SFEBES2009 Oral Communications Diabetes and metabolism (8 abstracts)
Cortisol metabolism and hepatic expression of 11β-hydroxysteroid dehydrogenase type 1 in patients with non-alcoholic fatty liver disease
Adeeba Ahmed 1, , Theresa Brady 2 , Claire Bailey 2 , Phillip Guest 2 , Anton Wagenmakers 1 , Phillip Newsome 1, , Stephan Hubscher 1, , Elwyn Elias 1, , David Adams 1, , Jeremy Tomlinson 1, & Paul Stewart 1,
1University of Birmingham, Birmingham, UK; 2University Hospital Birmingham Foundation Trust, Birmingham, UK.
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. The role of glucocorticoids (GC) in its pathogenesis, is highlighted in patients with GC excess, Cushing’s syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although circulating cortisol levels are normal in patients with NAFLD, hepatic cortisol availability is controlled by enzymes that regenerate cortisol from inactive cortisone (11β-hydroxysteroid dehydrogenase type 1,11β-HSD1) or inactivate cortisol through A-ring metabolism (5α- and 5β-reductase, 5αR and 5βR).
We characterised hepatic cortisol metabolism in 16 patients with histologically proven NAFLD (eight steatosis, eight steatohepatitis (NASH)) and 32 BMI-matched controls. We also analysed 11β-HSD1 mRNA expression and protein expression by immunohistochemistry in liver from five NASH patients and five normal controls.
In patients with steatosis 5αR activity was increased (urine 5αTHF/THF ratio: controls 0.80±0.07, steatosis 1.31±0.21, P<0.05), paralleled by a decrease in hepatic 11β-HSD1 activity (cortisol generation curve (CGC) after oral cortisone acetate 25 mg AUC±S.E.M.: controls 382±22, steatosis 304±27 μg/l per min, P<0.05, urine cortols/cortolones ratio: controls 0.43±0.02 versus steatosis 0.33±0.02, P<0.05). Furthermore, total cortisol metabolites were increased consistent with increased GC production rate (12 168±1028 vs 8690±786 μg/24 h, P<0.01).
Patients with NASH had increased cortisol generation consistent with increased hepatic 11β-HSD1 activity compared with controls and with steatosis (CGC AUC±S.E.M.: controls 382±22, steatosis 304±27, NASH 496±22 μg/l per min; NASH versus controls, P<0.05, NASH versus steatosis, P<0.01).
Immunohistochemical analysis in patients with NASH showed markedly increased 11β-HSD1 expression in peri-septal areas and within the inflammatory infiltrate. In addition 11β-HSD1 mRNA expression was also increased when compared with controls (dCT 9.65±0.29 vs 11.96±0.29, P<0.01).
Patients with hepatic steatosis have increased clearance and decreased regeneration of cortisol, a possible protective mechanism to decrease local GC availability to preserve hepatic metabolic phenotype. With progression to NASH, increased 11β-HSD1 activity driven cortisol regeneration may serve to limit hepatic inflammation. These results provide a crucial insight into the pathophysiology of the NAFLD disease spectrum.
Volume 21
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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