Liver, Cardiovascular and Infectious Outcomes in Alcohol-Associated Liver Disease With Cardiometabolic Risk Factors.

Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD), is the primary cause of illness and mortality. In particular, MASLD affects more than 30% of the global population, while ALD accounts for 5.1% of all diseases and injuries worldwide. The SLD spectrum includes a variety of clinical conditions, from mild fatty liver and inflammation to different stages of liver fibrosis. Additionally, both conditions (MASLD and ALD) can be complicated by hepatocellular carcinoma (HCC), while around one-third of ALD patients can also develop at least one alcohol‐associated hepatitis (AH) episode. Both of these diseases are also associated with multiple extrahepatic complications, such as cardiovascular disease, chronic kidney disease, and malignancies. In MASLD, the rapid rise in global obesity and type 2 diabetes mellitus (T2DM) prevalence due to Westernized lifestyles has led to an increase in the prevalence of MASLD. Thus, the prevention and control of cardiometabolic risk factors (CMRFs) are the cornerstone of its treatment. Hypertension and atherogenic dyslipidemia are also important CMRFs associated with MASLD. Susceptible individuals with MASLD are adversely affected by even a small amount of alcohol consumption (though there is no agreed definition of a small amount), increasing the risk of severe outcomes and a faster progression of liver disease. This review explores factors that play a role in the development of SLD, especially focusing on the management of CMRFs and levels of alcohol use to prevent liver disease progression.

Assessment of metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and metabolic dysfunction and alcohol-associated steatotic liver disease in open Mexican population.

Steatotic liver disease predicts cardiovascular disease and advanced liver fibrosis: A community-dwelling cohort study with 20-year follow-up

Prevalence and Clinical Correlation of Cardiometabolic Risk Factors in Alcohol-Related Liver Disease and Metabolic Dysfunction and Alcohol Associated Liver Disease (MetALD).

Validation and Epidemiologic Definition of the Novel Steatotic Liver Disease Nomenclature in a National United States Cohort With Cirrhosis.

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

Alcohol-associated liver disease (ALD) is a major public health issue that significantly contributes to human morbidity and mortality, with no FDA-approved therapeutic intervention available. The health burden of ALD has worsened during the COVID-19 pandemic, which has been associated with a spike in alcohol abuse, and a subsequent increase in hospitalization rates for ALD. A key knowledge gap that underlies the lack of novel therapies for ALD is a need to better understand the pathogenic mechanisms that contribute to ALD initiation, particularly with respect to hepatic lipid accumulation and the development of fatty liver, which is the first step in the ALD spectrum. The goal of this review is to evaluate the existing literature to gain insight into the pathogenesis of alcohol-associated fatty liver, and to synthesize alcohol’s known effects on hepatic lipid metabolism. To achieve this goal, we specifically focus on studies from transgenic mouse models of ALD, allowing for a genetic dissection of alcohol’s effects, and integrate these findings with our current understanding of ALD pathogenesis. Existing studies using transgenic mouse models of ALD have revealed roles for specific genes involved in hepatic lipid metabolic pathways including fatty acid uptake, mitochondrial β-oxidation, de novo lipogenesis, triglyceride metabolism, and lipid droplet formation. In addition to reviewing this literature, we conclude by identifying current gaps in our understanding of how alcohol abuse impairs hepatic lipid metabolism and identify future directions to address these gaps. In summary, transgenic mice provide a powerful tool to understand alcohol’s effect on hepatic lipid metabolism and highlight that alcohol abuse has diverse effects that contribute to the development of alcohol-associated fatty liver disease.

Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), a nicotinamide adenine dinucleotide (NAD+) synthetase in Preiss-Handler and salvage pathways, governs nuclear NAD+ homeostasis. This study investigated the role of NMNAT1 in alcohol-associated liver disease (ALD). Decreased NMNAT1 expression and activity were observed in the liver of patients with alcohol-associated hepatitis and either liver or primary hepatocytes from ALD mice. F-box and WD repeat domain containing 7 (FBXW7)-regulated interferon regulatory factor 1 (IRF1) ubiquitination degradation contributed to the alcohol-inhibited NMNAT1 transcriptional level. Hepatic NMNAT1 knockout aggravated alcohol-induced hepatic NAD+ decline and further hepatic steatosis and liver injury. Metabolomics and transcriptomics interaction revealed that the cysteine sulfinic acid decarboxylase (CSAD)-regulated taurine pathway was involved in NMNAT1-disrupted hepatic lipid metabolism in ALD. Hepatic CSAD overexpression or taurine supply attenuated hepatic NMNAT1 knockout-aggravated ALD. Hepatic NMNAT1 loss inhibited NMN-protected ALD. Replenishing hepatic NMNAT1 reversed liver lipid accumulation in ALD mice. These findings identified NMNAT1 as a promising therapeutic target for ALD.

Background: Alcohol associated liver disease (AALD) and cardiovascular diseases (CVD) represent significant health burdens worldwide. This study aims to provide a comprehensive overview of the association between AALD and CVD outcomes including heart failure (HF) which was incompletely understood. Methods: The current study utilizes data from the National Health and Nutrition and Examination Survey (NHANES) from 2011 - 2020; using a stratified, multistage probability cluster design. AALD in the NHANES was defined using clinical laboratory data and self-reported alcohol use, among which fibrosis-4 score of >2.67. CVD was defined as participants who self-reported heart failure, coronary artery disease or stroke. Data from NHANES were combined with death certificate data from the National Center of health Statistics from the National Death Index to ascertain mortality rates. All models were adjusted for potential confounding variables such as age, gender, race/ethnicity, education, income/poverty ratio, insurance, smoking, body mass index, systolic/diastolic blood pressure, and diabetes status. Analysis is conducted using weighted, logistic and cox linear regression. Results: The initial sample included 23,206 participants aged 20 and older, with recorded cardiovascular status and AST/ALT levels. After excluding participants with hepatitis B, hepatitis C, metabolic dysfunction-associated fatty liver disease, and pregnant patients, the final unweighted sample size was 13,413. Participants reporting AALD had a higher percentage of college degrees (p<0.001) and were more likely to be daily smokers. Asians exhibited the highest rates of AALD compared to other demographics (p<0.001). Those with AALD also had higher mean systolic and diastolic blood pressure, as well as elevated fasting glucose levels (p<0.001). Comorbidities such as heart failure (HF), stroke, and coronary artery disease (CAD) were prevalent. The mortality rate among AALD participants with CVD was 25%, compared to 3% among those without CVD (p<0.001). After adjusting for potential confounding variables, no statistically significant associations were found between AALD status and HF or CAD. However, a clinically significant increase in the odds of stroke was observed within the AALD group (p<0.001). Conclusions: Our findings indicate Asians have the highest rates of AALD. There is an increased prevalence of AALD with HF, CAD and stroke, and a significant increase in mortality with stroke.

Cardiometabolic Risk Factors Impair Recompensation and Survival in Alcohol-associated Liver Disease.

Chronic liver disease is a major cause of mortality, with approximately 2 million deaths worldwide each year, and it poses a significant economic burden. The most common cause of chronic liver disease in the United States and Europe is steatotic liver disease (SLD), which includes metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, and alcohol-associated liver disease (ALD). Effective treatment of these conditions is essential to reduce the liver disease burden, with promising approaches including treating cardiometabolic risk factors and excessive alcohol intake. Glucagon-like peptide 1 receptor agonists, both as monotherapy and in combination with other drugs, are gaining attention for their beneficial impact on cardiometabolic risk factors and excessive alcohol intake. In this review, we examine the molecular and clinical effects of glucagon-like peptide 1 receptor agonists, focusing on their direct hepatic steatohepatitis and liver fibrosis but also the indirect influence on cardiometabolic risk factors and excessive alcohol intake as key features of SLD. We also explore the future implications of glucagon-like peptide 1 receptor agonists for treating metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, alcohol-associated liver disease, and the potential challenges.

As hepatology providers, we assemble a toolbox of interventions to treat acute and chronic liver diseases with a goal to prevent fibrosis progression, HCC, and hepatic decompensation while also improving the quality of life and survival of our patients (Figure 1). This toolbox has been built based on our experiences during clinical training and the practice of routine patient care. We are comfortable with a diverse set of tools, from antivirals to immunosuppressive medications, vasoactive medications to beta-blockers, as well as performing interventions such as endoscopy, banding, paracentesis, and liver biopsies. Hepatology providers have accepted that in the setting of chronic liver disease, we are primarily responsible for prescribing interventions, which treat the underlying liver insult and follow-up on outcomes and side effects using a multidisciplinary approach. Yet, when it comes to the management of alcohol use disorder (AUD) in the setting of alcohol-associated liver disease (ALD), our discipline seems to have made an exception. Although treatment of AUD has been identified as a quality metric in the care of patients with liver disease,1 rates of AUD treatment in those with ALD are astonishingly low,2,3 and current societal recommendations are to refer elsewhere for AUD management once identified.4,5 Why has this culture evolved among hepatology providers? Is it a lack of knowledge and/or comfort in AUD treatment? Do patients with AUD and their providers have difficulty accessing the tools when needed? Importantly, can social stigma and sociocultural considerations influence patient participation in AUD treatment? The answer is all of the above.FIGURE 1: The hepatology toolbox—how do we include alcohol use disorder treatment?.DESPITE THE BENEFIT, TREATMENT OF AUD IN ALD RARELY HAPPENS It is universally agreed that alcohol abstinence is the cornerstone of ALD management, as it is associated with improved liver-related outcomes3 and is cost-effective and even cost-saving in those with ALD cirrhosis.6 Yet despite this, 2 large cohort studies of individuals with AUD and ALD cirrhosis have shown that only ~15% receive AUD behavioral therapy and a mere 1% receive pharmacotherapy.2,3 Why are AUD treatment rates so low? To begin, data have suggested that apart from psychiatry and addiction medicine, physicians receive minimal training in AUD identification and management and do not feel equipped to treat it. Surveys by GI/hepatology providers suggest that almost all screen universally for frequency and quality of alcohol consumption; however, almost half never/rarely screen for AUD, and 70% never/rarely prescribe AUD therapy.7 The most common provider-perceived barriers to prescribing AUD pharmacotherapy were lack of training, unfamiliarity, and lack of time. Other studies have identified patient-perceived barriers, including lack of apparent benefit to treatment, financial and insurance obstacles, and access to transportation.8 However, in addition to these hurdles, other patient-related barriers are faced disproportionately by those most vulnerable in society. SOCIOCULTURAL AND EQUITY CONSIDERATIONS INFLUENCING DELIVERY OF AUD/ALD THERAPY A significant proportion of individuals with AUD/ALD are from historically underrepresented racial/ethnic, sex/gender, and sociocultural groups9 and those vulnerable in their social determinants of health, creating additional barriers to AUD treatment (Figure 2). These disparities are complex and historically rooted in patterns of systemic discrimination and socioeconomic disadvantage.10 Overall, AUD treatment is most effective as a combination of pharmacologic and behavioral interventions, yet most studies evaluating AUD treatment underrepresent those of diverse cultural, racial/ethnic, and sex/gender backgrounds and have not been designed to address important dimensions of diversity. In considering those vulnerable in social determinants of health, pharmacologic treatments require public and/or private insurance to cover costs, while in addition to cost, behavioral therapy also requires significant time and social resources to participate. These include the ability to take time from work in those employed and/or the ability to delay home obligations if caring for dependents. Individuals must also secure transportation and be in proximity to AUD behavioral treatment, or if able to be delivered remotely, have access to technological resources for participation. Finally, culturally and linguistically appropriate AUD services are required to provide safe and equitable access to AUD treatment to all but are not universally accessible. Moving forward, these important aspects of diversity will need to be considered in the development and delivery of AUD services.FIGURE 2: Barriers to alcohol use disorder treatment in vulnerable populations.SPECIAL CONSIDERATIONS FOR WOMEN AND YOUTHS Women and youths have been identified as populations experiencing a disproportionate increase in harm from AUD/ALD and have emerged as priority groups in need of AUD treatment.11,12 Women and youths with AUD have a high prevalence of co-morbid mental health conditions and have experienced mental, physical, and/or sexual abuse, which can impact participation and outcomes of treatment. Although outcomes of AUD treatment are comparable between sexes, women are less likely to receive treatment than men.12 Unique factors among women that can influence participation in AUD treatment include issues surrounding motherhood, such as the need for childcare to participate and perceived or experienced social stigma creating fear of the involvement of child protective services if AUD is disclosed.12 Further, no AUD pharmacotherapy has been shown to be safe for women who are pregnant or breastfeeding, limiting treatment options during this time. Similarly, for youths, no pharmacotherapies are FDA-approved to treat AUD in those ≤18 years of age, and no trials of AUD treatment among youths with ALD have been conducted. Despite the knowledge that most adults with AUD began using alcohol during the teenage years, the majority of efforts developed to treat AUD have not focused on identification and intervention during adolescence, which may be a key time for behavioral change. Further, the delivery of AUD behavioral therapy for youths is best if the family and caregivers partake, which again will be dependent on the ability of not only the individuals but also their social circle to participate. POTENTIAL SOLUTIONS Several provider, hospital, research, and societal solutions to address barriers in AUD management in ALD are outlined in Figure 3. On an individual GI/Hepatology provider level, the universal implementation of standardized screening tools for AUD to all patients with ALD at the time of the first clinical encounter should be straightforward to implement. In addition to this, the delivery of an AUD pharmacotherapy curriculum to GI/Hepatology trainees, nurses, and clinicians could empower them with the knowledge and skills to initiate AUD pharmacotherapy among their ALD patients. This would be especially important in settings where access to addiction medicine is limited. From a hospital level, providing language and transportation services to facilitate access to AUD behavioral therapy would be specifically helpful to engage vulnerable populations. Further, universal and quick access to inpatient and outpatient addiction medicine consultative services, social work, and psychiatry are essential. From an academic level, the development of studies, which evaluate AUD treatment and outcomes among those with advanced ALD, are needed in addition to the inclusion of previously understudied and vulnerable populations as outlined above. From a society level, it is vital to address the stigma attached to a diagnosis of AUD to empower patients to seek appropriate help without worry about judgment or discrimination. This could involve public education campaigns that emphasize AUD as a disease as opposed to a personal choice and highlight how appropriate treatment of AUD can lead to disease remission and improve other alcohol-associated harms including ALD.FIGURE 3: Potential solutions to address disparities in AUD treatment among those with ALD. Abbreviations: ALD, alcohol-associated liver disease; AUD, alcohol use disorder.CONCLUSIONS AND FUTURE CONSIDERATIONS AUD is a preventable cause of liver-related morbidity and mortality, and AUD treatment is associated with improved outcomes, especially among those with ALD. Yet the use of AUD treatment in those with ALD is discouragingly low due to the paucity of well-executed clinical trials and patient and provider barriers, with additional unique barriers faced by underrepresented and vulnerable members of society. As hepatology providers caring for these patients, our discipline needs to begin gathering AUD treatment tools to put in our toolbox. Importantly, these tools will need to incorporate considerations surrounding stigma, culture, diversity, and equity in order to provide the best care for our diverse patient population.

Comment on: Impact of the COVID-19 pandemic on liver disease-related mortality rates in the United States

PurposePatients with liver disease often experience nutritional insufficiency due to an interplay of metabolic disturbances and dietary alterations leading to decreased muscle mass and the development of protein-calorie malnutrition (PCM). This study aimed to evaluate the prevalence of PCM in patients with steatotic liver disease (alcohol associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD)) and their impacts on mortality and healthcare utilization.MethodsWe identified hospitalizations with ALD, MASLD, and PCM using International Classification of Diseases codes in the National Inpatient Sample from 2016 to 2020. Descriptive analyses compared hospitalizations with and without PCM. Multivariable linear models adjusting for confounders evaluated the association between PCM and inpatient mortality, length of stay (LOS), and total charges.ResultsPCM was found to be significantly more prevalent among hospitalizations with ALD or MASLD than those with neither (ALD: 175.5 vs 51.7; MASLD: 69.2 vs 52.9; neither: 51.5 per 1000 hospitalizations; P < 0.001). Among hospitalizations with ALD or MASLD, PCM was significantly associated with higher mortality (ALD: adjusted odds ratio [aOR] 1.85, 95% CI 1.79–1.91; MASLD: aOR 2.30, 95% CI 2.10–2.52), LOS (ALD: 3.91 days, 95% CI 3.80–4.01; MASLD: 5.17 days, 95% CI 5.00–5.33), and total charges (ALD: $47k higher charges, 95% CI $45k–$50k; MASLD: $60k higher charges, 95% CI $57k–$64k).ConclusionWe found a higher prevalence of PCM among individuals with ALD compared to those with MASLD or neither condition. PCM was associated with increased mortality, LOS, and total charges in those with ALD and MASLD. Our findings underscore the importance of early identification and management of PCM in patients with steatotic liver disease to mitigate adverse outcomes and reduce healthcare utilization.

Background & AimsMetabolic dysfunction-associated steatotic liver disease (MASLD) with increased alcohol consumption (MetALD) is an important, yet understudied cause of liver disease. This study aimed to examine hepatocellular carcinoma (HCC) rates in patients with MetALD and compare them with MASLD, alcohol-associated liver disease (ALD), and controls.MethodsWe conducted a retrospective cohort study of veterans with MetALD, MASLD, ALD, or no SLD. We used Poisson regression to estimate incidence rates within stratifications of patient characteristics, and a multivariable time-updated Fine and Gray model with death as a competing risk to examine HCC risks.ResultsWe included 666,428 participants (392,286 MASLD, 104,065 MetALD, 40,230 ALD, and 129,847 controls) between 1 January 2011 and 31 December 2022, with a follow-up until 31 May 2023. All participants underwent abdominal imaging or transient elastography, confirming the presence (among SLD) or absence (among controls) of steatosis, along with identification of harmful alcohol use and ascertainment of cardiometabolic risk factors. In patients without cirrhosis, the adjusted HCC rates per 100,000 person-years were lowest for MASLD, higher for MetALD, and highest for ALD. The cumulative incidence of HCC at 5 years was highest with ALD, followed by MASLD and MetALD, with rates similar in the latter two groups. At 10 years, the cumulative incidence of HCC per 100,000 individuals was the highest with ALD (1,176.65), followed by MetALD (814.16), and MASLD (762.86).ConclusionsThe risk of HCC associated with MetALD is higher than MASLD, significantly lower than ALD, and likely driven by alcohol. Although HCC rates in non-cirrhotic patients with MetALD are not high enough to justify surveillance, this study identifies a relatively higher risk group compared to MASLD, which warrants counselling on alcohol cessation.Impact and implicationsLimited data exist on the risk of hepatocellular carcinoma (HCC) in patients with MetALD (metabolic dysfunction-associated steatotic liver disease [MASLD] with increased alcohol consumption) and how it compares with other steatotic liver diseases. In this retrospective study of 666,428 patients from the Veterans Analysis of Liver Disease cohort, we observed that the risk of HCC per 100,000 person-years in patients without cirrhosis with MetALD was 80.24 (95% CI 73.23–87.94), which was intermediate between MASLD (71.64, 95% CI 68.14–75.32) and ALD (104.83, 91.59–119.98). The cumulative incidence of HCC per 100,000 persons at 5 years was the highest with ALD (663.79, 581.77–754.83), followed by MASLD (450.71, 428.46–473.89), MetALD (449.89, 407.56-495.74), and controls (76.03, 61.47–93.46). The limitations of the study include its retrospective design and a study population enriched with male veterans with a higher prevalence of metabolic syndrome.