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Background and Aims: Recently proposed "Rule-of-Five" criteria define compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) using liver stiffness (LS) and platelet count. We aimed to validate these criteria by determining whether they are associated with risk of adverse outcomes., Approach and Results: Patients without prior hepatic decompensation or HCC who underwent LS and platelet measurements (n = 17,076) were categorized as follows: no cACLD (LS: 2.5-9.9 kPa); probable cACLD (LS: 10-14.9 kPa); certain cACLD-no CSPH (LS: 15-19.9 kPa and platelets ≥110,000/µL or LS 20-24.9 kPa and platelets ≥150,000/µL); probable CSPH (LS 15-19.9 kPa and platelets <110,000/µL or LS 20-24.9 and platelets <150,000/µL); and certain CSPH (LS ≥25 kPa), which we further subdivided into 25-49.9 and 50-75 kPa.During a median follow-up of 2.82 years, each increase in the "Rule-of-Five" category was associated linearly with higher risks of death (HR: 1.22, 95% CI: 1.18-1.25) and decompensation (HR: 1.52, 95% CI: 1.46-1.58). Compared to patients with LS 25-49.9 kPa, those with LS 50-75 kPa ("critical" CSPH) had approximately double the risk of decompensation (11.24 vs. 4.20 per 100 patient-years) and death (9.85 vs. 6.98 per 100 patient-years)., Conclusions: The Baveno VII "Rule-of-Five" criteria provide a valid system for stratifying risks of death and hepatic decompensation and should be used routinely in patients with chronic liver disease. Among patients with CSPH (LS ≥25 kPa), the subgroup with LS 50-75 kPa ("critical" CSPH) has approximately double the risk of death and hepatic decompensation than LS 25-49.9 kPa., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Patients with cirrhosis have an increased risk of postoperative mortality, which is partially attributable to portal hypertension. Preoperative TIPS placement may reduce operative risk. Studies suggesting the benefits of preoperative TIPS are limited by residual confounding and lack of longitudinal laboratory data. To address these limitations, we used granular longitudinal data from the Veterans Health Administration., Methods: This retrospective cohort study of Veterans Health Administration patients with cirrhosis who underwent major surgery from 2008 to 2022 identified patients who underwent TIPS placement within 6 months before surgery. Demographics, comorbidities, surgery type, and longitudinal laboratory data were incorporated into a propensity score using 5:1 caliper matching for receipt of TIPS. The propensity-matched cohort included 39 patients with preoperative TIPS and 171 without., Results: Baseline characteristics were similar between groups. In Cox regression, recent TIPS was associated with an increased risk of postoperative mortality (HR: 2.69, 95% CI: 1.37-5.30, p = 0.004), redemonstrated in 500 random resampling events (median HR: 1.71). TIPS and non-TIPS patients had similar albumin, bilirubin, and international normalized ratio 6 months before surgery; however, immediately before surgery, TIPS patients had lower albumin (p = 0.009), higher bilirubin (p = 0.001), and higher international normalized ratio (p = 0.001)., Conclusions: In a propensity-matched analysis of patients with cirrhosis undergoing major surgery, recent TIPS was associated with increased postoperative mortality and worsened liver synthetic function in the immediate preoperative period. TIPS placement should be carefully considered in patients with cirrhosis who may undergo surgery., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Fibrosis-4 (FIB4) is a recommended noninvasive test to assess hepatic fibrosis among patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we used FIB4 trajectory over time (ie, "slope" of FIB4) as a surrogate marker of liver fibrosis progression and examined if FIB4 slope is associated with clinical and genetic factors among individuals with clinically defined MASLD within the Million Veteran Program Cohort., Methods: In this retrospective cohort study, FIB4 slopes were estimated through linear regression for participants with clinically defined MASLD and FIB4 <2.67 at baseline. FIB4 slope was correlated with demographic parameters and clinical outcomes using logistic regression and Cox proportional hazard models. FIB4 slope as a quantitative phenotype was used in a genome-wide association analysis in ancestry-specific analysis and multiancestry meta-analysis using METAL., Results: FIB4 slopes, generated from 98,361 subjects with MASLD (16,045 African, 74,320 European, and 7996 Hispanic), showed significant associations with sex, ancestry, and cardiometabolic risk factors (p < 0.05). FIB4 slopes also correlated strongly with hepatic outcomes and were independently associated with time to cirrhosis. Five genetic loci showed genome-wide significant associations (p < 5 × 10-8) with FIB4 slope among European ancestry subjects, including 2 known (PNPLA3 and TM6SF2) and 3 novel loci (TERT 5.1 × 10-11; LINC01088, 3.9 × 10-8; and MRC1, 2.9 × 10-9)., Conclusions: Linear trajectories of FIB4 correlated significantly with time to progression to cirrhosis, with liver-related outcomes among individuals with MASLD and with known and novel genetic loci. FIB4 slope may be useful as a surrogate measure of fibrosis progression., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background and Aims: Although refractory hepatic hydrothorax (RH) is a serious complication of cirrhosis, waitlisted patients do not receive standardized Model for End-stage Liver Disease (MELD) exemption because of inadequate evidence suggesting mortality above biochemical MELD. This study aimed to examine liver-related death (LRD) associated with RH compared to refractory ascites (RA)., Approach and Results: This was a retrospective cohort study of Veterans with cirrhosis. Eligibility criteria included participants with RH or RA, followed from their first therapeutic thoracentesis/second paracentesis until death or transplantation. The primary outcome was LRD with non-LRD or transplantation as competing risk. Of 2552 patients with cirrhosis who underwent therapeutic thoracentesis/paracentesis, 177 met criteria for RH and 422 for RA. RH was associated with a significantly higher risk of LRD (adjusted HR [aHR] 4.63, 95% CI 3.31-6.48) than RA overall and within all MELD-sodium (MELD-Na) strata (<10 aHR 4.08, 95% CI 2.30-7.24, 10-14.9 aHR 5.68, 95% CI 2.63-12.28, 15-24.9 aHR 4.14, 95% CI 2.34-7.34, ≥25 aHR 7.75, 95% CI 2.99-20.12). LRD was higher among participants requiring 1 (aHR 3.54, 95% CI 2.29-5.48), 2-3 (aHR 4.39, 95% CI 2.91-6.63), and ≥4 (aHR 7.89, 95% CI 4.82-12.93) thoracenteses relative to RA. Although participants with RH and RA had similar baseline MELD-Na, LRD occurred in RH versus RA at a lower MELD-Na (16.5 vs. 21.82, p =0.002) but higher MELD 3.0 (27.85 vs. 22.48, p <0.0001)., Conclusions: RH was associated with higher risk of LRD than RA at equivalent MELD-Na. By contrast, MELD 3.0 may better predict risk of LRD in RH., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Diabetes is associated with HCC; however, the impact of longitudinal blood glucose (BG) control on HCC risk in cirrhosis is not well known. We investigated this knowledge gap in a cohort of United States Veterans with cirrhosis from 2015 to 2021., Methods: We used repeated hemoglobin A1c measurements to categorize follow-up time according to BG control (defined as hemoglobin A1c < 7%) state over time: uncontrolled, nonsustained control (≤2 y), or sustained control (>2 y). We performed a sensitivity analysis using hemoglobin A1c < 8% to define BG control. We used Fine and Gray Cox proportional hazards regression with death and transplant as competing events to compare rates of incident HCC., Results: Our study included 81,907 individuals, 56.2% of whom had diabetes at baseline. There were 8,002 incident HCCs. The rate of HCC was 18% higher in diabetes (95% CI: 13% - 24%), and the relative increase in the rate of HCC varied by etiology of cirrhosis from nonsignificant (HCV) to an increase of 120% (HBV). Uncontrolled and nonsustained BG control was associated with 1.80 (95% CI: 1.70-1.91) and 2.34 (95% CI: 2.21-2.48) times the rate of HCC compared to sustained BG control, respectively. Using Hgb A1c < 8% to define BG control, HCC rates in uncontrolled and nonsustained BG control were 2.43 (2.28-2.58) and 2.23 (2.11-2.36) times that observed in sustained BG control., Conclusions: Associations between diabetes and HCC in cirrhosis vary according to the longitudinal BG control state. Inadequate BG control is consistently associated with a higher risk of HCC, and long-term BG control should be considered in comprehensive cirrhosis care., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Cirrhosis care and outcomes are improved with access to subspecialty gastroenterology and hepatology care. In qualitative interviews, we investigated clinicians' perceptions of factors that optimize or impede cirrhosis care., Methods: We conducted 24 telephone interviews with subspecialty clinicians at 7 Veterans Affairs medical centers with high- and low-complexity services. Purposive sampling stratified Veterans Affairs medical centers on timely post-hospitalization follow-up, a quality measure. We asked open-ended questions about facilitators and barriers of care coordination, access to appointments, procedures, transplantation, management of complications, keeping up to date with medical knowledge, and telehealth use., Results: Key themes that facilitated care were structural: multidisciplinary teams, clinical dashboards, mechanisms for appointment tracking and reminders, and local or virtual access to transplant and liver cancer specialists through the "specialty care access network extension for community health care outcomes" program. Coordination and efficient communication between transplant and non-transplant specialists and between transplant and primary care facilitated timely care. Same-day access to laboratory, procedural, and clinical services is an indicator of high-quality care. Barriers included lack of on-site procedural services, clinician turnover, patient social needs related to transportation, costs, and patient forgetfulness due to HE. Telehealth enabled lower complexity sites to obtain recommendations for complex patient cases. Barriers to telehealth included lack of credit (eg, VA billing equivalent), inadequate staff, lack of audiovisual technology support, and patient and staff discomfort with technology. Telehealth was optimal for return visits, cases where physical examination was nonessential, and where distance and transportation precluded in-person care. Rapid telehealth uptake during the COVID-19 pandemic was a positive disruptor and facilitated use., Conclusions: We identify multi-level factors related to structure, staffing, technology, and care organization to optimize cirrhosis care delivery., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Mental health diagnoses are common and known to impact key outcomes in patients with chronic illnesses including cirrhosis. However, the independent impact of psychiatric comorbidities on mortality in these patients and potential mitigating effects of outpatient mental health-related care has not been well characterized., Methods: This was a retrospective cohort study of patients with cirrhosis in the Veterans Health Administration between 2008 and 2021. Adjusted Cox regression was performed to evaluate the association between mental health-related diagnoses [groups: alcohol use disorder (AUD)/substance use disorder (SUD) alone, non-AUD/SUD alone, and any mental health diagnosis (AUD/SUD or non-AUD/SUD)] and all-cause mortality. In subgroup analyses, the impact of regular outpatient mental health visits was also assessed., Results: We identified 115,409 patients, 81.7% of whom had any mental health diagnosis at baseline. During the study window there was a significant increase in the number of mental health clinic visits per person-year (β=0.078, 95% CI: 0.065-0.092, p < 0.001), but a decrease in AUD/SUD clinic utilization (p < 0.001). In regression models, there was a 54% increased hazard in all-cause mortality for any mental health diagnosis, 11% for non-AUD/SUD, and 44% for AUD/SUD (each p < 0.001). Regular mental health visits resulted in a 21% decreased risk in all-cause mortality for AUD/SUD diagnosis, compared with 3% and 9% for any mental health diagnosis and non-AUD/SUD diagnosis, respectively (each p < 0.001)., Conclusions: Mental illness is associated with an increased risk of all-cause mortality in veterans with cirrhosis. Regular outpatient mental health care may be protective against all-cause mortality, particularly among patients with AUD/SUD. Future studies should focus on relevant clinical practice changes, including implementing integrated care programs., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Medications for alcohol use disorder (MAUD) are highly effective in achieving and maintaining abstinence in patients with alcohol use disorder (AUD). Our aim was to evaluate the effect of MAUD on all-cause mortality in patients with alcohol-associated cirrhosis and active alcohol use., Methods: This was a retrospective cohort study of patients with alcohol-associated cirrhosis and high-risk alcohol use disorder in the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) database. Propensity score matching for exposure to MAUD (acamprosate or naltrexone) within a year after cirrhosis diagnosis was performed to account for potential confounders, and the association between MAUD and all-cause mortality was subsequently evaluated using Cox regression analysis., Results: A total of 9131 patients were included, of whom 886 (9.7%) were exposed to MAUD (naltrexone: 520, acamprosate: 307, both medications: 59). The duration of MAUD exposure was >3 months in 345 patients (39%). The strongest positive predictor of MAUD prescription was an inpatient diagnosis code for AUD, followed by a concurrent diagnosis of depression; the strongest negative predictor was a history of cirrhosis decompensation. After propensity score matching (866 patients in each group) with excellent covariate balance (absolute standardized mean differences <0.1), MAUD exposure was associated with improved survival, with an HR of 0.80 relative to no MAUD exposure (95% CI: 0.67-0.97, p = 0.024)., Conclusion: MAUD are underutilized in patients with alcohol-associated cirrhosis with high-risk alcohol use behavior but are associated with improved survival after adjustment for confounders such as the severity of liver disease, age, and engagement in the healthcare system., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background and Aims: Little is known about the effectiveness of nonselective beta blockers (NSBBs) in preventing hepatic decompensation in routine clinical settings. We investigated whether NSBBs are associated with hepatic decompensation or liver-related mortality in a national cohort of veterans with Child-Turcotte-Pugh (CTP) A cirrhosis with no prior decompensations., Approach and Results: In an active comparator, new user (ACNU) design, we created a cohort of new users of carvedilol ( n = 123) versus new users of selective beta blockers (SBBs) ( n = 561) and followed patients for up to 3 years. An inverse probability treatment weighting (IPTW) approach balanced demographic and clinical confounders. The primary analysis simulated intention-to-treat ("pseudo-ITT") with IPTW-adjusted Cox models; secondary analyses were pseudo-as-treated, and both were adjusted for baseline and time-updating drug confounders. Subgroup analyses evaluated NSBB effects by HCV viremia status, CTP class, platelet count, alcohol-associated liver disease (ALD) etiology, and age. In pseudo-ITT analyses of carvedilol versus SBBs, carvedilol was associated with a lower hazard of any hepatic decompensation (HR 0.59, 95% CI 0.42-0.83) and the composite outcome of hepatic decompensation/liver-related mortality (HR 0.56, 95% CI 0.41-0.76). Results were similar in pseudo-as-treated analyses (hepatic decompensation: HR 0.55, 95% CI 0.33-0.94; composite outcome: HR 0.62, 95% 0.38-1.01). In subgroup analyses, carvedilol was associated with lower hazard of primary outcomes in the absence of HCV viremia, higher CTP class and platelet count, younger age, and ALD etiology., Conclusions: There is an ongoing need to noninvasively identify patients who may benefit from NSBBs for the prevention of hepatic decompensation., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background and Aims: Immunity to SARS-CoV-2 can be infection or vaccine-induced. Cirrhosis is associated with vaccine hyporesponsiveness, but whether there is decreased immunity after SARS-CoV-2 infection in unvaccinated patients with cirrhosis is unknown.The objective of our study was to compare infection-induced and vaccine-induced immunity against COVID-19 among patients with cirrhosis., Methods: This was a retrospective cohort study among US Veterans with cirrhosis between November 27, 2020, and November 16, 2021, comparing a vaccine-induced immunity group, defined as participants without a documented SARS-CoV-2 infection but fully vaccinated with two doses of an mRNA vaccine, and infection-associated immunity group, defined as unvaccinated participants who had a positive SARS-CoV-2 polymerase chain reaction (PCR). Both groups were propensity score matched for observed characteristics, including location, and the date of the immunity acquiring event, to control for the community prevalence of COVID-19 variants. The outcome was a positive SARS-CoV-2 PCR more than 60 days after previous infection in the infection-induced, or after full vaccination in the vaccine-induced immunity group., Results: We compared 634 participants in the infection-induced immunity group with 27,131 participants in the vaccine-induced immunity group using inverse propensity of treatment weighting. Vaccine-induced immunity was associated with a reduced odds of developing SARS-CoV-2 infection (adjusted hazard ratio [aHR], 0.18; 95% confidence interval [CI], 0.16-0.20, p < 0.0001). On multivariable logistic regression, vaccine-induced immunity was associated with reduced odds of developing symptomatic (adjusted odds ratio [aOR], 0.36; 95% CI, 0.33-0.41, p < 0.0001), moderate/severe/critical (aOR, 0.27; 95% CI, 0.22-0.31, p < 0.0001), and severe or critical COVID-19 (aOR, 0.20; 95% CI, 0.16-0.26, p < 0.001), compared with infection-induced immunity., Conclusions: In participants with cirrhosis, vaccine-induced immunity is associated with reduced risk of developing COVID-19, compared with infection-induced immunity., (Copyright © 2022 American Association for the Study of Liver Diseases.)

The coronavirus disease 2019 (COVID-19) pandemic has disrupted health care delivery in the United States, with increased reliance on telemedicine visits as opposed to in-person outpatient appointments. We used national data to evaluate shifts in modes of hepatology outpatient care for patients with cirrhosis during the pandemic. This was a retrospective cohort study among U.S. veterans with cirrhosis. We used linear regression to evaluate absolute and percentage changes from baseline in hepatology in-person visits and telemedicine visits from January 1, 2020, to August 11, 2020. The proportion of in-person and telemedicine visits were plotted geographically to demonstrate state-level shifts in care delivery over time. Patient-level characteristics in the pre-COVID and during-COVID periods were also compared. We identified 5,618 in-person and 6,210 telemedicine hepatology visits among patients with cirrhosis. In-person visits significantly declined (-16.0% per week; 95% confidence interval [CI] -20.7, -11.2; P < 0.001), while telemedicine visits significantly increased (61.3% per week; 95% CI 45.1, 77.5; P < 0.001) in the early during-COVID period. At the U.S. state level, we found that nearly all states experienced a significant shift toward telemedicine over the course of several weeks. Patients over the age of 70 years and Black patients were less likely to receive telemedicine visits in the pre-COVID period (each P < 0.05), although these differences were eliminated in the during-COVID periods. Conclusion: Among patients with cirrhosis, hepatology outpatient care delivery has shifted heavily toward telemedicine due to COVID-19. This occurred across the United States, and changes have been sustained through August 2020. Expanded telemedicine visits among older patients and Black patients may reflect dedicated efforts to increased access to care among these groups., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Aims: Patients develop breakthrough COVID-19 infection despite vaccination. The aim of this study was to identify outcomes in patients with cirrhosis who developed postvaccination COVID-19., Methods: We performed a retrospective cohort study among US veterans with cirrhosis and postvaccination or unvaccinated COVID-19. Patients were considered fully vaccinated if COVID-19 was diagnosed 14 days after the second dose of either the Pfizer BNT162b2, the Moderna 1273-mRNA, or the single-dose Janssen Ad.26.COV2.S vaccines and partially vaccinated if COVID-19 was diagnosed 7 days after the first dose of any vaccine but prior to full vaccination. We investigated the association of postvaccination COVID-19 with mortality., Results: We identified 3242 unvaccinated and 254 postvaccination COVID-19 patients with cirrhosis (82 after full and 172 after partial vaccination). In a multivariable analysis of a 1:2 propensity-matched cohort including vaccinated (n = 254) and unvaccinated (n = 508) participants, postvaccination COVID-19 was associated with reduced risk of death (adjusted HR [aHR], 0.21; 95% CI, 0.11-0.42). The reduction was observed after both full (aHR, 0.22; 95% CI, 0.08-0.63) and partial (aHR, 0.19; 95% CI, 0.07-0.54) vaccination, following the 1273-mRNA (aHR, 0.12; 95% CI 0.04-0.37) and BNT162b2 (aHR, 0.27; 95% CI, 0.10-0.71) vaccines and among patients with compensated (aHR, 0.19; 95% CI, 0.08-0.45) and decompensated (aHR, 0.27; 95% CI, 0.08-0.90) cirrhosis. Findings were consistent in a sensitivity analysis restricted to participants who developed COVID-19 after vaccine availability., Conclusions: Though patients with cirrhosis can develop breakthrough COVID-19 after full or partial vaccination, these infections are associated with reduced mortality., (© 2022 American Association for the Study of Liver Diseases.)

Background and Aims: The impact of sex on the postcirrhosis progression of primary biliary cholangitis (PBC) has not been well defined. Prior studies have suggested that men have worse outcomes but present at more advanced stages of fibrosis than women. This observation, however, has been limited by small numbers of men and even fewer patients with cirrhosis., Approach and Results: We investigated the association of sex with the development of all-cause and liver-related mortality or transplantation, decompensation, and hepatocellular carcinoma (HCC), using competing-risk time-updating Cox proportional hazards models in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. In a cohort of 532 participants (418 male) with PBC-related cirrhosis with a total follow-up of 3,231.6 person-years (PY) from diagnosis of compensated cirrhosis, male participants had a higher unadjusted rates of death or transplantation (8.5 vs. 3.8 per 100 PY; P < 0.0001), liver-related death or transplantation (5.5 vs. 2.7 per 100 PY; P < 0.0001), decompensation (5.5 vs. 4.0 per 100 PY; P = 0.002), and HCC (0.9 vs. 0.3 per 100 PY; P < 0.0001). After adjusting for confounders, male sex was associated with a higher risk of death or transplantation (adjusted hazard ratio, 1.80; 95% CI, 1.01-3.19; P = 0.046), and liver-related death or transplantation (subhazard ratio, 2.17; 95% CI, 1.15-4.08; P = 0.02). A sensitivity analysis that defined ursodeoxycholic acid response as normalization of alkaline phosphatase and total bilirubin revealed similar findings., Conclusions: In patients with PBC and well-compensated cirrhosis, male sex is associated with a higher risk of both death and liver-related death or transplantation., (© 2021 by the American Association for the Study of Liver Diseases. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Cirrhosis poses an increased risk of postoperative mortality, yet it remains challenging to accurately risk stratify patients in clinical practice. The VOCAL-Penn cirrhosis surgical risk score was recently developed and internally validated in the national Veterans Affairs health system; however, to date this score has not been evaluated in independent cohorts. The goal of this study was to compare the predictive performance of the VOCAL-Penn to the Mayo risk, Model for End-Stage Liver Disease (MELD), and MELD-sodium (MELD-Na) scores in 2 large health systems. We performed a retrospective cohort study of patients with cirrhosis undergoing surgical procedures of interest at the Beth Israel Deaconess Medical Center or University of Pennsylvania Health System from January 1, 2008, to October 1, 2015. The outcomes of interest were 30-day and 90-day postoperative mortality. Concordance statistics (C-statistics), calibration curves, Brier scores, and the index of prediction accuracy (IPA) were compared for each predictive model. A total of 855 surgical procedures were identified. The VOCAL-Penn score had the numerically highest C-statistic for 90-day postoperative mortality (eg, 0.82 versus 0.79 Mayo versus 0.78 MELD-Na versus 0.79 MELD), although differences were not statistically significant. Calibrations were excellent for the VOCAL-Penn, MELD, and MELD-Na; however, the Mayo score consistently overestimated risk. The VOCAL-Penn had the lowest Brier score and highest IPA at both time points, suggesting superior overall predictive model performance. In subgroup analyses of patients with higher MELD scores, the VOCAL-Penn had significantly higher C-statistics compared with the MELD and MELD-Na. The VOCAL-Penn score (www.vocalpennscore.com) has excellent discrimination and calibration for postoperative mortality among diverse patients with cirrhosis. Overall performance is superior to the Mayo, MELD, and MELD-Na scores. In contrast to the MELD/MELD-Na, the VOCAL-Penn retains excellent discrimination among patients with higher MELD scores., (Copyright © 2021 by the American Association for the Study of Liver Diseases.)

Obeticholic acid (OCA) is approved for the treatment of patients with primary biliary cholangitis (PBC) who are partial responders or intolerant to ursodeoxycholic acid. Reports of serious liver injury have raised concerns about its safety in cirrhosis. We investigated the effects of treatment with OCA on hepatic decompensation and liver-related mortality or transplantation in a cohort with compensated PBC cirrhosis. This was a retrospective cohort study using national data of US veterans with PBC and cirrhosis. We performed a propensity score model using variables associated with OCA prescription to control for baseline risk of decompensation. New OCA users were matched to nonusers. We identified 509 subjects with compensated PBC cirrhosis. We developed a propensity score model using variables associated with OCA prescription; 21 OCA users were matched with 84 nonusers. Over 569 and 3,847 person-months, respectively, of follow-up, 5 (23.8%) OCA users and 22 (26.2%) OCA nonusers decompensated. The C-statistic of the propensity score model was 0.87. On multivariable analysis, after adjusting for potential confounders, OCA use was associated with an increased risk of hepatic decompensation (adjusted hazard ratio, 3.9; 95% confidence interval, 1.33-11.57; P  = 0.01). There was no association between OCA use and liver-related mortality or transplantation (adjusted hazard ratio, 1.35; 95% confidence interval, 0.35-5.21; P  = 0.66). Conclusion: OCA use was associated with an increase in hepatic decompensation but not liver-related mortality or transplantation in patients with compensated PBC cirrhosis. Additional studies are recommended to prospectively investigate these findings., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

With a rising burden of cirrhosis surgeries, understanding risk factors for postoperative mortality is more salient than ever. The role of baseline frailty has not been assessed in this context. We evaluated the association between patient frailty and postoperative risk among diverse patients with cirrhosis and determined if frailty improves prognostication of cirrhosis surgical risk scores. This was a retrospective cohort study of U.S. veterans with cirrhosis identified between 2008 and 2016 who underwent nontransplant major surgery. Frailty was ascertained using the Hospital Frailty Risk Score (HFRS). Cox regression analysis was used to investigate the impact of patient frailty on postoperative mortality. Logistic regression was used to identify incremental changes in discrimination for postoperative mortality when frailty was added to the risk prediction models, including the Model for End-Stage Liver Disease (MELD), MELD-sodium (MELD-Na), Child-Turcotte-Pugh (CTP), Mayo Risk Score (MRS), and Veterans Outcomes and Costs Associated With Liver Disease (VOCAL)-Penn. A total of 804 cirrhosis surgeries were identified. The majority of patients (48.5%) had high-risk frailty at baseline (HFRS >15). In adjusted Cox regression models, categories of increasing frailty scores were associated with poorer postoperative survival. For example, intermediate-risk frailty (HFRS 5-15) conferred a 1.77-fold increased hazard relative to low-risk frailty (HFRS, <5; 95% confidence interval [CI], 1.06-2.95; P = 0.03). High-risk frailty demonstrated a similarly increased hazard (hazard ratio, 1.74; 95% CI, 1.05-2.88; P = 0.03), suggesting a threshold effect of frailty on postoperative mortality. The incorporation of frailty improved discrimination of MELD, MELD-Na, and CTP for postoperative mortality, but did not do so for the MRS or VOCAL-Penn score. Patient frailty was an additional important predictor of cirrhosis surgical risk. The incorporation of preoperative frailty assessments may help to risk stratify patients, especially in settings where the MELD-Na and CTP are commonly applied., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

The burden of cirrhosis hospitalizations is increasing. The admission Model for End-Stage Liver Disease-lactate (MELD-lactate) was recently demonstrated to be a superior predictor of in-hospital mortality compared with MELD in limited cohorts. We identified specific classes of hospitalizations where MELD-lactate may be especially useful and evaluated the predictive role of lactate clearance. This was a retrospective cohort study of 1036 cirrhosis hospitalizations for gastrointestinal bleeding, infection, or other portal hypertension-related indications in the Veterans Health Administration where MELD-lactate was measured on admission. Performance characteristics for in-hospital mortality were compared between MELD-lactate and MELD/MELD-sodium (MELD-Na), with stratified analyses of MELD categories (≤15, >15 to <25, ≥25) and reason for admission. We also incorporated day 3 lactate levels into modeling and tested for an interaction between day 1 MELD-lactate and day 3 lactate clearance. MELD-lactate had superior discrimination for in-hospital mortality compared with MELD or MELD-Na (area under the curve [AUC] 0.789 versus 0.776 versus 0.760, respectively; P < 0.001) and superior calibration. MELD-lactate had higher discrimination among hospitalizations with MELD ≤15 (AUC 0.763 versus 0.608 for MELD, global P = 0.01) and hospitalizations for infection (AUC 0.791 versus 0.674 for MELD, global P < 0.001). We found a significant interaction between day 1 MELD-lactate and day 3 lactate clearance; heat maps were created as clinical tools to risk-stratify patients based on these clinical data. MELD-lactate had significantly superior performance in predicting in-hospital mortality among patients hospitalized for infection and/or with MELD ≤15 when compared with MELD or MELD-Na. Incorporating day 3 lactate clearance may further improve prognostication., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Background and Aims: Outcomes with anticoagulation (AC) are understudied in advanced liver disease. We investigated effects of AC with warfarin and direct oral anticoagulants (DOACs) on all-cause mortality and hepatic decompensation as well as ischemic stroke, major adverse cardiovascular events, splanchnic vein thrombosis, and bleeding in a cohort with cirrhosis and atrial fibrillation (AF)., Approach and Results: This was a retrospective, longitudinal study using national data of U.S. veterans with cirrhosis at 128 medical centers, including patients with cirrhosis with incident AF, from January 1, 2012 to December 31, 2017 followed through December 31, 2018. To assess the effects of AC on outcomes, we applied propensity score (PS) matching and marginal structural models (MSMs) to account for confounding by indication and time-dependent confounding. The final cohort included 2,694 veterans with cirrhosis with AF (n = 1,694 and n = 704 in the warfarin and DOAC cohorts after PS matching, respectively) with a median of 4.6 years of follow-up. All-cause mortality was lower with warfarin versus no AC (PS matched: hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.55-0.76; MSM models: HR, 0.54; 95% CI, 0.40-0.73) and DOACs versus no AC (PS matched: HR, 0.68; 95% CI, 0.50-0.93; MSM models: HR, 0.50; 95% CI, 0.31-0.81). In MSM models, warfarin (HR, 0.29; 95% CI, 0.09-0.90) and DOACs (HR, 0.23; 95% CI, 0.07-0.79) were associated with reduced ischemic stroke. In secondary analyses, bleeding was lower with DOACs compared to warfarin (HR, 0.49; 95% CI, 0.26-0.94)., Conclusions: Warfarin and DOACs were associated with reduced all-cause mortality. Warfarin was associated with more bleeding compared to no AC. DOACs had a lower incidence of bleeding compared to warfarin in exploratory analyses. Future studies should prospectively investigate these observed associations., (© 2020 by the American Association for the Study of Liver Diseases.)

Background and Aims: Patients with cirrhosis are at increased risk of postoperative mortality. Currently available tools to predict postoperative risk are suboptimally calibrated and do not account for surgery type. Our objective was to use population-level data to derive and internally validate cirrhosis surgical risk models., Approach and Results: We conducted a retrospective cohort study using data from the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) cohort, which contains granular data on patients with cirrhosis from 128 U.S. medical centers, merged with the Veterans Affairs Surgical Quality Improvement Program (VASQIP) to identify surgical procedures. We categorized surgeries as abdominal wall, vascular, abdominal, cardiac, chest, or orthopedic and used multivariable logistic regression to model 30-, 90-, and 180-day postoperative mortality (VOCAL-Penn models). We compared model discrimination and calibration of VOCAL-Penn to the Mayo Risk Score (MRS), Model for End-Stage Liver Disease (MELD), Model for End-Stage Liver Disease-Sodium MELD-Na, and Child-Turcotte-Pugh (CTP) scores. We identified 4,712 surgical procedures in 3,785 patients with cirrhosis. The VOCAL-Penn models were derived and internally validated with excellent discrimination (30-day postoperative mortality C-statistic = 0.859; 95% confidence interval [CI], 0.809-0.909). Predictors included age, preoperative albumin, platelet count, bilirubin, surgery category, emergency indication, fatty liver disease, American Society of Anesthesiologists classification, and obesity. Model performance was superior to MELD, MELD-Na, CTP, and MRS at all time points (e.g., 30-day postoperative mortality C-statistic for MRS = 0.766; 95% CI, 0.676-0.855) in terms of discrimination and calibration., Conclusions: The VOCAL-Penn models substantially improve postoperative mortality predictions in patients with cirrhosis. These models may be applied in practice to improve preoperative risk stratification and optimize patient selection for surgical procedures (www.vocalpennscore.com)., (© 2020 by the American Association for the Study of Liver Diseases.)

There is significant interest in identifying risk factors associated with acute-on-chronic liver failure (ACLF). In transplant candidates, frailty predicts wait-list mortality and posttransplant outcomes. However, the impact of frailty on ACLF development and mortality is unknown. This was a retrospective study of US veterans with cirrhosis identified between 2008 and 2016. First hospitalizations were characterized as ACLF or non-ACLF admissions. Prehospitalization patient frailty was ascertained using a validated score based on administrative coding data. We used logistic regression to investigate the impact of an increasing frailty score on the odds of ACLF hospitalization and short-term ACLF mortality. Cox regression was used to analyze the association between frailty and longterm survival from hospitalization. We identified 16,561 cirrhosis hospitalizations over a median follow-up of 4.19 years (interquartile range, 2.47-6.34 years). In adjusted models, increasing frailty score was associated with significantly increased odds of ACLF hospitalization versus non-ACLF hospitalization (odds ratio, 1.03 per point; 95% CI 1.02-1.03; P < 0.001). By contrast, frailty score was not associated with ACLF 28- or 90-day mortality (P = 0.13 and P = 0.33, respectively). In an adjusted Cox analysis of all hospitalizations, increasing frailty scores were associated with poorer longterm survival from the time of hospitalization (hazard ratio, 1.02 per 5 points; 95% confidence interval, 1.01-1.03; P = 0.004). Frailty increases the likelihood of ACLF hospitalization among patients with cirrhosis, but it does not impact short-term ACLF mortality. These findings have implications for clinicians caring for frail outpatients with cirrhosis, including tailored follow-up, risk mitigation strategies, and possible expedited transplant evaluation., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Background and Aims: Acute on chronic liver failure (ACLF) results in extremely high short-term mortality in patients with underlying cirrhosis. The European Association for the Study of the Liver criteria grade ACLF severity from 1 (least severe) to 3 (most severe) based on organ failures (OFs) that develop after an acute decompensation (AD). However, the implications of surviving low-grade ACLF in terms of risk of subsequent high-grade ACLF are unclear., Approach and Results: We conducted a retrospective cohort study of patients with compensated cirrhosis in the Veterans Health Administration database from January 2008 to June 2016. Propensity matching for grade 1 (G1) ACLF, followed by Cox regression, was used to model risk of subsequent grade 3 (G3) ACLF. Stratified analyses of different ADs and OFs were also performed. We identified 4,878 patients with well-matched propensity scores. G1 ACLF events conferred a significantly increased risk of subsequent G3 ACLF relative no previous G1 ACLF (hazard ratio, 8.69; P < 0.001). When stratified by AD, patients with ascites or hepatic encephalopathy were significantly more likely to develop G3 ACLF relative to those with gastrointestinal bleed or infection as an AD (P < 0.001). Risk of G3 ACLF also varied significantly by type of OF characterizing previous G1 ACLF, with liver, coagulation, and circulatory failure posing the highest increased risk., Conclusions: Patients who recover from G1 ACLF have substantially increased risk of later developing G3 ACLF as compared to those who never have G1 ACLF. Moreover, reversible decompensations for G1 ACLF have a lower risk of G3 ACLF, and liver-intrinsic OFs confer a much higher risk of G3 ACLF. These findings have implications for prognosis, future surveillance, and triaging early transplant evaluation., (© 2019 by the American Association for the Study of Liver Diseases.)

Decompensated cirrhosis is associated with high morbidity and mortality. However, no standardized quality measures (QMs) have yet been adopted widely. The Veterans Affairs (VA) Advanced Liver Disease Technical Advisory Group recently developed a set of six internal QMs to guide quality improvement efforts in cirrhosis in the domains of access to care, hepatocellular carcinoma surveillance, variceal surveillance, quality of inpatient care for upper gastrointestinal bleeding, and cirrhosis-related rehospitalizations. We aimed to (1) quantify adherence to cirrhosis QMs and (2) determine whether adherence was associated with all-cause mortality and health care use within a large national cohort of veterans with cirrhosis. We performed a retrospective study using data from the Veterans Outcomes and Costs Asociated with Liver Disease cohort of 121,129 patients newly diagnosed with cirrhosis from January 1, 2008, to December 31, 2016, at 128 VA facilities. The mean follow-up time was 2.7 years (interquartile range, 1.1-5.1 years). Adherence to outpatient access to specialty care was 71%, variceal surveillance was 32%, and early postdischarge care was 54%. In adjusted analyses, outpatient access to specialty care (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.78-0.82), hepatocellular carcinoma surveillance (HR, 0.92; 95% CI, 0.90-0.95), variceal surveillance (HR, 0.93; 95% CI, 0.89-0.99), and early postdischarge care (HR, 0.57; 95% CI, 0.54-0.60) were associated with lower all-cause mortality. Readmissions after 30 days (HR, 1.53; 1.46-1.60) and 90 days (HR, 1.88; 95% CI, 1.54-1.70) were associated with higher all-cause mortality. Higher adherence to QMs was also associated with lower inpatient health care use. Conclusion: Five of the six proposed VA cirrhosis QMs were measurable using existing data sources, associated with mortality and health care use, and may be used to guide future quality improvement efforts in cirrhosis., (© 2019 by the American Association for the Study of Liver Diseases.)

The tyrosine kinase inhibitor sorafenib improves hepatopulmonary syndrome (HPS) in an experimental model. However, the efficacy and adverse effect profile in patients with HPS are unknown. We aimed to determine the effect of sorafenib on the alveolar-arterial oxygen gradient (AaPO 2 ) at 3 months in patients with HPS. We performed a randomized, double-blind, placebo-controlled parallel trial of sorafenib in patients with HPS at 7 centers. A total of 28 patients with HPS were randomized to sorafenib 400 mg by mouth daily or a matching placebo in a 1:1 ratio. We found no statistically significant difference in the median change in AaPO 2 from baseline to 12 weeks between the patients allocated to sorafenib (4.5 mm Hg; IQR, -3.8 to 7.0 mm Hg) and those allocated to placebo (-2.4 mm Hg; IQR, -4.8 to 8.2 mm Hg; P = 0.70). There was also no difference between the groups in terms of degree of intrapulmonary shunting by contrast echocardiography. Sorafenib significantly reduced circulating levels of angiogenic markers, including vascular endothelial growth factor receptors (P < 0.01) and TIE2-expressing M2 monocytes (P = 0.03), but it reduced the mental component scores of the Short Form 36 (P = 0.04), indicating a worse quality of life. In conclusion, sorafenib did not change the AaPO 2 or other disease markers at 3 months in patients with HPS. Alternative antiangiogenic therapies or treatments targeting other pathways should be investigated., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

The term acute-on-chronic liver failure (ACLF) is intended to identify patients with chronic liver disease who develop rapid deterioration of liver function and high short-term mortality after an acute insult. The two prominent definitions (European Association for the Study of the Liver [EASL] and Asian Pacific Association for the Study of the Liver [APASL]) differ, and existing literature applies to narrow patient groups. We sought to compare ACLF incidence and mortality among a diverse cohort of patients with compensated cirrhosis, using both definitions. This was a retrospective cohort study of patients with incident compensated cirrhosis in the Veterans Health Administration from 2008 to 2016. First ACLF events were identified for each definition. Incidence rates were computed as events per 1,000 person-years, and mortality was calculated at 28 and 90 days. Among 80,383 patients with cirrhosis with 3.35 years median follow-up, 783 developed EASL and APASL ACLF, 4,296 developed EASL ACLF alone, and 574 developed APASL ACLF alone. The incidence rate of APASL ACLF was 5.7 per 1,000 person-years (95% confidence interval [CI]: 5.4-6.0), and the incidence rate of EASL ACLF was 20.1 (95% CI: 19.5-20.6). The 28-day and 90-day mortalities for APASL ACLF were 41.9% and 56.1%, respectively, and were 37.6% and 50.4% for EASL ACLF. The median bilirubin level at diagnosis of EASL-alone ACLF was 2.0 mg/dL (interquartile range: 1.1-4.0). Patients with hepatitis C or nonalcoholic fatty liver disease had among the lowest ACLF incidence rates but had the highest short-term mortality. Conclusion: There is significant discordance in ACLF events by EASL and APASL criteria. The majority of patients with EASL-alone ACLF have preserved liver function, suggesting the need for more liver-specific ACLF criteria., (© 2019 by the American Association for the Study of Liver Diseases.)

Goals: To examine patient, provider, and health system barriers to clinical follow-up among US veterans with chronic hepatitis B virus (HBV)., Background: Studies have demonstrated deficiencies in clinical care and follow-up in HBV; however, patient, provider, and health-system barriers in non-Asian populations are understudied., Study: A retrospective cohort of 517 US veterans with chronic HBV at 3 diverse Veterans Affairs sites from 1999 to 2015. Laboratory testing and completion of clinical appointments were collected for 2 years following initial presentation., Results: Among HBV patients, 36% had drug abuse, 41% alcohol misuse, and 45% had psychiatric disorders. Patients had an average of 4.4 primary care visits within 2 years of the index hepatitis B surface antigen positive result, 38% had psychiatry visits, 21% had a psychiatric hospitalization; 26% saw gastroenterology/hepatology specialists. Within 1 year of the index hepatitis B surface antigen positive result, 75% had alanine aminotransferase testing, 14% had HBV entered into the problem list, and 8% had serologic confirmation. In multivariable analyses, cirrhosis [odds ratio (OR)=3.42; 95% confidence interval (CI), 1.84-6.36] was associated with higher odds of appropriate laboratory testing, alcohol misuse (OR=0.45; 95% CI, 0.29-0.80) was associated lower odds. Cirrhosis (OR=2.03; 95% CI, 1.11-3.72) and ≥2 primary care visits per year (OR=1.06; 95% CI, 1.01-1.11) were associated with higher odds of completing gastroenterology/hepatology consultation, whereas ≥1 psychiatric hospitalization in 2 years was associated with lower odds (OR=0.53; 95% CI, 0.34-0.82)., Conclusions: In a diverse cohort of veterans with high psychiatric comorbidity and substance abuse, important patient and provider factors influence appropriate follow-up care. Future studies should evaluate the impact of provider education and care coordination strategies in HBV.

Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality in cirrhosis patients. This provides an opportunity to target the highest-risk population, yet surveillance rates in the United States and Europe range from 10% to 40%. The goal of this study was to identify barriers to HCC surveillance, using data from the Veterans Health Administration, the largest provider of liver-related health care in the United States. We included all patients 75 years of age or younger who were diagnosed with cirrhosis from January 1, 2008, until December 31, 2010. The primary outcome was a continuous measure of the percentage of time up-to-date with HCC surveillance (PTUDS) based on abdominal ultrasound (secondary outcomes included computed tomography and magnetic resonance imaging). Among 26,577 patients with cirrhosis (median follow-up = 4.7 years), the mean PTUDS was 17.8 ± 21.5% (ultrasounds) and 23.3 ± 24.1% when any liver imaging modality was included. The strongest predictor of increased PTUDS was the number of visits to a specialist (gastroenterologist/hepatologist and/or infectious diseases) in the first year after cirrhosis diagnosis; the association between visits to a primary care physician and increasing surveillance was very small. Increasing distance to the closest Veterans Administration center was associated with decreased PTUDS. There was an inverse association between ultrasound lead time (difference between the date an ultrasound was ordered and requested exam date) and the odds of it being performed: odds ratio = 0.77, 95% confidence interval 0.72-0.82 when ordered > 180 days ahead of time; odds ratio = 0.90, 95% confidence interval 0.85-0.94 if lead time 91-180 days., Conclusions: The responsibility for suboptimal surveillance rests with patients, providers, and the overall health care system; several measures can be implemented to potentially increase HCC surveillance, including increasing patient-specialist visits and minimizing appointment lead time. (Hepatology 2017;65:864-874)., (© 2016 by the American Association for the Study of Liver Diseases.)

Unlabelled: Previous studies have identified gaps in hepatitis B care. The objectives of this study were to evaluate the delivery of care among a national cohort of US veterans with chronic hepatitis B infection and examine risk factors for adverse clinical outcomes. We conducted a retrospective cohort study using the Veterans Health Administration Corporate Data Warehouse from 1999 to 2013 to evaluate (1) care delivery and (2) clinical outcomes such as hepatocellular carcinoma, hepatic decompensation, and mortality among US veterans with hepatitis B. Incidence rates with 95% confidence intervals were calculated and Cox regression models were used to evaluate clinical outcomes. We identified 21,419 veterans with a positive hepatitis B surface antigen, and 97% of patients had alanine aminotransferase and 44% had hepatitis B virus DNA testing; hepatitis B e antigen and hepatitis B e antibody were tested <50% of the time. Patients receiving specialty care had a higher prevalence of recommended laboratory testing. Patients with elevated alanine aminotransferase in specialty care were more likely to receive antiviral therapy (50% versus 24% for specialty care versus no specialty care, P < 0.001). Among patients with cirrhosis, 69% received one-time liver imaging. The proportion of follow-up time adherent to annual imaging was 0.39 (standard deviation = 0.42), and the proportion was 0.28 (standard deviation = 0.33) for biannual imaging; both proportions were higher in the specialty care group (all P < 0.05). Antiviral therapy (hazard ratio = 0.85, 95% confidence interval 0.76-0.95, P = 0.005) and liver imaging (hazard ratio = 0.84, 95% confidence interval 0.76-0.91, P < 0.001) were independently associated with decreased mortality in adjusted analyses., Conclusion: We observed a low prevalence of recommended laboratory testing, antiviral therapy initiation, and liver imaging among a national cohort of veterans with hepatitis B infection; antiviral therapy and liver imaging were independently associated with decreased mortality. (Hepatology 2016;63:1774-1782)., (© 2015 by the American Association for the Study of Liver Diseases.)

Background: Acute hepatitis C (AHCV) provides a diagnostic challenge with diverse clinical presentations., Goals: This study was aimed to examine the clinical and demographic features as well as outcomes in AHCV patients identified from inpatient and outpatient hospital settings., Study: Patients with suspected AHCV were recruited from Philadelphia VA Medical Center, Hospital of University of Pennsylvania and Brooklyn VA Medical Center between 2000 and 2010. AHCV was diagnosed by acute serum alanine aminotransferase elevation with anti-hepatitis C virus (HCV) seroconversion, HCV-RNA fluctuations above 1 log, and/or recent high-risk exposure without prior HCV infection, excluding those with human immunodeficiency virus infection. Clinical and therapeutic outcomes were monitored for at least 6 months., Results: A total of 40 AHCV patients were enrolled with a median follow-up of 129 weeks. They were mostly men (68%) and whites (73%) with median age of 43 years, diverse risk factors (33% injection drugs, 20% health care-associated, 3% sexual, and 45% unknown), and wide variations in peak alanine aminotransferase (143 to 3435 U/L) and total bilirubin levels (0.4 to 19.3 mg/dL). Viremia resolved spontaneously in 23% and persisted without therapy in 27%, whereas 50% received interferon α-based therapy with 90% cure (18/20). Distinct clinical scenarios included: (1) wide viremic fluctuations >1 log (65%) and intermittent HCV-RNA negativity; (2) autoantibodies (25% antinuclear antibodies, 69% antismooth muscle antibodies) or autoimmune features; (3) delayed spontaneous viral clearance in 2 patients; (4) rapid cirrhosis progression in 2 patients., Conclusions: AHCV is a heterogenous disease that requires careful monitoring. The lack of apparent risk factor in high proportion of patients and its diverse presentations warrant diagnostic vigilance.

Unlabelled: Hepatic progenitor cells (HPC) play important roles in both liver regeneration and carcinogenesis. Combined hepatocellular-cholangiocarcinoma (CHC), a malignant primary liver tumor with poor prognosis, is thought to be of HPC origin. However, the prognostic significance of this etiology is not well defined. Therefore, we retrospectively investigated the relationship of HPC-related pathological features and long-term outcome in patients with CHC in our department. In a cohort of 80 patients identified between 1997 and 2003, including 70 patients who underwent resection with curative intent, overall survival (OS) and disease-free survival (DFS) were correlated with the proliferative activity of nontumor ductular reaction (DR) and the expression levels of HPC and biliary markers including α-fetoprotein (AFP), keratin 7 (K7), keratin 19 (K19), oval cell (OV)-6, epithelial cell adhesion molecule (EpCAM), and c-Kit in both tumor and nontumor liver. We found that nontumor ductular reactions (DRs), specifically the proliferating cell nuclear antigen (PCNA) labeling index of the ductular reaction (PI-DR), a surrogate for transit-amplifying compartments, was an independent prognostic factor for both OS and DFS. By contrast, intratumoral expression of only one marker, absence of AFP, was associated with OS. PI-DR was also independently associated with synchronous "multicentric occurrence" in hepatocellular carcinoma components, a feature of CHC that may predispose to metachronous multifocal tumorigenesis., Conclusion: Proliferative ductular reaction related to HPC activation is associated with recurrence of CHC. Background HPC activation is strongly associated with multifocal occurrence and related tumor recurrence, highlighting the critical role of background liver disease, a "field effect," in the recurrence of CHC., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Unlabelled: Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma (HCC). Both advanced solid tumors and HCV have previously been associated with memory B-cell dysfunction. In this study, we sought to dissect the effect of viral infection, cirrhosis, and liver cancer on memory B-cell frequency and function in the spectrum of HCV disease. Peripheral blood from healthy donors, HCV-infected patients with F1-F2 liver fibrosis, HCV-infected patients with cirrhosis, patients with HCV-related HCC, and non-HCV-infected cirrhotics were assessed for B-cell phenotype by flow cytometry. Isolated B cells were stimulated with anti-cluster of differentiation (CD)40 antibodies and Toll-like receptor (TLR)9 agonist for assessment of costimulation marker expression, cytokine production, immunoglobulin (Ig) production, and CD4(+) T-cell allostimulatory capacity. CD27(+) memory B cells and, more specifically, CD27(+) IgM(+) B cells were markedly less frequent in cirrhotic patients independent of HCV infection. Circulating B cells in cirrhotics were hyporesponsive to CD40/TLR9 activation, as characterized by CD70 up-regulation, tumor necrosis factor beta secretion, IgG production, and T-cell allostimulation. Last, blockade of TLR4 and TLR9 signaling abrogated the activation of healthy donor B cells by cirrhotic plasma, suggesting a role for bacterial translocation in driving B-cell changes in cirrhosis., Conclusion: Profound abnormalities in B-cell phenotype and function occur in cirrhosis independent of HCV infection. These B-cell defects may explain, in part, the vaccine hyporesponsiveness and susceptibility to bacterial infection in this population., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: The outcome of hepatitis C virus (HCV) infection has been associated with antiviral CD4 T cell response, human leukocyte antigens (HLA) class II genotypes, and ethnicity. However, HLA class II molecules restrict the nature of CD4 T cell response, and HLA distributions differ between ethnic groups. In this study, we asked whether HLA class II genotypes associated with HCV clearance are shared between Caucasian and African Americans and whether they contribute to enhanced antiviral CD4 T cell response. In a cohort of 93 HCV-seropositive subjects from Northeast America with defined ethnicity, virological outcome, and HCV-specific CD4 T cell proliferation, we confirm the previously reported associations between HCV clearance and two HLA types (DQB1*03, DRB1*11) while identifying a new association with DRB3*02. Strikingly, these associations were identified only among Caucasian [DQB1*03: odds ratio (OR), 10.4; P = 0.031, DRB1*11: OR, 7.0, P = 0.019; DRB3*02: OR, 8.3, P = 0.005; DQB1*03-DRB3*02: OR, 13.5, P = 0.001) but not among African American patients. Furthermore, although HLA DQB1*03, DRB1*11, and DRB3*02 genotypes were associated with increased HCV-specific CD4 T cell response in univariate analyses, these associations were lost when controlling for virological outcomes., Conclusion: We conclude that the immunogenetic basis for HCV clearance differs between ethnic groups and that the association between HLA class II and HCV clearance is not directly explained by antiviral CD4 T cell response.

Viral genotype and host ethnicity are important predictors of viral clearance during antiviral therapy for chronic hepatitis C virus (HCV) infection. Based on the role of T cells in natural HCV clearance, we hypothesized that T cells may contribute to the genotypic and ethnic difference in treatment outcome. To test this hypothesis, T-cell response to HCV antigens (core, nonstructural NS3/4 and NS5) and control phytohemagglutinin (PHA) was monitored prospectively and was correlated with virological outcome in 41 patients chronically infected with HCV (27 genotype 1, 14 genotype 2 or 3; 19 black persons, 22 white persons) undergoing combined interferon alfa and ribavirin therapy. Interestingly, in patients with genotype 2 or 3 infection, enhanced virological response coincided with a greater T-cell response to HCV NS3/4 antigen at baseline (50% vs. 15%; P = .026) that augmented further during therapy (29% vs. 4%; P = .035) compared with genotype 1-infected patients. However, HCV-specific T-cell response remained weak in genotype 1-infected patients regardless of virological outcome or ethnicity. Furthermore, virological outcome was associated with a suppressed baseline proliferative response to phytohemagglutinin (P < .03) that increased during therapy (P < .003) independent of ethnicity or genotype. In conclusion, HCV-specific T-cell response was associated with HCV genotype but not with therapeutic clearance of HCV infection. The association between treatment outcome and phytohemagglutinin response suggests more global and antigen-nonspecific mechanisms for therapeutic HCV clearance.