MicroRNA-122 and cytokeratin-18 have potential as a biomarkers of drug-induced liver injury in European and African patients on treatment for mycobacterial infection.

Rupprechter, Sarah A E; Sloan, Derek J; Oosthuyzen, Wilna; Bachmann, Till T; Hill, Adam T; Dhaliwal, Kevin; Templeton, Kate; Matovu, Joshua; Sekaggya-Wiltshire, Christine; Dear, James W

AIM Patients on anti-tuberculosis (anti-TB) therapy are at risk of drug-induced liver injury (DILI). MicroRNA-122 (miR-122) and cytokeratin-18 (K18) are DILI biomarkers. To explore their utility in this global context, circulating miR-122 and K18 were measured in UK and Ugandan populations on anti-TB therapy for mycobacterial infection. METHODS Healthy subjects and patients receiving anti-TB therapy were recruited at the Royal Infirmary of Edinburgh, UK (ALISTER-ClinicalTrials.gov Identifier: NCT03211208). African patients with HIV-TB coinfection were recruited at the Infectious Diseases Institute, Kampala, Uganda (SAEFRIF-NCT03982277). Serial blood samples, demographic and clinical data were collected. In ALISTER samples, MiR-122 was quantified using PCR. In ALISTER and SAEFRIF samples, K18 was quantified by ELISA. RESULTS The study had 235 participants (healthy volunteers (n=28); ALISTER: active TB (n=30), latent TB (n=88), non-tuberculous mycobacterial infection (n=25); SAEFRIF: HIV-TB coinfection (n=64)). In the absence of DILI, there was no difference in miR-122 and K18 across the groups. Both miR-122 and K18 correlated with alanine transaminase activity (ALT) (miR-122:r=0.52,95%CI=0.42-0.61,P<0.0001. K18:r=0.42,95%CI=0.34-0.49,P<0.0001). miR-122 distinguished those patients with ALT>50U/L with higher sensitivity/specificity than K18. There were two DILI cases: baseline ALT,18 and 28 IU/L, peak ALT 431 and 194 IU/L; baseline K18, 58 and 219 U/L, peak K18 1247 and 3490 U/L; baseline miR-122 4 and 17 fM, peak miR-122 60 and 336 fM, respectively. CONCLUSION In patients treated with anti-TB therapy miR-122 and K18 correlated with ALT and increased with DILI. Further work should determine their diagnostic and prognostic utility in this global context-of-use.