Hepatology Research最新文献

Aim: To identify autoimmune hepatitis (AIH)-specific autoantibodies using a high-content human protein microarray and evaluate their diagnostic performance.

Methods: Pretreatment sera from untreated patients with AIH (n = 68), primary biliary cholangitis (PBC, n = 19), metabolic dysfunction-associated steatotic liver disease (MASLD, n = 39), chronic hepatitis C (CHC, n = 27), and drug-induced liver injury (DILI, n = 18) and healthy controls (HC, n = 37) were screened with a wheat-germ, cell-free microarray displaying > 16,000 proteins. Candidate antigens were validated by ELISA, and antibody titers were correlated with clinical variables, treatment response, and outcomes.

Results: Mitochondrial ribosomal protein S27 (MRPS27) emerged as the dominant AIH-associated antigen. The mean anti-MRPS27 antibody titer in untreated patients with AIH (50.2 AU) exceeded that in patients with PBC (9.3 AU), MASLD (12.8 AU), CHC (24.8 AU), DILI (19.8 AU), and HC (7.5 AU, all p < 0.01). A cutoff of 35.4 AU (HC mean + 2 SD) yielded a sensitivity of 61.8%, a specificity of 87.1%, a positive predictive value of 70.0%, and a negative predictive value of 82.4%. Positivity was unrelated to baseline histology, biochemistry or IgG, and titers were unchanged after corticosteroid induction. Interestingly, patients with low titers experienced more liver-related events during follow-up.

Conclusion: The anti-MRPS27 antibody is a promising adjunctive serological marker that enhances the specificity of AIH diagnosis. The pathogenic significance and prognostic value of this antibody warrant prospective validation.

Aim: We aimed to determine the associations between the pretreatment Advanced Lung Cancer Inflammation Index (ALI) and survival outcomes in patients with unresectable hepatocellular carcinoma (u-HCC) who received atezolizumab plus bevacizumab (Atez/Bev).

Methods: This retrospective study analyzed 563 patients with u-HCC who were treated with Atez/Bev (Sept 2020-Dec 2024). The ALI was calculated according to Body Mass Index × serum albumin level/neutrophil-to-lymphocyte ratio. Associations between ALI and overall survival (OS) and progression-free survival (PFS) were evaluated by Cox proportional hazards regression analysis.

Results: An ALI cutoff value of 27.04, determined by receiver operating characteristic curve analysis, was used to classify patients into low- and high-ALI groups. High-ALI patients had longer median OS (26.1 vs. 13.7 months, p < 0.001) and PFS (9.3 vs. 5.2 months, p < 0.001), and a higher disease control rate (82.5% vs. 69.1%, p < 0.001) compared to low-ALI patients. Multivariate Cox regression analysis confirmed that a high ALI value was a significant prognostic marker for OS (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.54-0.88, p = 0.003) and PFS (HR: 0.75, 95% CI: 0.61-0.92, p = 0.006). Subgroup analyses showed that the trend toward improved outcomes was consistent for high ALI values in all clinically relevant subgroups.

Conclusions: A high pretreatment ALI value was associated with improved survival and disease control in u-HCC patients receiving Atez/Bev, underscoring its potential utility as a prognostic marker for clinical management and further studies.

Aim: Chronic hepatitis B virus (HBV) infection remains a major cause of liver cirrhosis and hepatocellular carcinoma. NASVAC is a therapeutic vaccine containing hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg), which has shown clinical potential to induce loss of HBsAg and acquisition of anti-HBs antibodies. Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan into kynurenine, plays a key role in viral persistence by suppressing effector T cell activity and promoting immunoregulatory pathways. This study aimed to elucidate the role of IDO in modulating immune responses to NASVAC.

Methods: Wild-type and IDO knockout (KO) mice were immunized with NASVAC, and some wild-type mice received an IDO inhibitor. Serum amino acids and anti-HBc and anti-HBs titers, cellular immune responses, splenic CD4/CD8 T cell ratios, and IL-2 production from splenocytes were assessed. Additionally, pretreatment and posttreatment serum samples from NASVAC clinical trial were analyzed for tryptophan and kynurenine levels to assess their association with the efficacy of vaccination.

Results: Genetic deletion of IDO markedly enhanced NASVAC-induced humoral and cellular immune responses in mice, whereas pharmacological inhibition partially increased cellular responses. NASVAC treatment modulated the splenic CD4/CD8 ratio, with more pronounced effects in IDO-KO mice. In human participants, lower pretreatment serum kynurenine level was associated with successful acquisition of anti-HBs following NASVAC administration.

Conclusions: These findings suggest that IDO activity negatively regulates both humoral and cellular immune responses to NASVAC. Modulation or suppression of IDO may potentially enhance the therapeutic efficacy of NASVAC, and serum kynurenine may represent a predictive biomarker for treatment outcomes in chronic HBV infection. REGISTRY AND THE REGISTRATION NO.

Of the study/trial: The clinical trial was registered in the UMIN Clinical Trials Registry (no. UMIN000027442) and the Japan Registry of Clinical Trials (no. jRCTs061180100).

Background: Signal intensity on the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-magnetic resonance imaging (MRI) reflects Wnt/β-catenin signaling activity in hepatocellular carcinoma (HCC), and has been associated with poor response to immune monotherapy. However, whether such imaging findings predict resistance to combination immunotherapy has not been prospectively validated.

Methods: This multicenter prospective study enrolled 152 patients with unresectable HCC treated with atezolizumab plus bevacizumab across 12 Japanese centers. All had Child-Pugh class A liver function and underwent Gd-EOB-DTPA-MRI prior to treatment. Hyperintensity was defined as a relative enhancement ratio ≥ 0.9. Treatment outcomes, including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and time to partial response (TtPR), were compared between patients with and without hyperintense nodules.

Results: Of the 152 patients, 82 received immunotherapy as the first-line and 70 as a later-line therapy. Hyperintense nodules were identified in 57 (37.5%) patients. The hyperintense group showed a higher ORR (36.8% vs. 22.1%) and comparable PFS (8.9 vs. 7.9 months) and OS (16.7 vs. 23.9 months), though not statistically significant. The TtPR was significantly shorter in the hyperintense group (median 26.0 months vs. not reached, p = 0.033), although mainly influenced by prior systemic therapy. Overall, hyperintense lesions were not associated with reduced efficacy and tended to show more favorable responses.

Conclusion: This prospective multicenter study demonstrates that hepatobiliary hyperintensity on Gd-EOB-DTPA-enhanced MRI-an imaging surrogate of Wnt/β-catenin activation-does not indicate resistance to atezolizumab plus bevacizumab. These findings support the use of combination immunotherapy in molecularly "immune-cold" HCC.

Background and aims: Lean metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized; however, its long-term hepatic risk relative to obese MASLD remains elusive. This study evaluated differential risk of progressive hepatic outcomes and identified predictors of adverse outcomes within the lean phenotype.

Methods: A large, multicenter retrospective cohort study was conducted using the TriNetX Global Health Research Network, including adults with noncirrhotic MASLD between 2010 and 2024. Lean MASLD was defined as the body mass index (BMI) < 25 kg/m². Primary analyses compared lean versus nonlean MASLD (BMI ≥ 25 kg/m²), with a prespecified secondary analysis comparing lean versus obese MASLD (BMI ≥ 30 kg/m²), excluding overweight individuals. Outcomes included incident fibrosis, cirrhosis, portal hypertension and related complications, hepatocellular carcinoma (HCC), liver transplantation, and all-cause mortality over 3-year, 5-year, and 10-year follow-up. Propensity score matching and multivariable Cox regression were applied.

Results: Among 1,130,297 patients with MASLD, 229,084 had lean MASLD. After matching, lean MASLD was associated with consistently higher odds of fibrosis, cirrhosis, portal hypertensive complications, HCC, liver transplantation, and mortality compared with nonlean, overweight, and obese MASLD across all time horizons (all p < 0.001). Within the lean MASLD cohort, those with older age, diabetes, hypoalbuminemia, thrombocytopenia, and elevated aspartate aminotransferase independently predicted adverse hepatic outcomes.

Conclusions: Lean MASLD is associated with substantial long-term hepatic morbidity and mortality. Currently, obesity-centered paradigms guide MASLD screening and risk stratification. Thus, efforts should be made to ensure that lean individuals with MASLD are not systematically under-screened or under-surveilled for progressive liver disease as they carry a higher risk of worsening.

Aim: This study evaluated surveillance impact on outcomes in 1143 patients with first-onset hepatocellular carcinoma (HCC) treated between 2003 and 2023, focusing on the etiological shift toward non-B non-C (NBNC) liver disease.

Methods: Patients were stratified by etiology: hepatitis B virus (HBV, n = 182), hepatitis C virus (HCV, n = 555), and NBNC (n = 375). Surveillance was defined as ≥ 1 annual imaging examination. We assessed surveillance impact on overall survival (OS) using multivariable Cox regression analysis and analyzed diagnostic modalities and tumor markers stratified by etiology.

Results: Over the 20-year period, HCV-related HCC decreased whereas NBNC--HCC significantly increased, mainly driven by SLD. A total of 654 patients (58.8%) underwent regular surveillance. Compared with nonsurveilled patients, surveillance patients had significantly higher early-stage diagnosis (79.8% vs. 36.9% and p < 0.001) and curative treatment rates (52.8% vs. 21.6% and p < 0.001). Multivariable analysis confirmed surveillance as an independent prognostic factor for OS (n = 1,085, hazard ratio: 0.61, and p < 0.001). Notably, in the NBNC group, nearly 60% of early-stage cases were detected via CT/MRI, significantly higher than in viral etiologies. Furthermore, des-gamma-carboxy prothrombin (DCP)-only positivity was highest in patients with NBNC (22.4%), whereas AFP-only positivity was rare (4.5%).

Conclusions: Although regular surveillance provides a robust survival benefit independent of liver function, a critical "surveillance gap" persists in the rapidly expanding NBNC population. The high reliance on CT/MRI and DCP in NBNC patients suggests that standard ultrasound and AFP-based strategies may have limitations in this group. Etiology-specific protocols integrating cross-sectional imaging and combined biomarkers warrant further consideration to bridge this gap.

Aim: Systemic therapy is required for unresectable hepatocellular carcinoma (HCC). Atezolizumab plus bevacizumab (ATZ/BEV) is the recommended first-line treatment for HCC; however, the development of anti-drug antibodies (ADAs) against ATZ may impair its therapeutic efficacy. Although ADAs have been reported in other cancers treated with immune checkpoint inhibitors, the incidence and clinical relevance in HCC remain unclear.

Methods: We retrospectively analyzed 50 patients with unresectable HCC who received ATZ/BEV between April 2020 and December 2024. Serum samples were obtained at baseline and after treatment initiation, primarily at the third cycle, and ATZ-ADA levels were measured using ELISA. Tumor response was assessed by modified RECIST, and survival was evaluated by the Kaplan-Meier method and Cox regression analysis.

Results: Median ATZ-ADA levels after treatment initiation were higher in patients with progressive disease than in those with disease control (0.46 vs. 0.37, p = 0.02). Longitudinal analysis demonstrated a greater increase in ATZ-ADA levels from baseline in the progressive group (p = 0.04) than that in the other groups. ROC analysis identified a cutoff of 0.40 for predicting progression (AUC = 0.69), and 17 patients (34%) were classified as ATZ-ADA-positive (OD value ≥ 0.40). Progression-free survival (PFS) was significantly shorter in the ATZ-ADA-positive group than in the ATZ-ADA-negative group (3.8 vs. 9.4 months, HR = 2.24, p = 0.03), whereas no difference was observed in overall survival.

Conclusions: ATZ-ADAs were detected in 34% of patients with unresectable HCC and were associated with inferior PFS. ATZ-ADAs may serve as a promising biomarker for predicting treatment response and optimizing therapeutic strategies in HCC.

Aim: We investigated whether the baseline fibrosis-4 (FIB-4) index stratifies long-term cancer risk in patients with biopsy-proven MASLD and compared its discrimination for HCC and extrahepatic malignancies against other noninvasive fibrosis markers.

Methods: In this single-center retrospective cohort study, 417 adults with biopsy-proven MASLD (2001-2024) were followed for incident malignancy (median follow-up, 4.75 years). Patients were categorized using standard FIB-4 thresholds (< 1.3, 1.3-2.67, ≥ 2.67). Cause-specific Cox models and Fine-Gray competing-risk models were used to estimate adjusted hazard ratios (HRs) for HCC and extrahepatic cancer. Discriminative performance was evaluated using Harrell's C-index and time-dependent area under the curve (AUC) values at 3, 5, and 10 years.

Results: During followup, 24 patients (5.8%) developed HCC, whereas 40 (9.6%) developed extrahepatic cancer. The ≥ 2.67 category was associated with markedly increased risks of HCC (adjusted HR 35.31) and extrahepatic cancer (adjusted HR 13.10) compared with < 1.3. Associations remained robust in competing-risk and age-adjusted sensitivity analyses. FIB-4 showed the highest and most consistent discriminative performance among the evaluated indices (C-indices of 0.83 for HCC and 0.78 for extrahepatic cancer). Time-dependent AUCs improved over time and exceeded 0.80 for HCC after 5 years.

Conclusion: The FIB-4 index provides consistent long-term risk stratification for HCC and shows an association with extrahepatic cancer among commonly used noninvasive fibrosis markers. Its strong time-dependent discrimination for HCC and moderate discrimination for extrahepatic cancer support its potential role as a simple, widely accessible tool for long-term risk stratification in MASLD.