Hepatology Research最新文献

Aim: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by inflammation and fibrosis. We aimed to elucidate the antifibrotic advantage of Sacubitril/Valsartan (Sac/Val) and molecular mechanisms using a rat MASH model and cells.

Methods: A connexin 32 dominant negative transgenic rat MASH model was induced using a high-fat diet plus dimethylnitrosamine and treated with Val (5 mg/kg/day) or Sac/Val (10 mg/kg/day) for 17 weeks. Histological evaluation, immunohistochemistry, RT-PCR, western blot, and RNA sequencing were performed to assess steatohepatitis, fibrosis, hepatocarcinogenesis, and signaling pathways. Direct modulatory effects were analyzed using a rat hepatic stellate cell (HSC) line.

Results: Sac/Val significantly reduced steatohepatitis and hepatic fibrosis histologically compared with Val alone, with fewer α-smooth muscle actin (SMA)-positive activated HSCs. Hepatic preneoplastic lesions were also reduced. Sac/Val suppressed Nlrp3, reactive oxygen species levels, and phosphorylated p38 mitogen-activated protein kinase, and cleaved gasdermin D, mitigating oxidative stress and inflammasome signaling. RNA sequencing revealed integrin alpha 8 (Itga8), a key regulator of HSC activation, was downregulated by Sac/Val compared with Val, correlating with HSC activation and fibrosis. Immunohistochemistry revealed decreased Itga8 protein expression in fibrotic regions with Sac/Val treatment. Sac/Val inhibited transforming growth factor (TGF)-β1-induced HSC activation, proliferation, and collagen production, further supporting its direct antifibrotic effects. Conversely, stable Itga8 overexpression in HSC enhanced proliferation and upregulated Tgfb1 and α-SMA, supporting the role of Itga8 in HSC activation.

Conclusions: Sac/Val attenuated fibrosis and inflammation in MASH, potentially through suppression of Itga8 expression, oxidative stress, and inflammasome signaling, highlighting Sac/Val as a promising MASH therapy.

Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease, yet its underlying mechanisms remain incompletely understood. Beyond hemostasis, platelets actively participate in inflammation, fibrosis, and vascular remodeling. This study investigated platelet proteomic alterations across MASLD stages to explore their potential contribution to disease progression.

Methods: We analyzed 25 MASLD patients undergoing hepatic catheterization and 21 viral-hepatitis controls. Platelets were isolated from sinusoidal and peripheral blood and profiled using high-throughput, mass spectrometry-based proteomics. Differential-abundance and pathway analyses were performed with appropriate statistical correction and exploratory evaluation.

Results: A total of 1052 platelet proteins were identified. Several proteins showed large effect sizes and are reported as putative markers: histidine-rich glycoprotein and ADP-ribosylation factor-like protein 8B were less abundant in MASLD than in controls. In advanced disease, perforin-1 and macro-H2A1 were increased in sinusoidal blood, suggesting immune activation and endothelial injury. Docking protein 1 and TGF-β-induced protein IG-H3 were enriched in patients with perisinusoidal fibrosis and obliterative venopathy.

Conclusions: Putative platelet-derived proteins associated with immune regulation, vascular remodeling, and metabolic dysfunction were identified in MASLD. These exploratory findings will be validated in a prospective, metabolically matched cohort to confirm disease specificity.

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: Full approval for new non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) therapies requires demonstrating improved mortality. As cardiovascular disease (CVD) is the leading cause of death in metabolic dysfunction-associated steatotic liver disease (MASLD), we identified factors of all-cause mortality in a nationally representative cohort, focusing on aspirin and diet.

Methods: We analyzed 4541 adults (40-79 years) with MASLD from the National Health and Nutrition Examination Survey (NHANES) 2011-2018. Key exposures were aspirin use and adherence to the Mediterranean diet, assessed by the Mediterranean diet score (MDS). Advanced fibrosis was defined as FIB-4 > 2.67 and included as a covariate in all multivariable Cox models. To adjust for confounding, propensity scores were estimated using multivariable logistic regression that incorporated the complex NHANES survey design.

Results: In a cohort of 2175 patients with MASLD followed for a mean of 4.5 years, 124 deaths occurred. Among adults > 65 years without prior history of CVD, aspirin use was associated with higher all-cause mortality (hazard ratio [HR] 9.82; 95% confidence interval [CI] 1.15-83.69); this association was weaker at higher MDS (interaction p = 0.04). In adults with a history of CVD, aspirin use was not associated with survival, whereas higher MDS was independently associated with lower mortality (HR 0.61; 95% CI 0.41-0.93). No material associations were observed in younger adults. MDS was inversely related to inflammatory markers in older patients.

Conclusions: Aspirin use is independently associated with a several-fold increased mortality risk in older MASLD patients without prior CVD, an effect partly mitigated by high adherence to the Mediterranean diet. Aspirin for primary CVD prevention should be used with caution in this population. Aspirin use and diet are important, often uncontrolled factors associated with mortality in MASLD clinical trials.

Aim: Most existing evidence regarding liver transplantation (LT) for autoimmune hepatitis (AIH) originates from European cohorts, hindering the applicability of current guidelines to other populations because of possible geographic variations. There is an urgent need for region-specific prognostic models.

Methods: We analyzed 164 AIH patients from Brazil and Venezuela undergoing LT between 2002 and 2025, the largest AIH LT cohort from Latin America to date. Random survival forests (RSF) identified key predictors of overall survival (OS), graft survival (GS), and AIH recurrence (rAIH). Clustering based on predicted risks identified high-risk groups with significantly worse outcomes (p < 0.001 for all). Penalized models with the most important variables from the RSF assessed risk stratification.

Results: 5-, 10-, and 20-year OS were 83%, 78%, and 49%. rAIH rates increased from 6% at 5 years to 34% at 20 years. Mycophenolate sodium use in maintenance therapy was ranked as the most important factor for OS (Hazard ratio [HR] = 0.44) and GS (HR = 0.46) prediction, while younger age was the most important risk factor for rAIH. LASSO models accurately predicted early outcomes (1-year AUCs: OS 0.73, GS 0.73, rAIH 0.81). In a landmark analysis (6 months post-LT), infectious complications emerged as the main determinant for long-term OS, and a new model improved 5- and 10-year OS prediction (AUCs: 0.76 and 0.79, respectively).

Conclusion: This analysis identifies key predictors that define high-risk clusters for early and long-term outcomes in Latin American AIH patients post-LT, highlighting potential region-specific factors.

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.