Non alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. The potential role of glucocorticoids (GC) in the pathogenesis of NAFLD, is highlighted by patients with GC excess, Cushings syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although in most cases of NAFLD, circulating cortisol levels are normal, 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 metabolic phenotype and hepatic cortisol metabolism in patients with histologically proven NAFLD (n=15) compared with a BMI-matched control group (n=30).
Intra-hepatic fat (measured by liver:spleen attenuation ratio (L:S) on CT) was significantly higher in the NAFLD group (L:S 0.81±0.08 vs 1.13±0.04, P<0.01). Twenty-four hours urinary steroid metabolite analysis by GC/MS showed increased 5αR activity in patients with NAFLD (5αTHF/THF ratio, 1.12±0.22 vs 0.80±0.07, P<0.01). Absolute values of all 5α-, and not 5β-reduced metabolites, were significantly increased in the NAFLD group. Furthermore, total cortisol metabolites were increased in the NAFLD group indicative of increased GC production rate (12168±1028 vs 8690±786 μg/24 h, P<0.01). Fasting serum free fatty acids were increased in the NAFLD group (422±54.9 vs 335±16.9 μmol/l, P<0.05) and correlated with the 5αTHF/THF ratio in both groups (r=0.4, P<0.05).
Endorsing these clinical observations, immunohistochemical analysis of NAFLD liver biopsies confirmed increased 5αR1 and 2 expression. 11β-HSD1 activity measured by both urinary steroid metabolite ratios and cortisol generation profiles after oral cortisone acetate 25 mg, did not differ between NAFLD and controls.
In conclusion, patients with NAFLD have increased hepatic metabolism of cortisol due to increased 5αR activity with concomitant HPA axis activation. We propose that this represents a compensatory mechanism to decrease local GC availability in an attempt to preserve hepatic metabolic phenotype.