Hepatology Research最新文献

Background: Steatotic liver disease (SLD) is a hepatic phenotype of metabolic syndrome (MetS). However, little is known about the relationship between SLD and the onset of each MetS-related disease (type 2 diabetes [T2D], hypertension, and dyslipidemia). In this study, we examined the relationship between the onset of MetS-related diseases and SLD using health checkup data at baseline and 7 years later.

Methods: A total of 2167 individuals who underwent a health examination were initially recruited to the study. After excluding cases with a history of hepatic disease, a total of 714 subjects were selected and received an abdominal ultrasound test at baseline and again 7 years later. New-onset cases were defined as subjects who were free of each disease at baseline but developed one by the 7-year follow-up. Logistic regression analysis was used to estimate odds ratios and quantify the impact of SLD on the development of MetS-related diseases.

Results: We found the following results: (1) SLD at baseline is an independent risk factor for the incidence of MetS-related disease 7 years later. (2) T2D and hypertension are not independent risk factors for the incidence of SLD 7 years later. Dyslipidemia and obesity are independent risk factors for the incidence of SLD. Obesity is the only independent risk factor for the new development of SLD within 7 years. (3) No individual MetS-related disease is an independent risk factor for the development of SLD.

Conclusion: The presence of SLD is more associated with the incidence of MetS-related diseases than obesity.

Aim: This study evaluated the relationship between longitudinal dosing patterns and clinical outcomes of cabozantinib used as third- or later-line therapy in advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICIs), focusing on disease control (DC).

Methods: We retrospectively analyzed 33 patients with unresectable HCC who had received atezolizumab plus bevacizumab and lenvatinib, followed by cabozantinib. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1, and patients were classified into DC (complete response/partial response/stable disease) or non-DC (progressive disease/not evaluable) groups. Initial dose, longitudinal dosing, and treatment outcomes were compared.

Results: Most patients (90.9%) started at reduced doses (40 mg/day: n = 18; 20 mg/day: n = 12), with only three starting at 60 mg/day. Objective response rate was 3.0%, and DC rate was 51.5%. Compared with the non-DC group, the DC group had significantly longer median progression-free survival (4.4 vs. 1.2 months; p < 0.0001), overall survival (10.7 vs. 3.0 months; p = 0.0456), and treatment duration (134 vs. 22 days; p < 0.0001). Time to first dose reduction and average daily dose over the first 6 weeks did not differ significantly between groups. Child-Pugh class A was independently associated with DC and survival.

Conclusions: In real-world practice, cabozantinib is often initiated at reduced doses, yet DC can be achieved even at ∼20 mg/day. For patients with preserved liver function, long-term stable disease is attainable, and individualized dose-reduction strategies represent an effective and feasible approach in later-line HCC treatment after ICIs.

Aim: Pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator (SPPARMα), improves liver enzymes in metabolic dysfunction-associated steatotic liver disease (MASLD). Whether treatment response is influenced by PNPLA3 genotype remains unclear.

Methods: We retrospectively analyzed 93 Japanese patients with MASLD and dyslipidemia treated with pemafibrate for 48 weeks. Changes in controlled attenuation parameter (CAP), liver stiffness measurement (LSM), and FibroScan-AST (FAST) score were compared according to PNPLA3 genotype.

Results: Overall, ALT, AST, GGT, and lipid parameters decreased significantly, and FAST improved, whereas CAP showed no overall change. Stratified analysis revealed CAP decreased in PNPLA3 CC and CG but not in GG, with greater reduction in CC compared to CG or GG. Among patients with weight loss, the reduction in CAP did not differ significantly between genotypes. LSM changes were not genotype dependent.

Conclusions: Pemafibrate reduced hepatic steatosis preferentially in PNPLA3 CC carriers, whereas PNPLA3 G-allele carriers showed attenuated CAP improvement without weight loss. PNPLA3 polymorphism may influence steatosis-lowering efficacy of pemafibrate, underscoring the need for genotype-informed therapeutic strategies.

Aim: Immune checkpoint inhibitor (ICI)-associated cholangitis is a rare immune-related adverse event (irAE). However, large-scale clinical studies specifically investigating this toxicity are still lacking. The aim was to describe ICI-associated cholangitis reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS).

Methods: Reports of irAEs were extracted from the FAERS database (Q1 2011 to Q4 2024). Cases of ICI-associated cholangitis were identified using the following Preferred Terms from the Medical Dictionary for Regulatory Activities (version 27.1): "cholangitis," "sclerosing cholangitis," and "immune-mediated cholangitis". Reporting odds ratio (ROR) method was performed to evaluate the association between cholangitis and different ICI therapies. Additionally, the clinical features of ICI-associated cholangitis were characterized, and the time-to-onset (TTO) of cholangitis following ICI treatment was assessed.

Results: A total of 1102 patients with ICI-associated cholangitis were identified. Male patients (n = 628, 56.99%) outnumbered females (n = 334, 30.31%). Most patients were aged ≥ 65 years (n = 540, 49.00%). Hospitalization (n = 454, 41.20%) was the most frequent clinical outcome. Programmed cell death protein 1 inhibitors showed the strongest risk association (ROR = 24.65 and 95% confidence interval [CI]: 22.84-26.59), followed by programmed death-ligand 1 inhibitors (ROR = 19.03 and 95% CI: 16.41-22.08). In contrast, cytotoxic T-lymphocyte-associated protein 4 inhibitors showed no significant association (ROR = 2.08 and 95% CI: 0.93-4.64). The median TTO was 77 days (interquartile range: 31-164 days).

Conclusion: From a pharmacovigilance perspective, this study characterizes certain clinical features of ICI-associated cholangitis, elucidates distinct risk profiles across ICI classes, and emphasized the importance of constant monitoring. However, further studies remain essential to fully understand this rare irAE.

Aim: The aim of this study was to identify clinical factors associated with fecal Streptococcus spp. load in patients with chronic liver disease (CLD) and to evaluate its potential utility, measured through digital polymerase chain reaction (dPCR), as a noninvasive biomarker for liver fibrosis.

Methods: Data from 146 patients with CLD enrolled in a prospective single-center cohort were retrospectively analyzed. Fecal Streptococcus spp. load was quantified using dPCR with a 16S rRNA gene primer-probe set. Given the substantial effect of proton pump inhibitor (PPI) use, PPI users were analyzed separately and excluded from fibrosis-specific analyses. Associations with clinical parameters were examined using Spearman's rank correlation, and receiver operating characteristic (ROC) curve analysis was carried out to evaluate diagnostic performance for cirrhosis.

Results: Among 146 patients, 45 (30.8%) were PPI users and 101 (69.2%) were nonusers. Median Streptococcus spp. load was significantly higher in PPI users than in nonusers (470.8 vs. 107.8 copies/μL and p < 0.001). In nonusers, cirrhotic patients had higher loads than noncirrhotic patients (276.8 vs. 43.6 copies/μL and p < 0.001). ROC analysis yielded an area under the curve of 0.728 (cutoff: 28.5 copies/μL; sensitivity 71.4% and specificity 71.4%), which was lower than that of liver stiffness and the Fibrosis-4 index. Streptococcus spp. load correlated positively with age and negatively with body mass index (BMI). Patients aged > 65 years with BMI ≤ 25 kg/m² showed higher loads.

Conclusions: Fecal Streptococcus spp. load measured by dPCR may complement existing noninvasive fibrosis markers in CLD, although host-related factors, such as age and BMI, may limit diagnostic accuracy.

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: 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.