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

Definition and Clinical Presentation

Addison's disease (primary adrenal insufficiency) results from destruction of the adrenal cortex, causing deficiency of both cortisol and aldosterone, and requires lifelong hormone replacement therapy to prevent potentially fatal adrenal crisis. 1

Key Clinical Features

• Symptoms develop insidiously over months to years and include fatigue, weight loss, malaise, anorexia, nausea, and the highly specific finding of salt craving 1, 2
• Hyperpigmentation of skin and mucous membranes is a distinguishing feature of primary adrenal insufficiency due to elevated ACTH, whereas secondary adrenal insufficiency presents with normal skin color 2, 3
• Hypotension and orthostatic symptoms reflect mineralocorticoid deficiency 1, 3
• Muscle pain, cramps, and abdominal pain may occur 2

Laboratory Findings

• Hyponatremia is present in 90% of newly diagnosed cases 1, 2
• Hyperkalemia occurs in only approximately 50% of cases, so its absence does not exclude the diagnosis 1, 2
• Low serum cortisol with elevated plasma ACTH levels 1
• Elevated renin with low aldosterone 1
• Increased creatinine from prerenal renal failure may be present 4
• Mild hypercalcemia occasionally occurs 4, 2

Diagnostic Approach

Initial Testing

Paired measurement of early morning (8 AM) serum cortisol and plasma ACTH is the first-line diagnostic test. 1, 2

• 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 (<14.5 μg/dL) with elevated ACTH generates strong suspicion 2
• Morning cortisol between 250-400 nmol/L (9-14.5 μg/dL) requires confirmatory testing 2

Confirmatory Testing: Cosyntropin Stimulation Test

When initial cortisol is equivocal, perform the cosyntropin (Synacthen) stimulation test to definitively confirm or exclude adrenal insufficiency. 1, 2

Test Protocol

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

Critical Testing Pitfalls

• Exogenous steroids (prednisolone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound results 2
• Hydrocortisone must be held for 24 hours before testing; other steroids require longer washout periods 2
• If diagnostic testing is needed but treatment cannot be delayed, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 2

Etiologic Workup

• Measure 21-hydroxylase (anti-adrenal) autoantibodies to identify autoimmune etiology, which accounts for approximately 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

Distinguishing Primary from Secondary Adrenal Insufficiency

• Primary adrenal insufficiency: high ACTH with low cortisol, plus hyponatremia and hyperkalemia (when present) 2
• Secondary adrenal insufficiency: low or inappropriately normal ACTH with low cortisol, hyponatremia without hyperkalemia 2
• Primary requires both glucocorticoid and mineralocorticoid replacement; secondary requires only glucocorticoids 2

Treatment

Maintenance Therapy

All patients with Addison's disease require lifelong replacement of both glucocorticoids and mineralocorticoids. 1

Glucocorticoid Replacement

• Hydrocortisone 15-25 mg daily in 2-3 divided doses is the preferred glucocorticoid 1, 2
• Typical regimens: 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 effective regimens include 15+5 mg, 10+10 mg, or 10+5+5 mg 2
• Cortisone acetate 25-37.5 mg daily in divided doses is an acceptable alternative 1, 2
• Prednisolone 4-5 mg daily may be considered in select patients with marked energy fluctuations 2
• Avoid dexamethasone for chronic replacement therapy 2

Mineralocorticoid Replacement

• Fludrocortisone 0.05-0.1 mg (50-100 mcg) daily is the standard mineralocorticoid replacement 1, 5
• Dosage range: 50-200 mcg daily, but doses up to 500 mcg daily may be needed in younger adults 2
• Adjust based on blood pressure (supine and standing), salt cravings, peripheral edema, and plasma renin activity 1, 2
• Unrestricted sodium salt intake is essential alongside hormone replacement 2

Monitoring Adequacy of Replacement

• Dosage should be adjusted based on clinical assessment rather than laboratory values 1
• For glucocorticoids: assess energy levels, weight, blood pressure, and symptoms of over- or under-replacement 1
• For mineralocorticoids: evaluate salt cravings, orthostatic blood pressure, peripheral edema 2
• Under-replacement presents with lethargy, nausea, poor appetite, weight loss, and increased pigmentation 2

Management of Adrenal Crisis

Adrenal crisis is a life-threatening emergency requiring immediate treatment—never delay for diagnostic procedures. 4, 1, 2

Emergency Treatment Protocol

• Immediately administer hydrocortisone 100 mg intravenously or intramuscularly 4, 1, 2
• Rapid infusion of 0.9% isotonic saline at 1 L/hour until hemodynamic improvement 4, 1, 2
• Draw blood for serum cortisol, ACTH, electrolytes, glucose, and precipitating causes before treatment if possible, but do not delay treatment 4, 1
• Continue hydrocortisone 100 mg IV/IM every 6-8 hours until the patient can eat and drink 4, 1
• Continue isotonic saline infusion at slower rate for 24-48 hours 4
• Taper parenteral glucocorticoids over 1-3 days to oral replacement 4

Clinical Features of Adrenal Crisis

• Malaise, severe fatigue, nausea, vomiting, abdominal pain (sometimes with peritoneal irritation) 4, 2
• Muscle pain or cramps 4, 2
• Dehydration leading to hypotension and shock 4, 2
• Confusion, loss of consciousness, or coma 4, 2
• Precipitating events: vomiting/diarrhea, infections, surgery, trauma, myocardial infarction 4

Stress Dosing Guidelines

Patients must increase glucocorticoid doses during illness, fever, or physical stress to prevent adrenal crisis. 1, 2

Minor Stress (fever, mild illness)

• Double the usual daily dose for 1-2 days 2
• Return to normal dose when recovered 2

Moderate Stress (persistent fever, significant illness)

• Hydrocortisone 50-75 mg daily or prednisone 20 mg daily 2
• Continue until illness resolves 2

Major Stress (severe illness, major surgery)

• Hydrocortisone 100 mg IV/IM just before anesthesia 4
• Continue 100 mg every 6 hours for 24-48 hours 4
• Then double oral dose for 24-48 hours, then taper to normal dose 4

Minor Surgery and Dental Procedures

• Hydrocortisone 100 mg IV/IM just before procedure 4
• Double oral dose for 24 hours, then return to normal dose 4
• For dental procedures: extra morning dose 1 hour prior 4

Labor and Vaginal Birth

• Hydrocortisone 100 mg IM at onset of labor 4
• Double oral dose for 24-48 hours after delivery, then taper 4

Patient Education and Safety Measures

Comprehensive patient education is the cornerstone of preventing adrenal crisis. 1, 2

• 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 hydrocortisone 100 mg IM injection kit with self-injection training for emergencies 2
• Educate on recognizing warning signs of impending crisis 2
• Provide written instructions on stress dosing 1, 2
• Instruct on doubling or tripling dose during illness, fever, or physical stress 2

Follow-up and Screening

Annual follow-up should include comprehensive assessment and screening for associated conditions. 1

• Assessment of health, well-being, weight, and blood pressure 1
• Monitoring of serum electrolytes 1
• Screen annually for thyroid function, diabetes, vitamin B12 deficiency, and celiac disease (tissue transglutaminase antibodies) 1, 2
• Assessment for complications of glucocorticoid therapy 1
• Approximately 50% of patients with autoimmune primary adrenal insufficiency have other co-existing autoimmune diseases 1

Associated Autoimmune Polyendocrine Syndromes

• Autoimmune polyendocrine syndrome type-1 (APS-1): primary adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous candidiasis 1
• Autoimmune polyendocrine syndrome type-2 (APS-2): primary adrenal insufficiency with primary hypothyroidism and other autoimmune conditions 1
• When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 2

Drug Interactions Affecting Replacement Therapy

Medications Increasing Hydrocortisone Requirements

• Anti-epileptics, antituberculosis drugs, antifungal medications, etomidate, topiramate 2

Medications Interfering with Fludrocortisone

• Diuretics, acetazolamide, carbenoxolone, liquorice, NSAIDs 2

Medications Decreasing Hydrocortisone Requirements

• Grapefruit juice and liquorice should be avoided 2

Prognosis

With proper treatment, Addison's disease is a manageable chronic condition, but premature death from adrenal crises remains a risk. 1 The frequency of acute adrenal crises is 6-8 per 100 patient-years, emphasizing the critical importance of patient education and adherence to stress dosing protocols 4.