What are the causes of adrenal crisis?

Causes of Adrenal Crisis

Adrenal crisis is most commonly precipitated by gastrointestinal illness with vomiting or diarrhea (accounting for 30-50% of cases), followed by other infections, inadequate stress dosing during illness or surgery, and abrupt discontinuation of glucocorticoid therapy. 1, 2, 3, 4

Primary Precipitating Factors

Infectious Causes

• Gastrointestinal infections with vomiting/diarrhea represent the single most common trigger for adrenal crisis, as patients cannot absorb their oral replacement medication precisely when cortisol demands are highest 1, 2, 3
• Any type of infection (respiratory, urinary, systemic) can precipitate crisis due to increased cortisol requirements and enhanced pro-inflammatory cytokine release in the absence of adequate cortisol response 5, 4
• Febrile illnesses account for a substantial portion of crisis events, with fever itself being a significant stressor 4, 6

Medication-Related Causes

• Abrupt discontinuation or inadequate dosing of glucocorticoid replacement therapy is a critical and preventable cause of adrenal crisis 4, 6
• Failure to increase glucocorticoid doses during intercurrent illness ("sick day rules") despite patient education remains a common precipitant 7, 3
• Inability to take or absorb oral medications due to nausea, vomiting, or gastrointestinal dysfunction leads to rapid deterioration 2, 3

Surgical and Traumatic Causes

• Surgical procedures performed without adequate perioperative steroid coverage can trigger crisis due to the stress response 1, 2
• Physical injuries or trauma increase cortisol demands beyond baseline replacement capacity 1, 2

Cardiovascular and Metabolic Stressors

• Myocardial infarction can precipitate adrenal crisis through severe physiological stress 1, 2
• Severe hypoglycemia in diabetic patients with adrenal insufficiency can trigger crisis 1, 2
• Severe allergic reactions and anaphylaxis represent acute stressors that can precipitate crisis 1, 2

Underlying Pathophysiology

Why These Triggers Cause Crisis

• Lack of increased cortisol concentrations during stress enhances pro-inflammatory cytokine release (particularly tumor necrosis factor alpha) and increases sensitivity to their toxic effects 5
• Pro-inflammatory cytokines may further impair glucocorticoid receptor function, creating a vicious cycle that aggravates glucocorticoid deficiency 5
• The combination of increased cortisol demand and inability to mount an appropriate cortisol response leads to cardiovascular collapse and metabolic derangement 5

Iatrogenic and Management-Related Causes

Patient Education Failures

• Despite patient education on stress dosing, many patients and physicians remain reluctant to increase glucocorticoid doses or switch to parenteral administration, leading to preventable crises 3
• Recent evidence demonstrates that current patient education strategies do not prevent many adrenal crisis events, though the reasons are not fully understood 8

Mineralocorticoid Issues

• Chronic under-replacement with fludrocortisone combined with low salt consumption can contribute to recurrent adrenal crises 7
• Poor compliance with mineralocorticoid therapy may predispose to crisis 7

Drug Interactions

• Medications that accelerate cortisol clearance (such as other hormones in patients with multiple pituitary deficiencies) can precipitate crisis if glucocorticoid doses are not adjusted appropriately 7
• Starting thyroid hormone replacement before adequate glucocorticoid replacement in patients with multiple hormone deficiencies can trigger crisis 7

Special Populations and Situations

Immune Checkpoint Inhibitor Therapy

• Patients treated with immune checkpoint inhibitors who develop hypophysitis or adrenal insufficiency are at risk for crisis, particularly when high-dose corticosteroids used for other immune-related adverse events are tapered too rapidly 7
• Isolated central adrenal insufficiency can develop in patients receiving corticosteroids for other conditions, placing them at risk when steroids are discontinued 7

Critical Clinical Pearls

• Even mild gastrointestinal upset can rapidly progress to crisis because patients cannot absorb oral medications when they need them most 2
• The annual incidence of adrenal crisis in patients with known adrenal insufficiency is 5-10 events per 100 patient-years, with a mortality rate of approximately 0.5 per 100 patient-years 8, 5
• Underlying psychiatric disorders and poor compliance should be investigated in patients with recurrent crises 7