What is Addison’s disease?

Addison’s disease involves the underproduction of cortisol & aldosterone by the adrenal cortex

The disease is very rare with around 8 in a million people developing the disease.

It generally affects individuals between the ages of 20-50 however it can occur at any age.

It’s essential you first understand the hypothalamic-pituitary-adrenal axis in normal individuals

It will then be easier to understand how this system goes wrong in disease

So check out the adrenal axis article first which can be found here

What does the adrenal cortex do?

The Adrenal Cortex is responsible for producing Cortisol and Aldosterone 

Cortisol 

Cortisol is a steroid hormone (glucocorticoid)which is released under stress & low steroid levels

It’s main function is to increase blood glucose levels by promoting gluconeogenesis

Cortisol also suppresses the immune system & increases fat, protein & carb metabolism

 

Random Fact!

You may recognise cortisol’s pharmaceutical name which is Hydrocortisone

Hydrocortisone is used to reduce inflammation leveraging Cortisol’s immunosuppresive effect

.

 

Aldosterone 

Aldosterone is also a steroid hormone (mineralocorticoid )

It’s main function is to increase blood volume

It causes reabsorption of sodium and water as well as causing excretion of potassium

 

Random Fact!

Drugs that interfere with the secretion or action of Aldosterone are in use as antihypertensives

An example is Spironolactone which blocks Aldosterone receptors

Causes

Autoimmune destruction

Autoimmune destruction of the adrenal cortex is the most common cause of Addison’s disease- 70%

Antibodies are produced against the adrenal cortex or an enzyme called 21-hydroxylase

These antibodies cause destruction of the adrenal cortex & deficiency in cortisol & aldosterone

A rarer disorder known as Autoimmune Polyglandular Deficiency can also cause addison’s disease

This disease occurs due to autoimmune attack against multiple endocrine organs

These includeparathyroid, adrenal, thyroid, pituitary, pancreas

These disorders are genetic in origin and often involve the Auto Immune Regulator Gene (AIRE)

Genetic Disorders

Adrenoleukodystrophy (Schilder’s disease)
A rare, inherited disorder of fatty acid metabolism
Presents in childhood
Leads to progressive brain damage, failure of the adrenal glands & eventually death

Malignancy

Adrenal Metastasis - common in lung, breast & kidney cancer

However very few result in development of addison’s disease

 

Infection 

Tuberculosis -  in rare circumstances it can spread to adrenals and destroy the cortex

Opportunistic infections – cryptococcosis, candidiasis, histoplasmosis (common in AIDS)

 

Vascular

Waterhouse-Friderichsen syndrome:

• Massive haemorrhage of adrenals
• Usually due to meningococcal septicaemia.

Infarction – a thrombus from another site occludes blood supply of adrenal gland

 

Adrenal dysgenesis

Very rare

Almost always caused by genetic mutations

Congenital Adrenal Hypoplasia is an example – caused by mutations in DAX1 gene

 

Impaired Steroid Production

The adrenal glands produce steroid hormones from cholesterol you consume

This process involves many enzymes, and a mutation in any of these can cause problems

Congenital Adrenal Hyperplasia is caused by mutations in some of these enzymes

 

Infiltration

Haemochromotosis:

- Disorder of increased intestinal iron absorption
- Leading to high levels of body iron
- This excess iron is deposited in the adrenal tissue as well as the liver, heart, pancreas etc
- The iron accumulates and becomes toxic causing death of the adrenal tissue

 

Iatrogenic (caused by doctors!)

Adrenal haemorrhage as a result of anticoagulant therapy

Removal of adrenal glands – e.g. in malignancy

Fluconazole & Ketoconazole inhibit cortisol production

Phenytoin & Rifampicin induce enzymes which increase cortisol metabolism by the liver

Signs & Symptoms

Anorexia & Weight Loss – 90% of cases

Fatigue & Lethargy

.

Hyperpigmentation;

- Due to increased POMC
- Even in areas not exposed to sun
- Hand creases, Nipple, Buccal Mucosa (pathognomonic)
- Darkening of scars

.

Generalised Weakness

GI symptoms - nausea, vomiting, diarrhoea

Postural Hypotension - due to lack of aldosterone

Decreased libido in males

Calcification of the Pinna of the Ear - in longstanding disease – rare but amazing if you spot it!

Decreased axillary & pubic hair

Symptoms of other endocrine disease - due to possibility of autoimmune polyendocrine syndrome

Addisonian Crisis

Addisonian crisis is a collection of serious symptoms which indicate severe adrenal insufficiency

This is a medical emergency and if not managed promptly it can lead to death

Causes

An individual with undiagnosed addison’s disease,

A patient not adhering to treatment

Any other problem that has caused sudden loss of adrenal function (haemorrhage, infection)

 

Symptoms

Hypotension

Severe abdominal pain

Severe Vomiting & Diarrhoea

High fever

Shock

Confusion

Convulsions

Death

 

Management 

Clinical suspicion + a low serum cortisol is sufficient to diagnose

Do not delay treating by waiting for confirmatory tests

Treat dehydration with 0.9% saline (beware of worsening electrolyte disturbances)

High doses of hydrocortisone should be given

Glucose may be required if hypoglycaemic

Investigate the cause of the crisis and attempt to treat it

Investigations

Biochemical tests

Common abnormalities include:

• Hypercalcaemia
• Hypoglycaemia
• Hyponatraemia
• Hyperkalaemia
• Eosinophilia
• Metabolic Acidosis

 

Autoantibodies

Adrenal Cortex Antibodies

21-Hydroxylase antibodies – present in 80%

 

Imaging

CT abdomen

Atrophic adrenal glands seen in autoimmune adrenalitis

Enlarged adrenals seen in infective, infiltrative and metastatic causes

Diagnosis

ACTH Stimulation Test 

This involves giving the patient an IM injection of synthetic ACTH (Synacthen)

Cortisol is measured at 30 & 60 mins then at 2, 4, 8, 12, 24 hours

Serum cortisol should rise substantially during this period of time

In Addison’s disease cortisol will not rise

In secondary adrenal failure the cortisol will steadily begin to rise

Management

The treatment strategy is to replace the hormones the adrenal cortex produces

Cortisol (glucocorticoid) replacement

Hydrocortisone is the treatment of choice for cortisol replacement

It is reliable due to it’s predictable absorption rate

It is given in 3 daily doses (morning, midday and evening) to mimic the bodies circadian rhythm

 

Aldosterone (mineralocorticoid) replacement

Fludrocortisone is the treatment of choice for aldosterone replacement

The dose is usually around 100mcg once daily

 

DHEA replacement

DHEA is also produced by the adrenal cortex

It is a precursor of oestrogen and testosterone

It also acts as a weak androgen itself

Replacement can improve mood and general well being

Prognosis

Individual who receive adequate therapy should live a normal healthy life

However if not managed properly addisonian crisis can lead to death