PAT-DILI
Research type
Research Study
Full title
A Study Investigating the Role of Porphyrins in Anti-Tuberculous Drug-Induced Liver Injury
IRAS ID
162047
Contact name
Munir Pirmohamed
Contact email
Sponsor organisation
University of Liverpool
Clinicaltrials.gov Identifier
15/NW/0364, REC Reference
Duration of Study in the UK
2 years, 0 months, 0 days
Research summary
Tuberculosis is a major global health problem: there were approximately 9.0 million new cases and 1.5 million deaths in 2013 alone. The cornerstone of TB management is combined drug therapy with isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E). Although these drugs are effective, they are associated with a number of adverse drug reactions (ADRs). Liver injury is the most severe of these and is associated with three of the four first-line drugs (H, R and Z), occurring in 2-28% of patients with combined therapy. The deleterious consequences of anti-tuberculous drug-induced liver injury (ATDILI) include treatment interruptions, treatment failure and increased risk of drug-resistance. Moreover, ATDILI itself can lead to acute liver failure and, even, death.
Although AT-DILI has been recognized for numerous decades, the underlying mechanisms are still not well understood. As a result, our strategies to prevent and manage AT-DILI when it occurs are lacking. An increased understanding of the pathophysiology of this important ADR is needed.
Recent findings from an animal model have proposed a novel hypothesis: anti-tuberculous drugs may cause liver injury via a disturbance of porphyrin metabolism in the liver, leading to an accumulation of a toxic substance called protoporphyrin IX (PPIX). This is seen in a rare inherited disease (Erythropoietic Protoporphyria) in which profound liver impairment occurs.
The role of porphyrins in AT-DILI has not been investigated in humans before. This study seeks to address this knowledge gap. We want to know what happens to the levels of porphyrins in a patient’s blood and urine, as well as the activity of certain genes controlling the ‘porphyrin pathway’, when started on TB drugs, and how these changes relate to alterations in liver function. This is the vital next step to determine in investigating the role of porphyrins in AT-DILI.
REC name
North West - Greater Manchester West Research Ethics Committee
REC reference
15/NW/0364
Date of REC Opinion
5 Jun 2015
REC opinion
Further Information Favourable Opinion