Phosphatidylethanol in Steatotic Liver Disease: Unveiling Alcohol Use and Enhancing Diagnostic Precision

Changing Epidemiology of Cirrhosis and Hepatic Encephalopathy

We read with great interest the recent article by Ward et al.,1 “Diabetes mellitus in alcohol-associated liver disease: Prevalence and outcomes.” This retrospective, multinational study from the WALDO cohort provides valuable insights into the impact of diabetes mellitus on patients with alcohol-associated liver disease (ALD). While this work is timely and has clinical significance, we would like to raise several comments that merit further clarification and discussion. A strength of this study was the inclusion of patients with biopsy-proven ALD. The authors also discussed the new category of steatotic liver disease, namely, metabolic and alcohol-associated liver disease (MetALD), in the subanalysis. This was an important update, but it was unclear what criteria the authors used to identify MetALD. Key metabolic risk factors, such as high triglycerides, low HDL cholesterol, hypertension, and waist circumference, were not captured. Were only patients with diabetes mellitus considered to have MetALD? In that case, the actual rate of MetALD could be underestimated. Even though the histological findings of metabolic dysfunction–associated steatotic liver disease (MASLD) and ALD are similar, details of biopsy results, such as the degree of steatosis, presence of ballooning degeneration, and Mallory bodies, would enhance the analysis. In this cohort, 181 patients were reported to have acute alcoholic hepatitis. It was not stated whether liver biopsies were performed during the acute phase; it could have significantly influenced the degree of inflammation and fibrosis. In addition, what was the short-term 90-day mortality of these patients with alcoholic hepatitis with and without diabetes? The modifications of the natural history of the diseases can directly affect the clinical outcomes. The authors reported that 128 patients discontinued alcohol use at follow-up. That provided an opportunity to compare the prognosis of those with and without alcohol abstinence in addition to the impact of diabetes. Similarly, it would be informative to explore the effects of low-level alcohol intake versus complete abstinence, and how alcohol acts synergistically with diabetes. Equally important, the influence of diabetes management on clinical outcomes needs to be considered. It was unclear what proportion of patients with controlled diabetes by following lifestyle interventions, taking oral hypoglycemic agents, or insulin were included in the study. Notably, patients from the 1970s and 1980s were included; the awareness and management of MASLD and the standard-of-care for diabetes were different from current guidelines. Understanding how alcohol abstinence and optimized diabetes management influence clinical outcomes would provide insights into modifiable risk factors and individualized care. The cohort enrollment spanned 5 decades from 1971 to 2022; we found it difficult to understand why the median follow-up was only 4.8 years (IQR: 1.2–9.5). The lack of difference in the rates of hepatocellular carcinoma between those with and without diabetes could be due to the relatively short follow-up duration. In a recent publication in the United States, ALD and MASLD were identified as the dominant causes of HCC-associated mortality, currently with an upward trend projected through 2040.2 Comprehensive long-term follow-up studies to address the impact of diabetes mellitus on HCC risks among patients with ALD are critical to inform HCC surveillance strategies and policies. In summary, we congratulate the authors for their important contributions to understanding the roles of diabetes mellitus in ALD. Future studies should provide detailed MetALD criteria, documentation of quantities of alcohol intake and diabetes management, as well as longer follow-up duration to capture HCC incidence. These considerations would shed additional light on this complex and evolving field.

The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease

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

Early alcohol use identification can prevent morbidity/mortality for alcohol-associated liver disease (ALD). Innovative wearable alcohol biosensors (biosensors) that identify alcohol use through perspiration are an emerging technology with potential application for patients with ALD. Our primary aim was to determine biosensor acceptability and feasibility for patients with ALD. We describe participant acceptance and challenges using biosensor technology in a pilot study of biosensors with patients with ALD. Participants had a recent diagnosis or hospitalization for decompensated ALD, had to be drinking within the past 3 months, and had to be followed at our center. Participants wore the biosensor daily for 3 months. Quantitative data using the Technology Acceptance Model 2 (TAM2) measure were collected at intake and study conclusion. The TAM2's 13 items cover four scales: perceived usefulness, ease of use, attitude toward technology, and intention to use on a 7-point Likert scale. Lower scores indicate higher acceptance. Participants were asked open-ended questions about issues wearing the biosensor. Among 27 participants, 60% were women with an average age of 45 (10) years, and 89% were White. TAM2 subscales indicated initially high acceptance (mean scores = 1.2-2.2) and remained high (mean scores = 1.3-2.3) without a statistically significant decline at study conclusion. From open-ended questions, several themes regarding problems with device wear emerged a) uncomfortable or cumbersome to wear, b) problems with biosensor appearance, and c) issues with usability. Challenges to biosensor usage included data being lost when devices were damaged and devices being lost during the study. Alcohol biosensors seem to be acceptable to ALD participants. However, improving the appearance, comfort, durability, and functionality of biosensor devices is critical to clinical deployment.Trial Registration:Clinicaltrials.gov identifier NCT03533660: Alcohol biosensor monitoring for alcohol liver disease.

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.

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.

Environmental factors as disease accelerators during chronic hepatitis C

Peer Reviewed

Alcohol-associated liver disease (ALD) is a leading cause of liver disease worldwide, caused by hazardous alcohol use. Many patients with ALD also have alcohol use disorder (AUD), a chronic mental health condition characterized by a cluster of behavioral, cognitive, and physiological symptoms that indicate continued alcohol use despite significant alcohol-related problems. Comprehensive care of ALD often requires treatment of AUD, and evidence has demonstrated that treating the latter improves patient outcomes. However, only a minority of patients with AUD/ALD receive treatment. Integrative care models where hepatologists work alongside AUD specialists have been developed. These partnerships have been associated with improved outcomes, including decreased rates of return to alcohol use, decreased healthcare utilization, and even improved mortality. We review the epidemiology, diagnosis, and treatment of AUD and ALD, examples of successful integrated care models, and outcomes. We also discuss knowledge gaps and areas where future research is needed, including the role of integrated care in the peri-transplantation period for ALD, harm reduction approaches, and the need for efforts to support collaboration for integrative care. In conclusion, the dual pathologies of AUD and ALD necessitate multidisciplinary care, and integrated care models have been shown to be both feasible and effective.

Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C

Implementation of evidence-based alcohol policies to reduce alcohol-related harm and liver disease to advance public health in Europe.

Backgound & AimsSteatotic liver disease (SLD), which includes metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic- and alcohol-associated liver disease (MetALD), and alcohol-associated liver disease (ALD), is the leading cause of chronic liver disease in the US. However, the risk of disease progression varies by subtype. We aimed to evaluate long-term risks of cirrhosis and mortality across SLD subtypes in a longudinal cohort of US veterans.MethodsAdults with MASLD, MetALD, and ALD were identified using the national Veterans Affairs health system database (2010-2023). Incidence of cirrhosis and all-cause mortality was stratified by SLD subtype and analyzed using competing risks and Cox proportional hazards models, adjusted for demographic and clinical covariates.ResultsOverall, 682,274 veterans had MASLD, 517,464 had MetALD, and 305,692 had ALD, with a median follow up of 7.2 years. The highest cirrhosis incidence was observed in ALD (0.66 per 100 person-years vs. 0.43 and 0.39 per 100 person-years in MASLD and MetALD, respectively, p <0.001). Mortality incidence was likewise highest in ALD (0.32 per 100 person-years), compared with MASLD (0.24 per 100 person-years) and MetALD (0.19 per 100 person-years) (p <0.001). Across subtypes, relative to non-Hispanic Whites, Hispanics had higher risk and African Americans lower risk of cirrhosis. The additive effect of concurrent obesity and diabetes was associated with 36% and 22% increased risk of cirrhosis in MASLD and MetALD, respectively, compared to patients without obesity or diabetes.ConclusionsAmong US veterans with SLD, the long-term risk of cirrhosis was highest in ALD, followed by MASLD and MetALD. Concurrent metabolic dysfunction and alcohol use exert a synergistic effect on cirrhosis risk, underscoring the need to aggressively address metabolic comorbidities and implement early screening and treatment for harmful alcohol use.Impact and implicationsGiven the growing burden of steatotic liver disease (SLD) in the US, it is crucial to understand how different causes – namely alcohol use and metabolic dysfunction – contribute to the risk of developing cirrhosis. This large, national study demonstrates that patients with alcohol-related liver disease face the highest risk, with notable variation by race and ethnicity. These findings are especially important for clinicians and healthcare systems caring for diverse populations, as they highlight groups at elevated risk who may benefit from targeted prevention and early intervention strategies. Practically, these results support the need for integrated care approaches that address both harmful alcohol use and metabolic conditions like obesity and diabetes to reduce progression to advanced liver disease.

More than meets the eye: Severe alcoholic hepatitis can present as acute-on-chronic liver failure

Alcohol-related liver disease: A global perspective