Introduction

Addison’s disease (or Primary Adrenal Insufficiency), is rare endocrine condition; one type of adrenal insufficiency whereby the adrenal glands cease to function and the body no longer produces enough mineralocorticoid or glucocorticoid hormones. In adrenal insufficiency, the hormones that the body no longer produces enough of are:

• Cortisol, aldosterone and DHEA (primary adrenal insufficiency).
• Cortisol and DHEA (secondary adrenal insufficiency).
  

Types of Adrenal Insufficiency:

1. Primary: Diseases of the adrenal gland e.g. Addison’s Disease, Congenital Adrenal Hyperplasia (CAS), Adrenoleukodystrophy
2. Secondary: Diseases of the pituitary gland (ACTH deficiency) or hypothalamus e.g. Hypopituitarism; Craniopharyngioma/other suprasellar tumours; and head injuries
3. Iatrogenic (chronic corticosteroid treatment): e.g. Crohn’s disease, Juvenile arthritis, SLE, Asthma, Nephrotic syndrome, Haemangiomas

Adrenal crisis is a life threatening emergency caused by the adrenal glands inability to produce sufficient cortisol in response to major stress. Between 5% to 10% of all people with diagnosed and treated adrenal insufficiency will experience at least one adrenal crisis per year. There is an uneven distribution in the occurrence of crises, as some people do not experience a single adrenal crisis for decades, while others do so recurrently. The incidence of an adrenal crisis increases with age, especially above 50 years of age.

An adrenal crisis can be precipitated by a significant illness, trauma or stress and/or non-compliance with medications. The most frequent causes of adrenal crises in people with already diagnosed chronic adrenal insufficiency are infections, particularly gastroenteritis (“stomach flu” with diarrhoea and vomiting), pneumonia / lower respiratory tract infections and urinary tract infections. In addition surgery, strenuous exercise, emotional stress, dehydration and accidents can contribute and/or lead to an adrenal crisis. An adrenal crisis usually takes several hours to develop but can occur more quickly. If left untreated, it can be fatal. 

Symptoms

Acute phase

Adrenal Crisis presents with the following signs and symptoms:

• Nausea, vomiting & diarrhoea
• Mottled appearance, peripheral shutdown
• Abdominal pain, weakness
• Low blood pressure, postural hypotension
• High fever
• Hypoglycaemia
• Lethargy, pallor
• Dizziness, mental confusion/loss of consciousness
• Rapid heart rate
• Rarely, patients in adrenal crisis may present with severe psychosis

Note: Any, or all, of the above signs and symptoms may be present

Primary care diagnosis

Patients with adrenal failure typically report overwhelming exhaustion, weight loss, poor appetite and dizziness on standing. Nausea, muscle weakness with cramps, abdominal, joint or back pains are often present. A preference for salty foods and increased thirst/urination are common. Key signs are deepening skin pigmentation, low blood pressure and a drop in blood pressure on standing (postural hypotension; a 20 mmHg drop on standing from a seated position indicates clear postural hypotension). Psychosis is occasionally documented; anxiety or minor depression may be observed accompanying chronic exhaustion.

A family medical history will often identify endocrine or autoimmune conditions linked with Addison’s among the extended family. There are typically:

• Thyroid disorders
• Diabetes
• Premature ovarian failure
• B12 deficiency
• Vitiligo
• Coeliac disease.

Symptoms reported by patients are shown below; few patients report the full complement of symptoms.

• A - Always tired (94%)
• D - Dizzy when standing (79%)
• D - Drop in blood pressure on standing (77%)
• I - Inexplicable weight loss (86%)
• S - Skin colour changes (80%)
• O - Only eating sparingly (anorexia) (76%)
• N - No strength in hand grip or limbs (91%)
• S - Sick or nauseous (73%)

Epidemiology

The occurrence of Addison disease is rare. The reported prevalence in countries where data are available is approximately 40-60 cases per 1 million population and affects males and females in equal numbers. Because cases of Addison’s disease may go undiagnosed, it is difficult to determine its true frequency in the general population. Addison’s disease can potentially affect individuals of any age and whilst almost half of all diagnoses occur outside of the most common age of onset, it usually occurs in individuals between 30-50 years of age.

Risk Factors

Autoimmune (primary) Addison’s is often associated with conditions such as:

• Hypothyroidism (range 43-44%)
• Asthma (13-15%)
• Vitiligo (9-10%)
• Vitamin B12 deficiency (7-9%)
• Type 1 diabetes (5-6%)
• Premature ovarian failure (5-12%)
• Coeliac (3-6%) Disease
• Hyperthyroidism (4-5%)

Adrenal failure may be the first autoimmune condition to manifest; pre-existing associated conditions are more likely in women. In established diabetes, a marked reduction in the insulin requirement can be a warning sign of developing hypoadrenalism. Commencing thyroid replacement in early stage adrenal failure may precipitate hypoadrenal symptoms/crisis, as thyroid hormones increase the metabolic rate and breakdown of thyroid hormone.

Elevated TSH in isolation may be an indicator of hypoadrenalism in an ill patient with extreme fatigue but without the typical features of hypothyroidism, and may return to normal with steroid replacement.

Management

Where the patient shows signs of adrenal crisis – typically, persistent vomiting with profound muscle weakness, hypotension, headache, extreme sleepiness or even coma – the patient should be admitted to hospital as an emergency. Paramedics must ensure the patient is stabilised by a saline infusion (for volume repletion) prior to transfer and preferably also by a 100mg hydrocortisone injection. If too much hydrocortisone is administered during an adrenal crisis, it will do no harm. There is no known toxic dose of hydrocortisone.

Hydrocortisone sodium succinate or hydrocortisone sodium phosphate may be used for injection, but not hydrocortisone acetate (Hydrocortistab) This is a specific slow acting preparation for joint injections.

Complications

Untreated Addison’s disease is universally fatal and the patient may die quite rapidly from adrenal crisis. In adrenal crisis, hypovolaemic shock, cardiac arrest, stroke or other circulatory complications can occur even in young, fit patients; complications from hypoxia may leave the patient permanently disabled. Children with adrenal crisis are particularly susceptible to hypoglycaemia, which can cause permanent brain damage if not quickly reversed. Where the patient has severe hyponaetremia, rapid or over-correction can lead to cerebral oedema or central pontine myelinolysis.

It should be noted that there are a subset of Addison's Disease patients' whom are known as 'ultra-rapid metabolisers' of steroid medication. The cytochrome P450s (CYPs) are a superfamily of oxidative liver enzymes of which the CYP3A subfamily is responsible for the metabolism of approximately 50% of all drugs; in this subset of patients, there is variability in the expression of CYP3A4 enzyme, which can cause unpredictable inter-individual drug responses. These patients typically require up to 3x the normal amount of hydrocortisone in adrenal crisis; these administrations should be spaced 15-20 minutes apart and be given only if the patient remains symptomatic.