Addison disease - Symptoms, Causes, Treatment & Prevention

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Overview

Addison disease, also called primary adrenal insufficiency, is a rare, chronic disorder in which the adrenal glands (situated atop each kidney) do not produce enough of the hormones cortisol and, often, aldosterone. These hormones are essential for regulating metabolism, blood pressure, stress response, and the balance of electrolytes.

The condition is named for Dr. Thomas Addison, who first described it in 1855. It accounts for roughly 0.5 to 5 cases per 100,000 people worldwide (CDC, 2023). Women are diagnosed slightly more often than men (about 55% vs 45%) and the condition can occur at any age, though the average age at diagnosis is 35–45 years.

Because the cortisol deficiency can be life‑threatening during stress (infection, injury, surgery), prompt recognition and lifelong treatment are crucial.

Symptoms

Symptoms develop slowly and may be vague at first, which often delays diagnosis. They tend to worsen during periods of physical or emotional stress.

General symptoms

• Fatigue and Weakness: Persistent tiredness that does not improve with rest.
• Weight Loss & Decreased Appetite: Loss of 5–10 kg (10–20 lb) over months.
• Low Blood Pressure (Hypotension): Especially orthostatic (drop when standing).
• Dizziness or Light‑headedness: Often after rising quickly.

Skin & Pigmentation

• Hyperpigmentation: Darkening of the skin, especially on knuckles, elbows, knees, gums, and scar tissue. Caused by increased ACTH (a precursor hormone) that stimulates melanin.
• Hyperpigmented “salt cravings”: Some patients note a craving for salty foods.

Gastrointestinal

• Nausea, vomiting, and abdominal pain: Often mistaken for viral gastroenteritis.
• Diarrhea or constipation: Variable.

Electrolyte‑related

• Salt Craving & Low Sodium (Hyponatremia): Leads to dehydration.
• High Potassium (Hyperkalemia): May cause muscle weakness or irregular heartbeats.

Mental & Neurologic

• Depression, irritability, or difficulty concentrating.
• Low blood sugar (hypoglycemia): Tremors, sweating, or fainting, especially in children.

Other

• Muscle or joint pain.
• Decreased libido or menstrual irregularities in women.

Causes and Risk Factors

In primary Addison disease, the problem originates in the adrenal cortex itself.

Autoimmune Destruction (≈70–80% of cases)

The immune system mistakenly attacks adrenal cells, often in association with other autoimmune conditions such as:

• Hashimoto thyroiditis
• Type 1 diabetes mellitus
• Primary hypoparathyroidism (APS‑1)
• Systemic lupus erythematosus

Infectious Causes (≈10–20%)

• Tuberculosis (TB): Historically the leading cause worldwide; still prevalent in low‑income regions.
• Fungal infections: Histoplasmosis, cryptococcosis.
• HIV/AIDS: Opportunistic infections can involve the adrenals.

Other Causes

• Adrenal hemorrhage or infarction: Waterhouse‑Friderichsen syndrome (meningococcal sepsis).
• Metastatic cancer: Lung, breast, melanoma spreading to adrenals.
• Genetic disorders: Triple‑A syndrome (achalasia, alacrimia, adrenal insufficiency), congenital adrenal hyperplasia (rare forms).
• Medications: Long‑term high‑dose ketoconazole or metyrapone can suppress cortisol production.

Risk Factors

• Family history of autoimmune disease.
• Personal history of other autoimmune conditions.
• Living in an area where TB is endemic.
• Use of drugs that affect adrenal steroid synthesis.

Diagnosis

Diagnosing Addison disease requires a combination of clinical suspicion, laboratory testing, and sometimes imaging.

Baseline Blood Tests

• Early morning serum cortisol: < 3 µg/dL strongly suggests insufficiency; > 18 µg/dL essentially rules it out.
• Plasma ACTH: Elevated (> 2× upper limit) when cortisol is low indicates primary adrenal failure.
• Electrolytes: Hyponatremia, hyperkalemia, and sometimes metabolic acidosis.
• Glucose: May be low (hypoglycemia) especially in children.

Dynamic Testing

The ACTH (cosyntropin) stimulation test is the gold standard:

1. Baseline cortisol drawn.
2. IV or IM 250 µg cosyntropin administered.
3. Cortisol measured at 30 and 60 minutes.

A peak cortisol < 18 µg/dL confirms adrenal insufficiency. If the baseline ACTH is high, the disease is primary; a low/normal ACTH points to secondary causes.

Additional Tests

• Autoantibody panels: 21‑hydroxylase antibodies (most specific for autoimmune Addison).
• Chest X‑ray or CT scan: To look for TB, lymphoma, or metastasis.
• Adrenal CT/MRI: Assesses gland size, hemorrhage, or infiltrative disease.

Diagnostic Criteria Summary

Diagnosis is confirmed when a low morning cortisol is accompanied by an inadequate response to ACTH stimulation and either a high ACTH level (primary) or evidence of adrenal destruction on imaging/autoantibodies.

Treatment Options

Addison disease requires lifelong hormone replacement and careful adjustment during stress.

Glucocorticoid Replacement

• Hydrocortisone: Most commonly used; divided into 2–3 doses (e.g., 10–20 mg upon waking, 5 mg at noon, 2–5 mg late afternoon).
• Prednisone or Prednisolone: Longer‑acting alternatives, useful if adherence to multiple daily doses is challenging.
• Dexamethasone: Rarely used due to potency and lack of mineralocorticoid activity.

Mineralocorticoid Replacement

• Fludrocortisone acetate (0.05–0.2 mg daily): Replaces aldosterone, helping maintain sodium balance and blood pressure.
• Patients on high‑dose glucocorticoids may need lower fludrocortisone because cortisol has some mineralocorticoid effect.

Stress‑Dose Adjustments

During fever, surgery, trauma, or severe emotional stress, glucocorticoid doses must be increased (often 2–3× the usual dose) for the duration of the stress plus 24 hours after.

Adjunctive Therapies

• Salt supplementation: Especially for patients with persistent hyponatremia or extensive salt cravings.
• Patient‑controlled emergency injection kit: 100 mg hydrocortisone IM/SC for adrenal crisis when oral meds cannot be taken.

Procedural Interventions

Rarely needed, but surgical removal of an adrenal tumor, drainage of an adrenal abscess, or treatment of TB with appropriate antibiotics may be required if an identifiable cause is present.

Monitoring

Regular follow‑up (every 3–6 months) includes:

• Clinical review of symptoms, blood pressure, weight.
• Serum electrolytes, glucose, and occasional cortisol levels.
• Adjustment of fludrocortisone based on blood pressure and potassium.

Living with Addison Disease

While the condition is chronic, most patients lead active, normal lives with proper management.

Medication Adherence

• Take glucocorticoids exactly as prescribed; never skip a dose.
• Carry a copy of your prescription and a medical alert bracelet indicating “Adrenal Insufficiency”.

Emergency Preparedness

• Keep an emergency hydrocortisone injection kit with you at all times.
• Educate family, friends, coworkers, and school staff on how to administer the injection.
• Know the signs of adrenal crisis (see below) and seek help immediately.

Stress‑Dose Guidelines (quick reference)

Situation	Glucocorticoid Adjustment
Fever > 38 °C (100.4 °F)	Double usual hydrocortisone dose until fever resolves.
Minor surgery (local anesthesia)	Double dose the day of procedure.
Major surgery or severe trauma	IV hydrocortisone 100 mg bolus, then 200 mg/24 h infusion, taper over 24‑48 h.

Nutrition & Lifestyle

• Consume a balanced diet with adequate salt (unless advised otherwise for hypertension).
• Stay well‑hydrated; aim for 2–3 L of fluids daily, more during hot weather or illness.
• Regular moderate exercise is safe; avoid extreme endurance events without prior dose adjustment.
• Limit caffeine and alcohol, which can exacerbate dehydration.

Regular Health Screening

• Annual blood pressure and electrolyte panel.
• Screen for associated autoimmune diseases (thyroid function tests, fasting glucose, celiac antibodies).
• Vaccinations: stay up‑to‑date with influenza, pneumococcal, and COVID‑19 vaccines; they reduce infection‑related stress.

Psychological Support

Chronic disease can cause anxiety and depression. Consider counseling, support groups, or patient organizations such as the Addison’s Disease Self‑Help Group (ADSHG) for peer support.

Prevention

Because primary Addison disease often stems from autoimmune destruction or infections, complete prevention is not possible. However, risk reduction strategies include:

• TB Prevention: Vaccination (BCG where recommended), prompt treatment of active TB.
• Autoimmune Monitoring: Early detection and treatment of other autoimmune disorders may limit adrenal auto‑antibody formation.
• Avoid unnecessary long‑term high‑dose steroid therapy: Use the lowest effective dose and taper when possible.
• Medication vigilance: Discuss any new drugs with your endocrinologist, especially antifungals like ketoconazole.

Complications

If untreated or poorly managed, Addison disease can lead to serious health problems.

• Adrenal crisis (acute adrenal insufficiency): Life‑threatening collapse characterized by severe hypotension, shock, hyponatremia, hyperkalemia, hypoglycemia, and possible death.
• Chronic electrolyte imbalances: Persistent hyponatremia or hyperkalemia can affect cardiac rhythm and muscle function.
• Persistent fatigue and reduced quality of life: May worsen if dosing is suboptimal.
• Increased susceptibility to infections: Cortisol modulates immune response; both deficiency and overtreatment with steroids can alter immunity.
• Bone loss (osteoporosis): Long‑term glucocorticoid therapy, especially high‑dose regimens, can reduce bone density.

When to Seek Emergency Care

Sources: Mayo Clinic, CDC, National Institutes of Health (NIH), World Health Organization (WHO), Cleveland Clinic, J. Lancet Diabetes Endocrinol 2022; 10: 489‑509; Endocrine Society Clinical Practice Guidelines 2023.

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