Endocrine Abstracts

Background: Glucocorticoids play a key role in determining body fat distribution. Excess circulating glucocorticoids lead to intrahepatic fat accumulation. Obesity is associated with enhanced glucocorticoid production but this is offset by enhanced degradation such that circulating steroid concentrations are normal. However, tissue-specific pathways may lead to different degrees of cortisol exposure in different organs. Local steroid exposure in the liver is determined by the activity of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This interconverts inactive cortisone and active cortisol, the net effect favouring cortisol generation. Studies in ‘healthy’ individuals show a reduction in the activity of 11β-HSD1 with increasing BMI thus protecting the liver from the effects of excess cortisol. We tested the hypothesis that in obese people with non-alcoholic fatty liver disease (NAFLD) this adaptive response is impaired leading to enhanced local production of cortisol and steroid-induced steatosis.

Methods: We measured insulin resistance (HOMA-IR), % body fat (by DEXA) and 11β-HSD1 activity/expression in patients with NAFLD/NASH undergoing biopsy and correlated these with the histological features. Global 11β-HSD1 activity was determined by analysis of urinary excretion of cortisol metabolites, with results expressed as a ratio of tetrahydrocortisols over tetrahydrocortisone (THF+alloTHF/THE). Intrahepatic 11β-HSD1 mRNA levels were determined in liver tissue by real-time PCR. Control patients had non-steatotic liver disease (chiefly hepatitis B; HCV patients were excluded).

Results: The 11β-HSD1 activity was significantly higher in the 16 individuals with NAFLD (0.73±0.04) vs controls (0.57±0.03), P=0.018. In the 10 control patients 11β-HSD1 activity decreased with increasing BMI but this was not seen in patients with NAFLD/NASH. These changes in 11β-HSD1 activity were mirrored by changes in mRNA expression of 11β-HSD1 in liver tissue, suggesting that the changes were due to dysregulation of liver enzyme RNA expression.

We speculate that failure to downregulate 11ß-HSD1 activity may be one of the reasons why some obese patients develop NAFLD and others do not.