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Endocrine · Clinical Topics
Addison's Disease
Addison's disease is primary adrenal insufficiency caused by the destruction of the adrenal cortex, leading to a deficiency in cortisol, aldosterone, and adrenal androgens. The most common cause in the UK is autoimmune destruction. Presentation is often chronic with lethargy, hyperpigmentation, and hypotension, but it can manifest acutely as a life-threatening adrenal crisis.
📌 Learning Objectives
- Describe the pathophysiology of primary adrenal insufficiency (Addison's disease).
- Explain the clinical features and diagnostic approach for Addison's disease.
- Identify the causes of Addison's disease, particularly in the UK context.
- Apply principles of acute and chronic management for Addison's disease and adrenal crisis.
- Differentiate primary from secondary adrenal insufficiency based on clinical and biochemical findings.
📋 Overview
Addison's disease is a rare but critical diagnosis. It involves the progressive destruction of the adrenal cortex, which only results in clinical symptoms when over 90% of the gland is lost. In the UK, 80% of cases are autoimmune (autoimmune polyendocrine syndrome types I or II). Globally, tuberculosis remains a frequent cause. Other causes include metastases, sarcoidosis, and adrenal haemorrhage (Waterhouse-Friderichsen syndrome). Because the primary defect is in the adrenal gland, ACTH levels rise via feedback, leading to hyperpigmentation. This contrasts with secondary adrenal insufficiency (pituitary failure), where ACTH is low and aldosterone secretion is usually preserved (as it is mainly regulated by the Renin-Angiotensin system). Patients with Addison's are at constant risk of an Addisonian crisis, often triggered by illness, trauma, or surgery, requiring emergency steroid replacement. Chronic management involves 'physiological' replacement of glucocorticoids and mineralocorticoids.
🔬 Basic Science
The adrenal cortex has three zones: Zona Glomerulosa (Aldosterone), Zona Fasciculata (Cortisol), and Zona Reticularis (Androgens). Autoimmune Addison's involves antibodies against 21-hydroxylase, an enzyme essential for steroidogenesis. Loss of cortisol leads to increased CRH and ACTH. ACTH is a cleavage product of Pro-opiomelanocortin (POMC), which also yields Melanocyte Stimulating Hormone (MSH); high ACTH thus causes increased melanin production (hyperpigmentation). Loss of aldosterone leads to renal sodium wasting and potassium retention, causing hypotension and hyperkalaemia. Low androgens in women lead to loss of axillary and pubic hair. In secondary insufficiency, the Renin-Angiotensin-Aldosterone System (RAAS) remains intact, so hyponatraemia and hyperkalaemia are less common.
🏥 Clinical Relevance
Chronic symptoms: Insidious onset of fatigue, anorexia, weight loss, nausea, and 'salt craving'. Signs: Postural hypotension and hyperpigmentation (especially in new scars, palmar creases, and buccal mucosa). Addisonian Crisis: This is a medical emergency. Features include severe hypotension (shock) unresponsive to fluids, abdominal pain, fever, and vomiting. Chronic complications: Increased risk of other autoimmune conditions (e.g., Vitiligo, T1DM, Hypothyroidism). During physiological stress, the body cannot mount a cortisol response, leading to cardiovascular collapse.
🧪 Investigations
Bloods: U&Es (Hyponatraemia and Hyperkalaemia), glucose (Hypoglycaemia), FBC (Eosinophilia). Diagnosis: 1. Morning (9 am) cortisol (if <100nmol/L, suggestive; if >500nmol/L, unlikely). 2. Short Synacthen Test (Gold Standard): Give 250mcg IM/IV Synacthen (ACTH analogue); measure cortisol at 30 and 60 mins. A normal response is a rise to >450-500 nmol/L. 3. ACTH levels: High in primary, low in secondary. Imaging: CT Adrenals (if non-autoimmune cause suspected) – may show calcification in TB or haemorrhage. Antibodies: 21-hydroxylase antibodies.
💊 Management
Chronic: 1. Glucocorticoid replacement: Oral Hydrocortisone (usually 15-25mg split into breakfast, lunch, and late afternoon doses to mimic circadian rhythm). 2. Mineralocorticoid replacement: Fludrocortisone (50-200mcg daily). 3. Education: 'Sick day rules' (double glucocorticoid dose for fever/illness; IM hydrocortisone for vomiting). Adrenal Crisis: 1. IV access and aggressive fluid resuscitation (0.9% saline). 2. IV Hydrocortisone (100mg stat, then 100mg every 6-8 hours). 3. Correction of hypoglycaemia. Do not wait for Synacthen test results to treat a suspected crisis.
Revision Resources – expand the sections below for high-yield notes, exam pearls, key facts and further reading.
MLA High-Yield Notes & Quick Revision ⌄
In an exam, look for the 'tanned' patient with low sodium and high potassium. Remember: Secondary adrenal insufficiency (pituitary) does NOT cause hyperpigmentation because ACTH is low. Patients should never stop their steroids abruptly due to the risk of crisis.
Adrenal insufficiency
Hyperpigmentation
Hypotension
Electrolyte imbalance (hyponatraemia, hyperkalaemia)
Endocrine emergencies
- Addison's disease is primary adrenal insufficiency.
- Caused by destruction of the adrenal cortex, often autoimmune in the UK.
- Leads to deficiency of cortisol, aldosterone, and adrenal androgens.
- Key symptoms: fatigue, weight loss, hyperpigmentation, hypotension, salt craving.
- Diagnosed by low morning cortisol and high ACTH; confirmed by Synacthen test.
- Adrenal crisis is a medical emergency requiring IV hydrocortisone and fluids.
Exam Pearls ⌄
⭐ High Yield
Addison's disease is primary adrenal insufficiency due to adrenal cortex destruction, leading to cortisol, aldosterone, and androgen deficiency.
The most common cause in the UK is autoimmune destruction of the adrenal glands.
Clinical features include lethargy, hyperpigmentation (due to high ACTH), hypotension, and salt craving.
Diagnosis involves measuring morning cortisol and ACTH, often confirmed with a short synacthen test.
An adrenal crisis is a life-threatening emergency requiring immediate IV hydrocortisone and fluid resuscitation.
Long-term management involves physiological replacement with hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid).
💡 Clinical Pearl
Autoimmune Polyendocrine Syndromes (APS): Addison's disease is a key component of APS type 1 and type 2, highlighting its autoimmune aetiology and association with other endocrine disorders.
Sepsis: Severe infection can precipitate an adrenal crisis in patients with Addison's disease or cause adrenal haemorrhage (Waterhouse-Friderichsen syndrome) in previously healthy individuals.
Hypoglycaemia: Cortisol deficiency impairs gluconeogenesis, making hypoglycaemia a potential feature of adrenal crisis, especially in children.
⚠️ Exam Tip — Common Mistakes
Confusing primary (Addison's) with secondary adrenal insufficiency (pituitary cause).
Failing to recognise the urgency of an adrenal crisis and delaying treatment.
Not appreciating the role of mineralocorticoid replacement (fludrocortisone) in primary adrenal insufficiency.
Misattributing hyperpigmentation to other causes and missing the diagnosis.
Forgetting to provide 'sick day rules' and emergency steroid cards to patients.
Key Facts ⌄
Primary adrenal insufficiency with deficiency of cortisol and aldosterone.
Most common cause in UK: Autoimmune (Addison’s disease).
Hyperpigmentation is a key sign (found in skin creases and buccal mucosa).
Biochemical markers: Hyponatraemia, hyperkalaemia, and hypoglycaemia.
Diagnosis: Short Synacthen Test (failure of cortisol to rise).
Treatment: Hydrocortisone (to replace cortisol) and Fludrocortisone (to replace aldosterone).
Patients must have a steroid alert card and an emergency injection kit.
'Sick day rules' involve doubling the steroid dose during illness.
Related Topics ⌄
References ⌄
- NICE CKS - Adrenal insufficiency
- Endocrine Society
- Kumar & Clark's Clinical Medicine
Further Resources
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