Residual Corticosteroid Production in Autoimmune Addison Disease

Abstract

Context: Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis.

Objective: To determine frequencies and clinical features of residual corticosteroid production in patients with AAD.

Design: Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography-tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test.

Results: Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P < 0.002) and in shorter disease duration (median 6 [0-44] vs 13 [0-53] years; P < 0.001). Residual MC production was found in 26 (13.5%) patients and associated with shorter disease duration (median 5.5 [0.5-26.0] vs 13 [0-53] years; P < 0.004), lower fludrocortisone replacement dosage (median 0.075 [0.050-0.120] vs 0.100 [0.028-0.300] mg; P < 0.005), and higher plasma renin concentration (median 179 [22-915] vs 47.5 [0.6-658.0] mU/L; P < 0.001). There was no significant association between residual production and frequency of adrenal crises or quality of life. None had a normal cosyntropin response, but peak cortisol strongly correlated with unstimulated cortisol (r = 0.989; P < 0.001) and plasma adrenocorticotropic hormone (ACTH; r = -0.487; P < 0.001).

Conclusion: In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life.

Trial registration: ClinicalTrials.gov NCT03793114.

Keywords: Adrenal failure; Autoimmune Addison disease; adrenal steroids; cortisol; primary adrenal insufficiency; residual function.

© Endocrine Society 2020.

Figures

Figure 1.

Flow chart of study procedures.

Figure 2.

Synthesis of adrenocortical steroids. The 3 main adrenocortical steroids (aldosterone, cortisol, and dihydroepiandrostendione sulphate) are shown in circles, while precursor steroids and metabolites are shown in rectangles. Bold borders mark steroids analyzed in this study. Cortisol and 11-deoxycortisol define residual glucocorticoid production and are marked in red. Aldosterone and corticosterone define residual mineralocorticoid production and are marked in blue. Red and blue arrows mark the enzymatic reactions for activation of cortisol and aldosterone, respectively. Cortisone is both a metabolite and precursor of cortisol and is marked in yellow.

Figure 3.

Stage 1: Corticosteroid levels in patients with residual glucocorticoid or mineralocorticoid production. The line marks median corticosteroid values and the whiskers the interquartile range. Triangles mark patients with both glucocorticoid and mineralocorticoid residual production. The patients with the highest quartile of 11-deoxycortisol and corticosterone values are marked in red and blue, respectively. (A) Serum cortisol at baseline (n = 58). (B) Serum 11-deoxycortisol values at baseline (n = 58). (C) Serum aldosterone values at baseline (n = 26). (D) Serum corticosterone values at baseline (n = 26).

Figure 4.

Correlation between corticosteroids. (A) Correlation between serum cortisol and 11-deoxycortisol (P < 0.001). (B) Correlation between serum aldosterone and corticosterone (P < 0.001).

Figure 5.

Cosyntropin testing. (A) Change in serum cortisol before (0 minutes) intravenous 250 μg cosyntropin to peak serum cortisol after 30 or 60 minutes. (B) Correlation between serum cortisol before (0 minutes) intravenous 250 μg cosyntropin and peak serum cortisol at 30 or 60 minutes (P < 0.001). (C) Correlation between plasma ACTH before (0 minutes) intravenous 250 μg cosyntropin and peak serum cortisol 30 or 60 minutes (P < 0.001). ACTH, adrenocorticotropic hormone.