Autoimmune addison’s disease: Genetic aetiology and pathophysiology

Abstract

Autoimmune Addison disease (AAD) is a rare but highly heritable endocrine condition. An autoimmune aetiology is implicated in over 80% of cases of primary adrenal insufficiency in developed countries. In AAD, an aberrant immune response directed against steroidogenic enzymes leads to destruction of the adrenal cortex and resultant mineralo— and glucocorticoid deficiency. The primary autoantigen in AAD is the steroid 21-hydroxylase (21-OH) enzyme and antibodies directed against it can be detected in 85% of patients. The presence of 21-OH antibodies and biochemical abnormalities including raised ACTH, raised renin with normal or low aldosterone, followed by subnormal basal and/or stimulated cortisol precede the development of clinical signs and symptoms of primary adrenal insufficiency. The clinical features are non-specific and include hyperpigmentation, fatigue, weight loss, hypotension and salt craving. AAD can occur in the context of autoimmune polyglandular syndrome type 1 (APS1) due to autoimmune regulatory (AIRE) gene mutations inherited in an autosomal recessive fashion. The clinical diagnosis of this entity is based on the presence of at least two out of three features: mucocutaneous candidiasis, hypoparathyroidism and AAD. APS1-affected individuals often have other associated autoimmune conditions. Dominant inheritance of a milder APS1 phenotype has been described recently due to heterozygous AIRE gene mutations that inactivate the normal allele (dominant negative mutations). The pathogenesis of isolated AAD and AAD in the context of APS2 (AAD with autoimmune thyroid disease and/or type 1 diabetes and/or other autoimmune diseases) is due to a complex interplay between genetic and environmental factors. The genetic basis involves multiple susceptibility variants. To date, the majority of genetic susceptibility loci encode proteins involved in antigen presentation and T cell activation. However, a number of common susceptibility variants have also been also described in genes involved in the activation of B lymphocytes and antigen presenting cells. The strongest association between disease susceptibility and allelic variability has been found with HLA class II molecules. Thus far however, the identified susceptibility variants appear to have only a modest effect in terms of disease risk contribution. Recent studies suggest that the risk of AAD development can be also affected by processes influencing gene expression, such as common copy number variation and epigenetic modification. The environmental triggers for AAD remain largely undefined.