Contents
Introduction
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.
Primary hypoadrenalism
Epidemiology
- 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.
Aetiology
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
Pathology
Presentation
It often presents as unexplained; fatigue, hyponatremia and hypotension. Other symptoms may include weight loss, anorexia, myalgia, dizziness, fainting. There may also be low self-esteem and depression.
In some cases an addisonian crisis occurs, whereby there is severe hypotension and dehydration, often with a precipitating event such as illness or trauma. In this case, the administration of a glucocorticoid is necessary, but the administration of sodium is more important than giving an aldosterone replacement. Features of an addisonian crisis include:
- Precipitating event – trauma, infection, surgery
- Hypotension
- Hypovolaemic shock
- Fever
- Vomiting
- Abdominal pain
In the chronic presentation, features may include:
- Features often insidious in onset and mild
- Fatigue and weakness
- Nausea
- Vomiting
- Anorexia
- Weight loss
- Abdominal pain
- Change in bowel habit
- Craving for salty foods
- Irritability
- 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.
Investigations
Sodium levels may be low (hyponatremia) and potassium levels will be high (hyperkalemia) due to low mineralocorticoids. Glucose may be low due to low cortisol levels. These features may only be present in advanced disease.
Indicated tests include:
- U+E
- Sodium low in 90%
- Potassium high in 50%
- Calcium raised in 10-20%
- Glucose
- 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.
Once the diagnosis has been made, consider a multiple endocrine disorder – e.g. polyglandular autoimmune syndrome (and involve an endocrinologist!)
Management
If hypoadrenalism is suspected, and the patient is hypotensive you should give 100mg hydrocortisone and saline immediately without confirmation of diagnosis.
- 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.
Once the patient is stable, oral doses of hydrocortisone can be given. Initially every 8 hours, 2-3 times a day.
- You should avoid giving it at night as it can induce insomnia.
Long term – treatment involves replacement glucocorticoids and mineralocorticoids. Also if TB is suspected then this should also be treated. Glucocorticoids should be monitored by restoration of suitable, but not excessive weight, and also by checking cortisol levels during the day. Mineralocorticoid (fludrocortisone) levels should be monitored by checking serum electrolytes, blood pressure (and response to posture), and suppression of plasma renin to normal levels.
Note that in severe hyponatraemia you should not normalise the levels of sodium too quickly or you may cause demyelination.
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
Patients need to be educated on the use of long-term steroids. They should carry a steroid card, or wear a bracelet. Patients should know to increase steroid therapy during times of illness (usually dose is doubled). Patients also need to know they should increase their dose of hydrocortisone by 5-10mg a day before strenuous exercise. They should also keep an injectable form of hydrocortisone at home in case they are unable for any reason to take an oral dose, in case of emergencies.
A very poor response to treatment suggests an associated autoimmune disease.
Glucocorticoid Therapies
Glucocorticoids are used to manage many non-endocrine diseases – for example – the use of steroids in COPD or asthma exacerbations.
In the short term (3 weeks or less) and / or in small doses (less than 10mg/day prednisolone) then this is usually not an issue. However, problems arise when patients are subjected to long-term therapy.
Essentially, long-term steroid use will mimic endogenous Cushing’s syndrome.
Essentially, long-term steroid use will mimic endogenous Cushing’s syndrome.
The use of any type of glucocorticoid (inhaled, systemic, etc) can affect the HPA (hypothalamic-pituitary-adrenal) axis. Generally, the longer the treatment, and the more systemic its effects, the more likely the HPA is to be affected, and the longer it will take to recover when treatment is stopped
You should never withdraw treatment suddenly.
You should never withdraw treatment suddenly.
The need for steroids needs to be constantly re-assessed due to their serious side effects. Wherever possible use the lowest dose or consider alternative drugs.
Side effects of long-term use of steroids include:
Review
Patients should have annual review including electrolytes and efficacy in treating symptoms. Those with an autoimmune cause should be screened annually for other autoimmune disease, including:
- TFTs
- Glucose and HbA1c
- FBC
- B12
- Consider coeliac screen
Other important factors of annual review are:
- Weight
- BP – including checking for postural drop
- U+E
- Check understanding about increasing doses when sick
- Ask about symptoms that suggest under-treatment
Prognosis
- 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
Secondary hypoadrenalism
This has two major causes:
- Hypothalamic-pituitary disease leading to inadequate ACTH production
- Long-term steroid therapy, leading to hypothalamic pituitary suppression
The second cause is by far the most common, but the disease only tends to become apparent on withdrawal of glucocorticoid therapy.
The first cause is often a result of pan hypopituitarism, and as a result patients may need T4 as well as replacement steroids.
Diagnosis and Management
The same investigations as for primary above, however, special note should be made of the usefulness of the ACTH level.
- 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.
Treatment will be similar to that for Addison’s, or may involve modification of steroid therapies
References
- 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.
