What are the differences between adrenal insufficiency (Addison disease) and primary aldosteronism?

Adrenal Insufficiency vs. Primary Aldosteronism: Key Differences

Adrenal insufficiency and primary aldosteronism are opposite disorders of the adrenal cortex—adrenal insufficiency results from deficient hormone production (particularly cortisol and often aldosterone), while primary aldosteronism results from excessive aldosterone production. 1, 2

Fundamental Pathophysiology

Adrenal Insufficiency (Addison's Disease)

• Primary adrenal insufficiency involves destruction or dysfunction of the adrenal cortex, causing deficiency of glucocorticoids (cortisol), mineralocorticoids (aldosterone), and adrenal androgens. 1, 3
• The hallmark laboratory pattern is low cortisol with markedly elevated ACTH (>300 pg/mL), reflecting the pituitary's attempt to stimulate a failing adrenal gland. 1, 2
• Autoimmune adrenalitis accounts for approximately 85% of cases in Western populations. 2, 3

Primary Aldosteronism

• Primary aldosteronism results from autonomous overproduction of aldosterone by the adrenal cortex, most commonly from a unilateral adenoma or bilateral adrenal hyperplasia. 4
• The characteristic laboratory pattern is elevated plasma aldosterone with suppressed renin activity, typically with an aldosterone-to-renin ratio greater than 30. 4
• This represents hormone excess rather than deficiency. 4, 5

Clinical Presentation: Contrasting Features

Adrenal Insufficiency Symptoms

• Profound fatigue and weakness, unintentional weight loss, orthostatic hypotension, and salt craving are cardinal features. 1, 3
• Hyperpigmentation (especially in sun-exposed areas, skin creases, and mucous membranes) is pathognomonic for primary adrenal insufficiency due to elevated ACTH stimulating melanocytes. 1, 2
• Nausea occurs in 20-62% of patients, with morning nausea particularly common. 1, 2
• Muscle pain or cramps, especially during acute crisis, are frequent complaints. 1, 2

Primary Aldosteronism Symptoms

• Hypertension is the dominant clinical feature, often resistant to standard antihypertensive therapy. 4
• Weakness and muscle cramps from hypokalemia are common when potassium depletion is severe. 4
• Patients typically do not have hyperpigmentation, weight loss, or profound fatigue. 4
• The clinical picture reflects mineralocorticoid excess rather than deficiency. 4

Laboratory Abnormalities: Opposite Patterns

Adrenal Insufficiency

• Hyponatremia is present in 90% of newly diagnosed cases, caused by sodium loss in urine and impaired free water clearance. 1, 2
• Hyperkalemia occurs in approximately 50% of cases due to aldosterone deficiency, though its absence does not exclude the diagnosis. 1, 2
• Low serum cortisol (<250 nmol/L or <9 μg/dL) with markedly elevated ACTH (>300 pg/mL) is diagnostic. 1, 2
• Elevated plasma renin activity reflects mineralocorticoid deficiency. 1, 2

Primary Aldosteronism

• Hypokalemia is common due to excessive aldosterone-driven potassium excretion. 4
• Hypernatremia or high-normal sodium from sodium retention. 4
• Elevated plasma aldosterone with suppressed renin activity (aldosterone-to-renin ratio >30). 4
• The electrolyte pattern is the mirror image of adrenal insufficiency. 4

Diagnostic Approach

Confirming Adrenal Insufficiency

• Morning cortisol <250 nmol/L (<9 μg/dL) with ACTH >300 pg/mL establishes the diagnosis without further testing. 2
• The cosyntropin stimulation test (0.25 mg IV/IM) is the gold standard when initial results are indeterminate—a peak cortisol <500 nmol/L (<18 μg/dL) at 30 or 60 minutes confirms adrenal insufficiency. 1, 2
• Measure 21-hydroxylase autoantibodies to identify autoimmune etiology (positive in ~85% of cases). 2
• If autoantibodies are negative, obtain adrenal CT imaging to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative disease. 2

Confirming Primary Aldosteronism

• Measure plasma aldosterone and renin activity—elevated aldosterone with low renin (ratio >30) suggests primary aldosteronism. 4
• Confirmatory testing with saline suppression test or salt loading test is indicated because false-positives and false-negatives can occur. 4
• Adrenal vein sampling is the gold standard for distinguishing unilateral adenoma from bilateral hyperplasia in surgical candidates. 4
• CT imaging helps identify adenomas but is not always reliable for lateralization. 4

Treatment: Replacement vs. Suppression

Adrenal Insufficiency Management

• Lifelong glucocorticoid replacement with hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) is mandatory. 1, 2
• For primary adrenal insufficiency, add fludrocortisone 50-200 µg daily for mineralocorticoid replacement. 1, 2
• All patients require stress-dose education, medical alert identification, and emergency injectable hydrocortisone 100 mg IM kit. 1, 2
• In acute adrenal crisis, give 100 mg IV hydrocortisone immediately plus 0.9% saline at 1 L/hour—never delay treatment for diagnostic testing. 1, 2, 6

Primary Aldosteronism Management

• Laparoscopic adrenalectomy is recommended for unilateral adenoma, which can cure hypertension in many cases. 4
• Medical management with spironolactone or eplerenone is recommended for bilateral adrenal hyperplasia and nonsurgical candidates. 4
• Open adrenalectomy is recommended when malignancy is suspected (irregular morphology, lipid-poor, >3 cm, or secreting multiple hormones). 4
• Treatment aims to suppress aldosterone excess rather than replace deficient hormones. 4

Critical Pitfalls to Avoid

Adrenal Insufficiency

• Do not rely solely on hyponatremia and hyperkalemia for diagnosis—sodium may be only marginally reduced and hyperkalemia is present in only ~50% of cases. 1, 2
• Never delay treatment of suspected acute adrenal crisis for diagnostic procedures—mortality is high if untreated. 1, 2, 6
• The insidious nature of symptom development often leads to delayed diagnosis, as symptoms are frequently nonspecific in early stages. 1
• Approximately 50% of patients with autoimmune primary adrenal insufficiency develop another autoimmune disorder during their lifetime, requiring continuous surveillance for thyroid dysfunction, type 1 diabetes, and pernicious anemia. 1, 3

Primary Aldosteronism

• CT imaging alone is not always reliable for distinguishing unilateral from bilateral disease—adrenal vein sampling should be considered in surgical candidates. 4
• It may be reasonable to exclude adrenal vein sampling in patients younger than 40 years when imaging shows only one affected gland, as bilateral hyperplasia is rare in this population. 4
• Malignancy should be suspected if the tumor is larger than 3 cm, has irregular morphology, is lipid-poor, does not wash out on contrast-enhanced CT, or secretes more than one hormone. 4

Summary of Key Distinctions

Feature	Adrenal Insufficiency	Primary Aldosteronism
Pathophysiology	Hormone deficiency [1]	Hormone excess [4]
Cortisol	Low [1,2]	Normal [4]
Aldosterone	Low (primary AI) [1]	High [4]
ACTH	High (primary AI) [1,2]	Normal [4]
Renin	High [1,2]	Low [4]
Sodium	Low [1,2]	Normal-high [4]
Potassium	High (~50% of cases) [1,2]	Low [4]
Blood Pressure	Low/orthostatic [1]	High [4]
Hyperpigmentation	Present (primary AI) [1,2]	Absent [4]
Treatment	Hormone replacement [1,2]	Surgery or aldosterone antagonists [4]