Addison’s Disease

Description

Addison’s disease, also known as primary adrenal insufficiency, is a rare, chronic endocrine disorder where the adrenal glands do not produce sufficient steroid hormones, namely glucocorticoids (cortisol) and often mineralocorticoids (aldosterone). The condition can be life-threatening and is characterised by weight loss, muscle weakness, fatigue, low blood pressure, and sometimes darkening of the skin.

Pathogenesis

The most common cause of Addison’s disease worldwide is tuberculosis, but in developed countries, the primary cause is autoimmune destruction of the adrenal cortex. Other causes include infections (such as HIV, fungal infections), metastatic cancer, haemorrhage into the adrenal glands, and certain medications.

Epidemiology, Risk Factors & Associations

• The estimated prevalence of Addison’s disease in developed countries is approximately 1 in 10,000 people.
• The disorder affects all age groups and both genders equally.
• Tuberculosis is most common cause globally
• Autoimmune diseases are the most common cause in developed countries (70% of cases in developed countries).

The autoimmune destruction of adrenal tissue is often a part of an autoimmune polyendocrine syndrome. The two most common syndromes include:

1. Autoimmune Polyglandular Syndrome Type 1 (APS1, also known as APECED): Addison’s disease occurs in about 60-80% of these patients. This syndrome is rare and also includes hypoparathyroidism and mucocutaneous candidiasis.
2. Autoimmune Polyglandular Syndrome Type 2 (APS2, also known as Schmidt’s Syndrome): Addison’s disease is seen in around 70-90% of cases. This syndrome is more common than APS1 and often includes type 1 diabetes and/or autoimmune thyroid disease.

In isolated autoimmune Addison’s disease (i.e., not part of a polyglandular syndrome), other autoimmune diseases can co-exist, although not as part of a defined syndrome. The most common are:

1. Autoimmune thyroid disease (20-50%)
2. Type 1 diabetes (10-15%)
3. Vitiligo (5-10%)
4. Pernicious anaemia (5-10%)
5. Coeliac disease (5-10%)

Other associations include:

• HIV, fungal infection
• Metastatic cancers involving the adrenal gland – lung (35 – 40%), breast (20%), melanoma (13 – 26%), colorectal (~10%), sometimes renal cell carcinoma.

Clinical Features

Typical clinical features of Addison’s disease include:

• Chronic fatigue and muscle weakness
• Loss of appetite and weight loss
• Hypotension (may be postural) – Sodium loss, alongside water, in the urine increases, and there is an increased tendency for fluid to shift into cells leading to extracellular fluid volume depletion.
• Hyperpigmentation of the skin – due to increased secretion of the hormone melanocyte-stimulating hormone (MSH) from the pituitary gland from lack of negative feedback inhibition usually provided by cortisol.

Complications

• Addisonian crisis: A life-threatening situation with severe abdominal pain, low blood pressure, and loss of consciousness. It is triggered by stress, such as from an injury, infection, or illness.
• Long-term complications: Poor quality of life due to chronic fatigue, depression, and reduced vitality.

Pathological Features

Histopathology

• The adrenal glands may appear atrophic with lymphocytic infiltration in autoimmune Addison’s disease, caseating granulomas in tuberculosis, or metastatic deposits in cases of malignancy.

Biochemistry

• Hyponatraemia – due to the deficiency of aldosterone, leading to impaired renal sodium conservation.
• Hyperkalaemia – due to the deficiency of aldosterone which normally regulates excretion of potassium from the kidneys.
• Hypoglycaemia – due to the deficiency of cortisol, which normally maintains blood glucose levels by promoting gluconeogenesis.
• There will be an increased ACTH level due to the lack of negative feedback and low cortisol levels.

Radiological Features

CT

• Autoimmune disease: Adrenal glands can appear normal in early disease, or show bilateral adrenal atrophy
• Adrenal tuberculosis: the adrenal glands may appear bilaterally enlarged in the early stages, with progressive calcification and atrophy as the disease advances.
• Metastatic disease: The adrenal glands may show irregular bilateral enlargement, with heterogeneous enhancement due to necrotic areas. Adrenal metastases are often a sign of widespread disease and poor prognosis.

MRI

• Adrenal enlargement in tuberculosis and metastatic disease.
• In metastatic disease, lesions may have variable signal characteristics depending on the primary tumour type.

Grading and Staging

Addison’s disease is not typically graded or staged. The severity of the disease is assessed based on the patient’s symptoms, biochemical abnormalities, and response to treatment.

Differential Diagnosis

• Secondary adrenal insufficiency: It is caused by a lack of ACTH, usually due to pituitary disease. Unlike primary adrenal insufficiency, hyperpigmentation and hyperkalaemia do not occur.
• Adrenal fatigue: A proposed condition characterised by chronic fatigue, which is not generally accepted by mainstream medicine.

Management

• Lifelong hormone replacement therapy is necessary to replace cortisol (hydrocortisone or prednisolone) and often aldosterone (fludrocortisone).
• During periods of stress, illnesses, or injury, increased doses of glucocorticoids are required.
• Immediate medical attention is needed for suspected Addisonian crises.