Reply:
Authors: Nadim Mahmud, David E. Kaplan, Tamar H. Taddei, David S. Goldberg
Journal: Hepatology (2019)

Supported by National Institutes of Health (2‐T32‐DK007740‐21A1 to N.M.). Potential conflict of interest: Nothing to report. We appreciate the interest in our manuscript evaluating and comparing the characteristics of Asian Pacific Association for the Study of the Liver (APASL) acute‐on‐chronic liver failure (ACLF) and European Association for the Study of the Liver (EASL) ACLF definitions in a large cohort of diverse patients with chronic liver disease1 and would like to respond to several queries raised by the hepatology community. First, Choudhury et al. echo our concern that EASL ACLF, which provides multiple pathways to meet criteria based on organ failures (OFs), is nonspecific and identifies many patients with high‐mortality events who ultimately die with near‐normal liver labs. We argue that a more liver‐specific definition would not only preserve the syndrome's face validity (i.e., "liver failure" should affect the liver) but would also be a more useful clinical tool in selecting patients for liver‐directed therapies. Indeed, the EASL liver OF cutoff of 12 mg/dL or greater comes directly from the Sequential Organ Failure Assessment score,2 which was based on expert opinion and not developed as a tool to classify liver‐specific events. Choudhury et al. also point out that EASL ACLF events occurred more often in obese patients in our study cohort as compared with APASL ACLF events (40.6% versus 29.7%). This is consistent with previously published data4 that increasing body mass index (BMI) is a risk factor for developing EASL ACLF but not APASL ACLF. Thus, we would hypothesize that obesity may be a surrogate for other comorbidities (such as hypertension, diabetes, and chronic kidney disease) that may cause many patients to rule in for nonhepatic EASL OFs and thus be classified as having EASL ACLF. To clarify this association, we plotted the relationship between BMI and the probability of developing ACLF in 1 year, by both definitions, in adjusted logistic regression models (Fig. 1A). Although the probability of APASL ACLF essentially does not vary with BMI, the relationship is in fact somewhat U‐shaped for EASL ACLF, in which patients with extremely low or extremely high BMIs are at increased risk of developing ACLF. Of note, obesity has not been shown to predict short‐term mortality once ACLF has developed, by either definition, including in our VOCAL cohort.Figure 1: Additional ACLF‐related analyses. (A) Relationship between BMI and probability of developing ACLF in 1 year*; (B) relative lead time of ACLF diagnosis for each definition; and (C) Kaplan‐Meier survival curves for patients meeting different ACLF definitions. *Models are adjusted for age, etiology of liver disease, albumin, platelet count, international normalized ratio, total bilirubin, and creatinine.Separately, Choudhary et al. raised two important questions aimed at identifying and potentially altering the management of ACLF patients at highest risk of short‐term mortality: (1) Which definition provided an earlier diagnosis of ACLF? and (2) Did patients meeting both EASL and APASL ACLF criteria have a worse survival than those meeting either criterion alone? To address the first question, we computed the relative lead times of ACLF diagnosis by each definition within 90 days of each other among patients who died from ACLF. The density distribution of these results is shown in Fig. 1B, where APASL criteria diagnosed ACLF a median of 2 days prior to EASL ACLF (interquartile range −6 days to +1 day; signed‐rank test: P < 0.001). We would caution that, in an administrative database such as VOCAL, these dates may vary by the coding algorithm used; however, these biases would be expected to impact both APASL and EASL definitions in this case. To address the second question, we plotted Kaplan‐Meier survival curves for patients meeting ACLF criteria by different definitions (Fig. 1C). As Choudhary et al. hypothesized, patients who ruled in for ACLF by both EASL and APASL definitions had poorer survival as compared to those with APASL or EASL ACLF alone (log‐rank test: P < 0.001). These analyses and others not presented here are part of ongoing research by our group to study differences in ACLF definitions and the implications of different classification schemes in clinical practice. It is our hope that the broader hepatology community continues to debate these important issues so that we arrive at consensus ACLF criteria that are parsimonious, amenable to meaningful research, and clinically useful for improving outcomes for patients suffering from this condition.