What are the diagnostic criteria and treatment options for a female patient presenting with fatigue, weight loss, and changes in skin pigmentation, suspected of having Addison's disease?

Diagnosis of Addison's Disease

For a female patient presenting with fatigue, weight loss, and skin pigmentation changes, diagnose Addison's disease using a two-step approach: first obtain paired early morning serum cortisol and plasma ACTH levels, then confirm with a synacthen stimulation test if initial results are equivocal. 1

Diagnostic Approach

Initial Screening Tests

• Paired measurement of serum cortisol and plasma ACTH is the first-line diagnostic test 1
• Obtain these samples in the early morning for optimal interpretation 2
• Serum cortisol <250 nmol/L (<9 µg/dL) with elevated ACTH during acute illness is diagnostic of primary adrenal insufficiency 1
• ACTH levels are typically markedly elevated (>2000 pg/mL in severe cases, normal range 7.2-63.3 pg/mL) 2

Confirmatory Testing

• When initial cortisol and ACTH results are equivocal, perform a synacthen (tetracosactide) stimulation test 1
• Administer 0.25 mg IM or IV 1
• Peak serum cortisol <500 nmol/L (<18 µg/dL) at 30 or 60 minutes confirms the diagnosis 1, 3

Supporting Laboratory Findings

The following abnormalities support the diagnosis but are not required:

• Hyponatremia is present in 90% of newly diagnosed cases 1, 4
• Hyperkalaemia occurs in approximately 50% of cases 1, 4
• Low DHEAS, androstenedione, and testosterone levels indicate androgen deficiency 4, 5
• Mild to moderate hypercalcemia occurs in 10-20% of patients 4

Critical pitfall: The absence of hyperkalemia cannot rule out Addison's disease, and some patients may have normal electrolytes at presentation 4

Clinical Features to Assess

Characteristic Symptoms

• Hyperpigmentation with uneven distribution, especially in sun-exposed areas, palmar creases, and frictional surfaces 4, 2
• Salt craving is a specific symptom reflecting mineralocorticoid deficiency 1, 4
• Fatigue and malaise (universal symptoms) 4, 6
• Weight loss (present in this patient) 4, 6
• Nausea occurs in 20-62% of patients, particularly morning nausea 4
• Hypotension 4, 6

Physical Examination Findings

• Diffuse, non-scaly hyperpigmented patches on face, dorsae of hands, and palms 2
• Hyperpigmentation of mucosal surfaces 6
• Hypotension 6

Important caveat: Symptoms develop insidiously over months to years, often leading to delayed diagnosis due to their non-specific nature in early stages 4

Etiological Investigation

Once diagnosis is confirmed, determine the underlying cause:

• In Europe, autoimmunity accounts for approximately 85% of cases 1
• Test for 21-hydroxylase antibodies (21OH-Ab) to confirm autoimmune etiology 7
• Screen for associated autoimmune conditions, as approximately half of patients have other co-existing autoimmune diseases 1
• Consider tuberculosis, adrenal hemorrhage, and genetic disorders as alternative causes 1

Screening for Polyendocrine Syndromes

• Autoimmune polyendocrine syndrome type-2 (APS-2): PAI with primary hypothyroidism and other autoimmune conditions 1
• Check thyroid function tests and screen for diabetes mellitus 1

Treatment Initiation

Once diagnosis is confirmed, immediate treatment is essential:

Glucocorticoid Replacement

• Hydrocortisone (HC) or cortisone acetate (CA) are the preferred glucocorticoids 7, 1
• Typical dosing: HC 15-25 mg per day in 2-3 divided doses 7, 1
• Standard regimen: HC 20 mg upon awakening, 10 mg at midday, 2.5 mg in late afternoon 7
• First dose should be taken upon awakening, with the last dose approximately 4-6 hours before bedtime 7

Mineralocorticoid Replacement

• Fludrocortisone 0.1 mg daily is the usual starting dose 8
• Dosage ranging from 0.1 mg three times weekly to 0.2 mg daily may be employed 8
• If transient hypertension or edema develops, reduce dose to 0.05 mg daily 8, 2

Monitoring Treatment Response

• Dosage adjustment should be based on clinical assessment rather than laboratory values 7, 1
• Signs of over-replacement: weight gain, insomnia, peripheral edema 7
• Signs of under-replacement: lethargy, nausea, poor appetite, weight loss, increased pigmentation 7
• Monitor serum electrolytes, weight, and blood pressure at follow-up visits 1

Patient Education and Safety

• Patients must wear a Medic Alert bracelet and carry a steroid card 7, 1
• Education on increasing steroid doses during illness or injury is essential 7, 1
• Training in intramuscular administration of hydrocortisone during acute adrenal crisis is critical 7
• Delays in emergency treatment can be fatal 7

Androgen Replacement Consideration

For this female patient specifically:

• If persistent lack of libido and/or low energy despite optimized glucocorticoid and mineralocorticoid replacement, offer a 6-month trial of DHEA 25-50 mg daily 5
• Continue if clinically effective 5
• Monitor serum DHEAS, androstenedione, and testosterone levels 5

Note: Evidence for DHEA benefit remains weak and inconsistent, so use with caution 5