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Addision disease

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Addison Disease (Primary Adrenocortical Insufficiency)

Definition

Addison disease is primary adrenocortical insufficiency - failure of the adrenal cortex to produce adequate glucocorticoids (cortisol), mineralocorticoids (aldosterone), and adrenal androgens. It affects approximately 1 in 10,000 individuals in the developed world.

Costanzo Physiology 7th Edition, p. 440
Tietz Textbook of Laboratory Medicine, 7th Edition, p. 2274

Etiology / Causes

Setting	Most Common Cause
Developed countries	Autoimmune adrenalitis (~70-80%)
Worldwide	Tuberculosis (still #1 globally)
Children (>80%)	Genetic causes

Autoimmune Addison Disease (AAD):

Most common between ages 30-50 years
Strongly associated with Autoimmune Polyglandular Syndrome (APS):
- APS type 2 (~70%): autosomal dominant, HLA-DRB1 mutation; co-occurs with type 1 diabetes, autoimmune thyroid disease, celiac disease
- APS type 1 (~10%): autosomal recessive, AIRE gene mutation (chromosome 21q22.3); classically presents with chronic candidiasis + hypoparathyroidism + AAD
- APS type 4 (~10%): miscellaneous autoimmune endocrinopathies not fitting APS 1/2/3
Autoantibodies likely target 21-hydroxylase enzyme → destruction of adrenocortical cells

Other causes:

Infections: TB, Neisseria meningitidis (Waterhouse-Friderichsen syndrome), fungal, viral
Drugs inhibiting steroidogenesis: ketoconazole, fluconazole, posaconazole, etomidate, rifampicin
Neoplastic infiltration, hemorrhage, amyloidosis, hemochromatosis
In young boys: adrenoleukodystrophy (ABCD1 gene mutation) - hyperpigmentation precedes neurologic signs; check very-long-chain fatty acids
Bilateral adrenalectomy, SLE, antiphospholipid syndrome
Tietz Textbook of Laboratory Medicine, p. 2274-2275

Pathophysiology

All three zones of the adrenal cortex are destroyed, leading to:

Lost Hormone	Consequence
Cortisol (glucocorticoid)	Hypoglycemia, anorexia, weight loss, nausea/vomiting, weakness
Aldosterone (mineralocorticoid)	Hyperkalemia, metabolic acidosis, hyponatremia, hypotension (decreased ECF volume)
DHEA/androstenedione (androgens)	Decreased pubic/axillary hair, decreased libido (women especially)

Low cortisol removes negative feedback on the hypothalamic-pituitary axis → ACTH rises markedly. ACTH contains the α-MSH fragment, which binds to melanocortin-1 receptors → hyperpigmentation.

Costanzo Physiology, p. 440

Clinical Features

Systemic:

Fatigue, muscle weakness, anorexia, weight loss
Nausea, vomiting, diarrhea
Hypotension, lightheadedness on standing (orthostatic)
Headaches, psychosis (in severe cases)

Laboratory:

Hypoglycemia
Hyponatremia
Hyperkalemia
Hypercalcemia
Metabolic acidosis

Cutaneous (hallmark sign):

Hyperpigmentation is the most striking and diagnostically important skin finding. It occurs due to ACTH-driven melanocortin receptor stimulation.

Distribution of hyperpigmentation:

Sun-exposed areas (face, neck, hands)
Pressure/trauma sites (knees, elbows, knuckles, spine)
Palmar creases
Nipples, areolae, axillae, perineum, genitalia
Mucous membranes
Recent scars, nevi

Note: "White Addison disease" - rare form where pigmentation does NOT occur.

In women, decreased axillary and pubic hair occurs because androgen production primarily comes from the adrenals (not the ovaries).

Clinical photo - hyperpigmentation of hands in Addison disease:

Hyperpigmentation in Addison disease - darkening of the hands, knuckles, and nail beds

Hyperpigmentation in Addison disease. (Courtesy Steven Binnick, MD.) - Andrews' Diseases of the Skin

Andrews' Diseases of the Skin, p. 579; Fitzpatrick's Dermatology, p. 1391

Addisonian Crisis (Acute Adrenal Insufficiency)

A life-threatening emergency triggered by stress (infection, trauma, surgery).

Features:

Circulatory collapse and shock
Severe weakness and vomiting
Tachycardia + hypotension
Hyponatremia + hyperkalemia + acidosis
Cortisol < 5 µg/dL

Glucocorticoid deficiency typically precedes mineralocorticoid deficiency during disease progression - making early diagnosis difficult because symptoms are nonspecific.

Tietz Textbook of Laboratory Medicine, p. 2276

Diagnosis

Step 1: Morning plasma cortisol + ACTH

Step 2: Cosyntropin (ACTH analog) stimulation test

Failure to rise above 18-20 µg/dL (or delta < 7-10 µg/dL) after 1 hour = abnormal
Elevated plasma ACTH confirms primary adrenal insufficiency (vs. secondary, where ACTH is normal/low)

Diagnostic algorithm:

Diagnostic flowchart for Addison disease showing cortisol levels and cosyntropin stimulation test pathways

Diagnostic algorithm - Tietz Textbook of Laboratory Medicine

Step 3: CT adrenals - to exclude infiltration, infection, or hemorrhage

Andrews' Diseases of the Skin, p. 579; Tietz Textbook of Laboratory Medicine

Treatment

Glucocorticoid replacement - hydrocortisone (or equivalent)
Mineralocorticoid replacement - fludrocortisone
Stress dosing during illness, surgery, or trauma
Patient education: sick-day rules, medical alert bracelet
Costanzo Physiology, p. 440; Andrews' Diseases of the Skin, p. 579

Key Distinguishing Points (Primary vs. Secondary Adrenal Insufficiency)

Feature	Primary (Addison)	Secondary (pituitary/hypothalamic)
ACTH level	HIGH	Low or normal
Hyperpigmentation	Present	Absent
Mineralocorticoid deficiency	Yes	No (aldosterone regulated by renin-angiotensin)
Cause	Adrenal destruction	ACTH deficiency

Sources: Costanzo Physiology 7th Ed. | Tietz Textbook of Laboratory Medicine 7th Ed. | Andrews' Diseases of the Skin | Fitzpatrick's Dermatology | Bradley and Daroff's Neurology in Clinical Practice

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