Bajaj, Jasmohan S.

Acute on chronic liver failure (ACLF) is the culmination of chronic liver disease and extrahepatic organ failures, which is associated with a high short‐term mortality and immense health care expenditure. There are varying definitions for organ failures and ACLF in Europe, North America, and Asia. These differing definitions need to be reconciled to enhance progress in the field. The pathogenesis of ACLF is multifactorial and related to interactions between the immunoinflammatory system, microbiota, and the various precipitating factors. Individual organ failures related to the kidney, brain, lungs, and circulation have cumulative adverse effects on mortality and are often complicated or precipitated by infections. Strategies to prevent and rapidly treat these organ failures are paramount in improving survival. With the aging population and paucity of organs for liver transplant, the prognosis of ACLF patients is poor, highlighting the need for novel therapeutic strategies. The role of liver transplant in ACLF is evolving and needs further investigation across large consortia. A role for early palliative care and management of frailty as approaches to alleviate disease burden and improve patient‐reported outcomes is being increasingly recognized. Conclusion: ACLF is a clinically relevant syndrome that is epidemic worldwide and requires a dedicated multinational approach focused on prognostication and management; investigations are underway worldwide to prepare ACLF for prime time. (Hepatology 2018; 00:000‐000)

Hepatic encephalopathy (HE) is a major cause of morbidity in cirrhosis. However, its severity assessment is often subjective, which needs to be studied systematically. The aim was to determine how accurately trainee and nontrainee practitioners grade and manage HE patients throughout its severity. We performed a survey study using standardized simulated patient videos at 4 US and 3 Canadian centers. Participants were trainees (gastroenterology/hepatology fellows) and nontrainees (faculty, nurse practitioners, physician assistants). We determined the accuracy of HE severity identification and management options between grades <2 or ≥2 HE and trainees/nontrainees. In total, 108 respondents (62 trainees, 46 nontrainees) were included. For patients with grades <2 versus ≥2 HE, a higher percentage of respondents were better at correctly diagnosing grades ≥2 compared with grades <2 (91% versus 64%; P < 0.001). Specialized cognitive testing was checked significantly more often in grades <2, whereas more aggressive investigation for precipitating factors was ordered in HE grades >2. Serum ammonia levels were ordered in almost a third of grade ≥2 patients. For trainees and nontrainees, HE grades were identified similarly between groups. Trainees were less likely to order serum ammonia and low‐protein diets, more likely to order rifaximin, and more likely to perform a more thorough workup for precipitating factors compared with nontrainee respondents. There was excellent concordance in the classification of grade ≥2 HE between nontrainees versus trainees, but lower grades showed discordance. Important differences were seen regarding blood ammonia, specialized testing, and nutritional management between trainees and nontrainees. These results have important implications at the patient level, interpreting multicenter clinical trials, and in the education of practitioners. Liver Transplantation 24 587–594 2018 AASLD.

The North American Consortium for the Study of End‐Stage Liver Disease's definition of acute‐on‐chronic liver failure (NACSELD‐ACLF) as two or more extrahepatic organ failures has been proposed as a simple bedside tool to assess the risk of mortality in hospitalized patients with cirrhosis. We validated the NACSELD‐ACLF's ability to predict 30‐day survival (defined as in‐hospital death or hospice discharge) in a separate multicenter prospectively enrolled cohort of both infected and uninfected hospitalized patients with cirrhosis. We used the NACSELD database of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 2,675). The cohort was randomly split 60%/40% into training (n = 1,605) and testing (n = 1,070) groups. Organ failures assessed were (1) shock, (2) hepatic encephalopathy (grade III/IV), (3) renal (need for dialysis), and (4) respiratory (mechanical ventilation). Patients were most commonly Caucasian (79%) men (62%) with a mean age of 57 years and a diagnosis of alcohol‐induced cirrhosis (45%), and 1,079 patients had an infection during hospitalization. The mean Model for End‐Stage Liver Disease score was 19, and the median Child score was 10. No demographic differences were present between the two split groups. Multivariable modeling revealed that the NACSELD‐ACLF score, as determined by number of organ failures, was the strongest predictor of decreased survival after controlling for admission age, white blood cell count, serum albumin, Model for End‐Stage Liver Disease score, and presence of infection. The c‐statistics were 0.8073 for the training set and 0.8532 for the validation set. Conclusion: Although infection status remains an important predictor of death, NACSELD‐ACLF was independently validated in a separate large multinational prospective cohort as a simple, reliable bedside tool to predict 30‐day survival in both infected and uninfected patients hospitalized with a diagnosis of cirrhosis. (H epatology 2018;67:2367‐2374).

In smaller single‐center studies, patients with cirrhosis are at a high readmission risk, but a multicenter perspective study is lacking. We evaluated the determinants of 3‐month readmissions among inpatients with cirrhosis using the prospective 14‐center North American Consortium for the Study of End‐Stage Liver Disease cohort. Patients with cirrhosis hospitalized for nonelective indications provided consent and were followed for 3 months postdischarge. The number of 3‐month readmissions and their determinants on index admission and discharge were calculated. We used multivariable logistic regression for all readmissions and for hepatic encephalopathy (HE), renal/metabolic, and infection‐related readmissions. A score was developed using admission/discharge variables for the total sample, which was validated on a random half of the total population. Of the 1353 patients enrolled, 1177 were eligible on discharge and 1013 had 3‐month outcomes. Readmissions occurred in 53% (n = 535; 316 with one, 219 with two or more), with consistent rates across sites. The leading causes were liver‐related (n = 333; HE, renal/metabolic, and infections). Patients with cirrhosis and with worse Model for End‐Stage Liver Disease score or diabetes, those taking prophylactic antibiotics, and those with prior HE were more likely to be readmitted. The admission model included Model for End‐Stage Liver Disease and diabetes (c‐statistic = 0.64, after split‐validation 0.65). The discharge model included Model for End‐Stage Liver Disease, proton pump inhibitor use, and lower length of stay (c‐statistic = 0.65, after split‐validation 0.70). Thirty percent of readmissions could not be predicted. Patients with liver‐related readmissions consistently had index‐stay nosocomial infections as a predictor for HE, renal/metabolic, and infection‐associated readmissions (odds ratio = 1.9‐3.0). Conclusions: Three‐month readmissions occurred in about half of discharged patients with cirrhosis, which were associated with cirrhosis severity, diabetes, and nosocomial infections; close monitoring of patients with advanced cirrhosis and prevention of nosocomial infections could reduce this burden. (Hepatology 2016;64:200–208)

Because Model for End‐Stage Liver Disease (MELD) scores at the time of liver transplantation (LT) increase nationwide, patients are at an increased risk for delisting by becoming too sick or dying while awaiting transplantation. We quantified the risk and defined the predictors of delisting or death in patients with cirrhosis hospitalized with an infection. North American Consortium for the Study of End‐Stage Liver Disease (NACSELD) is a 15‐center consortium of tertiary‐care hepatology centers that prospectively enroll and collect data on infected patients with cirrhosis. Of the 413 patients evaluated, 136 were listed for LT. The listed patients' median age was 55.18 years, 58% were male, and 47% were hepatitis C virus infected, with a mean MELD score of 2303. At 6‐month follow‐up, 42% (57/136) of patients were delisted/died, 35% (47/136) underwent transplantation, and 24% (32/136) remained listed for transplant. The frequency and types of infection were similar among all 3 groups. MELD scores were highest in those who were delisted/died and were lowest in those remaining listed (25.07, 24.26, 17.59, respectively; P < 0.001). Those who were delisted or died, rather than those who underwent transplantation or were awaiting transplantation, had the highest proportion of 3 or 4 organ failures at hospitalization versus those transplanted or those continuing to await LT (38%, 11%, and 3%, respectively; P = 0.004). For those who were delisted or died, underwent transplantation, or were awaiting transplantation, organ failures were dominated by respiratory (41%, 17%, and 3%, respectively; P < 0.001) and circulatory failures (42%, 16%, and 3%, respectively; P < 0.001). LT‐listed patients with end‐stage liver disease and infection have a 42% risk of delisting/death within a 6‐month period following an admission. The number of organ failures was highly predictive of the risk for delisting/death. Strategies focusing on prevention of infections and extrahepatic organ failure in listed patients with cirrhosis are required. Liver Transpl 21:881‐888, 2015. © 2015 AASLD.