Steroid resistance and Inflammatory bowel disease

Abstract

Background: Steroid resistance remains a significant issue amongst IBD patients and mechanisms of resistance remain poorly understood. Endogenous Glucocorticoid metabolism may represent a key regulatory pathway in IBD. 11-beta hydroxysteroid dehydrogenase type 1 and 2 are key isoenzymes which control the activation and inactivation of cortisol at a tissue level. The aims of this dissertation were to provide a better understanding of the molecular mechanisms of steroid metabolism in IBD and outline the role of the 11-beta hydroxysteroid dehydrogenase enzyme system in IBD overall and specifically determine if alterations in this pathway may play a role in IBD resistance. Methods: A retrospective observational study was undertaken to identify clinical predictors of resistance amongst IBD patients initially to determine current rates of resistance in a tertiary IBD centre. A literature review was then undertaken to identify potential mechanisms of steroid resistance in IBD and to examine the role of the 11-beta hydroxysteroid dehydrogenase enzyme system in IBD. Additional prospective studies were then undertaken to examine the11-beta hydroxysteroid dehydrogenase enzyme and its cofactors in IBD patients using real time PCR. We later went onto examine this system in relation to steroid responders and non-responders. Results: Rates of resistance remained significant at 22%. Clinical predictors of GCS failure included an elevated CRP, significant anaemia, hypoalbuminaemia, severe endoscopic disease and extensive disease. Our initial data concluded that 11-beta hydroxysteroid 2 gene expression was downregulated in patients with IBD with an increased 11-beta hydroxysteroid 1:2 ratio correlating with inflammatory activity in IBD patients. We later identified that resistant subjects demonstrated reduced levels of 11-beta hydroxysteroid dehydrogenase type 1, Hexose-6-phosphate-dehydrogenase (regulator) and the glucocorticoid receptor with an apparent upregulation of inflammatory cytokines compared with responders. Conclusions: Early identification of these critical clinical indicators of GCS failure could improve overall outcomes for the patients. Significant alterations in 11-beta hydroxysteroid enzyme system exists amongst steroid resistant groups. Further work on mechanisms GR upregulation and increased 11-beta hydroxysteroid type 1 expression may provide a potential therapeutic pathway to overcome GCS resistance. Alternatively, basal measurement of 11-beta hydroxysteroid, glucocorticoid receptor and cytokines amongst IBD subjects could enable earlier identification of patients likely to fail GCS, potentially avoiding cumulative side-effects and earlier escalation of therapies.