A retrospective Japanese study reviewed the medical charts of 137 adult patients receiving steroid replacement for established primary or secondary adrenal insufficiency. The authors noted a significant positive association between adrenal crisis and long-term steroid replacement (>4 years), concomitant mental disorder, and sex hormone deficiency. A combination of any of these factors further increased the risk.8
A more recent survey of 444 patients ages 17-81 assessed independent risk factors for adrenal crisis in the setting of primary (N=254) or secondary (N=190) adrenal insufficiency. The incidence of crisis was higher in primary versus secondary insufficiency. In patients with primary insufficiency, concomitant, non-endocrine disorders increased the risk of adrenal crisis, whereas diabetes insipidus and female gender increased risk in patients with secondary insufficiency. This same study also investigated events leading to a crisis and found gastrointestinal infection to be the most frequent factor, followed by other infectious or febrile illnesses. Overall, infection comprised 45% of all identified triggers.6
A similar study conducted by White and Arlt evaluated 841 Addison’s patients in the United Kingdom, Canada, Australia, and New Zealand.7 Again, gastrointestinal illness was the most common provoking factor, responsible for 56% of all reported crises. Flulike illness followed at 11%, followed by infections and surgical procedures at 6% each. This study found a higher risk of crisis in patients with diabetes (type I or II), premature ovarian failure, and asthma; the presence of multiple comorbidities further increased risk.
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Figure 1: Normal production and regulation of cortisol secretion.
Medications. Glucocorticoid therapy is known to suppress the HPA axis. Although it was once believed that the duration and dose of therapy correlated directly with the degree of HPA suppression, more recent studies have failed to find any definite relationship.9 Patients taking the equivalent of 5mg of prednisone per day should continue to have an intact HPA axis, as this dose mimics physiologic secretion of cortisol in a healthy individual.3
However, the dose and duration of therapy at which suppression occurs is highly variable between patients. In general, patients on 7.5mg of prednisone or more per day for at least three weeks should be considered to be suppressed.3,9 Additionally, progesterone derivatives (i.e., megestrol) have glucocorticoid activity and might suppress HPA function. Other medications that might have related effects are those that inhibit enzymes involved in cortisol synthesis; ketoconazole and etomidate are common examples. Rifampin and several classes of anti-epileptic drugs induce enzymes, which increase hepatic metabolism of cortisol (see Table 1, p. 18).
Hyperthyroidism. Thyroid hormone is involved in the metabolism of cortisol, thus an increase in T4 correlates with lower levels. Adrenal insufficiency and thyroid disease might coexist within the autoimmune polyglandular syndrome. Initiation or uptitration of thyroid replacement should be avoided if acute adrenal insufficiency is suspected, as this might provoke an adrenal crisis. Conversely, any patient with adrenal insufficiency who has uncontrolled hyperthyroidism should receive two to three times their usual glucocorticoid replacement.1,2
Pregnancy. Levels of cortisol-binding globulin increase throughout pregnancy. In women with intact adrenal function, free cortisol levels also rise during the third trimester. Therefore, glucocorticoid replacement should be increased by 50% during the last three months of pregnancy.2
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Figure 1: Normal production and regulation of cortisol secretion.
Acute illness. The cortisol response to stress is highly variable and dependent on a number of factors, including age, underlying health, and genetics. In general, most experts recommend doubling or tripling the daily replacement dose during mild to moderate illness until recovery (often referred to as the “sick-day rules”). What constitutes “recovery” is not clearly defined. When oral intake is compromised, as with vomiting or diarrhea, parenteral administration of steroids is recommended.1-5,9,10 Patients with adrenal insufficiency should be provided an emergency injection kit to use and further counseled to seek medical attention. Injection kits typically consist of 100mg of hydrocortisone or 4mg of dexamethasone, although other glucocorticoids may be used (see Table 2, above left, for conversions).
