Changing landscape of alcohol-associated liver disease in younger individuals, women, and ethnic minorities.

Alcohol use is the most important determinant of the development of alcohol-associated liver disease (ALD) and of predicting long-term outcomes in those with established liver disease. Worldwide, the amount, type, and pattern of use of alcohol vary. Alcohol use and consequent liver disease have been increasing in certain ethnic groups especially Hispanics and Native Americans, likely due to variations in genetics, cultural background, socio-economic status, and access to health care. Furthermore, the magnitude and burden of ALD have been increasing especially in the last few years among females and young adults who are at the prime of their productivity. It is critical to recognize the problem and care for these patients integrating cultural aspects in liver clinics. At the federal level, a societal approach is needed with the implementation of public health policies aiming to reduce alcohol consumption in the community. By addressing these challenges and promoting awareness, we can strive to reduce the burden of ALD, especially in high-risk demographic groups to improve their long-term health outcomes. Finally, we need studies and quality research examining these changing landscapes of demographics in ALD as a basis for developing therapeutic targets and interventions to reduce harmful drinking behaviours in these high-risk demographic groups.

Development and validation of nonalcoholic fatty liver disease test: a simple sensitive and specific marker for early diagnosis of nonalcoholic fatty liver disease.

AIM: This study aimed to develop a noninvasive test for identifying patients with nonalcoholic fatty liver disease (NAFLD) based on clinical and routine laboratory data. METHODS: The developed model 'NAFLD test' was compared to the most commonly used NAFLD scores and then validated in three groups of NAFLD patients from five centers in Egypt, China, and Chile. Patients were divided into the discovery cohort (n = 212) and the validation study (n = 859). The ROC curve and stepwise multivariate discriminant analysis were used to develop and validate the NAFLD test and evaluate its diagnostic performance, which was then compared to other NAFLD scores. RESULTS: Elevated C-reactive protein (CRP), cholesterol, BMI, and alanine aminotransferase (ALT) levels were significantly associated with NAFLD (P < 0.0001). NAFLD test is depicted as (-0.695 + 0.031 × BMI + 0.003 × cholesterol + 0.014 × ALT + 0.025 × CRP) to discriminate patients with NAFLD from healthy individuals. The area under the ROC curve (AUC) of the NAFLD test was 0.92 [95% confidence interval (CI): 0.88-0.96]. The NAFLD test was the most accurate diagnostic indicator of NAFLD when compared to widely used NAFLD indices. Upon validating the NAFLD test, its AUC (95% CI) for distinguishing patients with NAFLD from healthy individuals was 0.95 (0.94-0.97), 0.90 (0.87-0.93), and 0.94 (0.91-0.97) in Egyptian, Chinese, and Chilean patients with NAFLD respectively. CONCLUSION: The NAFLD test is a new validated diagnostic biomarker that can be utilized for the early diagnosis of NAFLD with high diagnostic performance.

Alcohol-Associated Liver Disease: Integrated Management With Alcohol Use Disorder.

Alcohol-associated liver disease (ALD) is the most common cause of cirrhosis and liver-related mortality in many regions worldwide. Around 75% of patients with cirrhosis are unaware of their disease until they are referred to the emergency department. An innovative, noninvasive screening approach is required for an earlier diagnosis of liver fibrosis. In patients with ALD the physician is inevitably dealing with 2 major disorders: the liver disease itself and the alcohol use disorder (AUD). Focus only on the liver disease will inevitably lead to failure because transient improvements in liver function are rapidly overturned if the patient returns to alcohol consumption. For this reason, integrated models of care provided by hepatologists and addiction specialists are an effective approach, which are, however, not widely available. There are multiple pharmacologic and non-pharmacologic therapies for AUD. Progress has recently been made in the management of patients with severe AH who have improved survival through better understanding of the concept of response to medical treatment, improved survival prediction, and the advent of early liver transplantation. The emerging concept is that listing for transplantation a patient with severe ALD could lead to adjusting the duration of abstinence according to the severity and evolution of liver dysfunction and the patient's addictive profile.

Public Health Measures and Prevention of Alcohol-Associated Liver Disease.

Hazardous alcohol consumption causes approximately 4% of deaths globally, constituting one of the leading risk factors for the burden of the disease worldwide. Alcohol has several health consequences, such as alcohol-associated liver disease, hepatocellular carcinoma, nonliver neoplasms, physical injury, cardiac disease, and psychiatric disorders. Alcohol misuse significantly affects workforce productivity, with elevated direct and indirect economic costs. Due to the high impact of alcohol consumption on the population, public health has led to the development of a range of strategies to reduce its harmful effects. Regulatory public health policies (PHP) for alcohol can exist at the global, regional, international, national, or subnational levels. Effective strategies incorporate a multilevel, multicomponent approach, targeting multiple determinants of drinking and alcohol-related harms. The World Health Organization categorizes the PHP into eight categories: national plan to fight the harmful consequences of alcohol, national license and production and selling control, taxes control and pricing policies, limiting drinking age, restrictions on alcohol access, driving-related alcohol policies, control over advertising and promotion, and government monitoring systems. These policies are supported by evidence from different populations, demonstrating that determinants of alcohol use depend on several factors such as socioeconomic level, age, sex, ethnicity, production, availability, marketing, and others. Although most policies have a significant individual effect, a higher number of PHP are associated with a lower burden of disease due to alcohol. The excessive consequences of alcohol constitute a call for action, and clinicians should advocate for developing and implementing a new PHP on alcohol consumption.

Current Medical Treatment for Alcohol-Associated Liver Disease.

Alcohol-associated liver disease is one of the main causes of chronic liver disease. It comprises a clinical-histologic spectrum of presentations, from steatosis, steatohepatitis, to different degrees of fibrosis, including cirrhosis and severe necroinflammatory disease, called alcohol-associated hepatitis. In this focused update, we aim to present specific therapeutic interventions and strategies for the management of alcohol-associated liver disease. Current evidence for management in all spectra of manifestations is derived from general chronic liver disease recommendations, but with a higher emphasis on abstinence and nutritional support. Abstinence should comprise the treatment of alcohol use disorder as well as withdrawal syndrome. Nutritional assessment should also consider the presence of sarcopenia and its clinical manifestation, frailty. The degree of compensation of the disease should be evaluated, and complications, actively sought. The most severe acute form of this disease is alcohol-associated hepatitis, which has high mortality and morbidity. Current treatment is based on corticosteroids that act by reducing immune activation and blocking cytotoxicity and inflammation pathways. Other aspects of treatment include preventing and treating hepatorenal syndrome as well as preventing infections although there is no clear evidence as to the benefit of probiotics and antibiotics in prophylaxis. Novel therapies for alcohol-associated hepatitis include metadoxine, interleukin-22 analogs, and interleukin-1-beta antagonists. Finally, granulocyte colony-stimulating factor, microbiota transplantation, and gut-liver axis modulation have shown promising results. We also discuss palliative care in advanced alcohol-associated liver disease.

Racial and Health Disparities among Cirrhosis-related Hospitalizations in the USA.

Background and Aims: Alcohol-associated liver disease (ALD) is the most common cause of advanced liver disease worldwide, including in the USA. Alcohol use and cirrhosis mortality is higher in American Indian/Alaska Native (AI/AN) compared to Whites. Data are scanty on ALD as a liver disease etiology in AI/AN compared to other races and ethnicities. Methods: The National Inpatient Sample on 199,748 cirrhosis-related hospitalizations, 14,241 (2,893 AI/AN, 2,893 Whites, 2,882 Blacks, 2,879 Hispanics, and 2,694 Asians or other races) matched 1:1 for race/ethnicity on demographics, insurance, and income quartile of the residence zip code analyzed. Results: After controlling for geographic location and hospital type, odds ratio (OR) and 95% confidence interval (CI) for ALD as cirrhosis etiology was higher among admissions in AI/AN vs. Whites [1.55 (1.37-1.75)], vs. Blacks [1.87 (1.65-2.11)], vs. Hispanic [1.89 (1.68-2.13)] and Asians/other races [2.24 (1.98-2.53)]. OR was also higher for AI/AN vs. all other races for alcohol-associated hepatitis (AH) as one of the discharge diagnoses. The findings were similar in a subgroup of 4,649 admissions with decompensated cirrhosis and in a cohort of 350 admissions with acute-on-chronic liver failure as defined by EASL-CLIF criteria. Alcohol use disorder diagnosis was present in 38% of admissions in AI/AN vs. 24-30% in other races, p<0.001. A total of 838 (5.9%) admissions were associated with in-hospital mortality. OR (95% CI) for in-hospital mortality in AI/AN individuals was 34% reduced vs. Blacks [0.66 (0.51-0.84)], but no difference was observed on comparison with other races. Conclusions: ALD, including AH, is the most common etiology among cirrhosis-related hospitalizations in the USA among AI/AN individuals. In-hospital mortality was observed in about 6% of admissions, which was higher for Blacks and similar in other races compared to admissions for AI/AN. Public health policies should be implemented to reduce the burden of advanced ALD among AI/AN individuals.

Early Diagnosis and Prevention of Infections in Cirrhosis.

Strategies to prevent infection and improve outcomes in patients with cirrhosis. HAV, hepatitis A virus; HBV, hepatitis B virus; COVID-19, novel coronavirus disease 2019; NSBB, nonselective ß-blocker; PPI, proton pump inhibitors.Cirrhosis is a risk factor for infections. Majority of hospital admissions in patients with cirrhosis are due to infections. Sepsis is an immunological response to an infectious process that leads to end-organ dysfunction and death. Preventing infections may avoid the downstream complications, and early diagnosis of infections may improve the outcomes. In this review, we discuss the pathogenesis, diagnosis, and biomarkers of infection; the incremental preventive strategies for infections and sepsi; and the consequent organ failures in cirrhosis. Strategies for primary prevention include reducing gut translocation by selective intestinal decontamination, avoiding unnecessary proton pump inhibitors' use, appropriate use of ß-blockers, and vaccinations for viral diseases including novel coronavirus disease 2019. Secondary prevention includes early diagnosis and a timely and judicious use of antibiotics to prevent organ dysfunction. Organ failure support constitutes tertiary intervention in cirrhosis. In conclusion, infections in cirrhosis are potentially preventable with appropriate care strategies to then enable improved outcomes.

Prophylactic Perioperative Terlipressin Therapy for Preventing Acute Kidney Injury in Living Donor Liver Transplant Recipients: A Systematic Review and Meta-Analysis.

Background: Acute kidney injury (AKI) is common in the perioperative transplant period and is associated with poor outcomes. Few studies reported a reduction in AKI incidence with terlipressin therapy by counteracting the hemodynamic alterations occurring during liver transplantation. However, the effect of terlipressin on posttransplant outcomes has not been systematically reviewed. Methods: A comprehensive search of electronic databases was performed. Studies reporting the use of terlipressin in the perioperative period of living donor liver transplantation were included. We expressed the dichotomous outcomes as risk ratio (RR, 95% confidence interval [CI]) using the random effects model. The primary aim was to assess the posttransplant risk of AKI. The secondary aims were to assess the need for renal replacement therapy (RRT), vasopressors, effect on hemodynamics, blood loss during surgery, hospital and intensive care unit (ICU) stay, and in-hospital mortality. Results: A total of nine studies reporting 711 patients (309 patients in the terlipressin group and 402 in the control group) were included for analysis. Terlipressin was administered for a mean duration of 53.44 ± 28.61 h postsurgery. The risk of AKI was lower with terlipressin (0.6 [95% CI, 0.44-0.8]; P = 0.001). However, on sensitivity analysis including only four randomized controlled trials (I2 = 0; P = 0.54), the risk of AKI was similar in both the groups (0.7 [0.43-1.09]; P = 0.11). The need for RRT was similar in both the groups (0.75 [0.35-1.56]; P = 0.44). Terlipressin therapy reduced the need for another vasopressor (0.34 [0.25-0.47]; P < 0.001) with a concomitant rise in mean arterial pressure and systemic vascular resistance by 3.2 mm Hg (1.64-4.7; P < 0.001) and 77.64 dyne cm-1.sec-5 (21.27-134; P = 0.007), respectively. Blood loss, duration of hospital/ICU stay, and mortality were similar in both groups. Conclusions: Perioperative terlipressin therapy has no clinically relevant benefit.

Identifying Alcohol Use Disorder in Patients With Cirrhosis Reduces 30-Days Readmission Rate.

AIMS: Readmission is frequent among patients with cirrhosis and is a complex multifactorial process. To examine the association of alcohol use disorder (AUD) and risk of readmission in patients with alcohol-associated cirrhosis. METHODS AND RESULTS: National Readmission Dataset (2016-2017) was used to extract a retrospective cohort of 53,348 patients with primary or secondary discharge diagnosis code of alcohol-associated cirrhosis with their first admission (26,674 patients with vs. propensity matched 26,674 without a primary or secondary discharge diagnosis code of AUD). Readmission within 30-day was lower (43.9 vs. 48%, P < 0.001) among patients identified to have AUD at the time of discharge. In a conditional logistic regression model, a diagnosis of AUD was associated with 15% reduced odds of 30-day readmission, 0.85 (0.83-0.88). Furthermore, the reason for readmission among patients identified vs. not identified to have AUD was less likely to be liver disease complication. The findings remained similar in a matched cohort of patients where the AUD diagnosis at discharge was listed as one of the secondary diagnoses only. CONCLUSION: Although, our study findings suggest that identification of AUD at the time of discharge among patients hospitalized for alcohol-associated cirrhosis reduces the risk of 30-day readmission, unavailable information on patient counseling, referral for mental health specialist and treatment received for AUD limit the causality assessment. Future studies are needed overcoming the inherent limitations of the database to establish the role of identification and treatment of AUD in reducing readmission and liver decompensation in patients with alcohol-associated cirrhosis.

The Mortality Index for Alcohol-Associated Hepatitis: A Novel Prognostic Score.

OBJECTIVE: To develop a new scoring system that more accurately predicts 30-day mortality in patients with alcohol-associated hepatitis (AH). METHODS: A cohort of consecutive adults diagnosed with AH at a single academic center from January 1, 1998, to December 31, 2018, was identified for model derivation. Multivariate logistic regression was used to create a new scoring system to predict 30-day mortality. External validation of this score was performed on a multicenter retrospective cohort. RESULTS: In the derivation cohort of 266 patients, the 30-day mortality rate was 19.2%. The following variables were found to be significantly associated with mortality on multivariate analysis: age (P=.002), blood urea nitrogen (P=.003), albumin (P=.01), bilirubin (P=.02), and international normalized ratio (P=.001). A model incorporating these variables, entitled the Mortality Index for Alcohol-Associated Hepatitis (MIAAH), achieved a C statistic of 0.86. Comparison of the accuracy of the MIAAH to existing prognostic models, including the Model for End-Stage Liver Disease and Maddrey Discriminant Function, showed that the highest concordance was achieved by the MIAAH and that this difference was significant. In the validation cohort of 249 patients, the MIAAH C statistic decreased to 0.73 and was found to be significantly superior to the Maddrey Discriminant Function but not to the Model for End-Stage Liver Disease. CONCLUSION: The MIAAH competes with the current prognostication models and is at a minimum as accurate as these existing scores in identifying patients with AH at high risk of short-term mortality. Furthermore, the MIAAH demonstrates advantageous performance characteristics in its ability to increasingly accurately dichotomize patients into those at highest risk of death and those likely to survive.

Factors Having an Impact on Relapse and Survival in Transplant Recipients With Alcohol-Induced Liver Disease.

OBJECTIVE: To assess the impact of standardized pretransplant alcohol abstinence and treatment guidelines on liver transplant outcomes. METHODS: This study assessed the posttransplant relapse and survival associated with a pretransplant guideline mandating alcohol abstinence, addiction treatment, and Alcoholics Anonymous (AA) attendance. This retrospective cohort study included liver recipients with alcohol-induced liver disease transplanted between January 1, 2000, and December 31, 2012, at a Midwest transplant center. Cox regression models tested for associations between pretransplant treatment, demographic and clinical characteristics, and outcome measures. RESULTS: Of 236 liver recipients (188 [79.7%] male; 210 [89%] white; mean follow-up, 88.6±55.0 months), 212 (90.2%) completed pretransplant treatment and 135 (57.2%) attended AA weekly. At 5 years, 16.3% and 8.2% had relapsed to any alcohol use and to high-dose drinking, respectively. Smoking during the 6 months before transplant was associated with any relapse (P=.0002) and high-dose relapse (P<.0001), and smoking at transplant was associated with death (P=.001). High-dose relapse was associated with death (hazard ratio, 3.5; P<.0001). CONCLUSION: A transplant center with a guideline requiring abstinence, treatment, and AA participation experienced lower posttransplant relapse rates from those previously reported in comparable large US transplant programs. Smoking cessation may further improve posttransplant outcomes.

Insights into Nonalcoholic Fatty-Liver Disease Heterogeneity.

The acronym nonalcoholic fatty-liver disease (NAFLD) groups a heterogeneous patient population. Although in many patients the primary driver is metabolic dysfunction, a complex and dynamic interaction of different factors (i.e., sex, presence of one or more genetic variants, coexistence of different comorbidities, diverse microbiota composition, and various degrees of alcohol consumption among others) takes place to determine disease subphenotypes with distinct natural history and prognosis and, eventually, different response to therapy. This review aims to address this topic through the analysis of existing data on the differential contribution of known factors to the pathogenesis and clinical expression of NAFLD, thus determining the different clinical subphenotypes observed in practice. To improve our understanding of NAFLD heterogeneity and the dominant drivers of disease in patient subgroups would predictably impact on the development of more precision-targeted therapies for NAFLD.

Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis.

Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNFα with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNFα/NF-κB signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment.

Alcohol-associated liver disease in the United States is associated with severe forms of disease among young, females and Hispanics.

BACKGROUND: Alcohol use and alcohol-associated liver disease (ALD) burden are increasing in young individuals. AIM: To assess host factors associated with this burden. METHODS: National Health and Nutrition Examination Survey (NHANES), National Inpatient Sample (NIS), and United Network for Organ Sharing (UNOS) databases (2006-2016) were used to identify individuals with harmful alcohol use, ALD-related admissions, and ALD-related LT listings respectively. RESULTS: Of 15 981 subjects in NHANES database, weighted prevalence of harmful alcohol use was 17.7%, 29.3% in <35 years (G1) versus 16.9% in 35-64 years (G2) versus 5.1% in ≥65 years (G3). Alcohol use was about 11 and 4.7 folds higher in G1 and G2 versus G3, respectively. Male gender and Hispanic race associated with harmful alcohol use. Of 593 600 ALD admissions (5%, 77%, and 18% in G1-G3 respectively), acute on chronic liver failure (ACLF) occurred in 7.2%, (7.2 in G2 vs 6.7% in G1 and G3, P < 0.001). After controlling for other variables, ACLF development among ALD hospitalizations was higher by 14% and 10% in G1 and G2 versus G3, respectively. Female gender and Hispanic race were associated with increased ACLF risk by 8% and 17% respectively. Of 20,245 ALD LT listings (3.4%, 84.4%, and 12.2% in G1-G3 respectively), ACLF occurred in 28% candidates. Risk of severe (grade 2 or 3) ACLF was higher by about 1.7 fold in G1, 1.5 fold in females and 20% in Hispanics. CONCLUSION: Young age, female gender, and Hispanic race are independently associated with ALD-related burden and ACLF in the United States. If these findings are validated in prospective studies, strategies will be needed to reduce alcohol use in high risk individuals to reduce burden from ALD.

Mineralocorticoid receptor modulation by dietary sodium influences NAFLD development in mice.

INTRODUCTION AND OBJECTIVES: Nonalcoholic-fatty-liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome (MetS). Mineralocorticoid receptor (MR) activation is associated with increased risk of MetS but few studies have assessed the role of liver MR on NAFLD. We aimed to evaluate the effect of MR modulation by sodium intake in liver injury in experimental models of NAFLD. MATERIALS AND METHODS: C57BL/6J mice were fed either a high-fat-diet (HFD) or a choline/methionine deficient (MCD) diet with different sodium concentrations. Hepatic concentration of lipid species, serum aldosterone levels, expression of MR, proinflammatory and profibrotic markers and liver histology were assessed. RESULTS: Mice fed with High-Na+/HFD showed a lower MR expression in liver (p = 0.01) and less steatosis on histology (p = 0.04). Consistently, animals from this group exhibited lower levels of serum aldosterone (p = 0.028) and lower hepatic triglyceride content (p = 0.008). This associated to a reduced expression of lipogenic genes, significant changes in lipid subspecies, lower HOMA-IR (p < 0.05), and lower expression of pro-inflammatory and profibrotic markers compared to those mice fed a Low-Na+/HFD. Additionally, mice fed a High-Na+/HFD showed higher expression of salt-inducible kinase (SIK)-1 and lower expression of serum-and-glucocorticoid-inducible kinase (SGK)-1. Similar results were observed with the MCD diet model. CONCLUSION: We identified in two experimental models of NAFLD that High-Na+ diet content is associated to lower serum aldosterone levels and hepatic MR downregulation, associated to decreased steatosis and reduced de novo hepatic lipogenesis, proinflammatory and profibrotic markers. Decreased activation of hepatic MR seems to generate beneficial downstream inhibition of lipogenesis in experimental NAFLD.

Hospitalizations for Acute on Chronic Liver Failure at Academic Compared to Non-academic Centers Have Higher Mortality.

BACKGROUND AND AIM: Acute on chronic liver failure (ACLF) in patients with cirrhosis has high short-term mortality. Data comparing ACLF admissions to academic centers (AC) and non-academic centers (NAC) are scanty. METHODS: National Inpatient Sample (2006-2014) was queried for admissions with cirrhosis and ACLF using the ICD-09 codes, and was stratified to AC or NAC. RESULTS: Of 1,928,764 admissions with cirrhosis (2006-2014), 112,174 (5. 9%) had ACLF. 6.7% of 1,018,568 cirrhosis admissions to AC had ACLF versus 5% of 910,196 admissions to NAC, P < 0.0001. Proportion of ACLF admissions to AC increased from 49% during 2006-2008 to 59% during 2012-2014. In a cohort of 73,630 ACLF admissions (36,615 each to AC and NAC) matched for patient demographics, cirrhosis etiology, number of comorbidities, elective versus emergent admission, ACLF grade, and type of organ failure. In-hospital mortality declined by 7% over the study period, but remained higher in AC (46% vs. 42%, P < 0.001), with 11% increased odds for in-hospital mortality compared to admission to NAC. Further admissions to AC versus NAC had higher median (IQR) length of stay at 13 (6-25) versus 11 (5-20) days, with higher median (IQR) hospital charges: 138,239 (66,772-275,603) versus 116,209 (55,767-232,699) USD, P < 0.001 for both. CONCLUSION: Patients with ACLF have high in-hospital mortality. Further, this is higher among admissions to AC. Although the in-hospital mortality is improving, strategies are needed on early identification of patients with futility of care for early discussion on goals of care, and optimal utilization of hospital resources among admissions with ACLF.