Addison's disease

Notes

Definition & classification

Addison’s disease (primary adrenocortical insufficiency) is caused by destruction or dysfunction of the adrenal cortex.

The adrenal glands sit atop each kidney. They are an important endocrine organ, the cortex is responsible for the release of glucocorticoids, mineralocorticoids and sex hormones. Addison's disease leads to a deficiency both glucocorticoids and mineralocorticoids.

Hypothalamic-pituitary-adrenal axis

Cortisol secretion is controlled by the hypothalamus-pituitary-adrenal axis.

1. Corticotropin-releasing hormone 

Corticotropin-releasing hormone (CRH) is released by the paraventricular nucleus of the hypothalamus. It is transported via the hypophyseal portal system to the anterior pituitary where it stimulates the release of adrenocorticotropic hormone (ACTH).

2. Adrenocorticotropic hormone

ACTH, released from the corticotrophs of the anterior pituitary, stimulates the release of cortisol.

The precursor of ACTH is POMC, this is also the precursor of beta-melanocyte-stimulating hormone. In addition, to this ACTH may be cleaved to form alpha-melanocyte-stimulating hormone. As a result ACTH excess results in hyperpigmentation (resulting from melanocyte stimulation), particularly affecting the oral mucosa and palmar creases.

ACTH excess is a feature of both Addison's disease (primary adrenocortical insufficiency) and ACTH dependent Cushing's syndrome.

3. Cortisol

Cortisol is released from the adrenal cortex in response to ACTH. It exerts negative feedback on the release of both ACTH and CRH. 

Cortisol exhibits diurnal variation, that is to say, the plasma concentration of cortisol levels vary during a 24 hour period. 

It reaches a zenith (highest point) at around 8 am and a nadir (lowest point) at around 4 am.

Renin-angiotensin system

Aldosterone release is primarily controlled by the renin-angiotensin system.

1. Renin

Renin, a proteolytic enzyme, is released by granular cells of the juxtaglomerular apparatus in response to:

  • Renal artery hypotension 
  • Sympathetic stimulation
  • Reduced sodium levels in the distal tubal

In the blood renin cleaves angiotensinogen into angiotensin I.

2. Angiotensin

Angiotensin-converting enzyme (ACE), found primarily in the vascular endothelium of the lungs, cleaves angiotensin I to give angiotensin II.

Angiotensin II has multiple functions:

  • Stimulates adrenal cortex to release aldosterone
  • Causes vasoconstriction
  • Increases sodium reabsorption
  • Stimulates the release of anti-diuretic hormone (ADH)
  • Increases sympathetic permissiveness

3. Aldosterone

Aldosterone is a mineralocorticoid released from the zona glomerulosa of the adrenal cortex. It is released in response to:

  • Angiotensin II (primary stimulus)
  • ACTH
  • Potassium levels

Its primary action is to increase the number of epithelial sodium channels in the distal tubule. 

This results in sodium and water reabsorption and potassium excretion.

Aetiology

Worldwide, the most common cause of adrenal insufficiency is tuberculosis.

Aetiology of addison disease

Autoimmune

The most common cause of adrenocortical insufficiency in the western world is the autoimmune destruction of the adrenal cortex. This is more common in women.

It is suggested that autoantibodies target enzymes involved in the biosynthesis of steroids. One of the main targets for autoimmune destruction is the enzyme 21-hydroxylase. 

Tuberculosis

Tuberculosis is the most common cause of adrenocortical insufficiency worldwide. This is the setting in which Thomas Addison first described the condition.

Other (rare)

The remaining causes of Addison's disease are uncommon. In Waterhouse-Friderichsen syndrome adrenal haemorrhage occurs secondary to meningococcal septicaemia.

Infiltrative disease as a result of malignant metastasis or amyloid deposits may cause adrenal insufficiency.

Bilateral adrenalectomy is an iatrogenic cause of Addison's disease.

Clinical features

Addison’s disease is often diagnosed late due to its non-specific presentation.

Addison's disease may present with an acute Addisonian crisis or (more commonly) with chronic disease.

Addisonian crisis

An Addisonian crisis is a potentially life-threatening presentation of Addison’s disease. It is caused by a significant deficiency in glucocorticoids and mineralocorticoids. 

It is most commonly seen in secondary adrenal insufficiency as a result of the sudden withdrawal of exogenous steroids.

It may also occur in primary adrenal insufficiency, typically following an acute decompensation where an additional stress (e.g. infection) results in an exacerbation of a pre-existing deficiency.  Bilateral adrenal gland haemorrhage can also result in a crisis.

It presents with symptoms of profound glucocorticoid deficiency. These include dehydration, hypotension and confusion. Blood tests may reveal hyponatraemia and hypoglycaemia.

Chronic disease

The majority of cases present with a chronic, insidious onset. Features may be vague and non-specific with patients complaining of fatigue, anorexia and abdominal pain.

A clinician may detect muscle wasting, examine for postural hypotension and note hyperpigmentation (particularly the mucous membranes and palmer creases).

Investigations & Diagnosis

The diagnosis of Addison’s may utilise both blood tests and stimulation tests.

1. Blood tests

A deficiency in aldosterone may lead to hyponatraemia and hyperkalaemia.

Serum cortisol, measured at 8-9 am (when it should be highest) may be used as a screening tool:

  • < 100 nanomol/L: admit to hospital
  • 100–500 nanomol/L: refer for synacthen test, consider admission if symptoms are severe
  • > 500 nanomol/L: Addison’s is unlikely

2. Synacthen test

This test involves the administration of 250 mg of tetracosactide, a synthetic analogue of ACTH.

Cortisol is then measured at three time points: 0, 30 and 60 minutes following administration. Time of day is not important.

A normal response sees a rise in cortisol to above 500–550 nanomol/L.

Management

The management of adrenal insufficieny involves replacement of deficient hormones.

Glucocorticoid replacement

Glucocorticoids are replaced with hydrocortisone, 15-30 mg/day given in divided doses.

An example regime may be 10 mg in the morning, 5 mg at noon and 5 mg in the evening. Regimes should follow the pattern of work in shift workers (i.e 10 mg dose on waking regardless of time of day).

Mineralocorticoid replacement

Mineralocorticoids are replaced with fludrocortisone, 50-300 mcg

Fludrocortisone is typically used, which has mineralocorticoid activity 125 times that of hydrocortisone. The dose of fludrocortisone can be adjusted to levels of exercise and metabolism.

Addisonian crisis

An Addisonian crisis is a medical emergency requiring prompt recognition and treatment. 

It is managed with IV hydrocortisone (100mg) and IV fluid rehydration. Close monitoring of electrolytes is necessary with ECGs if required.

100mg of hydrocortisone has sufficient mineralocorticoid activity and acutely fludrocortisone is not necessary. Following initial resuscitation, a hydrocortisone/dextrose infusion may be given with a target of 400mg of hydrocortisone  over a 24 hour period. This will need to be reduced over the coming days, specialist input should be sought. 

Patient education

Patients must understand that treatment for Addison’s disease is lifelong. Intercurrent illness requires adjustment of the glucocorticoid dose. For example, a temperature > 37.5oC should prompt a doubling of dose.

Patients should be able to promptly identify an Addisonian crisis as well as carry a steroid card and MediAlert identification.

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