What is Addison's disease, its diagnosis, treatment, and management in adults, particularly females with a history of autoimmune disorders?

Addison's Disease: Comprehensive Overview

Definition and Epidemiology

Addison's disease (primary adrenal insufficiency) is a rare endocrine disorder caused by destruction of the adrenal cortex, resulting in deficient production of cortisol and aldosterone, with a prevalence of 10-15 per 100,000 population. 1, 2

• In Europe, autoimmunity accounts for approximately 85% of cases, with tuberculosis, adrenal hemorrhage, and genetic disorders comprising the remainder 2, 3
• The disease affects both sexes but has particular implications for women due to loss of adrenal androgens, their primary androgen source 4

Clinical Presentation

Cardinal Symptoms

• Insidious onset over months to years with nonspecific manifestations including persistent fatigue, myasthenia, unintentional weight loss, and salt craving 2, 3
• Hyperpigmentation particularly in sun-exposed areas, skin creases, and areas of friction due to elevated ACTH 3, 5
• Hypotension and orthostatic symptoms from aldosterone deficiency 3, 5
• Gastrointestinal complaints including nausea, vomiting, abdominal pain, and anorexia 5, 6

Laboratory Abnormalities

• Hyponatremia is present in 90% of newly diagnosed cases 2, 7
• Hyperkalemia occurs in approximately 50% of patients at presentation 2, 7
• Additional findings include mild hypercalcemia, anemia, eosinophilia, lymphocytosis, and elevated liver transaminases 7
• Hypoglycemia may occur in children but is rare in adults 7

Associated Autoimmune Conditions

Approximately 50% of patients with autoimmune Addison's disease have coexisting autoimmune disorders, requiring systematic screening. 1, 2

Autoimmune Polyendocrine Syndrome Type 1 (APS-1)

• Caused by AIRE gene mutations 1
• Defined by presence of two of three components: PAI, hypoparathyroidism, and chronic mucocutaneous candidiasis 1, 2

Autoimmune Polyendocrine Syndrome Type 2 (APS-2)

• Most commonly combines PAI with primary hypothyroidism 1, 2
• May include Graves' disease, type 1 diabetes, autoimmune gastritis with vitamin B12 deficiency, premature ovarian insufficiency, vitiligo, and celiac disease 1, 2

Diagnostic Approach

Initial Testing

Paired measurement of serum cortisol and plasma ACTH is the cornerstone initial diagnostic test. 2, 7

• Serum cortisol <250 nmol/L with elevated ACTH during acute illness is diagnostic 2
• Low or inappropriately normal cortisol with markedly elevated ACTH strongly suggests PAI 7

Confirmatory Testing

When results are equivocal or partial adrenal insufficiency is suspected, perform a cosyntropin (synacthen) stimulation test. 2, 7

• Administer 0.25 mg cosyntropin intramuscularly or intravenously 2, 7
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes 7
• Peak serum cortisol <500-550 nmol/L confirms the diagnosis 2, 7

Etiologic Diagnosis

21-hydroxylase autoantibodies (21OH-Ab) should be the first test to establish autoimmune etiology. 7

• If 21OH-Ab is negative, proceed with CT imaging of adrenals, interferon-ω antibodies, and very long-chain fatty acid measurement 7
• Small or unidentifiable adrenal glands on imaging support autoimmune etiology, while enlarged glands suggest tuberculosis, metastatic disease, or infiltrative processes 5

Critical Caveat

If adrenal crisis is suspected clinically, never delay treatment for diagnostic testing—collect blood samples for cortisol and ACTH before administering hydrocortisone if possible, but immediate treatment takes absolute priority. 7

Treatment

Glucocorticoid Replacement

Hydrocortisone (HC) or cortisone acetate (CA) are the preferred glucocorticoids, with no evidence that one is superior to the other. 1, 2

Standard Dosing Regimen

• HC: 15-25 mg per day (equivalent to 5-10 mg/m² body surface area) divided into 2-3 doses 1, 2
• CA: 25 mg daily in divided doses 1, 8
• First dose upon awakening, last dose 4-6 hours before bedtime to approximate circadian rhythm 1

Dose Adjustment Strategy

Dosage adjustment relies primarily on clinical assessment rather than laboratory monitoring. 1, 2

• Signs of over-replacement: weight gain, insomnia, peripheral edema 1
• Signs of under-replacement: lethargy, nausea, poor appetite, weight loss, increased pigmentation 1
• Fine-tune dosing by assessing energy levels throughout the day, mental concentration, daytime somnolence, and pigmentation changes 1
• Serum or salivary cortisol day curves may guide dosing only when malabsorption is suspected 1

Drug Interactions

• CYP3A4 inducers and inhibitors significantly affect HC clearance and require dose adjustments 1

Mineralocorticoid Replacement

Fludrocortisone is required for aldosterone replacement in all patients with Addison's disease. 8

• Standard dose: 0.1 mg daily (range 0.1 mg three times weekly to 0.2 mg daily) 8
• If transient hypertension develops, reduce to 0.05 mg daily 8
• Increased sodium chloride intake may be necessary to compensate for renal losses 1

Management of Adrenal Crisis

Adrenal crisis is a life-threatening emergency requiring immediate aggressive treatment. 2

Immediate Treatment Protocol

• Hydrocortisone 100 mg IV or IM immediately, followed by 100 mg every 6-8 hours until recovery 2
• Rapid infusion of 0.9% sodium chloride solution at 1 L/hour initially until hemodynamic improvement 2

Androgen Replacement in Women

For women with persistent lack of libido and/or low energy despite optimized glucocorticoid and mineralocorticoid replacement, offer a 6-month trial of DHEA 25-50 mg daily. 4

• Continue DHEA if clinically effective 4
• Monitor serum DHEAS, androstenedione, and testosterone levels, targeting normal range 4
• Important caveat: Evidence for DHEA benefit remains weak and inconsistent, and long-term safety data are lacking—use with caution 4, 9
• Adrenal androgens are less clinically significant in men due to testicular testosterone production 4

Patient Education and Safety Measures

All patients must receive comprehensive education on stress dosing and emergency management, as delays in treatment can be fatal. 1, 2

Essential Patient Actions

• Wear a Medic Alert bracelet and carry a steroid card at all times 1, 2
• Learn intramuscular self-administration of hydrocortisone for adrenal crisis 1
• Increase steroid doses during concurrent illness, injury, or stress 1, 2
• Wake earlier to take first HC dose if experiencing morning nausea or poor appetite, then return to sleep 1

Common Pitfall

Many patients must advocate for themselves with emergency department staff to receive appropriate treatment—this barrier must be overcome through improved medical education 1

Follow-up and Monitoring

Annual follow-up should include systematic assessment for complications and new autoimmune conditions. 2

Annual Monitoring Protocol

• Assessment of health, well-being, weight, and blood pressure 2
• Serum sodium and potassium 7
• Thyroid function tests 7
• Plasma glucose and HbA1c 7
• Complete blood count 7
• Vitamin B12 levels 7
• Screening for new autoimmune disorders, particularly thyroid disease 7
• Assessment for glucocorticoid therapy complications including osteoporosis and cardiovascular disease 1

Prognosis

With proper treatment, Addison's disease is a manageable chronic condition, but premature death from adrenal crises and therapy-related complications remain significant risks. 1, 2

• Quality of life and work capacity are reduced in many patients despite standard replacement therapy 1
• Concerns include therapy-related osteoporosis, cardiovascular complications, and fertility issues in women due to premature ovarian insufficiency 1
• Many patients report persistent fatigue, weariness, and reduced stress tolerance on standard replacement therapy 9