Hepatology Communications最新文献

Background: Steatotic liver diseases (SLDs) and their subcategories-metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD), and alcohol-associated liver disease (ALD)-significantly contribute to liver-related and extrahepatic morbidity and mortality. This project aimed to assess the landscape of SLDs and clinically significant fibrosis (CSF) before (2017-2020) and during (2021-2023) the COVID-19 pandemic.

Methods: Using National Health and Nutrition Examination Survey (NHANES) data, we analyzed 8965 prepandemic and 6337 pandemic participants aged ≥18 years. The main evaluated outcomes were changes in age-adjusted mean CSF, mean controlled attenuation parameter score, and age-adjusted prevalence of MASLD, MetALD, and ALD before and during the pandemic.

Results: The age-adjusted prevalence of SLDs changed significantly (p=0.003) between the prepandemic and pandemic periods. ALD prevalence rose from 0.94% to 2.27%, MetALD from 2.60% to 4.42%, while MASLD declined from 30.13% to 25.46%. Vigorous and moderate physical activity decreased significantly (p<0.001), whereas moderate/excessive alcohol intake increased (p<0.001). The prevalence of CSF increased from 8.3% to 10.5% (p=0.028). Multivariable analyses showed the COVID-19 pandemic (adjusted OR: 1.47, 95% CI: 1.00-2.17) and moderate/excessive alcohol intake (adjusted OR: 2.13, 95% CI: 1.15-3.95) were associated with CSF. In addition, older age, higher body mass index, larger waist circumference, prediabetes/diabetes, and lower income were each independently associated with CSF.

Conclusions: Our study highlights a shift in SLDs in the United States during the COVID-19 pandemic, showing a decrease in MASLD and increases in MetALD and ALD, with an alarming increase in the prevalence of CSF, likely reflecting lifestyle changes, including physical inactivity and alcohol consumption.

Background: In Michigan, Asian Americans are disproportionately infected with HBV and HCV. As many infections are first diagnosed when patients present with advanced liver disease or liver cancer, HBV and HCV screening, awareness, and early treatment are critical to improving outcomes.

Methods: Using a theory-informed approach, we administered a bi-level qualitative study to identify determinants of viral hepatitis and liver cancer care and treatment in Michigan Asian American communities. We conducted a focus group involving representatives from public health agencies, cancer coalitions, and Asian diaspora organizations across the state. We then completed 1:1 interviews with leaders from the communities. Groups and interviews were taped, transcribed, and used to identify common and distinct themes according to the National Institute of Minority Health and Health Disparities framework.

Results: According to community leaders, language barriers, costs, and a lack of viral hepatitis education appeared among the top shared screening barriers between the 3 communities. Conversely, common facilitators included pre-existing health programs, interpretation services, and community partnerships. Such sentiments were also echoed by the stakeholder focus group. However, the communities also raised distinct concerns about medical mistrust and positive health messaging.

Conclusions: This qualitative report marks the first phase of a bi-level mixed methods study in Asian American Michigan communities to understand determinants of viral hepatitis and liver cancer care and treatment. This work lays the foundation for a quantitative survey that will gather data from community members to inform the development of a future intervention.

Background: Hepatic glycosphingolipid biosynthesis is implicated in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). While UDP-glucose ceramide glucosyltransferase (UGCG) serves as the rate-limiting enzyme in glycosphingolipid synthesis, its cell-specific roles in MASLD pathogenesis remain undefined. Our study investigates the mechanistic contribution of LSEC-expressed UGCG to high-fat diet (HFD)-induced insulin resistance and MASLD progression.

Methods: Primary cell sorting was used to analyze LSEC-specific enrichment of UGCG in wild-type mice under normal chow (NC) diet and high-fat diet (HFD) conditions. LSEC-specific Ugcg knockout mice (UgcgCdh5cre+) and littermate controls (UgcgCdh5cre-) were subjected to 12 weeks of HFD or NC feeding. Hepatic steatosis was assessed via histopathology; glucose tolerance and insulin sensitivity were evaluated functionally. Endothelial fenestration architecture was quantified using scanning electron microscopy (SEM). Ganglioside GM3 levels were measured via LC-MS. LSEC-hepatocyte cocultures were employed to investigate VLDL secretion and lipid metabolism-related gene/protein expression, with nitric oxide (NO) and endothelin-1 (ET-1) signaling verified by ELISA.

Results: Ugcg deficiency in LSECs attenuated hepatic steatosis, improved glucose tolerance and insulin sensitivity, and restored endothelial fenestration architecture without compromising vascular integrity. It also reduced LSEC defenestration and CD31+ capillarization, promoting endothelial homeostasis. Mechanistically, insulin receptor-β (IRβ) was predominantly localized in LSECs; HFD-induced IRβ downregulation was reversed by UGCG inhibition (Genz-123346), correlating with reduced GM3 levels. GM3 was shown to suppress IRβ in a dose-dependent manner. In cocultures, Ugcg deficiency increased VLDL secretion and elevated the expression of hepatocyte lipid metabolism-related genes and proteins through NO/ET-1 signaling pathways.

Conclusions: Our findings establish UGCG as a master regulator of LSEC metabolic functions through GM3-IRβ axis modulation. LSEC-targeted UGCG inhibition mitigates hepatic insulin resistance via NO/ET-1-mediated hepatocyte metabolic reprogramming, providing a novel therapeutic paradigm for MASLD.

Background: The approach to appropriate risk stratification for metabolic dysfunction-associated steatotic liver disease (MASLD) is variable, and the adoption of non-invasive liver disease assessments in clinical practice is suboptimal. In this study, we implemented an electronic decision support tool for primary care patients with MASLD to assess its influence on linkage to care.

Methods: We performed a prospective, before-and-after pilot study in which post-implementation providers were presented with an electronic decision aid automating non-invasive liver disease assessments with the Fibrosis-4 score and providing individualized, guideline-directed recommendations. Patients were included if attending an outpatient primary care visit with a study provider, had a pre-existing diagnostic code for MASLD, and had not established care with a hepatologist in the 3 years before the office visit. The primary outcome was linkage to care, defined as adherence to guideline-directed recommendations for the next step of care. A total of 503 encounters were included, accounting for 301 unique patients.

Results: Provider adherence to guideline-directed clinical recommendations increased from 29.7% to 45.8% post-implementation (p<0.001). The effect of this intervention remained significant when controlling for patient age, race, sex, resident physician involvement in the clinic visit, and concomitant comorbidities of diabetes, hypertension, and hyperlipidemia (OR 2.11 [95% CI 1.42-3.14]; p<0.001). There was a modest increase in the number of referrals to hepatology post-implementation (2.3%-7.1%; OR 3.27 [95% CI 1.33-9.18]; p=0.014).

Conclusions: In conclusion, we present a novel, electronically integrated, innovative methodology for direct delivery of individualized guidance for the management of patients with MASLD that significantly enhanced the direction of care toward necessary guideline-directed liver assessments.

Background: HCC is the leading form of primary liver cancer worldwide. Transcatheter arterial chemoembolization (T) is commonly used to treat unresectable tumors. T combined with antiangiogenic therapy and immunotherapy (AI) has shown significant progress in neoadjuvant treatment, although the underlying mechanisms remain unclear. This study aimed to explore the reasons for the enhanced efficacy of T+AI from a pathological perspective in the context of HCC.

Methods: A retrospective analysis was conducted on 49 patients with HCC who were treated with T before surgical resection. Twenty-three patients received T+AI, while 26 received only T. Immunohistochemistry was performed to evaluate clinical data, including disease-free survival. Immune cells were recorded based on 4 methods, including tumor-infiltrating lymphocyte (TIL) percentage (the percentage of positive lymphocytes in the central area of the tumor) and the other 3 methods. Blood vessels were classified on the basis of the presence of VETC (vessels that encapsulate tumor clusters).

Results: The group analysis results suggested that disease-free survival in the T+AI group was significantly better than that in the T group. Analysis revealed that CD8+TILs were a prognostic factor for neoadjuvant treatment and lower carbonic anhydrase 9 and VETC positivity in the T+AI group, with significant differences in immune cell infiltration and vascular classification. VETC positivity was associated with higher residual tumor rates and lower CD8+TIL levels.

Conclusions: Pathological assessment of CD8+TILs in cancer tissues may serve as an important indicator for evaluating the efficacy of neoadjuvant therapy in HCC. The presence of VETC and carbonic anhydrase 9 may also affect the efficacy of neoadjuvant therapy and could potentially serve as indicators.

Background: Double-negative T (DNT) cells (CD3+CD4-CD8-NK1.1-) demonstrate immunoregulatory functions in maintaining hepatic immune homeostasis. This study investigates how energy metabolism impacts DNT cell survival and immunoregulatory functions, exploring potential therapeutic applications for autoimmune hepatitis.

Methods: We compared DNT cells with conventional CD4+ T cells through lipidomic analysis, fatty acid β-oxidation (FAO) assessment, and single-cell RNA sequencing. Cells were treated with fatty acids (oleic acid and palmitic acid) and the FAO inhibitor Etomoxir (Eto). We evaluated cell survival, proliferation, and function through flow cytometry and reverse transcription-quantitative polymerase chain reaction. Transcriptome sequencing identified key regulatory molecules. The therapeutic potential was assessed in a Concanavalin A (ConA)-induced autoimmune hepatitis mouse model receiving DNT and DNT-Eto cell treatments.

Results: DNT cells showed higher fatty acid content, FAO levels, and related gene expression compared with CD4+ T cells. Fatty acid supplementation enhanced DNT cell proliferation and immunoregulatory function, whereas FAO inhibition significantly impaired cell survival and function. Transcriptome analysis identified OX40 as a key regulator of DNT cell survival and function, regulated by FAO-activated pSTAT4. In the ConA-induced murine model, therapeutic administration of DNT cells significantly ameliorated the severity of autoimmune hepatitis compared with the ConA-treated control group. Meanwhile, DNT-Eto-treated groups showed more severe liver injury and elevated liver enzymes compared with DNT-treated groups. In vivo analyses revealed that DNT cells exhibited superior survival, function, and CD4+ T cell inhibition compared with Eto-treated or OX40 KO-DNT cells.

Conclusions: FAO regulates DNT cell survival and immunoregulatory function through the pSTAT4-OX40 pathway, enhancing their protective effect against autoimmune hepatitis.

Aim: This study aimed to compare the clinical outcomes of carbon-ion radiotherapy (CIRT) to those of surgical resection (SR) in patients with HCC.

Methods: This retrospective study included 116 and 947 patients initially receiving CIRT and SR in Japanese institutions from September 2010 and June 2022. We used inverse probability of treatment weighting (IPTW) analysis to correct for imbalances in baseline patient characteristics between the 2 groups.

Results: The median observation period was 3.3 years (IQR: 1.4-5.8) in the SR group and 2.8 years (IQR: 1.6-4.5) in the CIRT group (p=0.2). Before IPTW analysis, the median recurrence-free survival (RFS) was 2.3 years in the SR group and 2.2 years in the CIRT group, with no statistical significance (p=0.3). After IPTW analysis, the median RFS was 2.5 years in the SR group and 2.3 years in the CIRT group, which remained statistically nonsignificant (p=0.9). The median overall survival (OS) was not reached in the SR group, while it was 7.4 years in the CIRT group. The SR group demonstrated better survival compared to the CIRT group (p=0.02). In the IPTW cohort, the median OS was not reached in the SR group, while it remained 7.4 years in the CIRT group, showing no significant difference (p=0.4). Multivariate analyses showed that treatment choice (SR vs. CIRT) was not identified as a predictive factor for both RFS and OS.

Conclusions: CIRT showed no statistically significant differences in RFS or OS compared with SR, suggesting its potential as a curative treatment option for early-stage HCC.

Background: Alcohol-associated hepatitis (AH) is the most life-threatening form of alcohol-associated liver disease (ALD). AH is characterized by severe inflammation attributed to increased levels of ethanol, microbes or microbial components, and damage-associated molecular pattern (DAMP) molecules in the liver. HSPB1 [Heat Shock Protein Family B (Small) Member 1; also known as Hsp25/27] is a DAMP released from stressed cells, including hepatocytes. The goal of this study was to define the role of HSPB1 in AH pathophysiology.

Methods: Serum HSPB1 was measured in a retrospective study of 184 healthy controls (HCs), heavy alcohol consumers (HA), patients with alcohol-associated cirrhosis (AC), and patients with AH recruited from major hospital centers.HSPB1 was also evaluated in liver tissue from HC and AH patients, existing RNA-seq data from ALD patient liver and monocytes, and livers from mice fed a Lieber-DeCarli diet. Cellular models of hepatocyte and macrophage interactions were used to evaluate the role of HSPB1 in inflammation during AH.

Results: Circulating HSPB1 was significantly increased in AH patients, and levels positively correlated with disease-severity scores. HSPB1 was also increased in the livers of patients with severe AH and ethanol-fed mice. In cellular models, ethanol-stressed hepatocytes released HSPB1, which then triggered TNFα-mediated inflammation in macrophages. Anti-HSPB1 antibody prevented TNFα release from macrophages exposed to media conditioned by ethanol-stressed hepatocytes.

Conclusions: Our findings support investigation of HSPB1 as both a biomarker and therapeutic target in ALD. Furthermore, this work demonstrates that anti-HSPB1 antibody is a rational approach to targeting HSPB1 with the potential to block inflammation and protect hepatocytes, without inactivating host defense.

Background: Mediterranean diet (MED) is recommended for managing metabolic dysfunction-associated steatotic liver disease (MASLD). However, associations between MED adherence, related metabolite signatures, and risks of liver-related events (LRE) and mortality in MASLD patients remain unclear.

Methods: We performed a prospective analysis using UK Biobank data, including 47,429 MASLD participants free of LRE at baseline. MED adherence was assessed as alternate Mediterranean Diet (aMED) score through a validated questionnaire. Metabolic biomarkers were measured using high-throughput nucleic magnetic resonance (NMR) spectroscopy. Cox regression and restricted cubic splines assessed the association of aMED, its components, with risk of LRE and mortality. Mediation analysis evaluated the role of metabolites in the relationship between aMED, its components, and MASLD progression.

Results: Over a median follow-up of 13.3 years, 296 LRE cases and 3616 deaths occurred. Higher aMED scores (6-9) were associated with lower risks of LRE (HR: 0.553, 95% CI: 0.351-0.874) and mortality (HR: 0.854, 95% CI: 0.762-0.956) compared with the lowest scores (0-3), with linear dose-response relationships. Vegetables and legumes were associated with lower LRE risk, while vegetables, nuts, fish, MUFA:SFA ratio, and moderate alcohol intake were linked to reduced mortality. Of 143 metabolites, 46 were significantly associated with aMED. Omega-3 fatty acids, the omega-3 to total fatty acid ratio, and albumin accounted for 7.9%, 11.9%, and 2.6% of the reduction in LRE, and 19.4%, 23.1%, and 4.7% of the mitigation in mortality, respectively.

Conclusions: Adherence to MED is linked to reduced LRE risk and mortality in MASLD patients. Metabolic biomarkers, particularly small HDL particles and omega-3 fatty acids, may mitigate MASLD progression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder globally, affecting 30% of the population and causing a significant healthcare burden due to its increasing incidence and limited therapeutic options. Arachidonic acid (AA) is a key bioactive lipid precursor that generates eicosanoids, such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acids, via 3 distinct enzymatic pathways: cyclooxygenase, lipoxygenase, and cytochrome P450. Emerging evidence indicates that AA-derived metabolites and pathway factors contribute to the progression and severity of MASLD and liver fibrosis. This review systematically summarizes the pathophysiological roles of AA metabolism in MASLD and liver fibrosis, focusing on mechanisms involving lipid accumulation, liver inflammation, fibrogenesis, and related cellular processes. In addition, we discuss potential therapeutic targets within the AA metabolic pathway in MASLD and liver fibrosis, highlighting emerging clinical advances targeting AA metabolites and pathway factors to improve these pathological conditions.