Louisville VA Medical Center

Background:It is unclear whether physical activity (PA) and advanced fibrosis are associated in alcohol-associated liver disease (ALD) and metabolic dysfunction and alcohol-associated liver disease (MetALD). We examined the association between work-related PA (WPA) or leisure-time PA (LTPA) and advanced fibrosis across the steatotic liver disease (SLD) spectrum.Methods:Data obtained from the National Health and Nutrition Examination Survey (2017-2020) in adults with hepatic steatosis were included and categorized into MASLD (n=2236), MetALD (n=1355), and ALD (n=457) based on alcohol use. PA was quantified as metabolic equivalent (MET)-minutes per week, and ≥600 MET-min/wk was used as the threshold for high activity. Adjusted logistic regression models for confounders (sex, race/ethnicity, education, income, metabolic risk factors, and etiology of SLD) were used to analyze the relationship of PA types with at-risk advanced fibrosis, according to an Agile 3+ score ≥0.45.Results:Among 4342 SLD participants, LTPA was strongly linked to a lower risk of at-risk advanced fibrosis in MASLD (OR=0.56, 95% CI: 0.34–0.93), as well as MetALD and ALD combined (OR=0.55, 95% CI: 0.34–0.89). WPA was not associated with improved advanced fibrosis. There were no interactions between WPA and SLD subtypes (p=0.98), and between LTPA and SLD subtypes (p=0.55).Conclusions:LTPA but not WPA is protective for at-risk advanced fibrosis in patients with MASLD and MetALD. These findings showcase the importance of structured LTPA interventions to mitigate fibrosis risk in SLD. Larger studies are needed to examine the benefits of PA in patients with ALD and to delineate exercise prescriptions for patients with SLD.

The term steatotic liver disease (SLD) is now used to describe conditions involving fat accumulation in the liver. SLD term includes a spectrum of defined and less defined disorders: metabolic dysfunction-associated SLD (MASLD), alcohol-associated liver disease (ALD), and metabolic and ALD (Met-ALD), where both cardiometabolic risk factors, such as obesity, diabetes, or dyslipidemia, and alcohol consumption function in disease development and progression. Met-ALD is defined as liver disease in men with at least 1 cardiometabolic risk factor who also consume 210–420 g of alcohol per week (approximately 30–60 g per day), whereas for women, it is defined as at least 1 cardiometabolic risk factor in addition to consumption of 140–350 g of alcohol per week (approximately 20–50 g per day). This level of alcohol intake exceeds the thresholds traditionally used to exclude alcohol as a contributing factor in MASLD, but it remains below the levels typically associated with classic ALD. Met-ALD is estimated to affect about 17 million people in the United States It is a unique disease with the risk of cirrhosis, hepatocellular carcinoma, and mortality different from those with MASLD or ALD. Its treatment relies mainly on weight loss, alcohol abstinence, and control of cardiometabolic risk factors. Novel medications such as glucagon-like peptide-1 agonists and fibroblast growth factor s21 analogs may be promising future therapies for the treatment of Met-ALD.

Data are limited regarding etiology-specific trends for delisting and recompensation for liver disease improvement among liver transplantation (LT)-listed candidates in the United States. A retrospective cohort (2002-2022) using United Network of Organ Sharing database examined etiology-specific trends for delisting and recompensation due to liver disease improvement among candidates listed for LT. Of 120,451 listings in adults, 34,444 (2002-2008), 38,296 (2009-2015), 47,711 (2016-2022) were analyzed. A total of 7,196 (6.2%) were delisted for liver disease improvement, with 5.6%, 7.2%, and 5.3% in 3 respective time periods, Armitage trend P < 0.001. Delisting for improvement of liver disease was 8.1%, 5.8%, 4.0%, 3.9%, and 3.1% among listings for alcohol-associated liver disease (ALD n = 41,647), hepatitis C virus infection (HCV n = 38,797), autoimmune (n = 12,131), metabolic-associated steatohepatitis (MASH n = 22,162), hepatitis B virus infection (HBV n = 3,027), and metabolic liver disease (MLD n = 2,687), respectively. One thousand one hundred twenty-two (15.6% or 0.9%) were delisted for improvement at 1 year with cumulative incidence competing for waitlist mortality and receipt of LT of 1.18, 1.17, 0.64, 0.59, 0.50, and 0.34 for ALD, HBV, HCV, MASH, MLD, and autoimmune, respectively. In a fine and gray model, compared with metabolic, subhazard ratio (95% confidence interval) on delisting at 1 year was 3.47 (31.6-3.81) and 3.44 (2.96-3.99), P < 0.001, for ALD and for HBV, respectively. Of 7,196 delisting for improvement, 567 of 5,750 (9.9%) decompensated at listing had recompensation, 19.5% for HBV, 16.6% for MLD and autoimmune, 9.9% ALD, 8.6% for HCV, and 6.9% for MASH. In a logistic regression model among delisted candidates for improved liver disease, HBV vs MASH etiology was associated with recompensation, 2.37 (1.40-4.03), P < 0.001. ALD and HBV are most frequent etiologies for delisting due to liver disease improvement. About 10% of delisted patients develop recompensation, with HBV etiology most likely to recompensate. Models and biomarkers are needed to identify these candidates for optimal use of deceased donor livers.

The interactions of different dietary doses of copper with fructose contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD) via the gut-liver axis. The underlying mechanisms remain elusive. The aim of this study was to identify the specific pathways leading to gut barrier dysfunction in the ileum using a proteomics approach in a rat model. Male weanling Sprague Dawley rats were fed diets with adequate copper (CuA), marginal copper (CuM), or supplemented copper (CuS) in the absence or presence of fructose supplementation (CuAF, CuMF, and CuSF) for 4 weeks. Ileum protein was extracted and analyzed with an LC-MS. A total of 2847 differentially expressed proteins (DEPs) were identified and submitted to functional enrichment analysis. As a result, the ileum proteome and signaling pathways that were differentially altered were revealed. Of note, the CuAF is characterized by the enrichment of oxidative phosphorylation and ribosome as analyzed with the KEGG; the CuMF is characterized by an enriched arachidonic acid metabolism pathway; and focal adhesion, the regulation of the actin cytoskeleton, and tight junction were significantly enriched by the CuSF. In conclusion, our proteomics analysis identified the specific pathways in the ileum related to the different dietary doses of copper-fructose interactions, suggesting that distinct mechanisms in the gut are involved in the development of MASLD.

The liver plays a vital role in the defense against infections. Porphyromonas gingivalis (P. gingivalis), a dominant etiologic oral bacterium implicated in periodontal disease (PD), has been associated with various systemic diseases. This study aimed to investigate the influence of P. gingivalis on alcohol-associated liver diseases (ALD). Mice were fed a Lieber–DeCarli liquid diet containing 5% ethanol for 10 days after an initial adaptation period on a diet with lower ethanol content for 7 days. Two days before tissue sample collection, the mice were administered P. gingivalis strain W83 (Pg) through intraperitoneal injection (IP). Pair-fed mice with Pg infection (PF+Pg) exhibited an activated immune response to combat infections. However, alcohol-fed mice with Pg infection (AF+Pg) showed liver injury with noticeable abscess lesions and elevated serum alanine aminotransferase (ALT) levels. Additionally, these mice displayed liver infiltration of inflammatory monocytes and significant downregulation of proinflammatory cytokine gene expression levels; and AF+Pg mice also demonstrated increased intrahepatic neutrophil infiltration, as confirmed by chloroacetate esterase (CAE) staining, along with elevated gene expression levels of neutrophil cytosol factor 1 (Ncf1), neutrophilic inflammation driver lipocalin 2 (Lcn2), and complement component C5a receptor 1 (C5ar1), which are associated with neutrophilic inflammation. Interestingly, compared to PF+Pg mice, the livers of AF+Pg mice exhibited downregulation of gene expression levels of NADPH oxidase 2 (Cybb), the leukocyte adhesion molecule Cd18, and the Toll-like receptor adaptor Myd88. Consequently, impaired clearance of P. gingivalis and other bacteria in the liver, increased susceptibility to infections, and inflammation-associated hepatic necrotic cell death were observed in AF+Pg mice, which is likely to have facilitated immune cell infiltration and contributed to liver injury. Furthermore, in addition to the Srebf1/Fasn pathway induced by alcohol feeding, Pg infection also activated carbohydrate response element-binding protein (ChREBP) in AF+Pg mice. In summary, this study demonstrates that P. gingivalis infection, acting as a “second hit”, induces dysfunction of immune response and impairs the clearance of bacteria and infections in alcohol-sensitized livers. This process drives the development of liver injury.

Lipids play a significant role in life activities and participate in the biological system through different pathways. Although comprehensive two-dimensional liquid chromatography-mass spectrometry (2DLC-MS) has been developed to profile lipid abundance changes, lipid identification and quantification from 2DLC-MS data remain a challenge. We created Lipid Wizard, open-source software for lipid assignment and isotopic peak stripping of the 2DLC-MS data. Lipid Wizard takes the peak list deconvoluted from the 2DLC-MS data as input and assigns each isotopic peak to the lipids recorded in the LIPID MAPS database by precursor ion m/z matching. The matched lipids are then filtered by the first-dimension retention time (1D RT), followed by the second-dimension retention time (2D RT), where the 2D RT of each lipid is predicted using an equivalent carbon number (ECN) model. The remaining assigned lipids are used for isotopic peak stripping via an iterative linear regression. The performance of Lipid Wizard was tested using a set of lipid standards and then applied to study the lipid changes in the livers of mice (fat-1) fed with alcohol.