Abstract #1408256: In Search of New Biomarkers of Thyroid Function: The Association Between Thyroid Dysfunction and 11-beta Hydroxysteroid Dehydrogenase 2 Activity

Abstract

The high prevalence of persistent hypothyroid symptoms in patients with normal thyrotropin and free thyroxine levels calls for research to identify alternative biomarkers of thyroid function. Animal studies have shown thyroid hormones regulate the renal 11-beta hydroxysteroid dehydrogenase 2 (11βHSD2), a key enzyme in glucocorticoid metabolism. This study examines the impact of hypothyroidism (Overt and subclinical) and hyperthyroidism (overt and subclinical) on 11βHSD2 activity. In this single center prospective study conducted between July 2022-Dec 2022, 24-hour urine samples were collected from 6 patients with newly diagnosed hyperthyroidism, 6 with newly diagnosed hypothyroidism, and 33 age and sex matched healthy reference subjects. A quantitative analysis of 26 steroid metabolites was done in the hydrolyzed urine samples. Given that 11bHSD2 is responsible for the conversion of active cortisol to inactive cortisone, the cortisol to cortisone (F/E) ratio was used to evaluate the enzymatic activity. Differences in total glucocorticoid production and F/E ratios were analyzed based on Z-score deviations from the controls’ reference intervals. The mean participants’ age was 50 years, and 73.3% were female. In patients with hypothyroidism, the mean total glucocorticoid production was 12316.8 ng/mL which was similar to the reference subjects (Z-score -0.03, p = 0.9, CI 95%: -4691.4 to 4666.3), and the mean F/E ratio was 0.5 which was lower than the reference group (Z-score 2.6, p<0.01, CI 95%: 0.06-0.25). In patients with hyperthyroidism, the mean total glucocorticoid production was 16933.7 ng/mL, which was non-statistically higher than the reference subjects (Z-score 1.2, p = 0.1, CI 95%: -794 to 10269), and the mean F/E ratio was 0.4 which was non-statistically higher than the reference group (Z-score 1.6, p = 0.09, CI 95%: 0.01-0.25). After adjustment analysis for total glucocorticoid production, only the differences in the F/E ratio of the hypothyroid patients remained statistically significant (p<0.01). In this proof of principle study, patients with hypothyroidism appeared to have normal total glucocorticoid production but impaired 11βHSD2 activity. Further studies are needed to confirm these findings, determine any clinical implications from cortisol excess in patients with thyroid dysfunction, and evaluate the utility of glucocorticoid metabolomics as a biomarker of peripheral thyroid function action.