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Context: Studies of palliative care (PC) in hospitalized patients with cirrhosis have been retrospective, with limited evaluation of patient-reported measures and outcomes.Objectives: To examine the relationship between PC, patient-reported measures (quality of life and functional status), and outcomes.Methods: We performed a prospective cohort study of patients with cirrhosis hospitalized from 2014 to 2019. We recorded PC consultation details, quality of life (chronic liver disease questionnaire), and functional status (functional status questionnaire). Patients were followed for 90 days to assess readmissions, costs, and mortality.Results: Seventy-four of 679 patients saw PC, often later in the hospitalization (median hospital day 8; IQR 4-16). Those who saw PC had greater Charlson comorbidity index (mean 6.8 vs. 5.9), MELD (mean 25 vs. 20), and prior 30-day admission (47% vs. 35%). Compared to those who did not see PC, PC patients had greater impairments in intermediate activities of daily living (83% vs. 72%), social activity (72% vs. 59%), quality of interactions (49% vs. 36%), abdominal symptoms (mean score 3.1 vs. 3.6), activity (mean 3.3 vs. 3.6), and overall quality of life (mean 3.6 vs. 3.8). PC was associated with fewer transfusions and upper endoscopies and with greater completion of advanced directives. After multivariable adjustment, PC was not associated with intensive care, 30-day readmissions, 90-day costs, or mortality.Conclusion: PC occurs infrequently and late in those with more severe liver disease and functional impairment. PC may be associated with reduction in utilization and greater completion of advanced directives. Randomized trials are needed to evaluate PC for this population. [ABSTRACT FROM AUTHOR]

Despite the release of a growing number of direct‐acting antivirals and evolving policy landscape, many of those diagnosed with hepatitis C virus (HCV) have not received treatment. Those from vulnerable populations are at particular risk of being unable to access treatment, threatening World Health Organization (WHO) HCV elimination goals. The aim of this study was to understand the association between direct‐acting antivirals approvals, HCV‐related policy changes and access to HCV virus treatment in Indiana, and to explore access to treatment by race, birth cohort and insurance type. We performed a retrospective cohort study of adults with HCV from 05/2011‐03/2021, using statewide electronic health data. Nine policy and treatment changes were defined a priori. A Lowess curve evaluated treatment trends over time. Monthly screening and treatment rates were examined. Multivariable logistic regression explored predictors of treatment. The population (N = 10,336) was 13.4% Black, 51.8% was born after 1965 and 44.7% was Medicaid recipients. Inflections in the Lowess curve defined four periods: (1) Interferon + DAA, (2) early direct‐acting antivirals, (3) Medicaid expansion/optimization and (4) Medicaid restrictions (fibrosis/prescriber) removed. The largest increase in monthly treatment rates was during period 4, when Medicaid prescriber and fibrosis restrictions were removed (2.4 persons per month [PPM] in period 1 to 72.3 PPM in period 4, p < 0.001; 78.0% change in slope). Multivariable logistic regression analysis showed being born after 1965 (vs. before 1945; OR 0.69; 95% 0.49–0.98) and having Medicaid (vs. private insurance; OR 0.47; 95% CI 0.42–0.53), but not race was associated with lower odds of being treated. In conclusion, DAAs had limited impact on HCV treatment rates until Medicaid restrictions were removed. Additional policies may be needed to address HCV treatment‐related age and insurance disparities. [ABSTRACT FROM AUTHOR]

The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model. Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case. Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients. Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis. The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty. [Display omitted] • The value of liver biopsy in DILI is unclear. • We performed a review of 50 patients with early liver biopsy performed in the work up for DILI. • Causality was assessed before and after expert hepatopathology review. • Liver histology review changed the causality score in 68% of patients. • Biopsy clarified the diagnosis of DILI in cholestatic or equivocal cases. [ABSTRACT FROM AUTHOR]

Uromodulin [Tamm-Horsfall protein (THP)] is a glycoprotein uniquely produced in the kidney. It is released by cells of the thick ascending limbs apically in the urine and basolaterally in the renal interstitium and systemic circulation. Processing of mature urinary THP, which polymerizes into supramolecular filaments, requires cleavage of an external hydrophobic patch (EHP) at the COOH-terminus. However, THP in the circulation is not polymerized, and it remains unclear if nonaggregated forms of THP exist natively in the urine. We propose that an alternative processing path, which retains the EHP domain, can lead to a nonpolymerizing form of THP. We generated an antibody that specifically recognizes THP with retained EHP (THP þ EHP) and established its presence in the urine in a nonpolymerized native state. Proteomic characterization of urinary THP þ EHP revealed its COOHterminus ending at F617. In the human kidney, THP þ EHP was detected in thick ascending limb cells and less strongly in the renal parenchyma. Using immunoprecipitation followed by proteomic sequencing and immunoblot analysis, we then demonstrated that serum THP has also retained EHP. In a small cohort of patients at risk for acute kidney injury, admission urinary THP þ EHP was significantly lower in patients who subsequently developed acute kidney injury during hospitalization. Our findings uncover novel insights into uromodulin biology by establishing the presence of an alternative path for cellular processing, which could explain the release of nonpolymerizing THP in the circulation. Larger studies are needed to establish the utility of urinary THP þ EHP as a sensitive biomarker of kidney health and susceptibility to injury. [ABSTRACT FROM AUTHOR]

Background & Aims: Guidelines recommend albumin as the plasma‐expander of choice for acute kidney injury (AKI) in cirrhosis. However, the impact of these recommendations on patient outcomes remains unclear. We aimed to determine the practice‐patterns and outcomes associated with albumin use in a large, nationwide‐US cohort of hospitalized cirrhotics with AKI. Methods: A retrospective cohort study was performed in hospitalized cirrhotics with AKI using Cerner‐Health‐Facts database from January 2009 to March 2018. 6786 were included for analysis on albumin‐practice‐patterns, and 4126 had available outcomes data. Propensity‐score‐adjusted model was used to determine the association between albumin use, AKI‐recovery and in‐hospital survival. Results: Median age was 61‐years (60% male, 70% white), median serum‐creatinine was 1.8 mg/dL and median Model for End‐stage Liver Disease Sodium (MELD‐Na) score was 24. Albumin was given to 35% of patients, of which 50% received albumin within 48‐hours of AKI‐onset, and 17% received appropriate weight‐based dosing. Albumin was used more frequently in patients with advanced complications of cirrhosis, higher MELD‐Na scores and patients admitted to urban‐teaching hospitals. After propensity‐matching and multivariable adjustment, albumin use was not associated with AKI‐recovery (odds ratio [OR] 0.70, 95% confidence‐interval [CI]: 0.59‐1.07, P =.130) or in‐hospital survival (OR 0.76 [95% CI: 0.46‐1.25], P =.280), compared with crystalloids. Findings were unchanged in subgroup analyses of patients with varying cirrhosis complications and disease severity. Conclusions: USA hospitalized patients with cirrhosis and AKI frequently do not receive intravenous albumin, and albumin use was not associated with improved clinical outcomes. Prospective randomised trials are direly needed to evaluate the impact of albumin in cirrhotics with AKI. [ABSTRACT FROM AUTHOR]

Background and Aims: Natural history and outcomes data in PSC are mostly derived from cohorts where Blacks have been underrepresented. It is unknown if there are differences in mortality between Blacks and Whites with PSC. Methods: PSC patients seen at our institution from June 1988 to Jan 2019 were identified by merging prospective ERCP hepatology‐clinic databases and liver‐transplant registry. Data on race, clinical events, and death was obtained through chart review. Data on community health were collected using indices from county health rankings. Cumulative incidence of death was calculated using liver transplant (LT) as a competing risk. Results: Of 449 patients, 404 were White and 45 were Black. The median‐duration of follow‐up was 7 years (IQR:3, 13). Black patients were younger at presentation than White patients (36.3 vs 42.5 years., P =.013). Disease severity as indicated by Mayo Risk Score categories (low 27% vs 31%, intermediate 54% vs 49% and high 19% vs 19%, P =.690), comorbidity burden and frequency of cirrhosis (42% vs 35%, P =.411) were similar between Blacks and Whites. Cumulative incidence of liver‐related death, with LT as a competing risk was significantly higher in Blacks compared to Whites (sHR 1.80, 95%CI 1.25, 2.61, P =.002). There was a significant interaction between race and community socioeconomic factors that attenuated the racial difference in mortality (sHR 1.01, 95%CI 0.99, 1.04, P =.345). Conclusions: Blacks with PSC present at a younger age with a similar disease severity as Whites but have higher liver related mortality that is mediated in part through community health. [ABSTRACT FROM AUTHOR]

Patients with cirrhosis and significant coronary artery disease (CAD) are at risk of peri-liver transplantation (LT) cardiac events. The coronary artery disease in liver transplantation (CAD-LT) score and algorithm aim to predict the risk of significant CAD in LT candidates and guide pre-LT cardiac evaluation. Patients who underwent pre-LT evaluation at Indiana University (2010-2019) were studied retrospectively. Stress echocardiography (SE) and cardiac catheterization (CATH) reports were reviewed. CATH was performed for predefined CAD risk factors, irrespective of normal SE. Significant CAD was defined as CAD requiring percutaneous or surgical intervention. A multivariate regression model was constructed to assess risk factors. Receiver-operating curve analysis was used to compute a point-based risk score and a stratified testing algorithm. A total of 1,771 pre-LT patients underwent cardiac evaluation, including results from 1,634 SE and 1,266 CATH assessments. Risk-adjusted predictors of significant CAD at CATH were older age (adjusted odds ratio 1.05; 95% CI 1.03–1.08), male sex (1.69; 1.16–2.50), diabetes (1.57; 1.12–2.22), hypertension (1.61; 1.14–2.28), tobacco use (pack years) (1.01; 1.00–1.02), family history of CAD (1.63; 1.16–2.28), and personal history of CAD (6.55; 4.33–9.90). The CAD-LT score stratified significant CAD risk as low (≤2%), intermediate (3% to 9%), and high (≥10%). Among patients who underwent CATH, a risk-based testing algorithm (low: no testing; intermediate: non-invasive testing vs. CATH; high: CATH) would have identified 97% of all significant CAD and potentially avoided unnecessary testing (669 SE [57%] and 561 CATH [44%]). The CAD-LT score and algorithm (available at www.cad-lt.com) effectively stratify pre-LT risk for significant CAD. This may guide more targeted testing of candidates with fewer tests and faster time to waitlist. The coronary artery disease in liver transplantation (CAD-LT) score and algorithm effectively stratify patients based on their risk of significant coronary artery disease. The CAD-LT algorithm can be used to guide a more targeted cardiac evaluation prior to liver transplantation. [Display omitted] • CAD-LT score guides preoperative evaluation process for liver transplantation. • Score predicts risk of significant coronary artery disease in transplant candidates. • Score is an easy-to-use clinical tool; can be employed in an office-based setting. • Algorithm detects significant coronary artery disease with high sensitivity (97%). • Algorithm provides a cost-effective approach to preoperative cardiac evaluation. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Esophageal varices are a well-characterized sequela of portal hypertension; however, less is known about varices arising in ectopic locations. We aimed to describe bleeding small intestine varices (SIV) in patients with cirrhosis and compare characteristics and outcomes to published case reports. METHODS: We performed an institutional chart review using billing codes and natural language processing between 2008 and 2019. Inclusion criteriawere adult patients with cirrhosis and SIV verified by endoscopy, video capsule, or imaging. Patientswith noncirrhotic portal hypertension and stomal varices were excluded. We examined demographic and clinical factors, characteristics of SIV, bleeding, intervention, and outcomes in our series and collated data from published cases identified during a literature review. RESULTS: We identified 71 patients with cirrhosis and SIV (18 bled). The literature search yielded 76 cases with bleeding SIV. Our series and published cases were matched for age, sex, liver disease etiology, and SIV location. Length of stay and transfusion requirementswere similar. Aggregate initial treatments (number, hemostasis rate) included medical (n = 7, 57%), endoscopic (n = 48, 56%), interventional radiology (n = 31, 77%), and surgery (n = 8, 87%). Hospital and overall mortality rates were higher in our series (22% and 38%) compared with the published cases (5.3% and 18.4%), respectively (P = 0.02 and P = 0.07). DISCUSSION: A quarter of patients with cirrhosis and SIV experience bleeding, with high transfusion requirements, frequent need for secondary interventions, and high mortality. These findings highlight the need for a multidisciplinary approach and second-line therapeutic modalities in the timely management of bleeding SIV in cirrhosis. [ABSTRACT FROM AUTHOR]

Introduction: Thromboelastography (TEG) provides a global assessment of hemostasis and may have value for patients with cirrhosis who have multiple hemostatic defects. We sought to examine the characteristics of TEG in hospitalized patients with cirrhosis and its relationship with outcomes.Methods: We performed a cohort study of all adults with cirrhosis hospitalized at Indiana University Hospital between November 2015 and October 2018 with a TEG. We examined the relationships among TEG, traditional measures of hemostasis, liver disease severity, and outcomes, including mortality, discharge to hospice, length of stay, and 30-day readmission.Results: A total of 344 patients met inclusion and exclusion criteria. R-value was elevated (≥10 min) in 4.5%, alpha angle was low (<45°) in 9.3%, and maximum amplitude (maximum amplitude) was low (<55 mm) in 72.1%. K-value, alpha angle, and maximum amplitude were all correlated with both platelet count and fibrinogen (absolute rho range 0.52-0.67); R-value and international normalized ratio (INR) were not strongly correlated with traditional measures or TEG, respectively. Patients with bleeding had hypercoagulable profiles, and patients with infection had increased R-value and decreased alpha angle. A total of 35.8% died or were discharged to hospice, and these patients had a greater R-value and smaller alpha angle. However, after adjustment for model for end-stage liver disease (MELD), neither R-value nor alpha angle were associated with discharge outcomes.Conclusions: TEG provides insight into the hemostatic state of patients with cirrhosis beyond that of standard measures of hemostasis. It is associated with liver disease severity and outcomes and may play a role complementary to standard measures of hemostasis in this population. [ABSTRACT FROM AUTHOR]

Background and Aims: Traditional laboratory markers are insensitive in distinguishing between patients with acute liver failure (ALF) who will require urgent liver transplantation (LT) from those who will recover spontaneously, particularly within 24 h of presentation. Coagulation factor-V (FV) may improve the accuracy of outcome prediction in ALF due to its predominant synthesis in the liver and short half-life in plasma. Methods: Patients enrolled in the ALF Study Group Registry from a single site had FV determined within 24 h of presentation (Derivation-Cohort). Area under the receiver operating characteristic curves (AUROC) dichotomized by ALF etiology [acetaminophen (APAP) or non-APAP] were constructed to evaluate the diagnostic performance of FV for transplant-free-survival (TFS). Multivariate logistic regression modeling was performed using FV and other clinical variables to predict TFS. Accuracy of FV and multivariable model were performed in a Validation-Cohort from a different site. Results: 90-patients (56% with APAP) were included in the Derivation-Cohort. Median FV was significantly higher in TFS versus those who died/LT (31% vs. 15%, respectively; p = 0.001). When dichotomized by etiology, AUROC for FV was 0.77 for APAP (cutoff, sensitivity, specificity 10.5%, 79%, 69%, respectively) and 0.77 for non-APAP (22%, 85%, 67%, respectively). When the optimal cutoffs for FV in the Derivation-Cohort were applied to the Validation-Cohort (N = 51; 59% with APAP), AUROC for FV was 0.75 for APAP (sensitivity/specificity 81/44) and 0.95 for non-APAP (sensitivity/specificity 90/73). In multivariate analyses, AUROC for FV model was 0.86 in the Derivation-Cohort and 0.90 in the Validation-Cohort. Conclusion: Admission FV may improve selection of patients who are likely to improve without LT. [ABSTRACT FROM AUTHOR]

Background and Aims: The nature and outcomes of infection among patients with cirrhosis in safety-net hospitals are not well described. We aimed to characterize the rate of and risk factors for infection, both present on admission and nosocomial, in this unique population. We hypothesized that infections would be associated with adverse outcomes such as short-term mortality.Methods: We used descriptive statistics to characterize infections within a retrospective cohort characterized previously. We used multivariable logistic regression models to assess potential risk factors for infection and associations with key outcomes such as short-term mortality and length of stay.Results: The study cohort of 1112 patients included 33% women with a mean age of 56 ± 10 years. Infections were common (20%), with respiratory and urinary tract infections the most frequent. We did not observe a difference in the incidence of infection on admission based on patient demographic factors such as race/ethnicity or estimated household income. Infections on admission were associated with greater short-term mortality (12% vs 4% in-hospital and 14% vs 7% 30-day), longer length of stay (6 vs 3 days), intensive care unit admission (28% vs 18%), and acute-on-chronic liver failure (10% vs 2%) (p < 0.01 for all). Nosocomial infections were relatively uncommon (4%), but more frequent among patients admitted to the intensive care unit. Antibiotic resistance was common (38%), but not associated with negative outcomes.Conclusion: We did not identify demographic risk factors for infection, but did confirm its morbid effect among patients with cirrhosis in safety-net hospitals. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a significant clinical event in cirrhosis yet contemporary population-based studies on the impact of AKI on hospitalized cirrhotics are lacking. We aimed to characterize longitudinal trends in incidence, healthcare burden and outcomes of hospitalized cirrhotics with and without AKI using a nationally representative dataset. Using the 2004–2016 National Inpatient Sample (NIS), admissions for cirrhosis with and without AKI were identified using ICD-9 and ICD-10 codes. Regression analysis was used to analyze the trends in hospitalizations, costs, length of stay and inpatient mortality. Descriptive statistics, simple and multivariable logistic regression were used to assess associations between individual characteristics, comorbidities, and cirrhosis complications with AKI and death. In over 3.6 million admissions for cirrhosis, 22% had AKI. AKI admissions were more costly (median $13,127 [IQR $7,367–$24,891] vs. $8,079 [IQR $4,956–$13,693]) and longer (median 6 [IQR 3–11] days vs. 4 [IQR 2–7] days). Over time, AKI prevalence doubled from 15% in 2004 to 30% in 2016. CKD was independently and strongly associated with AKI (adjusted odds ratio 3.75; 95% CI 3.72–3.77). Importantly, AKI admissions were 3.75 times more likely to result in death (adjusted odds ratio 3.75; 95% CI 3.71–3.79) and presence of AKI increased risk of mortality in key subgroups of cirrhosis, such as those with infections and portal hypertension-related complications. The prevalence of AKI is significantly increased among hospitalized cirrhotics. AKI substantially increases the healthcare burden associated with cirrhosis. Despite advances in cirrhosis care, a significant gap remains in outcomes between cirrhotics with and without AKI, suggesting that AKI continues to represent a major clinical challenge. Sudden damage to the kidneys is becoming more common in people who are hospitalized and have cirrhosis. Despite advances in cirrhosis care, those with damage to the kidneys remain at higher risk of dying. • Of an estimated 3.6 million US cirrhosis admissions, 22% had acute kidney injury. • Over time, acute kidney injury prevalence has doubled. • Acute kidney injury admissions were costlier than admissions without the condition. • Chronic kidney disease is strongly associated with acute kidney injury. • Chances of dying were higher for those with acute kidney injury. [ABSTRACT FROM AUTHOR]

INTRODUCTION: With increasing burden of obesity and liver disease in the United States, a better understanding of bariatric surgery in context of cirrhosis is needed. We described trends of hospital-based outcomes of bariatric surgery among cirrhotics and determined effect of volume status and type of surgery on these outcomes. METHODS: In this population-based study, admissions for bariatric surgery were extracted from the National Inpatient Sample using International Classification of Diseases, 9th and 10th Revision, Clinical Modification codes from 2004 to 2016 and grouped by cirrhosis status, type of bariatric surgery, and center volume. In-hospital mortality, complications, and their trends were compared between these groups using weighted counts, odds ratios [ORs], and logistic regression. RESULTS: Among 1,679,828 admissions for bariatric surgery, 9,802 (0.58%) had cirrhosis. Cirrhosis admissions were more likely to be in white men, had higher Elixhauser Index, and higher in-hospital complications rates including death (1.81%vs 0.17%), acute kidney injury (4.5%vs 1.2%), bleeding (2.9%vs 1.1%), and operative complications (2% vs 0.6%) (P < 0.001 for all) compared to those without cirrhosis. Overtime, restrictive surgeries have grown in number (12%-71%) and complications rates have trended down in both groups. Cirrhotics undergoing bariatric surgery at low-volume centers (<50 procedures per year) and nonrestrictive surgery had a higher inpatient mortality rate (adjusted OR 4.50, 95%confidence interval 3.14-6.45, adjusted OR 4.00, 95% confidence interval 2.68-5.97, respectively). DISCUSSION: Contemporary data indicate that among admissions for bariatric surgery, there is a shift to restrictivetype surgeries with an improvement in-hospital complications and mortality. However, patients with cirrhosis especially those at low-volume centers have significantly higher risk of worse outcomes (see Visual abstract, Supplementary Digital Content, http://links.lww.com/AJG/B648). [ABSTRACT FROM AUTHOR]

INTRODUCTION: In patients with cirrhosis, differences between acute kidney injury (AKI) at the time of hospital admission (community-acquired) and AKI occurring during hospitalization (hospital-acquired) have not been explored. We aimed to compare patients with hospital-acquired AKI (H-AKI) and communityacquired AKI (C-AKI) in a large, prospective study. METHODS: Hospitalized patients with cirrhosis were enrolled (N 5 519) and were followed for 90 days after discharge for mortality. The primary outcome was mortality within 90 days; secondary outcomes were the development of de novo chronic kidney disease (CKD)/progression of CKD after 90 days. Cox proportional hazards and logistic regressions were used to determine the independent association of either AKI for primary and secondary outcomes, respectively. RESULTS: H-AKI occurred in 10%, and C-AKI occurred in 25%. In multivariable Cox models adjusting for significant confounders, only patients with C-AKI had a higher risk for mortality adjusting for model for end-stage liver disease-Na: (hazard ratio 1.64, 95% confidence interval [CI] 1.04-2.57, P 5 0.033) and adjusting for acute on chronic liver failure: (hazard ratio 2.44, 95% CI 1.63-3.65, P < 0.001). In univariable analysis, community-acquired-AKI, but not hospital-acquired-AKI, was associated with de novo CKD/progression of CKD (odds ratio 2.13,95%CI 1.09-4.14, P50.027), but in multivariable analysis, C-AKI was not independently associated with de novo CKD/progression of CKD. However, when AKI was dichotomized by stage, C-AKI stage 3 was independently associated with de novo CKD/progression of CKD (odds ratio 4.79, 95% CI 1.11-20.57, P 5 0.035). DISCUSSION: Compared with H-AKI, C-AKI is associated with increased mortality and de novo CKD/progression of CKD in patients with cirrhosis. Patients with C-AKI may benefit from frequent monitoring after discharge to improve outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Mean arterial pressure is critically important in patients with cirrhosis in the ICU, however, there is limited data to guide therapies and targets.Design: Retrospective observational study.Setting: Tertiary care ICU.Patients: Two hundred and seventy-three critically ill patients with cirrhosis.Interventions: None.Measurements and Main Results: We performed a comprehensive time-weighted mean arterial pressure analysis (time-weighted-average-mean arterial pressure and cumulative-time-below various mean arterial pressure-thresholds) during the first 24-hours after ICU admission (median: 25 mean arterial pressure measurements per-patient). Time-weighted-average-mean arterial pressure captures both the severity and duration of hypotension below a mean arterial pressure threshold and cumulative-time-below is the total time spent below a mean arterial pressure threshold. Individual univariable and multivariable logistic regression models were assessed for each time-weighted-average-mean arterial pressure and cumulative-time-below mean arterial pressure threshold (55, 60, 65, 70, and 75 mm Hg) for ICU-mortality. Time-weighted-average-mean arterial pressure: for 1 mm Hg decrease in mean arterial pressure below 75, 70, 65, 60, and 55 mm Hg, the odds for ICU-mortality were 14%, 18%, 26%, 41%, and 74%, respectively (p < 0.01, all thresholds). The association between time-weighted-average-mean arterial pressure and ICU-mortality for each threshold remained significant after adjusting for model for end-stage liver disease-sodium score, mechanical ventilation, vasopressor use, renal replacement therapy, grade 3/4 hepatic encephalopathy, WBC count, and albumin. Cumulative-time-below: odds for ICU-mortality were 4%, 6%, 10%, 12%, and 12% for each-hour spent below 75, 70, 65, 60, and 55 mm Hg, respectively. In the adjusted models, significant associations only remained for mean arterial pressure less than 65 mm Hg (odds ratio, 1.07; 95% CI, 1.00-1.14; p = 0.05) and < 60 mm Hg (odds ratio, 1.10; 95% CI, 1.01-1.18; p = 0.04).Conclusions: These data suggest that maintaining a mean arterial pressure of greater than 65 mm Hg may be a reasonable target in patients with cirrhosis admitted to the ICU. However, further prospective randomized trials are needed to determine the optimal mean arterial pressure-targets in this patient population. [ABSTRACT FROM AUTHOR]

Objectives: Mean arterial pressure is critically important in patients with cirrhosis in the ICU, however, there is limited data to guide therapies and targets. Design: Retrospective observational study. Setting: Tertiary care ICU. Patients: Two hundred and seventy-three critically ill patients with cirrhosis. Interventions: None. Measurements and Main Results: We performed a comprehensive time-weighted mean arterial pressure analysis (time-weighted-average-mean arterial pressure and cumulative-time-below various mean arterial pressure-thresholds) during the first 24-hours after ICU admission (median: 25 mean arterial pressure measurements per-patient). Time-weighted-average-mean arterial pressure captures both the severity and duration of hypotension below a mean arterial pressure threshold and cumulative-time-below is the total time spent below a mean arterial pressure threshold. Individual univariable and multivariable logistic regression models were assessed for each time-weighted-average-mean arterial pressure and cumulative-time-below mean arterial pressure threshold (55, 60, 65, 70, and 75 mm Hg) for ICU-mortality. Time-weighted-average-mean arterial pressure: for 1 mm Hg decrease in mean arterial pressure below 75, 70, 65, 60, and 55 mm Hg, the odds for ICU-mortality were 14%, 18%, 26%, 41%, and 74%, respectively (p < 0.01, all thresholds). The association between time-weighted-average-mean arterial pressure and ICU-mortality for each threshold remained significant after adjusting for model for end-stage liver disease--sodium score, mechanical ventilation, vasopressor use, renal replacement therapy, grade 3/4 hepatic encephalopathy, WBC count, and albumin. Cumulative-time-below: odds for ICU-mortality were 4%, 6%, 10%, 12%, and 12% for each-hour spent below 75, 70, 65, 60, and 55 mm Hg, respectively. In the adjusted models, significant associations only remained for mean arterial pressure less than 65 mm Hg (odds ratio, 1.07; 95% CI, 1.00-1.14; p = 0.05) and < 60 mm Hg (odds ratio, 1.10; 95% CI, 1.01-1.18; p = 0.04). Conclusions: These data suggest that maintaining a mean arterial pressure of greater than 65 mm Hg may be a reasonable target in patients with cirrhosis admitted to the ICU. However, further prospective randomized trials are needed to determine the optimal mean arterial pressure-targets in this patient population. [ABSTRACT FROM AUTHOR]

Background: Palliative care (PC) and hospice care are underutilized for patients with end-stage liver disease, but factors associated with these patterns of utilization are not well understood. Objective: We examined patient-level factors associated with both PC and hospice referrals in patients with decompensated cirrhosis (DC). Design: Retrospective cohort study. Setting/Subjects: Patients with DC hospitalized at a single tertiary center and followed for one year. Measurements: We assessed PC and hospice referrals during follow-up and examined patient-level factors associated with the receipt of PC and/or hospice, as well as associated clinical outcomes. We also examined late referrals (within one week of death). Results: Of 397 patients, 61 (15.4%) were referred to PC, 71 (17.9%) were referred to hospice, and 99 (24.9%) were referred to PC and/or hospice. Two hundred patients (50.4%) died during the one-year follow-up. In multivariable logistic regression, referral to PC was associated with increased comorbidity burden, ascites, increased MELD (Model for End-Stage Liver Disease)-Na score, lack of listing for liver transplant, and unmarried status. Hospice referral was associated with increased comorbidities, portal vein thrombosis, and hepatocellular carcinoma. PC referrals were late in 68.5% of cases, and hospice referrals were late in 62.7%. Late PC referrals were associated with younger age and married status. Late hospice referrals were associated with younger age and recent alcohol use. Conclusions: PC and hospice is underutilized in patients with DC, and most referrals are late. Patient-level factors associated with these referrals differ between PC and hospice. [ABSTRACT FROM AUTHOR]

Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis. We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (−0.21, −0.45, −0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n = 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p = 0.06), the decrease being greater in those with higher baseline HVPG (p = 0.018), with a significant interaction between baseline HVPG (continuous, p = 0.024; dichotomous at 16 mmHg [median], p = 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups. Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated. Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients. Clinical Trials.gov # NCT02960204. • Phase III trial comparing emricasan vs. placebo in patients with NASH-related cirrhosis and severe portal hypertension. • Despite evidence of target engagement, emricasan did not reduce portal hypertension in the overall study population. • The portal pressure-reducing effect may be more evident in latter stages of portal hypertension. • Treatment-emergent adverse events were similar between emricasan and placebo. [ABSTRACT FROM AUTHOR]

Background & Aims: Ashwagandha (Withania somnifera) is widely used in Indian Ayurvedic medicine. Several dietary supplements containing ashwagandha are marketed in the US and Europe, but only one case of drug‐induced liver injury (DILI) due to ashwagandha has been published. The aim of this case series was to describe the clinical phenotype of suspected ashwagandha‐induced liver injury. Methods: Five cases of liver injury attributed to ashwagandha‐containing supplements were identified; three were collected in Iceland during 2017‐2018 and two from the Drug‐Induced Liver Injury Network (DILIN) in 2016. Other causes for liver injury were excluded. Causality was assessed using the DILIN structured expert opinion causality approach. Results: Among the five patients, three were males; mean age was 43 years (range 21‐62). All patients developed jaundice and symptoms such as nausea, lethargy, pruritus and abdominal discomfort after a latency of 2‐12 weeks. Liver injury was cholestatic or mixed (R ratios 1.4‐3.3). Pruritus and hyperbilirubinaemia were prolonged (5‐20 weeks). No patient developed hepatic failure. Liver tests normalized within 1‐5 months in four patients. One patient was lost to follow‐up. One biopsy was performed, showing acute cholestatic hepatitis. Chemical analysis confirmed ashwagandha in available supplements; no other toxic compounds were identified. No patient was taking potentially hepatotoxic prescription medications, although four were consuming additional supplements, and in one case, rhodiola was a possible causative agent along with ashwagandha. Conclusions: These cases illustrate the hepatotoxic potential of ashwagandha. Liver injury is typically cholestatic or mixed with severe jaundice and pruritus, but self‐limited with liver tests normalizing in 1‐5 months. [ABSTRACT FROM AUTHOR]

Background: Recent evidence cautions against the use of non-selective beta-blockers (NSBB) in patients with refractory ascites or spontaneous bacterial peritonitis while other data suggests a survival benefit in patients with advanced liver disease. The aim of this study was to describe the use and impact of NSBB in patients with cirrhosis referred for liver transplantation.Methods: A single-center cohort of patients with cirrhosis, who were referred and evaluated for liver transplantation between January and June 2012 were studied for baseline characteristics and clinical outcomes. Patients were grouped according to the use of NSBB at initial evaluation, with the endpoint of 90-day mortality.Results: Sixty-five (38%) of 170 consecutive patients evaluated for liver transplantation were taking NSBB. Patients taking NSBB had higher MELD and Child Pugh score. NSBB use was associated with lower 90-day mortality (6% vs. 15%) with a risk adjusted hazard ratio of 0.27 (95%CI .09-0.88, p = .03). Patients taking NSBB developed acute kidney injury (AKI) within 90 days more frequently than patients not taking NSBB (22% vs 11%), p = 0.048). However, this was related to increased stage 1 AKI episodes, all of which resolved. Twelve (27%) of 45 patients with > 90 day follow up discontinued NSBB, most commonly for hypotension and AKI, had increased subsequent MELD and mortality.Conclusions: NSBB use in patients with cirrhosis undergoing liver transplant evaluation is associated with better short-term survival. Nevertheless, ongoing tolerance of NSBB in this population is dynamic and may select a subset of patients with better hemodynamic reserve. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a common complication in hospitalized patients with cirrhosis. Uromodulin, a protein uniquely produced by the kidney and released both in the urine and circulation, has been shown to regulate AKI and is linked to tubular reserve. Although low levels of urine uromodulin are associated with AKI after cardiac surgery, it is unclear whether circulating uromodulin can stratify the risk of AKI, particularly in a susceptible population such as hospitalized patients with cirrhosis. Thus, we investigated whether plasma uromodulin measured at the time of admission is associated with subsequent hospital-acquired AKI (defined by a rise in serum creatinine >0.3mg/dL within 48 h or ≥ 1.5 times baseline) in patients with cirrhosis. A total of 98 patients [mean age 54 yr, Model for Endstage Liver Disease Sodium (MELD-Na) score 19, and baseline creatinine of 0.95 mg/dL] were included, of which 13% (n = 13) developed AKI. Median uromodulin levels were significantly lower in patients who developed AKI compared with patients who did not (9.30 vs. 13.35 ng/mL, P = 0.02). After adjusting for age, sex, diabetes, hypertension, albumin, and MELD-Na score as covariates on multivariable logistic regression, uromodulin was independently associated with AKI [odd ratios of 1.19 (95% confidence interval 1.02, 1.37; P = 0.02)]. Lower uromodulin levels on admission are associated with increased odds of subsequent AKI in hospitalized patients with cirrhosis. Further studies are needed to better understand the role of uromodulin in the pathogenesis and as a predictive biomarker of AKI in this population. NEW & NOTEWORTHY In this study, we found that admission plasma uromodulin levels are significantly lower in patients who developed subsequent acute kidney injury (AKI) during their hospital stay compared with patients who did not. Additionally, uromodulin is independently associated with AKI development after adjusting for clinically relevant parameters such as age, sex, diabetes, hypertension, severity of cirrhosis, and kidney function. To our knowledge, this is the first study linking plasma uromodulin with AKI development in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Background: The measurement of liver volume (LV) is considered to be an effective prognosticator for postoperative liver failure in patients undergoing hepatectomy. It is unclear whether LV can be used to predict mortality in cirrhotic patients. Methods: We enrolled 584 consecutive cirrhotic patients who underwent computerized topography (CT) of the abdomen for hepatocellular carcinoma surveillance and 50 age, gender, race, and BMI-matched controls without liver disease. Total LV (TLV), functional LV (FLV), and segmental liver volume (in cm3) were measured from CT imaging. Cirrhotic subjects were followed until death, liver transplantation, or study closure date of July 31, 2016. The survival data were assessed with log-rank statistics and independent predictors of survival were performed using Cox hazards model. Results: Cirrhotic subjects had significantly lower TLV, FLV, and segmental (all except for segments 1, 6, 7) volume when compared to controls. Subjects presenting with hepatic encephalopathy had significantly lower TLV and FLV than those without HE (p = 0.002). During the median follow-up of 1145 days, 112 (19%) subjects were transplanted and 131 (23%) died. TLV and FLV for those who survived were significantly higher than those who were transplanted or dead (TLV:1740 vs. 1529 vs. 1486, FLV 1691 vs. 1487 vs. 1444, p < 0.0001). In the Cox regression model, age, MELD score, TLV, or FLV were independent predictors of mortality. Conclusion: Baseline liver volume is an independent predictor of mortality in subjects with cirrhosis. Therefore, it may be useful to provide these data while performing routine surveillance CT scan as an important added value. Further studies are needed to validate these findings and to better understand their clinical utility. [ABSTRACT FROM AUTHOR]

Summary: Background: Metformin may protect against hepatocellular carcinoma and mortality among patients with type 2 diabetes. Aim: To investigate whether long‐term use of metformin improves survival and reduces liver‐related outcomes among patients with type 2 diabetes and non‐alcoholic steatohepatitis. Methods: A total of 191 diabetic patients with biopsy‐proven non‐alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis were retrospectively identified at Indiana University Medical Center between October 2004 and January 2016. Of them, 110 were users and 81 never‐users of metformin. Primary outcomes were transplant‐free survival, development of hepatocellular carcinoma or a first event of hepatic decompensation. Results: Cirrhosis was present in 85% of metformin users and 88% of nonusers. Metformin dose was greater than or equal to 1 g/d in 104 out of 110 users and its median duration of use was 6 (95% CI: 4.4‐7.9) years. The mean follow‐up was 6.92 and 6.80 years for metformin users and non‐users, respectively. During follow‐up, 28 patients developed hepatocellular carcinoma (metformin users: 7, nonusers: 21), and 52 died (metformin users: 7, nonusers: 24) or were transplanted (metformin users: 13, non‐users: 13). Metformin use was associated with lower risk of overall mortality or transplant (HR: 0.42; 95% CI: 0.24‐0.74, P = 0.003) and hepatocellular carcinoma (sHR: 0.25; 95% CI: 0.11‐0.58, P = 0.001), and remained independently associated with both outcomes after propensity‐score and covariate‐adjusted analyses. No instances of hepatotoxicity or lactic acidosis were observed. Conclusion: Our study demonstrated an association between long‐term metformin use and reduced the risk of all‐cause mortality/transplant and hepatocellular carcinoma in diabetics with non‐alcoholic steatohepatitis and advanced fibrosis. [ABSTRACT FROM AUTHOR]

Background: Endoscopic injection of cyanoacrylate into gastric varices may be performed by EUS-guided fine needle injection (EUS-FNI) or direct endoscopic injection (DEI). The aim of this study is to compare the rate of recurrent GV bleeding and adverse events between DEI and EUS-FNI for treatment of GV.Methods: In a single-center study, a retrospective cohort of patients with actively/recently bleeding or high-risk GV treated with DEI were compared with a prospective cohort of similar patients treated with EUS-FNI. Repeat endoscopy after index treatment was performed 3 months later or earlier if rebleeding occurred. The main outcomes assessed were rates of GV or overall rebleeding and adverse events.Results: Forty patients (mean age 57.2 ± 9.1 years, 73% male) and 64 patients (mean age 58.0 ± 12.5 years, 52% male) underwent DEI and EUS-FNI, respectively. Compared to the DEI group, the frequency of isolated gastric varices type 1 (IGV1) were higher (p < 0.001) but MELD scores were lower (p = 0.004) in the EUS-FNI group. At index endoscopy, EUS-FNI utilized a lower mean volume of cyanoacrylate (2.0 ± 0.8 mL vs. 3.3 ± 1.3 mL; p < 0.001) and injected a greater number of varices (1.6 ± 0.7 vs. 1.1 ± 0.4; p < 0.001) compared to DEI. Overall, GV rebleeding [5/57 (8.8%) vs. 9/38 (23.7%); p = 0.045] and non-GV-related gastrointestinal bleeding [7/64 (10.9%) vs. 11/40 (27.5%); p = 0.030] were less frequent in the EUS-FNI group compared to the DEI group, respectively. Adverse event rates were similar (20.3% vs. 17.5%, p = 0.723).Conclusions: EUS-guided CYA injection of active or recently bleeding GV in patients with portal hypertension appears to decrease the rate of GV rebleeding despite injection of more varices and less CYA volume during the initial endoscopic procedure. Adverse events are similar between the two groups. EUS-FNI appears to be the preferred strategy for treatment of these patients. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is rare in patients with autoimmune hepatitis (AIH). However, the overall burden of AIH cirrhosis in causing HCC and patients' risk factors are not well understood.Aims: To characterize the proportion of HCC linked to AIH at a large academic health center, and to identify variables associated with HCC in patients with AIH in a case-control study design.Methods: Over a 14.5-year period, medical records of all patients with HCC were reviewed. Cases are AIH patients identified from the cohort, and controls are patients with AIH without HCC. Three controls were randomly chosen from the Genetic Repository of Autoimmune Liver Disease and Coexisting Exposures database for each eligible case.Results: Out of 1250 eligible patients, 20 were linked to AIH (1.6%). Their median age was 64 years, 40% men and 100% Caucasian. Ten percent of AIH patients did not have evidence of cirrhosis at HCC diagnosis. The proportion of HCCs due to AIH decreased during the time intervals of the study. Compared to controls, cases were more likely men (40.0% vs. 18%, p = 0.049), with longer AIH duration (median 16 years vs. 5 years, p = 0.004). Prolonged AIH duration (OR 1.68, p = 0.006) and older age (OR 1.15, p = 0.049) were risk factors for HCC.Conclusions: AIH is a rare cause (1.6%) for HCC in Midwestern USA with a decreasing trend over 14.5 years. Ten percent of AIH-HCC patients did not have cirrhosis at time of HCC diagnosis. Patients with prolonged duration of the disease and older age are at high risk to develop HCC. [ABSTRACT FROM AUTHOR]

Background: Safety-net hospitals provide care for racially/ethnically diverse and disadvantaged urban populations. Their hospitalized patients with cirrhosis are relatively understudied and may be vulnerable to poor outcomes and racial/ethnic disparities. Aims: To examine the outcomes of patients with cirrhosis hospitalized at regionally diverse safety-net hospitals and the impact of race/ethnicity. Methods: A study of patients with cirrhosis hospitalized at 4 safety-net hospitals in 2012 was conducted. Demographic, clinical factors, and outcomes were compared between centers and racial/ethnic groups. Study endpoints included mortality and 30-day readmission. Results: In 2012, 733 of 1,212 patients with cirrhosis were hospitalized for liver-related indications (median age 55 years, 65% male). The cohort was racially diverse (43% White, 25% black, 22% Hispanic, 3% Asian) with cirrhosis related to alcohol and viral hepatitis in 635 (87%) patients. Patients were hospitalized mainly for ascites (35%), hepatic encephalopathy (20%) and gastrointestinal bleeding (GIB) (17%). Fifty-four (7%) patients died during hospitalization and 145 (21%) survivors were readmitted within 30 days. Mortality rates ranged from 4 to 15% by center (p = .007) and from 3 to 10% by race/ethnicity (p = .03), but 30-day readmission rates were similar. Mortality was associated with Model for End-stage Liver Disease (MELD), acute-on-chronic liver failure, hepatocellular carcinoma, sodium and white blood cell count. Thirty-day readmission was associated with MELD and Charlson Comorbidity Index >4, with lower risk for GIB. We did not observe geographic or racial/ethnic differences in hospital outcomes in the risk-adjusted analysis. Conclusions: Hospital mortality and 30-day readmission in patients with cirrhosis at safety-net hospitals are associated with disease severity and comorbidities, with lower readmissions in patients admitted for GIB. Despite geographic and racial/ethnic differences in hospital mortality, these factors were not independently associated with mortality. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study is to describe the effect of a dedicated paracentesis clinic on healthcare utilization by patients with decompensated cirrhosis and refractory ascites.Methods: This Institutional Review Board-approved retrospective study identified cirrhotic patients receiving paracenteses over a 6-month period before and after creating the paracentesis clinic. Patients were followed for 12 months to collect outcome data including characteristics of subsequent hospitalizations and paracenteses. Logistic regression was used to examine the association between the paracentesis clinic and outcomes.Results: There were 183 patients and 1364 paracenteses performed during the study time period. Age, gender, cirrhosis etiology, MELD, Child-Pugh, and Charlson comorbidity index were comparable between the two groups. Rates of mortality, transplant, and hospitalization were also similar during 1 year follow-up. After establishment of the paracentesis clinic, median paracenteses per patient increased from 2 (IQR 1-7) to 4 (IQR 2-11) (P = 0.01); albumin replacement after paracenteses ≥ 5 L improved from 76.3% to 91.7% (P < 0.001); and the fraction of outpatient paracenteses performed in the emergency department decreased from 13.4% to 3.8% (P < 0.001). Major complications remained negligible at 0.81% across both time periods. While fewer patients were admitted for ascites after the paracentesis clinic (39.6% vs. 20.8%, P = 0.009), more patients had acute kidney injury (AKI) during follow-up (47.2% vs. 65.9%, P = 0.02), with a trend towards more AKI admissions (22.6% vs. 35.4%, P = 0.09).Conclusion: A dedicated paracentesis clinic can improve access and wait times, while also reducing admissions for ascites and paracenteses performed in the emergency department. [ABSTRACT FROM AUTHOR]

Background and Aim: Hepatocyte apoptosis or necrosis from accumulation of bile salts may play an important role in the disease progression of primary sclerosing cholangitis (PSC). The aim of the current study was to measure serum markers of hepatocyte apoptosis (cytokeratin-18 fragments--K18) and necrosis (high-mobility group protein B1--HMGB1) in adults with PSC and examine the relationship with disease severity.Methods: We measured serum levels of K18 and HMGB1 in well-phenotyped PSC (N = 37) and 39 control subjects (N = 39). Severity of PSC was assessed biochemically, histologically, and PSC Mayo risk score. Quantification of hepatocyte apoptosis was performed using TUNEL assay.Results: The mean age of the study cohort was 49.7 ± 13.3 years and comprised of 67% men and 93% Caucasian. Serum K18 levels were significantly higher in the PSC patients compared to control (217.4 ± 78.1 vs. 157.0 ± 58.2 U/L, p = 0.001). However, HMGB1 levels were not different between the two groups (5.38 ± 2.99 vs. 6.28 ± 2.85 ng/mL, p = 0.15). Within the PSC group, K18 levels significantly correlated with AST (r = 0.5, p = 0.002), alkaline phosphatase (r = 0.5, p = 0.001), total bilirubin (r = 0.61, p ≤ 0.001), and albumin (r = -0.4, p = 0.02). Serum K18 levels also correlated with the level of apoptosis present on the liver biopsy (r = 0.8, p ≤ 0.001) and Mayo risk score (r = 0.4, p = 0.015).Conclusion: Serum K18 but not HMGB1 levels were increased in PSC and associated with severity of underlying liver disease and the degree of hepatocyte apoptosis. [ABSTRACT FROM AUTHOR]

Aims: To determine whether the presence of portal vein thrombosis (PVT) where venous flow within the liver may be altered may delay the diagnosis of HCC and be associated with more advanced disease. We characterized the incidence and imaging characteristics of patients diagnosed with hepatocellular carcinoma in a cohort of patients with PVT compared with those without PVT. Methods: This is a single-center retrospective study of a subset of HCC patients who underwent dynamic imaging for HCC screening and were found to have PVT. Data abstracted included demographic data, TNM stage, number/type of scans, AFP level, MELD score, and time to diagnosis. Results: Eighty-two patients newly diagnosed with HCC on screening were reviewed, of which 37 % (30/82) were found to have portal vein thrombosis. Patients with PVT had higher rates of atypical imaging associated with HCC compared with those without PVT (83 vs 56 %, p = 0.01) and had lower rates of portal venous washout (23 % vs 50 %, p = 0.018). Patients with PVT and HCC were also diagnosed at later TNM stage than those without PVT (70 vs 23 %, p < 0.001) and were significantly less likely to receive orthotopic liver transplant (3.6 vs 42 %, p < 0.001). Fourteen patients had preexisting PV clot without HCC; 16 developed PVT during screening or at diagnosis. Those with preexisting PVT were older (63. vs 55 years) and had higher rates of diagnosis of HCC using MRI (79 vs 21 % with CT, p = 0.01), compared with those without preexisting PVT. Conclusion: The presence of PVT found on dynamic imaging was associated with advanced stage of HCC at the time of diagnosis. Clinicians should have a high suspicion for HCC diagnosis in new liver lesions with atypical enhancement in the setting of PVT. In this setting, MRI was more frequently associated with HCC diagnosis. [ABSTRACT FROM AUTHOR]

Background With the growing numbers of liver transplant recipients, it is increasingly important to understand the risks of de novo malignancy after liver transplantation. Aim To characterize the incidence of de novo malignancy after liver transplantation compared with a control non-transplant population. Methods We studied 534 Indiana state residents undergoing liver transplantation at our center between 1997 and 2004, followed through August 2010. The incidence and predictors of malignancy were determined. The standardized incidence ratio ( SIR) of cancer in our cohort was compared with age-, gender-, and period-matched state population using the Indiana State Cancer Registry. Results After a mean follow-up of 5.7 ± 3.2 yr, 73 patients (13.7%) developed 80 cancers, with five- and 10-yr incidence rates of 11.7% and 24.8%, respectively. These included 24 (30%) skin, 16 (20%) hematologic, and 40 (50%) solid tumors. The most common solid cancers were aerodigestive. Compared with matched state population, liver transplant recipients had significantly higher incidence of all cancers ( SIR: 3.1, 95% CI [Confidence interval]: 2.9-3.2), skin (melanoma) ( SIR: 5.8, 95% CI: 4.7-7.0), hematologic ( SIR: 7.1, 95% CI: 6.3-8.0), and solid ( SIR: 2.7, 95% CI: 2.5-2.8) tumors. Conclusion There is a significantly increased risk of de novo malignancies after liver transplantation, highlighting the need for surveillance strategies in this population. [ABSTRACT FROM AUTHOR]

Dickson RC, Pungpapong S, Keaveny AP, Taner BC, Ghabril M, Aranda-Michel J, Satyanarayana R, Bonatti H, Kramer DJ, Nguyen JH. Improving graft survival for patients undergoing liver transplantation. Clin Transplant 2011: 25: E345-E355. © 2011 John Wiley & Sons A/S. Liver transplant (LT) outcomes are reported to be improving in non-HCV recipients but not for those infected with HCV. Our aim was to evaluate graft survival and predictors of outcome in HCV and non-HCV patients before and after 2003. Patients with primary LT between February 1, 1998, and December 31, 2005, were included. Patients were divided into Era 1 (1998-2002) and Era 2 (2003-2005) with follow-up through May 31, 2009. Graft survival was compared for HCV, non-HCV, and all patients. There was significant improvement in graft survival in Era 2 for HCV patients. Graft survival in Era 2 of HCV patients was equivalent to non-HCV patients. The most significant improvement between eras was in outcomes of grafts from donors ≥60 yr with three-yr graft survival 58.6 (51.3-65.9) vs. 75.4 (68.9-81.9), p = 0.002. The use of donors ≥60 did not change between eras: 31% vs. 34%; however, utilization in HCV recipients decreased from 36% to 3% (p < 0.001). In conclusion, graft survival of HCV patients has improved significantly since 2003 and was comparable to non-HCV patients up to three yr. The change in management of donor organs into HCV and non-HCV patients likely contributed to this outcome. [ABSTRACT FROM AUTHOR]

OBJECTIVES:The etiology of eosinophilic esophagitis (EoE) is not well understood. It has been proposed that eosinophils migrate to the esophagus in response to various ingested and inhaled allergens. Recent reports in children found an increased proportion of cases of EoE during months with higher outdoor aeroallergens. To our knowledge, this has not been evaluated in adults. We aimed to determine whether there is a seasonal distribution in the number of newly diagnosed cases of EoE in an adult population.METHODS:We conducted a retrospective review of consecutive adult cases newly diagnosed with EoE in 1 year. Cases were grouped based on the index month when the diagnosis was made at endoscopy. To test the consistency of the observations, a second cohort of consecutive cases of similar sample size diagnosed at a different period in time was also analyzed.RESULTS:In total, 41 patients were diagnosed with EoE at our center during the study period, providing an annual prevalence of 0.98%. More cases were diagnosed with EoE during the months of April and May than any other month (P<0.001). When patients were grouped seasonally, there was a significant increase of EoE cases in spring and summer months (n=28) when compared with the fall and winter months (n=13) (P=0.019). Analysis of the second cohort of cases (n=37) from 2002 to 2006 confirmed a similar seasonal diagnostic pattern for EoE during the outdoor seasons.CONCLUSIONS:Our data demonstrate that EoE has a seasonal prevalence in adults. The seasonal variation pattern found in newly diagnosed EoE cases in adults supports the potential role of aeroallergens in the pathogenesis of EoE.Am J Gastroenterol 2009; 104:828–833; doi:10.1038/ajg.2008.169; published online 24 February 2009 [ABSTRACT FROM AUTHOR]

Background: Liver transplantation (LT) using grafts from anti-HBVcore antibody-positive (anti-HBVcAB+) donors carry risk for development of hepatitis B virus (HBV) infection. The long-term course of hepatitis C virus (HCV) patients receiving anti-HBVcAB+ grafts is poorly understood. Patients and methods: A patient with chronic hepatitis C received an anti-HBVc+ graft and developed de novo hepatitis B after four months. We describe the 14 HCV patients who received antiHBVc+ grafts and the condition of disease. Results: Hepatitis B was treated successfully with lamivudine. One year later, breakthrough infection developed with a lamivudine-resistant mutant. Addition of adefovir led to HBV surface antigen to surface antibody seroconversion after two yr, which was maintained long term. Antiviral therapy was discontinued. Liver biopsy revealed minimal histologic changes up to eight yr post-LT. Survival of 14 recipients of antiHBVc+ allografts and 180 recipients of antiHBVc-negative grafts was equal (minimum follow up of five yr). Liver biopsies at four yr showed grade 0/1 and stage 0/1 in >70%; only two patients showed bridging fibrosis. A literature review of dual hepatitis virus infection revealed an overall milder course of hepatitis post-LT. Conclusion: The outcome of HCV patients receiving anti-HBc+ grafts is good and may be associated with a milder course of recurrent HCV. [ABSTRACT FROM AUTHOR]

Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non-heart-beating or donation after cardiac death (DCD) are encouraging. However, long-term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow-up >4.5 years. During 1998–2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart-beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non-function and biliary complications as compared with SCD and ECD. The overall one-, two-, and five-yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long-term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival. [ABSTRACT FROM AUTHOR]

In a recent letter to the editor, by Mohan et al,1 the authors make comments on our recently published paper 'Liver Injury due to Ashwagandha: A Case Series from Iceland and the US Drug-Induced Liver Injury Network'.2 The authors do not agree with the conclusions of the paper regarding the hepatotoxic potential of ashwagandha.2 In the paper, five cases of suspected liver injury after consumption of ashwagandha-containing herbal supplements were described. The patients developed liver injury with a distinct clinical phenotype, with mixed or cholestatic pattern and notable elevations in serum bilirubin which normalized in 1-5 months after these ashwagandha-containing supplements were discontinued. Ashwagandha-induced liver injury should be on the list of differential diagnoses if the patient has been using ashwagandha or multi-ingredient supplements containing ashwagandha. [Extracted from the article]

Objective: Clinical decision instruments (CDIs) could be useful to aid risk stratification and disposition of emergency department (ED) patients with cirrhosis. Our primary objective was to derive and internally validate a novel Cirrhosis Risk Instrument for Stratifying Post-Emergency department mortality (CRISPE) for the outcomes of 14- and 30-day post-ED mortality. Secondarily, we externally validated the existing Model for End-Stage Liver Disease (MELD) scores for explicit use in ED patients and prediction of the same outcomes., Methods: A cohort of 2093 adults with cirrhosis, at 16 sites in a statewide health system, was analyzed for 119 candidate variables available at ED disposition. LASSO with 10-fold cross-validation was used in variable selection for 14-day (CRISPE-14) and 30-day (CRISPE-30) logistic regression models. Area under the receiver operating characteristic curve (AUROC) was calculated for each variant of the CRISPE and MELD scores and compared via Delong's test. Predictions were compared to actual ED disposition for predictive value and reclassification statistics., Results: Median (interquartile range [IQR]) characteristics of the cohort were age 62 (53-70) years and MELD 3.0 13.0 (8.0-20.0). Mortality was 4.3% and 8.5% at 14 and 30 days, respectively. CRISPE-14 and CRISPE-30 outperformed each MELD variant, achieving AUROC of 0.824 (95% CI: 0.781-0.866) and 0.829 (0.796-0.861), respectively. MELD 3.0 AUROCs were 0.724 (0.667-0.781) and 0.715 (0.672-0.781), respectively. Compared to ED disposition, CRISPE-14, CRISPE-30, and MELD 3.0 significantly improved positive and negative predictive value and net reclassification index at multiple cutoffs. Applying CRISPE-30 (cutoff 4.5) favorably reclassified one net ED disposition for mortality for every 12 patients, while MELD 3.0 net reclassified one disposition per 84 patients., Conclusions: CDIs may be useful in risk-stratifying ED patients with cirrhosis and aiding disposition decision making. The novel CRISPE CDI showed powerful performance and requires external validation, while the existing MELD 3.0 score has moderate performance and is now externally-validated in an ED population for short-term mortality., (© 2025 The Author(s). Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Objectives: Concerns about drug-induced liver injury (DILI) may deter physicians from prescribing medications for alcohol use disorder (MAUD). We aim to explore DILI due to MAUD in Drug-Induced Liver Injury Network (DILIN) prospective study., Methods: High-confidence DILI cases (ie, definite, highly likely, or probable) due to MAUD in DILIN prospective study (2004-2024) were included. Demographic, clinical, laboratory data, and 6-month outcomes were analyzed. HLA allele frequency (AF) of disulfiram cases was compared to matched controls with DILI due to non-MAUD (DILI controls)., Results: Among 1975 high-confidence cases, 13 were attributed to MAUD (11 disulfiram; 1 naltrexone and 1 baclofen; and none from acamprosate). Median age was 45 years, with 77% female and 85% White. All had hepatocellular injury. In disulfiram group, the median time for DILI occurrence was 34 days. Eight patients developed jaundice, with 3 fatal or near-fatal cases (2 liver transplantation and 1 liver-related death). Five (71%) patients with severe or fatal disulfiram DILI had underlying liver disease. AF for HLA-C*01:02 (OR, 6.29; P = 0.02) and DRB1*09:01 (OR, 10.16; P = 0.02) were significantly higher in disulfiram cases than in DILI controls. DILI from baclofen and naltrexone was mild and self-limited with no chronic DILI., Conclusions: Disulfiram is the leading cause of DILI among MAUD and is most common in women. Disulfiram can cause severe DILI and is associated with HLA-C*01:02 and DRB1*09:01. Baclofen and naltrexone can cause mild to moderate self-limited DILI. There were no cases of acamprosate. These findings suggest DILI due to MAUD are less frequent., Competing Interests: Dr Chalasani has ongoing paid consulting activities (or had in preceding 12 months) with Madrigal, Zydus, Altimmune, Ipsen, GSK, Pfizer, and Merck. He has grant support from Exact Sciences. He has equity in Avant Sante, a contract research organization. These activities are not directly or significantly related to this paper. Dr Fontana conducts research supported by Kezar Pharmaceuticals and Takeda pharmaceuticals, but these activities are not related to this paper. Drs Gopalakrishna, Ghabril, Gu, Li, Kleiner, and Koh have no conflicts of interests to disclose., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Objective: Drug-induced liver injury (DILI) is a global problem and can develop from exposure to prescription or over-the-counter medications as well as herbal and dietary supplements. The diagnosis of DILI is clinically challenging, and liver injury can be severe leading to liver failure, death, or liver transplantation. Patients with underlying chronic liver diseases (CLD) may be at increased risk for DILI, which is associated with factors related to drug or liver disease., Methods: This review summarises current knowledge on the risk and outcomes of DILI in patients with CLD., Results: Patients with CLD may be at an increased risk for DILI. Additionally patients with underlying CLD are at risk for more severe liver injury and worse outcomes after DILI., Discussion: The risk for and poor outcomes from DILI are accentuated in patients with CLD and potentially leading to the worst-case scenario of acute-on-chronic liver failure. We highlight the key observations on DILI with a broad range of underlying liver diseases and the high-DILI risk agents implicated in those populations., (© 2025 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background: Liver transplantation is the only curative treatment of end-stage liver disease. Unfortunately, a significant number of patients on the organ waitlist die waiting for an organ. Living-donor liver transplantation (LDLT) is an approach that has been used to expand organ availability. Although LDLT has excellent outcomes, biliary complications remain a significant drawback. This meta-analysis aimed to precisely assess the predictors of biliary stricture and leak after LDLT., Methods: PubMed, Embase, and Web of Science databases were searched from inception to January 2024. Only studies that used a multivariate model to assess risk factors for post-LDLT biliary stricture or leak in adult participants were included. Studies reporting unadjusted risk factors were excluded. Pooled adjusted odds ratios (ORs) and pooled hazard ratios (HRs) with 95% CIs for risk factors reported in ≥2 studies were obtained within a random-effects model., Results: Overall, 22 studies with 9442 patients who underwent LDLT were included. The post-LDLT biliary stricture rate was 22%, whereas the post-LDLT biliary leak rate was 14%. In addition, 13 unique risk factors were analyzed. Postoperative bile leak (OR, 4.10 [95% CI, 2.88-5.83]; HR, 3.88 [95% CI, 2.15-6.99]) was the most significant predictor of biliary stricture after LDLT. Other significant predictors of biliary stricture after LDLT were right lobe graft (OR, 2.56; 95% CI, 1.23-5.32), multiple ducts for anastomosis (OR, 1.62; 95% CI, 1.08-2.43), ductoplasty (OR, 2.07; 95% CI, 1.36-3.13), ABO incompatibility (OR, 1.45; 95% CI, 1.16-1.81), and acute cellular rejection (OR, 4.10; 95% CI, 2.88-5.83). Donor bile duct size (HR, 0.82; 95% CI, 0.74-0.91; P = .001, I 2 = 0%) was found to be significantly associated with reduced risk of post-LDLT biliary stricture. Donor age, recipient age, recipient male sex, and duct-to-duct anastomosis were not associated with an increased risk of post-LDLT biliary strictures. Multiple ducts for anastomosis (OR, 1.86; 95% CI, 1.43-2.43) was a significant predictor of post-LDLT biliary leak. Recipient age, warm ischemia time, and duct-to-duct anastomosis were not associated with an increased risk of post-LDLT biliary leak., Conclusion: In this meta-analysis, 7 unique risk factors were shown to be predictive of post-LDLT biliary stricture, one of which was associated with both post-LDLT biliary stricture and leak. Donor bile duct size was found to be protective against post-LDLT biliary strictures. Identifying reliable predictors is crucial for recognizing high-risk patients. This approach can facilitate the implementation of preventive measures, surveillance protocols, and targeted interventions to reduce the incidence of biliary strictures after LDLT., Competing Interests: Declaration of competing interest M.A.G. is a consultant of Boston Scientific and Ambu and receives research support from Olympus and Cook Medical. The other authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Postoperative acute kidney injury after liver transplant (LT) has long-term implications for kidney health. LT recipients are at risk of acute kidney injury due to a number of factors related to the donor liver, intraoperative factors including surgical technique, as well as recipient factors, such as pre-LT kidney function and postoperative complications. This review discusses these factors in detail and their impact on posttransplant kidney function. Long-term risk factors such as calcineurin inhibitors have also been discussed. Additionally, the impact of liver allocation policies on pre- and post-LT kidney health is discussed., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To investigate how individual social determinants of health (SDOH) and cumulative social disadvantage (CSD) affect survival and receipt of liver transplant (LT) in patients with hepatocellular carcinoma (HCC)., Methods: We enrolled 139 adult patients from two Indianapolis hospital systems between June 2019 and April 2022. Structured questionnaires collected SDOH and social risk factor data. We compared SDOH and CSD by race, gender and disease aetiology, assigning one point per adverse SDOH. Multivariable competing risk survival analysis assessed associations between SDOH, CSD, survival and LT receipt., Results: Black patients experienced higher CSD than white patients in the cohort (5.4±2.5 vs 3.2±2.1, p<0.001). Black patients were significantly more likely to have household incomes

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care., (Copyright © 2024 American Association for the Study of Liver Diseases.)