3%. Furthermore, the random forest analysis identified that hepatic fibrosis and inflammation were the first and second responsible factors for the mid-term prognosis of patients with MASLD. CONCLUSIONS: In patients with biopsy-proven MASLD, the prevalence of MASH and advanced fibrosis was approximately 65% and 20%, respectively. The leading cause of mortality was liver-related events. Hepatic inflammation and fibrosis were significant factors influencing mid-term mortality. These findings highlight the importance of targeting inflammation and fibrosis in the management of patients with MASLD.

DOI： 10.1111/apt.17995

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study. METHODS: This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD. RESULTS: Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P<0.001), in addition to significantly lower levels of inflammation, ballooning, NAFLD activity score, and fibrosis stage based on liver histology. These 17 patients had a median follow-up of 5.9 years, equivalent to 115 person-years, with no deaths, liver-related events, cardiovascular events, or extrahepatic cancers. The results showed that the prognosis for pure MASLD was similar to that for the original CLIONE cohort, with 47 deaths and one patient who underwent orthotopic liver transplantation. The leading cause of death was extrahepatic cancer (n=10), while the leading causes of liver-related death were liver failure (n=9), hepatocellular carcinoma (n=8), and cholangiocarcinoma (n=4). CONCLUSION: Approximately 99% of NAFLD cases were considered MASLD based on the 2023 liver disease nomenclature. The NAFLD-only group, which is not encompassed by MASLD, had a relatively mild histopathologic severity and a favorable prognosis. Consequently, the prognosis of MASLD is similar to that previously reported for NAFLD.

DOI： 10.3350/cmh.2023.0515

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Refractory ascites affects the prognosis and quality of life in patients with liver cirrhosis. Peritoneovenous shunt (PVS) is a treatment procedure of palliative interventional radiology for refractory ascites. Although it is reportedly associated with serious complications (e.g., heart failure, thrombotic disease), the clinical course of PVS has not been thoroughly evaluated. OBJECTIVES: To evaluate the relationship between chronological course and complications after PVS for refractory ascites in liver cirrhosis patients. MATERIALS AND METHODS: This was a retrospective study of 14 patients with refractory ascites associated with decompensated cirrhosis who underwent PVS placement between June 2011 and June 2023. The clinical characteristics, changes in cardiothoracic ratio (CTR), and laboratory data (i.e., brain natriuretic peptide (BNP), D-dimer, platelet) were evaluated. Follow-up CT images in eight patients were also evaluated for ascites and complications. RESULTS: No serious complication associated with the procedure occurred in any case. Transient increases in BNP and D-dimer levels, decreased platelet counts, and the worsening of CTR were observed in the 2 days after PVS; however, they were improved in 7 days in all cases except one. In the follow-up CT, the amount of ascites decreased in all patients, but one patient with a continuous increase in D-dimer 2 and 7 days after PVS had thrombotic disease (renal and splenic infarction). The mean PVS patency was 345.4 days, and the median survival after PVS placement was 474.4 days. CONCLUSIONS: PVS placement for refractory ascites is a technically feasible palliative therapy. The combined evaluation of chronological changes in BNP, D-dimer, platelet count and CTR, and follow-up CT images may be useful for the early prediction of the efficacy and complications of PVS.

DOI： 10.3390/tomography10040036

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(公社)神奈川県医師会  

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記述言語：日本語   出版者・発行元：(公社)神奈川県医師会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：(株)診断と治療社  

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その他リンク： 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

記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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記述言語：日本語   出版者・発行元：(株)診断と治療社  

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その他リンク： 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

記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：The Korean Society of Neurogastroenterology and Motility  

DOI： 10.5056/jnm22162

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common liver disease. It has a rapidly growing patient population owing to the increasing prevalence of obesity and type 2 diabetes. Patients with MASLD are primarily treated by family physicians when fibrosis is absent or mild and by gastroenterologists/hepatologists when fibrosis is more advanced. It is imperative that a system for the appropriate treatment and surveillance of hepatocellular carcinoma be established in order to ensure that highly fibrotic cases are not overlooked among the large number of MASLD patients. Family physicians should check for viral hepatitis, autoimmune hepatitis, alcoholic liver disease, and drug-induced liver disease, and should evaluate fibrosis using NIT; gastroenterologists/hepatologists should perform liver biopsy, ultrasound elastography (260 units in Japan as of October 2023), and MR elastography (35 units in Japan as of October 2023). This review presents the latest findings in MASLD and the role, accuracy, and clinical use of NIT. It also describes the collaboration between Japanese primary care and gastroenterologists/hepatologists in Japan in the treatment of liver diseases, including MASLD.

DOI： 10.3390/life13112144

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語  

DOI： 10.21037/hbsn-23-342

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis-4 (FIB-4) index and body mass index (BMI) using an unsupervised machine learning method. METHODS: We conducted a multicenter study of 1335 biopsy-proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB-4 index and BMI, we investigated prognosis for these clusters. RESULTS: The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3-4) as assessed from liver biopsy. Median values of BMI and FIB-4 index were 27.3 kg/m2 and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all-cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB-4 index (median 5.23 and 2.23), cluster a presented the lowest FIB-4 index (median 0.78), and cluster c was associated with moderate FIB-4 level (median 1.30) and highest BMI (median 34.3 kg/m2 ). Clusters a and c had lower mortality rates than clusters b and d. However, all-cause of death in clusters a and c was unrelated to liver disease. CONCLUSIONS: Our clustering approach found that the FIB-4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non-liver-related diseases were identified as the causes of death in NAFLD patients with low FIB-4 index.

DOI： 10.1111/jgh.16326

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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掲載種別：研究論文（学術雑誌）   出版者・発行元：The Korean Society of Neurogastroenterology and Motility  

DOI： 10.5056/jnm22152

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/liv.15678

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語  

DOI： 10.1111/apt.17505

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/hepr.13884

Scopus

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記述言語：日本語   出版者・発行元：産業開発機構(株)  

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その他リンク： 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

記述言語：日本語   出版者・発行元：産業開発機構(株)  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s12328-023-01789-8

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その他リンク： https://link.springer.com/article/10.1007/s12328-023-01789-8/fulltext.html

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：日本語   出版者・発行元：(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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/app13063893

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Nonalcoholic fatty liver diseases (NAFLD) and nonalcoholic steatohepatitis (NASH) can cause hepatocellular carcinoma (HCC). We examined histological features and reported noninvasive markers/models for stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH. METHODS: A total of 1389 patients who had a histological diagnosis of NAFLD or NASH based on liver biopsy and underwent regular surveillance for HCC were included. The ability to predict HCC development was compared between histological features including liver fibrosis and NAFLD activity score, and noninvasive markers/models including aMAP (age, male, albumin-bilirubin, and platelet) score, FIB-4 (Fibrosis-4) index, and ALBI (albumin-bilirubin) score calculated at the time of biopsy. RESULTS: The C index of aMAP score was 0.887, which was consistent with the original report, comparable to FIB-4 index (0.878), and higher than those of ALBI score (0.789), histological liver fibrosis (0.723), and NAFLD activity score (0.589). The hazard ratios for HCC development in the aMAP intermediate and high-risk groups were 21.0 (95% confidence interval [CI], 3.6-402.0) and 110.3 (95% CI, 16.3-2251.4), respectively, in comparison to the aMAP score low-risk group. Those in the FIB-4 index moderate- and high-fibrosis groups were 10.3 (95% CI, 1.7-199.8) and 93.1 (95% CI, 16.3-1773.8), respectively, in comparison to the FIB-4 index mild-fibrosis group. No patients in the aMAP score low-risk group developed HCC during the study period. CONCLUSION: For stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH, both aMAP score and FIB-4 index showed high discriminative ability as noninvasive markers, which were superior histological features.

DOI： 10.1016/j.gastha.2023.07.018

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/hepr.13857

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掲載種別：研究論文（学術雑誌）   出版者・発行元：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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その他リンク： https://www.nature.com/articles/s41598-022-22767-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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その他リンク： 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

記述言語：日本語   出版者・発行元：(有)科学評論社  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/jgh3.12808

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jgh3.12808

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：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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その他リンク： https://www.nature.com/articles/s41598-022-17917-2

記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: No reports on both blood and fecal bile acids (BAs) in patients with nonalcoholic fatty liver disease (NAFLD) exist. We simultaneously assessed the serum and fecal BA patterns in healthy participants and those with NAFLD. METHODS: We collected stool samples from 287 participants from 5 hospitals in Japan (healthy control [HC]: n = 88; mild fibrosis: n = 104; and advanced fibrosis group: n = 95). Blood samples were collected and analyzed for serum BAs and 7α-hydroxy-4-cholesten-3-one (C4)-a surrogate marker for BA synthesis ability-from 141 patients. Concentrations of BAs, including cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid, ursodeoxycholic acid, and lithocholic acid (LCA), were measured using liquid chromatography-mass spectrometry. RESULTS: The total fecal BA concentration was significantly higher in the NAFLD group with worsening of fibrosis than in the HC group. Most of the fecal BAs were secondary and unconjugated. In the fecal BA fraction, CA, DCA, chenodeoxycholic acid, ursodeoxycholic acid, and LCA were significantly higher in the NAFLD than in the HC group. The total serum BA concentration was higher in the NAFLD group with worsening of fibrosis than in the HC group. In the serum BA fraction, CA, LCA, and C4 concentrations were significantly higher in the NAFLD than in the HC group. DISCUSSION: Fecal and serum BA and C4 concentrations were high in patients with NAFLD with worsening of fibrosis, suggesting involvement of abnormal BA metabolism in NAFLD with fibrosis progression. Abnormalities in BA metabolism may be a therapeutic target in NAFLD with fibrosis.

DOI： 10.14309/ctg.0000000000000503

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記述言語：日本語   出版者・発行元：(NPO)日本高齢消化器病学会  

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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(有)科学評論社  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：AME Publishing Company  

DOI： 10.21037/hbsn-21-579

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(株)医学出版  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：日本語   出版者・発行元：(株)南江堂  

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その他リンク： 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

記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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記述言語：日本語   出版者・発行元：(一社)日本アルコール・アディクション医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：日本語   出版者・発行元：梵天書房  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：John Wiley and Sons Inc  

DOI： 10.1111/apt.16596

Scopus

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：日本語   出版者・発行元：医学図書出版(株)  

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その他リンク： 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

記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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掲載種別：研究論文（学術雑誌）   出版者・発行元：American Medical Association (AMA)  

DOI： 10.1001/jamanetworkopen.2021.26334

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/hep4.1696

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/hep4.1696

記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(株)日本メディカルセンター  

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記述言語：日本語   出版者・発行元：(株)日本メディカルセンター  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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掲載種別：研究論文（学術雑誌）   出版者・発行元：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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その他リンク： http://www.nature.com/articles/s41389-021-00322-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(株)自然科学社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ Publishing Group  

DOI： 10.1136/gutjnl-2021-324243

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Taylor and Francis Ltd.  

DOI： 10.1080/14656566.2021.1912014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Society of Hepatology  

DOI： 10.2957/kanzo.61.504

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

DOI： 10.3389/fonc.2020.555963

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(株)ライフ・サイエンス  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00535-019-01635-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：日本語   出版者・発行元：(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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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記述言語：日本語   出版者・発行元：(株)じほう  

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記述言語：英語  

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.2894-19

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：S. Karger AG  

DOI： 10.1159/000502815

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/hepr.13349

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jgh.14559

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：日本語   出版者・発行元：(株)ライフメディコム  

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記述言語：日本語   出版者・発行元：(NPO)日本高齢消化器病学会  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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その他リンク： 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

記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/hepr.13382

PubMed

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

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記述言語：日本語   出版者・発行元：(一社)日本臨床内科医会  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/14656566.2018.1543403

PubMed

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記述言語：日本語   出版者・発行元：(株)響文社  

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記述言語：日本語   出版者・発行元：(株)響文社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(株)日本メディカルセンター  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(NPO)日本歯周病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jgh.14156

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記述言語：日本語   出版者・発行元：(公社)日本薬理学会  

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その他リンク： 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

記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-31886-5

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記述言語：日本語   出版者・発行元：(一社)日本臨床内科医会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-29735-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.cct.2018.04.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Tokyo  

DOI： 10.1007/s00535-018-1478-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Tokyo  

DOI： 10.1007/s00535-018-1474-y

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jgh.14294

PubMed

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記述言語：日本語   出版者・発行元：(株)響文社  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：(株)響文社  

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記述言語：日本語   出版者・発行元：(株)響文社  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing Ltd  

DOI： 10.1111/hepr.12992

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Tokyo  

DOI： 10.1007/s00535-017-1414-2

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1254/fpj.152.187

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/hepr.12877

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(株)ライフ・サイエンス  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：日本語   出版者・発行元：(一社)日本アルコール・アディクション医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12876-017-0652-3

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記述言語：日本語   出版者・発行元：(株)ライフ・サイエンス  

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記述言語：日本語   出版者・発行元：(株)ニュー・サイエンス社  

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記述言語：日本語   出版者・発行元：(株)響文社  

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記述言語：日本語   出版者・発行元：(株)響文社  

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記述言語：日本語   出版者・発行元：(株)響文社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/srep42477

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing Ltd  

DOI： 10.1111/hepr.12648

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/jimmunol.1502677

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