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Adrenal insufficiency: a commentary

Adrenal insufficiency (AI) due to corticosteroid administration occurs frequently in those on higher prolonged steroid doses; however, an exact threshold other than high clinical suspicion remains unknown. Outside of tertiary AI, adrenal failure is rare and for primary adrenal insufficiency (PAI) involves a combination of both glucocorticoid, mineralocorticoid and androgen deficiency, as outlined in this best practice on adrenal failure. Both PAI and secondary adrenal insufficiency (SAI) can take some time for diagnosis, as often signs and symptoms are nonspecific, with diagnosis involving clinical suspicion and combination of biochemistry testing and perhaps imaging for initial diagnosis. 4 Unfortunately, in modern clinical practice, many patients are not diagnosed until the present with an acute adrenal crisis and those with a previous crisis appear to be of greater risk of subsequent events. 6 Cortisol testing is clearly at the centre of the initial diagnosis with a widespread appreciation of its diurnal variation. The variability of cortisol results due to assay methodology is underappreciated with standard guidelines quoting single isolated cutoff values without consideration for the particular lab method involved. There is uncertainty in the lab analysis much like the uncertainty in the clinical assessment, as many patients present with vague symptoms. This should be borne in mind, in addition to the fact that as outlined in the best practice article, that most tests use serum total cortisol and therefore abnormalities of cortisolbinding globulin, for example, pregnancy, oral oestrogen contraceptive (OCP) treatment, cirrhosis and nephrotic syndrome, will affect the results. Betweenassay cortisol variability can have a SD of close to a 100 μmol/L (at values including the endocrine society cutoff value of 500 nmol/L) due to differences in matrix effects and antibody specificity. 11 It is of interest that some labs and handbooks recommend stopping the OCP prior to lab testing, which is surely fraught with potential consequence, when clearly the solution would be to have an appropriate adjusted cutoff. Despite being well known that cortisol has a diurnal variation, random add on testing to samples taken outside of morning hours is not uncommon, in the author’s experience. This is based on the theory that if the cortisol is low then this may explain the patient’s tiredness, for example. However, the obvious problem is that the cortisol may be low as a consequence of diurnal variation, which in turn will lead to more requests for short Synacthen tests (SSTs) and a potential for increase in false positives with unnecessary investigation and treatment. The initial test in the patient pathway should be highly sensitive to rule it out given the consequences of nondiagnosis, with a followup test being highly specific. This is in effect what an early morning cortisol followed by an SST is trying to achieve. However, a single cutoff value for serum cortisol is inevitably a tradeoff between sensitivity and specificity, higher cutoff values increase sensitivity but lower specificity—more false positives and more followup testing. This is important in terms of consideration of setting binary cutoffs and that consideration for localbased grey zone values—based on max sensitivity to specificity may aid clinical practice. This of course also has the added benefit of being method specific. The random cortisol, however, although with more appeal in terms of convenience does have a huge degree of overlap where an SST is required to separate those with AI, unless baseline values are very low. 13 14 Use of alternative samples such as saliva for diagnosis is not yet widespread or fully established. SST has also been validated against the gold standard insulin stress test for evaluating secondary hypoadrenalism and its use is more widespread and associated with fewer complications compared with the latter. Adrenocorticotrophic hormone (ACTH) testing is used to help differentiate between PAI and SAI, being elevated in the former compared with the latter. Hyponatraemia can occur in both and is the most common electrolyte abnormality occurring in approximately 80% with PAI and should serve as a trigger to check cortisol in unexplained hyponatraemia. Hyperkalaemia is less common occurring in approximately a third with PAI and hypercalcaemia, hypoglycaemia were uncommon/rare in adults. Moderate elevation of TSH at diagnosis, with a normal free T4 (FT4), usually reflects a lack of glucocorticoid inhibition on TSH release rather than any underlying hypothyroidism. Guidelines recommend checking renin and aldosterone at the diagnostic stage as early PAI may involve only the mineralocorticoids, with an elevated renin with a low or inappropriately normal aldosterone. However, the use of these results is again combined with clinical findings and electrolyte assessment after stabilisation on cortisol replacement. Studies of patients show that qualityoflife issues are far from solved for patients with AI, with mortality risk from acute crisis due to inappropriate or inadequate low cortisone replacement or longterm morbidity in the form of cardiovascular disease or osteoporosis resulting from overtreatment. 17 Unfortunately, subcutaneous pumps are the only effective method for mimicking circadian variation in cortisol. Otherwise, the standard approach to higher morning doses and avoiding late evening overreplacement (increased risk of insulin resistance), supplemented by clinical correlation of symptoms or sign of underreplacement, is the standard approach to dosing. Cortisol day curves are not sufficiently precise and lack evidence to support dosing in terms of outcome data, although they may play a role in the presence of potential malabsorption. 17 Similarly, renin testing has a limited role in dose adjustment outside of clinical features, due to the large number of other confounders that impact on its secretion.