Addison Disease (Primary Adrenocortical Insufficiency)

Definition

• Costanzo Physiology 7th Ed., p. 440
• Tietz Textbook of Laboratory Medicine 7th Ed.

Epidemiology

• Affects approximately 1 in 10,000 individuals in developed countries
• Autoimmune adrenalitis most common cause in adults (developed world); tuberculosis is the most common cause worldwide
• Most common presentation between ages 30-50 years
• In children, >80% of cases are genetic in origin

Etiology & Causes

• APS type 2 (~70% of autoimmune Addison cases) - autosomal dominant, HLA-DRB1 mutation on chromosome 6p21.32; also associated with type 1 diabetes, autoimmune thyroiditis, celiac disease
• APS type 1 (~10%) - autosomal recessive AIRE gene mutation (chromosome 21q22.3); triad of candidiasis, hypoparathyroidism, Addison disease

Note: In young boys with Addison disease, always consider adrenoleukodystrophy (ABCD1 gene mutation) - hyperpigmentation may precede neurological signs by years; check very-long-chain fatty acid levels.

Pathophysiology

1. Glucocorticoid (cortisol) deficiency → hypoglycemia, anorexia, weight loss, nausea, vomiting, weakness, fatigue
2. Mineralocorticoid (aldosterone) deficiency → hyponatremia, hyperkalemia, metabolic acidosis, hypotension (reduced ECF volume), high renin levels
3. Adrenal androgen deficiency → in women: decreased pubic and axillary hair, reduced libido
4. Compensatory ACTH elevation (due to loss of cortisol negative feedback on the pituitary) → ACTH contains the α-MSH fragment → hyperpigmentation

Clinical Features

Chronic Symptoms

• Fatigue, weakness, malaise
• Anorexia, weight loss, nausea, vomiting, diarrhea
• Hypotension (orthostatic or frank)
• Salt craving
• Psychosis, depression, cognitive symptoms
• In women: loss of axillary and pubic hair, decreased libido

Hallmark Sign - Hyperpigmentation

Fig. Hyperpigmentation in Addison disease - note darkening of knuckles, nail beds. (Andrews' Diseases of the Skin / Courtesy Steven Binnick, MD)

• Diffuse hyperpigmentation, most prominent in sun-exposed areas, pressure points (elbows, knees), nail beds, nipples, areolae, and recent scars
• Palmar crease darkening, darkening of mucous membranes, nevi, and hair
• Multifocal oral melanoacanthoma may occur
• Eruptive onset of multiple new nevi can be an early sign
• Occasionally absent ("white Addison disease")
• Key distinction from secondary adrenal insufficiency: hyperpigmentation does NOT occur in secondary (pituitary/hypothalamic) causes because ACTH levels are low or normal, not elevated

Cardiovascular Findings (Braunwald's Heart Disease)

• Low diastolic BP (<60 mmHg) with orthostatic changes
• ECG: low-amplitude P waves and peaked T waves (from hyperkalemia)
• Reduced LV end-systolic and end-diastolic dimensions
• Can progress to cardiovascular collapse

Laboratory Findings

Diagnosis

Diagnostic algorithm for Addison disease - Tietz Textbook of Laboratory Medicine

1. Obtain morning plasma cortisol (and ACTH simultaneously)
2. Cortisol <5 µg/dL = abnormal → proceed to confirmation
3. Cortisol 5-18 µg/dL = indeterminate → cosyntropin (ACTH) stimulation test
4. Cosyntropin 250 µg IV; measure cortisol at 30 and 60 min
   • Normal response: cortisol rises to ≥18-20 µg/dL (some sources use 550 nmol/L) with delta ≥7-10 µg/dL
   • Abnormal response + elevated ACTH = Addison disease (primary)
   • Abnormal response + normal/decreased ACTH = central (secondary) glucocorticoid deficiency
5. If clinical Addisonian crisis is already present (cortisol <5 µg/dL + hyponatremia + hyperkalemia + acidosis) - diagnosis is established clinically; begin treatment immediately
6. CT adrenal glands to exclude infiltration, hemorrhage, or infection

Addisonian Crisis (Acute Adrenal Insufficiency)

• Hydrocortisone 100 mg IV bolus immediately
• Then 100 mg IV every 8-12 hours for first 24 hours
• Taper over 72-96 hours as patient stabilizes
• Large volumes of normal saline + 5% dextrose to address volume deficit and hypoglycemia
• Identify and treat precipitating cause (infection, ischemia, intra-abdominal emergency)

Long-Term Treatment

• Dual-release hydrocortisone preparations can better mimic the cortisol circadian rhythm
• Sick day rules: patients must double (or triple) their glucocorticoid dose during illness, injury, or surgery
• Patients should carry a steroid emergency card and injectable hydrocortisone for emergencies
• Secondary (pituitary) adrenal insufficiency does not require mineralocorticoid replacement (aldosterone production relatively preserved)

Secondary vs. Primary Adrenal Insufficiency - Key Differences

Recent Evidence (2024-2026)

• A 2024 meta-analysis (PMID 39277840) found increased rates of adverse pregnancy and fetal outcomes in women with primary adrenal insufficiency - relevant for counseling reproductive-age women
• A 2025 meta-analysis (PMID 40966723) confirmed increased all-cause mortality in primary adrenal insufficiency compared to the general population, underscoring the importance of optimal replacement and education