Addison Disease

Addison Disease (Primary Adrenal Insufficiency)

Addison disease, or primary adrenal insufficiency, is a chronic endocrine disorder characterized by the destruction or dysfunction of the adrenal cortex, resulting in deficient glucocorticoid, mineralocorticoid, and often adrenal androgen production. It is a high-yield topic for exams because of its characteristic clinical presentation, classic electrolyte abnormalities, and potentially life-threatening acute presentations such as adrenal crisis.

Definition

Addison disease is defined as primary adrenal insufficiency caused by intrinsic disease of the adrenal cortex leading to inadequate secretion of cortisol and, in most cases, aldosterone. In primary adrenal insufficiency, adrenocorticotropic hormone (ACTH) levels are elevated due to loss of negative feedback, distinguishing it from secondary and tertiary adrenal insufficiency, where pituitary or hypothalamic dysfunction predominate.

Epidemiology

Addison disease is rare but clinically important.

• Prevalence: approximately 100–140 cases per 1 million population in many Western countries.
• Incidence: about 4–6 new cases per 1 million people annually.
• Sex: slight female predominance, especially in autoimmune forms.
• Age: can occur at any age but most commonly presents in young to middle-aged adults.
• Etiology shift: in high-income countries, autoimmune adrenalitis is the leading cause; worldwide, infections (especially tuberculosis) remain important.

Etiology and Risk Factors

Major Causes of Primary Adrenal Insufficiency

• Autoimmune adrenalitis (most common in developed countries)
  • Isolated autoimmune adrenalitis.
  • Autoimmune polyendocrine syndrome (APS) type 1 and type 2 (associated with autoimmune thyroid disease, type 1 diabetes, hypoparathyroidism, etc.).
• Infectious adrenalitis
  • Tuberculosis.
  • Fungal infections (e.g., histoplasmosis).
  • HIV-associated infections.
  • CMV and other opportunistic infections.
• Hemorrhage or infarction
  • Waterhouse–Friderichsen syndrome (classically Neisseria meningitidis sepsis).
  • Anticoagulation-associated adrenal hemorrhage.
  • Trauma, DIC.
• Infiltrative diseases
  • Metastatic carcinoma (e.g., lung, breast).
  • Amyloidosis, sarcoidosis, hemochromatosis.
• Genetic and congenital causes
  • Congenital adrenal hyperplasia (CAH).
  • Adrenoleukodystrophy and other peroxisomal disorders.
• Drug-induced
  • Drugs that inhibit steroid synthesis (e.g., ketoconazole, etomidate, metyrapone).
  • Immune checkpoint inhibitors (e.g., CTLA-4, PD-1 inhibitors causing autoimmune adrenalitis).

Risk Factors

• Personal or family history of autoimmune disease (thyroid disease, T1DM, vitiligo, pernicious anemia).
• Chronic infections, especially tuberculosis and HIV.
• Use of drugs that impair adrenal steroid synthesis.
• Known adrenal metastases or infiltrative disorders.

Pathophysiology

In Addison disease, destruction or dysfunction of the adrenal cortex leads to impaired synthesis and secretion of adrenal hormones. The extent of involvement of the zona glomerulosa, fasciculata, and reticularis explains the characteristic clinical and biochemical features.

Hormonal Deficiencies

• Glucocorticoid deficiency (cortisol)
  • Decreased gluconeogenesis and glycogenolysis → fasting hypoglycemia, fatigue, weakness.
  • Increased insulin sensitivity → further predisposition to hypoglycemia.
  • Decreased vascular responsiveness to catecholamines → hypotension and risk of shock.
  • Increased CRH and ACTH secretion due to loss of negative feedback → hyperpigmentation due to ACTH/MSH overlap.
• Mineralocorticoid deficiency (aldosterone)
  • Renal loss of sodium and water → hyponatremia, hypovolemia, orthostatic hypotension.
  • Impaired renal secretion of potassium and hydrogen ions → hyperkalemia and non–anion gap metabolic acidosis.
  • Activation of RAAS cannot compensate due to primary adrenal failure.
• Adrenal androgen deficiency (DHEA, DHEA-S)
  • More clinically apparent in females (loss of axillary and pubic hair, decreased libido).
  • Less prominent in males due to testicular androgen production.

Autoimmune Adrenalitis

Autoimmune adrenalitis typically involves cell-mediated destruction of adrenal cortical cells, often with circulating autoantibodies against 21-hydroxylase and other steroidogenic enzymes. It may occur as part of autoimmune polyendocrine syndromes, where shared genetic susceptibility (e.g., HLA associations, AIRE mutations in APS-1) leads to multiple endocrine gland failure.

Clinical Presentation

The clinical features of Addison disease are often insidious and nonspecific, which leads to delayed diagnosis. Recognition of the characteristic constellation of symptoms and signs is crucial.

Chronic Primary Adrenal Insufficiency

• General symptoms
  • Chronic fatigue and weakness.
  • Weight loss and anorexia.
  • Low-grade nausea, sometimes vomiting.
  • Abdominal pain and nonspecific GI discomfort.
  • Myalgias and arthralgias.
• Cardiovascular features
  • Orthostatic hypotension and dizziness.
  • Low blood pressure at baseline, small or collapsed IVC on imaging in severe hypovolemia.
• Skin and mucosal changes
  • Generalized hyperpigmentation (classic exam point), especially in sun-exposed areas, skin creases, scars, and pressure points.
  • Mucosal pigmentation (buccal mucosa, gingiva, palmar creases).
  • Hyperpigmentation results from elevated ACTH and melanocyte-stimulating hormone derived from proopiomelanocortin (POMC).
• Electrolyte abnormalities
  • Hyponatremia (due to mineralocorticoid deficiency and increased ADH from cortisol deficiency).
  • Hyperkalemia (specific for primary, not secondary insufficiency).
  • Non–anion gap metabolic acidosis (type IV RTA phenotype).
• Metabolic and endocrine features
  • Hypoglycemia, particularly in fasting states or children.
  • Salt craving due to renal sodium loss.
  • Loss of libido, decreased axillary and pubic hair in women.
• Associated autoimmune manifestations
  • Vitiligo, autoimmune thyroid disease, type 1 diabetes, pernicious anemia, hypoparathyroidism (in APS).

Acute Adrenal Crisis (Addisonian Crisis)

Acute adrenal crisis is a life-threatening exacerbation characterized by severe glucocorticoid and mineralocorticoid deficiency.

• Features:
  • Profound hypotension or shock, often refractory to fluids and vasopressors without steroids.
  • Severe vomiting, abdominal pain, and diarrhea.
  • Fever, confusion, or altered mental status.
  • Severe hyponatremia, hyperkalemia, hypoglycemia.
• Precipitating factors:
  • Stress without adequate steroid dose adjustment (infection, surgery, trauma).
  • Sudden cessation or nonadherence to glucocorticoid therapy in known Addison disease.
  • Destruction/hemorrhage of previously normal adrenal glands (e.g., sepsis, anticoagulation).

Diagnosis

Diagnosis of Addison disease relies on demonstrating adrenal insufficiency and then differentiating primary from secondary or tertiary causes.

Initial Laboratory Assessment

• Basic labs
  • Hyponatremia, hyperkalemia, and non–anion gap metabolic acidosis.
  • Hypoglycemia, mild normocytic anemia, eosinophilia, and lymphocytosis.
• Morning serum cortisol
  • Measure between 6–9 a.m.
  • Very low values (e.g., <3 µg/dL or <83 nmol/L) are strongly suggestive of adrenal insufficiency.
  • High-normal or elevated cortisol essentially excludes clinically significant adrenal insufficiency in most cases; intermediate values require dynamic testing.

Confirmatory Testing: ACTH Stimulation Test

The standard test is the cosyntropin stimulation test (short ACTH stimulation test).

• Procedure:
  • Obtain baseline serum cortisol and plasma ACTH.
  • Administer 250 µg synthetic ACTH (cosyntropin) IV or IM.
  • Measure serum cortisol at 30 and 60 minutes post-injection.
• Interpretation:
  • In normal individuals, cortisol should rise above a defined cutoff (often >18–20 µg/dL [>500–550 nmol/L], assay-dependent).
  • Lack of appropriate cortisol rise indicates adrenal insufficiency.
  • Simultaneous measurement of plasma ACTH distinguishes primary from central causes:
    • Primary adrenal insufficiency: low cortisol + high ACTH.
    • Secondary/tertiary: low cortisol + low or inappropriately normal ACTH.

Additional Evaluation for Etiology

• Plasma renin activity (or concentration) and aldosterone
  • Primary disease: high renin, low aldosterone (reflecting mineralocorticoid deficiency).
• Autoimmune testing
  • 21-hydroxylase (CYP21A2) autoantibodies support autoimmune adrenalitis.
  • Screen for additional autoimmune endocrine diseases: TSH, free T4, fasting glucose/HbA1c, B12, Ca/PTH.
• Imaging
  • Adrenal CT scan:
    • Autoimmune: small, atrophic adrenal glands.
    • Infectious/infiltrative: enlarged glands, calcifications (e.g., TB), masses.
• Other investigations
  • TB testing, HIV testing, evaluation for metastatic cancer or systemic infiltrative diseases where indicated.

Differential Diagnosis

It is important to distinguish Addison disease from other causes of fatigue, weight loss, hypotension, and electrolyte disturbances.

• Secondary or tertiary adrenal insufficiency
  • Pituitary or hypothalamic disease; chronic exogenous glucocorticoid use with HPA axis suppression.
  • ACTH and renin levels are low or inappropriately normal; no hyperkalemia; no hyperpigmentation; aldosterone production typically preserved.
• Other endocrine disorders
  • Hypothyroidism, hypopituitarism, type 1 diabetes.
• Non-endocrine causes of weight loss and fatigue
  • Malignancy, chronic infection, malabsorption, depression.
• Causes of hyperpigmentation
  • Hemochromatosis, chronic sun exposure, drugs (e.g., minocycline), and other pigmentary disorders.

Management

Management of Addison disease requires lifelong hormone replacement, careful patient education, and urgent recognition and treatment of adrenal crisis.

Chronic Replacement Therapy

Glucocorticoid Replacement

• Hydrocortisone is the preferred agent for most patients because of its physiologic profile.
  • Total daily dose typically 15–25 mg orally in 2–3 divided doses.
  • Example regimen: 10 mg on waking, 5 mg early afternoon; sometimes an additional 5 mg early evening.
  • Aim to minimize over-replacement (which can cause weight gain, hypertension, osteoporosis, and Cushingoid features).
• Alternative:
  • Prednisone 3–5 mg/day in 1–2 doses.
  • Dexamethasone rarely used long term due to risk of overtreatment and lack of circadian rhythm.
• Monitoring:
  • Clinical assessment (weight, blood pressure, energy level, symptoms of over/under-replacement).
  • Biochemical cortisol levels are not routinely used for dose titration in stable patients.

Mineralocorticoid Replacement

• Fludrocortisone is used for mineralocorticoid replacement.
  • Typical dose: 0.05–0.2 mg orally once daily.
  • Titrate based on blood pressure, presence of orthostatic symptoms, serum sodium and potassium, and plasma renin activity.
• Adequate mineralocorticoid replacement:
  • Normal blood pressure without orthostatic symptoms.
  • Normal serum sodium and potassium.
  • Renin activity in the upper normal range.

Adrenal Androgen Replacement

• Dehydroepiandrosterone (DHEA) treatment may be considered in some women with persistent fatigue, low libido, or impaired quality of life despite adequate glucocorticoid and mineralocorticoid replacement.
  • Typical dose: 25–50 mg orally once daily.
  • Monitor for androgenic side effects (acne, hirsutism).

Stress-Dose Steroids

Patients with Addison disease must adjust glucocorticoid doses during intercurrent illness or physiological stress.

• Mild illness (low-grade fever, minor infection): double usual oral glucocorticoid dose until recovery.
• Moderate to severe illness, surgery, or major trauma: parenteral hydrocortisone is typically required.
• Patients should be provided with written emergency plans and instructed on dose adjustments.

Management of Acute Adrenal Crisis

Acute adrenal crisis is an endocrine emergency and requires immediate treatment; do not delay therapy while awaiting test results.

• Immediate management priorities
  • Rapid IV isotonic saline resuscitation (with dextrose as needed for hypoglycemia).
  • High-dose parenteral glucocorticoids:
    • Hydrocortisone 100 mg IV bolus, then 50–100 mg IV every 6–8 hours (or continuous infusion).
    • Hydrocortisone provides both glucocorticoid and some mineralocorticoid activity at high doses.
  • Treat precipitating cause (e.g., infection, hemorrhage).
  • Monitor electrolytes, glucose, hemodynamics; treat hyperkalemia if severe.
• Once stable and tolerating oral intake, transition to usual chronic replacement of glucocorticoid and mineralocorticoid, tapering parenteral doses accordingly.

Patient Education and Long-term Follow-up

• Patients should carry a medical alert bracelet or card indicating adrenal insufficiency and steroid dependence.
• Provide an emergency steroid injection kit (e.g., hydrocortisone 100 mg IM) and train patients and family members to use it in case of vomiting or inability to take oral medications.
• Regular follow-up to reassess clinical status, blood pressure, electrolytes, renin, weight, and comorbid endocrine conditions.
• Vaccination and infection prevention strategies are important, especially in patients at risk of stress-induced crises.

Prognosis and Complications

• With appropriate lifelong hormone replacement and education, most patients can have normal life expectancy and good quality of life.
• Potential complications include:
  • Recurrent adrenal crises if stress dosing is inadequate or in the setting of infection or nonadherence.
  • Complications from chronic glucocorticoid over-replacement (weight gain, osteoporosis, hypertension, diabetes, Cushingoid features).
  • Associated autoimmune diseases (thyroid disease, type 1 diabetes, hypoparathyroidism) in autoimmune polyendocrine syndromes.

Key Clinical Pearls for Exams

• Primary vs secondary adrenal insufficiency:
  • Primary (Addison): hyperpigmentation, hyperkalemia, hyponatremia, high ACTH, high renin, low aldosterone.
  • Secondary/tertiary: no hyperpigmentation, no hyperkalemia, ACTH low or normal, aldosterone largely preserved.
• Classic triad for Addison disease on labs: hyponatremia, hyperkalemia, and hypotension in a patient with fatigue and weight loss.
• Hyperpigmentation mechanism: elevated POMC-derived peptides (ACTH and MSH) stimulate melanocytes.
• Autoimmune associations: always think about polyglandular autoimmune syndromes; screen for thyroid dysfunction and type 1 diabetes.
• ACTH stimulation test is the key diagnostic tool; lack of cortisol rise confirms adrenal insufficiency.
• Adrenal crisis can be precipitated by stress, infection, or abrupt interruption of glucocorticoid therapy.
• Hydrocortisone is the glucocorticoid of choice for chronic replacement; fludrocortisone is needed for mineralocorticoid replacement in primary disease.
• In an undifferentiated shock patient with suspected adrenal crisis, administer IV hydrocortisone promptly; treatment should not be delayed pending test results.
• Patients require stress-dose steroids during illness and should be educated on dose adjustment and emergency IM injection use.

Summary

Addison disease is a chronic, potentially life-threatening form of primary adrenal insufficiency characterized by inadequate cortisol and aldosterone production. Autoimmune adrenalitis is the most common cause in developed countries, whereas infectious, hemorrhagic, infiltrative, and genetic causes remain important globally. Clinically, Addison disease presents with fatigue, weight loss, orthostatic hypotension, hyperpigmentation, hyponatremia, hyperkalemia, and sometimes adrenal crisis. Diagnosis relies on low morning cortisol with high ACTH and impaired response to cosyntropin. Long-term management includes physiologic glucocorticoid and mineralocorticoid replacement, patient education on stress-dose steroids, and emergency preparedness to prevent adrenal crisis. Early recognition and appropriate therapy dramatically improve outcomes, making Addison disease a high-yield topic for medical students and exams.