Circulating microRNAs as potential markers of human drug-induced liver injury

✍ Scribed by Philip J. Starkey Lewis; James Dear; Vivien Platt; Kenneth J. Simpson; Darren G.N. Craig; Daniel J. Antoine; Neil S. French; Neeraj Dhaun; David J. Webb; Eithne M. Costello; John P. Neoptolemos; Jonathan Moggs; Chris E. Goldring; B. Kevin Park

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 217 KB
• Volume: 54
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.24538

✦ Synopsis

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 DDCt [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 5 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 5 0.006; miR-192: 1.2 [0.74, 1.9] versus 0.44 [0.30, 0.69], P 5 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 5 0.46, P 5 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 5 0.15). Conclusion: This work provides the first evidence for the potential use of miRNAs as biomarkers of human drug-induced liver injury.