What is Addison disease (primary adrenal insufficiency)?

What is Addison Disease (Primary Adrenal Insufficiency)?

Addison disease, also called primary adrenal insufficiency (PAI), is a rare endocrine disorder caused by destruction or failure of the adrenal cortex, resulting in deficiency of glucocorticoids (cortisol), mineralocorticoids (aldosterone), and adrenal androgens. 1

Pathophysiology and Etiology

• Autoimmune adrenalitis is the predominant cause in Europe and Western populations, accounting for approximately 85% of cases. 1, 2
• The immune system erroneously attacks and destroys adrenal cortical cells, leading to progressive hormone deficiency. 3
• Approximately 50% of patients with autoimmune PAI develop other co-existing autoimmune diseases, including autoimmune thyroid disease, type 1 diabetes mellitus, autoimmune gastritis with vitamin B12 deficiency, premature ovarian insufficiency, vitiligo, and celiac disease. 1
• These combinations are classified into autoimmune polyendocrine syndromes (APS-1 and APS-2). 1
• Other causes include tuberculosis and infectious agents, adrenal hemorrhage from trauma or coagulopathies, metastatic neoplasms, genetic disorders such as adrenoleukodystrophy, and medications that inhibit steroidogenesis. 3

Clinical Presentation

Chronic Manifestations

• Fatigue and persistent weakness are the most common presenting symptoms, often accompanied by unintentional weight loss, anorexia, and malaise. 4, 5, 3
• Hyperpigmentation of skin creases, scars, mucous membranes, palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa is a distinguishing feature caused by markedly elevated ACTH levels. 2, 6, 5
• Orthostatic hypotension and postural hypotension result from volume depletion due to aldosterone loss. 6, 5
• Salt craving is a specific clinical clue for primary adrenal insufficiency due to mineralocorticoid deficiency. 2, 4
• Gastrointestinal symptoms include nausea (occurring in 20-62% of patients), vomiting, diarrhea, and abdominal pain. 2, 6
• Muscle and joint pain are frequently reported. 4, 3
• Neuropsychiatric manifestations can include depression and psychosis. 3

Acute Adrenal Crisis

• Adrenal crisis is a life-threatening emergency characterized by severe hypotension or shock, unexplained collapse, severe vomiting and/or diarrhea, altered mental status including confusion or loss of consciousness, and severe abdominal pain. 1, 2, 6
• Treatment of suspected acute adrenal crisis must NEVER be delayed for diagnostic procedures—immediate administration of 100 mg IV hydrocortisone plus 0.9% saline infusion at 1 L/hour is mandatory. 1, 2, 6

Laboratory Findings

Electrolyte and Metabolic Abnormalities

• Hyponatremia is present in 90% of newly diagnosed cases, though often only marginally reduced. 1, 7, 6
• Hyperkalemia occurs in approximately 50% of patients at diagnosis due to aldosterone deficiency—its absence does NOT exclude the diagnosis. 1, 2, 6
• The classic combination of hyponatremia and hyperkalemia is not always present and is not a reliable diagnostic marker. 1, 7, 6
• In the presence of severe vomiting, hypokalaemia and alkalosis may paradoxically be present instead of hyperkalemia. 1, 6
• Hypoglycemia is more common in children but can occur in adults, with hypoglycemic seizures possible. 1, 6
• Mild to moderate hypercalcemia occurs in 10-20% of patients at presentation. 1, 6
• Acidosis, anemia, mild eosinophilia, lymphocytosis, and elevated liver transaminases may be present. 1, 6

Hormonal Findings

• Morning serum cortisol is usually below the normal range, and plasma ACTH is clearly increased. 1
• A morning cortisol <250 nmol/L (<9 μg/dL) with markedly elevated ACTH (>300 pg/mL) in the presence of acute illness is diagnostic of primary adrenal insufficiency without further testing. 2, 7
• Elevated plasma renin activity (PRA) with low aldosterone levels confirms mineralocorticoid deficiency. 7
• Low serum DHEAS reflects adrenal androgen deficiency. 7

Diagnostic Approach

Initial Testing

• Paired measurement of early morning (8 AM) serum cortisol and plasma ACTH is the first-line diagnostic test. 1, 2, 7
• A morning cortisol >550 nmol/L (>18-20 μg/dL) effectively rules out adrenal insufficiency. 2
• A morning cortisol <400 nmol/L (<14 μg/dL) with high ACTH raises strong suspicion for primary adrenal insufficiency. 2

Confirmatory Testing

• The cosyntropin (Synacthen) stimulation test is the gold standard for confirming adrenal insufficiency when initial results are indeterminate. 2
• Protocol: Administer 0.25 mg (250 μg) cosyntropin IV or IM, then measure serum cortisol at baseline and at exactly 30 minutes (and optionally at 60 minutes). 1, 2
• A peak cortisol <500 nmol/L (<18 μg/dL) at 30 or 60 minutes confirms adrenal insufficiency; a peak >550 nmol/L (>18-20 μg/dL) excludes the disorder. 1, 2
• The test should preferably be performed in the morning, though not strictly necessary. 1

Etiologic Evaluation

• Measuring 21-hydroxylase (anti-adrenal) autoantibodies is the first step in determining the underlying cause, as autoimmunity accounts for ~85% of cases in Western populations. 2, 8
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes. 2
• In males with negative autoantibodies, measure very-long-chain fatty acids to screen for X-linked adrenoleukodystrophy. 2

Critical Diagnostic Pitfalls

• Never rely solely on electrolyte abnormalities for diagnosis—between 10-20% of patients have normal electrolytes at presentation. 1, 2
• Exogenous steroids (prednisolone, dexamethasone) and inhaled steroids (fluticasone) can suppress the HPA axis and confound diagnostic testing. 1, 2, 6
• Approximately 10% of patients with the final diagnosis of primary adrenal insufficiency present with normal cortisol concentrations, so normal basal cortisol with clearly elevated ACTH is still indicative of early PAI when the clinical history is suggestive. 9
• If you need to treat suspected adrenal crisis but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays. 2

Treatment Principles

Maintenance Therapy

• Lifelong glucocorticoid replacement with hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5-5 mg at 4:00 PM) is required. 2, 8
• Primary adrenal insufficiency requires both glucocorticoid AND mineralocorticoid replacement with fludrocortisone 50-200 μg daily, adjusted based on blood pressure, salt cravings, and plasma renin activity. 2, 8
• Unrestricted sodium salt intake is essential alongside hormone replacement. 2

Stress Dosing and Emergency Management

• Patients must double or triple their usual dose during illness, fever, or physical stress. 2, 8
• For major surgical procedures, administer hydrocortisone 100 mg IM before anesthesia, followed by 100 mg IM every 6 hours until oral intake resumes. 2
• All patients must wear a medical alert bracelet indicating adrenal insufficiency and carry an emergency injectable hydrocortisone 100 mg IM kit with self-injection training. 2

Monitoring and Follow-up

• Patients should be reviewed at least annually with assessment of health, well-being, weight, blood pressure, and serum electrolytes. 2
• Screen periodically for new autoimmune disorders, particularly hypothyroidism, as up to 50% of patients develop another autoimmune condition during their lifetime. 1, 4
• Monitor bone mineral density every 3-5 years to assess for complications of glucocorticoid therapy. 2

Prognosis and Quality of Life

• Prior to the 1940s, PAI was always fatal; the synthesis of corticosteroids transformed it into a fully treatable chronic condition. 1
• Despite treatment availability, premature death from adrenal crises remains a problem, and patients are at risk of therapy-related osteoporosis and cardiovascular complications. 1
• Quality of life and ability to work is reduced in many patients. 1, 10
• The prevalence of PAI is 10-15 per 100,000 population, with recent data reporting an increasing prevalence. 1, 10