Medication burden and anticholinergic use are associated with overt HE in individuals with cirrhosis.

BACKGROUND: Polypharmacy and anticholinergic medications are associated with cognitive decline in elderly populations. Although several medications have been associated with HE, associations between medication burden, anticholinergics, and HE have not been explored. We examined medication burden and anticholinergics in patients with cirrhosis and their associations with HE-related hospitalization. METHODS: We conducted a retrospective cohort study of patients aged 18-80 with cirrhosis seen in hepatology clinics during 2019. The number of chronic medications (medication burden) and anticholinergic use were recorded. The primary outcome was HE-related hospitalization. RESULTS: A total of 1039 patients were followed for a median of 840 days. Thirty-seven percent had a history of HE, and 9.8% had an HE-related hospitalization during follow-up. The mean number of chronic medications was 6.1 ± 4.3. Increasing medication burden was associated with HE-related hospitalizations in univariable (HR: 1.09, 95% CI: 1.05-1.12) and multivariable (HR: 1.07, 95% CI: 1.03-1.11) models. This relationship was maintained in those with baseline HE but not in those without baseline HE. Twenty-one percent were taking an anticholinergic medication. Anticholinergic exposure was associated with increased HE-related hospitalizations in both univariable (HR: 1.68, 95% CI: 1.09-2.57) and multivariable (HR: 1.71, 95% CI: 1.11-2.63) models. This relationship was maintained in those with baseline HE but not in those without baseline HE. CONCLUSIONS: Anticholinergic use and medication burden are both associated with HE-related hospitalizations, particularly in those with a history of HE. Special considerations to limit anticholinergics and minimize overall medication burden should be tested for potential benefit in this population.

A Comprehensive Evaluation of Emergency Department Utilization by Patients With Cirrhosis.

INTRODUCTION: Emergency department (ED)-based care is required for cirrhosis management, yet the burden of cirrhosis-related ED healthcare utilization is understudied. We aimed to describe ED utilization within a statewide health system and compare the outcomes of high ED use (HEDU) vs non-HEDU in individuals with cirrhosis. METHODS: We retrospectively reviewed charts of adults with cirrhosis who presented to any of 16 EDs within the Indiana University Health system in 2021. Patient characteristics, features of the initial ED visit, subsequent 90-day healthcare use, and 360-day outcomes were collected. Multivariable logistic regression models were used to identify predictors HEDU status which was defined as ≥2 ED visits within 90 days after the index ED visit. RESULTS: There were 2,124 eligible patients (mean age 61.3 years, 53% male, and 91% White). Major etiologies of cirrhosis were alcohol (38%), metabolic dysfunction-associated steatohepatitis (27%), and viral hepatitis (21%). Cirrhosis was newly diagnosed in the ED visit for 18.4%. Most common reasons for ED visits were abdominal pain (21%), shortness of breath (19%), and ascites/volume overload (16%). Of the initial ED visits, 20% (n = 424) were potentially avoidable. The overall 90-day mortality was 16%. Within 90 days, there were 366 HEDU (20%). Notable variables independently associated with HEDU were model for end-stage liver disease-sodium (adjusted odds ratio [aOR] 1.044, 95% confidence interval [CI] 1.005-1.085), prior ED encounter (aOR 1.520, 95% CI 1.136-2.034), and avoidable initial ED visit (aOR 1.938, 95% CI 1.014-3.703). DISCUSSION: Abdominal pain, shortness of breath, and ascites/fluid overload are the common presenting reasons for ED visits for patients with cirrhosis. Patients with cirrhosis presenting to the ED experience a 90-day mortality rate of 16%, and among those who initially visited the ED, 20% were HEDU. We identified several variables independently associated with HEDU. Our observations pave the way for developing interventions to optimize the care of patients with cirrhosis presenting to the ED and to lower repeated ED visits.

Early Diagnostic Paracentesis Improves Outcomes of Hospitalized Patients With Cirrhosis and Ascites: A Systematic Review and Meta-Analysis.

INTRODUCTION: Diagnostic paracentesis is recommended for patients with cirrhosis admitted to the hospital, but adherence is suboptimal with unclear impact on clinical outcomes. The aim of this meta-analysis was to assess the outcomes of early vs delayed diagnostic paracentesis among hospitalized patients with cirrhosis and ascites. METHODS: We searched multiple databases for studies comparing early vs delayed diagnostic paracentesis among hospitalized patients with cirrhosis and ascites. The pooled odds ratio (OR) and mean difference with confidence intervals (CIs) for proportional and continuous variables were calculated using the random-effects model. Early diagnostic paracentesis was defined as receiving diagnostic paracentesis within 12-24 hours of admission. The primary outcome was in-hospital mortality. Secondary outcomes were length of hospital stay, acute kidney injury, and 30-day readmission. RESULTS: Seven studies (n = 78,744) (n = 45,533 early vs n = 33,211 delayed diagnostic paracentesis) were included. Early diagnostic paracentesis was associated with lower in-hospital mortality (OR 0.61, 95% CI 0.46-0.82, P = 0.001), length of hospital stay (mean difference -4.85 days; 95% CI -6.45 to -3.20; P < 0.001), and acute kidney injury (OR 0.62, 95% CI 0.42-0.92, P = 0.02) compared with delayed diagnostic paracentesis, with similar 30-day readmission (OR 1.11, 95% CI 0.52-2.39, P = 0.79). Subgroup analysis revealed consistent results for in-hospital mortality whether early diagnostic paracentesis performed within 12 hours (OR 0.51, 95% CI 0.32-0.79, P = 0.003, I2 = 0%) or within 24 hours of admission (OR 0.67, 95% CI 0.45-0.98, P = 0.04, I2 = 82%). Notably, the mortality OR was numerically lower when diagnostic paracentesis was performed within 12 hours, and the results were precise and homogenous ( I2 = 0%). DISCUSSION: Findings from this meta-analysis suggest that early diagnostic paracentesis is associated with better patient outcomes. Early diagnostic paracentesis within 12 hours of admission may be associated with the greatest mortality benefit. Data from large-scale randomized trials are needed to validate our findings, especially if there is a greater mortality benefit for early diagnostic paracentesis within 12 hours.

Hospital frailty risk score is superior to legacy comorbidity indices for risk adjustment of in-hospital cirrhosis cases.

Background & Aims: The hospital frailty risk score (HFRS) identifies older patients at risk of poor outcomes and may have value in cirrhosis. We compared the Charlson (CCI), Elixhauser (ECI), and cirrhosis (CirCom) comorbidity indices with the HFRS in predicting outcomes for cirrhosis hospitalisations. Methods: Using the National Inpatient Sample (quarter 4 of 2015-2019), we analysed cirrhosis hospitalisations. For each index, we described the prevalence of comorbid conditions and inpatient mortality. We compared the ability of CCI, ECI, CirCom, and HFRS to predict inpatient mortality. Raw and adjusted models predicting inpatient mortality were compared using the area under the receiver operating characteristic curve and the Akaike information criterion. Results: The cohort's (N = 626,553) median age was 61 years (IQR 52-68 years), 60% were male, cirrhosis was caused by alcohol in 43%, and 38% had ascites. The median comorbidity scores are as follows: ECI 4 (IQR 3-6), CCI 5 (IQR 4-8), and HFRS 5.6 (IQR 3.0-8.6). The most common CirCom score was 0 + 0 (44%). Across the range of values of each index, we observed different mortality ranges: CCI 1.9-13.1%, ECI 3.2-8.7%, CirCom 4.9-13.8%, and HFRS 1.0-15.2%. An adjusted model with HFRS had the highest area under the receiver operating characteristic curve in predicting mortality (HFRS 0.782 vs. ECI 0.689, CCI 0.695, and CirCom 0.692). We observed substantial variation in mortality with HFRS within each level of CCI, ECI, and CirCom. For example, for ECI 4, mortality increased from 0.6 to 16.4%, as HFRS increased from 0 to 15. Conclusions: Comorbidity indices predict inpatient cirrhosis mortality, but HFRS performs better than CCI, ECI, and CirCom. HFRS is an ideal tool for measuring comorbidity burden and disease severity risk adjustment in cirrhosis-related administrative database studies. Impact and Implications: We compared commonly used comorbidity indices to a more recently described risk score (hospital frailty risk score [HFRS]) in patients with cirrhosis using a national sample of hospital records. Comorbid conditions are common in hospitalised patients with cirrhosis. There is significant variability in mortality across the range of each index. HFRS outperforms the Charlson comorbidity index, Elixhauser comorbidity index, and CirCom (cirrhosis-specific comorbidity scoring system) in predicting inpatient mortality. HFRS is a valuable index for risk adjustment in inpatient administrative database studies.

Optimization of Kidney Health in Liver Transplant Candidates: Pretransplant Considerations and Modalities.

Patients with decompensated end-stage liver disease (ESLD) are at increased risk for mortality, and only liver transplantation (LT) offers meaningful hope for survival. These patients are at risk for kidney dysfunction through the continuum of care for ESLD including LT. We discuss the role of accurate estimation and measurement of baseline glomerular filtration rate in assessment of kidney dysfunction among those with ESLD. Optimizing kidney function is a vital goal in the management of these patients before LT. In this review, we summarize salient aspects of assessing and optimizing kidney function in this patient population. Precipitating factors and different causes of acute kidney injury are discussed, including hepatorenal syndrome. We further review treatment options for acute kidney injury including volume management. The role of vasopressor therapy, renal replacement therapy, and transjugular intrahepatic portosystemic shunting are discussed.

Thirty-Day Readmissions Are Largely Not Preventable in Patients With Cirrhosis.

INTRODUCTION: Hospital readmissions are common in patients with cirrhosis, but there are few studies describing readmission preventability. We aimed to describe the incidence, causes, and risk factors for preventable readmission in this population. METHODS: We performed a prospective cohort study of patients with cirrhosis hospitalized at a single center between June 2014 and March 2020 and followed up for 30 days postdischarge. Demographic, clinical, and socioeconomic data, functional status, and quality of life were collected. Readmission preventability was independently and systematically adjudicated by 3 reviewers. Multinomial logistic regression was used to compare those with (i) preventable readmission, (ii) nonpreventable readmission/death, and (iii) no readmission. RESULTS: Of 654 patients, 246 (38%) were readmitted, and 29 (12%) were preventable readmissions. Reviewers agreed on preventability for 70% of readmissions. Twenty-two (including 2 with preventable readmission) died. The most common reasons for readmission were hepatic encephalopathy (22%), gastrointestinal bleeding (13%), acute kidney injury (13%), and ascites (6%), and these reasons were similar between preventable and nonpreventable readmissions. Preventable readmission was often related to paracentesis timeliness, diuretic adjustment monitoring, and hepatic encephalopathy treatment. Compared with nonreadmitted patients, preventable readmission was independently associated with racial and ethnic minoritized individuals (odds ratio [OR] 5.80; 95% CI, 1.96-17.13), nonmarried marital status (OR 2.88; 95% CI, 1.18-7.05), and admission in the prior 30 days (OR 3.45; 95% CI, 1.48-8.04). DISCUSSION: For patients with cirrhosis, readmission is common, but most are not preventable. Preventable readmissions are often related to ascites and hepatic encephalopathy and are associated with racial and ethnic minorities, nonmarried status, and prior admissions.

Plasma exchange for acute and acute-on-chronic liver failure: A systematic review and meta-analysis.

Plasma exchange (PE) is a promising therapeutic option in patients with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). However, the impact of PE on patient survival in these syndromes is unclear. We aimed to systematically investigate the use of PE in patients with ALF and ACLF compared with standard medical therapy (SMT). We searched PubMed/Embase/Cochrane databases to include all studies comparing PE versus SMT for patients ≥ 18 years of age with ALF and ACLF. Pooled risk ratios (RR) with corresponding 95% CIs were calculated by the Mantel-Haenszel method within a random-effect model. The primary outcome was 30-day survival for ACLF and ALF. Secondary outcomes were overall and 90-day survival for ALF and ACLF, respectively. Five studies, including 343 ALF patients (n = 174 PE vs. n = 169 SMT), and 20 studies, including 5,705 ACLF patients (n = 2,856 PE vs. n = 2,849 SMT), were analyzed. Compared with SMT, PE was significantly associated with higher 30-day (RR 1.41, 95% CI 1.06-1.87, p = 0.02) and overall (RR 1.35, 95% CI 1.12-1.63, p = 0.002) survival in ALF patients. In ACLF, PE was also significantly associated with higher 30-day (RR 1.36, 95% CI 1.22-1.52, p < 0.001) and 90-day (RR 1.21, 95% CI 1.10-1.34, p < 0.001) survival. On subgroup analysis of randomized controlled trials, results remained unchanged in ALF, but no differences in survival were found between PE and SMT in ACLF. In conclusion, PE is associated with improved survival in ALF and could improve survival in ACLF. PE may be considered in managing ALF and ACLF patients who are not liver transplant (LT) candidates or as a bridge to LT in otherwise eligible patients. Further randomized controlled trials are needed to confirm the survival benefit of PE in ACLF.

Clinical characteristics and prognosis of hospitalized patients with moderate alcohol-associated hepatitis.

BACKGROUND AND AIMS: Little is known about the clinical characteristics and prognosis of hospitalized patients with moderate alcohol-associated hepatitis (mAH) as compared to severe alcohol-associated hepatitis (sAH). Therefore, we aimed to describe the clinical characteristics and risk factors associated with mortality in hospitalized mAH patients. METHODS: Patients hospitalized with alcohol-associated hepatitis (AH) from 1 January 2010 to 31 December 2020 at a large US healthcare system [11 hospitals, one liver transplant centre] were retrospectively analysed for outcomes. Primary outcome was 90-day mortality. AH and mAH were defined according to NIAAA Alcoholic Hepatitis Consortia and Model for End-stage Liver Disease Score ≤ 20 respectively. Multivariable Cox regression analysis was performed to identify independent risk factors associated with 90-day mortality. RESULTS: 1504 AH patients were hospitalized during the study period, of whom 39% (n = 590) had mAH. Compared to sAH patients, mAH patients were older (50 vs. 48 years, p < 0.001) and less likely to have underlying cirrhosis (74% vs. 83%, p < 0.001). There were no differences between the two groups for median alcohol intake g/day (mAH 140.0 vs. sAH 112.0, p = 0.071). The cumulative proportion surviving at 90 days was 88% in mAH versus 62% in sAH (p < 0.001). On multivariable analysis, older age [HR 1.03 (95% CI 1.00-1.06), p = 0.020], corticosteroid use [HR 1.80 (95% CI 1.06-3.06), p = 0.030] and acute kidney injury (AKI) [HR 2.43 (95% CI 1.33-4.47), p = 0.004] were independently associated with 90-day mortality. CONCLUSIONS: mAH carries a 12% mortality rate at 90 days. Age, AKI and corticosteroid use were associated with an increased risk for 90-day mortality. Avoidance of corticosteroids and strategies to reduce the risk of AKI could improve outcomes in mAH patients.

Incidence, clinical characteristics, and risk factors associated with recurrent alcohol-associated hepatitis.

BACKGROUND: Alcohol relapse occurs frequently in alcohol-associated hepatitis (AH) survivors, but data on the frequency and course of recurrent alcohol-associated hepatitis (rAH) are sparse. We investigated the incidence, risk factors, and outcomes of rAH. METHODS: Hospitalized patients with AH from 2010 to 2020 at a large health care system were followed until death/liver transplant, last follow-up, or end of study (December 31, 2021). AH was defined by NIAAA Alcoholic Hepatitis Consortium criteria; rAH was defined a priori as a discrete AH episode >6 months from index AH hospitalization with interim >50% improvement or normalization of total bilirubin. Multivariable competing risk analysis was performed to identify factors associated with rAH. Landmark Kaplan-Meier analysis was performed to compare survival between patients who did versus those who did not develop rAH. RESULTS: Of 1504 hospitalized patients with AH, 1317 (87.6%) survived and were analyzed. During a 3055 person-year follow-up, 116 (8.8%) developed rAH at an annual incidence rate of 3.8% (95% CI: 2.8-4.8). On multivariable competing risk analysis, marital status [sub-HR 0.54 (95% CI: 0.34, 0.92), p=0.01] and medications for alcohol use disorder [sub-HR 0.56 (95% CI: 0.34, 0.91), p=0.02] were associated with a lower risk for rAH. On landmark Kaplan-Meier analysis, the cumulative proportion surviving at 1 year (75% vs. 90%) and 3 years (50% vs. 78%) was significantly lower in patients who developed rAH compared to those who did not develop rAH (log-rank p<0.001). CONCLUSIONS: rAH develops in ~1 in 10 AH survivors and is associated with lower long-term survival. Medications for alcohol use disorder lower the risk for rAH and, therefore, could be a key preventative strategy to improve outcomes.

Longer time to recovery from acute kidney injury is associated with major adverse kidney events in patients with cirrhosis.

BACKGROUND: In patients with cirrhosis and acute kidney injury (AKI), longer time to AKI-recovery may increase the risk of subsequent major-adverse-kidney-events (MAKE). AIMS: To examine the association between timing of AKI-recovery and risk of MAKE in patients with cirrhosis. METHODS: Hospitalised patients with cirrhosis and AKI (n = 5937) in a nationwide database were assessed for time to AKI-recovery and followed for 180-days. Timing of AKI-recovery (return of serum creatinine <0.3 mg/dL of baseline) from AKI-onset was grouped by Acute-Disease-Quality-Initiative Renal Recovery consensus: 0-2, 3-7, and >7-days. Primary outcome was MAKE at 90-180-days. MAKE is an accepted clinical endpoint in AKI and defined as the composite outcome of ≥25% decline in estimated-glomerular-filtration-rate (eGFR) compared with baseline with the development of de-novo chronic-kidney-disease (CKD) stage ≥3 or CKD progression (≥50% reduction in eGFR compared with baseline) or new haemodialysis or death. Landmark competing-risk multivariable analysis was performed to determine the independent association between timing of AKI-recovery and risk of MAKE. RESULTS: 4655 (75%) achieved AKI-recovery: 0-2 (60%), 3-7 (31%), and >7-days (9%). Cumulative-incidence of MAKE was 15%, 20%, and 29% for 0-2, 3-7, >7-days recovery groups, respectively. On adjusted multivariable competing-risk analysis, compared to 0-2-days, recovery at 3-7 and >7-days was independently associated with an increased risk for MAKE: sHR 1.45 (95% CI 1.01-2.09, p = 0.042), sHR 2.33 (95% CI 1.40-3.90, p = 0.001), respectively. CONCLUSION: Longer time to recovery is associated with an increased risk of MAKE in patients with cirrhosis and AKI. Further research should examine interventions to shorten AKI-recovery time and its impact on subsequent outcomes.

The prognostic impact of acute kidney injury recovery patterns in critically ill patients with cirrhosis.

BACKGROUND: The prognostic impact of acute kidney injury (AKI) recovery patterns in critically ill patients with cirrhosis is unknown. We aimed to compare mortality stratified by AKI recovery patterns and identify predictors of mortality in patients with cirrhosis and AKI admitted to the intensive care unit. MATERIALS AND METHODS: Patients with cirrhosis and AKI from 2016 to 2018 at 2 tertiary care intensive care units were analyzed (N=322). AKI recovery was defined by Acute Disease Quality Initiative consensus: return of serum creatinine <0.3 mg/dL of baseline within 7 days of AKI onset. Recovery patterns were categorized by Acute Disease Quality Initiative consensus: 0-2 days, 3-7 days, and no-recovery (persistence of AKI >7 d). Landmark competing risk univariable and multivariable models (liver transplant as competing risk) was used to compare 90-day mortality between AKI recovery groups and to determine independent predictors of mortality. RESULTS: Sixteen percent (N=50) and 27% (N=88) achieved AKI recovery within 0-2 and 3-7 days, respectively; 57% (N=184) had no-recovery. Acute on chronic liver failure was prevalent (83%) and patients with no-recovery were more likely to have grade 3 acute on chronic liver failure (N=95, 52%) compared to patients with AKI recovery [0-2: 16% (N=8); 3-7: 26% (N=23); p<0.001]. Patients with no-recovery had significantly higher probability of mortality [unadjusted-sub-HR (sHR): 3.55; 95% CI: 1.94-6.49; p<0.001] compared to patients with recovery within 0-2 days, while the probability was similar between 3-7 and 0-2 days (unadjusted-sub-HR: 1.71; 95% CI: 0.91-3.20; p=0.09). On multivariable analysis, AKI no-recovery (sub-HR: 2.07; 95% CI: 1.33-3.24; p=0.001), severe alcohol-associated hepatitis (sub-HR: 2.41; 95% CI: 1.20-4.83; p=0.01), and ascites (sub-HR: 1.60; 95% CI: 1.05-2.44; p=0.03) were independently associated with mortality. CONCLUSION: AKI no-recovery occurs in over half of critically ill patients with cirrhosis and AKI and is associated with worse survival. Interventions that facilitate AKI recovery may improve outcomes in this patient population.

Liver Injury Associated with Turmeric-A Growing Problem: Ten Cases from the Drug-Induced Liver Injury Network [DILIN].

BACKGROUND: Turmeric is a commonly used herbal product that has been implicated in causing liver injury. The aim of this case series is to describe the clinical, histologic, and human leukocyte antigen (HLA) associations of turmeric-associated liver injury cases enrolled the in US Drug-Induced Liver Injury Network (DILIN). METHODS: All adjudicated cases enrolled in DILIN between 2004 and 2022 in which turmeric was an implicated product were reviewed. Causality was assessed using a 5-point expert opinion score. Available products were analyzed for the presence of turmeric using ultra-high-performance liquid chromatography. Genetic analyses included HLA sequencing. RESULTS: Ten cases of turmeric-associated liver injury were found, all enrolled since 2011, and 6 since 2017. Of the 10 cases, 8 were women, 9 were White, and median age was 56 years (range 35-71). Liver injury was hepatocellular in 9 patients and mixed in 1. Liver biopsies in 4 patients showed acute hepatitis or mixed cholestatic-hepatic injury with eosinophils. Five patients were hospitalized, and 1 patient died of acute liver failure. Chemical analysis confirmed the presence of turmeric in all 7 products tested; 3 also contained piperine (black pepper). HLA typing demonstrated that 7 patients carried HLA-B*35:01, 2 of whom were homozygous, yielding an allele frequency of 0.450 compared with population controls of 0.056-0.069. CONCLUSION: Liver injury due to turmeric appears to be increasing in the United States, perhaps reflecting usage patterns or increased combination with black pepper. Turmeric causes potentially severe liver injury that is typically hepatocellular, with a latency of 1 to 4 months and strong linkage to HLA-B*35:01.

Measuring Medication Use, Obstacles, and Knowledge in Individuals With Cirrhosis.

BACKGROUND & AIMS: Although patient knowledge is modifiable, there are no widely accepted tools to measure patient understanding during cirrhosis care. We aimed to develop and validate "My Cirrhosis Coach" (MCC), a personalized, self-administered questionnaire to evaluate cirrhosis-related medication use, obstacles, and understanding. METHODS: Adults with cirrhosis were prospectively enrolled at 3 tertiary centers from July 2016 through July 2020. Psychometrics including confirmatory factor analysis was used to develop and validate a final questionnaire. Content validity was measured via the content validity index and expert performance. Discriminant validity was assessed by comparing scores between groups hypothesized to have varying performance. RESULTS: The MCC was tested in a diverse cohort (n = 713) with cirrhosis and its complications including ascites (45%) and hepatic encephalopathy (33%) with median Model for End-Stage Liver Disease-Sodium 10 (interquartile range, 9-15). A 6-factor model of the MCC fit the data well (root mean square error of approximation, 0.22; comparative fit index, 0.96; standardized root mean squared residual, 0.104; final domains: Medication Use & Accessibility, Medication Obstacles, Lactulose Use, Diuretic Use, Beta Blocker Use, and Dietary Sodium Use). The MCC had excellent content validity (content validity index, 81%-94%) and accuracy (91%-100%) ratings by experts. Mean domain scores ranged from 1.1 to 2.6 (range, 0-3; 3 indicating better performance). Those with a cirrhosis complication scored higher in the relevant medication domain (ie, diuretic use score in ascites). Compared with outpatients, inpatients scored higher in all knowledge domains except salt use and reported more medication obstacles. Scores differed by income, education level, and having an adult at home. CONCLUSIONS: In a large, diverse cohort, we validated the MCC, which can serve to standardize medication use and knowledge measurement in clinical practice and education-based studies in cirrhosis.

Acute kidney disease is common and associated with poor outcomes in patients with cirrhosis and acute kidney injury.

BACKGROUND & AIMS: Acute kidney disease (AKD) is the persistence of acute kidney injury (AKI) for up to 3 months, which is proposed to be the time-window where critical interventions can be initiated to alter downstream outcomes of AKI. In cirrhosis, AKD and its impact on outcomes have been scantly investigated. We aimed to define the incidence and outcomes associated with AKD in a nationwide US cohort of hospitalized patients with cirrhosis and AKI. METHODS: Hospitalized patients with cirrhosis and AKI in the Cerner-Health-Facts database from 1/2009-09/2017 (n = 6,250) were assessed for AKD and were followed-up for 180 days. AKI and AKD were defined based on KDIGO and ADQI AKD and renal recovery consensus criteria, respectively. The primary outcome measure was mortality, and the secondary outcome measure was de novo chronic kidney disease (CKD). Competing-risk multivariable models were used to determine the independent association of AKD with primary and secondary outcomes. RESULTS: AKD developed in 32% of our cohort. On multivariable competing-risk analysis adjusting for significant confounders, patients with AKD had higher risk of mortality at 90 (subdistribution hazard ratio [sHR] 1.37; 95% CI 1.14-1.66; p = 0.001) and 180 (sHR 1.37; 95% CI 1.14-1.64; p = 0.001) days. The incidence of de novo CKD was 37.5%: patients with AKD had higher rates of de novo CKD (64.0%) compared to patients without AKD (30.7%; p <0.001). After adjusting for confounders, AKD was independently associated with de novo CKD (sHR 2.52; 95% CI 2.01-3.15; p <0.001) on multivariable competing-risk analysis. CONCLUSIONS: AKD develops in 1 in 3 hospitalized patients with cirrhosis and AKI and it is associated with worse survival and de novo CKD. Interventions that target AKD may improve outcomes of patients with cirrhosis and AKI. LAY SUMMARY: In a nationwide US cohort of hospitalized patients with cirrhosis and acute kidney injury, acute kidney disease developed in 1 in 3 patients and was associated with worse survival and chronic kidney disease. Interventions that target acute kidney disease may improve outcomes of patients with cirrhosis and acute kidney injury.

The kidney releases a nonpolymerizing form of uromodulin in the urine and circulation that retains the external hydrophobic patch domain.

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 + EHP) and established its presence in the urine in a nonpolymerized native state. Proteomic characterization of urinary THP + EHP revealed its COOH-terminus ending at F617. In the human kidney, THP + 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 + 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 + EHP as a sensitive biomarker of kidney health and susceptibility to injury.NEW & NOTEWORTHY In this work, we discovered and characterized a novel form of uromodulin that does not polymerize because it retains an external hydrophobic patch at the COOH-terminus. These findings establish an alternative form of cellular processing of this protein and elucidate new aspects of its biology. We also provide evidence suggesting that measuring urinary nonpolymerizing uromodulin could be a promising assay to assess the risk of acute kidney injury.

Patient-reported outcomes in HCC: A scoping review by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

BACKGROUND AND AIMS: HCC is a leading cause of mortality in patients with advanced liver disease and is associated with significant morbidity. Despite multiple available curative and palliative treatments, there is a lack of systematic evaluation of patient-reported outcomes (PROs) in HCC. APPROACH AND RESULTS: The American Association for the Study of Liver Diseases Practice Metrics Committee conducted a scoping review of PROs in HCC from 1990 to 2021 to (1) synthesize the evidence on PROs in HCC and (2) provide recommendations on incorporating PROs into clinical practice and quality improvement efforts. A total of 63 studies met inclusion criteria investigating factors associated with PROs, the relationship between PROs and survival, and associations between HCC therapy and PROs. Studies recruited heterogeneous populations, and most were cross-sectional. Poor PROs were associated with worse prognosis after adjusting for clinical factors and with more advanced disease stage, although some studies showed better PROs in patients with HCC compared to those with cirrhosis. Locoregional and systemic therapies were generally associated with a high symptom burden; however, some studies showed lower symptom burden for transarterial radiotherapy and radiation therapy. Qualitative studies identified additional symptoms not routinely assessed with structured questionnaires. Gaps in the literature include lack of integration of PROs into clinical care to guide HCC treatment decisions, unknown impact of HCC on caregivers, and the effect of palliative or supportive care quality of life and health outcomes. CONCLUSION: Evidence supports assessment of PROs in HCC; however, clinical implementation and the impact of PRO measurement on quality of care and longitudinal outcomes need future investigation.

Severe Alcohol-Associated Hepatitis Is Associated With Worse Survival in Critically Ill Patients With Acute on Chronic Liver Failure.

Differences in mortality between critically ill patients with severe alcohol-associated hepatitis (sAH) and acute-on-chronic liver failure (ACLF) and non-sAH ACLF (i.e., ACLF not precipitated by sAH) are unknown. Such differences are important, as they may inform on prognosis and optimal timing of liver transplantation (LT). Thus, we aimed to compare short-term and longer-term mortality between patients with sAH ACLF and patients with non-sAH ACLF who were admitted to the intensive care unit. Patients with ACLF admitted from 2016-2018 at two tertiary care intensive care units were analyzed. SAH was defined by the National Institute on Alcohol Abuse and Alcoholism's Alcoholic Hepatitis Consortium and Model for End-Stage Liver Disease score >20. Mortality without LT was compared between sAH ACLF and non-sAH ACLF using Fine and Gray's competing-risks regression. A total of 463 patients with ACLF (18% sAH and 82% non-sAH) were included. Compared to patients with non-sAH ACLF, patients with sAH ACLF were younger (49 vs. 56 years; P < 0.001) and had higher admission Model for End-Stage Liver Disease (MELD) (35 vs. 25; P < 0.001) and Chronic Liver Failure Consortium (CLIF-C) scores (61 vs. 57; P = 0.002). There were no significant differences between the two groups for vasopressor, mechanical ventilation, and hemodialysis use. The cumulative incidence of death was significantly higher in patients with sAH ACLF compared to patients with non-sAH ACLF: 30-day 74.7% versus 45.3%; 90-day 81.9% versus 57.4%; 180-day 83.2% versus 63.0% (unadjusted subdistribution hazard ratio [sHR] 1.88 [95% confidence interval (CI) 1.44-2.46]; P < 0.001). After adjusting for CLIF-C score and infection in a multivariable competing-risk model, patients with sAH ACLF had significantly higher risk of death (sHR 1.57 [95% CI 1.20-2.06]; P = 0.001) compared to patients with non-sAH ACLF. Conclusion: Critically ill patients with sAH ACLF have worse mortality compared to patients with non-sAH ACLF. These data may inform prognosis in patients with sAH and ACLF, and early LT referral in potentially eligible patients.

Patient-Reported Outcome Measures Modestly Enhance Prediction of Readmission in Patients with Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis have high rates of hospital readmission, but prediction models are suboptimal and have not included important patient-reported outcome measures (PROMs). In a large prospective cohort, we examined the impact of PROMs on prediction of 30-day readmissions. METHODS: We performed a prospective cohort study of adults with cirrhosis admitted to a tertiary center between June 2014 and March 2020. We collected clinical information, socioeconomic status, and PROMs addressing functional status and quality of life. We used hierarchical competing risk time-to-event analysis to examine the impact of PROMs on readmission prediction. RESULTS: A total of 654 patients were discharged alive, and 247 (38%) were readmitted within 30 days. Readmission was independently associated with cerebrovascular disease, ascites, prior hospital admission, admission via the emergency department, lower albumin, higher Model for End-Stage Liver Disease, discharge with public transportation, and impaired basic activities of daily living and quality-of-life activity domain. Reduced readmission was associated with cancer, admission for infection, children at home, and impaired emotional function. Compared with a model including only clinical variables, addition of functional status and quality-of-life variables improved the area under the receiver-operating characteristic curve from 0.72 to 0.73 and 0.75, with net reclassification indices of 0.22 and 0.18, respectively. Socioeconomic variables did not significantly improve prediction compared with clinical variables alone. Compared with a model using electronically available variables only, no models improved prediction when examined with integrated discrimination improvement. CONCLUSIONS: PROMs may marginally add to the prediction of 30-day readmissions for patients with cirrhosis. Poor social support and disability are associated with readmissions and may be high-yield targets for future interventions.

Quality measures in HCC care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

The burden of HCC is substantial. To address gaps in HCC care, the American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) aimed to develop a standard set of process-based measures and patient-reported outcomes (PROs) along the HCC care continuum. We identified candidate process and outcomes measures for HCC care based on structured literature review. A 13-member panel with content expertise across the HCC care continuum evaluated candidate measures on importance and performance gap using a modified Delphi approach (two rounds of rating) to define the final set of measures. Candidate PROs based on a structured scoping review were ranked by 74 patients with HCC across 7 diverse institutions. Out of 135 measures, 29 measures made the final set. These covered surveillance (6 measures), diagnosis (6 measures), staging (2 measures), treatment (10 measures), and outcomes (5 measures). Examples included the use of ultrasound (± alpha-fetoprotein [AFP]) every 6 months, need for surveillance in high-risk populations, diagnostic testing for patients with a new AFP elevation, multidisciplinary liver tumor board (MLTB) review of Liver Imaging-Reporting and Data System 4 lesions, standard evaluation at diagnosis, treatment recommendations based on Barcelona Clinic Liver Cancer staging, MLTB discussion of treatment options, appropriate referral for evaluation of liver transplantation candidacy, and role of palliative therapy. PROs include those related to pain, anxiety, fear of treatment, and uncertainty about the best individual treatment and the future. The AASLD PMC has developed a set of explicit quality measures in HCC care to help bridge the gap between guideline recommendations and measurable processes and outcomes. Measurement and subsequent implementation of these metrics could be a central step in the improvement of patient care and outcomes in this high-risk population.

Practice patterns and outcomes associated with intravenous albumin in patients with cirrhosis and acute kidney injury.

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.