What is the diagnosis and treatment for a patient with suspected Addison's disease, presenting with fatigue, weight loss, and electrolyte imbalances, and possibly a history of autoimmune disorders or adrenal gland damage?

Addison's Disease: Diagnosis and Management

Diagnosis

Addison's disease (primary adrenal insufficiency) is diagnosed through a two-step approach: paired measurement of morning serum cortisol and plasma ACTH, followed by a cosyntropin stimulation test in equivocal cases. 1

Initial Diagnostic Testing

• Draw morning (8 AM) serum cortisol and plasma ACTH simultaneously as the first-line diagnostic test 1
• Serum cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH during acute illness is diagnostic of primary adrenal insufficiency 1, 2
• Serum cortisol <400 nmol/L (<15 μg/dL) with elevated ACTH generates strong suspicion and warrants further testing 2
• Obtain basic metabolic panel to assess for hyponatremia (present in 90% of newly diagnosed cases) and hyperkalemia (present in only ~50% of cases) 1, 2

Critical pitfall: The absence of hyperkalemia cannot rule out adrenal insufficiency—it occurs in only half of patients 1, 2

Confirmatory Testing: Cosyntropin Stimulation Test

When initial cortisol levels are indeterminate (between 250-400 nmol/L or 9-15 μg/dL):

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 2
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 2
• Peak cortisol <500 nmol/L (<18 μg/dL) at either 30 or 60 minutes confirms adrenal insufficiency 1, 2
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes the diagnosis 2

Important consideration: If the patient is clinically unstable with suspected adrenal crisis, never delay treatment to perform diagnostic testing—give hydrocortisone 100 mg IV immediately and draw blood for cortisol/ACTH beforehand if possible 3, 1, 2

Etiologic Workup After Diagnosis

• Measure 21-hydroxylase (anti-adrenal) autoantibodies as the first step, since autoimmunity accounts for ~85% of cases in Western populations 1, 2
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tuberculosis, metastatic disease, or other structural causes 1, 2
• In male patients with negative antibodies, assay very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 2

Screening for Associated Autoimmune Conditions

• Approximately 50% of patients with autoimmune Addison's disease have other co-existing autoimmune disorders 1
• Screen annually for thyroid dysfunction, type 1 diabetes, pernicious anemia (vitamin B12), and celiac disease (tissue transglutaminase antibodies with total IgA) 1, 2

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Treatment

Patients with Addison's disease require lifelong replacement of both glucocorticoids and mineralocorticoids to prevent potentially fatal adrenal crisis. 1

Glucocorticoid Replacement

• Hydrocortisone 15-25 mg daily in divided doses is the preferred glucocorticoid 1, 2
• Typical regimen: 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5-5 mg at 4:00 PM to approximate physiological cortisol secretion 2
• Alternative regimens: 15+5 mg, 10+10 mg, or 10+5+5 mg depending on individual response 2
• Cortisone acetate 25-37.5 mg daily in divided doses is an acceptable alternative 1, 2
• Prednisolone 4-5 mg daily may be used in select patients with marked energy fluctuations on hydrocortisone 2

Avoid dexamethasone for chronic replacement therapy 2

Mineralocorticoid Replacement

• Fludrocortisone 0.1 mg daily is the standard mineralocorticoid replacement 1, 4
• Dosing range: 0.05-0.2 mg daily, with some younger adults requiring up to 0.5 mg daily 2, 4
• If transient hypertension develops, reduce dose to 0.05 mg daily 4
• Monitor adequacy by assessing for salt cravings, orthostatic blood pressure changes, and peripheral edema 2
• Measure plasma renin activity to guide dosing adjustments 2

Unrestricted sodium salt intake is essential alongside hormone replacement 2

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Management of Adrenal Crisis

Adrenal crisis is a life-threatening emergency requiring immediate treatment without delay for diagnostic procedures. 3, 1

Emergency Treatment Protocol

• Immediately administer hydrocortisone 100 mg IV or IM 3, 1
• Rapidly infuse 0.9% sodium chloride solution at 1 L/hour until hemodynamic improvement 3, 1
• Continue hydrocortisone 100 mg IV/IM every 6-8 hours for the first 24-48 hours 3, 1
• Continue isotonic saline infusion at a slower rate for 24-48 hours 3
• Draw blood for cortisol, ACTH, electrolytes, glucose, and creatinine before treatment if possible, but do not delay therapy 3
• Identify and treat precipitating causes (infection, trauma, gastrointestinal illness) 3

Tapering After Crisis Resolution

• Taper parenteral glucocorticoids over 1-3 days to oral replacement once the patient can eat and drink 3
• Double oral dose for 24-48 hours after switching from IV, then return to maintenance dose 3

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Stress Dosing Guidelines

Minor Stress (Fever, Minor Illness, Dental Procedures)

• Double the usual daily dose for 24-48 hours 3, 2
• For dental procedures: take extra morning dose 1 hour prior 3

Moderate Stress (Major Dental Surgery, Minor Surgery)

• Hydrocortisone 100 mg IM just before the procedure 3
• Double oral dose for 24 hours postoperatively, then return to normal dose 3

Major Stress (Major Surgery with Long Recovery)

• Hydrocortisone 100 mg IM just before anesthesia 3
• Continue 100 mg hydrocortisone IM every 6 hours until able to eat and drink 3
• Then double oral dose for 48+ hours before tapering to normal dose 3

Labor and Vaginal Birth

• Hydrocortisone 100 mg IM at onset of labor 3
• Double oral dose for 24-48 hours after delivery, then taper to normal dose 3

Strenuous Exercise

• For prolonged intense activity (e.g., marathon): take extra 5 mg hydrocortisone before the event 3
• Increase fluid and salt intake to replace sweat losses in hot conditions 3

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Patient Education and Safety Measures

Essential Patient Education

• All patients must wear a medical alert bracelet or necklace indicating adrenal insufficiency 1, 2
• Carry a steroid emergency card at all times 1
• Prescribe and train patients on self-injection of hydrocortisone 100 mg IM emergency kit for use during severe vomiting or inability to take oral medications 2
• Educate on recognizing warning signs of impending adrenal crisis: severe nausea, vomiting, diarrhea, abdominal pain, confusion, severe weakness 3, 1
• Instruct patients to double or triple their dose during illness, fever, or physical stress 2

Drug Interactions to Avoid

• Medications that increase hydrocortisone requirements: anti-epileptics, rifampin, phenytoin, carbamazepine, etomidate, topiramate 2
• Medications that interfere with fludrocortisone: diuretics, acetazolamide, NSAIDs 2
• Avoid grapefruit juice and licorice as they decrease hydrocortisone requirements 2

Annual Follow-Up

• Assess health status, weight, and blood pressure 1
• Monitor serum electrolytes (sodium, potassium) 1
• Screen for development of new autoimmune disorders (thyroid, diabetes, celiac disease, pernicious anemia) 1, 2
• Assess for complications of glucocorticoid therapy (osteoporosis, weight gain, glucose intolerance) 1

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Special Considerations

Concurrent Hypothyroidism

When treating patients with both adrenal insufficiency and hypothyroidism, corticosteroids must be started several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 2

Persistent Hypotension Despite Treatment

If a patient remains hypotensive on chronic hydrocortisone:

• First, optimize fludrocortisone dosing (may need up to 0.5 mg daily in younger adults) 2
• Evaluate glucocorticoid timing and dosing adequacy 2
• Check for drug interactions that may increase steroid requirements 2
• Consider having the patient wake earlier to take the first hydrocortisone dose, then return to sleep 2

Testing Considerations with Exogenous Steroids

• Exogenous steroids (prednisone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound diagnostic testing 2
• Do not attempt diagnostic testing while patients are on corticosteroids—wait until treatment is discontinued with adequate washout time 2
• If emergency treatment is needed but diagnostic testing is still desired, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 2