Adrenal Insufficiency

Fig.1: Pigmented face of primary adrenal insufficiency (illustration from Addison's 1855 book On the constitutional and local effects of disease of the supra-renal capsules.)Adrenal insufficiency occurs when the adrenal glands produce inadequate amounts of the hormones cortisol, and on occasions, aldosterone. It can be divided into primary, secondary and tertiary types:

1. Primary adrenal insufficiency (Addison's disease)
   - results from damage to or dysfunction of the adrenal gland itself; it occurs in 1 in 100,000 people, affecting slightly more women than men
2. Secondary adrenal insufficiency
   - results from inadequate pituitary ACTH secretion resulting in low cortisol release
3. Tertiary adrenal insufficiency
   - results from inadequate CRH release from the hypothalamus and the resultant decrease in ACTH release.

Primary adrenal insufficiency is clinically distinct from secondary and tertiary insufficiency.

In primary insufficiency there is a decrease in both mineralocorticoids (aldosterone) and glucocorticoids (cortisol), whereas in secondary and tertiary insufficiency the aldosterone levels are virtually normal as the zona glomerulosa is largely independent of ACTH (see webpage on adrenal Function).

Causes

Primary Adrenal Insufficiency (Addison's Disease)

• autoimmune diseases (most common cause - 80%)
  - approximately 50% of patients with autoimmune adrenal insufficiency have one or more other autoimmune endocrine disorders, whereas patients with the more common autoimmune endocrine disorders, such as type 1 diabetes mellitus, Hashimoto's autoimmune thyroiditis, or Graves' disease, rarely develop adrenal insufficiency. The combination of autoimmune adrenal insufficiency with other autoimmune endocrine disorders is referred to as the polyglandular autoimmune syndromes types I and II
  
• infectious diseases (e.g. TB, fungal infections & HIV)
• haemorrhage, often as a result of anticoagulant therapy
• meningococcal septicaemia (Waterhouse-Friderichsen syndrome) - septicaemia followed by adrenal haemorrhage & failure
• metastatic malignancies (spread of cancers e.g. lung or breast cancer to the adrenal gland)
• surgical removal of both adrenal glands
• drugs (e.g. ketaconazole, aminoglutethimide or metyrapone)
• rare hereditary diseases

Secondary and Tertiary Adrenal Insufficiency

• suppression of the adrenals after long-term use of steroids (most common cause)
• following the cure of Cushing's syndrome
• hypothalamic or pituitary lesion (e.g: tumours, trauma, surgery or radiation)

Symptoms

The symptoms of adrenal insufficiency depend on the degree of loss of adrenal function and whether mineralocorticoid production is preserved. The onset of adrenal insufficiency is often gradual and may go undetected until an illness or other stress precipitates an adrenal crisis. Clinically, adrenal insufficiency is divided up into acute and chronic.

Acute Primary Adrenal Insufficiency - Adrenal Crisis

Adrenal or Addisonian crisis may result from an acute exacerbation of chronic insufficiency, usually precipitated by serious infection or surgical stress. This can occur if a previously diagnosed  Addisonian patient does not increase their glucocorticoid replacement during a major illness.

The major symptoms of a patient with acute adrenal primary insufficiency are:

• Shock
• Anorexia
• Nausea & vomiting
• Abdominal pain
• Lethargy & weakness
• Confusion
• Hypotension
• Hyperpigmentation

The most important underlying factor in the precipitation of adrenal crisis is aldosterone deficiency and the main clinical problem is hypotension (low blood pressure). Adrenal crisis is rare in patients with secondary or tertiary adrenal insufficiency because the renin-angiotensin system functions normally.

Chronic Adrenal Insufficiency

Patients with chronic primary adrenal insufficiency have clinical signs and symptoms of glucocorticoid, mineralocorticoid and androgen deficiency. Patients with secondary or tertiary adrenal insufficiency usually maintain mineralocorticoid function.

The clinical features of chronic adrenal insufficiency usually have an insidious, slow onset with many non-specific symptoms. The most common signs and symptoms of chronic primary adrenal insufficiency are listed below:

• Lethargy & weaknessFig.2: Hyperpigmentation of face and armpits (illustration from Addison's 1855 book On the constitutional and local effects of disease of the supra-renal capsules.)
• Nausea & vomiting
• Abdominal pain
• Anorexia & weight loss
• Hypotension
• Hyperpigmentation - occurs on the exposed areas of the body, points of friction or in palmar creases (Fig. 2). Pigmentation is also seen in the buccal mucosa (the lining of the mouth), in scars and in the conjunctivae (the lining of the eye). It is caused by excessive melanin production in the skin due to the melanocyte-stimulating hormone (MSH) produced in the pituitary.

The clinical features of secondary adrenal insufficiency are similar to those above except that hyperpigmentation is not present (as ACTH and MSH are not elevated).

Diagnosis

As with most endocrine problems the important steps are:

• to establish the diagnosis of hypoadrenalism (adrenal insufficiency)
• to establish the cause to enable the appropriate treatment decisions to be made

1. Confirmation of the biochemical diagnosis of hypoadrenalism

The diagnosis of adrenal insufficiency depends on demonstrating an inappropriately low adrenal cortical hormone level.

• Measurement of Basal Cortisol Secretion
  A low plasma cortisol level (<140nmol/L) in the morning is evidence of adrenal insufficiency. Plasma cortisol levels exhibit diurnal variation (Fig. 3) and are normally high in the early morning and increase with stress.
  Fig.3: Normal diurnal variation of serum cortisol
• Response to ACTH Stimulation
  An impaired response in a low dose ACTH stimulation test (Synacthen Test), using the ACTH analogue Tetracosactrin confirms adrenal insufficiency. A normal response is a rise in plasma cortisol levels after 30-60 minutes.

2. Distinguishing between primary, secondary and tertiary adrenal insufficiency

In primary adrenal insufficiency, basal early morning plasma ACTH concentrations are elevated compared to the low normal levels found in secondary and tertiary disease.

Primary adrenal insufficiency can also be distinguished from secondary and tertiary by using a prolonged ACTH stimulation test. Stimulation of the adrenal gland in primary disease will not result in the release of cortisol. In secondary and tertiary insufficiency the atrophic adrenal glands still produce some cortisol when exposed to ACTH.

Secondary can be distinguished from tertiary adrenal insufficiency by monitoring the ACTH response to stimulation with CRH (CRH stimulation test). There is little or no ACTH response in patients with secondary adrenal insufficiency, but there is a significant ACTH response in patients with tertiary adrenal insufficiency.

3. Establishing the cause of this insufficiency

This is done by considering the following:

• Patient age (certain causes are more prevalent at certain ages)
• Other autoimmune disorders (indicates probability of an autoimmune cause)
• CT scan of adrenals
• CT or MRI scan of pituitary (if secondary / tertiary disease suspected)
• CXR (for suspected TB)
• Drugs

Treatment

There are different treatment protocols depending on the nature of the insufficiency.

Acute Adrenal Insufficiency: ADRENAL CRISIS

Adrenal Crisis is a life-threatening emergency that requires immediate treatment.

The first stage is to treat the hypotension (low blood pressure) and correct the electrolyte abnormalities. Large volumes (2-3 litres) of saline (or dextrose in saline) should be given intravenously without delay.

Hydrocortisone (converted by the body to cortisol) or dexamethasone is immediately injected intravenously to replace the cortisol. After the initial management, the precipitating cause can be treated. In primary adrenal insufficiency, mineralocorticoid replacement using fludrocortisone, is also given when the patient is stable.

Once the patient's condition is stable, and the diagnosis has been confirmed, parenteral glucocorticoid therapy should be tapered over 3-4 days and converted to an oral maintenance dose. Patients with primary adrenal insufficiency will then require lifelong glucocorticoid and mineralocorticoid replacement therapy.

Chronic Primary Adrenal Insufficiency

The patient's own management of the disease is the key to successful treatment, so patient education is vital. At all times a medical alert bracelet should be worn with an emergency medical card indicating the diagnosis and daily medications. The patient can lead a normal active life, but must take precautions against an emergency situation.

The aim of the therapy is to replace the glucocorticoids (with hydrocortisone or dexamethasone) and in some cases mineralocorticoids (with fludrocortisone). Higher doses of glucocorticoids are given during times of illness or major stress (e.g. surgery) to prevent Addisonian crisis.

Chronic Secondary and Tertiary Adrenal Insufficiency

The treatment of secondary and tertiary adrenal insufficiency is identical to that of primary adrenal insufficiency except that mineralocorticoid replacement is rarely required.