How do primary adrenal insufficiency (Addison disease) and secondary adrenal insufficiency differ regarding etiology, clinical presentation, laboratory findings, diagnostic approach, and treatment?

Primary vs Secondary Adrenal Insufficiency: Key Differences

Primary adrenal insufficiency (Addison's disease) is distinguished from secondary adrenal insufficiency by the presence of mineralocorticoid deficiency, hyperpigmentation, markedly elevated ACTH, and hyperkalemia, whereas secondary adrenal insufficiency presents with low or inappropriately normal ACTH, no hyperpigmentation, and preserved mineralocorticoid function. 1, 2

Etiology

Primary Adrenal Insufficiency

• Autoimmune destruction accounts for approximately 85% of cases in Western populations, confirmed by measuring 21-hydroxylase autoantibodies 1, 3
• Other causes include congenital adrenal hyperplasia, pharmacological inhibition (high-dose azole antifungals), infections (tuberculosis, fungal), hemorrhage, tumors, or surgical removal of adrenal tissue 4
• Approximately 50% of patients with autoimmune primary adrenal insufficiency develop another autoimmune disorder during their lifetime, particularly in autoimmune polyendocrine syndrome type-1 (APS-1) or type-2 (APS-2) 2

Secondary Adrenal Insufficiency

• Pituitary disorders including tumors, hemorrhage, inflammatory conditions (hypophysitis, sarcoidosis, hemochromatosis), surgery, or radiation therapy impair ACTH production 4, 5
• Iatrogenic suppression from prolonged supraphysiological glucocorticoid administration (≥20 mg/day prednisone or equivalent for ≥3 weeks) is the most common cause, far exceeding the prevalence of primary adrenal insufficiency 1, 4, 6
• Medications that suppress corticotropin production, such as opioids, can cause secondary adrenal insufficiency 4

Clinical Presentation

Distinguishing Features of Primary Adrenal Insufficiency

• Hyperpigmentation is pathognomonic, with uneven distribution especially in sun-exposed areas, skin creases, scars, mucous membranes, palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa 1, 2, 7
• Salt craving is highly specific, reflecting mineralocorticoid deficiency 1, 2
• Orthostatic hypotension is a cardinal manifestation due to aldosterone deficiency 2, 3, 7

Distinguishing Features of Secondary Adrenal Insufficiency

• Normal skin coloration (absence of hyperpigmentation) because ACTH levels are low 1, 2
• No salt craving because the renin-angiotensin-aldosterone system remains intact 1
• No orthostatic hypotension from mineralocorticoid deficiency (though may occur from other causes) 1

Shared Clinical Features

• Profound fatigue and weakness (50-95% of patients) 2, 4
• Nausea and vomiting (20-62%), with morning nausea particularly common 1, 2, 4
• Anorexia and unintentional weight loss (43-73%) 2, 4
• Muscle pain or cramps 1, 2
• Malaise and insidious symptom development over months to years 2, 7

Laboratory Findings

Primary Adrenal Insufficiency

• Morning cortisol <250 nmol/L (<9 μg/dL)** with **markedly elevated ACTH (often >300 pg/mL) is diagnostic 1, 3, 4
• Hyponatremia present in 90% of newly diagnosed cases, caused by sodium loss in urine and impaired free water clearance 1, 2, 3
• Hyperkalemia occurs in approximately 50% of cases at diagnosis due to aldosterone deficiency 1, 2, 3
• Elevated plasma renin activity reflects mineralocorticoid deficiency 2
• Low DHEAS, androstenedione, and testosterone indicate androgen deficiency 2

Secondary Adrenal Insufficiency

• Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH 1, 4
• Hyponatremia without hyperkalemia is characteristic, distinguishing it from primary adrenal insufficiency 1
• Normal plasma renin activity because mineralocorticoid function is preserved 1
• May have additional pituitary hormone deficiencies 1

Critical Pitfall

• The absence of hyperkalemia does NOT exclude primary adrenal insufficiency, as it is present in only about 50% of cases 1, 2

Diagnostic Approach

Initial Testing

• Paired early morning (8 AM) serum cortisol and plasma ACTH are the first-line diagnostic tests 1, 4
• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1, 3
• Morning cortisol >550 nmol/L (>18-20 μg/dL) effectively rules out adrenal insufficiency 1

Confirmatory Testing: Cosyntropin Stimulation Test

• Indicated when morning cortisol is indeterminate (5-18 μg/dL) or when clinical suspicion remains high 1, 8
• Protocol: Administer 0.25 mg (250 μg) cosyntropin IV or IM, measure serum cortisol at baseline, 30 minutes, and optionally 60 minutes 1, 3
• Interpretation: Peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency; peak >550 nmol/L (>18-20 μg/dL) excludes it 1, 3, 4
• The high-dose (250 μg) test is preferred over low-dose (1 μg) due to easier administration, comparable diagnostic accuracy, and FDA approval 1

Etiologic Workup for Primary Adrenal Insufficiency

• Measure 21-hydroxylase autoantibodies as the first step; positive in ~85% of autoimmune cases 1, 3
• If antibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumors, tuberculosis, or infiltrative disease 1, 3
• In males with negative antibodies, measure very-long-chain fatty acids to screen for X-linked adrenoleukodystrophy 1

Etiologic Workup for Secondary Adrenal Insufficiency

• Pituitary MRI to evaluate for tumors, hemorrhage, or infiltrative conditions 5
• Assess other pituitary hormone axes (thyroid, gonadal, growth hormone) 1
• Detailed medication history for glucocorticoid exposure or opioid use 4

Critical Management Principle

• Treatment of suspected acute adrenal crisis must NEVER be delayed for diagnostic procedures 1, 2, 3, 8
• If clinically unstable, give 100 mg IV hydrocortisone immediately plus 0.9% saline infusion at 1 L/hour 1, 3
• Draw blood for cortisol and ACTH before treatment if possible, but do not wait for results 1, 3

Treatment Differences

Primary Adrenal Insufficiency

• Requires both glucocorticoid AND mineralocorticoid replacement 1, 4
• Glucocorticoid: Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at 12 PM, 2.5-5 mg at 4 PM) or prednisone 3-5 mg daily 1, 4
• Mineralocorticoid: Fludrocortisone 50-200 μg daily, adjusted based on blood pressure, salt cravings, orthostatic symptoms, and plasma renin activity 1, 4
• Unrestricted sodium salt intake is essential 1

Secondary Adrenal Insufficiency

• Requires only glucocorticoid replacement because the renin-angiotensin-aldosterone system remains intact 1, 5
• Glucocorticoid: Hydrocortisone 15-25 mg daily in divided doses or prednisone 3-5 mg daily 1, 4, 5
• No mineralocorticoid needed 1
• Critical pitfall: When treating concurrent hypothyroidism and secondary adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 1

Universal Patient Education Requirements

• All patients must wear a medical alert bracelet indicating adrenal insufficiency 1, 4
• All patients should be prescribed an emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1, 4
• All patients need education on stress dosing: double or triple usual dose during illness, fever, or physical stress 1, 4
• All patients require annual screening for associated autoimmune conditions (thyroid function, diabetes, pernicious anemia, celiac disease) 1