Addison’s disease is the most common form of adrenal insufficiency.
Adrenal insufficiency occurs where there is destruction of the adrenal cortex and reduced output of adrenal hormones. There are two types of adrenal insufficiency:
- Primary hypoadrenalism (aka Addison’s disease)
- Usually due to autoimmune disease
- Secondary hypoadrenalism
- Due to inadequate secretion of pituitary hormones and thus reduced stimulation of the adrenal glands
In primary hypoaldosteronism conditions, there is destruction of the adrenal cortex. The presentation is notoriously varied and vague. It is potentially fatal if untreated. There will be a lack of secretion of cortisol, aldosterone and sex hormone.
This differs from secondary (pituitary) hypoadrenalism, where aldosterone secretion may remain at normal levels due to stimulation from pituitary independent mechanisms – namely via angiotensin II.
In Addison’s disease, lack of cortisol will lead to feedback induced high levels of CRH and ACTH – and thus induce hyperpigmentation in some cases.
- Addison’s disease is rare – it has an incidence of 3-4 per 1,000,000 per year, and a prevalence of 40-60 per 1,000,000.
- It is more common in women
- Typical age of onset 30 to 50
- >90% of cases are a result of autoimmune disease
- The remainder are mostly a result of TB.
In autoimmune disease:
- 40% of cases solely affect the adrenal glands
- 60% are part of a multiple endocrine immune disorder
- Antibodies against 21-hydroxylase are present in 85% of patients
- Clinical and biochemical signs only occur after destruction of >90% of the adrenal glands
- Precipitating event – trauma, infection, surgery
- Hypovolaemic shock
- Abdominal pain
- Features often insidious in onset and mild
- Fatigue and weakness
- Weight loss
- Abdominal pain
- Change in bowel habit
- Craving for salty foods
- Muscle cramps
- Joint pains
- Pigmentation (dull, slaty brown) is present in over 90% of cases.
- Hypotension as a result of hypovolaemia is present in 80-90% of cases, however, in may cases the hypotension is only postural and systolic.
This hypotension is a result of mineralocorticoid deficiency.
- Sodium low in 90%
- Potassium high in 50%
- Calcium raised in 10-20%
- Often low in children
- Random serum cortisol will often be low, but it can be normal, and so again, you can not use this test diagnostically. However, if random cortisol is very high, it is unlikely to be hypoadrenalism
- Best practice is to take a level at 8-9am when levels will be highest
- Shift work, long term steroids and pregnancy can all alter the result making interpretation difficult
- <100 nmol/L is highly suggestive of Addison’s
- 100 – 150 nmol/L should prompt further investigation
- ACTH stimulation test aka Synacthen test – the patient is given a dose of synthetic ACTH in an attempt to stimulate cortisol production. Ideally you would then take cortisol blood levels at 0 and 30 minutes. The cortisol should rise sharply. Addison’s can be ruled out if the cortisol rises to above 550nmol/L.
- Note that during pregnancy or whist on the oral contraceptive, levels may be falsely high due to raised cortisol binding globulin.
- 0900 levels of ACTH will usually be high in Addison’s disease, but they will be low in secondary hypoadrenalism.
- Adrenal antibodies
- Often used to confirm the cause, once the diagnosis of adrenal insufficiency has already been made. If negative – consider other causes (e.g. TB)
- CXR/AXR – may show evidence of TB and calcified adrenal glands
- CT abdomen – if antibodies negative – to assess anatomy of adrenal glands
- Hypercalcaemia and anaemia
- Serum aldosterone may be low.
- Ideally, you should do this as soon as a measurement of cortisol has been taken.
- Give further 0.9% saline and 6 hourly infusion of 100mg hydrocortisone until patient is stable.
- Also consider glucose if patient is hypoglycaemic.
- You should avoid giving it at night as it can induce insomnia.
Note that in severe hyponatraemia you should not normalise the levels of sodium too quickly or you may cause demyelination.
- Glucocorticoid typical dose – 15-30mg in three divided doses – with the highest dose in the morning. This mimics the normal diurnal rhythm
- Dose increased in times of illness – typically 2-4x in minor illness and up to 10x in serious illness or surgery
- Mineralocorticoid typical dose 50-300mcg per day, varying with activity, weight and metabolism
- Monitor BP – if high, consider reducing dose
- Monitor electrolytes
Essentially, long-term steroid use will mimic endogenous Cushing’s syndrome.
You should never withdraw treatment suddenly.
- Glucose and HbA1c
- Consider coeliac screen
Other important factors of annual review are:
- BP – including checking for postural drop
- Check understanding about increasing doses when sick
- Ask about symptoms that suggest under-treatment
- Untreated, adrenal insufficiency is fatal
- Before synthetic corticosteroids, developed in 1949, all patients with adrenal insufficiency died
- Treatment is lifelong
- Prognosis depends on the underlying cause
- There is an increased risk of mortality due to infection, sudden death and acute renal failure
- Hypothalamic-pituitary disease leading to inadequate ACTH production
- Long-term steroid therapy, leading to hypothalamic pituitary suppression
Diagnosis and Management
- In an ACTH stimulation test the likely result is similar to that of Addison’s disease – i.e. there is not a large enough rise in cortisol.
- An ACTH level is likely to be very high in primary disease, whilst in secondary disease the level is likely to be low.
- Adrenal Insufficiency – patient.info
- Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
- Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.