Addison Disease: University of Washington-Style Q&A
Clinical Presentation and Diagnosis
What are the key clinical features that should prompt consideration of Addison disease?
Suspect Addison disease in any patient presenting with unexplained collapse, hypotension, vomiting, or diarrhea, particularly when accompanied by hyperpigmentation, hyponatremia, hyperkalemia, or hypoglycemia 1. The hyperpigmentation is pathognomonic for primary adrenal insufficiency and appears particularly in sun-exposed areas, skin creases, mucosal membranes, scars, and areola of the breast 2. Common symptoms include profound fatigue, weight loss, and low blood pressure with postural drop 2.
Laboratory findings at presentation:
- Hyponatremia: Present in 90% of cases
- Hyperkalemia: Present in approximately 50% of cases (note: may have hypokalaemia if severe vomiting present)
- Hypoglycemia: More common in children than adults
- Mild hypercalcemia: 10-20% of patients
- Anemia, eosinophilia, lymphocytosis: May be present 1
How do you definitively diagnose Addison disease?
The diagnostic test is paired measurement of serum cortisol and plasma ACTH 1. In acute illness with suspected adrenal crisis, serum cortisol <250 nmol/L with elevated ACTH is diagnostic; cortisol <400 nmol/L with elevated ACTH raises strong suspicion 1.
For equivocal cases, perform a cosyntropin (synacthen) stimulation test: administer 0.25 mg IM or IV, then measure serum cortisol at 30 and/or 60 minutes. Peak cortisol <550 nmol/L (or <500 nmol/L per some guidelines) confirms primary adrenal insufficiency 1.
Critical caveat: Never delay treatment for diagnostic testing if adrenal crisis is suspected—draw blood for cortisol and ACTH, then immediately start treatment 1.
Etiology Determination
What is the etiologic workup after confirming Addison disease?
Start by measuring 21-hydroxylase (anti-adrenal) autoantibodies, as autoimmunity accounts for approximately 85% of cases in Western populations 1. If antibodies are negative, obtain CT imaging of the adrenal glands to look for tumors or calcifications typical of tuberculosis 1.
In males, always measure very long-chain fatty acids to screen for adrenoleukodystrophy, an X-linked condition with variable presentation 1. Consider NR0B1 (DAX1) gene mutations in males with delayed/incomplete puberty and hypogonadotropic hypogonadism 1.
Note that previously antibody-positive patients may become negative over time, so absence of antibodies doesn't exclude autoimmunity 1.
Glucocorticoid Replacement
What is the optimal glucocorticoid replacement regimen?
Use hydrocortisone 15-25 mg daily in divided doses (2-3 times daily), with the first dose immediately upon awakening and the last dose at least 4-6 hours before bedtime 1. Typical regimens include 10+5+2.5 mg or 10+5+5 mg 1. Cortisone acetate is an acceptable alternative at 25-37.5 mg daily 1.
For children: Use hydrocortisone 8 mg/m² body surface area in 3-4 divided doses 2. Avoid synthetic long-acting glucocorticoids (prednisolone, dexamethasone) in children 2.
Avoid dexamethasone in all patients, especially pregnant women, as it crosses the placenta 2. Prednisolone may be considered only in select patients with marked energy fluctuations despite optimized hydrocortisone therapy 1.
Monitoring is entirely clinical—plasma ACTH and serum cortisol are not useful for dose adjustment 1. Assess for:
- Over-replacement: Weight gain, insomnia, peripheral edema, hypertension
- Under-replacement: Lethargy, nausea, poor appetite, weight loss, increased pigmentation 1
Mineralocorticoid Replacement
What is the appropriate fludrocortisone dosing?
Most patients require fludrocortisone 50-200 µg daily as a single morning dose 1. Children, younger adults, and pregnant women (especially third trimester) may require higher doses up to 500 µg daily due to progesterone's anti-mineralocorticoid effects 1.
Patients should consume salt and salty foods ad libitum and avoid potassium-containing salts 1. Avoid liquorice and grapefruit juice, which potentiate mineralocorticoid effects 1.
Monitor clinically by assessing:
- Salt cravings or lightheadedness
- Blood pressure (supine and standing)
- Peripheral edema
- Serum electrolytes 1
Important: Under-replacement is common and may predispose to recurrent adrenal crises. If essential hypertension develops, reduce but do not stop fludrocortisone; add a vasodilator instead 1.
Stress Dosing and Special Situations
How should glucocorticoid doses be adjusted during illness?
For fever or minor illness: Double or triple the usual daily dose until recovery 1. Patients must be educated to increase doses at the first sign of illness, as even mild gastrointestinal upset can precipitate crisis when medication isn't absorbed 1.
For major surgery with long recovery: 100 mg hydrocortisone IM just before anesthesia, then 100 mg IM every 6 hours until able to eat/drink, then double oral dose for 48+ hours before tapering 1.
For labor and vaginal delivery: 100 mg hydrocortisone IM at onset of labor, repeated every 6 hours as needed, then double oral dose for 24-48 hours postpartum 1.
For minor surgery/dental procedures: 100 mg hydrocortisone IM before procedure, then double oral dose for 24 hours 1.
Pregnancy Management
How should Addison disease be managed during pregnancy?
Increase hydrocortisone dose during the third trimester by 2.5-10 mg daily 1. Monitor at least once per trimester for signs of over- and under-replacement 2.
Use hydrocortisone over cortisone acetate, prednisolone, or prednisone, and never use dexamethasone as it crosses the placenta 2. Fludrocortisone dose often needs increasing in late pregnancy due to progesterone's anti-mineralocorticoid effects; monitor salt cravings, blood pressure, and electrolytes rather than plasma renin activity 1.
Adrenal Crisis Management
How do you treat suspected adrenal crisis?
Immediately administer 100 mg hydrocortisone IV (or IM if no IV access), followed by 100 mg every 6-8 hours until recovery 1. Simultaneously give 1 liter of 0.9% saline over the first hour 1. The high-dose hydrocortisone saturates 11β-HSD type 2, providing mineralocorticoid effect 1.
Draw blood for cortisol, ACTH, electrolytes, glucose, and infection workup before treatment, but never delay treatment for diagnostic procedures 1.
Typical crisis presentation includes malaise, nausea, vomiting, abdominal pain, dehydration, hypotension, confusion, or loss of consciousness. Laboratory findings show hyponatremia, hyperkalemia, increased creatinine (prerenal failure), and sometimes hypoglycemia or hypercalcemia 1.
Patient Education and Follow-up
What essential education must patients receive?
Patients must:
- Wear a medical alert bracelet and carry a steroid emergency card 1
- Have injectable hydrocortisone available and know how to self-inject 1
- Understand when and how to increase oral doses (fever, illness, stress) 2
- Recognize early signs of adrenal crisis and seek immediate help 2
Follow-up schedule: Adults should see an endocrinologist at least annually; infants every 3-4 months 2, 1. Annual screening should include assessment of symptoms/signs of over- and under-replacement, weight, blood pressure, and serum electrolytes 2, 1. Screen periodically for other autoimmune diseases (especially hypothyroidism) in patients with autoimmune Addison disease 2.
Drug Interactions
What medications affect hydrocortisone requirements?
May need MORE hydrocortisone with:
- Anti-epileptics/barbiturates
- Antituberculosis drugs
- Etomidate
- Topiramate 1
May need LESS hydrocortisone with:
- Grapefruit juice
- Liquorice 1
Avoid with fludrocortisone:
- Diuretics
- Acetazolamide
- NSAIDs
- Liquorice/carbenoxolone 1
Drospirenone-containing contraceptives may increase fludrocortisone requirements 1.