Oxidative stress induced by excess ethanol is an important factor in the progression of alcoholic liver disease (ALD). In recent years, inhibiting Kelch-like ECH-associated protein 1 (KEAP1) to activate the antioxidant regulator Nuclear factor erythroid 2-related factor 2 (NRF2) has been considered an effective strategy for treating oxidative stress-related diseases, but its application in ALD remains insufficiently explored. This study aims to discover high-affinity inhibitors targeting the KEAP1 receptor. We conducted virtual screening of a compound library based on a structure-based pharmacophore model, ultimately identifying the candidate compound Timosaponin B II (TBII). Subsequently, we established ALD models in AML-12 cells and C57BL/6 mice, and evaluated the therapeutic effects and mechanisms of TBII on ALD using methods including Immunofluorescence, Western blotting, RT-qPCR, Biochemical assays, and histological staining. Results indicate that TBII significantly improved ethanol-induced liver injury, inhibited the elevation of serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Total Cholesterol (T-CHO), and Triglycerides (TG) levels, and reduced lipid droplet accumulation in liver tissues. Furthermore, TBII treatment enhanced the antioxidant capacity of AML-12 cells and mouse liver, increasing Glutathione (GSH) and Superoxide Dismutase (SOD) levels while reducing Malondialdehyde (MDA) and Reactive Oxygen Species (ROS) levels. Mechanistic studies indicated that TBII inhibited the ethanol-induced increase in KEAP1 and reversed the ethanol-induced changes in NRF2 and its downstream targets. In conclusion, this study suggests that TBII may become a potential therapeutic agent for ALD by modulating the KEAP1-NRF2 pathway to alleviate oxidative stress and lipid metabolism abnormalities.

Alcoholic liver disease (ALD) is characterized by aberrant lipid metabolism and chronic inflammation that eventually give rise to cirrhosis and hepatocellular carcinoma. In the present study we investigated the contribution of CC motif chemokine ligand 11 (CCL11) to ALD pathogenesis.

ALD was induced in mice by binge ethanol gavage or chronic ethanol feeding.

Bioinformatic analysis of sequencing data indicated that CCL11 expression was up-regulated in hepatocytes from mice subjected to ethanol feeding compared to those from the control mice. Exposure to ethanol led to CCL11 up-regulation in primary murine hepatocytes in vitro. Consistently, Oil Red O (ORO) staining detected elevated lipid accumulation whereas quantitative PCR (qPCR) detected augmented expression of pro-inflammatory mediators in primary murine hepatocytes treated with recombinant CCL11. On the contrary, CCL11 knockout mice (KO) developed a less severe form of ALD compared to wild type littermates when subjected to either binge or chronic ethanol feeding. Finally, CCL11 antagonism by administration with an inhibitor to CCL11 receptor CCR3 (CCR3i) attenuated ALD in mice.

Our data support a role for CCL11 in ALD pathogenesis and provide proof-of-concept that targeting CCL11 can be considered as a therapeutic approach for ALD intervention.

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.

Chronic liver diseases, such as those encountered with obesity, chronic/abusive alcohol consumption or viral infections, represent not only major public health concerns with limited therapeutic options but also important risk factors for the onset of hepatocellular carcinoma (HCC). Deciphering the molecular traits underlying these disorders is of high interest for designing new and effective treatments. The tristetraprolin (TTP) family members are of particular importance given their ability to control the expression of a wide range of genes involved in metabolism, inflammation and carcinogenesis at the post-transcriptional level. This regulation can occur within small cytoplasmic granules, namely, processing bodies (P-bodies), where the mRNA degradation occurs. Increasing evidence indicates that TTP family members and P-bodies are involved in the development of chronic liver diseases and cancers. In this review, we discuss the role of this regulatory mechanism in metabolic-dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), hepatic viral infections and HCC.

Hepatotoxicity is a critical health hazard, primarily contributing to the increased incidence of deaths globally. The liver is one of the major and extremely vital organs of the human body. Autoimmune diseases, viruses, exposure to toxicants such as carcinogens, and changes in eating habits can all cause liver problems, among other things. Free radical generation, together with raised enzyme levels including SGOT, SGPT, and total bilirubin, are among the pathological changes set off by liver injury. Hepatotoxicity causes changes in cells, such as eosinophilic cytoplasm, nuclear pyknosis, fatty degeneration, too many liver lesions, and hepatic centrilobular necrosis due to lipid peroxidation. Researchers have used animal models to investigate liver diseases and toxicities. Drugs such as azathioprine, alcoholism, paracetamol intoxication, and anti-tuberculosis drugs are some of the most common causes of liver toxicity. These toxins cause calcium ions (Ca2+), reactive oxygen species (ROS), and inflammatory mediators to be released inside cells. This activates immune cells like NK cells, NKT cells, and Kupffer cells. These signaling pathways also play roles in hepatotoxicity. Due to its pathogenesis, no effective drug is currently available for hepatotoxicity due to a lack of understanding related to the signaling factors involved in it. The paper primarily examines different experimental models of hepatotoxicity, including non-invasive and invasive methods, as well as genetic models. As such, these models are crucial tools in advancing our understanding of hepatotoxicity, thus paving the way for new therapeutic interventions.

Alcohol-associated liver disease (ALD) rates have increased substantially in the United States and elsewhere around the globe. These increases are largely the result of increases in alcohol use. While there are many levels at which alcohol use interventions can be implemented in order to reduce alcohol use and its negative health consequences, public policy initiatives have emerged as a powerful way to intervene across a population. In this narrative review, we will review major US national as well as worldwide alcohol-associated public health policies with a particular focus on describing how such policies have influenced rates of ALD and its complications and outcomes. We will describe global alcohol public health policy frameworks, review key alcohol policy models, describe existing notable policies and their impacts, and highlight gaps in ALD policy literature where further research and policy interventions could reduce rates of mortality from ALD.

Severe alcohol-associated hepatitis (SAH) is the most critical, acute, inflammatory phenotype within the alcohol-associated liver disease (ALD) spectrum, characterized by high 30- and 90-day mortality. Since several decades, corticosteroids (CS) are the only approved pharmacotherapy offering highly limited survival benefits. Contextually, there is an evident demand for 3PM innovation in the area meeting patients' needs and improving individual outcomes. Fecal microbiota transplantation (FMT) has emerged as one of the new potential therapeutic options. In this study, we aimed to address the crucial 3PM domains in order to assess (i) the impact of FMT on mortality in SAH patients beyond CS, (ii) to identify factors associated with the outcome to be improved (iii) the prediction of futility, (iv) prevention of suboptimal individual outcomes linked to increased mortality, and (v) personalized allocation of therapy.

We conducted a prospective study (NCT04758806) in adult patients with SAH who were non-responders (NR) to or non-eligible (NE) for CS between January 2018 and August 2022. The intervention consisted of five 100 ml of FMT, prepared from 30 g stool from an unrelated healthy donor and frozen at - 80 °C, administered daily to the upper gastrointestinal (GI) tract. We evaluated the impact of FMT on 30- and 90-day mortality which we compared to the control group selected by the propensity score matching and treated by the standard of care; the control group was derived from the RH7 registry of patients hospitalized at the liver unit (NCT04767945). We have also scrutinized the FMT outcome against established and potential prognostic factors for SAH - such as the model for end-stage liver disease (MELD), Maddrey Discriminant Function (MDF), acute-on-chronic liver failure (ACLF), Liver Frailty Index (LFI), hepatic venous-portal pressure gradient (HVPG) and Alcoholic Hepatitis Histologic Score (AHHS) - to see if the 3PM method assigns them a new dimension in predicting response to therapy, prevention of suboptimal individual outcomes, and personalized patient management.

We enrolled 44 patients with SAH (NR or NE) on an intention-to-treat basis; we analyzed 33 patients per protocol for associated factors (after an additional 11 being excluded for receiving less than 5 doses of FMT), and 31 patients by propensity score matching for corresponding individual outcomes, respectively. The mean age was 49.6 years, 11 patients (33.3%) were females. The median MELD score was 29, and ACLF of any degree had 27 patients (81.8%). FMT improved 30-day mortality (p = 0.0204) and non-significantly improved 90-day mortality (p = 0.4386). Univariate analysis identified MELD ≥ 30, MDF ≥ 90, and ACLF grade > 1 as significant predictors of 30-day mortality, (p = 0.031; p = 0.014; p = 0.034). Survival was not associated with baseline LFI, HVPG, or AHHS.

In the most difficult-to-treat sub-cohort of patients with SAH (i.e., NR/NE), FMT improved 30-day mortality. Factors associated with benefit included MELD ≤ 30, MDF ≤ 90, and ACLF < 2. These results support the potential of gut microbiome as a therapeutic target in the context of 3PM research and vice versa - to use 3PM methodology as the expedient unifying template for microbiome research. The results allow for immediate impact on the innovative concepts of (i) personalized phenotyping and stratification of the disease for the clinical research and practice, (ii) multilevel predictive diagnosis related to personalized/precise treatment allocation including evidence-based (ii) prevention of futile and sub-optimally effective therapy, as well as (iii) targeted prevention of poor individual outcomes in patients with SAH. Moreover, our results add to the existing evidence with the potential to generate new research along the SAH's pathogenetic pathways such as diverse individual susceptibility to alcohol toxicity, host-specific mitochondrial function and systemic inflammation, and the role of gut dysbiosis thereof.

The online version contains supplementary material available at 10.1007/s13167-024-00381-5.

Although binge alcohol-induced gut leakage has been studied extensively in the context of reactive oxygen species-mediated signaling, it was recently revealed that post-transcriptional regulation plays an essential role as well. Ethanol (EtOH)-inducible cytochrome P450-2E1 (CYP2E1), a key enzyme in EtOH metabolism, promotes alcohol-induced hepatic steatosis and inflammatory liver disease, at least in part by mediating changes in intestinal permeability. For instance, gut leakage and elevated intestinal permeability to endotoxins have been shown to be regulated by enhancing CYP2E1 mRNA and CYP2E1 protein levels. Although it is understood that EtOH promotes CYP2E1 induction and activation, the mechanisms that regulate CYP2E1 expression in the context of intestinal damage remain poorly defined. Specific miRNAs, including miR-132, miR-212, miR-378, and miR-552, have been shown to repress the expression of CYP2E1, suggesting that these miRNAs contribute to EtOH-induced intestinal injury. Here, we have shown that CYP2E1 expression is regulated post-transcriptionally through miRNA-mediated degradation, as follows: (1) the RNA-binding protein AU-binding factor 1 (AUF1) binds mature miRNAs, including CYP2E1-targeting miRNAs, and this binding modulates the degradation of corresponding target mRNAs upon EtOH treatment; (2) the serine/threonine kinase mammalian Ste20-like kinase 1 (MST1) mediates oxidative stress-induced phosphorylation of AUF1. Those findings suggest that reactive oxygen species-mediated signaling modulates AUF1/miRNA interaction through MST1-mediated phosphorylation. Thus, our study demonstrates the critical functions of AUF1 phosphorylation by MST1 in the decay of miRNAs targeting CYP2E1, the stabilization of CYP2E1 mRNA in the presence of EtOH, and the relationship of this pathway to subsequent intestinal injury.

Given the increasing burden of liver cancer in Europe, it is crucial to investigate how social determinants of health (SDoH) affect liver cancer risk factors and access to care in order to improve health outcomes equitably. This paper summarises the available evidence on the differential distribution of liver cancer risk factors, incidence, and health outcomes in the European Economic Area and the United Kingdom from an SDoH perspective. Vulnerable and marginalised populations have low socio-economic and educational levels and are the most affected by liver cancer risk factors. Reasons for this include varied access to hepatitis B virus vaccination and limited access to viral hepatitis B and C screening, harm reduction, and treatment. Additionally, alcohol-related liver disease remains highly prevalent among individuals with low education, insecure employment, economic instability, migrants, and deprived populations. Moreover, significant variation exists across Europe in the proportion of adults with steatotic liver disease, overweight/obesity, and diabetes, based on geographical area, gender, socio-economic and educational background, and density of ultra-processed food outlets. Inequities in cirrhosis mortality rates have been reported, with the highest death rates among individuals living in socio-economically disadvantaged areas and those with lower educational levels. Furthermore, insufficient healthcare access for key populations with primary liver cancer is influenced by complex healthcare systems, stigmatisation, discrimination, low education, language barriers, and fear of disclosure. These challenges contribute to inequities in liver cancer care pathways. Future studies are needed to explore the different SDoH-interlinked effects on liver cancer incidence and outcomes in European countries. The ultimate goal is to develop evidence-based multilevel public health interventions that reduce the SDoH impact in precipitating and perpetuating the disproportionate burden of liver cancer in specific populations.

To explore the incidence of alcohol-related hepatocellular carcinoma (HCC), evaluate possible synergisms between alcohol and well-known risk factors associated with HCC and establish a nomogram to predict alcohol-associated liver disease (ALD)-related HCC risk.

A database of 136 571 inpatients in the Fifth Medical Center of Chinese PLA General Hospital from 2002 to 2018 with chronic liver disease was established. Data were collected by medical records review. Multivariate logistic regression was used to identify the independent high-risk factors associated with HCC, and then were incorporated into a novel nomogram. Afterward, the new established model was validated using external cohort by receiver operating characteristic curves analysis. For external cohort, 1646 patients with ALD admitted to our hospital from 2019 to 2021 were included. ALD was diagnosed on the basis of a history of sustained heavy alcohol intake greater than 40 g/day for men and 20 g/day for women for >5 years, clinical evidence of liver disease and supporting laboratory abnormalities.

Over the last 17 years, trends showed obviously increases in ALD. ALD-related HCC experienced a significant increase from 5.8% to 30.7%, whereas hepatitis B virus (HBV)-related HCC declined from 77.6% to 52.0%. In patients with ALD-related HCC (5119), 3816 (74.54%) cases had HBV infection, 493 (9.63%) cases had hepatitis C virus (HCV) infection, 71 (1.39%) cases were coinfected with both HBV and HCV, and 739 (14.44%) cases had neither HBV nor HCV infection. Drinking years (OR 1.009, 95% CI (1.000 to 1.017)), age (OR 1.060, 95% CI (1.051 to 1.069)), diabetes mellitus (OR 1.314, 95% CI (1.123 to 1.538)), HBV infection (OR 4.905, 95% CI (4.242 to 5.671)), liver cirrhosis (OR 4.922, 95% CI (3.887 to 6.232)) and male sex (OR 17.011, 95%CI (2.296 to 126.013)) were associated with increased risk of HCC in patients with ALD. A nomogram had a concordance index of 0.786 (95% CI 0.773 to 0.799) and had well-fitted calibration curves. These results were successfully validated both in the internal cohort and external cohort.

The prevalence of ALD and ALD-related HCC has been increased dramatically. The nomogram model established here with its high accuracy and easy-to-use features achieved an optimal prediction of HCC development in patients with ALD, which can help clinicians to develop an individualised and precise treatment strategy.

Alcohol-associated liver disease (ALD) is the most common cause of advanced hepatic disease and frequent indication for liver transplantation worldwide. With harmful alcohol use as the primary risk factor, increasing alcohol use over the past decade has resulted in rapid growth of the ALD-related healthcare burden. The spectrum of ALD ranges from early asymptomatic liver injury to advanced disease with decompensation and portal hypertension. Compared with those with other etiologies of liver disease, patients with ALD progress faster and more often present at an advanced stage. A unique phenotype of advanced disease is alcohol-associated hepatitis (AH) presenting with rapid onset or worsening of jaundice, and acute on chronic liver failure in severe forms conveying a 1-month mortality risk of 20%-50%. The model for end stage disease score is the most accurate score to stratify AH severity (>20 defined as severe disease). Corticosteroids are currently the only available therapeutic with proven efficacy for patients with severe AH, providing survival benefit at 1 month in 50%-60% of patients. Abstinence of alcohol use, a crucial determinant of long-term outcomes, is challenging to achieve in ALD patients with concurrent alcohol use disorder (AUD). As patients with ALD are rarely treated for AUD, strategies are needed to overcome barriers to AUD treatment in patients with ALD and to promote a multidisciplinary integrated care model with hepatology, addiction medicine providers, and social workers to comprehensively manage the dual pathologies of liver disease and of AUD. Liver transplantation, a definitive treatment option in patients with advanced cirrhosis, should be considered in selected patients with AH, who are unresponsive to medical therapy and have a low risk of relapse to posttransplant alcohol use. Level of evidence and strength of recommendations were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations system. This guideline was developed under the American College of Gastroenterology Practice Parameters Committee.

Frequent binge drinking is a known contributor to alcohol-related harm, but its impact on systemic and hepatic inflammation is not fully understood. We hypothesize that changes in immune markers play a central role in adverse effects of acute alcohol intake, especially in patients with early liver disease.

To investigate the effects of acute alcohol intoxication on inflammation-related markers in hepatic and systemic venous plasma in people with alcohol-related liver disease (ArLD), non-alcoholic fatty liver disease (NAFLD) and healthy controls.

Thirty-eight participants (13 with ArLD, 15 with NAFLD and 10 healthy controls) received 2.5 mL of 40% ethanol per kg body weight via a nasogastric tube. Seventy-two inflammation-related markers were quantified in plasma from hepatic and systemic venous blood, at baseline, 60 and 180 min after intervention.

Alcohol intervention altered the levels of 31 of 72 and 14 of 72 markers in the systemic and hepatic circulation. All changes observed in the hepatic circulation were also identified in the systemic circulation after 180 min. Only FGF21 and IL6 were increased after alcohol intervention, while the remaining 29 markers decreased. Differences in response to acute alcohol between the groups were observed for 8 markers, and FGF21 response was blunted in individuals with steatosis.

Acute alcohol intoxication induced changes in multiple inflammation-related markers, implicated in alcohol metabolism and hepatocellular damage. Differences identified between marker response to binge drinking in ArLD, NAFLD and healthy controls may provide important clues to disease mechanisms and potential targets for treatment.

NCT03018990.

Alcohol-related liver disease (ALD) is a major cause of liver-related morbidity and mortality. Epidemiological trends indicate recent and predicted increases in the burden of disease. Disease progression is driven by continued alcohol exposure on a background of genetic predisposition together with environmental cofactors. Most individuals present with advanced disease despite a long history of excessive alcohol consumption and multiple missed opportunities to intervene. Increasing evidence supports the use of non-invasive tests to screen for and identify disease at earlier stages. There is a definite role for public health measures to reduce the overall burden of disease. At an individual level, however, the ability to influence subsequent disease course by modifying alcohol consumption or the underlying pathogenic mechanisms remains limited due to a comparative lack of effective, disease-modifying medical interventions. Abstinence from alcohol is the key determinant of outcome in established ALD and the cornerstone of clinical management. In those with decompensated ALD, liver transplant has a clear role. There is consensus that abstinence from alcohol for an arbitrary period should not be the sole determinant in a decision to transplant. An increasing understanding of the mechanisms by which alcohol causes liver disease in susceptible individuals offers the prospect of new therapeutic targets for disease-modifying drugs. Successful translation will require significant public and private investment in a disease area which has traditionally been underfunded when compared to its overall prevalence.

Alcohol is a prominent cause of liver disease worldwide with higher prevalence in developed nations. The spectrum of alcohol-associated liver disease (ALD) encompasses a diverse range of clinical entities, from asymptomatic isolated steatosis to decompensated cirrhosis, and in some cases, acute or chronic liver failure. Consequently, it is important for healthcare practitioners to maintain awareness and systematically screen for ALD. The optimal evaluation and management of ALD necessitates a collaborative approach, incorporating a multidisciplinary team and accounting for concurrent medical conditions. A repertoire of therapeutic interventions exists to support patients in achieving alcohol cessation and sustaining remission, with complete abstinence being the ultimate objective. This review explores the existing therapeutic options for ALD acknowledging geographical discrepancies in accessibility. Recent innovations, including the inclusion of alcohol consumption biomarkers into clinical protocols and the expansion of liver transplantation eligibility to encompass severe alcohol-associated hepatitis, are explored.

Schizandrae Fructus (SF), fruits of Schisandra chinensis (Turcz.) Baill. and Hoveniae Semen cum Fructus (HSCF), the dried peduncle of Hovenia dulcis Thunb., have long been used for alcohol detoxification in the traditional medicine of Korea and China. In the current study, we aimed to evaluate the potential synergistic hepatoprotective effect of a combination mixture (MSH) comprising fermented SF pomace (fSFP) and HSCF hot water extracts at a 1:1 (w:w) ratio against ethanol-induced liver toxicity. Subacute ethanol-mediated hepatotoxicity was induced by the oral administration of ethanol (5 g/kg) in C57BL/6J mice once daily for 14 consecutive days. One hour after each ethanol administration, MSH (50, 100, and 200 mg/kg) was also orally administered daily. MSH administration significantly reduced the serum activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase. Histological observation indicated that MSH administration synergistically and significantly decreased the fatty changed region of hepatic parenchyma and the formation of lipid droplet in hepatocytes. Moreover, MSH significantly attenuated the hepatic triglyceride accumulation through reducing lipogenesis genes expression and increasing fatty acid oxidation genes expression. In addition, MSH significantly inhibited protein nitrosylation and lipid peroxidation by lowering cytochrome P450 2E1 enzyme activity and restoring the glutathione level, superoxide dismutase and catalase activity in liver. Furthermore, MSH synergistically decreased the mRNA level of tumor necrosis factor-α in the hepatic tissue. These findings indicate that MSH has potential for preventing alcoholic liver disease through inhibiting hepatic steatosis, oxidative stress, and inflammation.

Alcohol-related liver disease (ALD) is among the most common indications for liver transplantation (LTX) in Europe and North America, with good five-year survival rates post-LTX. Here we evaluated survival up to and beyond 20 years after LTX for patients with ALD compared to a comparison group.

Patients with ALD and a comparison group transplanted in the Nordic countries between 1982 and 2020 were included. Data were analyzed using descriptive statistics, Kaplan-Meier curves and predictors of survival were assessed with Cox-regressions.

831 patients with ALD and 2979 patients in the comparison group were included in the study. Patients with ALD were older at the time of LTX (p < .001) and more likely to be male (p < .001). The estimated median follow-up time was 9.1 years for the ALD-group and 11.1 years for the comparison group. 333 (40.1%) patients with ALD and 1010 (33.9%) patients in the comparison group died during follow-up. The overall survival was impaired for patients with ALD compared to the comparison group (p < .001) and was evident for male and female patients, patients transplanted before and after 2005, and observed in all age-groups except patients over 60 years. Age at transplant, waiting time, year of LTX and country of LTX were associated with decreased survival after LTX for patients with ALD.

Patients with ALD have a decreased long-term survival following LTX. This difference was evident in most sub-groups of patients and warrants close follow-up of liver transplanted patients with ALD with focus on risk reduction.

Fatty liver diseases, including alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease nonalcoholic fatty liver disease (NAFLD), affect a large number of people worldwide and become one of the major causes of end-stage liver disease, such as liver cirrhosis and hepatocellular carcinoma (HCC). Unfortunately, there are currently no approved pharmacological treatments for ALD or NAFLD. This situation highlights the urgent need to explore new intervention targets and discover effective therapeutics for ALD and NAFLD. The lack of properly validated preclinical disease models is a major obstacle to the development of clinical therapies. ALD and NAFLD models have been in the development for decades, but there are still no models that recapitulate the full spectrum of ALD and NAFLD. Throughout this review, we summarize the current in vitro and in vivo models used for research on fatty liver diseases and discuss the advantages and limitations of these models.

Limited data exist on the association between per capita alcohol consumption and incidence of alcohol related liver disease (ARLD). The aims were to analyse this relationship and assess prevalence of ARLD in Iceland and among patients treated for alcohol use disorder (AUD) and its impact on outcomes.

A retrospective study on all patients diagnosed with severe ARLD: alcohol related cirrhosis (ARC) and alcohol related hepatitis (ARH) in Iceland 1984-2020. Medical records were scrutinized for clinical features, severity of ARLD, proportion undergoing treatment for AUD, data on abstinence and long-term outcomes.

A total of 314 patients, males 76%, median age 56 years, fulfilled the predetermined criteria for ARLD. Median MELD was 17, 73% with Child-Pugh B/C and 70/314 (22%) who had ARH. Incidence of ARLD increased from 0.77 cases per 100 000 inhabitants annually 1984-2000 to 6.1 per 100 000 in 2016-2020. Per capita alcohol consumption increased from 4.3 Liters to 7.5 L in in the same time periods. Overall 220/314 (70%) with ARLD had undergone treatment for AUD. Of all individuals who had AUD treatment during the study period (n = 21.845), 1% were diagnosed with ARLD. Patients who underwent treatment for AUD after the ARLD diagnosis had better prognosis than those who had treatment prior to ARLD diagnosis (hazard ratio 2.5 [95% CI 1.3-5.0]).

The incidence of ARLD increased 8-fold during the study period coinciding with 74% increase in per capita alcohol consumption. Patients with prior diagnosis of AUD had worse prognosis that needs special attention.

The etiology of liver diseases has changed in recent years, but its impact on the comparative burden of liver cancer between males and females is unclear. We estimated sex differences in the burden of liver cancer across 204 countries and territories from 2010 to 2019.

We analyzed temporal trends in the burden of liver cancer using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age-standardized rates (ASRs) of liver cancer incidence, death, and disability-adjusted life-years (DALYs) by sex, country, region, and etiology of liver disease. Globally in 2019, the frequency of incident cases, deaths, and DALYs due to liver cancer were 376,483, 333,672, and 9,048,723 in males, versus 157,881, 150,904, and 3,479,699 in females. From 2010 to 2019, the incidence ASRs in males increased while death and DALY ASRs remained stable; incidence, death, and DALY ASRs in females decreased. Death ASRs for both sexes increased only in the Americas and remained stable or declined in remaining regions. In 2019, hepatitis B was the leading cause of liver cancer death in males, and hepatitis C in females. From 2010 to 2019, NASH had the fastest growing death ASRs in males and females. The ratio of female-to-male death ASRs in 2019 was lowest in hepatitis B (0.2) and highest in NASH (0.9).

The overall burden of liver cancer is higher in males, although incidence and death ASRs from NASH-associated liver cancer in females approach that of males.

In recent years, it has become clear that gut microbiota plays a major role in the human body, both in health and disease. Because of that, the gut microbiome and its impact on human well-being are getting wider and wider attention. Studies focused on the liver are not an exception. However, the majority of the analyses are concentrated on the bacterial part of the gut microbiota, while the fungi living in the human intestines are often omitted or underappreciated. This review is focused on the gut mycobiome as an important factor that should be taken into consideration regarding liver homeostasis and its perturbations. We have collected the findings in this field and we discuss their importance. We aim to emphasize the fungal compositional changes related to liver diseases and, by that, provide novel insights into the directions of liver research and gut microbiota as a therapeutic target for liver diseases.

Heavy alcohol consumption is a major cause of morbidity and mortality. Globally, alcohol per-capita consumption rose from 5.5 litres in 2005 to 6.4 litres in 2016 and is projected to increase further to 7.6 litres in 2030. In 2019, an estimated 25% of global cirrhosis deaths were associated with alcohol. The global estimated age-standardized death rate (ASDR) of alcohol-associated cirrhosis was 4.5 per 100,000 population, with the highest and lowest ASDR in Africa and the Western Pacific, respectively. The annual incidence of hepatocellular carcinoma (HCC) among patients with alcohol-associated cirrhosis ranged from 0.9% to 5.6%. Alcohol was associated with approximately one-fifth of global HCC-related deaths in 2019. Between 2012 and 2017, the global estimated ASDR for alcohol-associated cirrhosis declined, but the ASDR for alcohol-associated liver cancer increased. Measures are required to curb heavy alcohol consumption to reduce the burden of alcohol-associated cirrhosis and HCC. Degree of alcohol intake, sex, older age, obesity, type 2 diabetes mellitus, gut microbial dysbiosis and genetic variants are key factors in the development of alcohol-associated cirrhosis and HCC. In this Review, we discuss the global epidemiology, projections and risk factors for alcohol-associated cirrhosis and HCC.

Cachexia occurs in late stages of liver cirrhosis, and a low-fat mass is potentially associated with poor outcome. This study compared different computed tomography (CT)-derived fat parameters with respect to its prognostic impact on the development of complications and death before and after liver transplantation. Between 2001 and 2014, 612 patients with liver cirrhosis without hepatocellular carcinoma listed for liver transplantation met the inclusion criteria, including abdominal CT scan (±200 days to listing). A total of 109 patients without cirrhosis served as controls. The subcutaneous fat index (SCFI), the paraspinal muscle fat index, and the visceral fat index were assessed at L3/L4 level and normalized to the height (cm² /m² ). Data were collected and analyzed retrospectively. Low SCFI was associated with a higher rate of ascites and increased C-reactive protein levels (p < 0.001). In addition, multivariate Cox regression analysis adjusting for sex, age, body mass index (BMI), and Model for End-Stage Liver Disease showed that decreasing SCFI was also associated with an increased risk of cirrhosis-related complications (p = 0.003) and death on the transplant wait list (p = 0.013). Increased paraspinal and visceral fat were not only positively correlated with creatinine levels (p < 0.001), BMI, and metabolic comorbidities (all p < 0.001) before transplantation, but also predictive for 1-year mortality after transplantation. Conclusion: The distribution of body fat is a major determinant for complications and outcome in cirrhosis before and after liver transplantation.

The prevalence of fatty liver disease is potentially increasing in adolescents and young adults (AYAs) due to the obesity and alcohol pandemics. The aim of this study was to assess the prevalence of alcohol-associated fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) in a representative U.S. cohort utilizing transient elastography to directly measure hepatic steatosis and suspected fibrosis.

AYAs (age 15-39 years) with valid FibroScan® measurements in the National Health and Nutrition Examination Survey (NHANES) database (2017-2018) were included in the analyses. Those with viral hepatitis, pregnancy, or ALT/AST > 500 U/L were excluded. The population was divided into those with excessive alcohol consumption (ALQ130) and those without. Controlled attenuation parameter (CAP) score ≥ 248 dB/m was used to identify suspected ALD and NAFLD. In those with evidence of ALD, the following cutoffs of liver stiffness measurement (LSM) were used for suspected fibrosis: F ≥ F2 at LSM ≥ 7.5 kPa and F ≥ F3 at ≥ 9.5 kPa, respectively. In those with suspected NAFLD, the following LSM cutoffs were used: F ≥ F2 at 6.1 and F ≥ F3 at ≥ 7.1, respectively. Cutoffs were chosen based on published literature to maximize sensitivity.

Comparing to those without, subjects with excessive alcohol consumption tended to be older (29.8 vs 28.5 years), have a higher BMI (29.3 vs 28.9 kg/m2), and be from a White ethnicity (65.3% vs. 55.4%). In subjects with excessive alcohol consumption, suspected ALD was present in 56.59% (95% CI 41.57-70.49). In those with suspected ALD, suspected significant fibrosis (F ≥ F2) was present in 12.3% (95% CI 4.74-28.34) and advanced fibrosis (F ≥ F3) was present in 6.31% (95% CI 0.69-39.55). Similarly, in subjects without excessive alcohol consumption, suspected NAFLD was present in 40.04% (36.64-43.54). In those with suspected NAFLD, suspected significant fibrosis (F ≥ F2) was present in 31.07% (27.25-35.16) and suspected advanced fibrosis (F ≥ F3) was present in 20.15% (16.05-24.99).

A significant percentage of AYAs are at risk for ALD and NAFLD and a subset of these subjects is at risk for significant fibrosis. Efforts should focus on increasing awareness of the prevalence of ALD and NAFLD in this population and to mitigate modifiable risk factors.

Liver cancer epidemiology is changing due to increasing alcohol consumption, rising prevalence of obesity, and advances in hepatitis B virus (HBV) and hepatitis C virus (HCV) treatment. However, the impact of these changes on global liver cancer burden remains unclear. We estimated global and regional temporal trends in the burden of liver cancer and the contributions of various liver disease etiologies using the methodology framework of the Global Burden of Disease study. Between 2010 and 2019, there was a 25% increase in liver cancer deaths. Age-standardized death rates (ASDRs) increased only in the Americas and remained stable or fell in all other regions. Between 2010 and 2019, non-alcoholic steatohepatitis (NASH) and alcohol had the fastest growing ASDRs, while HCV and HBV declined. Urgent measures are required at a global level to tackle underlying metabolic risk factors and slow the growing burden of NASH-associated liver cancer, especially in the Americas.

Alcohol-related liver disease (ALD) is a major cause of liver-related death worldwide, yet understanding of the three key pathological features of the disease-fibrosis, inflammation and steatosis-remains incomplete. Here, we present a paired liver-plasma proteomics approach to infer molecular pathophysiology and to explore the diagnostic and prognostic capability of plasma proteomics in 596 individuals (137 controls and 459 individuals with ALD), 360 of whom had biopsy-based histological assessment. We analyzed all plasma samples and 79 liver biopsies using a mass spectrometry (MS)-based proteomics workflow with short gradient times and an enhanced, data-independent acquisition scheme in only 3 weeks of measurement time. In plasma and liver biopsy tissues, metabolic functions were downregulated whereas fibrosis-associated signaling and immune responses were upregulated. Machine learning models identified proteomics biomarker panels that detected significant fibrosis (receiver operating characteristic-area under the curve (ROC-AUC), 0.92, accuracy, 0.82) and mild inflammation (ROC-AUC, 0.87, accuracy, 0.79) more accurately than existing clinical assays (DeLong's test, P < 0.05). These biomarker panels were found to be accurate in prediction of future liver-related events and all-cause mortality, with a Harrell's C-index of 0.90 and 0.79, respectively. An independent validation cohort reproduced the diagnostic model performance, laying the foundation for routine MS-based liver disease testing.

Alcohol use disorder (AUD) is one of the main causes of global death and disability. The liver represents the main target of alcohol damage, and alcohol-associated liver disease (ALD) represents the first cause of liver cirrhosis in Western countries. Alcohol abstinence is the main goal of treatment in AUD patients with ALD, as treatments for ALD are less effective when drinking continues. Moreover, the persistence of alcohol consumption is associated with higher mortality, increased need for liver transplantation, and graft loss. The most effective treatment for AUD is the combination of psychosocial interventions, pharmacological therapy, and medical management. However, the effectiveness of these treatments in patients with ALD is doubtful even because AUD patients with ALD are usually excluded from pharmacological trials due to concerns on liver safety. This narrative review will discuss the treatment options for AUD-ALD patients focusing on controversies in pharmacological therapy.

Because of the high prevalence of chronic liver disease (CLD), it is crucial that general practitioners (GPs, in contact with the general population) and diabetologists (in contact with the most at-risk non-alcoholic fatty liver disease population) identify patients with advanced CLD requiring specialized management. The aim of this study was to evaluate CLD and CLD management awareness among diabetologists and GPs.

A questionnaire was sent to diabetologists within the Francophone Diabetes Society and to GPs in southern and western France. The questionnaire sounded participant characteristics and knowledge of CLD and its management.

678 questionnaires were completed by 500 GPs and 178 diabetologists. CLD prevalence was underestimated by 90% of GPs and 59% of diabetologists (p<0.001). For biological CLD follow-up, liver injury explorations (transaminases) were systematically included whereas severity explorations (prothrombin time, bilirubin) were prescribed for less than 50% of blood samples; GPs were more likely to prescribe severity explorations than diabetologists were (p<0.001). 74% of GPs and 97% of diabetologists (p<0.001) were familiar with non-invasive tests, Fibroscan and Fibrotest being the two most-frequently mentioned of them. In contrast, the simple blood test Fibrosis-4 was cited by less than 15% of GPs and 30% of diabetologists (p<0.001).

GPs and diabetologists have limited knowledge of CLD, despite its high prevalence. Continuing medical education among GPs and diabetologists is therefore necessary to enable the discovery of patients with advanced fibrosis and early management for them so as to avoid liver-related complications.

There is increasing evidence of associations between residential proximity to livestock farms and respiratory morbidity, but less is known about potential effects on respiratory mortality among residents.

We aimed to assess potential associations between respiratory mortality and residential proximity to (intensive) livestock farming.

In DUELS, a national census-based cohort, we selected all inhabitants from rural and semi-urban areas of the Netherlands, aged ≥30 years and living at the same address for five years up to baseline (2004). We followed these ∼4 million individuals for respiratory mortality (respiratory system diseases, chronic lower respiratory diseases, pneumonia) from 2005 to 2012. We computed the average number of cattle, pigs, chicken, and mink present in 500 m, 1000 m, 1500 m and 2000 m of each individual's residence in the period 1999-2003. Analyses were conducted using Cox proportional hazards regression, adjusting for potential confounders at individual and neighbourhood level.

We found evidence that living up to 2000 m of pig farms was associated with respiratory mortality, namely from chronic lower respiratory diseases, with Hazard Ratios ranging from 1.06 (1.02, 1.10) in people living close to low numbers (<median number of animals) of pigs in 1000 m and 1.18 (1.13, 1.24) in those living near high numbers (≥median) of pigs in 2000 m. We also found indications of higher pneumonia mortality in people living near mink farms.

Our results are in line with previous findings of adverse respiratory effects in people living near livestock farms. Little is known about the physical, chemical, and biological exposures leading to respiratory morbidity and mortality warranting further explorations of air contaminants in the vicinity of livestock farms.

Intestinal microbiota, dominated by bacteria, plays an important role in the occurrence and the development of alcohol-associated liver disease (ALD), which is one of the most common liver diseases around the world. With sufficient studies focusing on the gut bacterial community, chronic alcohol consumption is now known as a key factor that alters the composition of gut bacterial community, increases intestinal permeability, causes intestinal dysfunction, induces bacterial translocation, and exacerbates the process of ALD via gut-liver axis. However, gut non-bacterial communities including fungi, viruses, and archaea, which may also participate in the disease, has received little attention relative to the gut bacterial community. This paper will systematically collect the latest literatures reporting non-bacterial communities in mammalian health and disease, and review their mechanisms in promoting the development of ALD including CLEC7A pathway, Candidalysin (a peptide toxin secreted by Candida albicans), metabolites, and other chemical substances secreted or regulated by gut commensal mycobiome, virome, and archaeome, hoping to bring novel insights on our current knowledge of ALD.

Socioeconomic inequalities in alcohol-related mortality in Spain exists, and are postulated to contribute to inequalities in all-cause mortality. We aim to assess absolute and relative educational inequalities in alcohol-related mortality, and to estimate the role of alcohol in educational inequalities in both life expectancy and lifespan variation in Spain.

We used multiple cause-of-death (MCOD) mortality data for individuals aged 30 and over for Spain (2016-2018) by educational attainment. We estimated by sex and educational attainment age-standardised alcohol-attributable mortality rates, relative and absolute indices of educational inequalities; and total life expectancy and lifespan variation at age 30 for all-cause mortality and after eliminating alcohol-attributable mortality.

The use of MCOD resulted in an additional 2543 annual alcohol-related deaths (+75% among men and +50% among women) compared with estimates derived from underlying causes of death. In absolute terms, educational inequalities were the highest among men aged 45-84 and among women aged 45-64. In relative terms, higher inequalities raised in working ages, whereas at older ages inequalities tended to be lower, although still important among men. Alcohol contributed to educational inequalities in life expectancy (men: 0.13 years (3.2%); women 0.02 years (0.7%)) and lifespan variation (2.1% and 1.4% for men and women, respectively).

Alcohol consumption remains an important lifestyle habit to be tackled in order to reduce socioeconomic inequalities in mortality in Spain, particularly among men.

Betaine is a kind of water-soluble quaternary amine-type alkaloid widely existing in food, such as wheat germ, beet, spinach, shrimp and wolfberry. As an important methyl donor and osmotic pressure regulator in human body, betaine plays an important role in a variety of physiological activities. In recent years, a large number of literatures have shown that betaine has good preventive and therapeutic effects on many liver diseases, including chemical or drug-induced liver injury, nonalcoholic fatty liver disease, alcoholic fatty liver disease, liver fibrosis, hepatitis B and hepatitis C. Therefore, by searching the databases of Web of Science, PubMed, SciFinder and CNKI, this paper has summarized the molecular mechanisms of betaine in improving liver diseases. The results show that the improvement of liver diseases by betaine is closely related to a variety of molecular mechanisms, including inhibition of inflammatory response, improvement of insulin resistance, reduction of endoplasmic reticulum stress, alleviation of liver oxidative stress, increase of autophagy, remodeling of intestinal flora and regulation of epigenetic modification. More importantly, nuclear transcription factor kappa (NF-κB), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor α/γ (PPAR-α/γ), liver X receptor α (LXRα), protein kinase B (Akt), toll-like receptor 4 (TLR4) and cysteinyl aspartate specific proteinase-3 (Caspase-3) signaling pathways are considered as important molecular targets for betaine to improve liver diseases. These important findings will provide a direction and basis for further exploring the pathogenesis of various liver diseases and tapping the potential of betaine in the clinical treatment.

Chronic infection with the hepatitis B virus (HBV) is an important risk factor for the development of hepatocellular carcinoma (HCC). Even though treatment options for HCC are constantly improving, preventive measures must not be neglected.

The vaccination against hepatitis B has proven effective in preventing infection with HBV. As shown more than 20 years ago in Taiwan, vaccination programs lower not only the prevalence of HBsAg carriers but also decrease the incidence of HCC. By achieving immunity against HBV, the infection with hepatitis D virus can also be prevented. This is important in the light of HCC prevention as HBV/HDV coinfection is known to drastically increase the risk of HCC. New approaches aim for the development of therapeutic HBV vaccines ideally curing chronic infections. Beside the prevention of infections, it is pivotal to detect existing infections. This helps to minimize the HCC risk by initiating treatment in those who need it.

To compare the safety and effectiveness of coil versus glue embolization of gastroesophageal varices during transjugular intrahepatic portosystemic shunt (TIPS) creation.

In this monocentric retrospective study 104 (males: 67 (64%)) patients receiving TIPS with concomitant embolization of GEV and a minimum follow-up of one year (2008-2017) were included. Primary outcome parameter was overall survival (6 week; 1 year). Six-week overall survival was assessed as a surrogate for treatment failure as proposed by the international Baveno working group. Secondary outcome parameters were development of acute-on-chronic liver failure (ACLF), variceal rebleeding and hepatic encephalopathy (HE). Survival analysis was performed using Kaplan-Meier with log-rank test and adjusted Cox regression analysis.

Indications for TIPS were refractory ascites (n = 33) or variceal bleeding (n = 71). Embolization was performed using glue with or without coils (n = 40) (Group G) or coil-only (n = 64) (Group NG). Overall survival was significantly better in group G (p = 0.022; HR = -3.333). Six-week survival was significantly lower in group NG (p = 0.014; HR = 6.945). Rates of development of ACLF were significantly higher in group NG after 6 months (NG = 14; G = 6; p = 0.039; HR = 3.243). Rebleeding rates (NG = 6; G = 3; p = 0.74) and development of HE (NG = 22; G = 15; p = 0.75) did not differ significantly between groups.

Usage of glue in embolization of GEV may improve overall survival, reduce treatment failure and may be preferable over coil embolization alone.