Common Genetic Variants of the Human Steroid 21-Hydroxylase Gene (CYP21A2) Are Related to Differences in Circulating Hormone Levels

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Hungarian Scientific Research Fund (OTKA, PD100648 (AP)) Technology Innovation Fund, National Developmental Agency (KTIA-AIK-2012-12-1-0010). AP is the recipient of a “Lendület” grant from the Hungarian Academy of Sciences

A Switch in Hepatic Cortisol Metabolism across the Spectrum of Non Alcoholic Fatty Liver Disease

Context: Non alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of liver disease ranging from reversible hepatic steatosis, to non alcoholic steato-hepatitis (NASH) and cirrhosis. The potential role of glucocorticoids (GC) in the pathogenesis of NAFLD is highlighted in patients with GC excess, Cushing's 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 (F) from inactive cortisone (E) (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1), or inactivate cortisol through A-ring metabolism (5α- and 5β-reductase, 5αR and 5βR). Objective and Methods: In vitro studies defined 11β-HSD1 expression in normal and NASH liver samples. We then characterised hepatic cortisol metabolism in 16 patients with histologically proven NAFLD compared to 32 obese controls using gas chromatographic analysis of 24 hour urine collection and plasma cortisol generation profile following oral cortisone. Results: In patients with steatosis 5αR activity was increased, with a decrease in hepatic 11β-HSD1 activity. Total cortisol metabolites were increased in this group consistent with increased GC production rate. In contrast, in patients with NASH, 11β-HSD1 activity was increased both in comparison to patients with steatosis, and controls. Endorsing these findings, 11β-HSD1 mRNA and immunostaining was markedly increased in NASH patients in peri septal hepatocytes and within CD68 positive macrophages within inflamed cirrhotic septa. Conclusion: Patients with hepatic steatosis have increased clearance and decreased hepatic regeneration of cortisol and we propose that this may represent a protective mechanism to decrease local GC availability to preserve hepatic metabolic phenotype. With progression to NASH, increased 11β-HSD1 activity and consequent cortisol regeneration may serve to limit hepatic inflammation

Concordance of the late night salivary cortisol in patients with Cushing's syndrome and elevated urine-free cortisol

The concordance of the late night salivary cortisol (LNSC) results with the 24-h urine-free cortisol (UFC) results in the biochemical screening for Cushing’s syndrome is unknown. We investigated this in a population of Cushing’s syndrome subjects. We used meta-analytic methods to pool proportions of LNSC-positive subjects from diagnostic evaluations of Cushing’s syndrome subjects where both tests were performed and the UFC was elevated (any level). Cushing’s syndrome was confirmed in all subjects by two out of three conventional tests. LNSC was collected between 22:00 to 24:00 h and measured around the same time period as the UFC. Minimum cutoffs of ≥4 and ≥10 nmol/L were used to determine concordance with the UFC and studies were limited to those that used radioimmunoassays or electrochemiluminiscence immunoassays for LNSC. The concordance of LNSC ≥4 nmol/L was 97 % (95 % CI 95–99 %) and studies were homogeneous. With LNSC ≥10 nmol/L, there was heterogeneity and two groups were discernible with a pooled concordance of 69 % (95 % CI 60–77 %) and 95 % (95 % CI 92–97 %). Within these sub-groups, studies were homogeneous and there was no difference between them in collection methods, assays used, geographic location, year of publication, or the quality of the underlying studies. The LNSC at a very specific cutoff detects at best 95 % of cases and at worst 69 % of cases of Cushing’s syndrome that are UFC positive. The two tests become equivalent at the more sensitive cutoff (>4 nmol/L). We conclude that, given its many benefits and the currently documented equivalence to the UFC, the LNSC should replace the conventional 24-h UFC as the frontline test when screening for Cushing’s syndrome