Adrenal Insufficiency: Symptoms and Treatment
Clinical Presentation
Adrenal insufficiency presents with a constellation of nonspecific symptoms that often delay diagnosis, but recognizing these features is critical to prevent life-threatening adrenal crisis.
Cardinal Symptoms
- Profound fatigue and malaise occur in 50-95% of patients, representing the most common presenting complaint 1, 2
- Unintentional weight loss and anorexia affect 43-73% of patients 1, 2
- Nausea, vomiting, and abdominal pain are present in 20-62% of cases, with abdominal pain sometimes mimicking an acute abdomen with peritoneal irritation 3, 1
- Postural hypotension and orthostatic symptoms develop due to mineralocorticoid deficiency in primary adrenal insufficiency 3, 2
- Muscle pain and cramps are common musculoskeletal manifestations 3, 4
Distinguishing Features of Primary vs. Secondary Adrenal Insufficiency
Primary adrenal insufficiency (Addison's disease) has unique features:
- Hyperpigmentation of skin due to elevated ACTH levels, a pathognomonic sign absent in secondary disease 3, 4
- Salt craving from aldosterone deficiency 2
- Both glucocorticoid AND mineralocorticoid deficiency, leading to more severe electrolyte abnormalities 3
Secondary adrenal insufficiency lacks:
- Hyperpigmentation (ACTH is low, not elevated) 3
- Salt craving and severe electrolyte disturbances (aldosterone production is preserved) 3
Laboratory Abnormalities
- Hyponatremia is present in approximately 90% of newly presenting cases 3
- Hyperkalemia occurs in about 50% of patients with primary adrenal insufficiency 3, 4
- Hypoglycemia is more common in children but can occur in adults 3, 4
- Mild hypercalcemia is found in 10-20% of patients 3, 4
- Increased creatinine and BUN from prerenal renal failure due to volume depletion 4
- Metabolic acidosis from impaired renal function and aldosterone deficiency 4
Adrenal Crisis: The Life-Threatening Emergency
Adrenal crisis represents acute, severe adrenal insufficiency and requires immediate recognition:
- Severe hypotension and shock that may not respond to fluids alone 3, 4
- Profound dehydration requiring aggressive fluid resuscitation 3, 4
- Altered mental status, confusion, loss of consciousness, or coma in severe cases 3, 4
- Severe gastrointestinal symptoms with intractable vomiting preventing oral medication absorption 3, 4
Common precipitating factors for adrenal crisis include:
- Gastrointestinal illness with vomiting/diarrhea (most common trigger) 4
- Infections of any type 3, 4
- Surgical procedures without adequate steroid coverage 3, 4
- Physical trauma or injuries 3, 4
- Myocardial infarction 3, 4
- Failure to increase glucocorticoid doses during intercurrent illness 4
Diagnostic Approach
The diagnosis requires two steps: confirming adrenal insufficiency and establishing the etiology.
Initial Diagnostic Testing
- Early-morning (8 AM) serum cortisol, plasma ACTH, and DHEAS are the first-line tests 3, 1
- Serum cortisol <250 nmol/L (<5 µg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency 3, 5, 1
- Serum cortisol 5-10 µg/dL with low or low-normal ACTH suggests secondary or glucocorticoid-induced adrenal insufficiency 1
- Serum cortisol >500 nmol/L (>18 µg/dL) effectively rules out adrenal insufficiency 3
Confirmatory Testing for Equivocal Cases
- Cosyntropin (Synacthen) stimulation test: administer 250 µg IM or IV, measure cortisol at baseline and 60 minutes 3, 1
- Peak cortisol <500 nmol/L (<18 µg/dL) confirms adrenal insufficiency 3
- Insulin tolerance test is the gold standard for secondary adrenal insufficiency but carries risks 6
Establishing Etiology
For primary adrenal insufficiency:
- Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmune disease accounts for ~85% of cases in Western Europe 3, 4
- If antibodies are negative, obtain CT imaging of adrenals to evaluate for hemorrhage, metastases, tuberculosis, or infiltrative processes 3
- In males, assay very long-chain fatty acids to check for adrenoleukodystrophy 3
For secondary adrenal insufficiency:
- MRI of pituitary to evaluate for tumors, hemorrhage, hypophysitis, or infiltrative conditions 1
- Assess other pituitary hormone axes as multiple deficiencies often coexist 1
Critical Diagnostic Pitfall
Treatment must NEVER be delayed for diagnostic testing when adrenal crisis is suspected. Draw blood for cortisol, ACTH, and electrolytes, then immediately initiate treatment 3, 5, 4
Treatment of Chronic Adrenal Insufficiency
Glucocorticoid Replacement
Hydrocortisone is the preferred glucocorticoid for physiologic replacement:
- Hydrocortisone 15-25 mg daily in divided doses (typically 10-20 mg in morning, 5-10 mg in early afternoon) 3, 5, 1
- Alternative: Prednisone 3-5 mg daily or 5-10 mg daily for moderate symptoms 3, 1
- Dosing mimics physiologic cortisol secretion with higher morning doses 5
Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)
- Fludrocortisone 0.05-0.3 mg daily is required for primary adrenal insufficiency 3, 5, 1
- Not needed in secondary adrenal insufficiency as aldosterone production is preserved 3
- Restart fludrocortisone when hydrocortisone dose falls below 50 mg/day during stress-dose tapering 3, 5, 4
Monitoring Maintenance Therapy
- Assess clinical symptoms: energy level, appetite, weight stability, orthostatic symptoms 5
- Monitor blood pressure including postural measurements 3, 5
- Check electrolytes periodically to ensure adequate mineralocorticoid replacement 5
- Postural hypotension reflects insufficient mineralocorticoid therapy or low salt intake 3
Treatment of Adrenal Crisis
Adrenal crisis is a medical emergency requiring immediate treatment without waiting for diagnostic confirmation.
Immediate Emergency Management
- Hydrocortisone 100 mg IV bolus immediately without delay 3, 5, 4
- Rapid IV fluid resuscitation with 0.9% normal saline: 1 L over first hour, followed by 2-3 additional liters at slower rate 3, 5, 4
- Draw blood for cortisol, ACTH, electrolytes, glucose before treatment but do NOT delay therapy 3, 5, 4
- Frequent monitoring of vital signs, particularly blood pressure and heart rate 5
Continued Hospital Management
- Continue IV hydrocortisone 50-100 mg every 6-8 hours (total 100-300 mg/day) for first 24-48 hours 3, 5, 4
- Monitor electrolytes frequently, particularly sodium and potassium 5, 4
- Identify and treat precipitating cause, especially infections 3, 5, 4
- Consider ICU admission for severe cases with persistent hypotension or altered mental status 3, 4
Transition to Maintenance Therapy
- Taper stress-dose corticosteroids over 3-7 days after clinical improvement 3, 5, 4
- Transition to oral hydrocortisone 15-25 mg daily in divided doses once patient can tolerate oral medications 3, 5
- Restart fludrocortisone 0.05-0.1 mg daily when hydrocortisone dose falls below 50 mg/day 3, 5, 4
Prevention of Future Adrenal Crises
Patient education is paramount to preventing recurrent crises and unnecessary deaths.
Stress-Dose Guidelines ("Sick Day Rules")
- Minor illness (fever, cold, gastroenteritis): double or triple oral glucocorticoid dose 3, 4, 1
- Moderate illness (persistent vomiting, high fever): use parenteral hydrocortisone 3, 4, 1
- Severe illness, surgery, or trauma: immediate medical attention with stress-dose IV hydrocortisone 3, 4
Essential Patient Resources
- Emergency injectable hydrocortisone kit (100 mg IM) with training on self-administration 5, 1, 2
- Medical alert bracelet or necklace indicating adrenal insufficiency 5, 1
- Steroid emergency card to inform healthcare providers 2
- Written instructions on stress dosing and when to seek emergency care 3, 4
Structured Education Programs
- Active and repeated patient education on managing adrenal insufficiency 3, 2
- Training for family members on parenteral hydrocortisone administration 2
- Regular follow-up to reinforce education and assess compliance 3
Critical Pitfalls to Avoid
- Delaying treatment while waiting for diagnostic confirmation can be fatal 5, 4
- Inadequate fluid resuscitation alongside corticosteroid administration is a common error 5, 4
- Failing to identify and treat the precipitating cause of adrenal crisis 5, 4
- Tapering corticosteroids too quickly before clinical stabilization 5, 4
- Overlooking the need for mineralocorticoid replacement in primary adrenal insufficiency 5, 4
- Starting thyroid hormone replacement before adequate glucocorticoid replacement in patients with multiple hormone deficiencies can trigger adrenal crisis 3, 4
- Underestimating the frequency of adrenal crises: approximately 50% of patients experience at least one crisis after diagnosis 2
Special Considerations
Glucocorticoid-Induced Adrenal Insufficiency
- Most common form of adrenal insufficiency from supraphysiological glucocorticoid doses 1
- Suspect in patients who recently tapered or discontinued glucocorticoids 1
- Recovery of HPA axis may take months to over a year after discontinuation 7, 1
Drug Interactions
- Medications accelerating cortisol clearance (rifampin, phenytoin, barbiturates) may require dose adjustment 7, 8
- Azole antifungals in high doses can cause pharmacological adrenal insufficiency 1
- Opioids can suppress ACTH production causing secondary adrenal insufficiency 1