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.

Nutritional deficiencies in alcohol use disorder/alcohol-associated liver disease.

PURPOSE OF REVIEW: To delineate common and uncommon dietary and nutritional deficiencies in individuals with chronic heavy alcohol use and alcohol use disorder and to highlight important advances in the nutrition field in patients ranging from those with alcohol use disorder (AUD) and no liver disease to those with decompensated alcohol-associated liver disease (ALD). RECENT FINDINGS: Patients with AUD may have nutritional deficiencies, especially isolated nutrient deficiencies, such as thiamine or zinc deficiencies. This should not be surprising, as alcohol is a major source of "empty calories." It is devoid of critical macronutrients, such as protein, and micronutrients including important vitamins and minerals. Patients with AUD frequently drink much more than often appreciated (10-20 drinks a day). Patients with AUD and early ALD often begin to develop more apparent nutritional deficiencies. Healthcare providers need to be aware of the presenting features of individual nutrient deficiencies, such as thiamine deficiency, and to provide prompt treatment. In patients with more advanced liver disease, malnutrition correlates with severity of liver disease. It is important to understand the value of nutritional support throughout the spectrum of AUD. SUMMARY: We review nutritional deficiencies in the spectrum of patients with AUD and ALD and highlight new information and recommendations.

Positive blood phosphatidylethanol concentration is associated with unfavorable waitlist-related outcomes for patients medically appropriate for liver transplantation.

BACKGROUND: Excessive alcohol use is a leading etiology of liver disease and indication for liver transplantation. Accurate measurement of alcohol use remains a challenge in the management of patients in the pre-, peri-, and post-liver transplant settings. Blood 16:0-18:1 phosphatidylethanol (PEth) concentration is a sensitive and specific biomarker of binge and moderate, chronic alcohol use. As PEth has the longest detection window of available blood-based direct alcohol biomarkers for moderate to heavy drinking, it shows promise as an indicator of patterns and chronicity of drinking. However, the utility of PEth in clinical liver transplantation is understudied. This study examines the association of PEth results with liver transplantation waitlist-focused patient outcomes. METHODS: Retrospective data for all patients tested for PEth for a one-year period at a tertiary care medical center with an active liver transplantation program were abstracted. Indications for PEth testing, liver transplantation waitlist-related outcomes (e.g., listing and delisting) following testing and associations of PEth results with other parameters were analyzed. RESULTS: Over a one-year period, 153 PEth tests were performed on 109 individuals. The most frequent indications for PEth testing were as an objective indicator of alcohol use patterns (86.3%) and to assess alcohol as a putative etiology of liver injury (13.7%). Of the 109 patients, 56 were medically appropriate for liver transplantation. Medically acceptable candidates with unfavorable transplantation waitlist-related outcomes (delisting, deferment of transplant evaluation, deferment of listing until completion of recommended alcohol rehabilitation, and being deemed not a transplant candidate) were at least 3.41 times more likely to have a positive PEth test than those with favorable transplantation waitlist-related outcomes (odds ratio 3.41, confidence interval 3.41 to ∞, p = 0.001). CONCLUSION: This single-center study reporting a comprehensive account of PEth utilization at a liver transplant center demonstrates that liver transplantation waitlist-related outcomes are associated with PEth test results. Patients with positive PEth tests were more likely to have unfavorable transplant waitlist-related outcomes. PEth testing has not been validated as a predictor of relapse to drinking in post-transplant patients and because its utility in the pre-transplant setting is unclear its use could lead to disparities in the selection of patients for liver transplantation.

Theragnostic Efficacy of K18 Response in Alcohol Use Disorder with Clinically Significant Fibrosis Using Gut-Liver Axis.

(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard of care (SOC) treatment in the improvement in liver injury. (2) Methods: Forty-eight heavy-drinking AUD patients aged 21−65 yrs. without clinical manifestations of liver injury were grouped by Fibrosis-4 (FIB-4) score, as negative (Gr.1 < 1.45, n = 21) or positive (Gr.2 ≥ 1.45, n = 27). Patients received 2-weeks (2 w) inpatient SOC. Data on demographics, drinking patterns, liver-injury, immune markers, and liver cell death (K18s) markers were analyzed at baseline (BL) and after 2 w SOC. (3) Results: Lifetime drinking (LTDH, yrs.) and acute heavy drinking (Heavy Drinking Days Past 90 Days [HDD90]) markers were significantly higher in Gr.2 vs. Gr.1. BL ALT, AST, AST:ALT and K18M65 were considerably higher in Gr.2. Dysregulated gut dysfunction and elevated immune activity were evident in Gr.2 characterized by TNF-α, IL-8 and LPS levels. After SOC, Gr.2 showed improvement in AST, ALT, AST/ALT ratio; and in the K18M65, K18M30 and K18M65/M30 ratio vs. Gr.1. The true positivity of BL IL-8 response to predict the improvement in K18M65 to normal levels among Gr.2 patients against those who did not have improvement after 2 w SOC was very high (AUROC = 0.830, p = 0.042). (4) Conclusions: Gut dysfunction, elevated cytokine response and necrotic liver cell death were elevated in AUD patients with early-stage ALD. K18 showed promise as a predictive theragnostic factor to differentiate among the AUD patients with early-stage ALD and baseline fibrosis who had improvement in liver injury against those who did not, by the levels of baseline IL-8.

Provider Attitudes and Practices for Alcohol Screening, Treatment, and Education in Patients With Liver Disease: A Survey From the American Association for the Study of Liver Diseases Alcohol-Associated Liver Disease Special Interest Group.

BACKGROUND & AIMS: While abstinence-promoting behavioral and pharmacotherapies are part of the therapeutic foundation for alcohol use disorder (AUD) and alcohol-associated liver disease (ALD), these therapies, along with alcohol screening and education, are often underutilized. Our aim was to examine provider attitudes and practices for alcohol screening, treatment and education in patients with liver disease. METHODS: We conducted a survey of primarily (89%) hepatology and gastroenterology providers within (80%) and outside the United States (20%). Surveys were sent to 921 providers with 408 complete responses (44%), of whom 343 (80%) work in a tertiary liver transplant center. RESULTS: While alcohol screening rates in liver disease patients was nearly universal, less than half of providers reported practicing with integrated addiction providers, using alcohol biomarkers and screening tools. Safe alcohol use by liver disease patients was felt to exist by 40% of providers. While 60% of providers reported referring AUD patients for behavioral therapy, 71% never prescribed AUD pharmacotherapy due to low comfort (84%). Most providers (77%) reported low addiction education and 90% desired more during GI/hepatology fellowship training. Amongst prescribers, baclofen was preferred, but with gaps in pharmacotherapy knowledge. Overall, there was low adherence to the 2019 AASLD practice guidance for ALD, although higher in hepatologists and experienced providers. CONCLUSIONS: While our survey of hepatology and gastroenterology providers demonstrated higher rates of alcohol screening and referrals for behavioral therapy, we found low rates of prescribing AUD pharmacotherapy due to knowledge gaps from insufficient education. Further studies are needed to assess interventions to improve provider alignment with best practices for treating patients with AUD and ALD.

Performance of echocardiography for detection of portopulmonary hypertension among liver transplant candidates: Meta-analysis.

BACKGROUND: Evaluation of pulmonary arterial pressure is crucial among cirrhotic patients, considering that moderate portopulmonary hypertension (POPH) is a contraindication for liver transplantation. Although right heart catheterization (RHC) is the most accurate method to diagnose POPH, it is invasive. OBJECTIVE: The aim of the study is to evaluate the performance of echocardiography in detecting POPH in liver transplant candidates. METHODS: A Literature search was performed, and pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, and area under the summary receiver operating curve (AUC) were calculated. Subgroup analyses were performed based on different cutoff values for echocardiography and diagnostic criteria of RHC. RESULTS: Sensitivity, specificity, positive LR, negative LR, and AUC of echocardiography for detection of POPH were 0.86 (0.74, 0.94), 0.87 (0.84, 0.90), 7.17 (3.59, 14.31), 0.22 (0.13, 0.38), and 0.807 while they were 0.82 (0.74, 0.89), 0.81 (0.78, 0.84), 117.75 (16.03, 865.08), 0.28 (0.16, 0.50), and 0.876for detection of moderate POPH, respectively. Performance of echocardiography was not significantly different in the subgroup analyses of stringency of POPH criteria and pulmonary arterial systolic pressure (ePASP) cutoffs. CONCLUSIONS: Our meta-analysis supports utilization of echocardiography for screening of POPH. However, RHC remains essential in highly suspicious cases. Echocardiographic data other than ePASP should be evaluated in future studies.

Incidence and Risk Factors Associated With 30-Day Readmission for Alcoholic Hepatitis.

BACKGROUND: Alcohol abuse and liver disease are associated with high rates of 30-day hospital readmission, but factors linking alcoholic hepatitis (AH) to readmission are not well understood. We aimed to determine the incidence rate of 30-day readmission for patients with AH and to evaluate potential predictors of readmission. METHODS: We used the Nationwide Readmissions Database to determine the 30-day readmission rate for recurrent AH between 2010 and 2014 and examined trends in readmissions during the study period. We also identified the 20 most frequent reasons for readmission. Multivariate survey logistic regression analysis was used to identify factors associated with 30-day readmission. RESULTS: Of the 61,750 index admissions for AH, 23.9% were readmitted within 30-days. The rate of readmission did not change significantly during the study period. AH, alcoholic cirrhosis, and hepatic encephalopathy were the most frequent reasons for readmission. In multivariate analysis female sex, leaving against medical advice, higher Charlson comorbidity index, ascites, and history of bariatric surgery were associated with earlier readmissions, whereas older age, payer type (private or self-pay/other), and discharge to skilled nursing-facility reduced this risk. CONCLUSIONS: The 30-day readmission rate in patients with AH was high and stable during the study period. Factors associated with readmission may be helpful for development of consensus-based expert guidelines, treatment algorithms, and policy changes to help decrease readmission in AH.

Hepatic stellate cells retain retinoid-laden lipid droplets after cellular transdifferentiation into activated myofibroblasts.

Loss of retinyl ester (RE)-rich lipid droplets (LDs) from hepatic stellate cells (HSCs) is cited as a key event in their cellular transdifferentiation to activated, pro-fibrotic myofibroblasts; however, it remains unclear if changes in LD morphology or RE content are causal for transdifferentiation. To better understand LD dynamics in vitro within a common model of HSC activation, we used novel approaches preserving LD morphology and allowing for quantitation of RE. The size and quantity of LDs within in vitro and in vivo bile duct ligation (BDL)-activated HSCs were quantitated using adipocyte differentiation-related protein (ADRP) labeling and oil red o (ORO) staining (gold standard), and RE content was determined using fluorescence microscopy. We found during HSC activation in vitro that LD number differed significantly when measured by ADRP and ORO, respectively ( day 1: 56 vs. 5, P = 0.03; day 4: 101 vs. 39, P = 0.03; day 14: 241 vs. 12, P = 0.02). Ex vivo HSCs activated in vivo contained the same number of LDs as day 4 in vitro activated HSCs (118 vs. 101, P = 0.54). Decline in LD RE occurred beyond day 4 in vitro and day 1 ex vivo , after HSC transdifferentiation was underway. Lastly, in situ HSCs examined using electron microscopy show LDs tend to be smaller but are ultimately retained in BDL injured livers. Therefore, we conclude that during HSC transdifferentiation, LDs are not lost but are retained, decreasing in size. Additionally, RE content declines after transdifferentiation is underway. These data suggest that these LD changes are not causal for HSC transdifferentiation. NEW & NOTEWORTHY Loss of retinoid-laden lipid droplets from hepatic stellate cells has long been held as a hallmark of their transdifferentiation into activated myofibroblasts, the dominant cells that drive hepatic fibrosis. This study demonstrates that stellate cells activated in culture and after liver injury in vivo retain their lipid droplets and that these droplets become smaller and more numerous, with decreases in droplet retinoid concentration occurring only after cellular transdifferentiation is underway.

Domestic global health: a curriculum teaching medical students to evaluate refugee asylum seekers and torture survivors.

BACKGROUND: Seven to 12% of foreign-born patients in the United States has experienced torture. We aimed to teach medical students to identify and care for asylum seekers/torture survivors. DESCRIPTION: One hundred twenty-five students participated in a program consisting of a workshop covering sequelae of torture, asylum law, and an approach to patient evaluation; twice-monthly clinical sessions; and mentored preparation of medical affidavits. We observed clinical encounters; evaluated medical affidavits; and assessed students' knowledge, attitudes, and skills pre- and postcurriculum. EVALUATION: Students successfully performed physical and psychological evaluations and prepared affidavits resulting in 89% asylum application approval. We observed improvement in student attitudes toward working with survivors (p < .05), knowledge of sequelae of torture (p < .001), and self-efficacy in clinical evaluation (p < .001). CONCLUSIONS: Medical students learned necessary skills to provide services for survivors, which will also serve them in caring for other vulnerable populations. As an advocacy, cultural competency, and domestic global health opportunity, this training was feasible and achieved its educational goals.

Past, Present, and Future Therapies for Alcohol-associated Hepatitis.

PURPOSE: Alcohol-associated hepatitis (AH) is a unique presentation of cholestatic steatohepatitis with liver dysfunction and malaise preceded by heavy alcohol intake. Although AH exists on a spectrum, in its most severe form, 28-day mortality approaches 50%. Clinical trials of therapeutic interventions over the last 50 years have yielded few durable therapies, none of which convey benefit beyond the short term. METHODS: A qualitative systematic review was performed via searches of PubMed, the International Clinical Trials Registry Platform, and ClinicalTrials.gov for therapeutic interventions for AH. FINDINGS: Prior to 2005, clinical trial results for AH were identified within PubMed. From 2005 to the present, trials were well catalogued within online registries and included information regarding trial status (eg, complete, terminated, actively enrolling). Most clinical trials for AH have used existing medications broadly targeting pathogenic themes of AH (eg, inflammation, cell death) in an off-label manner. The trend of initially promising pilot studies answered by larger trials showing lack of efficacy or safety signals have ended the hopes of many new therapeutics. The emergence of theragnostics to identify patients who may benefit from existing therapies and trials of agents with novel mechanisms of action, including epigenetic modifications and hyaluronic acid signaling targeted to AH pathogenesis, are currently under investigation. IMPLICATIONS: This review of AH treatments details the historical interventions and clinical trials that have led to the current treatment algorithm and active studies shaping the therapeutic pipeline for AH.

Takotsubo cardiomyopathy following liver transplantation and COVID-19 infection.

Takotsubo cardiomyopathy involves transient systolic dysfunction of the left ventricle thought to be caused by a physiologic stress response and associated catecholamine release. We present a previously undocumented cause of this stress response involving a 53-year-old man with hepatocellular carcinoma and alcohol-associated cirrhosis who initially presented for liver transplantation. Shortly after successful transplantation, the patient developed a COVID-19 infection and takotsubo cardiomyopathy.

Investigating the Acute Metabolic Effects of the N-Methyl Carbamate Insecticide, Methomyl, on Mouse Liver.

Many pesticides have been identified as endocrine and metabolism-disrupting chemicals with hepatotoxic effects. However, data are limited for insecticides in the n-methyl carbamate class, including methomyl. Here, we investigate the liver and systemic metabolic effects of methomyl in a mouse model. We hypothesize that methomyl exposure will disrupt xenobiotic and intermediary metabolism and promote hepatic steatosis in mice. Male C57BL/6 mice were exposed daily to 0-5 mg/kg methomyl for 18 days. Mice were fed water and regular chow diet ad libitum. Metabolic phenotyping was performed, and tissue samples were collected. Effects were generally greatest at the highest methomyl dose, which induced Cyp1a2. Methomyl decreased whole body weight while the liver:body weight and testes:body weight ratios were increased. Hepatic steatosis increased while plasma LDL decreased. Fasting blood glucose and the glucose tolerance test area under the curve decreased along with hepatic glycogen stores. Methomyl, however, did not increase liver oxidative stress or injury. Collectively, these data demonstrate that methomyl disrupts hepatic xenobiotic and intermediary metabolism while increasing the testes:body weight ratio, suggesting that it may be an endocrine disrupting chemical. Besides methomyl's known action in cholinesterase inhibition, it may be involved in aryl hydrocarbon receptor activation. The potential impact of n-methyl carbamate insecticides on metabolic health and diseases, including toxicant-associated steatotic liver disease (TASLD), warrants further investigation.

Liver Biopsy in Patients With Alcohol-Associated Liver Disease With Acute-on-Chronic Liver Failure.

Patients with alcohol-associated liver disease may develop severe forms of presentation of acute-on-chronic liver failure, with a high risk for short-term mortality. Alcoholic hepatitis should be suspected among patients with alcohol-associated liver disease who present with acute-on-chronic liver failure. In this review, we discuss the need and feasibility of liver biopsy in the diagnosis of alcoholic hepatitis and predicting its prognosis among decompensated patients with alcohol-associated liver disease and acute-on-chronic liver failure.

Increased Morbidity and Mortality of Patients with Non-cirrhotic Portal Vein Thrombosis After Abdominal and Pelvic Surgeries: a Study of the National Inpatient Sample 2002 to 2015.

BACKGROUND: A higher rate of postoperative morbidity and mortality in patients with portal hypertension from cirrhosis is well recognized; however, the rate of postoperative morbidity and mortality among patients with portal hypertension from non-cirrhotic portal vein thrombosis (NCPVT) is largely unknown. METHOD: All adults undergoing abdominal and pelvic surgery were identified from the National Inpatient Sample database from 2002 to 2015. Patients were then categorized into three groups: non-cirrhotic non-portal vein thrombosis (NCNPVT), NCPVT, and cirrhotic portal vein thrombosis (CPVT). Inpatient mortality, type of disposition, transfusions, length of stay, postoperative complications, and total charges were compared. Logistic regression and ordinary least squares regression analyses were performed for factors associated with inpatient mortality, transfusions, surgery-related complications, and log length of stay. RESULTS: Patients with NCPVT had significantly higher inpatient mortality rates, surgery-related complications, and longer length of stays compared with patients with NCNPVT (2.64% vs. 0.34%, 10.26% vs. 3.26%, 8 vs. 2 days) but less than patients with CPVT (2.64% vs. 6.31%, 10.26% vs. 17.48%, 8 vs. 11 days). In multiple logistic regression analyses, NCPVT groups remained associated with increased inpatient mortality rate, transfusions, and postoperative complications with odds ratios of 3.71 (1.88, 7.32), 3.43 (2.54, 4.62), and 3.08 (2.16, 4.39), respectively. NCPVT was also associated with 2.4 times increased length of stay. DISCUSSION: Patients with NCPVT had significantly higher risks of postoperative morbidity and mortality than patients with NCNPVT but less than patients with CPVT. Future studies with detail regarding the characteristics of PVTs are needed to confirm the findings in this study.

Incidence and predictors of 30-day hospital readmissions for liver cirrhosis: insights from the United States National Readmissions Database.

BACKGROUND: Cirrhosis is associated with substantial inpatient morbidity and mortality. This study aimed to determine the trends in 30-day hospital readmission rates among patients with cirrhosis and identify factors associated with these readmissions. METHODS: We conducted a retrospective analysis of data retrieved from the Nationwide Readmissions Database to determine trends in 30-day readmission for patients discharged with a diagnosis of cirrhosis in 2010 through 2014. Multivariate logistic regression analysis was used to identify predictors of readmission. RESULTS: Among 303,346 patients identified from the database, the 30-day readmission rate for patients with a discharge diagnosis of cirrhosis was 31.4% (n=95,298). The trends in the readmission rates remained steady during the study period. On multivariate analysis, female sex, age 45 years or older, esophagogastroduodenoscopy (EGD) during admission, and disposition to a short-term care facility or skilled nursing facility protected against readmissions. In contrast, coverage by Medicaid insurance, admission during a weekend, nonalcoholic cause of cirrhosis, and history of hepatic encephalopathy and ascites were associated with readmission. CONCLUSIONS: We found an exceptionally high 30-day readmission rate in patients with cirrhosis, although it remained stable during the study period. This study identified some modifiable factors such as disposition to a short-term care facility or skilled nursing facility and patients' attendance of alcohol rehabilitation facilities that could decrease the likelihood of readmission and could inform local and national healthcare policymakers.

Stress-Induced Takotsubo Cardiomyopathy After Transjugular Intrahepatic Portosystemic Shunt.

This report presents the first known documented case of Takotsubo cardiomyopathy, characterized by transient left ventricular systolic dysfunction after a transjugular intrahepatic portosystemic shunt procedure. A 59-year-old woman with decompensated cirrhosis underwent transjugular intrahepatic portosystemic shunt procedure with subsequent new-onset heart failure without previous diagnostic evidence of underlying cardiovascular disease, including cirrhotic cardiomyopathy. After 2 weeks of medical management with ß-blockade and diuretics, the patient had recovery of a left ventricular ejection fraction.