Joint last author.
Article first published online: 28 OCT 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 5, pages 1767–1776, November 2011
How to Cite
Starkey Lewis, P. J., Dear, J., Platt, V., Simpson, K. J., Craig, D. G.N., Antoine, D. J., French, N. S., Dhaun, N., Webb, D. J., Costello, E. M., Neoptolemos, J. P., Moggs, J., Goldring, C. E. and Park, B. K. (2011), Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatology, 54: 1767–1776. doi: 10.1002/hep.24538
Potential conflict of interest: Nothing to report.
Part of this work was funded by Novartis in the form of a PhD studentship (to P.S.L.) as part of the Center for Drug Safety Science supported by the Medical Research Council (grant no.: G0700654).
Joint first author.
- Issue published online: 28 OCT 2011
- Article first published online: 28 OCT 2011
- Accepted manuscript online: 11 JUL 2011 12:31PM EST
- Manuscript Accepted: 24 JUN 2011
- Manuscript Received: 26 APR 2011
New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver-enriched microRNAs (miR-122 and miR-192) are promising biomarkers of acetaminophen-induced acute liver injury (APAP-ALI) in mice. We have examined these molecules, for the first time, in humans with APAP poisoning. Serum miR-122 and miR-192 were substantially higher in APAP-ALI patients, compared to healthy controls (median ΔΔCt [25th, 75th percentile]) (miR-122: 1,265 [491, 4,270] versus 12.1 [7.0, 26.9], P < 0.0001; miR-192: 6.9 [2.0, 29.2] versus 0.44 [0.30, 0.69], P < 0.0001). A heart-enriched miR-1 showed no difference between APAP-ALI patients and controls, whereas miR-218 (brain-enriched) was slightly higher in the APAP-ALI cohort (0.17 [0.07, 0.50] versus 0.07 [0.04, 0.12]; P = 0.01). In chronic kidney disease (CKD) patients, miR-122 and -192 were modestly higher, compared to controls (miR-122: 32.0 [21.1, 40.9] versus 12.1 [7.0, 26.9], P = 0.006; miR-192: 1.2 [0.74, 1.9] versus 0.44 [0.30, 0.69], P = 0.005), but miR-122 and -192 were substantially higher in APAP-ALI patients than CKD patients (miR-122: P < 0.0001; miR-192: P < 0.0004). miR-122 correlated with peak ALT levels in the APAP-ALI cohort (Pearson R = 0.46, P = 0.0005), but not with prothrombin time. miR-122 was also raised alongside peak ALT levels in a group of patients with non-APAP ALI. Day 1 serum miR-122 levels were almost 2-fold higher in APAP-ALI patients who satisfied King's College Criteria (KCC), compared to those who did not satisfy KCC, although this did not reach statistical significance (P = 0.15). Conclusion: This work provides the first evidence for the potential use of miRNAs as biomarkers of human drug-induced liver injury. (HEPATOLOGY 2011;)