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

Abstract

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] 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. (HEPATOLOGY 2011;54:1767-1776 T he development of informative biomarkers of drug-induced liver injury (DILI) remains a primary aim in clinical and preclinical settings. The challenge is to develop biomarkers that are stable, that can be rapidly and accurately quantified in standard hospital laboratories, are minimally invasive, tissue specific, and add true diagnostic/prognostic value to detect and monitor the level of a pathogenic insult to the liver.1 The current battery of available biomarkers to assess liver integrity includes circulating protein markers of hepatocellular injury, such as the aminotransferases, markers of liver functional impairment, such as prothrombin time, markers of blood chemistry, and a number of novel mechanistic biomarkers of tissue injury (e.g., cytokeratin-18 and high-mobility group box-1 protein). 2 Deficiencies discovered with current blood-based biomarkers include the unacceptable frequency of false positives/negatives, poor

MicroRNAs in Liver Disease: Bench to Bedside

“…40,44,45 Serum/plasma levels of miR-122 correlate with hepatic necro-inflammation, liver damage, cell death and increased aminotransferase levels in acute and chronic liver diseases. 44,[46][47][48][49] Interestingly, hepatic and circulating miR-122 levels do not correlate in NAFLD 14,39,[50][51][52][53][54][55] or viral hepatitis 41,47,49,56 although both have been statistically associated with various measures of disease severity in these studies. Together these studies show that miR-122 may play a role in most liver diseases.…”

“…18 They were not only found to be significantly higher but also detected earlier in patients with acetaminopheninduced liver injury as compared with healthy controls. 46 MiR-122 levels correlated with peak ALT levels but not with prothrombin time, serum bilirubin or creatinine. 46 This may be explained by circulatory kinetics of these markers and it is possible that miR-122 release is an earlier event than the cessation of hepatic-clotting factor production or heme-metabolism alteration during DILI.…”

“…46 MiR-122 levels correlated with peak ALT levels but not with prothrombin time, serum bilirubin or creatinine. 46 This may be explained by circulatory kinetics of these markers and it is possible that miR-122 release is an earlier event than the cessation of hepatic-clotting factor production or heme-metabolism alteration during DILI. However, miR-122 was significantly higher in nonacetaminophen DILI patients, compared to healthy controls.…”

Liver Specific Serum Micro RNA122 as a Prognostic Marker in Egyptian Patients with Liver Cirrhosis

“…(miRNAs, miRs) are small (18)(19)(20)(21)(22)(23)(24)(25) ribonucleotides) non-coding RNAs which function in transcriptional and post-transcriptional regulation of gene expression [11]. Circulating miRs are,in large part, derived from cells with damaged plasma membrane [12] and circulate in the blood freely and in a relatively stable form [13,14].…”

Circulating microRNAs: macro-utility as markers of prostate cancer?

“…In a recent study, we used the TRAMP model of PCa in the discovery (profiling) phase and then validated a subset of circulating miRNAs in human patient samples (Selth et al 2011). Other recent studies have further highlighted the utility of mouse models of disease for the discovery of blood-derived miRNA markers (Cacchiarelli et al 2011, LaConti et al 2011, Mizuno et al 2011, Starkey Lewis et al 2011. We believe that animal models will be increasingly used for this purpose in the coming years in order to fast track the development of novel clinical biomarkers and therapeutics.…”