Understanding the pathophysiological regulatory role of microRNAs in acute liver failure
Authors: Daniel J. Antoine, James W. Dear, Christopher E. Goldring, B. Kevin Park
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: We read with great interest the recent article by John et al. in Hepatology that described a potential role for microRNAs (miRNAs) in spontaneous recovery from acute liver failure (ALI).1 These potentially important data demonstrate elevated circulating miRNAs, especially miR‐122, in human subjects with ALI, which confirms published work from our group and elsewhere.2 However, we have significant concerns about a number of the findings reported in this article. The investigators report that higher circulating and liver levels of miR‐122 relate to spontaneous survival and contribute to regeneration and enhanced proliferation. These conclusions directly conflict with the well‐established, replicated findings that miR‐122 knockout mice and mice with deletions in miR‐122 regulators, such as Dicer1, have enhanced levels of hepatocyte proliferation,3 that the loss of miR‐122 from hepatocytes results in reduced differentiation and enhanced proliferation,4 and that the levels of miR‐122 are decreased in liver, yet increased in blood, of rodent models of ALI.5 Furthermore, we feel that robust conclusions cannot be based on liver miR‐122 expression data from a very low number of patients (n = 4 and n = 6 for recovery and nonrecovery, respectively). We appreciate that liver tissue cannot always be obtained; but for the small patient cohort where liver samples were collected, it would be very interesting to determine the intrapatient correlation between hepatic and circulating miR‐122 expression levels in order to determine the nature of this relationship and how it relates to patient outcome, rather than drawing conclusions based on averages between the heterogeneous groups. The circulating miR‐122 data presented, although from a larger cohort, could have been heavily influenced by a few potential outliers. Indeed, this is reflected by the weak association from the receiver operating characteristic analysis. The observations published by John et al. are in conflict with our results published in a larger, well‐defined cohort of patients with ALI induced by acetaminophen that show a trend toward increased circulating levels in patients with worse prognosis and outcome.2 We are concerned that the conclusions from this present study are based on patient cohorts with etiologies of ALI that are very diverse and differ substantially between survivors and nonsurvivors, which further complicates the interpretation of liver miR‐122 expression data. It is possible, even probable, that the natural histories of these underlying disease processes are diverse enough to explain differences in miRNA expression, and the conclusions of this study should be interpreted in light of this. In addition, we have shown that the kinetics of miR‐122 are significantly different, compared with other biomarkers, and that miR‐122 is raised earlier in blood, compared with more established biomarkers.6 The current conclusions on the quantifiable level of circulating miR‐122 reflecting patient outcome would be easier to interpret if these variables had been presented (i.e., time taken from biomarker measurement to outcome for each group). In summary, we welcome the important contributions of this current study. Once our concerns can be addressed, the field can move forward together to define the context of use of miRNAs as biomarkers of liver injury with the possibility of their application in patient stratification.