Hepatology Communications最新文献

Background: Social drivers of health (SDoH) contribute to health disparities among patients with chronic liver disease (CLD). Little is known about the feasibility and acceptability of SDoH screening in hepatology clinics. This study aimed to define SDoH prevalence among CLD patients, identify a feasible and acceptable screening approach, and assess the convergent validity of a locally developed screener.

Methods: Among adult patients with CLD receiving care in hepatology clinics, 2 SDoH screeners were administered to eligible participants: (1) default electronic medical record (EMR) questions and (2) Screener for Intensifying Community Referrals for Health (SINCERE). The primary outcomes were (1) prevalence of SDoH, (2) SDoH screening feasibility and acceptability, and (3) factors associated with screening acceptability. As a secondary outcome, the convergent validity of SINCERE to EMR was assessed.

Results: Among 250 participants, the mean age was 56 years, 56% were women, 22% were Hispanic, 7% were American Indian/Alaska Native, 58% had cirrhosis, 29% completed high school or less, 22% were unemployed/disabled, and 29% had an annual income <$35,000. Based on SINCERE, 26% had food insecurity, 8% transportation needs, 43% financial strain, 5% lack of social support, and 24% housing instability. Most respondents (69%) were comfortable or very comfortable completing SDoH screening. Using the McNemar test, there were statistically significant differences between screeners for financial strain and housing instability.

Conclusions: Among CLD patients at our center, SDoH were prevalent, and screening within the hepatology clinic was feasible and acceptable. To detect social needs, SINCERE, a locally developed screener, had overall acceptable convergent validity. These data support SDoH screening in hepatology clinics. Future multicenter studies evaluating the effective implementation of SDoH screening for CLD patients, including contextualized care plans and connection to available resources, should be conducted.

Background: Steatotic liver disease (SLD) is a significant cause of chronic liver disease. However, the relative prevalence and prognostic significance of various disease entities according to recently defined classification systems (MAFLD vs. the SLD-spectrum of MASLD, Met-ALD, and ALD) is understudied in older adults.

Methods: Post hoc analysis of the ASPirin in Reducing Events in the Elderly (ASPREE) study involving 16,703 Australian community-dwelling adults aged ≥70 years free from significant disability, prior cardiovascular disease events, and with a life expectancy ≥5 years. Steatosis was identified by Fatty Liver Index (FLI) ≥60. Alcohol intake was self-reported. SLD subtypes were classified according to European Association for the Study of the Liver (EASL)/American Association for the Study of Liver Diseases (AASLD) guidelines. Cox regression was used to estimate hazard ratios for adjudicated outcomes: mortality, major adverse cardiovascular events (MACE), and persistent physical disability.

Results: Of 9847 participants with calculable FLI and a median 8.6 years follow-up, 3748 (38.1%) had hepatic steatosis. Substratifying by MAFLD criteria versus the SLD type, 3743 had MAFLD (38.0%), and 3464 (35.2%) met SLD criteria (MASLD 3132 [90.4%], Met-ALD 262 [7.6%], ALD 74 [2.0%]) (excluding steatogenic medication users). There was no increased mortality risk with MAFLD or SLD. MAFLD and MASLD were associated with MACE when adjusted for age and sex (HR 1.42 [95% CI 1.17-1.71] and HR 1.40 [95% CI 1.15-1.71], respectively), but not in the fully adjusted model. MAFLD, MASLD, and ALD were associated with an increased risk of persistent physical disability even when fully adjusted (HR 1.46 [95% CI 1.19-1.79], HR 1.49 [95% CI 1.20-1.83], HR 2.53 [95% CI 1.27-5.05], respectively), but not Met-ALD.

Conclusions: MAFLD and the metabolic-SLD spectrum are common in community-dwelling older adults. No subclassification is associated with increased mortality in this group, although there is an association between both MACE and persistent physical disability with SLD.

Background: As the role of hepatic progenitor cells (HPCs) in constituting ductular reactions in pathogenesis remains ambiguous, we aimed to establish the in vivo cause-and-effect relationship between HPCs and chronic liver disease progression. We previously demonstrated that peritumoral ductules are associated with angiogenesis in liver tumors, and forkhead box L1 (Foxl1)-expressing murine HPCs secrete angiogenic factors in vitro. Therefore, we hypothesized that HPCs are capable of remodeling the portal vascular microenvironment and regulating overall liver disease progression, and this function of HPCs is dependent on recombination signal binding protein for immunoglobulin kappa J region (RBPJ), a key effector of the Notch signaling pathway.

Methods: We generated HPC-specific Rbpj conditional knockout mice (CKO) using Foxl1-Cre, treated them with the DDC diet to induce chronic liver disease, and performed serum biochemistry, gene expression analysis, and immunostaining analysis.

Results: CKO mice exhibited a significant reduction in serum levels of liver injury markers, ductular reactions, vascular and fibrotic areas, and hepatic expression of fibrosis and inflammation markers compared to control mice (WT). Single-nucleus RNA sequencing comparing CKO and WT livers detected transcriptome changes across multiple cell types, including endothelial cells, HSCs, and cholangiocytes. Expression of several reactive cholangiocyte markers, including vascular cell adhesion molecule 1 (VCAM1), in HPCs was significantly downregulated in response to anti-Rbpj shRNAs in vitro. Immunofluorescence analysis indicated that the percentage of VCAM1+ cells was reduced in both HPC and cholangiocyte populations in CKO compared to WT in vivo.

Conclusions: Our findings reveal Rbpj-dependent expression of reactive cholangiocyte markers in HPCs and demonstrate that Rbpj deletion in HPCs attenuates not only endothelial responses but also liver injury, fibrosis, and VCAM1 expression in cholangiocytes, highlighting the crucial role of HPCs in pathogenic progression.

Background: Acute-on-chronic liver failure (ACLF), which develops in patients with acutely decompensated cirrhosis, is characterized by multiple extrahepatic organ failures leading to high short-term mortality. Although major advances in the understanding of ACLF have been accomplished in the last years, the understanding of driving mechanisms underlying ACLF is hindered by the lack of proper animal models that faithfully reproduce both the systemic hyperinflammatory response and the full spectra of extrahepatic organ failures present in this condition.

Methods: ACLF was induced by acute induction of polymicrobial peritonitis secondary to the ligation and puncture of the cecum (CLP) in mice with chronic carbon tetrachloride (CCl4)-induced cirrhosis. The study included three groups: CCl4+CLP (n=10) mice with cirrhosis which underwent CLP surgery; CCl4+sham mice (n=10) and control mice (n=10).

Results: As compared to CCl4+sham, CCl4+CLP mice had higher short-term mortality and exhibited more severe hypoalbuminemia and hyperbilirubinemia, significantly higher AST and GGT levels and higher liver inflammatory burden. CCl4+CLP mice also showed increased serum creatinine and BUN levels and up-regulated expression of Kim-1, Il-6 and Tnf in the kidney, lower oxygen saturation (SpO2), higher serum renin concentration, higher international normalized ratio (INR) and worse neurological behavior test scores than CCl4+sham and control mice. In addition, CCl4+CLP mice showed widespread bacterial tissue colonization and exhibited increased serum cytokine levels, which correlated with the intensity of organ impairments.

Conclusion: The CCl4+CLP model reproduces the full spectra of extrahepatic organ impairments present in patients with ACLF and represents an optimized murine model to experimentally explore the pathophysiology of this disease as well as new therapeutic approaches.

Background: Metabolic-associated steatotic liver disease (MASLD), caused by insulin resistance and the metabolic syndrome, may result in progressive liver fibrosis. Animal studies suggest that dietary content modulates liver fibrosis progression. Our aim was to identify dietary components and food-related behaviors that may be associated with fibrosis progression and liver-related outcomes in a well-characterized human MASLD cohort.

Methods: Patients with MASLD who had completed a detailed Lifestyle Survey, including a semiquantitative Food Frequency Questionnaire in the Veterans Health Administration Million Veteran Program, were included. The primary outcome was liver fibrosis progression using the Fibrosis-4 slope; the secondary outcome was time to cirrhosis by ICD9/10 codes. Key baseline covariates included: race/ethnicity, body mass index, diabetes mellitus, AUDIT-C score, and baseline Fibrosis-4 score. Using bootstrapped Elastic Net regression in R, self-reported food intake and scaled nutrient variables of interest associated with the outcomes were identified and then validated using multivariable Generalized Linear Model and Cox models.

Results: A total of 84,024 individuals with MASLD with nutritional data were included in this study. Median age at MASLD diagnosis was 56 years (IQR 49-63). Frequency of consumption of coffee, tea, vegetables (broccoli, spinach/collard greens), legumes, nuts, modest alcohol, white meat, rice/pasta, dairy, and intakes of specific nutrients including nitrate/vitamin K, caffeine, betaine, amino acids, and beta carotene were associated with reduced fibrosis progression. Consumption of white bread, cookies, breakfast cereals, and specific nutrients such as iron (non-heme), B vitamins, and flavanones were all significantly associated with increased fibrosis progression in MASLD (p<0.05).

Conclusions: Dietary choices such as intake of processed foods, high-fructose foods, and refined carbohydrates may be associated with MASLD progression, while intake of vegetables, nuts, whole grains, and caffeine may be protective.

Background: HBV, which contributes to liver fibrosis and HCC, is associated with autophagy and epithelial-mesenchymal transition (EMT). However, the relationship between HBV infection, autophagy, and EMT remains unknown.

Methods: In this study, we used HBV cell lines (HepAD38, Huh7.5.1-NTCP) to evaluate this relationship.

Results: HBV replication or infection promoted autophagy, EMT, and liver fibrogenesis. HBV-induced EMT/fibrogenesis was dependent on autophagy. HBV X and HBV core (C) were each involved during this process. TGF-β1 partially participated in HBV-induced autophagy/EMT/fibrosis. c-Jun N-terminal kinase (JNK) expression was increased in HepAD38 cells, HBV-X (HBV-C)-transfected Huh7.5.1 cells, and HBV-infected Huh7.5.1-NTCP cells. JNK silencing attenuated HBV-induced autophagy and EMT/fibrosis signaling as well. Moreover, overexpression of HBV-X(C) and augmentation of autophagy were shown to promote pJNK expression. Finally, we confirmed an HBV-JNK-autophagy-EMT/fibrosis signaling pathway in a primary human hepatocyte model.

Conclusions: In conclusion, HBV induces autophagy through JNK, thus triggering downstream EMT and fibrogenesis signaling pathways. These findings suggest that JNKs could be potential targets for the treatment of HBV-related liver diseases.

Background: Racial and ethnic minority populations are disproportionately impacted by HCC due to more advanced tumor burden and underuse of treatments. We explored racial and ethnic differences in medical mistrust, barriers to treatment, and health literacy among patients with HCC.

Methods: We conducted a multicenter survey among patients with newly diagnosed HCC between September 2018 and July 2023 at 4 large U.S. health systems. The survey assessed medical mistrust [Group-Based Medical Mistrust Scale (GBMMS)], health literacy (CHEW Assessment of Health Literacy), and barriers to HCC treatment. We performed multivariable logistic regression to evaluate associations between race and ethnicity and survey measures.

Results: Of 1245 eligible patients, 833 (66.9%) completed the survey (45.9% Hispanic, 35.9% White, and 14.2% Black). A higher proportion of Black and Hispanic patients had high medical mistrust than White patients (14.2% and 3.3% vs. 0.7%, respectively; p<0.001). In multivariable analysis, Black race (OR: 19.2, 95% CI: 4.2-87.7) but not Hispanic ethnicity (OR: 3.72, 95% CI: 0.80-17.2) was significantly associated with high mistrust. Compared to White patients, Black and Hispanic patients both reported greater barriers to HCC treatment, with the most common barriers being concerns about pain (41.6%), financial burden (37.6%), and time commitment (31.1%). Limited health literacy was reported by 38.1% of patients (46.8% Hispanic, 41.0% Black, 26.2% White; p<0.001).

Conclusions: Medical mistrust, barriers to treatment, and limited health literacy are prevalent among Black and Hispanic patients with HCC. Understanding the interplay between race, ethnicity, and these factors is essential to address HCC disparities.

Background: HCC is a significant health concern. CTNNB1 mutations are implicated in HCC progression and resistance to transarterial chemoembolization (TACE), potentially through the ITGB1/PI3K/AKT pathway.

Methods: HCC was induced in mice using diethylnitrosamine, and TACE-resistant models were established. Tumor tissue analysis, single-cell and whole-exome sequencing identified gene mutations and cellular interactions. CRISPR/Cas9 was used to generate HCC cells with CTNNB1 mutations, and functional assays evaluated their proliferation, migration, and invasion. Cocultivation with HUVEC cells and animal models assessed angiogenesis and tumorigenesis.

Results: The study successfully established a TACE-resistant mouse model, identifying mesenchymal cell alterations and enhanced cellular communication in resistant mice. Signaling pathways like SPP1 were implicated in epithelial-mesenchymal transition. Analysis revealed a CTNNB1 (c.890T>C) mutation in TACE-resistant patients, with subsequent experiments confirming enhanced proliferation, migration, and epithelial-mesenchymal transition in CTNNB1 mutant HCC cells. Cocultivation studies with HUVEC cells indicated a pro-angiogenic effect of CTNNB1 mutant HCC cells, mediated by the ITGB1 pathway. Animal experiments demonstrated tumorigenic properties of CTNNB1 mutant cells, further validated by histopathological and immunohistochemical analyses.

Conclusions: CTNNB1 mutations elevate ITGB1, activate PI3K/AKT, induce epithelial-mesenchymal transition, enhancing proliferation, migration, and angiogenesis, contributing to TACE resistance, suggesting novel therapeutic targets in HCC through signaling pathway interventions.

Background: To investigate the role of nucleoside diphosphate kinase 2 (NME2) in HCC progression, assessing its therapeutic potential.

Methods: Utilizing transcriptome sequencing data from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of tissue microarrays, we analyzed NME2 expression in HCC tumor tissues. The effects of NME2 on HCC cell proliferation and autophagy flux were assessed through knockdown and overexpression experiments. Additionally, the relationship between NME2 and 4EBP1 phosphorylation was explored through specific site mutation analysis.

Results: NME2 overexpression in HCC correlated with poor prognosis. NME2 knockdown significantly hindered HCC cell proliferation and induced autophagy flux. Notably, NME2 modulates 4EBP1 phosphorylation (Thr37/46) independently of mTOR, unveiling a novel axis in HCC pathogenesis. Additionally, NME2 modulates eukaryotic translation initiation factor 4F (eIF4F) complex formation and autophagy flux.

Conclusions: NME2 plays a crucial role in HCC development by modulating 4EBP1 phosphorylation and autophagy through an mTOR-independent pathway. Our research underscores NME2's significance as a potential therapeutic target in HCC, meriting further exploration of its underlying mechanisms and clinical applicability.