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.

MANAGEMENT OF ENDOCRINE DISEASE: Residual adrenal function in Addison’s disease

“…In the two largest studies around 10% had detectable serum cortisol concentration ≥100 nmol/l and 5% had concentrations ≥150nmol/l. 19,20 Residual adrenal function comprised not just glucocorticoid secretion, but residual mineralocorticoid secretion was also found in many patients, as might be predicted by the known sequence of adrenocortical cell migration (see below). In contrast, preserved adrenal androgen secretion was not frequent, and indeed because of preserved gonadal steroid secretion, was technically more difficult to evaluate.…”

“…17 These studies have recently been extended by 3 different groups using mass spectrometric steroid metabolome assays in a further 249 individuals with established AAD (Table 1). [18][19][20] In summary, these three additional studies have used more sensitive assays to establish beyond doubt that AAD patients are heterogeneous in terms of adrenal function, with around 30% having some low level, residual adrenal steroidogenesis for many years following diagnosis. In the two largest studies around 10% had detectable serum cortisol concentration ≥100 nmol/l and 5% had concentrations ≥150nmol/l.…”

“…Lastly, residual adrenal function did not correlate with lack of adrenal crisis or improved quality of life. 20…”

“…36 This rate of residual adrenal function is greater than that found spontaneously in the observational studies, where only 10% of individuals had serum cortisol concentrations ≥100nmol/l. [17][18][19][20] Could adrenal steroidogenesis be salvageable further into the course of the disease? With this question in mind, we administered high dose synacthen to 13 unselected patients with AAD established for more than a year.…”

“…19 However, these very low corticosteroid levels may be neither physiologically relevant nor indeed reflect true adrenal cortisol production, as extraadrenal cortisol generation is reported from many tissues including intestine, thymus, lung, skin and brain. 39,40 In the largest observational studies of AAD patients, 19,20 only around 10% had detectable serum cortisol concentration ≥100 nmol/l, with 5% having concentrations ≥150nmol/l. This means that although residual adrenal function was commoner than expected, in most AAD patients the mechanism by which it could be contributing to their health is not obvious at the moment.…”