Asrani, Sumeet K.

INTRODUCTION: Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS: The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS: In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4–11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION: NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

Background: Hepatorenal syndrome–acute kidney injury (HRS-AKI) is associated with high mortality in cirrhosis. Recent FDA approval of terlipressin and updated clinical guidance have expanded management options, but real-world practice patterns remain unknown. Methods: We conducted a nationwide survey of U.S. hepatology providers regarding HRS-AKI management practices. The 33-question survey assessed provider demographics, vasoconstrictor selection, treatment timing, and adherence to guideline recommendations. Results: Among 162 respondents, most were hepatologists (94%) at academic centers (83%). Only 11% obtained a nephrology consultation at AKI detection, with 44% waiting until worsening renal function. Terlipressin was available at 80% of institutions but more commonly at academic centers (84% vs. 53%, p =0.003). Consistent with guideline recommendations, 77% of providers initiate vasoconstrictors only after completing a trial of volume expansion (if no renal improvement), particularly in academic centers (80% vs. 60% non-academic, p =0.03). Terlipressin (49%) and midodrine/octreotide (44%) were preferred first-line treatments, with providers at academic centers more likely to use midodrine/octreotide (46% vs. 30%, p =0.008). Mean arterial pressure was used by 62% of providers to guide vasoconstrictor dosing. Most providers (73%) discontinued vasoconstrictor treatment after 4 days if no improvement. Conclusions: Significant variations exist between guideline recommendations and real-world HRS-AKI management, especially first-line treatment choice, treatment monitoring, and nephrology consultation. These findings highlight opportunities to improve guideline implementation and identify areas where practice patterns might inform provider education and future guidance updates.

Background: Blood-based biomarker panels, including GALAD, have been proposed as an alternative to abdominal ultrasound for hepatocellular carcinoma (HCC) surveillance. Studies suggest longitudinal evaluation of biomarkers can improve test performance; however, no large studies have validated these findings. Methods: We leveraged the HCC Early Detection Strategy (HEDS) study (n=1019 patients with cirrhosis; 99 incident HCC) and Texas HCC Consortium (THCCC) (n=2345 patients with cirrhosis; 126 incident HCC) to compare the performance of fixed-threshold GALAD (cutoff of −1.36), and 4 longitudinal algorithms: longitudinal GALAD, PALAD, mFB-ALAD, and mPEB-ALAD. The HEDS cohort was used to derive longitudinal algorithms, and external validation was performed in THCCC. Patient-level sensitivity and test-level false-positive rate (FPR) were examined overall and across subgroups by age, sex, and cirrhosis etiology. Results: In THCCC, fixed-threshold GALAD had higher sensitivity in the 6 months before HCC diagnosis (71.4%, 95% CI: 62.9%–81.7%) than longitudinal GALAD (55.1%, 95% CI: 49.3–66.4), PALAD (55.1%, 95% CI: 50.0%–70.5%), mPEB-ALAD (53.1%, 95% CI: 43.6%–62.0%), and mFB-ALAD (42.9%, 95% CI: 32.3–48.5). However, fixed-threshold GALAD had a higher FPR (25.4%, 95% CI: 23.7%–26.9%) compared with longitudinal GALAD (15.0%, 95% CI: 12.8%–15.8%), PALAD (13.0%, 95% CI: 10.2%–14.6%), and mFB-ALAD (11.2%, 95% CI: 9.6%–12.1%) but comparable to mPEB-ALAD (22.9%, 95% CI: 21.2%–23.8%). In subgroup analyses, fixed-threshold GALAD had the highest FPR in males (35.6%) and those aged ≥65 (43.5%); longitudinal algorithms had significantly lower FPRs in subgroups but with lower sensitivity for HCC. Conclusions: Improvements in FPRs with longitudinal GALAD algorithms, as compared with fixed-threshold GALAD, are offset by significantly decreased sensitivity for HCC detection.

INTRODUCTION: A Model for End-Stage Liver Disease-lactate (MELD-LA) score is an independent predictor of inpatient mortality and organ failure validated in more than 8,600 patients across diverse settings. However, its utility in sepsis, particularly when combined with lactate clearance (LA clearance), has not been fully evaluated. In this study, we examined the dynamic role of MELD-LA with 24-hour LA clearance as a predictor of 30-day mortality in critically ill patients with cirrhosis and sepsis. METHODS: We analyzed cirrhosis patients with sepsis admitted to the intensive care unit (ICU) in a large US healthcare system (20 hospitals) from 2014 to 2022, examining MELD-LA and LA clearance within 24 hours as predictors of 30-day mortality. We externally validated our findings in the Asian Pacific Association for the Study of the Liver-acute-on-chronic liver failure Research Consortium, a multinational Asian cohort (31 centers) from 2009 to 2019. RESULTS: A total of 3,879 cirrhosis patients with sepsis were admitted to the ICU (43.2% female, 20.5% Hispanic, 12.4% on dialysis; mean initial LA 4.5 mmol/L, MELD 20.8, MELD-LA 17.6). Survivors showed a median lactate change of −1.04 (35% clearance) compared with −0.4 (12%) for nonsurvivors. LA clearance within 24 hours was influenced by the presenting MELD-LA. In the North American cohort, ≥35% LA clearance was associated with improved 30-day survival (odds ratio 0.41, 95% CI 0.31–0.53; P < 0.001). Similarly, in the Asian Pacific Association for the Study of the Liver cohort (n = 1,259), ≥35% clearance was linked to a 60% reduction in mortality (odds ratio 0.42, 95% CI 0.28–0.62; P < 0.001). When stratified by LA clearance, patients with LA clearance of ≥35% had a higher percentage of early administration of resuscitative measures than those with LA clearance of < 10% especially regarding early antibiotic administration (82.5% vs 67.6%; P value <0.001). DISCUSSION: Early reduction in initial LA by one-third predicts 30-day mortality and may indicate treatment response in cirrhosis patients with sepsis in the ICU. Combining MELD-LA and LA clearance early enables better risk stratification and informs management.

Background and Aims: Severe alcohol-associated hepatitis (AH) is rising in incidence with a high mortality burden. While corticosteroids are recommended for eligible patients with severe AH, no guidance exists for the timing of steroid initiation, tapering regimens, and surveillance of adverse events. We aim to systematically review these variables and provide evidence-based recommendations for the inpatient and outpatient management of severe AH. Approach and Results: We performed a literature search from inception to May 30, 2024, to include clinical trials published in full form and assessed the quality of evidence using the Cochrane Risk of Bias tool. Data were collected on the timing of initiation, rate, and complications following steroid therapy, and taper regimens in the setting of severe AH. Of 28 studies that fulfilled our inclusion criteria, the median time from admission to steroid initiation was 6.5 days. The most common steroid dosing regimen was prednisolone 40 mg daily for 28 days. Twenty-five studies containing 3196 subjects reported adverse events, with exactly 50% in the steroid arm and the other half in the comparison arm. Infections, gastrointestinal bleeds, and renal impairment were the most frequently reported adverse events. Most infections occurred within the first month of the study. A 2-week steroid taper was the most frequently reported regimen. Conclusions: We recommend taking up to a week to systematically and thoroughly evaluate patients before initiating steroids, and vigilant monitoring in the first month of treatment. We also recommend the lowest possible steroid exposure with a 2-week steroid taper and close outpatient follow-up.

Acute kidney injury (AKI) frequently complicates the course of hospitalized patients with cirrhosis and negatively affects their prognosis. How AKI response influences the timing of liver transplantation (LT) remains unclear. We sought to assess the impact of AKI response to treatment on survival and LT rates in patients with cirrhosis awaiting LT. This was a retrospective multicenter study of cirrhosis patients waitlisted for LT and hospitalized with AKI in 2019. The exposure was AKI response versus no response during hospitalization. Outcomes were 90-day overall and transplant-free survival, and rates of LT with time to transplant. We adjusted for age, sex, race, cirrhosis etiology, site, and Model for End-Stage Liver Disease-Sodium (MELD-Na) score. Among the 317 patients in this study, 170 had an AKI response (53.6%), and 147 had no response (46.4%). Compared to nonresponders, responders had better 90-day overall survival (89.4% vs. 76.2%, adjusted subhazard ratio for mortality 0.34, p=0.001), and transplant-free survival (63.5% vs. 25.2%, aHR for probability of death or transplant 0.35, p<0.001). The LT rate was lower in responders (45.9% vs. 61.2%, adjusted subhazard ratio 0.55, p=0.005); 79% of transplants in responders occurred after discharge, at a median of 103 days, while 62% of transplants in nonresponders occurred during hospitalization, with the remainder occurring postdischarge at a median of 58 days. In patients with cirrhosis waitlisted for LT who are hospitalized with AKI, AKI response to therapy is associated with improved 90-day survival, despite a reduced LT rate and longer time to LT.

Summary Background & Aims The development of acute kidney injury (AKI) in the setting of alcohol‐associated hepatitis (AH) portends a poor prognosis. Whether the presence of AH itself drives worse outcomes in patients with cirrhosis and AKI is unknown. Methods Retrospective cohort study of 11 hospital networks of consecutive adult patients admitted in 2019 with cirrhosis and AKI. AKI phenotypes, clinical course, and outcomes were compared between AH and non‐AH groups. Results A total of 2062 patients were included, of which 303 (15%) had AH, as defined by National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria. Patients with AH, compared to those without, were younger and had higher Model for End‐stage Liver Disease‐Sodium (MELD‐Na) scores on admission. AKI phenotypes significantly differed between groups ( p < 0.001) with acute tubular necrosis occurring more frequently in patients with AH. Patients with AH reached more severe peak AKI stage, required more renal replacement therapy, and had higher 90‐day cumulative incidence of death (45% [95% CI: 39%–51%] vs. 38% [95% CI: 35%–40%], p = 0.026). Using no AH as reference, the unadjusted sHR for 90‐day mortality was higher for AH (sHR: 1.24 [95% CI: 1.03–1.50], p = 0.024), but was not significant when adjusting for MELD‐Na, age and sex. However, in patients with hepatorenal syndrome, AH was an independent predictor of 90‐day mortality (sHR: 1.82 [95% CI: 1.16–2.86], p = 0.009). Conclusions Hospitalised patients with cirrhosis and AKI presenting with AH had higher 90‐day mortality than those without AH, but this may have been driven by higher MELD‐Na rather than AH itself. However, in patients with hepatorenal syndrome, AH was an independent predictor of mortality.

Racial, ethnic, and socioeconomic disparities exist in the prevalence and natural history of chronic liver disease, access to care, and clinical outcomes. Solutions to improve health equity range widely, from digital health tools to policy changes. The current review outlines the disparities along the chronic liver disease health care continuum from screening and diagnosis to the management of cirrhosis and considerations of pre-liver and post-liver transplantation. Using a health equity research and implementation science framework, we offer pragmatic strategies to address barriers to implementing high-quality equitable care for patients with chronic liver disease.