Patient Stratification at Point of Care Using Rapid microRNA Detection

The electrochemical impedance spectroscopy biosensing platform is able to sense microRNA and proteins, and has the potential to be used at point of care to rapidly detect biomarkers which indicate disease state. Biomarkers which indicate liver injury have been found and shown to diagnose and predict acute liver injury in acetaminophen overdose. This PhD project going to further study these biomarkers, looking at liver injury as a result of anti-tuberculosis drugs in patients with tuberculosis (TB).
The three biomarkers of interest are, microRNA 122 (miR-122), High Mobility Group Box-1 (HMGB1) and keratin-18. These biomarkers have previously been shown to diagnose acute liver injury due to acetaminophen overdose and were more sensitive than serum aminotransferase (ALT) at predicting acute liver injury on presentation to the hospital. This project aims to determine if the biomarkers rise from baseline levels in patients with anti-tuberculosis drug-induced liver damage in latent TB and in active TB. The biomarkers also have the potential to be used as prognostic biomarkers to predict the need to halt medication in TB patients.
Treatment of TB relies on antibiotic therapy with a combination of antibiotics taken over 6-12 months. Three of the first-line treatments for TB are associated with elevated ALT levels and anti-tuberculosis drug-induced liver injury. 10-20% of patients treated with anti-tuberculosis drugs have elevated levels of ALT. 1% go on to develop acute liver injury with a mortality rate of 10%. The latent period between the start of therapy and development of acute liver injury can range from 1 week to 12 months, with a median period of 8 weeks. The risk of anti-tuberculosis drug-induced liver injury in patients means that monitoring of liver function is required, with levels of ALT currently used as an indicator of liver function.

A key part of this project is a clinical study which will take place at the Royal Infirmary Edinburgh TB clinic, which sees 60-90 new cases of active TB every year, as well as 150-200 new cases of latent TB and 20 new cases of environmental TB. Liver function in TB patients is monitored every month through levels of ALT. ALT levels greater than five times the upper limit of normal, or greater than three times the upper limit of normal in the presence of symptoms indicates liver injury. In these patients anti-tuberculosis treatment is either stopped and then later restarted, or modified to find a treatment which doesn't result in liver injury. The clinical study will collect blood samples (venepuncture and fingerprick) as well as clinical data to assess whether changes in biomarker levels can diagnose and predict anti-tuberculosis drug-induced liver injury.

Detecting these biomarkers from a fingerprick sample with electrochemical impedance spectroscopy will enable us to develop a rapid point of care test to both diagnose and predict the outcome of anti-tuberculosis drug-induced liver injury. Currently, anti-tuberculosis drug-induced liver injury is the most frequent side-effect of anti-tuberculosis therapy and this hinders the effective treatment of TB, particularly in the developing world, as it means that treatment regimens are not completed. A rapid point of care test for anti-tuberculosis drug-induced liver injury has the potential to guide anti-tuberculosis therapy, reduce the number of people with anti-tuberculosis drug-induced liver injury, and enable more patients to finish treatment regimens.