AIM:Radiofrequency ablation (RFA) is curative therapy for early-stage hepatocellular carcinoma (HCC), but a rare subset of patients develop aggressive intrasegmental recurrence shortly after complete ablation. We characterized the incidence, risk factors, and absolute risk. METHODS:This single-center retrospective study included consecutive patients with HCC treated with RFA from August 2002 to December 2024. Rapid progression was defined as recurrence at the ablation margin within 6 months that precluded further locoregional therapy. Cases were matched 1 to 4 with controls based on treatment era, prior RFA sessions, tumor diameter, and tumor number. Preablation imaging and tumor marker dynamics were compared, and absolute risk was estimated. RESULTS:Among 3163 patients who underwent 10,240 RFA treatments, 20 (0.20%) met criteria for rapid progression. Aggressive imaging features including nonsmooth margins (OR 5.87, 95% CI 1.80-19.12) and multinodular confluent growth (OR 3.84, 95% CI 1.30-11.36) were significantly more common in the rapid progression group, though positive predictive values remained below 1%. Irregular rim-like hyperenhancement was present in 15% of rapid progression cases but was absent in all controls. Periportal location accounted for half of the rapid progression cases (OR 2.84, 95% CI 0.97-8.29). Tumor markers including alpha-fetoprotein and des-gamma-carboxy prothrombin declined after RFA in controls but not in the rapid progression group. CONCLUSIONS:Aggressive imaging features and insufficient post-ablation tumor marker decline were associated with rapid progression, though individual predictive value was low. Tumor marker trends may help guide surveillance and earlier transition to systemic therapy.
BACKGROUND:Total ischemic time (TIT) is a key determinant of outcomes after deceased-donor liver transplantation (DDLT). In Japan, the nationwide organ allocation system, which does not include regional prioritization, often requires long-distance graft transport. However, the contributions of transport time, distance, and modality to TIT and post-transplant outcomes have not been fully clarified. METHODS:We performed a nationwide retrospective cohort study of DDLT cases in Japan between July 2019 and December 2023 using data from the Japan Organ Transplant Network. Associations among transport-related factors, TIT, and post-transplant outcomes were assessed. RESULTS:Among the 415 transplant recipients, TIT was significantly correlated with both transport time and transport distance (p < 0.01), although the strength of these correlations varied according to transport modality. Strong correlations were observed for ground and high-speed rail transportation, whereas the correlation was weaker for air transportation. Restricted cubic spline analyses demonstrated strong, monotonic associations between prolonged TIT and increased mortality risk and between prolonged transport time and mortality risk. Prolonged TIT was independently associated with poorer survival in the multivariable analysis, whereas transport time and modality were not. In the analyses stratified by the combination of TIT and transport time, favorable outcomes were observed in cases with a prolonged transport time when TIT was maintained at a lower level. CONCLUSION:Prolonged transport time contributes to increased TIT; however, optimization of perioperative management to minimize TIT may preserve post-transplantation outcomes in long-distance transplantation.
AIM:Although steatotic liver disease (SLD) has been associated with chronic kidney disease (CKD), it remains unclear whether CKD-related outcomes are driven by hepatic steatosis itself or by accompanying cardiometabolic abnormalities. We investigated the relative contribution of hepatic steatosis and cardiometabolic risk factors to CKD-related outcomes using a large Japanese health screening cohort. METHODS:In total, 30,648 SLD and 76,182 non-SLD participants enrolled in the MIRACLE-J cohort across 13 centers in Japan between 2014 and 2018 were analyzed. CKD-related outcomes were defined as reduced estimated glomerular filtration rate (eGFR< 60 mL/min/1.73 m2) and proteinuria. Multivariable logistic regression and trend analyses were performed to identify factors associated with these outcomes. RESULTS:Compared with non-SLD participants, those with SLD exhibited a higher burden of cardiometabolic abnormalities. Type 2 diabetes mellitus, obesity, and hyperuricemia were independently associated with proteinuria, whereas advanced age (≥ 65 years), low alcohol intake, and hyperuricemia were strongly associated with reduced eGFR. After multivariable adjustment, SLD showed an inverse association with CKD-related outcomes. In both SLD and non-SLD populations, the prevalence of CKD-related outcomes increased stepwise with a higher number of cardiometabolic risk factors. Incorporation of hyperuricemia significantly improved model fit for reduced eGFR (Δ-2 log likelihood = 119.4, p < 0.001) and modestly improved model fit for proteinuria (p = 0.002). CONCLUSIONS:CKD-related outcomes were more strongly associated with the burden of cardiometabolic abnormalities than with hepatic steatosis itself, and these associations were consistent in individuals with and without SLD. Hyperuricemia provided incremental value for renal risk stratification within this cardiometabolic framework, underscoring the importance of comprehensive metabolic risk assessment beyond liver fat status.
BACKGROUND AND AIM:Immune checkpoint inhibitor (ICI)-induced liver injury is a clinically important adverse event that may lead to interruption of anticancer therapy. Although systemic corticosteroids are recommended for severe cases, the optimal corticosteroid tapering strategy for relapse prevention and subsequent ICI rechallenge has not been established. We evaluated the clinical outcomes of an empirical institutional gradual corticosteroid tapering strategy developed with reference to Japanese AIH management. METHODS:We retrospectively analyzed 36 consecutive patients with grade ≥ 3 ICI-induced liver injury. Prednisolone (PSL) was generally initiated at 0.8 mg/kg/day and tapered gradually at a rate of 5 mg every 2 weeks. Steroid pulse therapy was selectively administered in patients with severe liver injury with signs of liver failure. The primary endpoint was relapse during corticosteroid tapering. RESULTS:Liver injury improved in 35 of 36 patients (97%). The median duration required to taper PSL to ≤ 10 mg/day was 73 (range, 50-168) days. Relapse during corticosteroid tapering occurred in only 1 patient (3%), and no patients required additional immunosuppressive therapy, including mycophenolate mofetil. ICI rechallenge was performed in 13 patients, including 6 with prior CTCAE grade 4 liver injury, and recurrence after rechallenge occurred in only 1 patient (8%). Histopathological findings were characterized predominantly by lobular inflammation with CD8-positive T-cell infiltration, whereas classical autoimmune hepatitis-associated features were relatively limited. CONCLUSIONS:An empirical gradual corticosteroid tapering strategy developed with reference to Japanese AIH management may contribute to relapse prevention and facilitate ICI rechallenge in patients with ICI-induced liver injury.
AIM:Alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) are widely used tumor markers for hepatocellular carcinoma (HCC); however, their relative prognostic significance in early-stage disease remains unclear. This study aimed to compare the prognostic impact of AFP and DCP in resected HCC and to explore their underlying molecular characteristics. METHODS:We retrospectively analyzed 482 patients who underwent curative resection for HCC. Patients were classified into four groups according to AFP and DCP levels: Negative, AFP-only, DCP-only, and Dual-positive. Recurrence-free survival (RFS) and prognostic factors were evaluated. In a subset of 204 patients, gene expression profiling was conducted to investigate molecular differences. RESULTS:Among BCLC stage 0/A patients (n = 406), RFS was stratified according to tumor marker status. The DCP-only group showed significantly worse RFS than the AFP-only group (5-year RFS: 39.5% vs. 52.7%, p = 0.026) and was characterized by larger tumor size (median, 39 vs. 18 mm, p < 0.001) and more frequent portal venous invasion (29% vs. 14%, p = 0.052). Multivariable analysis identified elevated DCP as an independent prognostic factor (hazard ratio 1.48, p = 0.004). In contrast, among stage B/C patients (n = 76), survival outcomes were uniformly poor and not stratified by tumor marker. Gene expression analysis revealed the upregulation of SFN and downregulation of DCN in DCP-elevated tumors, suggesting extracellular matrix destabilization that may contribute to tumor aggressiveness. CONCLUSIONS:Elevated DCP reflects aggressive tumor biology and identifies patients at high risk of recurrence after resection for BCLC stage 0/A HCC. These findings support the clinical utility of DCP for risk stratification and postoperative surveillance for early-stage HCC.
AIM:To investigate the expression and clinicopathological significance of indoleamine 2,3-dioxygenase 1 (IDO-1) in primary biliary cholangitis (PBC), particularly its potential role as an adjunctive histopathological marker for diagnosis in early or atypical cases and as an indicator of disease activity. METHODS:We retrospectively analyzed 83 liver biopsy specimens from patients clinically diagnosed with or suspected of having PBC between 2016 and 2025. IDO-1 expression in interlobular bile ducts was assessed by immunohistochemistry and correlated with clinical, biochemical, and histological features, including a new histological staging and grading system for PBC. Statistical analyses included univariate and multivariate logistic regression, and a subgroup analysis was performed for patients receiving ursodeoxycholic acid (UDCA). RESULTS:IDO-1 was expressed in 64 of 83 cases (77.1%). Our multivariate analysis identified UDCA treatment (OR = 0.105, 95% CI: 0.0138-0.794, p = 0.029) and the cholangitis activity (CA) score (OR = 2.91, 95% CI: 1.18-7.18, p = 0.021) as independent predictors of IDO-1 expression. IDO-1 positivity was significantly reduced in UDCA-treated patients (50.0%) compared with untreated patients (95.9%, p < 0.0001). In the UDCA subgroup, unlike other histological features, IDO-1 expression remained significantly associated with higher CA scores. CONCLUSIONS:IDO-1 reflects active cholangitis rather than chronic damage such as fibrosis or bile duct loss. It is a sensitive marker of dynamic immune activity that may serve as an adjunctive histopathological marker.
AIM:Evidence concerning the long-term efficacy of nalmefene in alcohol-related liver disease (ALD) remains insufficient, particularly regarding gut microbiota alterations. This study evaluated the 12-month effects of nalmefene on alcohol consumption, liver function, and microbiota in the gut of patients with ALD. METHODS:This single-center retrospective study comprised 15 patients with ALD and alcohol consumption disorder who received nalmefene for 12 months. We investigated the changes in heavy drinking days, total alcohol consumption, and drinking risk level. Liver function parameters and adverse events were assessed longitudinally. Gut microbiota composition was analyzed at baseline and at 12 months. RESULTS:Both heavy drinking days and total alcohol consumption showed a significant reduction from month 4 and were maintained through month 12. Drinking risk level improved in 7 patients (46.7%) and showed no change in 8 (53.3%), with no worsening. Liver enzymes, including aspartate aminotransferase and γ-glutamyl transpeptidase, showed marked improvement, whereas hepatic functional reserve parameters remained stable. At the phylum level, a significant decrease in Proteobacteria, accompanied by a Klebsiella reduction at the genus level, was observed after treatment. No significant differences were observed in α-diversity indices. Adverse events were generally mild, occurred predominantly within the first month, and did not increase in severity over the long term. CONCLUSIONS:Nalmefene was linked to sustained reductions in alcohol intake and improvements in liver enzyme levels over 12 months in patients with ALD. It may also play a role in beneficial modulation of the gut microbiota. Larger studies are required to validate these findings.
PURPOSE:Biliary atresia is a cholestatic liver disease that causes persistent inflammation and reduces the hepatic reserve. New therapeutic concepts are crucial to improve native liver survival. We investigated whether imeglimin, a mitochondria-targeting agent, has hepatoprotective effects on cholestatic liver disease using a murine bile duct ligation (BDL) model. METHODS:BDL was performed in 4-5-week-old mice. After BDL, the mice received intraperitoneal imeglimin or vehicle injections. Sham-operated mice received vehicle. Blood and liver samples were collected on days 7 and 14 for biochemical and histological analysis. Mitochondrial morphology was examined by transmission electron microscopy. Quantitative PCR and immunoblotting were performed for inflammation and mitochondrial stress markers. Metabolomic profiling was conducted using capillary electrophoresis-mass spectrometry. Transcriptome was analyzed by RNA sequencing. Seahorse assays, ATP quantification, and MitoSOX staining were used to evaluate mitochondrial function and oxidative stress. RESULTS:Imeglimin improved survival after BDL, and reduced serum AST, ALT, and bilirubin levels. Tissue fibrosis and Col1a1 and Acta2 expression were attenuated in imeglimin-treated livers. Glycolysis, amino acid metabolism, and mitochondrial electron transport activity were enhanced. Expression of genes associated with mitochondrial function, antioxidant defense, and metabolic regulation was upregulated. Mitochondrial morphology was preserved, and mitochondrial number and size increased. Imeglimin elevated oxygen consumption, extracellular acidification rates, and ATP levels of BDL mice livers, while reducing mitochondrial superoxide and oxidative protein modification by 4-hydroxynonenal. Expression levels of Il1β, Il6, and Tnf decreased. CONCLUSION:Imeglimin exerted hepatoprotective effects on BDL-operated mice, which are associated with preserved mitochondrial bioenergetic function and reduced oxidative stress.
BACKGROUND AND AIMS:Patients with chronic hepatitis C and advanced fibrosis remain at substantial risk of hepatocellular carcinoma (HCC) and non-liver-related death even after sustained virological response (SVR) to direct-acting antivirals (DAA). Serum agalactosyl IgG (agal-IgG) reflects chronic inflammation and fibrogenic activity, but its prognostic value after SVR is unknown. We investigated whether serum agal-IgG at end of treatment (EOT) predicts HCC and all-cause mortality in DAA-treated patients with advanced fibrosis. METHODS:Among 3550 patients with chronic hepatitis C treated with DAAs at Osaka University Hospital and affiliated centers, the stored sera of 136 patients with biopsy-proven F3-F4 fibrosis before DAA treatment, who achieved SVR, and had no history of HCC were available at EOT. Serum agal-IgG at EOT was measured using a 42B1-based ELISA. RESULTS:During a median follow-up of 68.7 months (interquartile range, 36.8-84.9) for HCC surveillance, 15 patients developed HCC. Over a median overall follow-up of 73.7 months (54.5-86.7), 11 patients died. Higher EOT agal-IgG levels were significantly associated with both HCC occurrence and all-cause mortality, and these associations remained independent after adjustment for age, sex, and baseline fibrosis (FIB-4 index). The adjusted hazard ratios per 1-unit increase in agal-IgG were 1.050 (95% CI, 1.008-1.094) for HCC and 1.085 (95% CI, 1.035-1.137) for all-cause mortality. Patients with EOT agal-IgG levels above the cohort median also showed significantly higher cumulative incidences of HCC and all-cause death than those with lower levels. CONCLUSIONS:Serum agalactosyl IgG measured at the end of DAA therapy independently predicts HCC and all-cause mortality after SVR in patients with chronic hepatitis C and advanced fibrosis. EOT agal-IgG may offer additional prognostic information for post-SVR risk stratification and help identify patients at higher risk of HCC and all-cause mortality after SVR.
BACKGROUND AND AIMS:Visceral adipose tissue (VAT) contributes to MASLD pathophysiology via the portal circulation, and weight loss is a cornerstone of treatment; however, its effect on skeletal muscle remains unclear. This study evaluated intra-abdominal area (IAA) at the superior mesenteric artery (SMA) level-a site capturing periportal adipose tissue-and examined the association between weight loss and muscle loss in non-cirrhotic obese chronic liver disease (CLD). METHODS:IAA and paraspinal muscle area were quantified by MRI at the SMA level. Longitudinal changes in IAA, muscle mass, proton density fat fraction (PDFF), ALT, and liver stiffness (LS) were annualized. Cross-sectional associations were evaluated in the overall cohort (BMI ≥ 25 kg/m2, n = 286); longitudinal relationships were assessed in CLD undergoing lifestyle intervention (n = 141, median follow-up: 36 months). RESULTS:In the cohort (MASLD 60%), IAA was independently associated with lower muscle mass and higher LS beyond FIB-4. In the longitudinal cohort, IAA reduction was independently associated with improvements in PDFF and LS, whereas muscle mass declined nonlinearly with greater IAA reduction (R2 = 0.336, p < 0.001). In MASLD, a ≥ 4% IAA reduction significantly improved PDFF, ALT, and LS but was accompanied by muscle loss (-3.9%/y), whereas albumin remained unchanged (p = 0.968). CONCLUSIONS:In obese CLD, IAA at the SMA level serves as a practical marker of periportal VAT. Although its reduction benefits the liver, it may be accompanied by muscle loss. Preserved serum albumin does not exclude ongoing skeletal muscle catabolism. Enhanced protein intake during weight loss may help mitigate muscle catabolism.
BACKGROUND AND AIM:Epithelial-myoepithelial carcinoma (EMC), a malignant tumor with biphasic epithelial and myoepithelial differentiation, is typically a salivary gland neoplasm. Contrastingly, myoepithelial carcinoma (MEC) predominantly comprises myoepithelial cells. In salivary gland pathology, biphasic ductal tumors are classified as EMC, even with a predominant myoepithelial component. Primary hepatic tumors showing myoepithelial and epithelial-myoepithelial differentiation are rare, with uncertain definition and clinical behavior owing to limited reported hepatic carcinoma with MEC/EMC spectrum cases. Here, we report a unique case with intrahepatic recurrence that was successfully managed with repeat hepatectomies. CASE:A 66-year-old woman presented with pain in the right hypochondrium. Imaging revealed a 13 cm tumor in the right hepatic lobe, and biopsy suggested squamous cell carcinoma. After portal vein embolization, right trisectionectomy was performed. Histopathology revealed a biphasic structure with duct-forming epithelial cells surrounded by myoepithelial cells, confirming hepatic carcinoma with epithelial-myoepithelial differentiation. After 2 years, multiple intrahepatic recurrences without extrahepatic disease were detected and repeat hepatectomies were performed. The patient remains recurrence-free 1 year post-reoperation. CONCLUSIONS:Hepatic carcinoma with epithelial-myoepithelial differentiation is rare, with uncertain definition and clinical behavior. Careful exclusion of extrahepatic primaries, detailed immunophenotyping, and long-term surveillance are essential. Repeat hepatectomies may be a curative option for intrahepatic recurrence in selected patients.
AIM:Early mobility impairment is increasingly recognized as an early manifestation of systemic and metabolic dysfunction. Although metabolic dysfunction-associated steatotic liver disease (MASLD) is considered a hepatic component of metabolic disease, its association with early functional decline remains unclear. We investigated whether early mobility impairment is associated with MASLD in a large health examination cohort. METHODS:This retrospective cross-sectional study included 7776 adults who underwent abdominal ultrasonography and mobility assessment. MASLD was defined as hepatic steatosis, at least one cardiometabolic risk factor, and alcohol intake below the established thresholds. Early mobility impairment was assessed using the locomotive syndrome framework based on the stand-up test, two-step test, and 25-question Geriatric Locomotive Function Scale. Multivariable logistic regression analyses were performed after adjusting for demographic, lifestyle, and comorbidity factors. RESULTS:MASLD was present in 27.5% of participants. Early mobility impairment was more frequent in participants with MASLD than in those without MASLD (29.4% vs. 22.5%; p < 0.001). In the fully adjusted model, early mobility impairment was independently associated with MASLD (odds ratio 1.54, 95% confidence interval 1.36-1.74; p < 0.001). Using modified Poisson regression with robust variance, the association remained significant in the same direction as that of the logistic regression models (prevalence ratio 1.315, 95% CI 1.215-1.424; p < 0.001). The association was stronger in participants aged < 65 years than in those aged ≥ 65 years (p for interaction = 0.0097). CONCLUSIONS:Early mobility impairment was independently associated with MASLD. Incorporating mobility-oriented assessments into MASLD care may broaden risk evaluation.
BACKGROUND AND AIMS:Primary biliary cholangitis (PBC) frequently impairs health-related quality of life (HRQOL); however, longitudinal changes in symptoms and their relationship with prognosis remain unclear. We aimed to elucidate the current status of symptoms and HRQOL in Japanese patients with PBC, evaluate 10-year changes in PBC-40 scores, and examine associations with long-term outcomes. METHODS:This multicenter observational study comprised three analyses: (i) a 2025 cross-sectional study assessing associations between clinical parameters, PBC-40 (symptom indicators), and EQ-5D-5 L (HRQOL indicators); (ii) a longitudinal PBC-40 study comparing scores from 2015 to 2025; and (iii) a longitudinal outcome study evaluating 2015 PBC-40 scores and clinical parameters in relation to survival through 2025. RESULTS:In 2025%, 20%-50% of all patients (n = 239) had moderate/severe PBC-40 scores in each domain. EQ-5D-5L scores were significantly lower in women < 59 years versus general population, with multivariable analysis identifying itch, fatigue, and social domains as independent contributors to impaired HRQOL. Across a 10-year follow-up, overall significant deterioration was observed in symptoms (p = 0.0015), itch (p = 0.0039), and cognitive (p = 0.0011) domains, while interindividual variability was greatest in itch and emotional and smallest in symptoms. In longitudinal outcome study (n = 410), no PBC-40 domain predicted death or liver transplantation. CONCLUSIONS:HRQOL in patients with PBC was significantly impaired in younger female. Over 10 years, overall and interindividual changes in domain scores greatly varied, suggesting that symptom burdens are driven by heterogeneous underlying mechanisms. HRQOL impairment represents distinct dimensions of disease impact in PBC, independently of long-term outcomes.
BACKGROUND AND AIM:Atezolizumab plus bevacizumab (Atez/Bev) and durvalumab plus tremelimumab (Dur/Tre) are widely used first-line immune checkpoint inhibitor (ICI)-based regimens for unresectable hepatocellular carcinoma (uHCC). However, reliable biomarkers to inform treatment choice remain limited. This study evaluated whether the simplified BALAD-based score (BALAD-S) is associated with differential treatment outcomes. MATERIALS AND METHODS:This multicenter retrospective study included 752 Japanese patients with uHCC who received first-line Atez/Bev (n = 645) or Dur/Tre (n = 107) between October 2020 and March 2026. BALAD-S was calculated using bilirubin, albumin, AFP, AFP-L3, and des-γ-carboxy prothrombin, and patients were stratified into BALAD-S low (≤ 2) and high (≥ 3) groups. Treatment response, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS:In the BALAD-S low group, Atez/Bev showed longer PFS than Dur/Tre (10.5 vs. 4.3 months; p < 0.001), with longer OS also observed (28.3 vs. 19.4 months; p = 0.049). In the BALAD-S high group, PFS did not differ significantly (7.0 vs. 5.3 months with Dur/Tre and Atez/Bev, respectively, p = 0.210), whereas OS was longer with Dur/Tre than with Atez/Bev (27.3 vs. 16.4 months; p = 0.022). Treatment effects differed by BALAD-S category (HR for Dur/Tre vs. Atez/Bev: 1.50 in BALAD-S low and 0.55 in BALAD-S high; p for interaction = 0.005). In patients treated from 2023 onward, similar treatment-effect heterogeneity was observed (HR 1.61 in BALAD-S low and 0.59 in BALAD-S high; p for interaction = 0.007). CONCLUSION:Outcomes with Atez/Bev and Dur/Tre differed according to BALAD-S score. BALAD-S may help identify patients with differential outcomes between first-line ICI-based regimens and represents a candidate stratification marker requiring validation.
BACKGROUND AND AIM:Pemafibrate, a selective PPARα modulator (SPPARMα), improves cholestatic liver enzymes in primary biliary cholangitis (PBC). However, whether these effects depend on PBC-specific autoimmune mechanisms or reflect broader anti-cholestatic actions remains unclear. This study evaluated the effects of pemafibrate on cholestatic markers by PBC status and explored bile acid and immunological changes in patients with PBC. METHODS:This post hoc analysis used data from a 52-week phase III study of pemafibrate in patients with hypertriglyceridemia, including 9 with PBC. Cholestatic markers (ALP, total bilirubin, GGT, and LAP) were assessed serially. Linear regression examined associations between baseline levels and response by PBC status. In patients with PBC, bile acids, FGF19, FGF21, C4, IgM, IgG, and M2BPGi were also evaluated. RESULTS:Pemafibrate significantly reduced all cholestatic markers from week 4-52, regardless of the presence of PBC. Greater reductions were observed in patients with higher baseline levels. In patients with PBC, C4 decreased without significant change in FGF19, suggesting suppression of de novo bile acid synthesis independent of intestinal feedback. The bile acid profile shifted toward a more hydrophilic composition with reduced hydrophobic species. IgM, IgG, and M2BPGi decreased, whereas FGF21 increased. CONCLUSIONS:Pemafibrate improved cholestatic markers in a baseline-dependent manner, regardless of the presence of PBC, suggesting mechanisms beyond PBC-specific pathology. These findings support a broader anti-cholestatic effect, potentially mediated by coordinated modulation of bile acid metabolism and immunological activity through PPARα activation. TRIAL REGISTRATION:The trials were registered at ClinicalTrials.gov under the identifiers NCT04716595.
BACKGROUND:Obesity is a known risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and cirrhosis, but the long-term effects of childhood thinness and body size changes across life are unclear. We aimed to assess how body size and child-to-adult body size trajectories relate to major liver outcomes. METHODS:We studied 375,125 UK Biobank participants without liver disease at baseline. Childhood body size (thinner, average, and plumper) and adulthood body size (normal, overweight, and obesity) were combined into nine trajectories. Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MASLD and cirrhosis. Kaplan-Meier survival curves assessed the association between body size trajectories and liver diseases. Sensitivity and subgroup analyses tested robustness. RESULTS:Compared with average childhood body size, childhood thinness was associated with higher risks of MASLD (HR 1.18, 95% CI 1.11-1.27) and cirrhosis (HR 1.15, 95% CI 1.03-1.27). Relative to persistently normal body size, the "thinner to obesity" trajectory showed the greatest risks of MASLD (HR 3.95, 95% CI 3.29-4.76) and cirrhosis (HR 3.97, 95% CI 3.30-4.77). The "plumper to normal" trajectory was not associated with increased MASLD or cirrhosis. CONCLUSION:Childhood thinness is associated with increased risks of MASLD and cirrhosis in adulthood. Achieving a normal BMI in adulthood may mitigate liver-related risks linked to childhood overweight.
BACKGROUND AND AIM:Sarcopenia is associated with poor outcomes in patients with chronic liver disease (CLD), but current screening based on reduced muscle strength may fail to identify early skeletal muscle loss. This study aimed to develop a risk-estimation model for identifying patients at risk of early skeletal muscle mass loss before patients meet the diagnostic criteria for overt sarcopenia. METHODS:This retrospective study included 1276 CLD patients who underwent handgrip strength testing and computed tomography-based skeletal muscle index (SMI) assessment between 2015 and 2026. SMI ratio and grip ratio were defined as relative deviations from sex-specific reference values established by the Japan Society of Hepatology. Early skeletal muscle mass loss was defined as an SMI ratio < 0.05. A multivariable logistic regression model incorporating grip ratio, age, sex, platelet count, albumin-bilirubin score, creatinine, body mass index, hepatocellular carcinoma status, and the interaction between grip ratio and sex was developed (MYO-SCAN score). RESULTS:The model demonstrated good discrimination for identifying patients with an SMI ratio < 0.05 with an area under the receiver operating characteristic curve (AUC) of 0.847. The optimal cutoff value was 0.435, yielding sensitivity and specificity of 0.777 and 0.764, respectively. Risk-estimation performance was significantly superior to grip ratio alone (AUC 0.847 vs. 0.614, p < 0.001). Bootstrap validation showed minimal optimism with an optimism-corrected AUC of 0.843. CONCLUSION:The MYO-SCAN score may facilitate early identification of CLD patients at risk of skeletal muscle mass loss, including those who may be overlooked by grip-strength-based screening.
AIM:Avacopan is an oral C5a receptor antagonist approved for anti-neutrophil cytoplasmic antibody-associated vasculitis. Recent post-marketing safety information has raised concern regarding serious hepatobiliary injury, including vanishing bile duct syndrome (VBDS). We compared Japanese and FAERS post-marketing reporting profiles for avacopan-associated adverse events. METHODS:FAERS public dashboard data and PMDA CSV data downloaded in May 2026 were searched using Japanese and English avacopan/Tavneos terms and analyzed at the case report and adverse-event/preferred-term row levels. FAERS Public Dashboard aggregate data were searched using the avacopan generic-name listing as the primary definition and the Tavneos product-name listing as a sensitivity definition. RESULTS:PMDA/JADER contained 397 avacopan-related reports and 744 adverse-event/preferred-term rows. FAERS contained 5770 reports in the avacopan generic-name listing and 5216 reports in the Tavneos product-name listing. Hepatobiliary preferred terms were prominent in PMDA/JADER, including hepatic function abnormal (n = 86), liver disorder (n = 44), drug-induced liver injury (n = 40), and VBDS (n = 29). Among PMDA/JADER VBDS reports with available dates, the median time to onset was 44.0 days (interquartile range, 39.5-52.0). CONCLUSIONS:Post-marketing reports of avacopan-associated hepatobiliary injury, including VBDS, warrant clinical attention, particularly during the early treatment period. PMDA/JADER and FAERS findings should be interpreted as differences in reporting profiles rather than direct comparisons of incidence or risk.
