Hepatology Research最新文献

Background: Alcohol consumption and metabolic dysfunction are risk factors for esophageal squamous cell carcinoma (ESCC); however, their combined effects on recurrence remain unclear. This study aimed to evaluate whether metabolic dysfunction-associated steatotic liver disease (MASLD) with moderate alcohol intake (MetALD) independently contributes to ESCC recurrence following curative endoscopic submucosal dissection (ESD).

Methods: We conducted a multicenter cohort study involving 63 moderate drinkers with early-stage ESCC who underwent curative ESD. MetALD was defined as MASLD with moderate alcohol consumption. Recurrence-free survival was compared between patients with MetALD and those without steatotic liver disease. Multivariable Cox regression, decision tree, random forest analyses, and directed acyclic graphs assessed independent predictors of recurrence.

Results: During a median follow-up of 2.3 years, 25.4% of patients experienced recurrence. Multivariable analyses identified alcohol non-abstinence and MetALD as independent predictors. In supplementary analyses, hepatic steatosis and alcohol non-abstinence-but not metabolic dysfunction alone-were significantly associated with recurrence. Decision tree and random forest analyses highlighted alcohol non-abstinence and MetALD as the most influential predictors. Directed acyclic graphs demonstrated direct causal pathways from both factors to ESCC recurrence. Among non-abstinent patients, those with MetALD had a markedly higher recurrence rate (54%) compared with moderate drinkers without SLD (27%), underscoring the synergistic oncogenic effect of alcohol and metabolic dysfunction.

Conclusions: MetALD is an independent risk factor for ESCC recurrence after curative ESD, especially among non-abstainers. These findings suggest the synergistic oncogenic potential of moderate alcohol intake and MASLD, and underscore the importance of lifestyle and metabolic interventions in post-ESD management.

Chronic liver disease (CLD), including metabolic dysfunction-associated steatotic liver disease (MASLD), has emerged as a major public health concern. As CLD often progresses silently to cirrhosis and hepatocellular carcinoma, early detection and timely intervention are crucial. A significant gap exists between clinical risk perception and low public awareness regarding elevated alanine aminotransferase (ALT) levels. To address this discrepancy, the Japan Society of Hepatology launched the “Nara Declaration,” a nationwide initiative promoting a new clinical action: “Consult a primary care physician if ALT level is > 30 U/L.” The Nara Declaration proposes a clear clinical pathway. Individuals with ALT > 30 U/L are directed to a primary care physician who assesses the underlying etiology, including viral hepatitis, MASLD, alcohol-related liver disease, or autoimmune liver diseases. For patients with suspected MASLD, physicians utilize the FIB-4 index or platelet count to stratify the risk of advanced fibrosis. Patients identified as high risk are then referred to a gastroenterologist/hepatologist for further evaluation and management. This structured approach is significant, as it establishes a systematic and collaborative framework between primary care physicians and gastroenterologists/hepatologists. This system enables the early detection of CLD and facilitates timely intervention for individuals at risk of disease progression. Accordingly, this declaration has the potential not only to reduce CLD-related mortality and medical costs but also to improve healthy lifespans and social productivity. This special article outlines the Nara Declaration, providing a comprehensive overview. Furthermore, we introduce recent clinical studies that examine the impact of the Nara Declaration.

Aim: The incidence of nonviral hepatocellular carcinoma (N-HCC) is increasing due to improvements in hepatitis control. Patients are often diagnosed at an advanced stage owing to a lack of surveillance systems. We previously reported the usefulness of a liquid biopsy test based on a sensitive methylated septin 9 (m-SEPT9) assay for detecting HCC. In this study, we validated the diagnostic ability of m-SEPT9 and developed a novel integrated index to improve HCC prediction.

Methods: A total of 1450 samples (464 healthy individuals, 202 patients with chronic liver disease without HCC, and 784 patients with HCC) were analyzed using the combined restriction digital polymerase chain reaction assay for m-SEPT9.

Results: The sensitivity and specificity of m-SEPT9 were 68.1% (95% confidence interval [CI], 0.649-0.714) and 84.9% (95% CI: 0.817-0.882), respectively, with an area under the curve (AUC) of 0.831; however, the lower limit of the 95% CI for specificity did not exceed the threshold of our setting (> 85%). Multivariable analysis identified age, sex, des-gamma carboxy prothrombin, alpha-fetoprotein, and m-SEPT9 as independent diagnostic markers. Based on these markers, the ASDAm-S9 index was developed, demonstrating a sensitivity of 89.9% and specificity of 90.9% (healthy individuals vs. HCC, AUC: 0.961), regardless of HCC etiology or stage.

Conclusions: The diagnostic performance of m-SEPT9 alone could not be fully verified; however, the ASDAm-S9 index demonstrated excellent accuracy for detecting HCC, including its early stages. This index shows promise as a blood-based cancer screening tool for early-stage HCC in the general population.

Aim: To investigate whether lymphocyte-to-monocyte ratio (LMR) can predict outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with durvalumab plus tremelimumab (Dur/Tre).

Methods: A total of 70 patients with unresectable HCC treated with Dur/Tre were included. Survival and adverse events were analyzed in this cohort.

Results: The median progression-free survival (PFS) was 2.8 months (95% confidence interval [CI]: 2.1-8.8) and the median overall survival (OS) was 16.2 months (95% CI: 11.1-not reached [NR]). PFS and OS in the low/high LMR group were 2.3 (95% CI: 1.6-3.8)/3.3 (95% CI: 2.4-6.9) months (p = 0.042) and 11.4 (95% CI: 4.5-NR)/NR (95% CI: 16.2-NR) months (p = 0.001), respectively. The hazard ratio (HR) for PFS in the high LMR group, adjusted for inverse probability weighting (IPW), was 0.556 (95% CI: 0.285-1.084, p = 0.085), and the HR for OS was 0.155 (95% CI: 0.045-0.538, p = 0.003). The distribution of response was 2.9% for complete response, 20.0% for partial response, 28.6% for stable disease, and 37.1% for progressive disease, with no significant difference by LMR. Regarding adverse events, immune-related liver injury of any grade differed significantly among patients with low and high LMR. HR spline curve analysis for OS showed that when LMR ranged from approximately 2.5-4.0, the upper limit of the 95% CI remained at or below 1.

Conclusions: LMR can predict outcomes in patients with unresectable HCC treated with Dur/Tre. An appropriate LMR cutoff for predicting OS ranges from approximately 2.5-4.0.

Background and aims: Genetic polymorphisms in alcohol dehydrogenase 1 B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) modify susceptibility to alcoholic cirrhosis. This study investigated the association between the polymorphisms and patients' self-recognition of their genetic predisposition.

Methods: We enrolled 50 patients with alcoholic cirrhosis, 46 patients with nonalcoholic cirrhosis, and 25 healthy controls without liver disease between January 2024 and March 2025. The ADH1B and ALDH2 genotypes were determined from dried saliva samples using SNP analysis, and the participants predicted their genotypes prior to testing.

Results: Self-recognition accuracy was 70.0% for alcoholic cirrhosis, 89.1% for nonalcoholic cirrhosis, and 92.0% for controls (p < 0.05). ALDH2 wild-type was present in 90.0% of patients with alcoholic cirrhosis versus 30.4% of patients with nonalcoholic cirrhosis (p < 0.01). The inactive ALDH2 genotype (*2/*2) was observed in 6.5% of patients with nonalcoholic cirrhosis, but not in those with alcoholic cirrhosis.

Conclusions: ALDH2 wild-type was associated with alcoholic cirrhosis; however, 30% of patients misjudged their genotypes. Early genetic screening may improve self-awareness and contribute to preventive strategies for alcoholic cirrhosis.

Introduction: Recurrent hepatocellular carcinoma (HCC) after hepatectomy remains a major clinical challenge, necessitating effective prognostic stratification. The oncological resectability criteria recently proposed by the Japan Liver Cancer Association and the Japanese Society of Hepato-Biliary-Pancreatic Surgery have not yet been validated in recurrent settings. This study aimed to evaluate the prognostic utility of these criteria in patients with recurrent HCC after hepatectomy.

Methods: This retrospective study included 505 patients with recurrent HCC following initial hepatectomy. Patients were classified into three groups-resectable (R), borderline resectable 1 (BR1), and borderline resectable 2 (BR2)-based on the oncological resectability criteria. Post-recurrence survival was evaluated using the Kaplan-Meier method, and multivariate analysis was performed to identify clinical factors associated with post-recurrence survival.

Results: Among the 505 patients, 248 patients were classified as R, 80 as BR1, and 177 as BR2. The median post-recurrence survival was 73.4 months for the R group, 33.6 months for the BR1 group, and 12.4 months for the BR2 group (p < 0.001). Multivariate analysis identified BR1/BR2 classification (p < 0.001), modified albumin-bilirubin grade 2b or 3 (p < 0.001), and recurrence within 1 year (p = 0.004) as independent predictors of poor post-recurrence survival.

Conclusions: The oncological resectability criteria effectively stratified post-recurrence survival in patients with recurrent HCC. These findings suggest that a multidisciplinary approach may benefit patients with BR1 or BR2 recurrence. Further studies are warranted to explore optimal treatment strategies for recurrent HCC.

Background and aims: Hepatocellular carcinoma (HCC) management has markedly evolved in Japan. We evaluated temporal changes in patient characteristics and outcomes between 2004-2013 and 2014-2023.

Methods: In this multicenter retrospective study, 7275 treatment-naïve HCC patients were analyzed (3832 vs. 3443). Propensity score matching (PSM) for age, sex, albumin-bilirubin (ALBI) score, and viral status yielded 4754 patients. Overall survival (OS) was compared by the Barcelona Clinic Liver Cancer (BCLC) stage and treatment modality. Cox regression identified independent prognostic factors.

Results: After PSM, baseline characteristics were balanced. OS significantly improved in BCLC-0/A patients in 2014-2023 (p < 0.0001), but not in BCLC-B, C, or D. Among BCLC-A patients, surgical resection (p = 0.0042) and ablation (p = 0.0019) showed improved outcomes in the recent era, whereas TACE and systemic therapy did not. Subgroup analysis revealed survival gains were confined to viral HCC, with minimal improvement in nonviral HCC. Multivariate analysis confirmed the recent era (HR 0.800, 95%CI 0.658-0.972, p = 0.025), curative therapy, and ALBI score as independent prognostic factors.

Conclusions: Survival outcomes in Japan improved primarily for early-stage viral HCC, reflecting advances in curative treatments and antiviral management. Nonviral HCC showed minimal improvement, highlighting the need for novel therapeutic strategies for this growing population.

Clinical trial registration: This study is a retrospective study using anonymized database data, and clinical trial registration was not performed.

Background: Alcohol consumption in patients with steatotic liver disease (SLD) with metabolic dysfunction (MD) increases the risk of liver fibrosis and mortality. However, whether these risks vary by age remains poorly understood.

Methods: Data from NHANES-III were used, including participants with data on SLD, alcohol consumption, and mortality. SLD was determined using ultrasonography, MD was defined according to the guidelines as ≥ 1 metabolic risk factor, and mild-to-moderate alcohol consumption as 10-50 g/day (females) or 20-60 g/day (males). Mortality data were obtained from the National Death Index until December 31, 2015. The impact of SLD with MD and alcohol consumption on mortality was evaluated using multivariable Cox regression, including age (categorized as 20-< 40, 40-< 60, and 60-< 80 years) as an interaction term, and adjusted for demographic and cardiometabolic factors. The risk of fibrosis was determined using two distinct, validated, non-invasive tests: the Metabolic Dysfunction Associated Fibrosis-5 (MAF-5) score and the Fibrotic NASH Index (FNI).

Results: We included 13,062 participants (aged 20-< 40: 3097; 40-< 60: 3960; 60-< 80: 3008). SLD with MD was present in 31% (20-< 40: 23%; 40-< 60: 28%; 60-< 80: 41%), and 11% reported mild-to-moderate alcohol use (mean intake: 5.4 g/day, 6.2 g/day, and 3.7 g/day, respectively). Over a median follow-up of 23 years, 30% of participants died. Both SLD with MD (aHR: 1.29, 95% CI: 1.01-1.65) and alcohol consumption (aHR: 1.63, 95% CI: 1.21-2.19) were associated with increased all-cause mortality. Significant interactions with age were observed for SLD with MD (p = 0.037) and alcohol use (p < 0.001), with younger adults experiencing highest relative mortality risks. A similar age-dependence was seen for fibrosis risk.

Conclusions: Young adults face the highest fibrosis and mortality risk associated with SLD with MD and alcohol consumption, likely reflecting years lived with these risk factors. Our findings highlight the need to prioritize lifestyle interventions in younger adults to prevent fibrosis and premature mortality.