What are the signs, symptoms, and treatment options for Addison's disease?

Addison's Disease: Signs, Symptoms, and Treatment

Clinical Presentation and Diagnosis

Addison's disease should be suspected in any patient presenting with unexplained collapse, hypotension, vomiting, or diarrhea, particularly when accompanied by hyperpigmentation and electrolyte abnormalities. 1

Cardinal Signs and Symptoms

Early and Nonspecific Manifestations:

• Persistent fatigue and myasthenia (muscle weakness) are among the earliest symptoms 2
• Unintentional weight loss develops progressively 2
• Orthostatic (postural) hypotension occurs before supine hypotension develops and represents a critical early warning sign 3
• Hyperpigmentation of the skin, especially in areas subjected to friction, results from elevated ACTH levels 3, 2

Gastrointestinal Symptoms:

• Nausea and vomiting, often severe 3
• Abdominal pain 3
• Morning nausea and poor appetite 4
• Salt cravings due to aldosterone deficiency 4

Neuropsychiatric Manifestations:

• Depression and psychosis can occur 2
• Impaired cognitive function and confusion 3
• In severe cases, loss of consciousness and coma 3

Laboratory Findings at Diagnosis

Electrolyte Abnormalities:

• Hyponatremia is present in approximately 90% of newly presenting cases, though often only marginally reduced 1, 3
• Hyperkalemia occurs in approximately 50% of patients at diagnosis (not in all cases) 1, 3
• Mild to moderate hypercalcemia in 10-20% of patients 1, 3

Hormonal Findings:

• Serum cortisol below the normal range (or inappropriately low for the disease state) 1
• Markedly elevated plasma ACTH level is diagnostic of primary adrenal insufficiency 1, 3
• Increased plasma renin activity with low serum aldosterone 1
• Low dehydroepiandrosterone sulphate (DHEAS) 1

Other Laboratory Abnormalities:

• Increased creatinine and BUN due to prerenal renal failure 3
• Hypoglycemia (more common in children, less frequent in adults) 1, 3
• Metabolic acidosis 3
• Mild eosinophilia, lymphocytosis, and increased liver transaminases may be present 1
• TSH levels in the range of 4-10 IU/L due to lack of cortisol's inhibitory effect 1

Diagnostic Testing

Confirmatory Tests:

• Paired measurement of serum cortisol and plasma ACTH is the diagnostic test for primary adrenal insufficiency 1
• Serum cortisol <250 nmol/L with increased ACTH in the presence of acute illness is diagnostic 1, 3
• Serum cortisol <400 nmol/L with increased ACTH raises strong suspicion 1
• In equivocal cases, a synacthen (tetracosactide) stimulation test (0.25 mg IM or IV) with peak serum cortisol <500 nmol/L is diagnostic 1

Etiologic Workup:

• Measure serum 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmune adrenalitis accounts for approximately 85% of cases in Western Europe 1, 3
• If antibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative processes 1, 3
• In male patients, assay very long-chain fatty acids to check for adrenoleukodystrophy 1, 3

Treatment

Chronic Maintenance Therapy

Glucocorticoid Replacement: Hydrocortisone 15-25 mg daily in 2-3 divided doses is the first-line treatment, with the first dose immediately after waking and the last dose at least 6 hours before bedtime to mimic natural cortisol rhythm. 5

• Use the lowest effective dose to minimize side effects while maintaining well-being 5
• In children, dose hydrocortisone at 6-10 mg/m² of body surface area 5
• Hydrocortisone is preferred over longer-acting agents like prednisone 3

Mineralocorticoid Replacement:

• Fludrocortisone 50-200 μg (0.05-0.2 mg) once daily to replace aldosterone 5, 6
• Children and younger adults may require higher doses 5
• If essential hypertension develops, reduce the fludrocortisone dose but do not completely discontinue 5, 4
• Patients should consume salt and salty foods freely and avoid licorice and grapefruit juice 5

Management of Adrenal Crisis

Immediate Emergency Management: Administer hydrocortisone 100 mg IV bolus immediately upon clinical suspicion—treatment must never be delayed by diagnostic procedures. 1, 3

• Draw blood for cortisol, ACTH, electrolytes, creatinine, urea, and glucose before treatment, but do not delay therapy waiting for results 3
• Initiate aggressive fluid resuscitation with 0.9% isotonic saline at 1 liter over the first hour 5, 3

Subsequent Management:

• Continue hydrocortisone 100 mg every 6-8 hours (or 100-300 mg per day as continuous IV infusion) until recovery 5, 3
• Administer 3-4 liters of isotonic saline total over 24-48 hours, adjusting based on hemodynamic response 5, 3
• Monitor serum electrolytes frequently to guide fluid management 3
• Do not add separate mineralocorticoid (fludrocortisone) during acute crisis, as high-dose hydrocortisone provides adequate mineralocorticoid activity 3
• Identify and treat the underlying precipitant (e.g., infection) 5, 3

Transition to Maintenance:

• Taper parenteral glucocorticoids over 1-3 days to oral therapy once the patient can tolerate oral medications 3
• Restart fludrocortisone when hydrocortisone dose falls below 50 mg per day 3

Dose Adjustments for Special Situations

Minor Illness or Stress:

• Double or triple the oral glucocorticoid dose during minor illness 5, 3

Surgery and Invasive Procedures:

• Major surgery requires 100 mg hydrocortisone IM before anesthesia, followed by increased oral doses 5
• Use IV or IM hydrocortisone for surgical procedures 5

Pregnancy:

• Small adjustments to hydrocortisone and fludrocortisone doses may be needed, particularly in the third trimester 5, 4
• Administer parenteral hydrocortisone during delivery 5

Exercise:

• Unaccustomed intense or prolonged exercise may require increased hydrocortisone and salt intake 5

Patient Education and Monitoring

Essential Patient Education

All patients must receive education on dose adjustments during illness, use of emergency injectable hydrocortisone, and when to seek medical attention. 5, 3

• Patients should wear medical alert identification (bracelet/necklace) and carry an emergency steroid card 5, 4, 3
• Teach patients to use parenteral hydrocortisone during severe illness or inability to take oral medications 3
• Emphasize that even mild upset stomach may precipitate adrenal crisis as patients cannot absorb oral medication when they need it most 3
• Patient education is paramount to preventing recurrent crises and unnecessary deaths 3

Annual Follow-up

Patients should be reviewed at least annually with assessment of general health, weight, blood pressure, and serum electrolytes. 5, 4

• Measure weight and blood pressure at each visit to detect over-replacement or under-replacement 4
• Check serum electrolytes (sodium and potassium) annually 4
• Assess health and well-being with specific questioning about energy levels, morning nausea, appetite, and timing of symptoms 4
• Monitor for development of new autoimmune disorders, particularly hypothyroidism 5, 4
• Assess bone mineral density every 3-5 years to monitor for glucocorticoid-induced osteoporosis 5, 4

Monitoring Limitations

Important caveats:

• Serum cortisol levels are not useful for monitoring adequacy of replacement therapy, as hydrocortisone produces highly variable peaks and troughs 4
• ACTH levels do not guide dose adjustments in established Addison's disease, as they remain elevated regardless of replacement adequacy 4

Common Precipitating Factors for Adrenal Crisis

The most common triggers are gastrointestinal illness with vomiting/diarrhea and infections. 3, 7

• Failure to increase glucocorticoid doses during intercurrent illness 3
• Surgical procedures without adequate steroid coverage 3
• Physical injuries or trauma 3
• Chronic under-replacement with fludrocortisone combined with low salt consumption 3
• Poor compliance with mineralocorticoid therapy 3
• Medications that accelerate cortisol clearance without dose adjustment 3
• Starting thyroid hormone replacement before adequate glucocorticoid replacement in patients with multiple hormone deficiencies 3