Workup and management of liver transplantation in alcohol-related liver disease.

Alcohol-related liver disease (ALD) represents the most common indication for liver transplantation (LT) worldwide. Outcomes of LT for ALD are comparable with those of LT for other etiologies; however, ALD is still considered a controversial indication for LT, mainly because it is considered a self-inflicted disease with a high risk of return to alcohol use after LT. Pre-LT evaluation criteria have changed over time, with a progressive re-evaluation of the required pre-transplant duration of abstinence. Despite the fact that some transplant programs still require 6 months of abstinence in order to consider a patient suitable for LT, there is increasing evidence that a pre-transplant abstinence period of <6 months can be considered for well-selected patients. Early LT for severe alcohol-related hepatitis that has not responded to medical therapy has been shown to be an effective therapeutic option with high survival benefit when performed within strict and well-recognized criteria. However, high variability in LT access exists for these patients due to the presence of social and medical stigma. A psycho-social assessment, together with an evaluation by an addiction specialist, should be mandatory in patients with ALD who are potential candidates for LT in order to assess the risk of post-transplant return to alcohol use and to ensure good long-term outcomes. Finally, before LT, attention should be paid to the presence of other potential comorbidities (i.e., cardiovascular and neurological diseases), which could represent a potential contraindication to LT. Similarly, after LT, patients should be adequately monitored for the development of cardiovascular events and screened for "de novo" tumors, although standardized protocols for this monitoring do not exist at this time.

Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease Index at Diagnosis Is Associated with All-Cause Mortality during Follow-Up in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Background and Objectives: The purpose of this study was to investigate whether a new index related to chronic liver disease, the alcoholic liver disease/nonalcoholic fatty liver disease index (ANI) at diagnosis, is associated with all-cause mortality during follow-up in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Materials and Methods: In this study, we included 270 patients with AAV. ANI was calculated using the following equation: ANI = -58.5 + 0.637 (adjusted mean corpuscular volume) + 3.91 (adjusted aspartate transaminase/alanine transaminase) - 0.406 (body mass index) + 6.35 (if male sex). All-cause mortality was defined as death from any cause during follow-up. Results: The median age of the 270 patients with AAV was 61.0 years (34.4% male and 66.6% female). The median ANI was significantly higher in deceased patients than in surviving patients. In the receiver operating characteristic curve analysis, ANI at diagnosis exhibited a statistically significant area under the curve for all-cause mortality during follow-up, and its cut-off was determined to be -0.59. Patients with ANI at diagnosis ≥ -0.59 exhibited a significantly higher risk for all-cause mortality and a significantly lower cumulative patient survival rate than those without. In the multivariable Cox analysis, ANI at diagnosis ≥ -0.59, together with age at diagnosis, was independently associated with all-cause mortality. Conclusions: This study is the first to demonstrate the predictive potential of ANI at diagnosis for all-cause mortality during follow-up in AAV patients without significant chronic liver diseases.

ACG Clinical Guideline: Alcohol-Associated Liver Disease.

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

Management of alcohol withdrawal syndrome in patients with alcohol-associated liver disease.

Alcohol-associated liver disease is a common and severe sequela of excessive alcohol use; effective treatment requires attention to both liver disease and underlying alcohol use disorder (AUD). Alcohol withdrawal syndrome (AWS) can be dangerous, is a common barrier to AUD recovery, and may complicate inpatient admissions for liver-related complications. Hepatologists can address these comorbid conditions by learning to accurately stage alcohol-associated liver disease, identify AUD using standardized screening tools (eg, Alcohol Use Disorder Identification Test), and assess risk for and symptoms of AWS. Depending on the severity, alcohol withdrawal often merits admission to a monitored setting, where symptom-triggered administration of benzodiazepines based on standardized scoring protocols is often the most effective approach to management. For patients with severe liver disease, selection of benzodiazepines with less dependence on hepatic metabolism (eg, lorazepam) is advisable. Severe alcohol withdrawal often requires a "front-loaded" approach with higher dosing, as well as intensive monitoring. Distinguishing between alcohol withdrawal delirium and HE is important, though it can be difficult, and can be guided by differentiating clinical characteristics, including time to onset and activity level. There is little data on the use of adjuvant medications, including anticonvulsants, dexmedetomidine, or propofol, in this patient population. Beyond the treatment of AWS, inpatient admission and outpatient hepatology visits offer opportunities to engage in planning for ongoing management of AUD, including initiation of medications for AUD and referral to additional recovery supports. Hepatologists trained to identify AUD, alcohol-associated liver disease, and risk for AWS can proactively address these issues, ensuring that patients' AWS is managed safely and effectively and supporting planning for long-term recovery.

Prognostic Factors in Alcohol-associated Liver Disease Patients Presenting With First Evidence of Ascites.

GOALS: To identify factors associated with transplantation and death in alcohol-associated liver disease (ALD) patients presenting with first evidence of ascites. BACKGROUND: Ascites development is a poor prognostic sign for patients with cirrhosis. Among ALD patients, the baseline factors at time of ascites development that are associated with eventual transplantation or death are currently unknown. STUDY: Adult patients with ascites in the "Evaluating Alcohol Use in Alcohol-related Liver Disease Prospective Cohort Study" (NCT03267069 clinicaltrials.gov) were identified from 2016 to 2020. Demographic, clinical, and laboratory factors at initial ascites presentation were identified as potential predictors of transplant and death as competing risks. RESULTS: A total of 96 patients were identified. Median (interquartile range) follow-up time was 2.00 years (0.87 to 3.85). By last follow-up, 34/96 patients had been transplanted (35.4%) and 11/96 had died (11.4%). Prognostic factors for transplant included age per decade [hazard ratio (HR): 0.52 (95% CI, 0.33 to 0.83)], employed status [HR: 0.35 (95% CI, 0.14 to 0.90)], and sodium [HR: 0.94 (95% CI, 0.90 to 0.99)], whereas prognostic factors for death were body mass index [HR: 1.11 (95% CI, 1.00 to 1.22)], Charlson index [HR: 2.14 [95% CI, 1.13 to 4.08]), Maddrey Discriminant Function >32 (HR: 5.88 (95% CI, 1.18, 29.39)], aspartate aminotransferase [HR: 0.99 (95% CI, 0.98 to 0.997)], and a prior 12-month abstinence period [HR: 5.53 (95% CI, 1.10 to 27.83)], adjusted for age, sex, and ALD subcategory. CONCLUSIONS: Several factors at initial ascites presentation are associated with increased risk of transplantation or death and validation in larger cohorts will allow for improved risk stratification for ALD patients.

Alcohol Use in Liver Transplant Recipients With Alcohol-related Liver Disease: A Comparative Assessment of Relapse Prediction Models.

BACKGROUND: The selection of liver transplant (LT) candidates with alcohol-related liver disease (ALD) is influenced by the risk of alcohol relapse (AR), yet the ability to predict AR is limited. We evaluate psychosocial factors associated with post-LT AR and compare the performance of high-risk alcoholism risk (HRAR), sustained alcohol use post-LT (SALT), and the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) scores in predicting relapse. METHODS: A retrospective analysis of ALD patients undergoing LT from 2015 to 2021 at a single US transplant center was performed. Risk factors associated with post-LT AR were evaluated and test characteristics of 3 prediction models were compared. RESULTS: Of 219 ALD LT recipients, 23 (11%) had AR during a median study follow-up of 37.5 mo. On multivariate analysis, comorbid psychiatric illness (odds ratio 5.22) and continued alcohol use after advice from a health care provider (odds ratio 3.8) were found to be significantly associated with post-LT AR. On sensitivity analysis, SIPAT of 30 was optimal on discriminating between ALD LT recipients with and without post-LT AR. SIPAT outperformed both the HRAR and SALT scores (c-statistic 0.67 versus 0.59 and 0.62, respectively) in identifying post-LT AR. However, all scores had poor positive predictive value (<25%). CONCLUSIONS: AR after LT is associated with comorbid psychiatric illness and lack of heeding health care provider advice to abstain from alcohol. Although SIPAT outperformed the HRAR and SALT scores in predicting AR, all are poor predictors. The current tools to predict post-LT AR should not be used to exclude LT candidacy.

Non-invasive markers of inflammation in alcohol-associated liver disease: A scoping review.

Clinical manifestations of liver inflammation in alcohol-associated liver disease (ALD) can range from asymptomatic to severe alcoholic hepatitis. While biopsy is the gold standard for identifying liver inflammation, it is an invasive procedure with risks of bleeding, visceral damage, and infection. We aim to establish the state of the current literature on non-invasive markers of inflammation in ALD. We searched Ovid MEDLINE, Embase, and the Cochrane Library for original studies on the association between one or more non-invasive biomarker(s) and histological inflammation or hepatitis in ALD patients. Exclusion criteria were lack of histological data, abstract only, non-English-language articles, and animal studies. Two independent reviewers screened abstracts, reviewed full texts, and extracted data from included papers. Our search identified 8051 unique studies. Title and abstract screening resulted in 563 studies, and full-text screening resulted in 31 studies for final inclusion. The majority were single-center observational cohorts with an average sample size of 124. Review of these studies identified 44 unique biomarkers and 8 calculated scores associated with histological inflammation and/or hepatitis, in addition to a metabolomic panel of 468 metabolites. Six studies examined diagnostic accuracy for histological inflammation and/or hepatitis. The highest area under the receiver operating characteristic curve was 0.932 using a model based on four metabolites. This review highlights the available literature on non-invasive markers of inflammation in ALD. There is a dearth of studies that evaluate the diagnostic accuracy of these biomarkers, and larger studies are needed to confirm findings identified in small cohorts.

Alcohol-associated liver disease: Epidemiology and management.

Alcohol is the leading cause of preventable liver morbidity and mortality worldwide, as it is also the most frequent cause of advanced liver disease. Alcohol-associated liver disease (ALD) covers different phenotypes ranging from steatosis to the development of inflammation (steatohepatitis), fibrosis and ultimately, in a proportion of patients, the development of liver cirrhosis and its associated complications. ALD has a complex pathogenesis that includes the interplay of both genetic and environmental factors, yet the precise mechanisms are largely unknown. Alcohol-associated hepatitis (AH) is a severe clinical presentation of ALD, which is characterized by abrupt jaundice and clinical decompensations of liver disease. AH occurs in a percentage of patients with underlying ALD and active alcohol consumption. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD and halt the progression of the disease, therefore alcohol abstinence is the most effective measure to improve prognosis in this patient population. In this regard, alcohol cessation remains the first-line treatment in all stages of alcohol disease. In patients with advanced ALD nonresponding to medical therapy, liver transplantation is the only approach that improves prognosis, and it should be considered in patients with decompensated cirrhosis. In the last years, AH has emerged as a new indication of early liver transplantation in non-responders to medical therapy, with promising results in highly selected patients. In this review, we provide an update on the epidemiology, risk factors, natural history, diagnosis, pathogenesis, and current treatments for ALD, taking into account the importance of assessing and managing alcohol consumption as the etiological factor and the main driver of prognosis in patients with ALD.

Closing the Care Gap: Management of Alcohol Use Disorder in Patients with Alcohol-associated Liver Disease.

Alcohol-associated liver disease (ALD)-related morbidity and mortality are rising in the United States. Although effective medications and behavioral interventions are available for the treatment of patients with alcohol use disorder (AUD), patients with ALD are profoundly undertreated for AUD. This article reviews the management of AUD in patients with ALD, with a focus on appropriate screening and diagnosis, management of alcohol withdrawal syndrome, pharmacotherapy for AUD, alcohol biomarkers, and behavioral interventions. Expanding access to AUD treatment is imperative for improving health outcomes in patients with ALD.

Prognostic models in alcohol-related liver disease and alcohol-related hepatitis.

Alcohol-associated liver disease (ALD) and alcohol-associated hepatitis (AH) are dynamic disorders whose prognosis can be challenging to determine. A number of prognostic models have been developed to determine likelihood of death, when to refer for liver transplant (LT) and the role for glucocorticoids. Often these models were created with a specific application in mind but were found to have additional applications with further study. Those prognostic models that have stood the test of time are easy to use, have clear interpretations and employ objective parameters. These parameters most often include total bilirubin, INR and creatinine among other data points. Ideally, these models could be utilized at all phases of disease but in most, it is important for clinicians to consider drinking history and how it might alter the determined scores. Herein we provide a brief review of prognostic models in ALD and AH and provide practical tips and considerations to successfully make use of these tools in a clinical setting.

Advances in the understanding and management of alcohol-related liver disease.

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

[Alcoholic liver disease - 2023]. / Alkoholos májbetegség ­ 2023.

Alcoholic liver disease represents a spectrum of liver injuries from fatty liver, steatohepatitis, fibrosis and cirrhosis to hepatocellular carcinoma. Progression of the disease depends on the amount of alcohol consumption and risk factors or comorbidities, e.g., genetic predisposition, female susceptibility, diet, smoking, obesity, viral infection. Patients with alcoholic liver disease have two pathologies to be diagnosed and treated: the liver disease per se, and the harmful, excessive alcohol consumption (alcohol use disorder) or even dependence. The early diagnosis is important for both conditions and for achieving abstinence. For the diagnosis, there are several biomarkers and non-invasive tests, including psychological tools. To maintain abstinence, pharmacological and non pharmacological interventions can be applied. Concerning the liver disease, the main aims of treatment are to decrease inflammation and oxidative stress, to inhibit cell injury and fibrosis, to modulate liver-gut axis and to support regeneration. Management of patients with alcoholic hepatitis and cirrhosis often needs a psychological support, delivered by a multidisciplinary integrated care model, a close cooperation between addiction experts and hepatologists. Patients with severe alcoholic hepatitis not responding to medical (corticosteroid) therapy should be carefully selected and considered for early liver transplantation. Orv Hetil. 2023; 164(47): 1846-1864.

Multidisciplinary Care of Alcohol-related Liver Disease and Alcohol Use Disorder: A Narrative Review for Hepatology and Addiction Clinicians.

PURPOSE: Models of integrated, multidisciplinary care are optimal in the setting of complex, chronic diseases and in the overlap of medical and mental health disease, both of which apply to alcohol-related liver disease (ALD). Alcohol use disorder (AUD) drives nearly all cases of ALD, and coexisting mental health disease is common. ALD is a complex condition with severe clinical manifestations and high mortality that can occasionally lead to liver transplantation. As a result, integrated care for ALD is an attractive proposition. The aim of this narrative review was to: (1) review the overlapping and concerning trends in the epidemiology of AUD and ALD; (2) use a theoretical framework for integrated care known as the "five-component model" as a basis to highlight the need for integrated care and the overlapping clinical manifestations and management of the 2 conditions; and (3) review the existing applications of integrated care in this area. METHODS: We performed a narrative review of epidemiology, clinical manifestations, and management strategies in AUD and ALD, with a particular focus on areas of overlap that are pertinent to clinicians who manage each disease. Previously published models were reviewed for integrating care in AUD and ALD, both in the general ALD population and in the setting of liver transplantation. FINDINGS: The incidences of AUD and ALD are rising, with a pronounced acceleration driven by the Coronavirus Disease 2019 pandemic. Hepatologists are underprepared to diagnose and treat AUD despite its high prevalence in patients with liver disease. A patient who presents with overlapping clinical manifestations of both AUD and ALD may not fit neatly into typical treatment paradigms for each individual disease but rather will require new management strategies that are appropriately adapted. As a result, the dimensions of integrated care, including collective ownership of shared goals, interdependence among providers, flexibility of roles, and newly created professional activities, are highly pertinent to the holistic management of both diseases. IMPLICATIONS: Integrated care models have proliferated as recognition grows of the dual pathology of AUD and ALD. Ongoing coordination across disciplines and research in the fields of hepatology and addiction medicine are needed to further elucidate optimal mechanisms for collaboration and improved quality of care.

Management of alcohol use disorder in patients with chronic liver disease.

Alcohol use disorder (AUD) rates have risen dramatically in the United States, resulting in increasing rates of alcohol-associated liver disease (ALD), but many patients struggle to access alcohol use treatment. AUD treatment improves outcomes, including mortality, and represents the most urgent means by which care can be improved for those with liver disease (including ALD and others) and AUD. AUD care for those with liver disease involves 3 steps: detecting alcohol use, diagnosing AUD, and directing patients to alcohol treatment. Detecting alcohol use can involve questioning during the clinical interview, the use of standardized alcohol use surveys, and alcohol biomarkers. Identifying and diagnosing AUD are interview-based processes that should ideally be performed by a trained addiction professional, but nonaddiction clinicians can use surveys to determine the severity of hazardous drinking. Referral to formal AUD treatment should be made, especially where more severe AUD is suspected or identified. Therapeutic modalities are numerous and include different forms of one-on-one psychotherapy, such as motivational enhancement therapy or cognitive behavior therapy, group therapy, community mutual aid societies (such as Alcoholics Anonymous), inpatient addiction treatment, and relapse prevention medications. Finally, integrated care approaches that build strong relationships between addiction professionals and hepatologists or medical providers caring for those with liver disease are crucial to improving care for this population.

Biomarkers for monitoring alcohol sobriety after liver transplantation for alcoholic liver disease.

Alcoholic liver disease (ALD) has become the most common indication for liver transplantation in Western countries, and its incidence is rapidly increasing in East Asia. Alcohol abstinence remains the standard of care for promoting liver transplantation for ALD and for preventing posttransplant graft loss. However, efficient monitoring methods are still being developed due to the limitations of traditional biomarkers, interviews, and questionnaires. The development of alcohol biomarkers has shifted from detecting alcohol and methanol to indirect byproducts, and to current mid-term and long-term direct alcohol metabolites, which provide higher accuracy and cover almost all types of alcohol relapse detection. However, in most clinical studies, biomarkers are used and validated in healthy individuals and alcohol use disorder (AUD) patients and for pretransplant evaluations. The evidence for their use in posttransplant abstinence monitoring is still lacking, but it is crucial for early detection of alcohol relapse and initiating intervention. This review aims to summarize the current evidence of the use of biomarkers for monitoring sobriety and alcohol relapse after liver transplantation, as well as to cover the diagnostic accuracy, detection window, and optimal multidisciplinary strategies.

Current and future treatment for alcoholic-related liver diseases.

The socioeconomic burden of alcohol-related liver disease has been increasing worldwide. Its prevalence is underestimated, and patients with alcohol-related liver disease are rarely diagnosed in the earlier phase of the disease spectrum. Alcoholic hepatitis is a distinct syndrome with life-threatening signs of systemic inflammation. In severe alcoholic hepatitis, prednisolone is indicated as the first-line treatment even with the possibility of various complications. Early liver transplantation can be another option for highly selected patients with a null response to prednisolone. Most importantly, abstinence is the mainstay of long-term care, but relapse is frequent among patients. Recent findings on the pathogenesis of alcoholic hepatitis have enabled us to discover new therapeutic targets. Preventing hepatic inflammation, reducing oxidative stress, improving gut dysbiosis, and enhancing liver regeneration are the main targets of emerging therapies. Herein, we review the pathogenesis, current treatment, and barriers to successful clinical trials of alcoholic hepatitis. Additionally, clinical trials for alcoholic hepatitis, either ongoing or recently completed, will be briefly introduced.