Autoimmune primary adrenal insufficiency -current diagnostic approaches and future perspectives

Abstract

The adrenal glands are small endocrine glands located on top of each kidney, producing hormones regulating important functions in our body like metabolism and stress. There are several underlying causes for adrenal insufficiency, where an autoimmune attack by the immune system is the most common cause. A number of genes are known to confer early onset adrenal disease in monogenic inheritance patterns, usually genetic encoding enzymes of adrenal steroidogenesis. Autoimmune primary adrenal insufficiency is usually a polygenic disease where our information recently has increased due to genome association studies. In this review, we go through the physiology of the adrenals before explaining the different reasons for adrenal insufficiency with a particular focus on autoimmune primary adrenal insufficiency. We will give a clinical overview including diagnosis and current treatment, before giving an overview of the genetic causes including monogenetic reasons for adrenal insufficiency and the polygenic background and inheritance pattern in autoimmune adrenal insufficiency. We will then look at the autoimmune mechanisms underlying autoimmune adrenal insufficiency and how autoantibodies are important for diagnosis. We end with a discussion on how to move the field forward emphasizing on the clinical workup, early identification, and potential targeted treatment of autoimmune PAI.

Keywords: 21-hydroxylase autoantibodies; Addisons disease; Genetic causes of PAI; glucococorticoids; primary adrenal insufficiency (PAI).

Figure 1

Steroidogenesis pathway. The enzymes specified are encoded by the genes stated in parenthesis under respective enzymes. The genes that are not stated in parenthesis are represented with symbols. The enzymes in red are targets for autoantibodies in autoimmune primary adrenal insufficiency. Figure created in BioRender.com. Modified from (1).

Figure 2

Hypothalamic-pituitary-adrenal (HPA) axis. The outline of the HPA axis between the hypothalamus, pituitary gland and the adrenal cortex is shown, including the negative feedback-loop. CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone. Figure created in BioRender.com.

Figure 3

PAI genetics. The most common monogenic genetic causes of PAI (green) and 8 genes/gene regions where specific variants cause extra risk for autoimmune PAI in a polygenic setting on a genome–wide basis (orange). Based on http://www.icped.org/, and (25, 26).

Figure 4

The natural cause of progression of autoimmune diseases. We are today posed to identify the genetic predisposition in AAD, and to provide replacement therapy in Stage 3, when overt disease is evident. Autoantibodies against 21OH can appear as early as in the pre-stage, as markers of the autoimmune reaction. Modified from (66) and created in BioRender.com.

Figure 5

Outlined screening possibilities for PAI. The figure suggests two different strategies for early identification of PAI. Population-based screening dependent on polygenic risk scores and genetic screening of risk variants (1) or 21-OH autoantibody measurements in high-risk groups either identified by genetic screens or family history (2). Figure created in BioRender.com.