What is the diagnostic approach for primary adrenal insufficiency, such as Addison's disease (Adrenal Disorder)?

From the Guidelines

To diagnose primary adrenal failure such as Addison's disease, I recommend a stepwise approach combining clinical assessment and laboratory testing, starting with morning serum cortisol and plasma ACTH levels, as suggested by the most recent guideline 1. Begin with a thorough history and physical examination, looking for characteristic symptoms like fatigue, weight loss, salt craving, hyperpigmentation, hypotension, and postural dizziness. Initial laboratory testing should include:

• Morning serum cortisol and plasma ACTH levels
• Basic metabolic panel (Na, K, CO2, and glucose)
• Renin and aldosterone levels, as recommended by 1 A morning cortisol below 3 μg/dL (83 nmol/L) with elevated ACTH (typically >100 pg/mL) strongly suggests primary adrenal insufficiency. The definitive test is the ACTH stimulation test (cosyntropin test), where 250 μg of synthetic ACTH is administered intravenously or intramuscularly, with cortisol levels measured at baseline, 30, and 60 minutes, as described in 1. A peak cortisol response below 18-20 μg/dL confirms adrenal insufficiency. Once adrenal insufficiency is confirmed, additional testing should determine the cause, including:
• Adrenal antibodies (for autoimmune etiology)
• Adrenal imaging (CT or MRI to rule out infiltrative diseases, hemorrhage, or infection), as recommended by 1
• Possibly tuberculosis testing Electrolyte abnormalities like hyponatremia, hyperkalemia, and metabolic acidosis often accompany primary adrenal failure due to mineralocorticoid deficiency. These diagnostic steps are crucial because untreated adrenal insufficiency can lead to life-threatening adrenal crisis, and proper diagnosis enables appropriate hormone replacement therapy with glucocorticoids and mineralocorticoids, as emphasized by 1.

Some key points to consider in the diagnosis of primary adrenal insufficiency include:

• The importance of measuring morning cortisol and ACTH levels, as suggested by 1
• The use of the ACTH stimulation test to confirm adrenal insufficiency, as described in 1
• The need to determine the underlying cause of adrenal insufficiency, including autoimmune etiology, infiltrative diseases, and infection, as recommended by 1
• The importance of monitoring electrolyte levels and managing electrolyte abnormalities, as emphasized by 1

Overall, the diagnosis of primary adrenal failure such as Addison's disease requires a comprehensive approach that includes clinical assessment, laboratory testing, and imaging studies, as suggested by the most recent guideline 1.

From the FDA Drug Label

Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance) The diagnosis of primary adrenal failure such as Addison’s disease is not directly addressed in the provided drug labels. Key points to consider in a clinical setting for diagnosing Addison’s disease include:

• Clinical presentation and medical history
• Laboratory tests, such as cortisol and ACTH levels
• Imaging studies to rule out other causes of adrenal insufficiency However, the provided drug labels do not offer guidance on the diagnostic process for Addison’s disease. 2 3

From the Research

Diagnostic Approach

To diagnose primary adrenal failure, such as Addison's disease, the following steps can be taken:

• Clinical suspicion is necessary to avoid misdiagnosing a life-threatening adrenal crisis, as the prevalence of Addison's disease is estimated to be one in 20,000 persons in the United States and Western Europe 4
• Patients with suspected Addison's disease should undergo a cosyntropin stimulation test to confirm the diagnosis 4
• Measurement of morning plasma adrenocorticotropic hormone (ACTH) and cortisol levels can be used as an initial screening procedure 5
• A short corticotropin test (250 μg) is recommended as the "gold standard" diagnostic tool to establish the diagnosis 5

Clinical Manifestations

The clinical manifestations of Addison's disease can be subtle and may include:

• Hyperpigmentation
• Fatigue
• Anorexia
• Orthostasis
• Nausea
• Muscle and joint pain
• Salt craving 4
• Elevated corticotropin concentrations (>300 pg/ml) are indicative of primary adrenal insufficiency when cortisol levels are below 140 nmol/l (5 μg/dl) 6

Laboratory Tests

Laboratory tests that can be used to diagnose Addison's disease include:

• Cosyntropin stimulation test 4
• Measurement of morning plasma ACTH and cortisol levels 5
• Short corticotropin test (250 μg) 5
• Determination of morning cortisol concentrations, with values of >350 nmol/l considered to safely rule out Addison's disease 6

Treatment and Management

Treatment of primary adrenal insufficiency requires replacement of mineralocorticoids and glucocorticoids, and may include:

• Once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) applied in two to three daily doses in adults 5
• Hydrocortisone (∼8 mg/m(2)/d) is recommended in children 5
• Patient education on stress dosing and emergency administration of glucocorticoids is essential 5