Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2009) 20 S9.3

Addison's disease from genetics to clinical outcome

Early subclinical Addison’s disease

Alberto Falorni


Department of Internal Medicine, University of Perugia, Perugia, Italy.

The adrenal autoimmune process that causes primary adrenal insufficiency is made evident by the appearance of circulating adrenal autoantibodies directed against the enzyme steroid 21-hydroxylase (21OHAb), in genetically predisposed individuals. Adrenal autoantibodies appear months to years before the appearance of clinical signs of adrenal insufficiency and a pre-clinical phase of the disease can be recognised. Subjects positive for 21OHAb present with a variable degree of pre-clinical adrenal insufficiency as revealed by the low-dose ACTH stimulation test (LDT) and by aldosterone concentration and plasmatic renin activity. The progression of the destructive process against the adrenal cortex is accompanied by a progressive increase in 21OHAb levels, more evident in subjects with an impaired response to the LDT. A spontaneous remission of early subclinical adrenal insufficiency is observed in the majority of subjects with normal response to the LDT. On the contrary, a pathologic LDT is invariably followed by progression of the adrenal dysfunction that ultimately leads to clinical Addison’s disease (AAD). Factors increasing significantly the risk of progression towards clinical adrenal insufficiency include: male gender, presence of other concomitant autoimmune diseases, impaired LDT and a high 21OHAb titre. Among genetic factors, HLA-DR3-DQ2, DR4-DQ8, MICA5.1 and CTLA gene polymorphism are significantly associated with appearance of 21OHAb, but do not influence the natural history of the disease and do not predict future clinical adrenal insufficiency. On the contrary, the presence of the DRB1*0403 allele in 21OHAb-positive subjects is significantly and negatively associated with progression to clinical Addison’s disease (AAD), and represents the major protective gene marker. The combined use of biochemical and genetic tests in 21OHAb-positive subjects enables the accurate estimate of the risk for future development of clinical AAD and paves the way to clinical studies aimed at preserving the residual adrenal function in subjects with early subclinical AAD.

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