P613 Regulators of glucocorticoid metabolism in inflammatory dowel disease and predicting response to steroid therapy
M. Hussey*1, A. Cannon2, G. Holleran1, J. O’Sullivan3, M. Sherlock4, D. McNamara1
1Adelaide and Meath Hospital, Trinity College Dublin, Gastroenterology, Trinity Academic Gastroenterology Group, Dublin, Ireland, 2St James’s Hospital, Trinity College Dublin, Surgery, Dublin, Ireland, 3St James’s Hospital, Trinity College Dublin, Gastroenterology, Dublin, Ireland, 4Adelaide & Meath Hospital, Dublin, Incorporating The National Children’s Hospital, Endocrinology, Dublin, Ireland
Steroid responsiveness remains an important therapeutic issue in IBD. Colonic tissue steroid metabolism is regulated by the 11 beta hydroxysteroid dehydrogenase (11βHSD) system. Further, 11βHSD1, an oxoreductase, converts inactive cortisone into active cortisol, whereas 11βHSD2 a dehydrogenase does the reverse. Variation in 11βHSD regulation and expression may affect local steroid availability in IBD. Aim: to determine expression of 11βHSD 1 and 2 and key regulators Hexose6Phosphate Dehydrogenase (H6PDH) and GRα receptor in colonic tissue in patients and controls, and to correlate levels with steroid response.
Patients undergoing colonoscopy for disease assessment/surveillance aged 18–80 yr were prospectively recruited. Demographics, Harvey–Bradshaw Index/Mayo Score (MS), CRP, and histological and endoscopic grade were recorded. Controls with a normal colonoscopy without a history of IBD were also recruited. Two biopsies were taken from inflamed and non-inflamed colon in patients, and a single left colonic biopsy was obtained in controls. Those who required a course of steroids after colonoscopy had repeat biochemical and clinical assessment within 2 weeks of completion. Response was defined as a CRP < 5 mg/l and a 3-point reduction in their HBI/MS. Biopsies were analysed in a batch, using quantitative real-time PCR (TaqMan) and commercially available probes. Relative transcript levels were determined, using 18S as a reference gene, and compared amongst groups and controlled for activity; a p-value of ˂ 0.05 was considered significant.
To date, 24 IBD (12 Crohn’s; 12 UC) and 12 controls have been recruited. Groups were demographically similar, 50% (n = 12) vs 75% (n = 9) female, mean age 42 vs 57 yr, respectively. Overall 50% (n = 12) had mild; 29% (n = 7) moderate; and 21% (n = 5) severe disease endoscopically. Overall mean HBI was 6; MS was 7; and CRP was 22mg/l. For clinically active patients, mean CRP was 37 vs 2.0 mg/l for inactive disease, p < 0.04, 95% CI 68.8–1.7. In all, 11 (46%) required steroids, of whom 2 (18%) had no response. Overall, between IBD patients and controls there was no difference in expression of 11βHSD1 416 au vs 166 au (p = 0.4); GR-α 4.5 au v 2.1au (p = 0.4); and H6PDH 3.4 au v 3.9 au (p = 0.2). Interestingly, 11βHSD2 levels were lower in patients: 13.8 au vs controls 318.4 au, p < 0.01, 95% CI -517.5–-91.7. As a result, there was an increased proportion of 11βHSD1 compared with 11βHSD2 in IBD patients: 81:1 vs 1.5:1, p < 0.006, 95% CI 57.7–78.5. Importantly within the treated IBD group the only difference was a lower GRα level in non-responders vs responders, 0.2 vs 5.8, p < 0.04.
Results show that 11βHSD2 down regulation and the resultant rise in tissue cortisol bioavailability might play a key role in response to inflammation in IBD. However response to steroid treatment appears to be GR α dependent and warrants further investigation.