Chronic consumption of large amounts of alcohol can lead to hepatic lipid accumulation and mitochondrial oxidative stress, resulting in alcoholic liver disease (ALD). Canagliflozin (Cana), an oral antidiabetic drug, regulates blood glucose by inhibiting sodium-glucose cotransporter-2 in renal tubulars, which also improves lipid metabolism and alleviates oxidative stress in hepatocyte. This study aims to determine the therapeutic effects of Cana on alcoholic liver injury and to explore the mechanistic pathways involved.

C57BL/6J male mice at 8 weeks were used to construct a model of alcoholic fatty liver disease using the chronic-plus-binge alcohol feeding model. Primary hepatocytes and AML12 cell lines were used as in vitro models. The effects and mechanisms of Cana on alcoholic liver injury were investigated by using immunofluorescence, ELISA, H&E and Oil Red O staining, RT-PCR, and western blotting analysis.

Cana treatment reduced hepatic lipid accumulation, decreased glutathione and TNF-α levels, alleviated oxidative stress and inflammation. Mechanistic studies revealed that Cana reduced FAS expression in the liver, decreasing hepatic fatty acid synthesis, and increased PPARα expression, promoting fatty acid oxidation. Additionally, Cana increased mitochondrial content and promoted mitophagy. These effects were mediated by the SIRT1-AMPK-mTORC1 signaling pathway.

Cana activates the SIRT1-AMPK-mTORC1 signaling pathway, inhibiting alcohol-induced fatty acid synthesis, promoting fatty acid degradation, thereby alleviating alcoholic liver injury.

Liver transplantation (LT) is the standard treatment for liver failure secondary to alcohol-associated liver disease, but limited literature and best practices exist for post-LT treatment of alcohol use disorder (AUD). This study explores current AUD management practices and providers' perceived barriers to effective post-LT AUD management.

A 45-item survey on post-LT AUD treatment practices was distributed to members of the American Society of Transplant Surgeons, the Association of Consult/Liaison Psychiatry Transplant Special Interest Group, and both the American Society of Transplantation's Liver and Intestine Community of Practice and Psychosocial and Ethics Community of Practice discussion boards, between December 2021 and April 2022. Univariate analysis of categorical variables was performed using the chi-square test. Data were analyzed using center volume tertiles, country region, and provider professional activity.

Two hundred thirty-two respondents from 70 LT centers across all 11 United Network for Organ Sharing regions completed the survey. Half of the them were attending physicians and 16.4% were nurse coordinators. Most centers (84%) aimed for alcohol abstinence for all post-LT patients. Perceived barriers to AUD treatment efficacy included ongoing desire to drink (18%), denial about alcohol misuse (14.9%), and lack of posttransplant support (14%). Additionally, 62.1% of centers had no policy for prescribing medication-assisted therapy to treat AUD, and 32.7% of centers reported no center-level changes in AUD care. Providers identified primary needs as hiring additional mental health professionals (30.8%), dedicating specific staff to AUD care (24.7%), and standardizing psychiatric/psychological care in transplant clinics (17.2%).

Despite the increasing volume of LT for alcohol-associated liver disease, significant perceived barriers to effective AUD treatment remain.

There are no FDA-approved therapies for alcohol-associated liver disease (ALD). Preclinical studies indicate that blocking IL-23/IL-17 signalling may reverse liver injury. Guselkumab, an IL-23-specific antibody approved for psoriasis, may be beneficial for ALD.

We aimed to assess the safety and tolerability of guselkumab in patients with ALD.

This phase-1 dose-escalation study included patients with ≥ 2 DSM-5 criteria for alcohol use disorder, significant steatosis (MRI-PDFF ≥ 8%) and MRE < 3.63 kPa (to exclude advanced disease). Guselkumab was given subcutaneously on Days 1 and 29 in 30, 70 or 100 mg dose cohorts. Primary endpoints were adverse events (AEs) and dose-limiting toxicity.

We enrolled 13 patients (three 30 mg, three 70 mg, and seven 100 mg). Eleven completed the study and two early discontinued in the 100 mg group. Of them, 77% were men, and the median age was 53 [IQR 49-61] years. The median MRI-PDFF and MRE were 18.4% [IQR 8.4%-34.0%] and 2.5 [2.2-2.6] kPa, respectively. The most frequent AEs were hyperuricemia (13%, mild only) and elevated lipase (11%, mild and moderate). There were no serious adverse events or significant variations in liver enzymes. There was a suppression of peripheral interleukin (IL)-17, IL-23, IL-1b and TNF-α in the 70 and 100 mg groups, and a significant decrease in alcohol consumption over time (AUDIT-C: 6 [3-7] vs. 5 [1-6], p = 0.023).

Guselkumab is safe in doses up to 100 mg and may reduce inflammation markers in ALD. These findings support further phase 2 studies to evaluate the efficacy of guselkumab in ALD, particularly in patients with severe phenotypes.

Early (i.e., without mandated period of abstinence) liver transplant (LT) for alcohol-associated hepatitis is the fastest-growing indication for LT in the United States and Europe. Harmful alcohol use after LT is associated with poor outcomes, but the distinction of establishing abstinence after return to drinking (i.e., reabstinence) is understudied. This study aims to characterize the survival outcomes of achieving reabstinence after post-LT harmful alcohol use.

We analyzed early LT recipients from 12 US LT centers between 2006 and 2021. Post-LT alcohol use was characterized as harmful using criteria of "binge" (≥5 [men] or ≥4 [women] drinks in < 24 hours) or "frequent" (≥4 days in one week) by interview or phosphatidylethanol >20 ng/mL. Reabstinence was defined as ≥12 consecutive months without harmful alcohol use after harmful alcohol use.

Among 347 LT recipients (64% male, median age 43, median Model for End-Stage Liver Disease-Sodium score 38) with median post-LT follow-up of 2.2 years (interquartile interval 1.1-3.6), 276 (80%) recipients had no evidence of harmful alcohol use, 35 (10%) recipients had reabstinence, and 36 (10%) recipients had continued harmful alcohol use without reabstinence. Five-year predicted survival, adjusted for age, sex, and Model for End-Stage Liver Disease-Sodium score, was lowest among LT recipients with continued harmful alcohol use (77%), but similar among those with no harmful use (93%) and reabstinence (94%).

Achieving reabstinence after post-LT harmful alcohol use is associated with similar 5-year post-LT survival compared with those without evidence of post-LT harmful alcohol use. Our findings highlight the importance of early detection and treatment of post-LT alcohol use.

Severe alcohol-associated hepatitis (SAH) is associated with high short-term mortality, and failure of response to corticosteroids is associated with a mortality of ~70%-80% within 6 months. Granulocyte colony-stimulating factor (G-CSF) has been studied in steroid non-responders; however, the data are limited.

This is a multicentre retrospective cohort study. The study period was from January 2016 to November 2023. SAH was defined as alcohol-associated hepatitis (ICD-10-CM codes) with serum bilirubin ≥ 5.0 mg/dL and INR ≥ 1.5. Other aetiologies of acute hepatitis and biliary obstruction were excluded. The primary outcome was 90-day median overall survival in SAH patients treated with G-CSF compared with standard medical therapy (SMT) or corticosteroids. Propensity score (1:1) matching was performed to control confounding variables.

Among 20 132 patients with SAH, 10800 (53.65%) were treated with corticosteroids and 224 (1.11%) G-CSF. The G-CSF group was younger (45.5 vs. 48.4) White (79.91% vs. 72.40%); however, there was no age or gender difference between G-CSF and corticosteroid groups. Whites and patients with more comorbidities received G-CSF more frequently than SMT or corticosteroids. After propensity score matching, 90-day overall survival was better in patients who received G-CSF (88.31% vs. 62.36%, p < 0.01) compared with SMT or corticosteroids (88.31% vs. 74.39%, p < 0.01). Patients on G-CSF had better 6-month transplant-free survival compared with SMT (83.53% vs. 55.36%, p < 0.001) or corticosteroids (82.89% vs. 60.21%, p < 0.001). Gastrointestinal bleeding was less common in G-CSF group compared with corticosteroids (5.02% vs. 10.50%, p < 0.001).

A small minority of patients with severe alcohol-associated hepatitis receive G-CSF. G-CSF improves 90-day overall survival in patients with severe alcohol-associated hepatitis and is non-inferior to corticosteroids.

In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial.

Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, with death treated as a competing event. Risk factors considered were age, sex, mean arterial pressure, white blood cell count, albumin, MELD, ascites, HE, and treatment arm. At baseline, no participants had AKI; 33% (n=49) developed AKI during follow-up. AKI incidence was higher in A+Z than in PRED (45% [n=33] versus 22% [n=16], p =0.001). AKI phenotypes were similar between the 2 treatment arms ( p =0.361), but peak AKI severity was greater in A+Z than PRED (stage 3 n=21 [63.6%] vs. n=8 [50.0%], p =0.035). At baseline, urine-neutrophil-gelatinase-associated lipocalin levels were similar between participants who developed AKI in both treatment arms ( p =0.319). However, day 7 and 14 urine-neutrophil-gelatinase-associated lipocalin levels were significantly elevated in participants treated with A+Z who developed AKI versus participants treated with PRED who developed AKI ( p =0.002 and 0.032, respectively). On multivariable competing risk analysis, only A+Z was independently associated with incident AKI (subdistribution hazard ratio 2.35, p =0.005).

AKI occurred more frequently and was more severe in participants treated with A+Z. A+Z-treated participants with AKI had higher urine-neutrophil-gelatinase-associated lipocalin, suggesting that A+Z maybe nephrotoxic in patients with severe alcohol-associated hepatitis.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise in reducing alcohol consumption, but their impact on clinical outcomes in patients with alcohol use disorder (AUD) remains unclear. We investigated the association between GLP-1RAs and the development and progression of alcohol-related liver disease (ArLD) in patients with AUD.

Using the TriNetX Research Network, we conducted two retrospective cohort studies comparing GLP-1RAs versus dipeptidyl peptidase-4 inhibitors (DPP-4is) in patients with type 2 diabetes. The first cohort included patients with AUD but without ArLD (n = 7132 after propensity score matching), while the second comprised patients with established ArLD (n = 1896 after matching). Primary outcomes were incident ArLD in the AUD cohort and hepatic decompensation in the ArLD cohort.

In the AUD cohort (median follow-up: 63.2 months), GLP-1RA users showed significantly lower risks of developing ArLD compared to DPP-4i users (incidence rate: 6.0 vs. 8.7 per 1000 person-years; HR: 0.62, 95% CI: 0.44-0.87, p = 0.006). GLP-1RAs were also associated with reduced risks of all-cause mortality (HR: 0.53, p < 0.001). In the ArLD cohort (median follow-up: 28.2 months), GLP-1RA users demonstrated lower risks of hepatic decompensation (incidence rate: 39.5 vs. 51.4 per 1000 person-years; HR: 0.66, 95% CI: 0.51-0.85, p = 0.001) and all-cause mortality (HR: 0.53, p < 0.001) compared to DPP-4i users.

GLP-1RAs were associated with reduced risks of developing and progressing ArLD in patients with AUD, suggesting potential therapeutic benefits in this population.

Alcohol use disorder (AUD) incidence is increasing, and alcohol-associated liver disease is the leading indication for liver transplantation (LT) in the United States. Many centers have adopted "early LT" (ELT) for patients with <6 mo of abstinence. This study evaluates whether ELT outcomes in acutely ill recipients are equivalent to standard LT (SLT).

We retrospectively analyzed LTs for alcohol-associated liver disease in patients with AUD at a single center between January 2019 and December 2021. Patients were categorized as ELT (<6 mo) or SLT (≥6 mo). Alcohol relapse was categorized as "abstinent," "slip," or "harmful," with use defined by phosphatidylethanol or self-reported consumption. Outcomes were post-LT relapse, graft, and patient survival.

Of 183 patients (ELT: 99 [54.1%]; SLT: 84 [45.9%]), ELT recipients were younger, had higher model for end-stage liver disease scores, shorter waitlist times, and were more frequently in intensive care unit pre-LT. Multivariable analysis showed no association in time to post-LT relapse, graft, or patient survival. Intensive care unit status was associated with lower relapse risk (hazard ratio, 0.17; 95% confidence interval, 0.07-0.43; P < 0.001), whereas higher education levels were associated with higher risk (hazard ratio, 2.31; 95% confidence interval, 1.18-4.49; P = 0.014).

Pre-LT alcohol abstinence duration does not significantly impact post-LT relapse or survival. ELT should be considered for acutely ill patients with AUD.

Fu Brick tea (FBT) extract has been demonstrated to lower blood lipids, protect liver, and prevent obesity. Despite these benefits, there are no products on the market that combine FBT with other foods or beverages.

In this study, we developed a novel product by combining FBT with high-alcohol Jiang-flavor baijiu, resulting in FBT-baijiu. High-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis revealed that FBT-baijiu contains health-promoting alkaloids, including eurocristatine (13.60 ± 0.13 mg/L), (-)-neoechinulin A (10.26 ± 0.09 mg/L), neoechinulin D (7.89 ± 0.05 mg/L), variecolorin G (6.94 ± 0.05 mg/L), and echinulin (25.46 ± 0.27 mg/L), which are known to be present in FBT. The aroma compounds of the FBT-baijiu and the base baijiu were analyzed using comprehensive gas chromatography-olfactometry-mass spectrometry (GC-O-MS) technology. The major volatile compounds of two baijiu samples were identified using relative odor activity values (r-OAVs) analysis. The FBT-baijiu showed a significant reduction in ester content, but a remarkable enhancement in aromatic properties. The findings show that combining FBT with baijiu not only offers functional components but also enhances the flavor profile.

This study highlights the potential of utilizing FBT as a functional food ingredient or additive, paving the way for the development of new health-promoting products. © 2024 Society of Chemical Industry.

The quantitative effects of alcohol consumption on cirrhosis and hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) infection are unknown. This study aimed to establish a dose-dependent model of alcohol consumption on the risks of cirrhosis and HCC.

PubMed, Embase, the Cochrane Library, Web of Science, and four Chinese databases were searched for studies published from their inception to 15 May 2024. A random-effects model was used to pool the data on the incidence of cirrhosis and HCC, and a dose-dependent model of alcohol's effect on cirrhosis and HCC was established.

A total of 33,272 HBV patients from 45 studies were included. Compared with non-drinkers, the overall pooled odds ratio (OR) for cirrhosis was 2.61 (95% confidence interval [CI]: 1.46-4.66; I2 = 94%, p < 0.001), and the OR for HCC was 2.27 (95% CI: 1.50-3.43; I2 = 90%, p < 0.001) among drinkers. Compared with low-level drinkers, the estimated pooled OR for cirrhosis was 2.34 (95% CI: 1.59-3.44; I2 = 87%, p < 0.001), and the OR for HCC was 2.42 (95% CI: 1.90-3.09; I2 = 80%, p < 0.001) among high-level drinkers. Furthermore, a linear dose-dependent analysis showed that each daily consumption of 12 g of alcohol increased the risk of cirrhosis by 6.2% and the risk of HCC by 11.5%.

Alcohol dose-dependently increases the risks of cirrhosis and HCC in patients with HBV infection, and patients with daily alcohol consumption of more than 12 g should be strictly monitored.

Liver histology is the classic method for staging the severity of liver fibrosis, which in turn is an important predictor of clinical outcome. Here, we have hypothesized that the susceptibility to develop fibrosis varies among racial groups.

We examined the histology of all patients over 18 years of age who underwent liver biopsy at the Medical University of South Carolina from 1/1/2013 to 7/1/2021. Patients with malignancy, liver metastases, or missing data were excluded. Fibrosis was quantified using the Batts-Ludwig system (F0 = no fibrosis to F4 = histological cirrhosis). Racial groups were propensity matched based on age, gender, diabetes, alcohol consumption, and CDC/ATSDR Social Vulnerability Index Themes to mitigate the risk of selection bias.

We identified 1101 patients with liver biopsy histological fibrosis scores. The cohort included 23% Black patients. After propensity matching, Black patients were significantly more likely to have Hepatitis C (73/228 (32%) vs 45/228 (20%), p < 0.001) and autoimmune hepatitis (34/228 (15%) vs 6/228 (3%), p < 0.001) than White patients, while White patients were significantly more likely to have metabolic dysfunction associated steatotic liver disease (71/228 (31%) vs 18/228 (8%), p < 0.001). White patients were significantly more likely to have cirrhosis than Black patients (White - 89/228 (39%) vs Black - 68/228 (30%), p < 0.05).

White patients had a greater overall burden of advanced fibrosis (F4/cirrhosis) than Black patients, independent of etiology. The data suggest that fibrosis risk and/or progression may be worse in White than Black patients.

Innate immunity provides the critical first line of defense against infection and sterile triggers. Cell death is a key component of the innate immune response to clear pathogens, but excessive or aberrant cell death can induce inflammation, cytokine storm, and pathology, making it a central molecular mechanism in inflammatory diseases. Alcohol-associated liver disease (ALD) is one such inflammatory disease, but the specific innate immune mechanisms driving pathology in this context remain unclear. Here, by leveraging RNAseq and tissue expression in clinical samples, we identified increased expression of the innate immune sensor Z-DNA binding protein (ZBP1) in patients with ALD. We discovered that ZBP1 expression correlated with ALD progression in patients, and that ethanol induced ZBP1-dependent lytic cell death, PANoptosis, in immune (macrophages, monocytes, Kupffer cells) and non-immune cells (hepatocytes). Mechanistically, the interferon regulatory factors (IRFs) IRF9 and IRF1 upregulated ZBP1 expression, allowing ZBP1 to sense Z-NAs through its Zα2 domain and drive PANoptosis signaling, cell membrane rupture through NINJ1, and DAMP release. Furthermore, the expressions of ZBP1 and NINJ1 were upregulated in both liver and serum samples from patients with ALD. In mouse models of chronic and acute ALD, ZBP1-deficient mice were significantly protected from disease pathology and liver damage. Overall, our findings establish the critical role of the ZBP1-NINJ1 axis regulated by IRFs in driving inflammatory cell death, PANoptosis, in liver cells, suggesting that targeting these molecules will have therapeutic potential in ALD and other inflammatory conditions.

Aminotransferases, particularly alanine aminotransferase (ALT), are commonly used in the detection, diagnosis, and management of chronic liver diseases. ALT, a sensitive and cost-effective marker of liver injury, remains pivotal in predicting clinical outcomes and guiding interventions in several chronic liver diseases including metabolic dysfunction-associated steatotic liver disease, and chronic viral hepatitis. This study aims to explore the evolving role of ALT as a biomarker. A comprehensive review of evidence was conducted, focusing on studies evaluating ALT thresholds, diagnostic accuracy, and integration with non-invasive liver assessment tools. Special emphasis was given to novel approaches, including artificial intelligence-driven algorithms. Expert opinions from hepatology care perspectives were considered to assess the practical implications of refining ALT-based diagnostic strategies. ALT levels are influenced by diverse factors such as age, gender, and metabolic risks, challenging the use of specific thresholds as biomarker of disease and prognosis. Emerging evidence suggests redefining ALT ranges to enhance sensitivity and accuracy in detecting liver abnormalities. The integration of ALT with advanced non-invasive diagnostic tools, artificial intelligence, and comprehensive patient assessments can optimize early detection of liver disease, thus reducing underdiagnosis, particularly in asymptomatic or vulnerable populations. This work highlights the urgency to tailor the diagnostic approaches in primary and specialized care, ensuring timely and targeted intervention to effectively address the global burden of liver diseases.

Alcohol use disorder and alcohol-associated liver disease is increasing in the US, with subsequent and expected increases in morbidity and mortality due to these conditions.

To determine the impact of an educational intervention regarding alcohol use disorder on gastroenterology fellows.

A before-after survey study was carried out. Subjects were gastroenterology fellows at an urban tertiary care facility, who completed a pre-questionnaire and then attended a one-hour educational lecture on alcohol use disorder, alcohol-related liver disease, and treatment/resources available for patients. Immediately after the 1-h lecture, fellows were asked to complete a post-questionnaire and then a delayed questionnaire three months later. Pre- and post-answers were averaged out of a scale of 5 and analyzed using t-tests.

The study included eight fellows. Post-intervention, 12% of fellows felt more confident in having adequate training to provide alcohol use disorder counseling to their patients, 25% felt more confident in who they should refer their patients to for alcohol use disorder, and 16% felt more comfortable in being able to speak with their patients regarding alcohol use disorder and help effectively reduce their patients' consumption of alcohol (p value < 0.05).

A 1-h presentation discussing the complexities associated with diagnosing and treating alcohol use disorder, and the methods of helping destigmatize the disease in the medical community, can increase trainees' confidence and knowledge base to help treat patients with alcohol use disorder in the clinic setting and reducing liver morbidity.

Chronic alcohol consumption leads to lipid accumulation, oxidative stress, cellular damage, and inflammation in the liver, collectively referred to as alcohol-associated liver disease (ALD). FAF2/UBXD8/ETEA (Fas-associated factor 2) is a ubiquitin ligase adaptor protein that plays a crucial role in the ubiquitin-mediated degradation of misfolded proteins in the endoplasmic reticulum. A recent genome-wide association study indicated an association between FAF2 and ALD; however, the exact contribution of FAF2 to ALD pathogenesis remains unclear.

FAF2 was knocked down using AAV-delivered shRNA in C57/BL6 mice. Mice were subjected to a chronic-plus-single binge ethanol feeding (NIAAA) model. Nine hours after gavage, liver, blood, and other organs of interest were collected for gene expression and biochemical analyses.

We first observed a significant elevation in hepatic FAF2 protein expression in individuals with ALD and in mice subjected to an ethanol-binge model. Interestingly, knocking down FAF2 in the liver using adeno-associated virus serotype 8-delivered short hairpin RNA conferred a protective effect against alcohol-induced liver steatosis in ethanol-binged mice. Transcriptomic analysis revealed that differentially expressed genes were enriched in multiple lipid metabolism regulation pathways. Further analysis of transcription factors regulating these differentially expressed genes suggested potential regulation by SREBP1. Several SREBP1 target genes, including Fasn, Scd1, Lpin1, and Pcsk9 (proprotein convertase subtilisin/kexin type 9), were dysregulated in the livers of ethanol-fed FAF2 knockdown mice. Additionally, Pcsk9 could be regulated through the FOXO3-SIRT6 pathway in the livers of ethanol-fed FAF2 knockdown mice, leading to increased liver low-density lipoprotein receptor expression and reduced plasma LDL cholesterol levels. Furthermore, FAF2 knockdown in mouse liver enhanced adipose triglyceride lipase lipolytic activity by upregulating the adipose triglyceride lipase activator, comparative gene identification-58, and downregulating the adipose triglyceridelipase transport inhibitor, Elmod2, contributing to the alleviation of liver steatosis.

Our study uncovers a novel mechanism involving FAF2 in the pathogenesis of ALD.

Alcohol-associated liver disease (ALD) disproportionately impacts men, racial and ethnic minorities, and individuals of low socioeconomic status; however, it's unclear how recent increases in ALD burden have impacted these disparities. We aimed to describe trends in racial, ethnic and socioeconomic disparities in alcohol-associated hospital encounters.

We conducted a retrospective cohort study of adult hospital encounters with alcohol-associated diagnoses from three health systems between January 2016 and December 2021. The cohort was divided into three eras: a 'Historical Era,' (Oct 2016-June 2018, used only for trends); 'Era 1' (July 2018-March 2020); and 'Era 2' (April 2020-December 2021). Kaplan Meier and Cox regression analyses were performed to identify factors associated with overall survival.

We identified 19,295 individuals with alcohol-associated encounters (44.7% White, 29.8% Hispanic, and 21.8% non-Hispanic Black (NHB) individuals), with a greater increase observed between eras 1 and 2 than the historical era and Era 1 (8.7% vs. 5.0%, p < 0.01). By age and sex, the greatest increases in encounters were observed in the youngest and oldest females but only the oldest males. By race and ethnicity, Hispanic individuals had greater increases in encounters compared to Black and White individuals (14.8% vs. 7.5% and 6.3%, p < 0.01). Older age (aSHR: 1.03, 95% CI: 1.03-1.0), higher MELD (aSHR: 1.08, 95% CI: 1.0-1.09), hepatic encephalopathy (aSHR: 1.42, 95% CI: 1.06-1.90), and hepatocellular carcinoma (HCC) (aSHR: 3.20, 95% CI: 2.29-4.49) were associated with increased mortality.

The highest increases of alcohol-associated encounters were observed amongst young Hispanic and NHB women, highlighting variation in trends by age, sex, race and ethnicity. These disparities merit further investigation to elucidate underlying mechanisms and develop tailored interventions to improve ALD burden and outcomes.

Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis.

Molecular (prognostic liver secretome signature with α-fetoprotein) and clinical (aMAP [age, male sex, albumin-bilirubin, and platelets] score) variable-based scores were integrated into PAaM (prognostic liver secretome signature with α-fetoprotein plus age, male sex, albumin-bilirubin, and platelets), which was subsequently validated in 2 phase 3 biomarker validation studies: the statewide Texas HCC Consortium and nationwide HCC Early Detection Strategy prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events.

Of 2156 patients with cirrhosis in the Texas HCC Consortium, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared with low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios for incident HCC of 7.51 (95% CI, 4.42-12.8) and 4.20 (95% CI, 2.52-7.01), respectively. Of 1328 patients with cirrhosis in the HCC early detection strategy, PAaM identified 201 high-risk (15%), 540 intermediate-risk (41%), and 587 low-risk (44%) patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate-risk groups were associated with sub-distribution hazard ratios for incident HCC of 6.54 (95% CI, 3.85-11.1) and 1.77 (95% CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease and cured hepatitis C infection.

PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies.

The enhanced liver fibrosis (ELF) test has good discrimination performance in detecting advanced liver fibrosis. The chronic liver disease (CLivD) risk score based on clinical data accurately predicts risk for future severe liver disease. Considering the ELF test as a surrogate marker for liver fibrosis, we analyzed predictors of elevated ELF (eELF) and its change.

The study cohort consisted of Finnish general population-based health surveys Health2000 and a follow-up study 10 years later Health2011 with 6084 and 2937 individuals, respectively with phenotype and ELF data. eELF was defined as ELF ≥ 9.8, and clinically relevant fibrosis progression as an ELF change ≥0.6. CLivD risk score was calculated at baseline. Analyses were age-adjusted.

Obesity measures and diabetes predicted eELF at baseline. Only waist-hip ratio (WHR) could predict clinically relevant fibrosis progression over the follow-up consistently among men and women (OR 1.35 and 1.41, respectively). High-risk alcohol use was a significant risk factor for eELF only among men (OR 1.72, p = 0.049), and it did not predict fibrosis progression in either sex. Although elevated transaminases were associated with eELF, in most individuals with eELF they were within reference limits. Increased CLivD scores correlated with baseline and the change of ELF values over the 10-year follow-up independent of baseline ELF (p < 0.001).

Liver fibrosis progression is difficult to predict based on single risk factors or liver enzymes. ELF had limited value to predict fibrosis progression. The CLivD score, based on multiple risk factors, predicted both occurrence of baseline eELF and its progression over a 10-year follow-up.

In order to understand and curb the harms related to alcohol, it will be necessary to think beyond patterns of use that meet criteria for a diagnosis of alcohol use disorder or addiction. Current research suggests that regular daily alcohol use does not confer a health benefit, and, for many persons, even relatively low consumption is associated with a health risk. Determining a safe limit for alcohol consumption is challenging both for the individual person and for society. We conclude that excessive drinking is always risky. We provide a list of circumstances, such as chronic illness, driving a vehicle, or pregnancy where persons should be advised to abstain from alcohol. We recognise the need to encourage less consumption of alcohol, particularly in young adults and older adults with co-morbid conditions (especially if taking multiple medications). Finally, we offer the modest proposal that, for persons without the contributing negative influences described above, consumption which adheres to one drink per session, with interspersed abstinent days, does not constitute a meaningful risk to health.

This consensus statement gives practical advice for the safe management of patients with harmful alcohol intake undergoing elective and emergency surgery. The wide spectrum of alcohol-related organ dysfunction observed in this cohort of patients may have a profound impact on care, and the additional effects of alcohol withdrawal may further exacerbate postoperative morbidity and mortality.

A working party was assembled based on clinical and/or academic expertise in the area. Recommendations were formulated using a modified Delphi process. An initial list of recommendations was produced following targeted literature reviews for all relevant phases of patient care throughout the peri-operative pathway. These recommendations were distributed among the authors who rated each as 'include', 'exclude'; or 'revise'. Recommendations with ≥ 75% inclusion decision were included.

The working party produced a list of 10 key peri-operative management recommendations. These include recommendations on how to screen effectively for excessive alcohol usage in the surgical population. To achieve this, a validated point-of-care tool is used with additional weighting provided by considering surgical urgency. This is combined with the use of scoring systems to facilitate decisions regarding peri-operative care including postoperative location. This document also provides clear explanation of the physiological and pharmacological issues relating to alcohol excess, highlighting the direct effects of alcohol and its secondary effects on organ systems.

This consensus statement offers strategies and solutions to minimise the impact of harmful alcohol intake on the safe conduct of anaesthesia.

The relationship between coronary artery calcium (CAC) and progression of diastolic dysfunction (DD) during longitudinal follow-up is uncertain. This study aimed to investigate the prevalence and progression of DD according to severity of CAC and understand their synergistic effect on mortality.

This was a population-based cohort study. All 15,193 adults who underwent a health screening exam with simultaneous echocardiography and CAC scan were enrolled. Definite DD (≥ 3/4 abnormal parameters for DD [e', E/e', tricuspid regurgitation velocity, and left atrial volume index]) and definite or probable DD (≥ 2/4) were defined. All-cause mortality was assessed based on the CAC and DD.

Among the population, 7995 participants (52.6%) had CAC = 0; 4661 (30.7%) had 0 < CAC < 100; and 2537 (16.7%) had CAC ≥ 100. The prevalence ratios for definite (adjusted ratio: 1.72, 95% CI: 1.23-2.22) and definite or probable DD (adjusted ratio: 1.83, 95% CI: 1.31-2.36) were significantly higher in individuals with CAC ≥ 100 than in those with CAC = 0. There was significant linear association of CAC with E/e' (adjusted p for linearity = 0.001). Compared with CAC < 100 without definite DD, the adjusted HRs with 95% CI for mortality of CAC ≥ 100 without definite DD, CAC < 100 with definite DD, and CAC ≥ 100 with definite DD were 2.56 (95% CI: 1.67-3.94), 3.08 (95% CI: 1.28-7.39), and 3.91 (95% CI: 1.68-9.10). Among participants without DD at CAC measurement who had at least two echocardiographic measurements, the presence of significant CAC (≥ 100) was significantly associated with accelerated progression in definite DD over time (adjusted HR: 1.46, 95% CI: 1.13-1.88), with more rapid elevation of E/e' during follow-up (difference: 0.06, 95% CI: 0.02-0.10, p = 0.003).

In the general population, there was a significant relationship between CAC and prevalence of DD, and both subclinical parameters were associated with increased mortality. Moreover, CAC ≥ 100 significantly affects the progression of DD independently of other clinical factors.

Excessive alcohol consumption is a major risk factor for liver disease, with significant variations in its impact across populations. BMI has been identified as a potential mediator in alcohol-related liver damage. This study aimed to examine the association between alcohol consumption and liver function and to explore the mediating role of BMI in a population from India, where both are rising public health concerns.

A cross-sectional study was conducted using data from adult participants. Liver function was assessed using serum levels of gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Alcohol consumption was self-reported, and BMI was calculated AST from height and weight measurements. Multiple linear regression models were used to evaluate the relationship between alcohol consumption and liver enzymes while adjusting for BMI as a mediator. Statistical significance was set at P < 0.05.

The results indicated that higher alcohol consumption was significantly associated with elevated levels of GGT, ALT, and AST. BMI was found to mediate this relationship, with individuals having higher BMI showing a greater increase in liver enzyme levels in response to alcohol consumption. However, no significant association was observed for ALP. BMI also independently correlated with higher levels of GGT, ALT, and AST.

This study highlights the mediating role of BMI in alcohol-induced liver dysfunction in the Indian population. Public health interventions focusing on both reducing alcohol intake and managing obesity may help mitigate the risk of liver disease in this high-risk population.

Alcohol use disorder is a prevalent and major but preventable cause of morbidity and mortality worldwide, causing several important health consequences, including chronic liver disease. Despite its substantial effects, most clinicians do not adequately assess alcohol intake in clinical practice, and there are several barriers to providing integrated management to patients with alcohol use disorder. Standardised questionnaires, such as the Alcohol Use Identification Test (AUDIT), can facilitate the identification of individuals at risk of alcohol use disorder, and alcohol biomarkers such as phosphatidylethanol aid in quantifying levels of alcohol consumption. Non-pharmacological interventions-including brief interventions, twelve-step facilitation, motivational enhancement therapy, contingency management, and cognitive behavioural therapy-are effective for patients with alcohol use disorder, regardless of the presence of advanced liver disease. Pharmacological treatments should be considered according to the severity of liver disease and other comorbidities, safety profile, and local availability. The management of patients with alcohol use disorder and associated liver disease should ideally be performed in the setting of integrated multidisciplinary teams.

Alcohol Use Disorder (AUD) significantly affects global health, leading to physical deterioration and impacting personal and social relationships. This study aims to evaluate the adverse event profiles (AEP) of three USFDA-approved medications for AUD, acamprosate, disulfiram, and naltrexone, using data from the USFDA Adverse Event Reporting System (AERS).

Reports related to acamprosate, disulfiram, and naltrexone from March 2004 to March 2024 were extracted from the USFDA AERS database. Data were verified, and disproportionality analysis was conducted using frequentist and Bayesian methods. Adverse events were assessed based on reporting odds ratio, proportional reporting ratio, and Bayesian measures. Outcomes such as death, life-threatening events, and hospitalization were also analyzed.

A total of 19,177 unique reports were analyzed (naltrexone: n = 18,544; acamprosate: n = 249; disulfiram: n = 384). Common adverse events included hepatobiliary, nervous system, and psychiatric disorders. Disulfiram was associated with coagulopathy and drug interactions, while naltrexone was linked to injection site reactions and hypersensitivity. Naltrexone had higher mortality reports, and disulfiram had more hospitalizations.

The study underscores the diverse AEPs of these medications, highlighting the need for careful monitoring and individualized treatment to ensure safety and efficacy in managing AUD.

The liver is a sexually dimorphic organ. Sex differences in prevalence, progression, prognosis, and treatment prevail in most liver diseases, and the mechanism of how liver diseases act differently among male versus female patients has not been fully elucidated. Biological sex differences in normal physiology and disease arise principally from sex hormones and/or sex chromosomes. Sex hormones contribute to the development and progression of most liver diseases, with estrogen- and androgen-mediated signaling pathways mechanistically involved. In addition, genetic factors in sex chromosomes have recently been found to contribute to the sex disparity of many liver diseases, which might explain, to some extent, the difference in gene expression pattern, immune response, and xenobiotic metabolism between men and women. Although increasing evidence suggests that sex is one of the most important modulators of disease prevalence and outcomes, at present, basic and clinical studies have long been sex unbalanced, with female subjects underestimated. As such, this review focuses on sex disparities of liver diseases and summarizes the current understanding of sex-specific mechanisms, including sex hormones, sex chromosomes, etc. We anticipate that understanding sex-specific pathogenesis will aid in promoting personalized therapies for liver disease among male versus female patients.

Alcoholic hepatitis (AH), a clinical syndrome precipitated by chronic alcohol consumption, constitutes about 0.9 % of total admissions in the United States. It presents a wide severity spectrum, from mild disease to severe cases associated with high mortality. Palliative care (PC) is a specialized medical approach focused on enhancing the quality of life for patients with serious or life-threatening illnesses. This study aims to investigate the national trends of palliative care (PC) utilization in AH hospitalizations and its impact on resource utilization.

We identified adult AH hospitalizations from the Nationwide Readmission Database, further categorized based on PC utilization. Multivariate regression analysis was employed to evaluate the impact of PC on the 90-day readmission rate.

Among the 68,062 AH patients, 3,784 (5.56 %) utilized PC services. PC utilization in AH hospitalizations was associated with a significantly lower 90-day readmission rate (adjusted hazard ratio (aHR) 0.45, P = 0.02). 90-day readmission benefits with PC were persistent on analysis of severe (North American Consortium for the Study of End-Stage Liver Disease-Acute-on-Chronic Liver Failure [NACSELD-ACLF] score ≥1) AH population as well (aHR 0.46, P < 0.01). Trend analysis of PC utilization in AH hospitalizations revealed a non-significant change from 5.39 % in 2016 to 5.69 % in 2020 (P = 0.07).

This study shows that PC utilization in AH hospitalizations reduces readmissions and healthcare burden. We advocate integrating PC into the comprehensive management of AH. Further research is needed to determine the optimal timing and components of PC interventions for AH patients.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

Larsucosterol is a DNA methyltransferase inhibitor in development for alcohol-associated hepatitis (AH), a disease for which there is no approved therapy.

In this phase 2b trial, patients with severe AH were randomly assigned 1:1:1 to receive 30 mg or 90 mg of larsucosterol or placebo; a second dose was administered after 72 hours if the patient remained hospitalized. All patients received supportive care as determined by investigators. Patients in the placebo group, if prescribed, received 32 mg of methylprednisolone, while patients in the larsucosterol groups received matching placebo capsules. The primary end point was 90-day mortality or liver transplant (LT) rate. The key secondary end point was 90-day mortality. We prespecified the reporting of U.S. results separately.

Among 307 enrolled patients, 301 received at least one treatment dose. The difference in 90-day mortality or LT between the 30-mg or 90-mg larsucosterol and placebo groups did not reach statistical significance. Ninety-day mortality in the placebo and the 30-mg and 90-mg groups was 25 out of 103, 15 out of 102, and 17 out of 102, respectively. Among U.S. patients (76% of all enrolled patients), there were 21 deaths and 4 LTs among 77 patients in the placebo group, 8 deaths and 5 LTs among 73 patients in the 30-mg larsucosterol group, and 10 deaths and 8 LTs among 77 patients in the 90-mg larsucosterol group. In patients who were treated within less than 10 days of hospitalization (75%), mortality in the placebo group was 20 out of 79 (U.S. patients 17/57), mortality in the 30-mg larsucosterol group was 7 out of 74 (U.S. patients 4/57), and mortality in the 90-mg larsucosterol group was 13 out of 77 (U.S. patients 9/66). Most adverse events arising during treatment were attributable to hepatic disease, and there was no imbalance in adverse events that could not be ascribed to liver disease.

The trial did not meet the primary end point of showing a beneficial effect of larsucosterol on 90-day mortality or LT in patients with severe AH. Equipoise has been established for a further trial of larsucosterol on AH survival. (The trial was funded by the DURECT Corporation; its ClinicalTrials.gov number is NCT04563026.).

Science is now in a new era of exposome research that strives to build a more all-inclusive, panoramic view in the quest for answers; this is especially true in the field of toxicology. Alcohol exposure researchers have been examining the multivariate co-exposures that may either exacerbate or initiate alcohol-related tissue/organ injuries. This manuscript presents selected key variables that represent the Alcohol Exposome. The primary variables that make up the Alcohol Exposome can include comorbidities such as cigarettes, poor diet, occupational hazards, environmental hazards, infectious agents, and aging. In addition to representing multiple factors, the Alcohol Exposome examines the various types of intercellular communications that are carried from one organ system to another and may greatly impact the types of injuries and metabolites caused by alcohol exposure. The intent of defining the Alcohol Exposome is to bring the newly expanded definition of Exposomics, meaning the study of the exposome, to the field of alcohol research and to emphasize the need for examining research results in a non-isolated environment representing a more relevant manner in which all human physiology exists.

We analyzed early outcomes regarding the impact of our integrated alcohol-associated liver disease (ALD) clinic on patients with ALD and alcohol use.

We conducted a retrospective study of patients with ALD who were evaluated in our integrated clinic from May 1, 2022, to December 31, 2023. Primary outcomes included differences in baseline clinical/demographic data between patients who accepted versus declined an appointment and changes in the severity of ALD, alcohol consumption, functional status, hospital utilization, and remission in alcohol use disorder for evaluated patients.

Patients who declined appointments (n=66) had higher median no-show rates (15.0 [8.0,30.0] vs. 8.5 [3.25,15.0], p<0.001), social vulnerability index (0.53 [0.26,0.79] vs. 0.38 [0.17,0.63], p=0.033), and proportions of cirrhosis (78.8% vs. 59.8%, p=0.017) versus evaluated patients. Comparison of baseline to first follow-up visit for evaluated patients (n=102) demonstrated significant reductions in median AST (59.5 [41.75, 89] vs. 44.5 [33.5, 56.25], p<0.001), alanine-aminotransferase (33.5 [20,45.25] vs. 26.5 [18.75,33.0], p=0.017), total bilirubin (1.6 [0.7,3.3] vs. 1 [0.5,1.9], p=0.001), phosphatidylethanol (263 [35, 784] vs. 0 [0, 163], p<0.001), MELD-3.0 and Sodium scores for patients with alcohol-associated hepatitis and cirrhosis (16 [11, 18.75] vs. 12 [9, 14], p<0.001), 14 [9.25, 17.75] vs. 11 [8.5, 14], p<0.001), and Child-Turcotte-Pugh scores for patients with cirrhosis (9 [6, 10.5] vs. 7 [6, 9], p<0.001). The proportion of patients with active-severe alcohol use disorder significantly decreased (85.2% vs. 51.9%, p<0.001). Additionally, patients had significant reductions in emergency department utilization (incidence rate ratio of 0.64 emergency department visits/month (p=0.002) and 0.71 hospital admissions/month (p=0.025). However, after considering the false discovery rate, the reduction in hospitalization admissions/month was not statistically significant (False Discovery Rate adjusted p=0.056).

Our integrated approach led to reductions in liver injury, degree of liver decompensation, alcohol use, and ED utilization, and remission in AUD in a population of both non-transplant ALD and post-transplant patients.

Alcohol consumption is a leading cause of preventable morbidity and mortality worldwide and the primary cause of advanced liver disease. Alcohol use disorder is a chronic, frequently relapsing condition characterized by persistent alcohol consumption despite its negative consequences. Alcohol-associated liver disease (ALD) encompasses a series of stages, from fatty liver (steatosis) to inflammation (steatohepatitis), fibrosis, and, ultimately, liver cirrhosis and its complications. The development of ALD is complex, involving both genetic and environmental factors, yet the exact mechanisms at play remain unclear. Alcohol-associated hepatitis (AH), a severe form of ALD, presents with sudden jaundice and liver failure. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD to stop the progression of the disease, making alcohol abstinence the most effective way to improve prognosis across all stages of ALD. For patients with advanced ALD who do not respond to medical therapy, liver transplantation is the only option that can improve prognosis. Recently, AH has become an early indication for liver transplantation in non-responders to medical treatment, showing promising results in carefully selected patients. This review provides an update on the epidemiology, natural history, pathogenesis, and current treatments for ALD. A deeper insight into novel targeted therapies investigated for AH focusing on new pathophysiologically-based agents is also discussed, including anti-inflammatory and antioxidative stress drugs, gut-liver axis modulators, and hepatocyte regenerative molecules.

Alcohol use is prevalent among hepatology clinic patients with chronic liver disease (CLD). We explored factors associated with the importance and confidence dimensions of motivation to reduce drinking.

Participants (N = 121) with unhealthy alcohol use (i.e., over NIH guidelines) receiving care in hepatology clinics from a safety-net hospital (SN, N = 54) and two Veterans Affairs Healthcare Systems (VA, N = 67) were enrolled in an alcohol intervention trial from March 2022 through October 2023. Baseline assessments included Generalised Anxiety Disorder (GAD-7), Patient Health Questionnaire (PHQ-8), Alcohol Use Disorders Identification Test (AUDIT), COVID-19 stress; and measures of importance and confidence to decrease alcohol use (readiness rulers, scales of 1-10). Liver disease aetiology and severity were extracted from electronic health records. We performed multivariable linear regression models with forward selection to assess pre-specified variables' associations with importance and confidence.

The sample was 84% male, 40% Latino, 31% White, 18% Black and 11% other races; median age was 61 years. Median (Q1-Q3) AUDIT score was 16 (12-24), importance was 9 (6-10) and confidence was 8 (5-9). On multivariable analysis, VA site (vs. SN) participants had a 0.97-point lower importance score (p = 0.02); higher symptoms of depression (PHQ-8 score ≥ 10 vs. < 10) and AUDIT scores (for each point increase) were associated with higher importance score (estimates 1.2 and 0.08, p < 0.05, respectively). Liver disease aetiology and severity were not significantly associated with outcomes.

Depression, alcohol problem severity and treatment site may influence motivation to reduce alcohol use and could inform future hepatology-based interventions.