Hypoadrenalism (underactivity of the adrenal glands)

Written by Shern Chew, consultant endocrinologist

What is the course of hypoadrenalism?
Autoimmune Addison's disease is chronic (ie long-standing), and antibodies to the adrenal cortex may be detected in a person's blood many years before damage to the adrenal cortex is apparent.

There is no evidence that treatment can prevent this autoimmune attack, which may also affect other organs in the same person. Thus, people suffering from Addison's disease are at increased risk of other organ-specific autoimmune diseases including vitiligo, autoimmune thyroid disease, pernicious anaemia, and hypoparathyroidism.

Patients with autoimmune diseases are also at increased risk of coeliac disease.

Who is affected?
Primary hypoadrenalism is relatively rare, for example it is found in about 6 in every 100,000 people in the North East Thames region.

Much more common is ACTH deficiency caused by the intake of cortisol-like steroids for conditions such as asthma.

Cortisol is required as part of the body's response to physical stress (eg emergency surgery). Failure to diagnose hypoadrenalism in an ill patient may lead to collapse and death.

What are the symptoms of hypoadrenalism?
The onset of symptoms in Addison's disease is usually subtle. Patients often feel faint and dizzy, and often experience weakness, fatigue and weight loss. At least 50 per cent of patients complain of vague stomachaches or other gut symptoms.

Increased pigmentation of the skin (like a sun tan) is common in Addison's disease. Some patients will have a persistent tan long after a holiday. This is due to raised ACTH levels, which stimulate pigment cells (melanocytes) in the skin.

Patients occasionally suffer mental problems, including depression. Some suffer joint and muscle pain. Very rarely, bleeding into the adrenal glands (see Figure 1 in appendix) causes acute severe back pain. This symptom should be particularly investigated in patients receiving anticoagulants, such as warfarin, which prevent blood clots. In some severe infections, particularly meningococcal septicaemia, bleeding may occur into the adrenal glands. The loss of cortisol results in hypotension (low blood pressure) that fails to respond to catecholamine hormones and medications (eg noradrenaline).

How is Addison's disease diagnosed?
The pigmentation of Addison's disease is characteristic, and is particularly evident on exposed or traumatised areas of the skin, such as the knuckles and elbows. Occasionally, the inner wall of the cheek, which is frequently bitten, also shows pigmentation. Any scars inflicted after the onset of the disease become pigmented.

Patients may also have signs of organ-specific autoimmune disease. These include patches of abnormal pale skin called vitiligo and sometimes evidence of thyroid disease, such as a goitre (swelling of the neck). Blood pressure control is abnormal in severe cortisol deficiency. The patient may have an abnormal fall in blood pressure on standing (called postural hypotension). The highest blood pressure in Addison's disease is usually less than 110mmHg. Very low blood pressure is a sign that the patient is in imminent danger of collapse.

A doctor suspecting Addison's disease will perform blood tests. Patients with a severe deficiency of cortisol and the related hormone aldosterone, often have a low sodium level and an increased potassium level. (However, potassium may be normal in 40 per cent of patients.) A high calcium level is also seen about 10 per cent of patients.

Sometimes the blood sugar is low, although this is rare except in children, or in patients who have been undernourished for long periods, eg after major surgery. During acute illness, a cortisol level of less than 500nmol/l may be consistent with hypoadrenalism, while a level of less than 200nmol/l is highly abnormal and strongly supports the diagnosis. A level of 550nmol/l or above excludes the diagnosis.

A blood count will show raised eosinophils (a type of white blood cell), and may reveal abnormally large red cells (macrocytes) because of co-existing pernicious anaemia. Blood tests should be carried out for thyroid function, vitamin B12, folate, iron and antibodies to other organs (thyroid, gastric parietal cells, endomysium) to check for associated autoimmune diseases.

Specialist investigations, usually performed by an endocrine unit, may include a measurement of other adrenal hormones including ACTH, aldosterone, plasma renin activity, noradrenaline and adrenaline and Synacthen tests.

In primary hypoadrenalism the ACTH level is usually greater than 80ng/l (high), because the pituitary gland tries to correct the cortisol deficiency by increasing the stimulus to the adrenal. If ACTH deficiency is due to pituitary disease or steroid suppression, the ACTH level is undetectable (generally less than 10ng/l).

In Synacthen tests synthetic ACTH is injected into a vein and blood is then drawn to measure the cortisol response. The 'low dose' (250 micrograms) or 'short Synacthen test' will be abnormal in any cause of hypoadrenalism. High doses of Synacthen (1mg), especially given over several days, often produce a normal cortisol level in patients with ACTH deficiency, whereas those with primary hypoadrenalism experience no rise.

Additional investigations should include a chest X-ray to check for tuberculosis. In some cases a CT scan of the adrenals may be performed to look for calcium deposits (a sign of tuberculosis). A skin test for tuberculosis may also be performed.

What else could it be?
Some patients with undiagnosed Addison's disease have been misdiagnosed as having an abdominal disease such as appendicitis. After operation a correct diagnosis may be reached because the scar turns brown and the appendix is normal.

The main problem with diagnosis is that hypoadrenalism is simply not considered. Once hypoadrenalism is confirmed, there may be diagnostic problems related to the underlying cause of the adrenal failure. In this case further specialist tests may be needed to narrow down the cause.

What can your family doctor do?
Your GP can take blood for electrolytes (salt balance), kidney function, and cortisol level. Hydrocortisone replacement for cortisol may be started immediately after a blood sample is taken. A referral will be made to a specialist endocrine unit.

What can you do yourself?
Treatment is almost always life long. Failure to comply with treatment may be fatal, so patients with hypoadrenalism must take some simple precautions. The main problem is that the need for cortisol increases during physical stress, eg major surgery.

All patients would be advised to carry a warning card stating their condition and explaining that they are dependent on adrenal replacement. This may save their life in the event of coma or collapse.

Patients with Addison's disease should also keep extra supplies of tablets at home or when on holiday, as well as a vial of hydrocortisone that they can inject. Any medical professional can administer this if the patient is unconscious or unable to take oral medication.

What can your specialist do?
The best replacement therapy for cortisol is oral hydrocortisone. This is very similar to normal cortisol, and the level is easily measurable in the blood.

The correct level of cortisol can be checked by taking blood samples before the first hydrocortisone tablet of the day and then at regular timed intervals after the tablets, called a 'hydrocortisone day curve'.

Samples should be taken into the early evening.

The aim is to keep the cortisol level high in the morning (but not more than 1000nmol/l), and lower in the afternoon and evening (between 100 and 300nmol/l). This mimics the normal swing in cortisol level of the body during the day. The usual dose is 10mg taken on waking, 5mg before lunch and before the evening meal.

Other corticosteroids may be used, including cortisone acetate, prednisolone and dexamethasone. However, it is difficult to judge the correct dose of prednisolone and dexamethasone. This may lead to the complications of long-term steroid treatment including avascular hip necrosis (destruction of the round head of the femur which forms the hip joint), osteoporosis, worsening of diabetes mellitus and hypertension. Cortisone acetate must be converted by the body into an active steroid, and the efficiency of conversion may vary between patients.

Most patients with primary hypoadrenalism are deficient in another adrenal cortex hormone called aldosterone. This requires replacement with a synthetic form of aldosterone called fludrocortisone. The usual dose is 100 micrograms as a single tablet taken on waking.

The main hormone produced by the central part of the adrenal glands (the medulla) is adrenaline (a catecholamine) and this is not usually replaced as other catecholamine hormones are secreted from the rest of the sympathetic nervous system (of which the adrenal medulla is a component).

Someone taking adrenal replacement therapy should double the dose of hydrocortisone for 48 or 72 hours if he or she develops an illness with fever or mild diarrhoea and vomiting. An injection of hydrocortisone into a muscle (intramuscular) or vein (intravenous) is required for the biological stress of a major illness or surgery.

All patients should be followed up at least annually at a specialist endocrine clinic, and should have 24-hour access to specialist advice and treatment.

What is the likely outcome?
With appropriate treatment and monitoring, life expectancy and quality of life are normal.

Figure 1: CT scan showing bleeding within the adrenal glands, causing hypoadrenalism
The patient depicted in Figure 1 suffered an adrenal haemorrhage eight days after major surgery.

Anticoagulants ('blood thinning drugs') had been given to prevent clots in the veins following the operation (deep vein thrombosis). The main symptom was pain in the back and upper abdomen.

The patient developed low blood glucose levels 14 days post operatively. The diagnosis was confirmed by an undetectable serum cortisol level and a CT scan of the abdomen showing enlarged adrenal glands (arrows) with abnormally high signal intensity consistent with the presence of blood. (L indicates the liver, and S the spleen).

Figure 2: Contents of the bathroom cabinet of a patient with hypoadrenalism due to ACTH deficiency
A patient was referred with tiredness and an undetectable cortisol level.

Our investigations revealed an undetectable ACTH level. There was no clinical evidence of pituitary disease, the rest of the pituitary hormones were normal and a MRI scan of the pituitary gland was normal.

The patient denied steroid use, but did use various skin creams. When asked to bring all the creams into the hospital, a steroid-containing skin cream was found (arrow). The patient had used this cream as an acne cure and the steroids in the cream were suppressing ACTH.

Three months after ceasing use of the steroid cream the patient had a normal serum cortisol level and a normal response to a Short Synacthen test.

Figure 3: Addison's disease caused by tuberculosis
The patient had vomiting and abdominal pain for several weeks. The serum cortisol was undetectable and the plasma ACTH was high.

Photograph 3A shows pigmentation of skin creases (arrow).

Photograph 3B shows patchy pigmentation on an elbow (arrows). The tubing for the patient's blood tests is also seen.

A CT scan of the abdomen showed both adrenals were enlarged and contained specks of calcium (3C, arrows). This is highly suggestive of tuberculosis affecting the adrenal glands. The tuberculin skin test for tuberculosis was strongly positive.

A full course of anti-tuberculosis drugs was started. Anti-tuberculosis drugs increase the breakdown of hydrocortisone, making careful assessment of the hydrocortisone levels in the blood essential to proper replacement. (Pictures shown with the full consent of the patient).

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