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.

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.

Patient Perspectives of High-Quality Care on the Liver Transplant Waiting List: A Qualitative Study.

The prevalence of advanced liver disease and listing for liver transplantation is increasing. Prior assessments of quality of care neither incorporate nor emphasize the patient perspective on quality of care, which may impact clinical outcomes. Our aim was to identify patients' perceptions on what constitutes high quality of care, comparing the findings to existing frameworks and assessments to determine if a patient-derived tool assessing quality of care could facilitate efforts to improve health care. We conducted semistructured interviews of patients wait-listed for liver transplantation, asking patients to describe the quality of their health care with a specific focus on how coordination, communication, office visits, hospitalizations, and cost affect their perceptions of the quality of their care. Data collection conducted concurrently with analyses determined emerging themes and saturation. Themes were mapped to an existing quality-of-care conceptual framework. Qualitative analysis revealed thematic saturation after 15 interviews, and an additional 15 interviews were analyzed that confirmed thematic saturation, maximizing the strength of the results. The 30 patients had a median age of 56 years (range, 32-72 years) and included 15 (50%) men. Although patients believed they received a high quality of care, which was substantiated on current existing measures, a qualitative analysis suggested that patient priorities emphasized 5 themes not currently assessed: managing expectations, providing education, responding to patient needs, executing the care plan efficiently, and utilizing interdisciplinary communication and coordination of care. In conclusion, transplant candidates perceived 5 themes that constitute quality of care, and existing quality-of-care measures do not assess these domains, suggesting a role for creating a patient-derived quality-of-care tool to improve health care and clinical outcomes.

A Call to Standardize Definitions, Data Collection, and Outcome Assessment to Improve Care in Alcohol-Related Liver Disease.

Alcohol-related liver disease (ALD) is highly prevalent and appears to be increasingly reported with worsening mortality; thus, optimizing care in this patient population is imperative. This will require a multidisciplinary, multifaceted approach that includes recognizing alcohol use disorder (AUD) and existing treatments for AUD. We must also acknowledge the full spectrum of ALD clinically and histologically. For example, our current clinical definitions of alcohol-related hepatitis (AH) do not address that >95% of severe AH occurs in the setting of cirrhosis with <60% of liver explants having hepatitis. Given that the majority of ALD studies rely on clinical diagnosis and lack pathologic confirmation, prior data on the efficacy of medical treatment or use of transplantation are likely limited by intertrial and intratrial heterogeneity. Added limitations of the current field include the inconsistent reporting of relapse with the use of varying definitions and unreliable assessments. Moreover, studies fail to consistently capture the data variables that likely influence the main outcomes of interest in this population-mortality and relapse-and a global effort to create a standardized data collection tool moving forward could help effectively and efficiently aid in the advancement of this field. Conclusion: To optimize patient care and make best use of a limited resource, a systematic change in the approach to research in this population must be undertaken that creates consistent definitions for use in future research to generate reliable and reproducible results. With this in mind, we concisely reviewed the literature to summarize the current state of treating and managing ALD, the heterogeneity in definitions, and the significant opportunities for clinical and research improvement.

Evaluation of Alcohol Taxes as a Public Health Opportunity to Reduce Liver Transplant Listings for Alcohol-Related Liver Disease.

BACKGROUND: Alcohol-related liver disease (ALD) is a leading indication for liver transplantation. METHODS: State consumption of spirits, wine, and beer was determined from published sources. Excise and ad valorem alcohol taxes of spirits, wine, and beer were calculated following standard practices and correlated using multiple logistic regression models to 2002 to 2015 ALD transplant listing data from the United Network for Organ Sharing database. RESULTS: 21.22% (29,161/137,440) of transplant listings were for ALD. Increased consumption of spirits was associated with increased ALD transplant listings (odds ratio [OR]: 1.67; 95% CI: 1.12 to 2.49, p = 0.01), but wine and beer consumption did not have a statistically significant association with ALD transplant listings. Spirits excise taxes on- and off-premise were inversely associated with ALD transplant listing (OR: 0.79 and 0.82, respectively, both p < 0.02). Beer and wine taxes were not significantly associated with ALD transplant listings. CONCLUSIONS: Transplant listings for ALD are directly associated with spirit consumption and inversely associated with spirits excise taxes. These findings suggest a possible public health benefit of increasing excise taxes for spirits.

Cost Effectiveness of Early Insertion of Transjugular Intrahepatic Portosystemic Shunts for Recurrent Ascites.

BACKGROUND & AIMS: Treatment options for recurrent ascites resulting from decompensated cirrhosis include serial large-volume paracentesis and albumin infusion (LVP+A) or insertion of a transjugular intrahepatic portosystemic shunt (TIPS). Insertion of TIPSs with covered stents during early stages of ascites (early TIPS, defined as 2 LVPs within the past 3 weeks and <6 LVPs in the prior 3 months) significantly improves chances of survival and reduces complications of cirrhosis compared with LVP+A. However, it is not clear if TIPS insertion is cost effective in these patients. METHODS: We developed a Markov model using the payer perspective for a hypothetical cohort of patients with cirrhosis with recurrent ascites receiving early TIPSs or LVP+A using data from publications and national databases collected from 2012 to 2018. Projected outcomes included quality-adjusted life-year (QALY), costs (2017 US dollars), and incremental cost-effectiveness ratios (ICERs; $/QALY). Sensitivity analyses (1-way, 2-way, and probabilistic) were conducted. ICERs less than $100,000 per QALY were considered cost effective. RESULTS: In base-case analysis, early insertion of TIPS had a higher cost ($22,770) than LVP+A ($19,180), but also increased QALY (0.73 for early TIPSs and 0.65 for LVP+A), resulting in an ICER of $46,310/QALY. Results were sensitive to cost of uncomplicated TIPS insertion and transplant, need for LVP+A, probability of transplant, and decompensated QALY. In probabilistic sensitivity analysis, TIPS insertion was the optimal strategy in 59.1% of simulations. CONCLUSIONS: Based on Markov model analysis, early placement of TIPSs appears to be a cost-effective strategy for management of specific patients with cirrhosis and recurrent ascites. TIPS placement should be considered early and as a first-line treatment option for select patients.

Timely Use of Probiotics in Hospitalized Adults Prevents Clostridium difficile Infection: A Systematic Review With Meta-Regression Analysis.

BACKGROUND & AIMS: Systematic reviews have provided evidence for the efficacy of probiotics in preventing Clostridium difficile infection (CDI), but guidelines do not recommend probiotic use for prevention of CDI. We performed an updated systematic review to help guide clinical practice. METHODS: We searched MEDLINE, EMBASE, International Journal of Probiotics and Prebiotics, and The Cochrane Library databases for randomized controlled trials evaluating use of probiotics and CDI in hospitalized adults taking antibiotics. Two reviewers independently extracted data and assessed risk of bias and overall quality of the evidence. Primary and secondary outcomes were incidence of CDI and adverse events, respectively. Secondary analyses examined the effects of probiotic species, dose, timing, formulation, duration, and study quality. RESULTS: We analyzed data from 19 published studies, comprising 6261 subjects. The incidence of CDI in the probiotic cohort, 1.6% (54 of 3277), was lower than of controls, 3.9% (115 of 2984) (P < .001). The pooled relative risk of CDI in probiotic users was 0.42 (95% confidence interval, 0.30-0.57; I2 = 0.0%). Meta-regression analysis demonstrated that probiotics were significantly more effective if given closer to the first antibiotic dose, with a decrement in efficacy for every day of delay in starting probiotics (P = .04); probiotics given within 2 days of antibiotic initiation produced a greater reduction of risk for CDI (relative risk, 0.32; 95% confidence interval, 0.22-0.48; I2 = 0%) than later administration (relative risk, 0.70; 95% confidence interval, 0.40-1.23; I2 = 0%) (P = .02). There was no increased risk for adverse events among patients given probiotics. The overall quality of the evidence was high. CONCLUSIONS: In a systematic review with meta-regression analysis, we found evidence that administration of probiotics closer to the first dose of antibiotic reduces the risk of CDI by >50% in hospitalized adults. Future research should focus on optimal probiotic dose, species, and formulation. Systematic Review Registration: PROSPERO CRD42015016395.

Multimodal multidisciplinary management of alcohol use disorder in liver transplant candidates and recipients.

Alcohol-related liver disease (ALD) is the most common indication for liver transplantation (LT) in the United States. The judicious allocation of organs and improvement in outcomes requires identification and monitoring of patients with ALD at high-risk for relapse post-transplantation. The controversial movement toward early LT for severe alcohol-related hepatitis (SAH) has also raised concern for alcohol relapse. While LT cures ALD, treatment of alcohol use disorder (AUD) must be included in the care plan to prevent a return to drinking and subsequent graft ALD. Patients with underlying AUD must be recognized, offered brief interventions and referred for multimodal multidisciplinary treatment that includes medications and psychotherapies along with sober support groups, family engagement, and a new dedication to healthy living in order to help sustain remission. Such comprehensive care will increase LT candidacy in patients with ALD while optimizing clinical outcomes of patients transplanted with AUD.

Identification of Quantifiable Predictors of Relapse in Patients with Alcohol-Associated Liver Disease.

Abstinence in patients with alcohol-associated liver disease (ALD) reduces mortality. Most predictors of relapse are not quantifiable, preventing objective analysis of relapse risk and targeted intervention to improve clinical outcomes. We prospectively enrolled patients with ALD from November 2016 to December 2019 and administered a survey with two previously published scales to assess insight into alcohol-use disorder (Hanil Alcohol Insight Scale [HAIS]) and social support (Community Assessment Inventory Scale [CAIS]). Relapse was assessed using surveys and metabolite testing. Unadjusted and prespecified adjusted regression analyses identified predictors of relapse. We enrolled 81% of eligible patients (n = 136), of whom 58 had follow-up data available at the time of analysis. Over a median follow-up of 1 year (interquartile range: 0.5-1.4), 10 patients relapsed (17%). Patients who relapsed were more likely to continue drinking despite either a diagnosis of liver disease or a decompensating event, and were less likely to have been transplanted (all P < 0.05). In unadjusted regression, the HAIS and the "support inside the home" subcategory of the CAIS were predictive of relapse, with odds ratio (OR) = 0.84 (95% confidence interval 0.72-0.97) and 0.85 (0.74-0.97). In adjusted regression, the HAIS was no longer significant, with adjusted OR = 0.70 (0.49-1.00, P = 0.05), whereas the "support inside the home' subcategory of CAIS remained significant, with adjusted OR = 0.69 (0.51-0.92, P = 0.01). Conclusions: Risk factors for relapse in patients with ALD were identified and quantified prospectively, suggesting opportunities to objectively identify patients at risk for relapse as well as to intervene to prevent relapse.

Systematic review with meta-analysis on transplantation for alcohol-related liver disease: Very low evidence of improved outcomes.

BACKGROUND: Alcohol-related liver disease (ALD) is a leading cause of liver failure and indication for liver transplantation that arises in the setting of alcohol use disorder (AUD). Previous reviews of transplantation for ALD are limited in scope of outcomes and type of ALD studied. A comprehensive systematic review could improve use of transplantation in ALD and improve future research. We hypothesize that while transplanting ALD may improve mortality and relapse, findings will be limited by pre-specified causes of heterogeneity - assessment and treatment of AUD, definition of ALD, spectrum of ALD studied, assessment and rates of relapse, and study quality and bias. AIM: To optimize liver transplantation for ALD, understanding existing research to guide future research, we conducted a systematic review with meta-analysis. METHODS: We conducted a systematic review, comparing liver transplant to no-transplant in patients with ALD, with a primary outcome of both short- and long-term mortality and relapse. We performed a comprehensive search of MEDLINE, EMBASE, Web of Science, and The Cochrane Library databases for peer-reviewed journal articles comparing use of liver transplant in ALD to no-transplant. Two reviewers independently conducted screening, full text review, and data extraction according to the PRISMA guidelines. We report the quality of the evidence according to the GRADE criteria. RESULTS: We analyzed data from 10 studies. Of 1332 participants, 34.2% (456/1332) had undergone liver transplantation, while 65.8% (876/1332) had not. While random effects meta-analysis suggested transplant in comparison to no-transplant had an association of reduced mortality that did not reach statistical significance, relative risk (RR) = 0.51 (0.25-1.05), but not relapse risk, RR = 0.52 (0.18-1.53), significant heterogeneity limited these findings. When restricted to prospective data, transplant compared to no-transplant significantly reduced mortality, RR = 0.25 (0.13-0.46, P < 0.01), and relapse, RR = 0.25 (0.14-0.45, P < 0.01), with insignificant heterogeneity but persistent small-study effects. The overall quality of the evidence was Very Low. Heterogeneity analysis suggested that AUD assessment and treatment was often not reported while ALD, relapse assessment and rate, and data collection were institutionally rather than standardly defined. CONCLUSION: Systematic review of liver transplantation for ALD suggests reduced mortality and relapse in heterogeneous, institution-specific populations with inherent bias. To understand efficacy of transplanting ALD, our research approach must change.