Addison's Disease

A 35-year-old woman presents to the clinic with fatigue, weight loss, and new skin pigmentation. She reports experiencing nausea, vomiting, and abdominal pain. Lab results show hyponatremia and hyperkalemia.

Pathophysiology

Addison's disease, also known as primary adrenal insufficiency, results from the destruction of the adrenal cortex, leading to deficient production of glucocorticoids (cortisol) and mineralocorticoids (aldosterone). Clinical manifestations arise when 90% of the adrenal cortex is destroyed.

  • Cortisol deficiency accounts for symptoms such as weakness, fatigue, anorexia, weight loss, nausea, vomiting, abdominal pain, hypoglycaemia, and hyperpigmentation. This hyperpigmentation results from elevated adrenocorticotropic hormone (ACTH) levels, which cross-react with melanin receptors, leading to increased pigmentation in sun-exposed areas and skin creases.
  • Aldosterone deficiency leads to hyponatraemia, hyperkalaemia, metabolic acidosis and hypotension.

Aetiology

The most common cause of Addison's disease in developed countries is autoimmune adrenalitis, accounting for ~75% of cases.  Autoimmune adrenalitis is characterised by the presence of circulating anti-adrenal antibodies in 70% of patients. Worldwide, tuberculosis (TB) is the most common cause.

Other causes include:

  • Infections: Fungal infections (e.g. histoplasmosis), HIV.
  • Malignancy: Metastatic cancers, particularly from the lung, breast, and kidney.
  • Haemorrhage: Waterhouse-Friderichsen syndrome (from Neisseria meningitidis infection), antiphospholipid syndrome, anticoagulation.
  • Genetic: Congenital adrenal hyperplasia (most commonly due to 21-hydroxylase deficiency), adrenoleucodystrophy (X-linked), familial glucocorticoid deficiency, triple A syndrome.
  • Drugs: Metyrapone, aminoglutethimide, ketoconazole, etomidate, rifampicin, phenytoin.

Epidemiology & Risk Factors

Addison's disease has a prevalence of approximately 5 per 100,000.

Risk factors include:

  • Female sex: Addison's disease is more common in women, with a female-to-male ratio of 3:1.
  • Genetic predisposition: Specific HLA alleles (HLA-DRB1 and DQB1) are associated with an increased risk of autoimmune diseases, including Addison's.
  • Other autoimmune disorders: Individuals with other autoimmune conditions, particularly those within the autoimmune polyglandular syndromes (APS), have a higher risk.  
    • Autoimmune polyglandular syndrome type 1 (APS-1) presents with the triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. 
    • APS-2 is characterised by Addison's disease in conjunction with autoimmune thyroid disease, and may also include type 1 diabetes mellitus, pleuritis, or pericarditis.

Clinical Features

Addison's disease often has a gradual onset, with symptoms developing slowly over time.

The most common symptoms include:

  • Constitutional: Weakness, fatigue, anorexia, weight loss.
  • Gastrointestinal: Nausea, vomiting, abdominal pain, diarrhoea, or constipation. Abdominal pain can be severe and mimic an acute abdomen.
  • Skin: Hyperpigmentation, especially in sun-exposed areas, palmar creases, buccal mucosa and scars. Vitiligo may also be present.
  • Cardiovascular: Hypotension, particularly postural hypotension, causing dizziness, syncope.
  • Neuropsychiatric: Depression, lethargy, confusion, and psychosis in severe cases.

Investigations

  • Electrolytes: Hyponatraemia and hyperkalaemia are key features.
  • Glucose: Hypoglycaemia is common.
  • Renal function: Elevated urea can occur due to dehydration.
  • Complete blood count: Normocytic normochromic anaemia, eosinophilia, lymphocytosis, and neutropenia may be present.
  • 8 am plasma cortisol and ACTH levels: A low cortisol level with an elevated ACTH level is characteristic of primary adrenal insufficiency. It is important to note that cortisol levels may be falsely reassuring in patients taking the contraceptive pill or during pregnancy due to elevated cortisol-binding globulin. NICE suggests the following interpretation of cortisol:
    • <100 nmol/L: highly suggestive of Addison’s - admission to hospital
    • 100 - 500 nmol/L: refer the patient for an ACTH stimulation test
    • >500 nmol/L: Addison’s is unlikely
  • Short ACTH stimulation test (Synacthen® test): This test measures the adrenal gland's response to 250μg IM synthetic ACTH (tetracosactide).  A blunted cortisol response (<550 nmol/L after 30 minutes) confirms adrenal insufficiency. This test may be unreliable in patients taking steroid medications.
  • Antibodies: Anti-adrenal antibodies are present in 70% of cases of autoimmune Addison's disease. Steroid 21-hydroxylase antibodies are present in 80% of patients with autoimmune disease.
  • Other:
    • Plasma renin and aldosterone levels: Elevated renin and angiotensin II levels are seen.
    • Chest X-ray: if concerned for TB.
    • Abdominal X-ray: May reveal adrenal calcification.
    • CT abdomen: May show adrenal enlargement or shrinkage in cases of TB adrenalitis.

Management

Lifelong hormone replacement therapy is the cornerstone of Addison's disease management.

Medical Management:

  • Glucocorticoid replacement:
    • Hydrocortisone is the most commonly used glucocorticoid, given in 2-3 divided doses to mimic the natural diurnal rhythm, typically totalling 20-30mg/day.
    • Other glucocorticoids like dexamethasone, methylprednisolone, triamcinolone, prednisolone, and cortisone acetate can also be used. Dosage should be adjusted according to individual needs, monitoring for signs and symptoms of over- or under-replacement.
  • Mineralocorticoid replacement:
    • Fludrocortisone is the drug of choice.
    • Dosage is adjusted based on blood pressure and electrolyte levels.

Lifestyle Modifications:

  • Patient education: Patients need to understand their condition and the importance of medication adherence, particularly "sick day rules".  Sick day rules involve increasing (usually doubling) glucocorticoid dosage during periods of stress, illness, or surgery to mimic the natural stress response.
  • MedicAlert bracelet: Wearing a MedicAlert bracelet or carrying a steroid card is essential.
  • Diet: A balanced diet with adequate salt intake is important, especially for patients on mineralocorticoid replacement.

Complications & Prognosis

Complications:

  • Electrolyte imbalances: Untreated Addison's disease can lead to severe hyponatraemia and hyperkalaemia, potentially causing cardiac arrhythmias.
  • Hypoglycaemia: Can lead to seizures, coma, and death.
  • Other autoimmune disorders: Patients with Addison's are at increased risk of developing other autoimmune conditions.
  • Cushing's disease: can occur with iatrogenic over-replacement of glucocorticoids.

Acute Adrenal Crisis (Addisonian Crisis)

This is a medical emergency with high mortality that requires prompt recognition and treatment. Any patient presenting with profound shock, particularly those with a history of longstanding steroid use or other autoimmune conditions, should be considered for Addisonian crisis.

Signs and symptoms include syncope, confusion, lethargy, convulsions, hypotension, hypothermia, hyponatraemia, hyperkalaemia, and hypoglycaemia.

Management:

  • IV fluids: Rapid infusion of 0.9% sodium chloride is essential to restore blood volume and electrolyte balance. Dextrose should be added if hypoglycaemia is present.
  • IV hydrocortisone: High-dose intravenous hydrocortisone is given as an initial bolus of 100-200 mg followed by 100 mg every 6 hours for 72 hours. Dexamethasone 8 mg IV can be used as it does not interfere with cortisol assays, but hydrocortisone is now more commonly used. The route of administration can then be switched to intramuscular (IM) hydrocortisone before transitioning back to oral steroids.
  • Treat precipitating factors: Address underlying infections with antibiotics.

Prognosis:

With appropriate lifelong hormone replacement therapy and careful management, the prognosis for individuals with Addison's disease is generally good. However, patients must remain vigilant about medication adherence and manage stress levels to prevent adrenal crises. Regular follow-up with an endocrinologist is crucial for monitoring hormone levels and adjusting treatment.

Summary

Addison's disease is a rare but potentially life-threatening endocrine disorder resulting from adrenal cortex destruction. The most common cause in developed countries is autoimmune adrenalitis, while TB remains the leading cause worldwide. Deficiencies in cortisol and aldosterone lead to various symptoms, including fatigue, weight loss, hyperpigmentation, hypotension, and electrolyte imbalances. Diagnosis involves biochemical testing, including cortisol and ACTH levels, and a short ACTH stimulation test. Lifelong hormone replacement therapy with glucocorticoids and mineralocorticoids is the mainstay of treatment. Adrenal crisis is a medical emergency that necessitates prompt IV fluids and hydrocortisone administration. Patient education, including "sick day rules," is paramount to ensure good outcomes.