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.

The current subclassification of steatotic liver disease (SLD) relies on validated questionnaires, such as Alcohol Use Disorders Identification Test (AUDIT) and Lifetime Drinking History (LDH), which, while useful, are impractical and lack precision for their use in routine clinical practice. Phosphatidylethanol (PEth) is a quantitative, objective alcohol biomarker with high sensitivity and specificity.

To assess the diagnostic accuracy of PEth for differentiating metabolic dysfunction and alcohol-associated liver disease (MetALD) from metabolic dysfunction-associated steatotic liver disease (MASLD) in a large, population-based, prospective, multiethnic cohort of individuals with overweight or obesity.

This is a cross-sectional analysis of a prospective study including 374 adults with overweight or obesity residing in Southern California who had SLD as defined by MRI-PDFF ≥ 5%. The clinical research visit included medical history, biochemical and PEth testing, standardised validated questionnaires (including AUDIT and LDH), physical examination, and advanced imaging using MRI-PDFF and MRE.

Among 374 adults with SLD, the prevalence of MASLD, MetALD, and ALD was 90.1%, 6.4%, and 3.5%, respectively. PEth had a robust diagnostic accuracy in the detection of MetALD (AUROC 0.81, 95%CI 0.73-0.89) and the Youden cut-off was 25 ng/mL. In head-to-head comparative efficacy analysis, PEth was both statistically and clinically superior to all previously used indirect alcohol biomarkers for diagnosing MetALD, including aspartate aminotransferase/alanine aminotransferase ratio, mean corpuscular volume, gamma glutamyltransferase, and ALD/NAFLD index (p < 0.05).

PEth outperforms previously used non-invasive tests in differentiating MetALD from MASLD and has the potential to change clinical practice by enhancing the subclassification of SLD.

Both metabolic dysfunction and alcohol consumption cause steatotic liver disease (SLD). The distinction between metabolic dysfunction-associated SLD (MASLD) and MetALD categories is based on arbitrary thresholds of alcohol intake. Thus, we assessed the impact of different levels of alcohol consumption on SLD severity and their interaction with metabolic comorbidities.

We performed a population-based study with transient elastography (FibroScan®) data from participants in Spain (derivation cohort) and the US (validation cohort). A controlled attenuation parameter ≥275 dB/m was used to define SLD. At least one cardiometabolic risk factor was required to define MASLD. Among patients with MASLD, low alcohol consumption was defined as an average of 5-9 drinks/week, moderate consumption as 10-13 drinks/week for females and 10-20 drinks/week for males, and increased alcohol intake (MetALD) as 14-35 drinks/week for females and 21-42 drinks/week for males. Significant fibrosis was defined as a liver stiffness measurement ≥8 kPa and at-risk metabolic dysfunction-associated steatohepatitis (MASH) as a FAST score ≥0.35.

The derivation cohort included 2,227 individuals with MASLD (9% reported low, 14% moderate alcohol consumption) and 76 cases with MetALD. Overall prevalences of significant fibrosis and at-risk MASH were 7.6% and 14.8%, respectively. In the multivariable analysis, alcohol consumption was independently associated with significant fibrosis and at-risk MASH. A dose-dependent increase in the prevalence of significant fibrosis and at-risk MASH was observed between the number of drinks/week and the number of cardiometabolic factors. The validation cohort included 1,732 participants with MASLD, of whom 17% had significant fibrosis and 13% at-risk MASH. This cohort validated the association between moderate intake and MASLD at risk of progression (odds ratio 1.69, 95% CI 1.06-2.71).

Moderate alcohol intake is commonly seen in MASLD and increases the risk of advanced disease to a level similar to that observed in MetALD.

Metabolic risk factors such as overweight, diabetes or dyslipidemia, and alcohol consumption can cause liver disease. These factors frequently coexist, but their joint effects on liver fibrosis remain uncertain. In this study, we have analyzed individuals from the general population with MASLD (metabolic dysfunction-associated steatotic liver disease) enrolled in Spain and the US. We show that moderate alcohol consumption has a supra-additive effect with metabolic risk factors, exponentially increasing the risk of liver fibrosis. These results suggest that there are no safe limits of daily alcohol intake in patients with unhealthy metabolic status and MASLD.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are commonly ordered tests in general medical practice. However, their distribution and significance in older adults are understudied. As such, we aimed to evaluate sex-stratified distribution of both ALT and AST in older adults (≥70 years) and assess for associations with mortality.

Post-hoc analysis of the ASPirin in Reducing Events in the Elderly (ASPREE) randomized, placebo-controlled trial of daily low-dose aspirin for initially relatively healthy older persons. Univariate analysis and multiple logistic regression were used to explore baseline characteristics. Cox regression and restricted cubic splines were used to examine links between transaminase levels and mortality.

Of the 11 853 participants with ALT and AST levels, 1 054 (8.9%) deaths were recorded over a median of 6.4 (interquartile range [IQR] 5.4-7.6) years. For ALT, the lowest quintiles for males and females were 6-15 and 5-13 U/L, respectively; for AST, the lowest quintiles were 8-18 and 7-17 U/L, respectively. On both univariate and models adjusted for covariates including age, body mass index, frailty, diabetes, and kidney disease, males and females in the lowest quintile of ALT had an increased hazard of mortality (aHR 1.51 [95% confidence interval {CI} 1.14-1.99] and aHR 1.39 [95% CI 1.03-1.88], respectively). For the lowest quintile of AST, only males were at increased risk (aHR 1.33 [95% CI 1.04-1.70]). Associations remained significant when removing outliers.

Low ALT levels independently confer an increased hazard of mortality for older males and females; low AST only affected older male survival. Further evaluation of mechanisms would be worthwhile, and re-evaluating the lower limit of normal for ALT in older adults should be considered.

Steatotic liver disease (SLD) encompasses metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (AALD) at extremes as well as an overlap group termed MASLD with increased alcohol intake (MetALD). The Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease Index (ANI) was proposed to differentiate ALD from nonalcoholic fatty liver disease (NAFLD). We analysed the performance of the ANI in differentiating within the SLD spectrum.

In a cross-sectional study at a tertiary care center, 202 adults (>18 years) who were prospectively diagnosed with SLD defined by magnetic resonance imaging-proton density fat fraction >6.4% were enrolled. Alcohol consumption (AC) was recorded according to thresholds for significant AC: 140-350 g/week (or 20-50 g/day) for females and 210-420 g/week (or 30-60 g/day) for males. The ANI was calculated, and area under the receiver operating characteristic curve (AUROC) was generated.

Of 202 patients (47 years [interquartile range, IQR, 38 to 55], 23.75% females, 77% obese, 42.1% with diabetes, 38.1% hypertensive, 28.7% statin use), 40.5% were ever-alcohol consumers; 120 (59%), 50 (24.7%), and 32 (15.8%) were MASLD (ANI, -3.7 [IQR, -7 to -1.6]; MetALD, - 1.45 [IQR, -2.4 to 0.28]; and AALD, 0.71 [IQR, -1.3 to 4.8], respectively; P<0.05 for all). The AUROC of the ANI for MASLD and AALD was 0.79 (IQR, 0.72 to 0.84; cut-off <-3.5) and 0.80 (IQR, 0.74 to 0.86; cut-off >-1.49), respectively. The ANI outperformed aspartate transaminase/alanine transaminase (AST/ALT) ratio (AUROC=0.75 [IQR, 0.69 to 0.81]) and gamma glutamyl transpeptidase (GGT) (AUROC=0.74 [IQR, 0.67 to 0.80]). Addition of GGT did not improve model performance (AUCdiff=0.004; P=0.33).

AC is common in MASLD. The ANI distinguishes MASLD and AALD, with individual cut-offs within the intermediate zone indicating MetALD. ANI also outperforms AST/ALT ratio or GGT.

Steatohepatitis with diverse etiologies is the most common histological manifestation in patients with liver disease. However, there are currently no specific histopathological features pathognomonic for metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, or metabolic dysfunction-associated steatotic liver disease with increased alcohol intake. Digitizing traditional pathology slides has created an emerging field of digital pathology, allowing for easier access, storage, sharing, and analysis of whole-slide images. Artificial intelligence (AI) algorithms have been developed for whole-slide images to enhance the accuracy and speed of the histological interpretation of steatohepatitis and are currently employed in biomarker development. Spatial biology is a novel field that enables investigators to map gene and protein expression within a specific region of interest on liver histological sections, examine disease heterogeneity within tissues, and understand the relationship between molecular changes and distinct tissue morphology. Here, we review the utility of digital pathology (using linear and nonlinear microscopy) augmented with AI analysis to improve the accuracy of histological interpretation. We will also discuss the spatial omics landscape with special emphasis on the strengths and limitations of established spatial transcriptomics and proteomics technologies and their application in steatohepatitis. We then highlight the power of multimodal integration of digital pathology augmented by machine learning (ML)algorithms with spatial biology. The review concludes with a discussion of the current gaps in knowledge, the limitations and premises of these tools and technologies, and the areas of future research.

In 2023, the nonalcoholic fatty liver disease (NAFLD) Nomenclature Consensus group proposed a new name and concept for NAFLD/nonalcoholic steatohepatitis. The Japanese Society of Gastroenterology and the Japanese Society of Hepatology have accepted these new names and concepts. It was reported that the terms "nonalcoholic" and "fatty" are misleading and inappropriate, because NAFLD does not reflect the etiology. Thus, appropriate disease names are discussed, and new concepts are published. First, the concept of steatotic liver disease (SLD) was proposed to encompass fatty liver diseases of various etiologies, which are classified into five categories. The diagnostic criteria for metabolic dysfunction-associated steatotic liver disease (MASLD) included fatty liver with at least one of the five cardiometabolic risk factors (body mass index or waist diameter, blood glucose or glycated hemoglobin, blood pressure, triglycerides, and high-density lipoprotein cholesterol) and the same restriction of alcohol consumption as NAFLD. A new fatty liver category was described, MetALD, to represent the intermediate drinker group (patients with MASLD with high weekly alcohol intake [140-350 g/week in women and 210-420 g/week in men]). The other five categories are alcohol-associated liver disease, fatty liver with an identifiable specific cause, and other fatty livers of unknown cause. Nonalcoholic steatohepatitis is an important pathological concept (metabolic dysfunction-associated steatohepatitis); however, its definition, including hepatocellular balloon-like degeneration, needs to be reassessed. In Japan, we should use these names and criteria to manage SLD, including hepatocellular carcinoma, which is markedly increasing.

Excessive alcohol consumption represents an important burden for health systems worldwide and is a major cause of liver- and cancer-related deaths. Alcohol consumption is mostly assessed by self-report that often underestimates the amount of drinking. While alcohol use disorders identification test - version C is the most widely used test for alcohol use screening, in patients with liver disease the use of alcohol biomarker could help an objective assessment. The amount of alcohol that leads to significant liver disease depends on gender, genetic background, and coexistence of comorbidities (i.e., metabolic syndrome factors). All patients with alcohol-associated liver disease are recommended to follow complete abstinence and they should be treated within multidisciplinary teams. Abstinence slows down and even reverses the progression of liver fibrosis and can help recompensate patients with complicated cirrhosis. Whether there is a safe amount of alcohol in the general population is a matter of intense debate. Large epidemiological studies showed that the safe amount of alcohol to avoid overall health-related risks is lower than expected even in the general population. Even one drink per day can increase cancer-related death. In patients with any kind of chronic liver disease, especially in those with metabolic-associated steatotic liver disease, no alcohol intake is recommended. This review article discusses the current evidence supporting the deleterious effects of small-to-moderate amounts of alcohol in the general population and in patients with underlying chronic liver disease.

Fatty liver disease (FLD) is associated with several metabolic derangements. We conducted a retrospective cross-sectional and longitudinal study to evaluate the role of FL severity in the risk of new-onset and co-existing hypertension (HTN) and diabetes mellitus (DM).

The cross-sectional cohort consisted of 41,888 adults who received health checkups in a tertiary hospital of Taiwan from 1999 to 2013. Of them, 34,865 without HTN and/or DM at baseline and within 1 year after enrollment were included as a longitudinal cohort (mean, 6.45 years for HTN; 6.75 years for DM). FL severity based on the degree of hepatic steatosis was assessed by ultrasound sonography.

In cross-sectional cohort, 22,852 (54.6%) subjects had FL (18,203 [43.46%] mild FL and 4,649 [11.10%] moderate/severe FL); 13.5% (n = 5668) had HTN; and 3.4% (n = 1411) had DM. Moderate/severe FL and mild FL had significantly higher risks of existing HTN (adjusted odds ratio/95% confidence interval [CI] 1.59/1.43-1.77 and 1.22/1.13-1.32, respectively). In longitudinal cohort, 3,209 and 822 subjects developed new-onset HTN and DM, respectively (annual incidence, 14.3 and 3.5 per 1000 person-years; 10-year cumulative incidence, 14.35% and 3.89%, respectively). Moderate/severe and mild FL had significantly higher risks of new-onset HTN (adjusted hazard ratio [aHR]/CI 1.54/1.34-1.77 and 1.26/1.16-1.37, respectively) and DM (aHR/CI 5.88/4.44-7.81 and 3.22/2.56-4.07, respectively). Resolved FL during follow-up decreased the risk of HTN and/or DM.

Patients with FL are at high risk of prevalent and incident HTN and/or DM. The risk increases with the severity of FL.

An association between environmental pollutants and alcohol-related liver disease (ALD) has not been determined until now. The objectives of this study were to examine the association of the pollutants with ALD, and whether the pollutants together increased the risk of ALD.

Data were extracted from the Korea National Health and Nutrition Examination Survey (2010-2013 and 2016-2017; n = 11,993). Blood levels of lead, cadmium, and mercury were measured. ALD was defined by a combination of excessive alcohol consumption and ALD/non-alcoholic fatty liver disease index > 0. The aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 score were used to evaluate ALD FIB.

The odds ratios (ORs) of ALD for the highest versus the lowest quartiles of exposure were for lead, 7.39 (95% confidence interval [CI], 5.51-9.91); cadmium, 1.68 (95% CI, 1.32-2.14); and mercury, 5.03 (95% CI, 3.88-6.53). Adjusting for age, gender, smoking, occupation, education, and personal income attenuated the associations but indicated significant positive trends (all Ptrend < 0.001). A positive additive interaction between cadmium and lead was observed. The relative excess OR due to the interaction was 0.96 (95% CI, 0.41-1.51); synergy index = 2.92 (95% CI, 0.97-8.80). Among 951 subjects with ALD, advanced FIB was associated with lead and cadmium (OR, 3.46, 95% CI, 1.84-6.53; OR, 8.50, 95% CI, 2.54-28.42, respectively), but not with mercury. The effect estimates for lead and cadmium remained significant even after adjustment for daily alcohol intake.

Blood levels of lead, cadmium, and mercury were significantly associated not only with the risk of ALD but also with ALD FIB. Cadmium and lead have synergistic effects that increase the risk of ALD.

Nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) are the leading causes of chronic liver disease worldwide. NAFLD and ALD share pathophysiological, histological and genetic features and both alcohol and metabolic dysfunction coexist as aetiological factors in many patients with hepatic steatosis. A diagnosis of NAFLD requires the exclusion of significant alcohol consumption and other causes of liver disease. However, data suggest that significant alcohol consumption is often under-reported in patients classified as having NAFLD and that alcohol and metabolic factors interact to exacerbate the progression of liver disease. In this Review, we analyse existing data on the interaction between alcohol consumption and metabolic syndrome as well as the overlapping features and differences in the pathogenesis of ALD and NAFLD. We also discuss the clinical implications of the coexistence of alcohol consumption, of any degree, in patients with evidence of metabolic derangement as well as the use of alcohol biomarkers to detect alcohol intake. Finally, we summarize the evolving nomenclature of fatty liver disease and describe a recent proposal to classify patients at the intersection of NAFLD and ALD. We propose that, regardless of the presumed aetiology, patients with fatty liver disease should be evaluated for both metabolic syndrome and alcohol consumption to enable better prognostication and a personalized medicine approach.

The use of probiotics, prebiotics, and synbiotics has become an important therapy in numerous gastrointestinal diseases in recent years. Modifying the gut microbiota, this therapeutic approach helps to restore a healthy microbiome. Nonalcoholic fatty liver disease and alcohol-associated liver disease are among the leading causes of chronic liver disease worldwide. A disrupted intestinal barrier, microbial translocation, and an altered gut microbiome metabolism, or metabolome, are crucial in the pathogenesis of these chronic liver diseases. As pro-, pre-, and synbiotics modulate these targets, they were identified as possible new treatment options for liver disease. In this review, we highlight the current findings on clinical and mechanistic effects of this therapeutic approach in nonalcoholic fatty liver disease and alcohol-associated liver disease.

Nonalcoholic fatty liver disease (NAFLD), once considered a benign condition, has been associated with several cardiometabolic complications over the past two decades. The worldwide prevalence of NAFLD is as high as 30%. NAFLD requires the absence of a "significant alcohol intake." Conflicting reports have suggested that moderate alcohol consumption may be protective; therefore, the diagnosis of NAFLD previously relied on negative criteria. However, there has been a significant increase in alcohol consumption globally. Apart from the rise in alcohol-related liver disease (ARLD), alcohol, a major toxin, is associated with an increased risk of several cancers, including hepatocellular carcinoma. Alcohol misuse is a significant contributor to disability-adjusted life years. Recently, the term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed instead of NAFLD to include the metabolic dysfunction responsible for the major adverse outcomes in patients with fatty liver disease. MAFLD, dependent on the "positive diagnostic criteria" rather than previous exclusion criteria, may identify individuals with poor metabolic health and aid in managing patients at increased risk of all-cause and cardiovascular mortality. Although MAFLD is less stigmatizing than NAFLD, excluding alcohol intake may increase the risk of already existing underreported alcohol consumption in this subgroup of patients. Therefore, alcohol consumption may increase the prevalence of fatty liver disease and its associated complications in patients with MAFLD. This review discusses the effects of alcohol intake and MAFLD on fatty liver disease.

The prevalence of alcohol use disorder (AUD) and metabolic dysfunction-associated fatty liver disease (MAFLD) are increasing worldwide, leading to the increasing likelihood of both etiologies contributing to a patient's liver disease. However, the effects of modest alcohol use in NAFLD are controversial and more studies are needed. We compared the intestinal viromes of patients with AUD and NAFLD in order to evaluate the effect of alcohol consumption on the intestinal viromes of NAFLD patients by extracting virus-like particles and performing metagenomic sequencing.

Viral nucleic acids were extracted from fecal samples and subjected to metagenomic sequencing. We demonstrate significant differences in the intestinal viromes of NAFLD and AUD patients, and that alcohol use in NAFLD patients reclassified to MAFLD accounted for significant differences in the intestinal viromes. The relative abundance of several Lactococcus phages was more similar between AUD patients and alcohol-consuming MAFLD patients than non-alcohol-consuming MAFLD patients and control subjects, and multivariate modeling using the most discriminating Lactococcus phages could better predict alcohol use in the MAFLD population than the alcohol-associated liver disease/NAFLD Index. Significant differences in the viral composition and diversity were also seen between MAFLD patients with low and moderate alcohol consumption compared with no alcohol consumption.

The intestinal virome of MAFLD patients who consume low to moderate amounts of alcohol are significantly different from those who do not, and many features of the intestinal virome of alcohol-consuming MAFLD patients resemble that of AUD patients.

Alcohol-associated hepatitis (AH) is a clinical syndrome of jaundice, abdominal pain, and anorexia due to prolonged heavy alcohol intake. AH is associated with changes in gene expression, cytokines, immune response, and the gut microbiome. There are limited biomarkers to diagnose and prognosticate in AH, but several non-invasive biomarkers are emerging. In this review, clinical risk-stratifying algorithms, promising AH biomarkers like cytokeratin-18 fragments, genetic polymorphisms, and microRNAs will be reviewed.

Alcohol-related liver disease (ALD) represents one of the leading causes of chronic liver disease and is a major cause of liver-related deaths worldwide. ALD encompasses a range of disorders including simple steatosis, alcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Patients with underlying ALD and continued heavy alcohol consumption can also develop an episode of acute-on-chronic liver injury called alcohol-associated hepatitis, the most severe form of the disease, which portends a poor prognosis. The most important risk factor for the development of ALD is the amount of alcohol consumed. Individual susceptibility to progression to advanced fibrosis among heavy drinkers is likely determined by a combination of behavioral, environmental, genetic, and epigenetic factors, but the mechanisms are largely unknown. The only effective therapy for ALD is prolonged alcohol abstinence. Diagnosis of ALD involves assessing patients for alcohol use disorder and signs of advanced liver disease. In clinical practice, the histological assessment for ALD diagnosis is uncommon, and it is usually based on the medical history, clinical manifestations, and laboratory and imaging tests. Several promising biomarkers that can have both diagnostic and prognostic value in patients with ALD have been identified in recent years. This review provides an overview of the clinical spectrum of ALD, the diagnostic approach of the disease from different perspectives as well as current diagnostic and prognostic biomarkers.

Elevated intraocular pressure (EIOP) is a major risk factor for glaucoma. Both EIOP and fatty liver share metabolic risk factors, which implies a possible link between EIOP and fatty liver. We aimed to determine the association of fatty liver with EIOP and estimate the effect of fatty liver on EIOP directly and indirectly through insulin resistance. Data from 16,240 adults who underwent health examinations at a single center were analyzed. Multiple logistic regression analyses revealed that fully adjusted odds ratio (OR) and 95% confidence interval (CI) for EIOP in the fatty liver group compared to the non-fatty liver group were 1.36 and 1.08-1.71. Alcoholic liver disease was associated with EIOP in subgroup analysis (OR = 1.80, 95% CI: 1.27-2.56). There was a linear dose-response relationship between EIOP and the severity of fatty liver. Mediation analysis revealed that the total effect of fatty liver on intraocular pressure was 0.90 (0.81-0.99), with a direct effect of 0.81 (0.71-0.90) and an indirect effect of 0.09 (0.06-0.11) through insulin resistance. Fatty liver is independently associated with EIOP. It primarily has a direct effect on intraocular pressure. This suggests that evaluation of EIOP should be considered in patients with fatty liver.

Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) cannot reliably be distinguished by routine diagnostics, and the role of alcohol consumption in metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear. We investigated alcohol consumption in patients with presumed NAFLD and ALD using novel objective alcohol markers.

In total, 184 consecutive patients were included in this prospective observational study. Alcohol intake was assessed by ethylglucuronide in hair (hEtG) and urine (uEtG); the utility of these measures for alcohol detection was compared to Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), carbohydrate deficient transferrin (CDT), mean corpuscular volume (MCV), gamma-glutamyltransferase (GGT), and ALD/NAFLD index (ANI). Clinical characteristics of patients with NAFLD and ALD were re-assessed after reclassification based on repeated moderate (≥10 g <60 g EtOH/day) and excessive (≥60 g EtOH/day) alcohol consumption, and patients were retrospectively reclassified based on MAFLD criteria.

Repeated moderate to excessive alcohol consumption was detected in 28.6%, 28.5%, and 25.0% of patients with presumed NAFLD, ALD or MAFLD, respectively. ANI score, AUDIT-C, uEtG, and hEtG showed AUCs of 0.628, 0.733, 0.754, and 0.927 for the detection of repeated moderate to excessive alcohol consumption, respectively. The indirect markers CDT, MCV and GGT were not reliable. Patients with repeated moderate or excessive alcohol consumption were significantly more often male, had a significantly lower BMI, and suffered significantly less often from type 2 diabetes or impaired glucose tolerance.

In total, 28.6% of patients with presumed NAFLD, and 25.0% with MAFLD are at risk of alcohol-related liver damage. AUDIT-C, uEtG and hEtG should be used to screen for alcohol consumption in patients with fatty liver disease.

Fatty liver disease can be caused by metabolic factors and/or alcohol consumption. The diagnosis of non-alcoholic fatty liver disease (NAFLD) is based on the exclusion of harmful alcohol consumption, while metabolic dysfunction-associated fatty liver disease (MAFLD), which has been proposed as a new name for NAFLD, is based on the presence of metabolic comorbidities and allows for alcohol consumption. Herein, we show that up to 29% of patients diagnosed with NAFLD and 25% with MAFLD are at risk of alcohol-related liver damage. We show that ethyl glucuronide (a metabolite of alcohol) in the hair and urine can accurately detect potentially harmful alcohol consumption in these patients - as such, these tests should be integrated into routine diagnostic work-up for patients with fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects, and deleterious consequences which include hepatocellular carcinoma.

Untreated non-alcoholic fatty liver disease (NAFLD) may have significant consequences including an increase in mortality and cardiovascular injury. Thus, early detection of NAFLD is currently believed not only to prevent liver-related but also cardiovascular mortality. However, almost nothing is known about coexisting NAFLD in patients with coronary artery disease (CAD). We investigated the impact of surrogate scores of fibrosis in NAFLD in a large cohort of patients referred to coronary angiography. Modeling the common NALFD and fibrosis scores, fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), as splines revealed significant associations with all-cause and cardiovascular mortality when Cox regression models were only adjusted for cardiovascular risk factors that were not already included in the calculation of the scores. Stratifying the scores into quartiles yielded hazard ratios [95% confidence interval (CI)] for all-cause and cardiovascular mortality for the 4th quartile versus the 1st quartile of 2.28 (1.90-2.75) and 2.11 (1.67-2.67) for FIB-4 and of 3.21 (2.61-3.94) and 3.12 (2.41-4.04) for NFS. However, we did not observe an independent association of FIB-4 or NFS with overall or cardiovascular mortality in our prospective CAD cohort after full adjustment for all cardiovascular risk factors [all-cause mortality: HR 1.13 (0.904-1.41) and 1.17 (0.903-1.52); cardiovascular mortality: HR 1.06 (0.8-1.41) and 1.02 (0.738-1.41)]. Thus, neither FIB-4 nor NFS, as surrogate markers for NAFLD/NASH, were independent risk factors for overall or cardiovascular mortality in patients with CAD. Our data show that surrogate risk scores for NAFLD-related fibrosis do not add information in assessing the CVD events in patients with CAD proven by angiography.NEW & NOTEWORTHY We investigated the impact of NAFLD surrogate markers in a large cohort of patients that had been referred to coronary angiography. In contrast to a repeatedly demonstrated increased link of cardiovascular events in patients with NALFD, we demonstrated that NAFLD surrogate markers were not independent risk factors for overall or cardiovascular mortality in patients with CAD. Thus, these markers may not be useful for primary prevention of cardiovascular events in patients with CAD.

Alcoholic hepatitis (AH) is a clinical syndrome of jaundice, abdominal pain, and anorexia due to prolonged heavy alcohol intake, and is associated with alterations in gene expression, cytokines, immune response, and the gut microbiome. Currently, we have limited biomarkers to diagnose and prognosticate in AH, but there are many novel noninvasive biomarkers under development. We evaluate the currently used algorithms to risk-stratify in AH (such as the Maddrey modified discriminant function), and discuss novel biomarkers in development, such as breath biomarkers, microRNAs, cytokeratin-18 fragments, and the AshTest. We also review the characteristics of an ideal biomarker in AH.

Alcohol-associated hepatitis (AH) is a unique clinical syndrome in patients with excessive and prolonged alcohol consumption, and negatively impacts the patient outcomes. Among patients with asymptomatic alcohol-associated liver disease with elevated liver enzymes and/or steatosis, liver biopsy is required to diagnose AH. Noninvasive assessment should be performed in these patients to determine risk of advanced fibrosis. In symptomatic patients with jaundice, liver biopsy is required when the clinical diagnosis is uncertain. Liver biopsy is not recommended to determine prognosis of patients with AH. Noninvasive biomarkers are emerging for diagnosis of and determining prognosis of patients with AH.

In contrast to nonalcoholic fatty liver disease (NAFLD), metabolic-associated fatty liver disease (MAFLD) as an innovative definition can coexist with significant alcohol consumption. Massive clinical observations have indicated that high-fat/-calorie diet induced metabolic dysfunction along with alcohol intake deteriorates steatotic liver injury. To explore the potential mechanisms of fatty diet together with alcohol-induced steatohepatitis, we adopted a rat model by comparing a half-dose combination of fat diet (20%) and alcohol (10%) with their corresponding double dose of 40% fat diet and 20% alcohol for 8 weeks. The notable alterations in histopathology, acceleration in the oxidation parameters (ROS, NO and lipid peroxidation) and serum transaminase levels were shown in the concomitant group. Concomitant use of a high-fat diet and alcohol provoked hepatic endoplasmic reticulum stress, but did not activate mitochondria-mediated apoptosis parameters compared to F. In contrast, the notable activation of caspase-12 and nuclear translocation of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) were observed only in the combined treatment group. The concomitant dietary fat intake and alcohol consumption lead to liver injury initially and later to steatohepatitis by the overdose of fat or alcohol, and in which the CHOP and caspase-12 might be involved in synergistic acceleration of steatohepatitis through a mitochondria-independent manner.

The term steatohepatitis is used for a heterogeneous group of diseases of various etiologies, characterized by a similar morphological picture. Earlier the diagnosis of non-alcoholic fatty liver disease implied the exclusion of other causes of steatohepatitis, in recent years it has been suggested that a combination of various etiological variants of steatohepatitis is possible. The review considers the terminological, epidemiological and pathogenetic aspects of the most common combination: metabolic and alcoholic genesis, the issues of the mutual influence of etiopathogenetic factors and the identification of the predominant process. Issues of existing and prospective pathogenetic and symptomatic therapy are discussed in detail. Treatment of steatohepatitis is based on the elimination of known causal factors and lifestyle modification; therapy includes medications, that have been proven to be effective in certain types of steatohepatitis and symptomatic therapy as well.

In alcoholic liver cirrhosis (LC) patients, obesity has become a problem that progresses into liver dysfunction. Herein, we investigated the relationship between the prognosis of steatohepatitis and body weight, along with fat accumulation in patients with alcoholic LC. We conducted a single-center retrospective study, enrolled 104 alcoholic LC patients without hepatocellular carcinoma (HCC) based on histological and clinical evidence, and investigated factors related to poor prognosis using multivariate Cox regression and cluster analyses. Cox regression analysis revealed three independent relevant factors: subcutaneous adipose tissue (SAT) index (median 34.8 cm2/m2, P = 0.009, hazard ratio [HR] 1.017, 95% confidence interval [CI] 1.004-1.030), total bilirubin level (median 1.7 mg/dL, P = 0.003, HR 1.129, 95% CI 1.042-1.223), and prothrombin time value (median 64%, P = 0.007, HR 0.967, 95% CI 0.943-0.991). In the cluster analysis, we categorized the patients into three groups: no adipose tissue accumulation (NAT group), SAT prior accumulation (SAT group), and visceral adipose tissue prior accumulation (VAT group). The results of the three groups revealed that the SAT group displayed a significantly poor prognosis of the Kaplan-Meier curve (67.1 vs 21.2 vs 65.3, P<0.001) of a 5-year survival rate. Propensity score matching analysis of the SAT and VAT groups was performed to adjust the patient's background, but no significant differences were found between them; however, the prognosis was poorer (21.2 vs 66.3, P<0.001), and hemostatic factors were still at a lower level in the SAT group. These findings suggest that SAT accumulation type of obesity is a poor prognostic factor in alcoholic LC patients without HCC, and the hemorrhagic tendency might worsen the poor prognosis in such cases.

Alcohol-related liver disease has become the leading indication for liver transplantation in the USA, partly due to an increase in the prevalence of high-risk drinking behaviour and alcohol use disorder, particularly among young women. Achieving sustained alcohol abstinence might not only prevent the development and progression of alcohol-related liver disease, but could also lead to clinically significant improvements, even in the advanced stages of disease. In this Series paper, we discuss the diagnosis and outpatient management of alcohol-related liver disease, with an emphasis on treatment options for alcohol use disorder and the assessment of nutritional status.

Alcoholic hepatitis is a frequent condition in the Mexican population. It is characterized by acute-on-chronic liver failure, important systemic inflammatory response, and multiple organ failure. The severe variant of the disease implies elevated mortality. Therefore, the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología brought together a multidisciplinary team of health professionals to formulate the first Mexican consensus on alcoholic hepatitis, carried out utilizing the Delphi method and resulting in 37 recommendations. Alcohol-related liver disease covers a broad spectrum of pathologies that includes steatosis, steatohepatitis, different grades of fibrosis, and cirrhosis and its complications. Severe alcoholic hepatitis is defined by a modified Maddrey's discriminant function score ≥ 32 or by a Model for End-Stage Liver Disease (MELD) score equal to or above 21. There is currently no specific biomarker for its diagnosis. Leukocytosis with neutrophilia, hyperbilirubinemia (> 3 mg/dL), AST > 50 U/l (< 400 U/l), and an AST/ALT ratio > 1.5-2 can guide the diagnosis. Abstinence from alcohol, together with nutritional support, is the cornerstone of treatment. Steroids are indicated for severe disease and have been effective in reducing the 28-day mortality rate. At present, liver transplantation is the only life-saving option for patients that are nonresponders to steroids. Certain drugs, such as N-acetylcysteine, granulocyte-colony stimulating factor, and metadoxine, can be adjuvant therapies with a positive impact on patient survival.

Excessive alcohol consumption is responsible for approximately 50% of all deaths due to cirrhosis. Although the duration and amount of alcohol consumption are the primary factors responsible for the liver injury caused by consuming alcohol, the pathogenesis of the 3 stages of alcohol-associated liver disease (ALD)-fatty liver, alcoholic hepatitis (AH), and cirrhosis- is likely multifactorial. Preexisting obesity, dysbiosis of the gut microbiome, activation of proinflammatory cytokines, and genetic factors can all contribute to the risk of developing ALD. The cornerstone of therapy for all stages of ALD is abstinence from drinking alcoholic beverages. Severe AH, defined by a Maddrey discriminant function greater than 32, warrants additional therapy. The results of multiple studies evaluating the use of glucocorticoids in the treatment of severe AH led to guidelines from international societies that recommend glucocorticoid therapy in patients with severe AH without active infection. Liver transplantation provides an effective treatment option for patients who fail glucocorticoid therapy. Recent advances in understanding the pathogenesis of AH have led to the investigation of potential therapies directed at preventing the development of steatosis, inhibiting the innate immune response, modifying the gut microbiome, and stimulating liver regeneration.

Data on the trends in the prevalence of chronic liver disease (CLD) in Korea are scarce. This study aimed to evaluate whether the CLD prevalence changed between 1998-2001 and 2016-2017. Data were extracted from the Korea National Health and Nutrition Examination Survey (1998-2001 to 2016-2017; n=25,893). Non-alcoholic fatty liver disease (NAFLD) was defined as a hepatic steatosis index >36 in the absence of any other evidence of CLD. The definition of alcoholrelated liver disease (ALD) was excessive alcohol consumption (≥210 g/week for men and ≥140 g/week for women) and an ALD/NAFLD index >0. The prevalence of NAFLD increased from 18.6% (95% confidence interval [CI], 17.8-19.5%) in 1998-2001 to 21.5% (95% CI, 20.6-22.6%) in 2016-2017. During the same time period, increases were observed in the prevalence of obesity (27.0 vs. 35.1%), central obesity (29.4 vs. 36.0%), diabetes (7.5 vs. 10.6%), and excessive drinking (7.3 vs. 10.5%). ALD prevalence also increased from 3.8% (95% CI, 3.4-4.2%) to 7.0% (95% CI, 6.4-7.6%). In contrast, chronic hepatitis B decreased from 5.1% (95% CI, 4.6-5.5%) to 3.4% (95% CI, 3.0-3.8%). The prevalence of chronic hepatitis C was approximately 0.3% in 2016-2017. The prevalence of NAFLD and ALD increase among Korean adults. Our results suggest potential targets for interventions to reduce the future burden of CLD.

Alcohol-related liver disease (ALD) is a major cause of advanced chronic liver disease in Latin-America, although data on prevalence is limited. Public health policies aimed at reducing the alarming prevalence of alcohol use disorder in Latin-America should be implemented. ALD comprises a clinical-pathological spectrum that ranges from steatosis, steatohepatitis to advanced forms such as alcoholic hepatitis (AH), cirrhosis and hepatocellular carcinoma. Besides genetic factors, the amount of alcohol consumption is the most important risk factor for the development of ALD. Continuous consumption of more than 3 standard drinks per day in men and more than 2 drinks per day in women increases the risk of developing liver disease. The pathogenesis of ALD is only partially understood and recent translational studies have identified novel therapeutic targets. Early forms of ALD are often missed and most clinical attention is focused on AH, which is defined as an abrupt onset of jaundice and liver-related complications. In patients with potential confounding factors, a transjugular biopsy is recommended. The standard therapy for AH (i.e. prednisolone) has not evolved in the last decades yet promising new therapies (i.e. G-CSF, N-acetylcysteine) have been recently proposed. In both patients with early and severe ALD, prolonged abstinence is the most efficient therapeutic measure to decrease long-term morbidity and mortality. A multidisciplinary team including alcohol addiction specialists is recommended to manage patients with ALD. Liver transplantation should be considered in the management of patients with end-stage ALD that do not recover despite abstinence. In selected cases, increasing number of centers are proposing early transplantation for patients with severe AH not responding to medical therapy.

Alcoholic hepatitis is a unique type of alcohol-associated liver disease characterized by acute liver inflammation caused by prolonged heavy alcohol use. Treatment is mostly supportive. The short-term prognosis of acute alcoholic hepatitis depends on liver recovery, and ranges widely from rapid improvement to grim multiorgan failure despite treatment. Refinement of scoring systems have enhanced prognostication to guide clinical decision making in alcoholic hepatitis. Recent advances in the treatment of alcoholic hepatitis have solidified corticosteroids as the cornerstone of treatment to enhance short-term survival, but not intermediate or long-term survival.

Excessive alcohol consumption can lead to a spectrum of liver histopathology, including steatosis, steatohepatitis, foamy degeneration, fatty liver with cholestasis, and cirrhosis. Although variability in sampling and pathologist interpretation are of some concern, liver biopsy remains the gold standard for distinguishing between steatohepatitis and noninflammatory histologic patterns of injury that can also cause the clinical syndrome of alcohol-related hepatitis. Liver biopsy is not routinely recommended to ascertain a diagnosis of alcohol-related liver disease in patients with an uncertain alcohol history, because the histologic features of alcohol-related liver diseases can be found in other diseases, including nonalcoholic steatohepatitis and drug-induced liver injury.

Liver diseases have been bound to environmental factors, inclusive of air pollution. The exposure of workers to petrochemicals counts as a possible cause of Liver diseases, whereas results are inconsistent with the previous studies. In this study, a meta-analysis is conducted to assess the pooled risk.

A systematic search was performed by related researchers. Correlations are analyzed among petroleum and liver cirrhosis mortality, fatty liver, alanine amino transferase (abbreviated as ALT), aspartate amino transferase (abbreviated as AST). Pooled risk ratios (RR) with 95% confidence interval (CI) and effect size(ES) with 95% confidence interval are calculated. Sensitivity analysis and publication bias are also tested. Data are analyzed from 5 studies involving 296 participants. Results are incorporated through adopting a random effects meta-analysis. Working in a petrochemical plant shall not increase the death risk posed by cirrhosis (RR = 0.44, 95% CI [0.36; 0.54]). Yet the incidence of fatty liver increases (RR = 1.22, 95% CI [1.21; 1.23]). Abnormal incidence of ALT and AST also increases.

Occupational exposure plays an important role in causing ALT abnormalities and fatty liver among oil workers, but not a risk factor of cirrhosis, AST abnormalities and liver cancer.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. Most cases are diagnosed incidentally in the primary care or hospital setting on the basis of elevated liver enzyme levels or hepatic steatosis on imaging. NAFLD encompasses a wide spectrum: The vast majority of patients have nonprogressive nonalcoholic fatty liver, and a few of those develop progressive liver injury, inflammation, and fibrosis, a condition termed nonalcoholic steatohepatitis. Cardiovascular disease is the leading cause of death in patients with nonalcoholic fatty liver disease. Persons with nonalcoholic steatohepatitis have increased liver-related mortality. In the absence of regulatory agency-approved drugs, lifestyle modification and weight loss remain the cornerstones of NAFLD therapy.

Leptin/leptin resistance has been suggested to play a role in nonalcoholic fatty liver disease (NAFLD), and therefore we investigated the correlation of leptin/leptin-receptor system with markers of hepatic steatosis (HS) and fibrosis (HF) in patients with type 2 diabetes (T2D).

In 159 T2D subjects with disease duration of 6.0 (0.0-27.0) years, HS was evaluated by semi-quantitative ultrasonographic scores and by clinical/biochemical variables: Fatty liver index and Hepatic steatosis index. HF was evaluated by NAFLD fibrosis score (NAFLD-FS). Serum leptin and leptin receptor (sObR) concentrations were measured and leptin resistance estimated by Free Leptin Index (FLpI). Both simple and multiple correlations between the HS and HF with the three parameters of interest were examined.

Leptin levels and FLpI correlated with diabetes duration (0.25 [95%CI: 0.09-0.39] and 0.24 [95%CI: 0.08-0.39]; P < 0.01 for both). 76.1% of T2D patients had HS and 29% had HF. The univariate analysis indicated positive correlations of HS indexes with serum leptin, FLpI, and negative correlations with serum sObR (P < 0.0001 for all). In the multiple regression analysis leptin, sObR, FLpI, waist-to-hip ratio, HbA1c, lipids, and HOMA-IR correlated independently with HS (P < 0.0001 for all). Although the univariate analyses indicated weak correlations of NAFLD-FS with leptin, sObR, and FLpI, in the multiple regression analyses, only age and waist independently predicted HF.

In patients with T2D, HS correlated positively with serum leptin and leptin resistance, and negatively with sObR, along with variables of adiposity and metabolic control, but neither of them made a significant contribution to HF.