Letter to the Editor: Tale of Two ACLF Definitions: Choices Are Getting Clearer
Authors: Ashok Choudhury, Shiv Kumar Sarin
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To The Editor: We read the study by Mahmud et al. that applies Asian Pacific Association for the Study of the Liver (APASL)1 and European Association for the Study of the Liver–Chronic Liver Failure (EASL‐CLIF)2 acute‐on‐chronic liver failure (ACLF) definitions to a large cohort of patients. The median bilirubin and creatinine at presentation in the EASL‐defined cohort were around 2 mg/dL each, and the 28‐day mortality was 37%.3 The median bilirubin and creatinine using APASL criteria were 6.5 mg/dL and 0.8 mg/dL, respectively, with a 28‐day mortality of 40%. The causes of death would be different. Likewise, Mahmud et al. state that APASL criteria identify high short‐term mortality events with liver‐specific injury, whereas the EASL criteria identify nonhepatotropic causes.3 In fact, the most commonly identified organ failure EASL grade was the kidney, whereas liver was the most infrequent. Indeed, a patient with cirrhosis may have three organ failures (circulatory, pulmonary, and renal) with normal bilirubin, and die. This would hardly justify being identified as ACLF. Mahmud et al. rightly propose that the EASL criteria for liver failure should not be so restrictive and be adjusted from ≥12 mg/dL to ≥5 mg/dL. The definition should ideally be parsimonious; the insult should act on the primary affected organ, and the nominal organ of the syndrome (i.e., liver) should be targeted. This thought should help in early identification of liver‐directed therapies, such as transplant, that might influence outcomes.1 We would like to draw attention to another concept from the APASL definition (i.e., of a therapeutic "golden window" of 1 week) (Fig. 1): the time between inflammation and development of systemic inflammatory response syndrome and sepsis.1 The APASL‐ACLF research Consortium (AARC) score is a dynamic, simple, bedside tool to prognosticate and guide the treatment (Table 1). It would be worthwhile to test the AARC score in the Western cohort of patients with hepatic ACLF.4Figure 1: Showing evolution of organ failure and complications in ACLF. Depicting the concept for development of ACLF syndrome as per APASL and EASL CLIF (modified from ref 8). Table 1 - AARC Score and ACLF Grade4 AARC Score Points Total Bilirubin (mg/dL) HE Grade PT INR Lactate (mmol/L) Creatinine (mg/dL) 1 <15 0 <1.8 <1.5 <0.7 2 15‐25 I‐II 1.8‐2.5 1.5‐2.5 0.7‐1.5 3 >25 III‐IV >2.50 >2.5 >1.5 Minimum 5, Maximum 15 AARC ACLF Grade Grade Score I 5‐7 II 8‐10 III 11‐15 Abbreviations: HE, hepatic encephalopathy; INR, international normalized ratio; and PT, prothrombin time. We are intrigued by the 28‐day mortality of 50% in patients with hepatitis C virus plus ethanol more than the hepatitis B virus and ethanol cohort using the APASL definition. The mortality was higher in the overweight compared with obese in the APASL‐defined cohort and almost similar using the EASL criteria. Does this mean that obese ACLF in the EASL cohort more often die of renal failure, which may be due to concurrent hypertension, diabetes, and chronic kidney disease than liver failure?5 Could the authors clarify the influence of body mass index on ACLF outcomes, using both criteria?