Alcoholic Liver Research Articles

Pueraria lobata-Prunus mume Complex Alleviates Alcoholic Liver Disease by Regulating Lipid Metabolism and Inhibiting Inflammation: A Transcriptome and Gut Microbiota Analysis.

Lipid metabolism disorder appears to be one of the early features of alcoholic liver disease (ALD), which can be speculated via omics analysis including liver transcriptomics and gut microbiota. A complex consisting of the roots of Pueraria lobata and dried fruits of Prunus mume (PPC), which possesses hepatoprotective effects, could serve as a drug or functional food. The lack of non-polysaccharide compounds in PPC with their moderation effects on gut microbiota suggests the necessity for a relevant study. Six groups of Kunming mice (control, Baijiu injury, silybin, low, medium, and high) were modelled by gavage with Baijiu (for 14 days) and PPC (equivalent to a maximum dose of 9 g/kg in humans). The liver transcriptome data were analyzed to predict gene annotation, followed by the verification of gut microbiota, serum, tissue staining, immunohistochemistry, and Western blotting. Liquid chromatography-mass spectrometry was used to detect the components. PPC normalized serum ALT (40 U/L), down-regulated TLR4-NF-κB signaling pathway to inhibit the release of TNF-α (90 pg/mL), improved the expression of occludin, claudin-4, and ZO-1, and restored the abundance of Muribaculaceae, Bacteroides and Streptococcus. PPC can alleviate ALD by regulating the gut microbiota with an anti-inflammatory and intestinal barrier, and has an application value in developing functional foods.

No causal relationship between serum vitamin D levels and alcoholic liver disease: a two-sample bidirectional Mendelian randomization study.

Numerous observational studies have presented an association between Vitamin D (VD) and Alcoholic Liver Disease (ALD). However, sufficient evidence from Randomized Controlled Trials (RCTs) substantiating this correlation is scarce, thus leaving the causality of this relationship ambiguous. To overcome the shortcomings of traditional observational studies, we performed a two-sample bidirectional Mendelian randomization (MR) analysis to ascertain the causal relationship between VD and ALD. We utilized summary statistics datasets from Genome-Wide Association Studies (GWAS) for VD and ALD. We selected genetic instruments that measure circulating VD levels (n = 64,979), and retrieved ALD statistics from GWASs, inclusive of 1,416 cases and 217,376 healthy controls, while excluding chronic liver diseases such as nonalcoholic fatty liver disease, toxic liver disease, and viral hepatitis. Subsequent, MR analyses were performed to obtain effect estimates using inverse variance weighted (IVW) random effect models. Cochran's Q statistic and MR-Egger regression intercept analyses were used to assess pleiotropy. Sensitivity analyses using the MR Egger, weighted median, simple mode, and weighted mode methods were also performed. Leave-one-out analysis was used to identify SNPs with potential effect. Reverse MR analysis was also performed. In IVW, our MR analysis incorporated 21 independent SNPs, circulating VD levels had no causal effect on ALD [OR = 0.624 (0.336-1.160), p = 0.136] and ALD had no causal effect on circulating VD [OR = 0.997 (0.986-1.008), p = 0.555]. No heterogeneity or pleiotropy was observed (p > 0.05). Other MR methods also agreed with IVW results. This study provides the causal relationship between genetically predicted circulating Vitamin D levels and ALD and provides new insights into the genetics of ALD.

Gamma-glutamyltransferase (GGT) is a predictor of NAFLD activity score for diagnosing non- alcoholic steatohepatitis (NASH)

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions ranging from simple steatosis to steatohepatitis, advanced fibrosis and end stage liver disease. Despite the high prevalence and severity of hepatic illness, NAFLD remains underdiagnosed, because of few symptoms, lack of accurate laboratory markers. The study was aimed at to evaluate a bio-chemical score for diagnosing non-alcoholic steatohepatitis. A hospital based cross-sectional observational study was carried out for a period of two years from July 2013 to June 2015 in the Department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. The study was conducted among 50 patients of NAFLD attending at department of Hepatology and underwent for biochemical investigations and liver biopsy with NAFLD Activity Score (NAS). All data were presented as mean ± SD and analyzed by SPSS (version 16). Qualitative data were analyzed by Chi-square test and quantitative data were analyzed by student’s t-test. Performance of the test were assessed by sensitivity and specificity test. Statistically significant result were considered when p value < 0.05. Total patients were divided into two groups 25 were NASH and 25 were non- NASH. Mean GGT was found 73.6±48.6 U/L in NASH group and 49.9±25.4 U/L in non-NASH group. There was significant difference in the NAFLD activity score for diagnosing NASH between elevated and normal GGT (P value 0.035). Higher GGT values correlated with higher specificity. The Gamma-lutamyltransferase (GGT) has been proposed as a noninvasive and available marker for assessment of NASH. Bangladesh Med J. 2023 May; 52(2): 6-10

Protective effects of fermented Rosa roxburghii Tratt juice against ethanol‑induced hepatocyte injury by regulating the NRF2‑AMPK signaling pathway in AML‑12 cells.

Alcohol‑related liver disease (ALD) is a major health concern worldwide. In recent years, there has been growing interest in natural products and functional foods for preventing and treating ALD due to their potential antioxidant and hepatoprotective properties. Rosa roxburghii Tratt, known for its rich content of bioactive compounds, has demonstrated promising health benefits, including anti‑inflammatory and antioxidant effects. Fermentation has been utilized as a strategy to enhance the bioavailability and efficacy of natural products. In the present study, using a mixture of Rosa roxburghii Tratt juice, lotus leaf extract and grape seed proanthocyanidins fermented by Lactobacillus plantarum HH‑LP56, a novel fermented Rosa roxburghii Tratt (FRRT) juice was discovered that can prevent and regulate ethanol‑induced liver cell damage. Following fermentation, the pH was significantly decreased, and the content of VC and superoxide dismutase (SOD) were significantly increased, along with a noticeable enhancement in hydroxyl and 2,2‑diphenyl‑1‑picrylhydrazyl free radical scavenging abilities. Alpha Mouse liver 12 cells were exposed to ethanol for 24 h to establish an in vitro liver cell injury model. The present study evaluated the effects of FRRT on cell damage, lipid accumulation and oxidative stress markers. The results revealed that FRRT pretreatment (cells were pre‑treated with 2.5 and 5 mg/ml FRRT for 2 h) significantly reduced lipid accumulation and oxidative stress in liver cells. Mechanistically, FRRT regulated lipid metabolism by influencing key genes and proteins, such as AMP‑activated protein kinase, sterol regulatory element binding transcription factor 1 and Stearyl‑CoA desaturase‑1. Furthermore, FRRT enhanced antioxidant activity by increasing SOD activity, glutathione and catalase levels, while reducing reactive oxygen species and malondialdehyde levels. It also reversed the expression changes of ethanol‑induced oxidative stress‑related genes and proteins. In conclusion, a novel functional food ingredient may have been discovered with extensive potential applications. These findings indicated that FRRT has antioxidant properties and potential therapeutic benefits in addressing ethanol‑induced liver cell damage through its effects on liver lipid metabolism and oxidative stress.

HYPERAMMONEMIA IS ASSOCIATED WITH INCREASING SEVERITY OF BOTH LIVER CIRRHOSIS AND HEPATIC ENCEPHALOPATHY

Hyperammonemia is a critical condition frequently observed in patients with liver cirrhosis and hepatic encephalopathy. Objectives: The study's main aim is to find that hyperammonemia is associated with increasing severity of both liver cirrhosis and hepatic encephalopathy. Methods: This retrospective cohort study was conducted at DHQ Hospital Nowshera Khyber Pakhtunkhwa from January 2023 to June 2023. A total of 175 patients diagnosed with liver cirrhosis were included in the study. Data collection was performed using the hospital's electronic medical records system. The variables collected included demographic data like patients’ age and sex and clinical data concerning the etiology of cirrhosis, Child-Pugh score, and MELD score. Results: The study included 175 patients with liver cirrhosis, with a mean age of 54.3 ± 12.7 years, of whom 64% were male and 36% female. The etiologies of cirrhosis were predominantly hepatitis C virus (45%), hepatitis B virus (30%), alcoholic liver disease (15%), and non-alcoholic steatohepatitis (10%). The mean Child-Pugh score was 8.7 ± 2.1, indicating moderate to severe liver disease, and the mean MELD score was 14.3 ± 4.5. The study found a strong positive correlation between ammonia levels and encephalopathy severity (r = 0.72, p < 0.001). Conclusion: It is concluded that hyperammonemia is significantly associated with the severity of liver cirrhosis and hepatic encephalopathy.

Alcohol- and Low-Iron Induced Changes in Antioxidant and Energy Metabolism Associated with Protein Lys Acetylation.

Understanding the role of iron in ethanol-derived hepatic stress could help elucidate the efficacy of dietary or clinical interventions designed to minimize liver damage from chronic alcohol consumption. We hypothesized that normal levels of iron are involved in ethanol-derived liver damage and reduced dietary iron intake would lower the damage caused by ethanol. We used a pair-fed mouse model utilizing basal Lieber-DeCarli liquid diets for 22 weeks to test this hypothesis. In our mouse model, chronic ethanol exposure led to mild hepatic stress possibly characteristic of early-stage alcoholic liver disease, seen as increases in liver-to-body weight ratios. Dietary iron restriction caused a slight decrease in non-heme iron and ferritin (FeRL) expression while it increased transferrin receptor 1 (TfR1) expression without changing ferroportin 1 (FPN1) expression. It also elevated protein lysine acetylation to a more significant level than in ethanol-fed mice under normal dietary iron conditions. Interestingly, iron restriction led to an additional reduction in nicotinamide adenine dinucleotide (NAD+) and NADH levels. Consistent with this observation, the major mitochondrial NAD+-dependent deacetylase, NAD-dependent deacetylase sirtuin-3 (SIRT3), expression was significantly reduced causing increased protein lysine acetylation in ethanol-fed mice at normal and low-iron conditions. In addition, the detection of superoxide dismutase 1 and 2 levels (SOD1 and SOD2) and oxidative phosphorylation (OXPHOS) complex activities allowed us to evaluate the changes in antioxidant and energy metabolism regulated by ethanol consumption at normal and low-iron conditions. We observed that the ethanol-fed mice had mild liver damage associated with reduced energy and antioxidant metabolism. On the other hand, iron restriction may exacerbate certain activities of ethanol further, such as increased protein lysine acetylation and reduced antioxidant metabolism. This metabolic change may prove a barrier to the effectiveness of dietary reduction of iron intake as a preventative measure in chronic alcohol consumption.

Alcoholic Liver Disease in China: A Disease Influenced by Complex Social Factors That Should Not Be Neglected.

Alcoholic liver disease (ALD) encompasses liver damage caused by chronic, excessive alcohol consumption. It manifests initially as marked hepatocellular steatosis and can progress to steatohepatitis, liver fibrosis, and cirrhosis. With China's rapid economic growth, coupled with a complex social background and the influence of a deleterious wine culture, the number of patients with ALD in China has increased significantly; the disease has become a social and health problem that cannot be ignored. In this review, we briefly described the social factors affecting ALD in China and elaborated on differences between alcoholic and other liver diseases in terms of complications (e.g., cirrhosis, upper gastrointestinal bleeding, hepatic encephalopathy, hepatocellular carcinoma, addiction, and other extrahepatic diseases). We also emphasized that ALD was more dangerous and difficult to treat than other liver diseases due to its complications, and that precise and effective treatment measures were lacking. In addition, we considered new ideas and treatment methods that may be generated in the future.

Sex and sobriety: Human brain structure and function in AUD abstinence

Women are drinking alcohol as much as men for the first time in history. Women experience more health-related consequences from alcohol use disorder (AUD), like increased prevalence of alcohol-related cancers, faster progression of alcohol-related liver disease, and greater risk for relapse compared to men. Thus, sex differences in chronic alcohol use pose a substantial public health problem. Despite these evident sex differences, our understanding of how these differences present during alcohol abstinence is limited. Investigations of brain structure and function are therefore critical for disentangling factors that lead to sex differences in AUD abstinence. This review will discuss current human neuroimaging data on sex differences in alcohol abstinence, focusing on structural and functional brain measures. Current structural imaging literature reveals that abstinent men have smaller gray and white matter volume and weaker structural connectivity compared to control men. Interestingly, abstinent women do not show differences in brain structure when compared to controls; instead, abstinent women show a relation between alcohol use and decreased measures of brain structure. Current functional brain studies reveal that abstinent men exhibit greater brain activation and stronger task-based functional connectivity to aversive stimuli than control men, while abstinent women exhibit lesser brain activation and weaker task-based functional connectivity than control women. Together, the current literature suggests that sex differences persist well into alcohol abstinence and impact brain structure and function differently. Understanding how men and women differ during alcohol abstinence can improve our understanding of sex-specific effects of alcohol, which will be critical to augment treatment methods to better serve women.

ALT levels, alcohol use, and metabolic risk factors have prognostic relevance for liver-related outcomes in the general population

Background & AimsA new nomenclature and subclassification for steatotic liver disease (SLD) was recently introduced. We validated the prognostic value of SLD subclasses in a Finnish population-based cohort and explored the impact of metabolic risk factors and alcohol consumption on liver-related outcomes and death. MethodsThe study included 23,910 individuals (47% men, mean age 50.5 ± 14.0 years, BMI 27.0 ± 4.7 kg/m2) from the FINRISK and Health 2000 health examination surveys with healthcare registry linkage for severe liver-related outcomes and deaths. SLD was identified by alanine aminotransferase (ALT) levels >20 U/L in women and >30 U/L in men (primary analysis) or fatty liver index (FLI) ≥60 (sensitivity analysis). ResultsThe prevalence of ALT-defined SLD was 43% (n = 10,380), with subclass rates of 34.5% for metabolic dysfunction-associated steatotic liver disease (MASLD), 4.2% for coexistent MASLD and alcohol-related liver disease (ALD) (i.e., MetALD), and 1.8% for ALD. During a median 13.3-year follow-up, we observed 129 liver-related events. MetALD and ALD increased the age- and sex-adjusted liver-related outcome risk by fourfold (HR 3.83, 95% CI 2.51–5.84, p <0.001) and eightfold (HR 7.90, 95% CI 5.16–12.30, p <0.001), respectively, compared with patients with MASLD. ALD was also associated with the highest risk for non-liver mortality. Metabolic risk factors were present in 93% and 96% of individuals with ALT-defined SLD and ALD, respectively. Alcohol use amplified the risk of liver-related outcomes in individuals with MASLD. Sensitivity analyses by the FLI were similar. ConclusionSLD is a significant public health concern. Nearly all ALD cases exhibit metabolic risk factors. Among ALT-defined SLD subclasses, ALD presents the highest risk for both liver-related and non-liver-related outcomes. Alcohol use increases the risk of liver-related outcomes in individuals with MASLD. Impact and implicationsThis study provides important information for physicians, researchers, and patients, demonstrating that the new classification of steatotic liver disease (SLD) has prognostic relevance at the population level. Evaluating the SLD subclass for a patient helps in understanding the magnitude of the risk for liver- and non-liver-related outcomes. In particular, the risks are highest in those with alcohol-related liver disease (ALD), but also increased in individuals with coexisting metabolic dysfunction-associated steatotic liver disease (MASLD) and ALD (MetALD) when compared with those with MASLD. However, alcohol use increased the risk of liver-related outcomes also in individuals with MASLD, highlighting the importance of evaluating alcohol use in every patient with SLD. Nearly all individuals with ALD have metabolic risk factors, and it is important to treat these factors to improve the survival of these patients.

A Prospective study on Prescribing patterns of drugs used in Alcoholic Liver disease patients at Tertiary Care Hospital in Vadodara – A Observational Study

A Prospective study on Prescribing patterns of drugs used in Alcoholic Liver disease patients at Tertiary Care Hospital in Vadodara – A Observational Study

Exploring the therapeutic potential of garlic in alcoholic liver disease: a network pharmacology and experimental validation study

ObjectiveEmploying network pharmacology and molecular docking, the study predicts the active compounds in garlic and elucidates their mechanism in inhibiting the development of alcoholic liver disease (ALD). ALD is a global chronic liver disease with potential for hepatocellular carcinoma progression.MethodsThe main active ingredients and targets of garlic were identified through screening the TCMSP, TCM-ID, and ETCM databases. ALD disease targets were sourced from DisGeNET, GeneCards, and DiGSeE databases, and intervention targets for garlic were determined through intersections. Protein interaction networks were constructed using the STRING platform, and GO and KEGG pathway enrichment analyses were performed with R software. The garlic component-disease-target network was established using Cytoscape software. Validation of active ingredients against core targets was conducted through molecular docking simulations using AutoDock Vina software. Expression validation of core targets was carried out using human sequencing data of ALD obtained from the GEO database.ResultsIntegration of garlic drug targets with ALD disease targets identified 83 target genes. Validation through an alcohol-induced ALD mouse model supported certain network pharmacology findings, suggesting that garlic may impede disease progression by mitigating the inflammatory response and promoting ethanol metabolism.ConclusionThis study provides insights into the potential therapeutic mechanisms of garlic in inhibiting ALD development. The identified active ingredients offer promising avenues for further investigation and development of treatments for ALD, emphasizing the importance of botanical remedies in liver disease management.

Malnutrition Severity Predicts Clinical Outcomes in Alcoholic Hepatitis: Evidence from National Data

Objective Alcoholic hepatitis (AH) represents a severe manifestation of alcoholic liver disease (ALD) associated with a wide severity spectrum. ALD is linked to nutritional deficiencies, with the gravity of malnutrition escalating as alcohol abuse and ALD progress. This study aims to delve into the impact of malnutrition on the clinical trajectory of AH. Methods We identified adult patients admitted with AH using the National Readmission Database (NRD) 2016–2020. We further classified AH patients based on the severity of malnutrition. We compared the outcomes of AH hospitalizations using a multivariate regression model. Results We included 82,367 AH patients, of whom 15,693 (19.00%) had malnutrition. 4,243 (5.15%) patients exhibited mild to moderate malnutrition, 5,862 (7.07%) patients had severe malnutrition, and 5,588 (6.78%) patients had unspecified severity of malnutrition. We found that adjusted in-hospital mortality due to AH was higher in patients with malnutrition, corresponding to the severity of malnutrition (adjusted odds ratio [aOR] 1.62 and 3.14 in mild-moderate malnutrition and severe malnutrition, respectively; p < .01). Additionally, patients with malnutrition had progressively elevated odds of septic shock, vasopressor requirement, mechanical ventilation, and intensive care unit (ICU) admission with escalating intensity of malnutrition. Liver-related complications, such as spontaneous bacterial peritonitis, coagulopathy, hepatorenal syndrome, and hepatic encephalopathy, were also found to have an increased likelihood in the presence of malnutrition. Furthermore, resource utilization showed a progressive increase with increasing severity of malnutrition. Conclusion Our findings indicate that malnutrition is a common comorbidity in AH patients, with varying degrees of severity, which correlates with higher mortality rates, emphasizing the critical role of nutritional status in the prognosis of AH. These findings underscore the importance of addressing and managing malnutrition in patients with AH, not only for its potential contribution to mortality but also because of its association with a spectrum of complications and increased healthcare resource utilization.

Inhibition of ethanol-induced eNAMPT secretion attenuates liver ferroptosis through BAT-Liver communication

Background & aimsExtracellular nicotinamide phosphoribosyltransferase (eNAMPT) has long been recognized as an adipokine. However, the exact role of eNAMPT in alcoholic liver disease (ALD) and its relevance to brown adipose tissue (BAT) remain largely unknown. This study aimed to evaluate the impact of eNAMPT on liver function and the underlying mechanisms involved in BAT-Liver communication. MethodsSerum eNAMPT levels were detected in the serum of both ALD patients and mice. Chronic and binge ethanol feeding was used to induce alcoholic liver injury in mice. An eNAMPT antibody, a coculture model of brown adipocytes and hepatocytes, and BAT-specific Nampt knockdown mice were used to investigate the role of eNAMPT in ALD. ResultsSerum eNAMPT levels are elevated in ALD patients and are significantly positively correlated with the liver injury index. In ALD mice, neutralizing eNAMPT reduced the elevated levels of circulating eNAMPT induced by ethanol and attenuated liver injury. In vitro experiments revealed that eNAMPT induced hepatocyte ferroptosis through the TLR4-dependent mitochondrial ROS-induced ferritinophagy pathway. Furthermore, ethanol stimulated eNAMPT secretion from brown adipocytes but not from other adipocytes. In the coculture model, ethanol-induced release of eNAMPT from brown adipocytes promoted hepatocyte ferroptosis. In BAT-specific Nampt-knockdown mice, ethanol-induced eNAMPT secretion was significantly reduced, and alcoholic liver injury were attenuated. These effects can be reversed by intraperitoneal injection of eNAMPT. ConclusionInhibition of ethanol-induced eNAMPT secretion from BAT attenuates liver injury and ferroptosis. Our study reveals a previously uncharacterized critical role of eNAMPT-mediated BAT-Liver communication in ALD and highlights its potential as a therapeutic target.

Prevalence and prognosis of patients with MASLD-related cirrhosis after an ICU hospitalization in France: A single-centre prospective study.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-related cirrhosis has been increasing these last decades. There are no data regarding the prevalence of MASLD-related cirrhosis in intensive care unit (ICU). Prospective single-centre study in a cohort of patients hospitalized in the ICU of Hepatology La Pitié-Salpêtrière Hospital between January 2019 and September 2021. We analysed three groups of patients: MASLD-cirrhosis (alcohol ≤210 g for men and 140 g weekly for women), ALD (alcohol-related liver disease, alcohol>140 g weekly for women or >210 g for men)-cirrhosis alone and MetALD (metabolic and alcohol-related liver disease)-cirrhosis. Endpoints were 1-year transplant-free survival (TFS), further acute decompensation (AD) and re-admission. A total of 410 patients were hospitalized, and 315 analysed: 39 in MASLD, 160 in ALD and 116 in MetALD groups. The global prevalence was 10% for MASLD, 41% ALD and 29.7% for MetALD. Patients in the MASLD group were significantly older (65 vs. 57 and 59 years, p < 0.001), and had lower Child-Pugh (8 vs. 11 vs. 10, p < 0.001) and MELD score (17 vs. 22 vs. 21, p < 0.001). The 1-year TFS was not different between groups (53% vs. 54% vs. 54%, p = 0.96). Cardiovascular mortality was <5% in all groups. The 1-year probability of developing hepatic encephalopathy was significantly higher in the MASLD group (73% vs. 27% and 21%, p < 0.001). There was no difference regarding the development of other complications between groups. MASLD or MetALD was responsible for 1/3 of the causes of cirrhosis in the ICU. MASLD-related cirrhosis is as severe as ALD-related cirrhosis. Liver transplantation should be rapidly discussed.

Blood Magnesium Level and Risk of Hepatocellular Carcinoma in a Prospective Liver Cirrhosis Cohort.

Higher magnesium intake was linked to a lower risk of hepatocellular carcinoma (HCC). However, the relationship between blood magnesium level and HCC has not been fully characterized, especially among patients with liver cirrhosis who are at a higher risk for HCC. In the Mass General Brigham Biobank, we developed a new prospective cohort of 1,430 patients with liver cirrhosis without liver cancer history using the validated International Classification of Diseases codes. We used Cox proportional hazards models to generate hazard ratios (HRs) with 95% confidence intervals (CI) for incident HCC and used generalized estimating equations to compare changes in liver biomarkers according to baseline blood magnesium, adjusting for age, sex, race, lifestyles, body mass index, type 2 diabetes, model for end-stage liver disease score, and hepatitis infection. During a median follow-up period of 4.26 years, 109 patients developed HCC. Magnesium deficiency (<1.70 mg/dL; N = 158) was associated with a higher risk of HCC (HR = 1.93; 95% CI, 1.12-3.30) compared with magnesium sufficiency (≥1.70 mg/dL;N= 1282). This association remained robust in the 1-year lag analysis (HR = 2.18; 95% CI, 1.11-4.28) and in sensitivity analysis excluding patients with alcoholic liver disease (HR = 2.41; 95% CI, 1.23-4.74). Magnesium in the lowest quartile was associated with a faster increase in alanine transaminase (β = 4.35; 95% CI, 1.06-7.63), aspartate aminotransferase(β = 6.46; 95% CI, 0.28-12.6), direct bilirubin (β = 0.18; 95% CI, 0.01-0.35), and total bilirubin (β = 0.21; 95% CI, 0.03-0.39), compared with the highest quartile. Lower blood magnesium level is associated with higher HCC risk and unfavorable liver biomarker changes. If confirmed, our findings may potentially enable better identification of high-risk patients for HCC and inform better management strategies for liver cirrhosis.

Connection of cirrhosis in the outcome of alcoholic liver disease with the PNPLA3 gene polymorphism rs738409

Connection of cirrhosis in the outcome of alcoholic liver disease with the PNPLA3 gene polymorphism rs738409

Apolipoprotein H deficiency exacerbates alcohol-induced liver injury via gut Dysbiosis and altered bile acid metabolism

BackgroundAPOH plays an essential role in lipid metabolism and the transport of lipids in the circulation. Previous studies have shown that APOH deficiency causes fatty liver and gut microbiota dysbiosis in mouse models. However, the role and potential mechanisms of APOH deficiency in the pathogenesis of alcoholic liver disease remain unclear. MethodsC57BL/6 WT and ApoH−/− mice were used to construct the binge-on-chronic alcohol feeding model. Mouse liver transcriptome, targeted bile acid metabolome, and 16S gut bacterial taxa were assayed and analyzed. Open-source human liver transcriptome dataset was analyzed. ResultsApoH−/− mice fed with alcohol showed severe hepatic steatosis. Liver RNAseq and RT-qPCR data indicated that APOH deficiency predominantly impacts hepatic lipid metabolism by disrupting de novo lipogenesis, cholesterol processing, and bile acid metabolism. A targeted bile acid metabolomics assay indicated significant changes in bile acid composition, including increased percentages of TCA in the liver and DCA in the gut of alcohol-fed ApoH−/− mice. The concentrations of CA, NorCA, and HCA in the liver were higher in ApoH−/− mice on an ethanol diet compared to the control mice (p < 0.05). Additionally, APOH deficiency altered the composition of gut flora, which correlated with changes in the liver bile acid composition in the ethanol-feeding mouse model. Finally, open-source transcript-level data from human ALD livers highlighted a remarkable link between APOH downregulation and steatohepatitis, as well as bile acid metabolism. ConclusionAPOH deficiency aggravates alcohol induced hepatic steatosis through the disruption of gut microbiota homeostasis and bile acid metabolism in mice.

A Comprehensive Investigation of Dietary Micronutrient Intakes and Risk of Alcoholic Liver Disease

BackgroundThe investigation of dietary micronutrient intakes and risk of alcoholic liver disease (ALD) based on observational studies was limited. ObjectivesOur study aimed to explore the associations of 30 dietary micronutrients intakes with risk of ALD, interactions between dietary micronutrients and genetic variation, and mediation effects of blood and urinary biomarkers on the associations between dietary micronutrients and risk of ALD. MethodsA case-control study was conducted within the UK Biobank cohort, with 231 incident ALD cases and 1386 controls. Dietary data were collected using a dietary questionnaire that relied on a 24-h dietary recall of the previous day. Logistic regression models were employed to assess the associations of dietary micronutrient intakes with risk of ALD. We conducted stratified analyses on the associations between dietary micronutrient intakes and risk of ALD by PNPLA3 rs738409 and tested the interactions between dietary micronutrients and genetic variation. In addition, we conducted mediation analyses to investigate the mediating effects of biomarkers on the associations between dietary micronutrients and risk of ALD. ResultsOur findings indicated significant inverse associations of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B-6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese with risk of ALD (all false discovery rate-Ptrend < 0.050). We also found a significant interaction between PNPLA3 rs738409 and magnesium (Pinteraction = 0.028). Creatinine (enzymatic) in urine, aspartate aminotransferase, and insulin-like growth factor 1 were the top 3 biomarkers with the highest number of significant mediation effects on the associations between the dietary micronutrients and risk of ALD. ConclusionsDietary intakes of thiamin, riboflavin, niacin equivalent, pantothenic acid, vitamin B-6, folate, vitamin E, calcium, magnesium, phosphorus, potassium, copper, iodine, and manganese were inversely associated with risk of ALD.

Etiology-Specific Effects of Impaired Functional Status on Liver Transplant Outcomes.

Pre-liver transplant (LT) functional status is an important determinant of prognosis post LT. There is insufficient data on how functional status affects outcomes of transplant recipients based on the specific etiology of liver disease. We stratified LT recipients by etiology of liver disease to evaluate the effects of functional status on post-LT prognosis in each subgroup. 2005-2019 United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) was used to select patients with liver transplant. A total of 14,290 patients were included in the analysis. These patients were stratified by functional status according to Karnofsky Performance Scale (KPS) score: no assistance, some assistance, or total assistance. They were then further divided into six diagnosis categories: metabolic dysfunction-associated steatotic liver disease (MASLD), hereditary disorders, hepatitis C, hepatitis B, autoimmune disease (AID), and alcoholic liver disease (ALD). Primary endpoints included all-cause mortality and graft failure, while secondary endpoints included organ-specific causes of death. Those under the age of 18 and those with non-whole liver or prior liver transplantation were excluded. Patients with MASLD requiring some assistance (aHR: 1.57, 95% CI 1.03-2.39, p = 0.04) and those requiring total assistance (aHR: 2.32, 95% CI 1.48-3.64, p < 0.001) had higher incidences of graft failure compared to those requiring no assistance. Those with MASLD requiring total assistance had a higher all-cause mortality rate than those needing no assistance (aHR: 1.62, 95% CI 1.38-1.89, p < 0.001). Patients with hereditary causes of liver disease showed a lower incidence of all-cause mortality in recipients needing some assistance compared with those needing no assistance (aHR: 0.52, 95% CI 0.34-0.80, p = 0.003). LT recipients with hepatitis C, AID, and ALD all showed higher incidences of all-cause mortality in the total assistance cohort when compared to the no assistance cohort. For the secondary endpoints of specific cause of death, transplant recipients with MASLD needing total assistance had higher rates of death due to general cardiac causes, graft rejection, general infectious causes, sepsis, general renal causes, and general respiratory causes. Patients with MASLD cirrhosis demonstrated the worst overall outcomes, suggesting that this population may be particularly vulnerable. Poor functional status in patients with end-stage liver disease from hepatitis B or hereditary disease was not associated with a significantly increased rate of adverse outcomes, suggesting that the KPS score may not be broadly applicable to all patients awaiting LT.

An alcohol-related liver disease multi-stakeholder hub (ARMS-Hub) to enhance research activity in underserved communities in the UK

Background Alcohol use is the third leading risk factor of death and disability in the UK and costs the NHS £3.5 billion per year. Despite the high prevalence and healthcare burden of Alcohol-related Liver Disease (ArLD), there has been minimal research addressing prevention, morbidity and mortality. Reasons for this include stigma and lack of interest from public, charitable and commercial funding bodies. The objectives of this project were to identify and develop interdisciplinary partnerships, to explore stigma in ArLD, to develop a representative Patient and Public Involvement and Engagement (PPIE) group, to build research capacity, and to develop interdisciplinary research proposals targeting key research priorities. Methods ArLD networks were identified by members of the Project Steering Group. Health Care Professionals (HCPs) from different backgrounds were invited to join the ARMS-Hub. PPIE representatives were invited through charities and support groups. Research areas were identified, discussed, prioritised and ranked. Research questions were refined during an in-person symposium. A mentorship programme was created to encourage and facilitate networking and knowledge exchange for early career researchers. Results We established the ARMS-Hub with 31 HCPs and 40 PPIE members. There were five stakeholder meetings, which included PPIE representation. Three virtual and three in-person PPIE meetings took place. Topics relevant to stigma in ARLD identified during the meetings were education and awareness, language, and access. Priorities identified were the disconnect between mental health and liver services, education around the wider harms of alcohol, and education of HCPs regarding stigma. We established a mentorship network that regularly meets to support development of new research ideas. Conclusions Stigma is central to lack of research engagement from professionals and PPIE. The main priority identified relates to the disconnect between mental health and liver services. This collaborative study has allowed development of a research agenda to address this priority.