Does Relative Hypoglycaemia &/or Sleep Disturbance Contribute to the Lethargy Observed in Addison's Disease

Patients with primary adrenal insufficiency (PAI) have impaired subjective health status (1, 2) and excess mortality (3, 4). Cardiovascular disease is the greatest contributor towards the excess mortality (3). How current glucocorticoid replacement translates into these adverse sequelea is not understood. Excess and inadequate glucocorticoid replacement likely both contribute. Endogenous cortisol levels rapidly increase from 2am, peaking before waking, and thereafter fall through the day to a nadir around midnight. Hydrocortisone is the preferred glucocorticoid used for replacement therapy in PAI. Current glucocorticoid replacement regimens try to mimic the normal diurnal cortisol rhythm (5). The most commonly used regimens involve use of hydrocortisone (bio-identical to cortisol) administered three times per day (6). As cortisol levels are highest in the morning and fall through the day, a larger dose of hydrocortisone is given on waking with small doses thereafter. It is important in the timing of these doses that there is overlap to avoid periods of cortisol insufficiency. Although regimens aim to replicate the daytime cortisol profile, they cannot currently provide replacement in the early morning hours (2am-7am). This leads to a period of glucocorticoid insufficiency during sleep. Studies using continuous subcutaneous infusion (CSII) of hydrocortisone deliver hydrocortisone in a manner that mimics the normal diurnal rhythm of cortisol, including the period between 2am and waking. Hydrocortisone delivered by CSII has been associated with improvements in well-being in patients with PAI (7), though have not been used in an adequate number of patients for long enough duration to assess the impact on the excess mortality.

Insulin sensitivity is greatest between 2am-4am consequent on the diurnal rhythm of insulin counter-regulatory hormones. Consequently type I diabetic patients are at greatest risk of hypoglycaemia at this time. Glucocorticoid insufficiency increases glucose oxidation and decreases glucose production translating to increased insulin sensitivity. PAI is associated with hypoglycaemic events, though generally in children rather than adults. Using continuous glucose monitoring (CGM) a single case report (8) and a small series identified two patients with nocturnal hypoglycaemia (9). The series did not contain a control group and therefore was unable to determine if nocturnal glucose levels were lower in the patients compared with the normal population.

Furthermore, glucocorticoids have been associated with disruption of sleep, particularly difficulties getting to sleep (10). Therefore taking of replacement hydrocortisone after 6pm in the evening is avoided so that the majority of the hydrocortisone will have been metabolised before the patients retires to sleep. There are however marked differences in the timing of doses of hydrocortisone with patients often taking their doses around other life commitments, or when they are most likely to remember (i.e. first thing in the morning and last thing at night). A significant proportion of patients therefore take their last dose of steroids in the late evening or immediately prior to trying to sleep (6). This can lead hydrocortisone being taken later than prescribed and potentially impacting on sleep. However, as the dose of replacement hydrocortisone is low when given in the evening it is not known if sleep is adversely affected in contrast to that observed with higher therapeutic doses of glucocorticoids?

Finally, much of the excess mortality of patients with primary adrenal insufficiency is reported to relate to vascular disease (3). Vascular risk factors are variably reported to be increased in PAI (11). However, the mechanism by which the excess vascular disease occurs remains incompletely understood.