Addison's Disease

Primary adrenal insufficiency, also known as Addison’s disease, is an autoimmune condition characterised by destruction of the adrenal gland resulting in deficiencies of cortisol and/or aldosterone.

Terminology

Getting to grips with the terminology can be a little confusing, so let’s start by making it a bit clearer.

• Adrenal insufficiency: Inadequate secretion of cortisol (a glucocorticoid) and/or aldosterone (a mineralocorticoid).
   
• Primary adrenal insufficiency: Something is wrong with the adrenal gland itself e.g. 
  • Addison's disease: Also known as autoimmune adrenalitis. It is the autoimmune destruction of the adrenal gland
  • Surgery: Adrenalectomy
  • Infection: Tuberculosis for example
  • Congenital: Congenital adrenal hyperplasia
  • Waterhouse-Friderichsen syndrome: A complication of meningococcal septicaemia/infection, causing bilateral haemorrhage of the adrenal glands.
     
• Secondary adrenal insufficiency: Inadequate amounts of ACTH i.e. a problem with the pituitary gland.
  • Pituitary Adenoma
  • Sheehan Syndrome: Significant blood loss at childbirth resulting in necrosis of the pituitary gland.
  • Base of skull fracture
     
• Tertiary adrenal insufficiency: Reduced secretion of CRH from the hypothalamus to promote pituitary release of ACTH
  • Long-term steroids: Exogenous administration of glucocorticoids over long periods of time effectively turns off the hypothalamic-pituitary system; you're essentially getting your steroid need met exogenously, so via negative feedback, the whole process shuts down. If a patient suddenly withdraws from their steroids, it can result in crisis due to dysfunction of the hypothalamic-pituitary axis.

We'll focus this set of notes on Addison's disease, because it's the most common cause of adrenal insufficiency.

Pathophysiology

Aldosterone

To understand the clinical features and electrolyte abnormalities typical of Addison’s, it is important to understand how aldosterone works. Aldosterone is a mineralocorticoid hormone (it regulates 'mineral' levels i.e. sodium and potassium, and is produced by the adrenal cortex). Its release is regulated by the renin angiotensin aldosterone system (RAAS). Angiotensin II regulates secretion of aldosterone from the adrenal gland. Aldosterone then binds to the receptors of the kidney to do the following:

1. Increase sodium reabsorption
2. Increase excretion of potassium

Cortisol

Ordinarily, you have the hypothalamic-pituitary-adrenal axis whereby:

1. Hypothalamus: Secretes corticotropin releasing hormone (CRH)
2. Anterior pituitary: Secretes adrenocorticotropic hormone (ACTH)
3. Adrenal cortex: Secretes cortisol

Cortisol has various actions in the body, including regulation of glucose levels in the body, increasing lipolysis, metabolism regulation, and blood pressure regulation.

In Addison’s disease, there is autoimmune destruction of the cortex of the adrenal gland, resulting in inadequate production of aldosterone and/or cortisol. This results in high levels of ACTH in attempts to cause the gland to release hormone. As a side, ACTH shares a precursor with melanocyte stimulating hormone. In order to make more ACTH, the body produces additional precursor which consequently results in increased levels of melanocyte stimulating hormone which is thought to be the cause of hyperpigmentation seen in Addison’s disease.

Clinical Features

Patients may either present with chronic features of Addison’s disease, or in an acute Addisonian crisis. Due to deficiencies in aldosterone and cortisol, patients can present with electrolyte abnormalities which tend to follow the profile of:

• Hyponatraemia: Low aldosterone = less sodium reabsorption
• Hyperkalaemia: Low aldosterone = less potassium excretion
• Hypercalcaemia
• Hypoglycaemia: Inadequate glucocorticoids

Chronic features include:

• Malaise, fatigue, and general weakness
• Salt cravings: Mineralocorticoid deficiency
• Muscle cramps
• Hypotension and postural hypotension
• Weight loss
• Hyperpigmentation
• Vitiligo: Tends to occur in patients with autoimmune Addison’s
• Loss of body hair
• Low libido

For features of a crisis, please see the crisis section of these revision notes.

Investigations

Bedside

• Lying/standing blood pressure

Bloods

• FBC, LFT, TFT
• U&E: Electrolyte abnormalities
• Blood glucose: May be low
• Calcium: Hypercalcaemia
• Serum cortisol: Usually measured in the morning between 8-9am as this is when cortisol levels peak. This is usually low.
• 21-hydroxylase adrenal autoantibodies: Can be positive in patients with autoimmune Addison’s disease

Special Tests

• Short synacthen test: This involves administering a synthetic ACTH, either IV/IM. Serum cortisol levels are checked before the injection, and then 30 minutes after the administration. Normally, cortisol levels should increase to >500-550 nanomol/L – if it fails to increase sufficiently, the patient has adrenal insufficiency.

Management

Management of Addison’s disease involves replacing the deficient glucocorticoid and mineralocorticoid hormones, usually with hydrocortisone and fludrocortisone respectively.

Patients are usually given a steroid emergency card and bracelets that notify other healthcare professionals of steroid use. Patients are also provided with education surrounding Addisonian Crisis and sick day rules i.e. during periods of acute illness, patients should be doubling the dose of steroids to mimic normal steroid physiology. Other instances where steroid doses need to be increased include strenuous exercise such as a marathon, injury, nausea, vomiting, and diarrhoea.

Individuals with Addison’s disease are also usually provided with an emergency syringe of hydrocortisone (usually 100mg) which they can self-administer in case of adrenal/Addisonian crisis.

Addisonian Crisis

An Addisonian crisis (or adrenal crisis) is a serious endocrinology emergency which occurs due to acute inadequacy of adrenal hormones. Patients with Addison’s disease may have their first presentation in crisis.

The cause of Addisonian crisis is usually due to an acute stress on the body e.g. infection/surgery. As the adrenals are unable to secrete sufficient cortisol in response to the physiological stress, patients can be pushed into crisis. Clinical features include:

• Nausea and vomiting
• Fever
• Abdominal pain
• Altered mental status

Management involves urgent administration of IM or IV hydrocortisone (usually 100mg STAT, and then 50mg QDS for 24 hours), as well as fluid resuscitation and glucose replacement. Fluid balance, electrolytes and blood glucose are also typically monitored. 

References

https://cks.nice.org.uk/topics/addisons-disease/management/management/

Ralston, S. H., Penman, I. D., Strachan, M. W. J., & Hobson, R. (Eds.). (2018). Davidson’s principles and practice of medicine (23rd ed.). Elsevier Health Sciences.