What types of issues could lead to adrenal crisis in patients with adrenal insufficiency or on long-term corticosteroid (corticosteroid) therapy?

Types of Issues That Could Lead to Adrenal Crisis

Infections, particularly gastroenteritis and fever, are the most common precipitating factors for adrenal crisis, followed by surgical procedures, medication errors, and any form of physiological stress in patients with adrenal insufficiency or on long-term corticosteroid therapy. 1

Primary Precipitating Factors

Infectious Triggers

• Gastroenteritis and fever represent the most frequent precipitants of adrenal crisis in patients with established adrenal insufficiency 1
• Other infections beyond gastrointestinal illness can trigger crisis, requiring immediate stress-dose glucocorticoid adjustment 2, 3
• The mechanism involves increased cortisol demand during infection that cannot be met by suppressed or damaged adrenal glands 1

Surgical and Procedural Stress

• Surgical procedures, especially when glucocorticoid doses are not appropriately increased, commonly precipitate adrenal crisis 1
• Anesthesia itself represents a significant physiological stressor requiring stress-dose coverage 3
• Any invasive procedure or trauma increases cortisol requirements beyond baseline replacement 1

Medication-Related Issues

• Omission of glucocorticoid doses or inadequate dosing during hospitalization frequently precipitates crisis 1
• Abrupt discontinuation of corticosteroids in patients on long-term therapy is a critical risk, as HPA axis suppression may persist for months after stopping treatment 4
• Drug interactions that increase corticosteroid metabolism (hepatic enzyme inducers like rifampin, phenytoin, carbamazepine) can precipitate crisis by effectively lowering glucocorticoid levels 4

Patient-Specific Risk Factors

Comorbidity Burden

• Patients with comorbidities, particularly asthma and diabetes, face substantially higher risk of adrenal crisis 1
• High comorbidity burden was identified as the most important risk factor for crisis in a large cohort study 5
• Multiple concurrent illnesses increase both physiological stress and complexity of medication management 5

Type of Adrenal Insufficiency

• Primary adrenal insufficiency (with mineralocorticoid deficiency) creates more instability than secondary adrenal insufficiency where aldosterone production remains intact 1
• Tertiary (glucocorticoid-induced) adrenal insufficiency shows the highest crisis rate at 15.1 per 100 person-years, compared to 5.2 for primary and 3.6 for secondary AI 5
• This 100-fold higher prevalence of tertiary AI (7 per 1,000 people on long-term corticosteroids) makes it the most common form encountered clinically 1

Previous Crisis History

• Prior adrenal crisis is itself a risk factor for subsequent crises, suggesting either inadequate patient education or particularly vulnerable physiology 5

Additional Precipitating Circumstances

Physiological Stressors

• Pregnancy represents a significant risk factor for adrenal crisis due to increased cortisol requirements 1
• Severe emotional stress can trigger crisis in susceptible patients, though less commonly than physical stressors 1
• Accidents, injuries, and any form of physical trauma increase cortisol demand acutely 3

Iatrogenic Causes

• All routes of corticosteroid administration can cause HPA axis suppression, including oral, inhaled, topical, intranasal, and intra-articular 6
• Inhaled corticosteroids can suppress adrenal response to ACTH even at recommended doses, creating unrecognized risk 1
• Doses as low as prednisolone 5 mg daily for more than 1 month can cause clinically significant HPA suppression 6

Critical Clinical Pitfalls

Underrecognized Glucocorticoid-Induced AI

• During ongoing oral glucocorticoid treatment or after withdrawal, approximately 50% of patients have adrenal insufficiency, yet less than 1% have documented adrenal testing 7
• More than 70% of glucocorticoid-induced AI cases are identified during acute hospital admission when symptoms overlap with the underlying condition, leading to missed diagnoses 7
• The nonspecific presentation (fatigue, nausea, anorexia) makes recognition challenging without high clinical suspicion 2, 7

Drug Interactions Requiring Vigilance

• Hepatic enzyme inhibitors (ketoconazole, macrolide antibiotics) can decrease corticosteroid metabolism by up to 60%, potentially masking inadequate dosing until the interacting drug is stopped 4
• Potassium-depleting agents (amphotericin B, diuretics) combined with corticosteroids increase hypokalemia risk and cardiac complications 4
• Anticholinesterase agents should be withdrawn 24 hours before initiating corticosteroid therapy in myasthenia gravis patients to avoid severe weakness 4

Thyroid Status Effects

• Hypothyroidism decreases metabolic clearance of corticosteroids while hyperthyroidism increases it, necessitating dose adjustments when thyroid status changes 4
• Failure to adjust glucocorticoid dosing with thyroid function changes can precipitate either crisis (in hyperthyroidism) or toxicity (in hypothyroidism) 4