Addison's disease

Adrenal failure causing glucocorticoid and mineralocorticoid insufficiency. The diagnosis typically refers to auto-immune destruction of the gland, and is confirmed using a Synacthen test.

Baseline investigations - all patients

Full blood count

Normocytic normochromic anaemia and eosinophilia may be seen with glucocorticoid deficiency.

Iron deficiency anaemia is a warning sign of possible malignancy and demands thorough investigation.

Serum B12, ferritin and red cell folate

Anaemia of any cause may mimic or complicate the symptoms of Addison’s disease and so should be excluded at diagnosis.

B12 deficiency may indicate associated pernicious anaemia or coeliac disease.

Urea and electrolytes

Hyperkalaemia and hyponatraemia are typical in glucocorticoid deficiency.

Liver function test

Liver function is a useful indicator of general health, and a simple screen for underlying disease or malignancy.

Bone profile

Hypercalcaemaia may occur with glucocorticoid deficiency of any cause, but frequently occurs with malignancy.

Fasting or random glucose

Hypoglycaemia may occur in glucocorticoid deficiency.

9am or random cortisol

Random cortisol levels should be taken in the acutely unwell patient in whom glucocorticoid deficiency is suspected immediately before emergency treatment commences.

In the sub acute patient, a synacthen test should be performed before treatment starts.

In non acute presentations, a waking cortisol is worth checking in the first instance as this may rule out Addison’s disease alone as recent studies have confirmed that levels above 500nmol/l exclude glucocorticoid deficiency. Levels below 100nmol/l are strongly associated with glucocorticoid deficiency, and so patients should be started on treatment immediately unless a synacthen test can be performed at the time.

Patients with serum cortisol levels below 500nmol/l and a strong clinical suspicion of glucocorticoid deficiency should proceed to a synacthen test of adrenal reserve.

Ensure patients have stopped sex steriod therapy, for example HRT or the combined oral contraceptive pill for six weeks prior to test. Estrogen replacement therapy leads to elevation of cortisol binding globulin, and hence serum cortisol, and so is difficult to interpret.

Thyroid stimulating hormone, free thyroxine

Patients presenting with lethargy and hyponatraemia may in fact have hypothyroidism rather than Addison’s disease - thyroid function testing is thus mandatory.

Auto-immune thyroid dysfunction is also more common in patients with Addison’s disease and so thyroid function should be screened annually in such patients.

Glucocorticoid deficiency may also be the first presentation of pituitary disease. For this reason, it is essential to assess both TSH and thyroxine as a normal TSH level does not indicate normal thyroid function in patients with pituitary disease.

Adrenal and thyroid auto-antibody screen

Auto-immune thyroid dysfunction is commonly associated with Addison’s.

Multiple different tests for auto-antibodies are available, with varying levels of sensitivity. Sensitive adrenal antibody testing can be extremely helpful in elucidating the cause of suspected adrenal failure, though assays vary in their utility. Similarly, thyroid peroxidise antibodies are commonly used as an initial screen, and if positive, mandate annual thyroid function.

Coeliac auto-antibody screen

Tissue transglutaminase and anti gliadin antibodies should be checked if there is clinical suspicion of coeliac disease.

Electrocardiogram

ECG should be performed in all patients at baseline, to document and confirm any arrhythmias, for example due to hyperkalaemia or other changes.

Glycosylated Haemoglobin and fasting glucose and lipids

Patients on glucocorticoid replacement therapy have an elevated mortality due to an excess of cardiovascular deaths, and so should be aggressively screened and treated for cardiovascular risk factors. Patients with Addison's disease are also at incresed risk of developing type 1 diabetes mellitus.

Further investigations - selected cases only

Short synacthen test

This must be performed if there is clinical or biochemical suspicion of Addison’s disease. However, a documented serum cortisol above 590nmol/l obviates the need for a synacthen test.

Treatment should not be deferred while awaiting a synacthen test in the acutely unwell patient. In this instance, a random cortisol should be tested as treatment commences.

The long term decision on treatment should be revisited when the patient has recovered sufficiently to safely withdraw replacement therapy in order to reassess with a synacthen test.

Chest radiograph

This should be performed at diagnosis if there is any possibility of malignancy and adrenal metastases as the cause of glucocorticoid deficiency.

Hydrocortisone day curve

This tests serum levels of cortisol before and after each hydrocortisone dose.

A typical and ideal peak is to approximately 500nmol/l one hour post the first dose, wih troughs between 50-150nmol/l prior to the second and third doses with complete resolution of symptoms.

ACTH

Serum ACTH levels may be very useful at diagnosis to exclude glucocorticoid deficiency due to pituitary disease or exogenous steroid use.

This can be usefully performed at the start of a synacthen test, or prior to the waking hydrocortisone dose in patients already on therapy. This is also useful in the monitoring of patients on treatment by testing before, and 120 minutes after, the morning dose of hydrocortisone.

Plasma renin activity

It is useful to monitor renin activity prior to, and 120 minutes post, dose with once daily fludrocortisone at the start of treatment to guide dose titration.

Bone densitometry

Bone mineral density should be assessed where there is clinical suspicion of osteoporosis in patients with other risk factors, for example on long term glucocorticoid replacement therapy.

Vitamin D levels

Patients with coeliac disease may well have low serum vitamin D levels.

In patients with known or suspected osteoporosis, serum vitamin D levels will guide whether routine calcium and vitamin D supplementation is enough, or whether specific high dose vitamin D replacement is required.