Background: No randomized controlled trial has directly compared the efficacy of pemafibrate to that of fenofibrate, or evaluated the dose–response relationship of pemafibrate in metabolic dysfunction–associated steatotic liver disease (MASLD). Therefore, we compared the efficacy and safety of high- and low-dose pemafibrate versus fenofibrate over 48 weeks in patients with MASLD and hypertriglyceridemia. Methods: This multicenter, open-label, randomized controlled trial included 360 patients with MASLD and hypertriglyceridemia at 29 sites in Japan. Participants were randomly assigned (1:1:1) to high-dose pemafibrate (0·4 mg/day; PEM-H), low-dose pemafibrate (0·2 mg/day; PEM-L), or fenofibrate (53·3-106·6 mg/day; FENO) groups. The primary endpoint was change in alanine aminotransferase (ALT) levels at Week 24. Secondary endpoints included liver fibrosis markers, renal parameters, magnetic resonance elastography (MRE), and adverse events. Findings: At Week 24, PEM-H and PEM-L produced significantly greater ALT reductions than FENO (p < 0·001 and p = 0·015, respectively). Exploratory comparison revealed greater reduction for PEM-H than PEM-L (p = 0·018, Holm adjustment), suggesting a dose-dependent effect. Higher baseline ALT levels and lean phenotypes were independently associated with ALT response. At Week 48, Mac-2 binding protein glycosylation isomer decreased significantly in PEM-H and PEM-L compared with a modest reduction in FENO (p < 0·001 and p < 0·001, respectively). MRE demonstrated significant decreases in liver stiffness in PEM-H and PEM-L compared with FENO (p < 0·05 and p = 0·02, respectively). Percentage change in serum creatinine levels was lower in PEM-H and PEM-L than in FENO. No treatment-related serious adverse events were observed in any of the three groups. Interpretations: Pemafibrate demonstrated greater reductions in ALT levels than fenofibrate, with a clear dose–response relationship and favorable safety profile, suggesting its therapeutic potential for patients with MASLD and hypertriglyceridemia.

Stepwise MASLD pathways based on the fibrosis-4 (FIB-4) index leave a large indeterminate subgroup requiring second-step assessment. We evaluated automated chemiluminescent enzyme immunoassay (CLEIA)-based type IV collagen 7S (COL4-7S) as a candidate second-line test for MRE-defined clinically significant fibrosis (≥F2). In this retrospective derivation-validation study, adults with MASLD underwent clinically indicated magnetic resonance elastography (MRE) with serum biomarkers measured within 30 days in a two-center derivation cohort (n=347) and an independent external validation cohort (n=126). COL4-7S was compared with ELF, M2BPGi, and FIB-4 using MRE-defined fibrosis stage (F0-F4). In the derivation cohort, MRE liver stiffness correlated with COL4-7S (r=0.59), ELF (r=0.58), M2BPGi (r=0.62), and FIB-4 (r=0.49; all p<0.001), with similar ordinal discrimination across F0-F4. Within the indeterminate FIB-4 range, second-step COL4-7S correctly classified 90/136 patients (66%) for MRE-defined ≥F2; ELF and M2BPGi correctly classified 90/136 (66%) and 73/136 (54%), respectively. In external validation, COL4-7S and ELF correctly classified 32/50 (64%) and 34/50 (68%) patients, respectively. These findings indicate numerically similar second-step performance of CLEIA-based COL4-7S and ELF for MRE-defined ≥F2 fibrosis in this retrospective cohort. Prospective studies are needed to determine whether COL4-7S improves workflow, cost-effectiveness, and patient outcomes in routine MASLD pathways.

AIM:Two-dimensional shear wave elastography (2D-SWE) is a non-invasive technique for assessing liver fibrosis. However, its clinical utility has not been fully established. This study evaluated the diagnostic accuracy of 2D-SWE using magnetic resonance elastography (MRE) as the reference standard in a retrospective, multicenter, large-scale cohort. METHODS:A total of 744 patients with chronic liver disease were included in the analysis. The association between 2D-SWE measurements and fibrosis stages determined by MRE was assessed. The correlation between 2D-SWE and MRE values was analyzed, and the diagnostic performance of 2D-SWE was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS:As 2D-SWE and MRE values were not normally distributed, they were log-transformed (Log-2D-SWE and Log-MRE) for analysis. A strong correlation was observed between Log-2D-SWE and Log-MRE values, with a correlation coefficient of 0.764 (p < 0.001). When 2D-SWE values were stratified according to the histological stages of liver fibrosis (F0-F4), based on MRE data, the corresponding median values were 4.61, 5.63, 6.18, 7.44, and 11.64 kPa, respectively (p < 0.001, Jonckheere-Terpstra test). The areas under the ROC curve (AUROCs) and cutoff values for 2D-SWE were 0.872 and 5.47 kPa for ≥ F1 (n = 285), 0.894 and 5.88 kPa for ≥ F2 (n = 217), 0.931 and 6.48 kPa for ≥ F3 (n = 137), and 0.937 and 7.39 kPa for F4 (n = 81), respectively. In subgroup analyses, AUROCs for detecting ≥ F2, ≥F3, and F4 exceeded 0.78, even among patients with elevated body mass index or advanced hepatic steatosis. CONCLUSIONS:2D-SWE represents a highly useful and reliable non-invasive modality for assessing of liver fibrosis.

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.

Accurate non-invasive assessment of hepatic steatosis is essential in metabolic dysfunction-associated steatotic liver disease. This study aimed to compare the diagnostic performance of the ultrasound-guided attenuation parameter (UGAP) and Hamaguchi score (HS) using ordinal-scale-specific statistical methods, with magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) as the reference standard. This multicenter cross-sectional study enrolled 1,010 patients with chronic liver disease at six tertiary hepatology centers. UGAP and HS were compared against MRI-PDFF-defined steatosis grades (S0: < 5.2

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits marked heterogeneity in fibrosis progression and liver-related outcomes. Liver biopsy is not feasible for longitudinal risk stratification at scale, creating a need for validated non-invasive biomarkers, particularly imaging biomarkers, that can predict clinically meaningful disease progression and liver-related outcomes. AIMS:To describe the design and rationale of the GOLDMINE study, established to determine whether non-invasive imaging biomarkers predict MASLD progression and liver-related clinical outcomes. METHODS:GOLDMINE is an investigator-initiated, multi-centre, international longitudinal cohort enrolling up to 1000 adults with either biopsy-proven MASLD or MASLD cirrhosis across the full fibrosis spectrum. Participants are recruited from 15 sites in the US and 4 international sites (Japan, Singapore and France). At baseline, participants undergo clinical phenotyping, vibration-controlled transient elastography, and advanced magnetic resonance imaging (MRI), including proton-density-fat-fraction and magnetic resonance elastography (MRE). MRI (and biospecimen banking) is repeated at 2-year intervals (years 2 and 4), with annual follow-up visits for up to 10 years. Baseline liver histology is centrally processed, digitized and reviewed by a single expert hepatopathologist; all MRI/MREs are centrally interpreted. RESULTS:The prespecified clinical outcomes include progression to cirrhosis, clinically significant portal hypertension, major adverse liver-related outcomes (ascites, hepatic encephalopathy, portal hypertensive bleeding, liver transplantation/qualification), hepatocellular carcinoma, major adverse cardiovascular events, and all-cause mortality, with independent central adjudication of all events. CONCLUSIONS:GOLDMINE establishes a rigorously phenotyped MASLD cohort integrating centralized histology, advanced MRI-based biomarkers, longitudinal biobanking, and adjudicated outcomes, providing a platform to validate imaging and blood-based prognostic biomarkers in MASLD.

BACKGROUND & AIMS:Two-dimensional shear-wave elastography is a practical method for assessing liver fibrosis. However, an optimal cutoff value to rule out significant fibrosis (≥F2) in metabolic dysfunction-associated steatotic liver disease remains unclear. This study aimed to determine the evidence-based rule-out cutoff through diagnostic meta-analysis. METHODS:A systematic review was of MEDLINE, EMBASE, and Cochrane CENTRAL was performed through December 2025 for studies evaluating 2-dimensional shear-wave elastography with liver biopsy as the reference standard. Pooled sensitivity, specificity, and summary area under the receiver operating characteristic curve were estimated. The rule-out cutoff was defined as the highest threshold achieving pooled sensitivity ≥80%. External validation was performed using an independent clinical cohort. RESULTS:Twenty-two studies involving 3171 adults with biopsy-proven metabolic dysfunction-associated steatotic liver disease were analyzed. The summary area under the receiver operating characteristic curve was 0.84 (95% confidence interval, 0.81-0.87), with pooled sensitivity of 79.6% and specificity of 76.0%. The rule-out cutoff of 6.6 kPa (95% confidence interval, 5.4-8.2 kPa) achieved sensitivity of 80.0% and specificity of 70.7%. At this threshold, negative predictive value exceeded 95% at prevalences of 5% and 10%. Diagnostic performance was generally preserved across subgroups but was modestly attenuated in populations with greater metabolic burden and in studies using Supersonic ultrasound platforms. External validation (N = 163) demonstrated consistent sensitivity (0.86) and specificity (0.68). CONCLUSIONS:Two-dimensional shear-wave elastography demonstrated good diagnostic accuracy for significant fibrosis in metabolic dysfunction-associated steatotic liver disease. A liver stiffness of 6.6 kPa can reliably rule out significant fibrosis. As 2-dimensional shear-wave elastography can be integrated into conventional ultrasound systems, it may facilitate broader implementation of fibrosis screening beyond specialized centers. CLINICAL TRIAL NUMBER:PROSPERO (International Prospective Register of Systematic Reviews), CRD42024616042.

Background Constipation, which is common in patients receiving palliative care, reduces quality of life and pain control. Ultrasound aids in diagnosis and treatment monitoring; however, evidence on managing rectal fecal retention is lacking. We aimed to compare the effectiveness of transanal (TA) and transoral (TO) treatments for rectal fecal retention diagnosed using point-of-care ultrasound. Methods A prospective observational study was conducted from July 2023 to July 2024, at the International University of Health and Welfare Narita Hospital, Japan. Forty-two newly registered palliative care inpatients with rectal fecal retention were enrolled. Twenty-one participants received TA treatment (bisacodyl 10 mg or sodium bicarbonate and anhydrous sodium dihydrogen phosphate once) and 21 received TO treatment (sennoside 24 mg once). The primary outcome was defecation rate within 24 h. Secondary outcomes included improvement rate in incomplete evacuation, loss of defecation desire (LODD) within 24 h, and treatment satisfaction. Results Defecation within 24 h occurred in 71% of patients in the TA group versus 33% in the TO group ( P = 0.01). Improvement in a sense of incomplete evacuation was achieved in 80% and 24% of patients in the TA and TO groups, respectively ( P = 0.001). LODD improved in 67% of patients in the TA group versus 31% in the TO group ( P = 0.049); treatment satisfaction was higher in the TA group (62%) than in the TO group (24%; P = 0.01). Conclusions TA treatment may be associated with improved bowel-related outcomes than TO treatment for rectal fecal retention in palliative care settings.

BACKGROUND:We compared the effectiveness of magnesium oxide (MgO) and elobixibat (EXB) in improving defecation desire (DD), rectal sensation, and colonic transit time (CTT) in patients with chronic constipation (CC). METHODS:This was a prospective, observational study conducted in real-world clinical practice. We included patients with CC who met the Rome IV criteria and underwent colon transit study and rectal sensory tests (RSTs). Loss of defecation desire (LODD) was subjectively assessed using a questionnaire, and the rectal sensation was objectively assessed using the balloon air volume, which was measured using the first defecation desire volume (FDDV). CTT was measured using radiopaque markers, and slow transit constipation (STC) and normal transit constipation (NTC) were diagnosed using marker residual rate. The shift rate from STC at baseline to NTC after each drug administration was calculated. Drugs were selected at the discretion of the attending physician. KEY RESULTS:Patients in the MgO (n = 30) and EXB (n = 43) groups had comparable demographic characteristics, an average prescription duration of 27 days, and average daily dosages of 1413 and 13 mg, respectively. Patients in the MgO and EXB groups showed different improvement rate of LODD (33% vs. 65%, p < 0.001), absolute changes in FDDV (-0.1 vs. 35 mL, p < 0.0001), and shift rate from STC to NTC (37% vs. 87%, p = 0.003, respectively). CONCLUSIONS AND INFERENCES:EXB demonstrated significantly greater improvements of LODD, rectal sensation, and CTT compared to MgO.

Purpose Hepatic steatosis, which is associated with liver diseases and adverse clinical outcomes, requires accurate, noninvasive diagnostic methods because of the limitations of liver biopsy. This study aimed to evaluate the effectiveness of the ultrasound-guided attenuation parameter (UGAP), a novel technique for assessing hepatic steatosis, and to compare its diagnostic performance with that of the controlled attenuation parameter (CAP), using magnetic resonance imaging (MRI)–derived proton density fat fraction (PDFF) as the reference standard. Methods A total of 255 patients with chronic liver disease who underwent CAP, UGAP, and MRI-PDFF were prospectively enrolled from three liver centers in Japan. Using the area under the receiver operating characteristic curve (AUROC) analysis, cutoff values for UGAP were determined according to steatosis grades based on MRI-PDFF. To minimize overfitting, diagnostic performance was validated using five-fold cross-validation. Results CAP and UGAP values followed normal distributions, whereas PDFF values deviated from normality and were therefore log-transformed, yielding the variable MRI-logPDFF. CAP and UGAP demonstrated significant correlations with MRI-logPDFF, with intraclass correlation coefficients of 0.696 and 0.797, respectively. For MRI-PDFF–based grading, the AUROC (95% confidence interval) values of CAP and UGAP were 0.878 (0.813–0.923) versus 0.926 (0.867–0.960) for S0 versus S1–S3 (P=0.041), 0.820 (0.763–0.865) versus 0.908 (0.861-0.940) for S0–S1 versus S2–S3 (P<0.001), and 0.863 (0.811–0.902) versus 0.897 (0.852-0.930) for S0–S2 versus S3 (P=0.128), respectively. The validation analysis produced results consistent with those of the primary cohort. Conclusion UGAP showed greater diagnostic accuracy than CAP for hepatic steatosis, notably in detecting grades ≥S1 and ≥S2.

BACKGROUND & AIMS:The growing burden of metabolic dysfunction-associated steatohepatitis (MASH) and the urgency for effective therapies have driven the adoption of surrogate endpoints for treatment evaluation. Consensus on the most appropriate measures for regulatory approval, clinical practice, or reimbursement remains limited. This study aimed to establish expert consensus on appropriate surrogate endpoints and potential surrogate outcome measures in MASH. METHODS:A modified Delphi process was conducted with 23 international experts across hepatology, gastroenterology, and others. A targeted literature review informed 2 structured survey rounds. Round 1 addressed measures relevant to establishing efficacy/effectiveness for reimbursement; Round 2 explored their application for monitoring treatment effectiveness in clinical practice. Consensus was defined as ≥75% agreement, and strong consensus as ≥95%. The process was conducted and reported in accordance with established frameworks, including Conducting and REporting DElphi Studies (CREDES). RESULTS:Histological endpoints-specifically, ≥1-stage fibrosis improvement without MASH worsening, and MASH resolution without fibrosis worsening-were considered appropriate for regulatory/reimbursement settings, mostly owing to current regulatory guidelines. In clinical practice, noninvasive tests (NITs) were preferred. There was consensus that a ≥30% reduction in liver stiffness measurement (LSM) assessed via vibration-controlled transient elastography (VCTE) or magnetic resonance elastography (MRE) is a meaningful indicator of treatment response and reasonably likely translates to improved long-term outcome benefit. Consensus also supported replacing liver biopsy with NITs in practice. CONCLUSIONS:This international Delphi study highlights histological and NIT-based measures as key for MASH treatment evaluation. It also supports a shift toward NITs-particularly LSM by VCTE or MRE-for disease monitoring in routine practice, with implications for trial design, reimbursement, and clinical guidelines.

Attenuation Imaging (ATI) and controlled attenuation parameter (CAP) are non-invasive ultrasound-based methods for diagnosing hepatic steatosis. However, reports on the clinical usefulness of ATI are limited. We aimed to compare the ability of ATI and CAP to diagnose hepatic steatosis with magnetic resonance imaging–based proton density fat fraction (MRI-PDFF) as the reference standard. We performed a prospective multicenter study of 562 patients with chronic liver disease who underwent ATI, CAP, and MRI-PDFF. Patients with skin-to-liver capsule distance (SCD) ≤ 25 mm underwent CAP with an M probe; those with SCD > 25 mm underwent CAP with an XL probe. MRI-PDFF was used as the reference standard: S0 corresponds to MRI-PDFF < 5.2

Background & Aims: Radiofrequency ablation (RFA) is the standard treatment for small hepatocellular carcinoma (HCC), specifically for tumors <3 cm in size and numbering fewer than three, excluding surgical candidates. Microwave ablation (MWA) is an innovative approach believed to have theoretical benefits over RFA; however, these advantages are yet to be empirically verified. Therefore, we evaluated and compared the effectiveness of MWA and RFA in managing HCC tumors up to 4 cm in size. Methods: In this multicenter randomized controlled trial conducted across five centers in Japan, eligible participants had up to 4 tumors, each up to 4 cm in size, and were not considered for surgery. Patients were randomly assigned to undergo MWA or RFA. The primary outcome was the rate of local tumor progression (LTP), whereas secondary outcomes included overall survival (OS) and intra- and extrahepatic recurrence-free survival (RFS) at the end of the 2-year follow up. Results: In total, 240 participants were screened from July 12, 2018, to December 7, 2021. Four participants were excluded: three did not meet inclusion criteria, and one died from an unknown cause during treatment. Consequently, 119 (130 lesions) and 117 (136 lesions) participants were treated with MWA and RFA, respectively. The proportion of lesions with LTP at the 2-year follow up was significantly lower in the MWA group (20 [16.4%] lesions) than in the RFA group (38 [30.4%] lesions) (risk ratio, 0.54; p = 0.007). OS and both intra- and extrahepatic RFS did not significantly differ between groups. Conclusions: MWA is more effective than RFA in reducing local tumor progression for HCC tumors up to 4 cm. However, no differences were observed in OS and RFS.

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.