What is an adrenal crisis in a patient with adrenal insufficiency?

Adrenal Crisis: Definition and Clinical Overview

Adrenal crisis is an acute, life-threatening medical emergency caused by severe glucocorticoid and/or mineralocorticoid deficiency that requires immediate treatment with intravenous hydrocortisone 100 mg and aggressive fluid resuscitation to prevent death. 1, 2

Core Pathophysiology

Adrenal crisis represents the acute decompensation of adrenal insufficiency, occurring when cortisol production cannot meet the body's physiological demands during stress. 3 This can arise from:

• Primary adrenal insufficiency (Addison's disease): Both cortisol and aldosterone deficiency due to adrenal gland destruction 4
• Secondary adrenal insufficiency: Cortisol deficiency only (aldosterone production remains intact) due to pituitary or hypothalamic dysfunction 4
• Tertiary (iatrogenic) adrenal insufficiency: The most common form, affecting 7 in 1,000 people on long-term corticosteroid therapy—approximately 100 times more prevalent than intrinsic adrenal disease 4, 1

Clinical Presentation

Patients with adrenal crisis present with a constellation of severe, rapidly progressive symptoms that can be fatal if untreated:

Cardiovascular Manifestations

• Profound hypotension and shock are hallmark features 2
• Orthostatic hypotension develops before supine hypotension and represents an early warning sign 2
• Progressive loss of vasomotor tone due to impaired alpha-adrenergic receptor responsiveness 2

Gastrointestinal Symptoms

• Severe nausea and vomiting 2
• Abdominal pain that can mimic an acute abdomen 2
• Inability to tolerate oral medications, which perpetuates the crisis 2

Neurological Features

• Altered mental status ranging from malaise and confusion to obtundation and coma 2
• Non-specific somnolence as an early warning sign 2

Other Clinical Signs

• Profound dehydration and volume depletion 2
• Fever (which may be due to the crisis itself, not just infection) 2
• Hyperpigmentation in primary adrenal insufficiency due to elevated ACTH 2

Laboratory Abnormalities

Critical laboratory findings that support the diagnosis include:

• Hyponatremia: Present in approximately 90% of newly presenting cases 4, 2
• Hyperkalemia: Found in approximately 50% of patients (its absence does NOT exclude the diagnosis) 2
• Hypoglycemia: More common in children than adults 4, 2
• Elevated creatinine and BUN: Due to prerenal renal failure from volume depletion 2
• Metabolic acidosis: From impaired renal function and aldosterone deficiency 2
• Mild hypercalcemia: Occurs in 10-20% of patients 2
• Anemia, eosinophilia, and lymphocytosis: May be present 1

Epidemiology and Mortality

The incidence and mortality data underscore the severity of this condition:

• Crisis frequency: 6-8 adrenal crises per 100 patient-years in those with established adrenal insufficiency 4, 5, 3
• Mortality risk: Patients with adrenal insufficiency have a risk ratio for all-cause mortality of 2.19 for men and 2.86 for women 4
• Documented mortality: Two deaths occurred during adrenal crisis in a prospective 2-year follow-up of 423 patients 4
• Preventable deaths: 8.6% of crises are caused by insufficient glucocorticoid medication during hospital stays due to medication errors 4

Common Precipitating Factors

Understanding triggers is essential for prevention:

Infectious Causes (Most Common)

• Gastroenteritis with vomiting/diarrhea: The single most common precipitant 2, 3, 6
• Fever and any type of infection: Account for approximately 45% of crises 1, 5

Surgical and Physical Stress

• Surgical procedures without adequate steroid coverage 4, 1, 2
• Physical trauma or injuries 2
• Major pain 5

Medication-Related Causes

• Failure to increase glucocorticoid doses during illness despite patient education on "sick day rules" 2
• Omission or inadequate dosing of maintenance glucocorticoids 4
• Medications that accelerate cortisol clearance without dose adjustment 2
• Starting thyroid hormone replacement before adequate glucocorticoid replacement in patients with multiple hormone deficiencies 2

Other Precipitants

• Pregnancy 1
• Severe emotional or psychological stress 1, 5
• Myocardial infarction 2
• Severe allergic reactions 2
• Heat exposure 5

High-Risk Populations

• Patients with comorbidities, especially asthma and diabetes 4
• Patients with mineralocorticoid or vasopressin dependency 4
• Patients on immune checkpoint inhibitors who develop hypophysitis, particularly during rapid corticosteroid tapers 2
• Patients with underlying psychiatric disorders and poor medication compliance 2

Critical Clinical Pearls

Key points that can prevent misdiagnosis and delayed treatment:

• Never delay treatment for diagnostic confirmation—mortality increases with delayed intervention 2, 7
• Even mild gastrointestinal upset can precipitate crisis because patients cannot absorb oral medications when they need them most 2
• Consider adrenal crisis in any patient with unexplained collapse, hypotension, vomiting, or diarrhea, especially with electrolyte abnormalities 2
• The absence of hyperkalemia does NOT exclude the diagnosis—it is present in only half of cases 2
• Normal or even elevated plasma cortisol levels do not exclude relative adrenal insufficiency in physiologically stressed patients 2
• Persistent fever may be due to adrenal insufficiency itself, not just infection, and should not prompt steroid withdrawal 2
• Approximately 50% of patients who experience one adrenal crisis will have another 4