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

Abstract

Over the last 10 years, evidence has accumulated that autoimmune Addison’s disease (AAD) is a heterogeneous disease. Residual adrenal function, characterised by persistent secretion of cortisol, other glucocorticoids and mineralocorticoids is present in around 30% of patients with established AAD, and appears commoner in men. This persistent steroidogenesis is present in some patients with AAD for more than 20 years, but it is commoner in people with shorter disease duration. The clinical significance of residual adrenal function is not fully clear at the moment, but as it signifies an intact adrenocortical stem cell population, it opens up the possibility of regeneration of adrenal steroidogenesis and improvement in adrenal failure for some patients.

Latent Adrenal Insufficiency: From Concept to Diagnosis

“…An algorithm depicting the proposed diagnostic approach in PAI in adults is shown in Figure 2. In PAI, adrenal glands are unresponsive to corticotropin stimulation because zona fasciculata is already maximally stimulated by elevated endogenous ACTH (54) and because adrenal cortex is replaced by fibrous tissue (48). In cases when confirmatory test is not possible, a morning serum cortisol of less than 140 nmol/L paired with a morning plasma ACTH above 2-fold the upper limit of normal is consistent with PAI.…”

“…Adrenocortical plasticity is a well-established concept defined by the ability of subcapsular adrenocortical stem cells to proliferate, then migrate into the three zones of the adrenal cortex where zone-specific differentiation occurs, and cells acquire steroidogenic function; all under the influence of ACTH (54). Adrenal mass is also influenced by ACTH: when deficient, adrenal atrophy and hypofunction develop, whereas when increased, adrenal hyperplasia and hyperfunction occur (54). Adrenocortical stem cells may hold the key to understanding the mechanisms of a new emerging concept in autoimmune adrenalitis; that of residual glucocorticoid function.…”

“…In contrast, residual mineralocorticoid production was only found in 13.5% of patients (80). It was hypothesized that the lack of expression by adrenocortical stem cells of 21-hydroxylase and other enzymes implicated in steroidogenesis, may protect adrenal cortex from complete autoimmune destruction by retaining the possibility of repopulation by intact stem cells (54). Also, turnover of adrenocortical stem cells differs according to sex in rodents and could possibly explain why endogenous residual function is more commonly observed in men (54).…”

Grand Challenge in Adrenal Endocrinology: Is the Legacy of the Past a Challenge for the Future of Precision Medicine?

“…In addition, 11-deoxycortisol in serum or urine could become a sensitive marker of residual adrenal function in the future. Indeed, thanks to the use of the LC-MS/ MS measure of the steroid metabolome, residual adrenal function has been suggested to be present in up to 30% of patients with Addison's disease (44). Finally, the possibility of measuring cortisol and cortisone with LC-MS/MS can consent to evaluate the degree of peripheral activation of cortisone in cortisol, which could become an important marker to evaluate the cortisol milieu in the individual patient (14,45).…”

Use of dual-release hydrocortisone in adrenal insufficiency

“…Thirdly, the authors have explained the difference in BP findings, stating that SAI patients might have some residual partial ACTH activity. Recently, the concept of 'residual adrenal function' is emerging and a detectable but low concentration of cortisol and other corticosteroids can be found in around 30% of auto-immune adrenalitis patients (3).Thus this explanation remains to be explored further in these two groups of patients in future studies.…”