Sub-clinical addison's disease.

As autoimmune adrenalitis is fast replacing tuberculosis as the most common etiology cause of adrenal insufficiency, subtler forms of the same are being recognised as subclinical addison's disease. In this article, we review what is known about this entity till date.

As a clinical entity, Addison's disease has travelled far since the publication of the wonderful, precise, and accurate treatise by Thomas Joseph Addison.[1] During Addison's time, infection especially due to Mycobacterium tuberculosis was the main etiological factor, which has given way to auto-immune adrenalitis over last few decades. As regards our current understanding of etio-pathogenesis, there are three main categories, namely [A] adrenal dysgenesis/hypoplasia (e.g. congenital adrenal hypoplasia {AHC}, mutations of steroidogenic factor-1 {SF-1}, and ACTH unresponsiveness etc.), [B] impaired steroidogenesis (e.g. congenital adrenal hyperplasia {CAH}, mitochondrial disorders, the Smith-Lemli-Opitz syndrome {SMOS}, an enzyme deficiency in cholesterol metabolism etc.), and [C] adrenal destruction (e.g. autoimmune polyglandular syndrome (APS), adrenoleukodystrophy (ALD), adrenal hemorrhage, adrenal metastases, infections, and amyloidoses etc. Infection still continues to be an important factor in developing countries.[2]

The classical sub-clinical Addison's disease has been discussed in the background of autoimmune adrenalitis, which is characterized by presence of adrenal auto-antibodies and more often than not the occurrence of other autoimmune endocrinopathies. Although it may be a part of autoimmune polyglandular syndrome (APS) I and II and IV conditions where involvement of many other hormonal deficiencies predate that of adrenal deficiency, its diagnosis may remain elusive because of difficulty in demonstrating it in the sub-clinical phase.[3] The natural history of Addison's disease can be divided into four distinct stages, each characterized by documentable biochemical changes, such as, stage 0: Normal adrenal function with normal plasma adrenocorticotropin (ACTH), basal and ACTH-stimulated cortisol, PRA, serum aldosterone, stage 1: Increase plasma renin activity (PRA) and normal or low serum aldosterone levels and appropriate response to ACTH, stage 2: Low cortisol response to ACTH, stage 3: Increase plasma ACTH, basal serum cortisol at lower end of normal, and absent cortisol response to ACTH, stage 4: Low serum or urinary cortisol along with highly elevated plasma adrenocorticotropin (ACTH) with evident features of adrenocortical failure.[45] Stage 1-3 would fall into sub-clinical category, while stage 4 is by and large clinical. Stage 0 would include all those healthy individuals with higher risk of developing adrenal failure. In other words, they belong to so-called potential stage.[3] There is great variation in the time taken by different individuals in progressing from stage 0 to stage 4, i.e. potential to clinical stage. Documentation of adrenal auto-antibodies, which are present in high-risk individuals irrespective of the aforesaid stages, is useful in segregating high-risk individuals from normal population. Auto-antibodies against the steroidogenetic enzyme 21-hydroxylase (21OHAb) has been found to be most useful in early identification at risk individuals.[6] The accuracy of risk prediction can be improved by inclusion of genetic risk alleles in the calculation, for example, genes of human leukocytic antigen (HLA) region such as DR3-DQ2, DR4-DQ8, MICA.[7]

Stimulation of the adrenal cortex by synthetic ACTH (synacthen, 250 μgm) to demonstrate either absolute or delta rise in cortisol is a well-validated test to confirm both primary and secondary adrenal insufficiency.[8] However, due to supra-physiological stimulation, this test lack the sensitivity to screen sub-clinical Addison′s disease successfully. Hence, a lower dose of ACTH has been proposed, with 1 μgm being studied most extensively.[9] However, others have claimed acceptable sensitivity even with dose of ACTH as low as 0.06 μgm.[8] There is increased acceptability of the low dose synacthen stimulation test (SST), specially for screening of patients for sub-clinical primary or secondary adrenal insufficiency.[1011]

Most of authors from the sub-continent working in this field have shown sub-clinical primary adrenal insufficiency during active phase of tubercular infection,[1213] which reverses when the infection is suppressed successfully with anti-tubercular chemotherapy.[14] Maximal reversal occurs following six months of chemotherapy and correlated well with cure of disease in most patients.