Addison Disease
Addison disease occurs when the adrenal glands are damaged and cannot produce enough cortisol and aldosterone, leading to severe fatigue, low blood pressure, weight loss, and skin darkening.
- Unexplained severe lower back/abdominal pain with intractable vomiting and confusion (impending Adrenal Crisis).
Emergency Management: Adrenal Crisis (Acute Adrenal Insufficiency): Suspect in any patient with Addison's presenting in shock. Immediate treatment is rapid IV fluid resuscitation (2-3 Liters of Normal Saline with 5% Dextrose) AND IV Hydrocortisone 100 mg stat, followed by 50 mg IV every 6 hours. Do not wait for lab results.
A rare, chronic endocrine disorder caused by the bilateral destruction of the adrenal cortex, leading to severe deficiencies in glucocorticoids (cortisol), mineralocorticoids (aldosterone), and adrenal androgens. The core pathology is primary failure of the adrenal glands, resulting in a loss of the normal stress response and fluid homeostasis.
Detailed Overview
Addison disease is most commonly an autoimmune condition. The loss of cortisol leads to hypoglycemia, severe fatigue, and an inability to mount a physiologic response to stress (infections, surgery). The loss of aldosterone results in renal sodium wasting and potassium retention, causing profound dehydration, hypotension, and salt cravings. Because the pituitary senses low cortisol, it hyper-secretes ACTH, which melanocyte-stimulating hormone as a byproduct, causing the classic generalized skin hyperpigmentation. Lifelong hormone replacement is mandatory.
Epidemiology & Demographics
Prevalence: 100-140 cases per million. Incidence: 4-6 per million annually. Peak age of onset is 30-50 years. Autoimmune Addison disease is more common in females.
Etiological Mechanism
In developed nations, >80% of cases are due to autoimmune adrenalitis (often involving 21-hydroxylase antibodies). In developing nations, Tuberculosis is the leading cause. Other causes include bilateral adrenal hemorrhage (Waterhouse-Friderichsen syndrome), metastasis, and systemic infections (CMV, fungal).
Primary Causes
Autoimmune destruction (isolated or as part of Autoimmune Polyendocrine Syndromes)
Tuberculosis
Metastatic cancer (lung, breast, melanoma)
Adrenal hemorrhage (sepsis, anticoagulation)
- Other autoimmune diseases: High concurrence with Type 1 Diabetes, Autoimmune Thyroiditis (Hashimoto's), and Vitiligo.
Autoimmune adrenalitis involves cell-mediated immune destruction of all three layers of the adrenal cortex (zona glomerulosa, fasciculata, reticularis). Clinical symptoms do not appear until >90% of the adrenal cortex is destroyed. The zona glomerulosa failure drops aldosterone levels, disabling the kidneys' ability to reabsorb sodium and excrete potassium and hydrogen ions in the distal tubule. This causes hyponatremia, hyperkalemia, and non-anion gap metabolic acidosis, leading to hypovolemia and hypotension. The zona fasciculata failure drops cortisol, reducing hepatic gluconeogenesis (causing hypoglycemia) and removing negative feedback on the hypothalamus and pituitary. The pituitary hyper-secretes Pro-opiomelanocortin (POMC), which is cleaved into ACTH and Melanocyte-Stimulating Hormone (MSH). MSH binds to melanocortin-1 receptors on skin, causing hyperpigmentation.
Characteristic Clinical Presentation
- Profound fatigue and weakness: Worsens throughout the day; inability to perform basic tasks.
- Weight loss and Anorexia: Significant unintentional weight loss, often accompanied by nausea and abdominal pain.
- Salt craving: A specific desire to eat excessively salty foods due to hyponatremia.
- Postural dizziness: Feeling faint upon standing due to severe volume depletion.
Physical Examination Signs
- Hyperpigmentation of skin creases, knuckles, elbows, and oral mucosa (gums).
- Orthostatic hypotension (>20 mmHg drop in systolic BP upon standing).
- Loss of axillary and pubic hair in females (due to lack of adrenal androgens).
- Adrenal Crisis: Acute, catastrophic failure of blood pressure maintenance leading to hypovolemic shock and coma.
- Severe Hypoglycemia: Can lead to seizures or loss of consciousness, particularly in children or fasting states.
Diagnostic Criteria & Guidelines
Low morning (8 AM) serum cortisol combined with a markedly elevated plasma ACTH. Confirmed by a Cosyntropin (synthetic ACTH) stimulation test showing failure of cortisol to rise above 18 mcg/dL at 30 or 60 minutes.
Differential Diagnosis
- Secondary Adrenal Insufficiency (pituitary cause; no hyperpigmentation, normal aldosterone)
- Anorexia Nervosa
- Chronic Fatigue Syndrome
- Hemochromatosis (causes bronze skin and fatigue)
Laboratory Tests & Biomarkers
- Cosyntropin Stimulation Test: Peak cortisol < 18 mcg/dL (indicates primary adrenal failure).
- Morning ACTH: Markedly elevated (> 100 pg/mL).
- Basic Metabolic Panel: Hyponatremia, Hyperkalemia, mild Hypercalcemia, Hypoglycemia.
- 21-Hydroxylase Antibodies: Positive in autoimmune adrenalitis.
Imaging Modalities & Findings
- CT Abdomen: Adrenal glands may be small and atrophic (autoimmune), or enlarged and calcified (tuberculosis/hemorrhage).
-
Latent
Presence of autoantibodies without clinical symptoms. Normal basal cortisol, but impaired stress response.
-
Clinical
Symptomatic with low basal cortisol and elevated ACTH; requires daily hormone replacement.
-
Adrenal Crisis
Life-threatening acute cardiovascular collapse and shock, usually triggered by illness.
Glucocorticoid replacement: Hydrocortisone 15-25 mg per day in divided doses (e.g., 15 mg on awakening, 5 mg early afternoon to mimic diurnal rhythm). Mineralocorticoid replacement: Fludrocortisone 0.05-0.1 mg PO daily.
Second-Line & Adjunctive Therapy
DHEA replacement (Dehydroepiandrosterone 25-50 mg daily) can be considered in females with impaired libido and severe fatigue despite adequate cortisol/aldosterone replacement.
Surgical & Procedural Management
None for the disease itself. However, surgery is a major stressor; patients MUST receive IV 'stress dose' steroids (e.g., Hydrocortisone 50-100 mg IV) prior to any surgical procedure.
Recommended Lifestyle Changes
- Wear a medical alert bracelet or necklace stating 'Addison Disease: Needs Cortisol'.
- Carry an emergency injection kit of Solu-Cortef (hydrocortisone) 100 mg at all times.
- Do not restrict salt intake; increase salt consumption during hot weather or heavy exercise.
Patient Counseling & Advice
Thoroughly educate the patient on 'Sick Day Rules': they MUST double or triple their oral hydrocortisone dose if they have a fever, infection, or severe stress. If they cannot keep pills down due to vomiting, they must inject the emergency IM hydrocortisone and go directly to the ER.
Follow-Up & Monitoring Schedule
Monitor clinical signs (blood pressure, orthostasis, energy levels, electrolytes) to titrate Fludrocortisone. Do not use ACTH levels to titrate therapy, as they will remain high. Watch for signs of over-replacement (Cushingoid features, weight gain, hypertension).
Preventive Strategies
No prevention for autoimmune Addison's. Prevention of adrenal crisis is achieved entirely through rigorous patient education on stress dosing.
With compliant hormone replacement, life expectancy is normal. Mortality is solely driven by unrecognized or inadequately treated adrenal crises during acute illnesses.
Frequently Asked Questions
View Official Guideline