Hepatocellular carcinoma after direct-acting antivirals for hepatitis C is associated with KIR-HLA types predicting weak NK cell-mediated immunity.

BACKGROUND AND AIMS: Second-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC. METHODS: Participants underwent full HLA class I/KIR typing and long-term HCV follow-up. RESULTS: A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC. CONCLUSION: Cirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.

National prevalence estimates for steatotic liver disease and subclassifications using consensus nomenclature.

BACKGROUND AND AIMS: The multisociety consensus nomenclature has renamed NAFLD to steatotic liver disease (SLD) with various subclassifications. There is a paucity of data regarding how the new nomenclature modifies our understanding of disease prevalence and patient phenotypes. APPROACH AND RESULTS: Using the National Health and Nutrition Examination Survey from January 2017 to March 2020, we included all participants aged 18 years or above with complete vibration-controlled transient elastography measures. SLD and its subclassifications [metabolic dysfunction-associated SLD (MASLD), MASLD + increased alcohol intake (MetALD), alcohol-associated liver disease (ALD), etiology-specific/cryptogenic] were defined according to consensus nomenclature. National SLD prevalence and subclassifications were estimated, and among key subgroups [age, sex, race/ethnicity, advanced liver fibrosis (liver stiffness measurement [LSM] ≥11.7 kPa)]. Among 7367 participants, 2549 had SLD (mean age 51 y, 57.7% male, 63.2% non-Hispanic White). The estimated prevalence of SLD was 34.2% (95% CI 31.9%-36.5%): MASLD 31.3% (29.2%-33.4%), MetALD 2% (1.6%-2.9%), ALD 0.7% (0.5-0.9%), etiology-specific/cryptogenic 0.03% (0.01%-0.08%). In exploratory analyses, participants classified as non-SLD with (vs. without) advanced fibrosis had a higher mean number of metabolic risk factors [2.7 (2.3-3.1) vs. 2.0 (1.9-2.0)] and a higher proportion with average alcohol use ≥20 g/d (women)/≥30 g/d (men) [20.9% (6.2%-51.3%) vs. 7.2% (6.1%-8.4%)]. In another exploratory analysis, increasing quantities of alcohol use remaining below the threshold for MASLD + increased alcohol intake were associated with advanced liver fibrosis in men, but not women. There was 99% overlap in cases of NAFLD and MASLD. CONCLUSIONS: Our findings highlight the utility of the new consensus nomenclature to address deficiencies present with the old nomenclature, and identify areas that require research to further refine classifications of SLD.

Association of Renin-Angiotensin System Inhibition With Liver-Related Events and Mortality in Compensated Cirrhosis.

BACKGROUND & AIMS: While renin-angiotensin system inhibition lowers the hepatic venous gradient, the effect on more clinically meaningful endpoints is less studied. We aimed to quantify the relationship between renin-angiotensin system inhibition and liver-related events (LREs) among adults with compensated cirrhosis. METHODS: In this national cohort study using the Optum database, we quantified the association between angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) use and LREs (hepatocellular carcinoma, liver transplantation, ascites, hepatic encephalopathy, or variceal bleeding) among patients with cirrhosis between 2009 and 2019. Selective beta-blocker (SBB) users served as the comparator group. We used demographic and clinical features to calculate inverse-probability treatment weighting-weighted cumulative incidences, absolute risk differences, and Cox proportional hazard ratios. RESULTS: Among 4214 adults with cirrhosis, 3155 were ACE inhibitor/ARB users and 1059 were SBB users. In inverse probability treatment weighting-weighted analyses, ACE inhibitor/ARB (vs SBB) users had lower 5-year cumulative incidence (30.6% [95% confidence interval (CI), 27.8% to 33.2%] vs 41.3% [95% CI, 34.0% to 47.7%]; absolute risk difference, -10.7% [95% CI, -18.1% to -3.6%]) and lower risk of LREs (adjusted hazard ratio [aHR], 0.69; 95% CI, 0.60 to 0.80). There was a dose-response relationship: compared with SBB use, ACE inhibitor/ARB prescriptions ≥1 defined daily dose (aHR, 0.65; 95% CI, 0.56 to 0.76) were associated with a greater risk reduction compared with <1 defined daily dose (aHR, 0.87; 95% CI, 0.71 to 1.07). Results were robust across sensitivity analyses such as comparing ACE inhibitor/ARB users with nonusers and as-treated analysis. CONCLUSIONS: In this national cohort study, ACE inhibitor/ARB use was associated with significantly lower risk of LREs in patients with compensated cirrhosis. These results provide support for a randomized clinical trial to confirm clinical benefit.

Emergency Department Utilization and Outcomes Among Adults With Cirrhosis From 2008 to 2022 in the United States.

BACKGROUND & AIMS: Globally, emergency departments (ED) are experiencing rising costs and crowding. Despite its importance, ED utilization and outcomes among patients with cirrhosis are understudied. METHODS: We analyzed Optum's de-identified Clinformatics Data Mart Database, between 2008 and 2022, including adults with at least 180 days of enrollment. Liver transplant recipients were censored at the year of transplant. ED visits (stratified by liver vs non-liver related) were identified using validated billing code definitions. Linear regression was used to assess ED visits per year, and logistic regression was used to assess 90-day mortality rates and discharge dispositions, with models adjusted for patient- and visit-level characteristics. RESULTS: Among 38,419,650 patients, 198,439 were with cirrhosis (median age, 66 [interquartile range, 57-72 years]; 54% male; 62% White). In age-adjusted analysis, ED visits per person-year were 1.72 (95% confidence interval [CI], 1.71-1.74) with cirrhosis vs 0.46 (95% CI, 0.46-0.46) without cirrhosis, 1.66 (95% CI, 1.66-1.66) for congestive heart failure (CHF), and 1.22 (95% CI, 1.22-1.22) for chronic obstructive pulmonary disease (COPD). Age-adjusted 90-day mortality rates were 12.2% (95% CI, 12.1%-12.4%) with cirrhosis vs 4.8% [95% CI, 4.8%-4.8%) without cirrhosis, 6.9% (95% CI, 6.9%-6.9%) for CHF, and 6.3% (95% CI, 6.3%-6.4%) for COPD. Non-liver (vs liver-related) ED visits were more likely to lead to discharge home among patients with compensated (52.8%; 95% CI, 52.2%-53.5% vs 39.2%; 95% CI, 38.5%-39.8%) and decompensated (42.2%; 95% CI, 41.5%-42.8% vs 29.5%; 95% CI, 29.0%-30.1%) cirrhosis. In exploratory analysis, among patients who remained alive and were not readmitted for 30 days after ED discharge, those without any outpatient follow-up had higher 90-day mortality (22.0%; 95% CI, 21.0%-23.0%) than those with both primary care and gastroenterology/hepatology follow-up within 30-days (7.9%; 95% CI, 7.3%-8.5%). CONCLUSIONS: Patients with cirrhosis have higher ED utilization and almost 2-fold higher post-ED visit mortality than CHF and COPD. These findings provide impetus for ED-based interventions to improve cirrhosis-related outcomes.

ChatGPT4 Outperforms Endoscopists for Determination of Postcolonoscopy Rescreening and Surveillance Recommendations.

BACKGROUND & AIMS: Large language models including Chat Generative Pretrained Transformers version 4 (ChatGPT4) improve access to artificial intelligence, but their impact on the clinical practice of gastroenterology is undefined. This study compared the accuracy, concordance, and reliability of ChatGPT4 colonoscopy recommendations for colorectal cancer rescreening and surveillance with contemporary guidelines and real-world gastroenterology practice. METHODS: History of present illness, colonoscopy data, and pathology reports from patients undergoing procedures at 2 large academic centers were entered into ChatGPT4 and it was queried for the next recommended colonoscopy follow-up interval. Using the McNemar test and inter-rater reliability, we compared the recommendations made by ChatGPT4 with the actual surveillance interval provided in the endoscopist's procedure report (gastroenterology practice) and the appropriate US Multisociety Task Force (USMSTF) guidance. The latter was generated for each case by an expert panel using the clinical information and guideline documents as reference. RESULTS: Text input of de-identified data into ChatGPT4 from 505 consecutive patients undergoing colonoscopy between January 1 and April 30, 2023, elicited a successful follow-up recommendation in 99.2% of the queries. ChatGPT4 recommendations were in closer agreement with the USMSTF Panel (85.7%) than gastroenterology practice recommendations with the USMSTF Panel (75.4%) (P < .001). Of the 14.3% discordant recommendations between ChatGPT4 and the USMSTF Panel, recommendations were for later screening in 26 (5.1%) and for earlier screening in 44 (8.7%) cases. The inter-rater reliability was good for ChatGPT4 vs USMSTF Panel (Fleiss κ, 0.786; 95% CI, 0.734-0.838; P < .001). CONCLUSIONS: Initial real-world results suggest that ChatGPT4 can define routine colonoscopy screening intervals accurately based on verbatim input of clinical data. Large language models have potential for clinical applications, but further training is needed for broad use.

Characteristics and Outcomes Among US Commercially Insured Transgender Adults With Cirrhosis: A National Cohort Study.

INTRODUCTION: The National Institute on Minority Health and Health Disparities has noted that transgender individuals experience unique health disparities. We sought to describe the landscape of transgender patients with cirrhosis. METHODS: We identified all transgender and cisgender adults in Optum's deidentified Clinformatics Data Mart Database between 2007 and 2022 using validated billing codes and calculating age-standardized prevalence of cirrhosis among cisgender vs transgender adults. Among those with incident cirrhosis diagnoses, we calculated age-standardized incidence densities of liver-related outcomes (decompensation, transplantation, hepatocellular carcinoma) and all-cause mortality. We examined 5-year survival using inverse probability treatment weighting to balance transgender and cisgender populations on demographic and clinical characteristics. RESULTS: Among 64,615,316 adults, 42,471 (0.07%) were transgender. Among 329,251 adults with cirrhosis, 293 (0.09%) were transgender. Trans- (vs cis-) genders had higher prevalence of cirrhosis (1,285 [95% confidence interval (CI) 1,136-1,449] per 100,000 vs 561 [559-563] per 100,000). Among adults with cirrhosis, trans- (vs cis-) genders had higher proportions of anxiety (70.7% [56.9-86.9] vs 43.2% [42.7-43.8]), depression (66.4% [53.3-81.7] vs 38.4% [37.9-38.9]), HIV/AIDS (8.5% [3.9-16.1] vs 1.6% [1.5-1.7]), and alcohol (57.5% [46.0-71.1] vs 51.0% [50.5-51.6]) and viral (30.5% [22.8-39.8] vs 24.2% [23.9-24.5]) etiologies, although etiologies had overlapping CIs. Trans- (vs cis-) genders had similar incidence densities of death (12.0 [95% CI 8.8-15.3] vs 14.0 [13.9-14.2] per 100 person-years), decompensation (15.7 [10.9-20.5] vs 14.1 [14.0-14.3]), and liver transplantation (0.3 [0.0-0.8] vs 0.3 [0.3-0.4]). In inverse probability treatment weighting survival analysis, transgender and cisgender individuals had similar 5-year survival probabilities (63.4% [56.6-71.1] vs 59.1% [58.7-59.4]). DISCUSSION: Trans- (vs cis-) gender adults have double the prevalence of cirrhosis, and the majority have a diagnosis of anxiety and/or depression. These results are informative for researchers, policymakers, and clinicians to advance equitable care for transgender individuals.

Glucagon-Like Peptide Receptor Agonists Use Before Endoscopy Is Associated With Low Retained Gastric Contents: A Multicenter Cross-Sectional Analysis.

INTRODUCTION: While ubiquity of glucagon-like peptide receptor agonists (GLP1-RAs) is rising, guidance from the gastroenterology societies and American Society of Anesthesiologist (ASA) remains in conflict on recommendations regarding preoperative holding before endoscopy. The aim of this study was to address this by evaluating the effect of GLP1-RAs on gastric retention during upper endoscopy. METHODS: This multicenter cross-sectional study included patients on confirmed GLP1-RAs receiving an endoscopy from 2021 to 2023. Demographics, prescribing practices, and procedure outcomes were captured. GLP1-RA management of preoperative holding was retroactively classified per ASA guidance. Multivariable logistic regression was performed to assess factors influencing retained gastric contents. RESULTS: Of 815 patients, 70 (8.7%) had retained gastric contents on endoscopy of whom 65 (93%) had type 2 diabetes mellitus. Only 1 (1.4%) of these patients required unplanned intubation, and none had aspiration events. Those with GLP1-RA held per ASA guidance (406, 49.8%) were less likely to have retained contents (4.4% vs 12.7%, P < 0.001), but there were no significant differences to intubation (0% vs 2%, P = 0.53) or aborting procedure rates (28% vs 18%, P = 0.40) due to gastric retention. On multivariable analysis, likelihood of food retention increased 36% (95% confidence interval 1.15-1.60) for every 1% increase in hemoglobin A1C after adjusting for GLP1-RA type and preoperative medication hold. DISCUSSION: In this multicenter study, very low rates of retained gastric contents were seen during endoscopy in patients on GLP1-RAs and most were in patients with type 2 diabetes mellitus. Our findings suggest an individualized approach rather than universal preoperative holding of medications before endoscopy.

The Survival Benefit of Reabstinence After Harmful Alcohol Use Following Early Liver Transplant for Severe Alcohol-Associated Hepatitis: A Multicenter ACCELERATE Study.

INTRODUCTION: Early (i.e., without mandated period of abstinence) liver transplant (LT) for alcohol-associated hepatitis is the fastest-growing indication for LT in the United States and Europe. Harmful alcohol use after LT is associated with poor outcomes, but the distinction of establishing abstinence after return to drinking (i.e., reabstinence) is understudied. This study aims to characterize the survival outcomes of achieving reabstinence after post-LT harmful alcohol use. METHODS: We analyzed early LT recipients from 12 US LT centers between 2006 and 2021. Post-LT alcohol use was characterized as harmful using criteria of "binge" (≥5 [men] or ≥4 [women] drinks in < 24 hours) or "frequent" (≥4 days in one week) by interview or phosphatidylethanol >20 ng/mL. Reabstinence was defined as ≥12 consecutive months without harmful alcohol use after harmful alcohol use. RESULTS: Among 347 LT recipients (64% male, median age 43, median Model for End-Stage Liver Disease-Sodium score 38) with median post-LT follow-up of 2.2 years (interquartile interval 1.1-3.6), 276 (80%) recipients had no evidence of harmful alcohol use, 35 (10%) recipients had reabstinence, and 36 (10%) recipients had continued harmful alcohol use without reabstinence. Five-year predicted survival, adjusted for age, sex, and Model for End-Stage Liver Disease-Sodium score, was lowest among LT recipients with continued harmful alcohol use (77%), but similar among those with no harmful use (93%) and reabstinence (94%). DISCUSSION: Achieving reabstinence after post-LT harmful alcohol use is associated with similar 5-year post-LT survival compared with those without evidence of post-LT harmful alcohol use. Our findings highlight the importance of early detection and treatment of post-LT alcohol use.

Safety of acamprosate for alcohol use disorder Post-Liver transplant: a pilot randomized controlled trial.

INTRODUCTION: Acamprosate is a therapy for alcohol use disorder but data on feasibility and safety in liver transplant (LT) recipients are lacking. METHODS: This was a single-center unblinded prospective pilot randomized controlled trial of adults (≥18 years) with LT for ALD enrolled between 2021-2023 who were randomized 2:1 to the intervention of acamprosate (666mg dose three times daily) or standard of care (SOC) over 14 weeks. Outcomes included safety [prevalence of adverse events (AE)], feasibility (weekly survey response rate >60%), adherence (self-reported acamprosate use>60%), and efficacy (reduction in Penn Alcohol Craving Scale [PACS]) and relapse-blood phosphatidylethanol≥20ng/mL/reported alcohol use) evaluated by standardized weekly surveys. The efficacy analysis was done in both the intention to treat (ITT) (excluding withdrawals before medication administration) and per-protocol (PP) population (excluding withdrawals/<4 weeks participation). RESULTS: Of 78 participants approached, 30 enrolled (19 acamprosate, 11 SOC) with similar baseline characteristics. Eight participants withdrew (6 acamprosate prior to medication administration and 2 SOC). AEs were similar between acamprosate and SOC groups (92.3% vs. 90.0%, p>0.99), including Grade 3 AEs (53.9% vs. 60.0%, p>0.99) with no reported grade 4/5 AEs. Survey response rates were similar in acamprosate vs SOC groups (61.0% vs. 76.0%, p=0.19), and 69.0% were acamprosate adherent. Baseline PACS values were low with no difference by group in median absolute change in PACS for ITT (0, IQR:-4-0 vs. 0, IQR:0-0, p=0.32) and PP analyses (-1, IQR:-6-0 vs. 0, IQR:0-0, p=0.36). There were no reported or biochemical evidence of alcohol relapse. CONCLUSION: In this pilot study, preliminary data suggests that acamprosate may be safe and feasible. These data can inform larger studies and clinician efforts to address alcohol use disorder in post-LT care. (ClinicalTrials.gov, Number: NCT06471686).

Quantifying days at home in patients with cirrhosis: A national cohort study.

BACKGROUND AND AIMS: Days at home (DAH) is a patient-centric metric developed by the Medicare Payment Advisory Commission, capturing annual health care use, including and beyond hospitalizations and mortality. We quantified DAH and assessed factors associated with DAH differences among patients with cirrhosis. APPROACH AND RESULTS: Using a national claims database (Optum) between 2014 and 2018, we calculated DAH (365 minus mortality, inpatient, observation, postacute, and emergency department days). Among 20,776,597 patients, 63,477 had cirrhosis (median age, 66, 52% males, and 63% non-Hispanic White). Age-adjusted mean DAH for cirrhosis was 335.1 days (95% CI: 335.0 to 335.2) vs 360.1 (95% CI: 360.1 to 360.1) without cirrhosis. In mixed-effects linear regression, adjusted for demographic and clinical characteristics, patients with decompensated cirrhosis spent 15.2 days (95% CI: 14.4 to 15.8) in postacute, emergency, and observation settings and 13.8 days (95% CI: 13.5 to 14.0) hospitalized. Hepatic encephalopathy (-29.2 d, 95% CI: -30.4 to -28.0), ascites (-34.6 d, 95% CI: -35.3 to -33.9), and combined ascites and hepatic encephalopathy (-63.8 d, 95% CI: -65.0 to -62.6) were associated with decreased DAH. Variceal bleeding was not associated with a change in DAH (-0.2 d, 95% CI: -1.6 to +1.1). Among hospitalized patients, during the 365 days after index hospitalization, patients with cirrhosis had fewer age-adjusted DAH (272.8 d, 95% CI: 271.5 to 274.1) than congestive heart failure (288.0 d, 95% CI: 287.7 to 288.3) and chronic obstructive pulmonary disease (296.6 d, 95% CI: 296.3 to 297.0). CONCLUSIONS: In this national study, we found that patients with cirrhosis spend as many, if not more, cumulative days receiving postacute, emergency, and observational care, as hospitalized care. Ultimately, up to 2 months of DAH are lost annually with the onset of liver decompensation. DAH may be a useful metric for patients and health systems alike.

Multicentered study of patient outcomes after declined for early liver transplantation in severe alcohol-associated hepatitis.

BACKGROUND: Early liver transplantation for alcohol-associated hepatitis is controversial in part because patients may recover, and obviate the need for liver transplantation. METHODS: In this retrospective study among 5 ACCELERATE-AH sites, we randomly sampled patients evaluated and then declined for liver transplantation for alcohol-associated hepatitis. All had Model of End-Stage Liver Disease (MELD) >20 and <6 months of abstinence. Recompensation was defined as MELD <15 without variceal bleeding, ascites, or overt HE requiring treatment. Multilevel mixed effects linear regression was used to calculate probabilities of recompensation; multivariable Cox regression was used for mortality analyses. RESULTS: Among 145 patients [61% men; median abstinence time and MELD-Na was 33 days (interquartile range: 13-70) and 31 (interquartile range: 26-36), respectively], 56% were declined for psychosocial reasons. Probability of 30-day, 90-day, 6-month, and 1-year survival were 76% (95% CI, 68%-82%), 59% (95% CI, 50%-66%), 49% (95% CI, 40%-57%), and 46% (95% CI, 37%-55%), respectively. Probability of 1-year recompensation was low at 10.0% (95% CI, 4.5%-15.4%). Among patients declined because of clinical improvement, 1-year probability of recompensation was 28.0% (95% CI, 5.7%-50.3%). Among survivors, median MELD-Na at 30 days, 90 days, and 1-year were 29 (interquartile range: 22-38), 19 (interquartile range : 14-29), and 11 (interquartile range : 7-17). Increased MELD-Na (adjusted HR: 1.13, p <0.001) and age (adjusted HR: 1.03, p <0.001) were associated with early (≤90 d) death, and only history of failed alcohol rehabilitation (adjusted HR: 1.76, p =0.02) was associated with late death. CONCLUSIONS: Liver recompensation is infrequent among severe alcohol-associated hepatitis patients declined for liver transplantation. Higher MELD-Na and age were associated with short-term mortality, whereas only history of failed alcohol rehabilitation was associated with long-term mortality. The distinction between survival and liver recompensation merits further attention.

Comparative outcomes of endoscopic mucosal resection for laterally spreading lesions in inflammatory bowel disease.

BACKGROUND: The role of endoscopic mucosal resection (EMR) for laterally spreading lesions (LSLs) in inflammatory bowel disease (IBD) remains controversial despite its effectiveness in the general population. We aimed to characterize outcomes of EMR for IBD-associated LSLs compared with controls without IBD. METHODS: We performed a retrospective observational cohort study of patients with IBD who underwent EMR and endoscopic follow-up for LSLs, compared with a control group without IBD. The primary outcome was histologic recurrence. Secondary outcomes included en bloc resection and adverse events. Factors associated with recurrence were identified using multivariate mixed effects logistic regression. RESULTS: 210 premalignant lesions in 155 patients were included. By histology, 91.0% were adenoma/low grade dysplasia or sessile serrated lesions. Median (IQR) lesion size was 25 (12-30) mm in the IBD group and 20 (12-30) mm in the control group. Recurrence was detected in 30.4% of IBD-associated lesions (7/23) compared with 20.9% of controls (39/187; odds ratio [OR] 2.51, 95%CI 0.59-10.71). En bloc resection was less common in the IBD group (2/23 [8.7%], 95%CI 1.1-28.0) versus controls (106/187 [56.7%], 95%CI 50.4-65.2). After adjusting for lesion size and histology, recurrence appeared more common in patients with IBD compared with controls (OR 3.08, 95%CI 1.04-9.13). CONCLUSIONS: Recurrence of LSLs after EMR appeared to be more frequent in patients with IBD. Given the added complexity, EMR in patients with IBD should be performed in expert centers with close endoscopic surveillance.

Healthcare affordability and effects on mortality among adults with liver disease from 2004 to 2018 in the United States.

BACKGROUND & AIMS: Liver disease is associated with substantial morbidity and mortality, likely incurring financial distress (i.e. healthcare affordability and accessibility issues), although long-term national-level data are limited. METHODS: Using the National Health Interview Survey from 2004 to 2018, we categorised adults based on report of liver disease and other chronic conditions linked to mortality data from the National Death Index. We estimated age-adjusted proportions of adults reporting healthcare affordability and accessibility issues. Multivariable logistic regression and Cox regression were used to assess the association of liver disease with financial distress and financial distress with all-cause mortality, respectively. RESULTS: Among adults with liver disease (n = 19,407) vs. those without liver disease (n = 996,352), those with cancer history (n = 37,225), those with emphysema (n = 7,937), and those with coronary artery disease (n = 21,510), the age-adjusted proportion reporting healthcare affordability issues for medical services was 29.9% (95% CI 29.7-30.1%) vs. 18.1% (95% CI 18.0-18.3%), 26.5% (95% CI 26.3-26.7%), 42.2% (95% CI 42.1-42.4%), and 31.6% (31.5-31.8%), respectively, and for medications: 15.5% (95% CI 15.4-15.6%) vs. 8.2% (95% CI 8.1-8.3%), 14.8% (95% CI 14.7-14.9%), 26.1% (95% CI 26.0-26.2%), and 20.6% (95% CI 20.5-20.7%), respectively. In multivariable analysis, liver disease (vs. without liver disease, vs. cancer history, vs. emphysema, and vs. coronary artery disease) was associated with inability to afford medical services (adjusted odds ratio [aOR] 1.84, 95% CI 1.77-1.92; aOR 1.32, 95% CI 1.25-1.40; aOR 0.91, 95% CI 0.84-0.98; and aOR 1.11, 95% CI 1.04-1.19, respectively) and medications (aOR 1.92, 95% CI 1.82-2.03; aOR 1.24, 95% CI 1.14-1.33; aOR 0.81, 95% CI 0.74-0.90; and aOR 0.94, 95% CI 0.86-1.02, respectively), delays in medical care (aOR 1.77, 95% CI 1.69-1.87; aOR 1.14, 95% CI 1.06-1.22; aOR 0.88, 95% CI 0.79-0.97; and aOR 1.05, 95% CI 0.97-1.14, respectively), and not receiving the needed medical care (aOR 1.86, 95% CI 1.76-1.96; aOR 1.16, 95% CI 1.07-1.26; aOR 0.89, 95% CI 0.80-0.99; aOR 1.06, 95% CI 0.96-1.16, respectively). In multivariable analysis, among adults with liver disease, financial distress (vs. without financial distress) was associated with increased all-cause mortality (aHR 1.24, 95% CI 1.01-1.53). CONCLUSIONS: Adults with liver disease face greater financial distress than adults without liver disease and adults with cancer history. Financial distress is associated with increased risk of all-cause mortality among adults with liver disease. Interventions to improve healthcare affordability should be prioritised in this population. IMPACT AND IMPLICATIONS: Adults with liver disease use many medical services, but long-term national studies regarding the financial repercussions and the effects on mortality for such patients are lacking. This study shows that adults with liver disease are more likely to face issues affording medical services and prescription medication, experience delays in medical care, and needing but not obtaining medical care owing to cost, compared with adults without liver disease, adults with cancer history, are equally likely as adults with coronary artery disease, and less likely than adults with emphysema-patients with liver disease who face these issues are at increased risk of death. This study provides the impetus for medical providers and policymakers to prioritise interventions to improve healthcare affordability for adults with liver disease.

National Experience on Waitlist Outcomes for Down-Staging of Hepatocellular Carcinoma: High Dropout Rate in All-Comers.

BACKGROUND & AIMS: The United Network for Organ Sharing (UNOS) grants priority listing for liver transplant for patients with hepatocellular carcinoma after successful down-staging to Milan criteria. We evaluated the national experience on down-staging by comparing 2 down-staging groups: tumor burden meeting UNOS down-staging (UNOS-DS) inclusion criteria, and all-comers (AC)-DS with initial tumor burden beyond UNOS-DS criteria vs patients always within Milan criteria. METHODS: We performed a retrospective analysis of the UNOS database of 23,398 patients listed for liver transplant who had submitted a hepatocellular carcinoma Model for End-Stage Liver Disease exception application from 2010 to 2019, classified as always within Milan (n = 20,579), UNOS-DS (n = 2151), and AC-DS (n = 668). RESULTS: The 2-year cumulative probabilities of dropout were 19% for Milan, 25% for UNOS-DS (P < .001), and 30% for AC-DS (P < .001). In multivariate analysis of the down-staging groups, factors predicting dropout included Model for End-Stage Liver Disease at listing (hazard ratio [HR], 1.06; P < .001) and initial total tumor diameter (HR, 1.04; P = .002). Compared with α-fetoprotein (AFP) level ≤20 ng/mL, AFP levels of 21 to 100, 101 to 1000, and greater than 1000 ng/mL were associated with a higher risk of dropout (HRs, 1.63, 2.06, and 4.58, respectively; P < .001). A subset of all-comers with AFP levels greater than 100 ng/mL had a 2-year probability of dropout of 52% vs 26% for all others beyond Milan criteria (P < .001). CONCLUSIONS: All-comers had a significantly higher risk for waitlist dropout compared with the UNOS-DS and Milan groups after initial successful down-staging to Milan criteria. In particular, the subgroup of AC-DS with an AFP level greater than 100 ng/mL had a greater than 50% probability of dropout in the next 2 years. These observations suggest a high likelihood of failure when expanding the indications for down-staging.

Geographic Density of Gastroenterologists Is Associated With Decreased Mortality From Alcohol-Associated Liver Disease.

BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality and has been increasing. To inform public health efforts to address the growing incidence of ALD, we assessed the association of geographic density of gastroenterologists with ALD-related mortality. METHODS: National data were obtained for adults aged ≥25 years with state-level demographics and 2010-2019 mortality estimates by linking federally maintained registries (WONDER, NSSATS, BRFSS, HRSA, US Census Bureau). Multivariable linear regression was used to assess the association of state-level geographic density of gastroenterologists with ALD-related mortality, adjusting for age, sex, race/ethnicity, and other potential confounders. RESULTS: Among 50 states and the District of Columbia, the national mean geographic density of gastroenterologists was 4.6 per 100,000 population, and annual ALD-related mortality rate was 85.6 per 1,000,000 population. There was greater than 5-fold differences in geographic density of gastroenterologists and ALD-related mortality across states. In multivariable analysis, the geographic density of gastroenterologists was significantly associated with lower ALD-related mortality (9.0 [95% confidence interval, 1.3-16.7] fewer ALD-related deaths per 1,000,000 population for each additional gastroenterologist per 100,000 population). The association appeared to peak at a threshold of ≥7.5 gastroenterologists per 100,000 population. We estimated that differences in geographic density of gastroenterologists across states may potentially represent 40% of national ALD-related mortality. Exploratory analyses to assess for confounding by generalized subspecialty care, transplant access, alcohol taxation, and substance use or mental health services, including negative control analyses, did not affect primary results. CONCLUSIONS: State-level geographic density of gastroenterologists is associated with lower ALD-related mortality. These results may inform medical societies and health policymakers to address anticipated workforce gaps to address the growing epidemic of ALD.

Strategies to increase primary care provider capacity for hepatitis C care: The California ECHO-PLUS study.

Expanding capacity to screen and treat those infected with the hepatitis C virus (HCV) is an essential element of the global elimination strategy. We evaluated the hub-and-spoke Project ECHO training versus telementoring models to educate, train and support HCV care by primary care providers in 13 targeted counties in northern California. A novel provider engagement strategy was used. Provider engagement and retention, time to readiness to treat HCV, and knowledge and confidence were the outcomes of interest. 94 participants from 60 unique clinics in the target counties participated in the ECHO-PLUS programme; 39.4% were physicians, 48.9% were advanced practice providers, and 11.7% were nurses. The median (range) participation time was 5 (1-49) hours. Confidence scores (minimum score = 13 and maximum score = 65) increased by a mean of 14.0 (SD:8.2) and 11.4 (SD:12.0) points for the hub-and-spoke and telementoring programmes, respectively (p = .53), with the largest changes in confidence seen in treating patients per guidelines, managing side effects and in serving as a consultant for HCV in their clinic. Among 24 participants with data on time to treatment, median time from beginner to experienced was 8 h (IQR:6-12) for hub-and-spoke and 2 h (IQR:1-2.4) for the telementoring programme (p = .01). A 'boots on the ground' approach to recruiting HCV champions was effective within rural communities. Both tele-ECHO hub-and-spoke and telementoring approaches to training primary care providers yielded increase in knowledge and confidence in HCV care and amplified the number of patients who were screened and treated. Telementoring accelerated the timeline of novice providers being 'ready to treat'.

Impact of Bacteria Types on the Clinical Outcomes of Spontaneous Bacterial Peritonitis.

BACKGROUND AND AIMS: Cirrhotic patients presenting with spontaneous bacterial peritonitis (SBP) have elevated risk of short-term mortality. While high Model for End-Stage Liver Disease-Sodium score (MELD-Na) and ascites culture yielding multi-drug resistance (MDR) bacteria are well established risk factors for further aggravating mortality, the impact of individual, causative microorganisms and their respective pathogenesis have not been previously investigated. METHODS: This is a retrospective study of 267 cirrhotic patients at two tertiary care hospitals undergoing paracentesis from January 2015 to January 2021 who presented with ascitic PMN count > 250 cells/mm3. The primary outcome was SBP progression defined as death or liver transplantation within 1-month of paracentesis stratified by microorganism type. RESULTS: Of 267 patients with SBP, the ascitic culture yielded causative microorganism in 88 cases [median age 57 years (IQR 52-64)]; 68% male; median MELD-Na 29 (IQR 23-35). The microbes isolated were E. coli (33%), Streptococcus (15%), Klebsiella (13%), Enterococcus (13%), Staphylococcus (9%) and others (18%); 41% were MDR. Cumulative incidence of SBP progression within 1-month was 91% (95% CI 67-100) for Klebsiella, 59% (95% CI 42-76) for E. coli, and 16% (95% CI 4-51) for Streptococcus. After adjusting for MELD-Na and MDR, risk of SBP progression remained elevated for Klebsiella (HR 2.07; 95% CI 0.98-4.24; p-value = 0.06) and decreased for Streptococcus (HR 0.28; 95% CI 0.06-1.21; p-value = 0.09) compared to all other bacteria. CONCLUSION: Our study found Klebsiella-associated SBP had worse clinical outcomes while Streptococcus-associated SBP had the most favorable outcomes after accounting for MDR and MELD-Na. Thus, identification of the causative microorganism is crucial not only for optimizing the treatment but for prognostication.

Impaired anti-HBV vaccine response in non-cirrhotic chronic HCV is not overcome by double dose regimen: randomized control trial.

INTRODUCTION AND OBJECTIVES: Some studies suggest chronic HCV infection diminishes responses to the anti-HBV vaccine. We evaluated the efficacy of double versus standard dose HBV vaccination among HCV patients without cirrhosis. PATIENTS AND METHODS: 141 adults with untreated chronic HCV were randomized to HBV vaccination with double dose (40µg) or standard dose (20µg) at 0, 1 and 6 months; 70 healthy HCV-negative patients given standard dose served as controls. Vaccine response was defined by anti-HBs ≥10 mIU/mL. RESULTS: 128 patients (60 double, 68 standard doses) completed the study. Patients were of median age 52 years, 61% female, 60% fibrosis <2 of 4, and 76% genotype 1 with median 6-log 10 IU/mL HCV RNA. Overall seroprotection rate was 76.7% (95% CI: 65-87) in the 40µg versus 73.5% (95% CI: 63-84) in the 20µg dose HCV-positive groups (p =0.68) and 91.2% (95%CI:84-99) in HCV-negative controls (p =0.011 and 0.003, respectively). In multivariate logistic regression, vaccine dose (double vs. standard dose) was not associated with vaccine response (OR=0.63, p =0.33). Of 32 HCV-infected patients who were non-responders to 3- doses, 25 received the fourth dose of vaccine. The fourth dose seroconversion rate for the 40µg and 20µg groups were 45.5% and 21.4%, respectively. CONCLUSIONS: In HCV-infected patients without cirrhosis, impaired responses to HBV vaccination cannot be overcome by the use of double dose HBV vaccination, but adding a fourth dose of vaccine for non-responders may be an effective strategy. Other adjuvant measures are needed to enhance seroconversion rates in these patients. TRIAL REGISTER: U 1111-1264-2343 (www.ensaiosclinicos.gov.br).

Food Insecurity is Associated With Mortality Among U.S. Adults With Nonalcoholic Fatty Liver Disease and Advanced Fibrosis.

BACKGROUND & AIMS: Food insecurity is a growing public health challenge in the United States (U.S.) and has been linked to nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis. However, little is known of how food insecurity impacts mortality risk and health care utilization in chronic liver disease. METHODS: Using a population-based cohort study of U.S. adults (≥20 years) in the National Health and Nutrition Examination Survey, 1999 to 2014, with NAFLD (estimated by the U.S. Fatty Liver Index) and advanced fibrosis (estimated by the NAFLD fibrosis score, aspartate aminotransferase-to-platelet ratio index, or Fibrosis-4 Index), food security was measured using the Department of Agriculture Food Security Survey Module. The primary outcome was all-cause mortality from National Death Index data and the secondary outcome was health care utilization, defined as ≥2 inpatient and ≥4 outpatient visits, with Cox and logistic regression, respectively, estimating associations between food insecurity and outcomes. RESULTS: Of 34,134 eligible participants (mean age, 47 years; 51% women; 14% in poverty), 4816 had NAFLD and 1654 had advanced fibrosis, with food insecurity present in 28% and 21%, respectively. All-cause age-adjusted mortality was 12 per 1000 person-years among participants with NAFLD (food-secure, 11; food-insecure, 15) and 32 per 1000 person-years among advanced fibrosis participants (food-secure, 28; food-insecure, 50). In multivariable analyses, food insecurity was independently associated with higher mortality among participants with NAFLD (hazard ratio, 1.46; 95% confidence interval [CI], 1.08-1.97) and advanced fibrosis (hazard ratio, 1.37; 95% CI, 1.01-1.86) and greater outpatient health care utilization in participants with NAFLD (odds ratio, 1.32; 95% CI, 1.05-1.67). CONCLUSIONS: Food insecurity is significantly associated with greater all-cause mortality in adults with NAFLD and advanced fibrosis. Interventions that address food insecurity among adults with liver disease should be prioritized to improve health outcomes in this population.

Diverging Incidence Trends for Hepatocellular Carcinoma in Rural and Urban Settings in the United States.

In the United States, hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths and was the 5th most common cause in 2020.1 One in 5 Americans lives in a rural area,2 yet little is known about temporal changes in HCC incidence by rural-urban residence. Area-specific data are critical to guide public health strategies and clinical interventions. Our study compared the overall and subgroup incidence trends for HCC across rural and urban communities in the United States over the past 20 years using the North American Association of Central Cancer Registries database, which covers 93% of the United States and well-represents the rural United States (North American Association of Central Cancer Registries 14.6% rural vs United States 14.8% rural).3.