Cortisol is the body’s natural steroid (glucocorticoid) which helps maintain blood pressure, blood glucose, sodium balance and suppress inflammation. It is a critical hormone, which, if not replaced when needed could result in a life-threatening adrenal crisis. In this article, we discuss diagnosis, emergency management and discuss steroid-induced adrenal suppression.
Contents
Cortisol and The Hypothalamic-Pituitary-Adrenal Axis
The hypothalamus within the brain secretes Corticotrophin-Releasing-Hormone (CRH) which triggers the release of Adrenocorticotrophic Hormone (ACTH) from the pituitary gland. ACTH results in the secretion of Cortisol from the adrenal cortex with a negative feedback loop to prevent the cycle from escalating out of control.
Cortisol is diurnal – the highest levels are found shortly after waking with nearly undetectable levels when deeply asleep. Its effects of reducing inflammation in a diurnal way are why asthma symptoms tend to be worse at night.
When undergoing physical stress, such as injury, infection, surgery, sepsis or labour, the body needs to produce a much higher amount of cortisol. If the body is unable to do this, this can lead to fatal insufficiency termed an adrenal crisis (or sometimes Addisonian crisis).
Adrenal Insufficiency
Primary insufficiency is when the adrenal gland itself is unable to produce cortisol. This is typically due to autoimmune destruction and also affects the production of other adrenal hormones like aldosterone. Without negative feedback, ACTH levels will rise trying to encourage the production of cortisol. The combined lack of cortisol and aldosterone makes hypotension and hyponatraemia more profound and the latter results in hyperkalaemia.
Secondary adrenal insufficiency is caused by the lack of ACTH which may be due to a pituitary adenoma, pituitary apoplexy or Sheehan’s syndrome. By far the most common cause is exogenous steroids, where long-term negative feedback caused by exogenous steroids reduces the production of ACTH and thereby cortisol – this is termed adrenal suppression. It may take weeks, months or even years for the HPA axis to recover. Exogenous steroids causing adrenal suppression could be due to topical steroid creams, steroid inhalers or sprays, steroid injections or swallowed. Steroids with a longer duration of action such as dexamethasone or prednisolone tend to be worse.
Presentation of an Adrenal Crisis
Presentations of adrenal insufficiency can be really subtle, gradual and are often overlooked with other diseases considered first. It is important to suspect this in any patient with any of the following features:
- Hypotension or vasodilatory shock
- Extreme fatigue, weakness or confusion
- Hypoglycaemia
- Hyponatraemia (hyperkalaemia may co-exist in those with primary adrenal insufficiency due to concomitant loss of aldosterone)
- History of steroid use
- Cerebral disease close to the pituitary or hypothalamus or adrenal disease
Other symptoms or signs may include abdominal pain or skin hyperpigmentation in primary adrenal insufficiency (due to increased production of a precursor of ACTH). Patients may carry a steroid warning card or steroid bracelet to help alert healthcare professionals.
Diagnosis of Adrenal Insufficiency
Measuring the ACTH & Cortisol can help confirm the diagnosis, but waiting for a confirmed diagnosis should never delay time-critical, life-saving treatment.
In the context of an emergency or an unwell patient, we send off a random cortisol because a significantly unwell patient should have a high cortisol. If routine tests are being used to ascertain whether hypocortisolism is a possibility, it is more helpful to send an early morning cortisol when the cortisol is expected to be highest. This is far better at both ruling in and ruling out the diagnosis.
We sometimes use a Short Synacthen Test (SST) where synthetic ACTH (usually tetracosactide) is injected to stimulate the adrenal glands. We measure the cortisol before and after to see whether the adrenal glands are able to produce cortisol in response to an instruction to make it. This is very helpful in primary adrenal insufficiency where the adrenal glands cannot produce cortisol. It is far less helpful in ACTH deficiency, as you’re simply giving the hormone they’re lacking and thus you may get a normal short synacthen test. Long-term ACTH deficiency causes the adrenal glands to atrophy over months and in this context, you would get an abnormal response on the SST. Given exogenous steroids is the most common cause of adrenal insufficiency which frequently has a normal SST, the SST is not a perfect test and other more specialised tests may be preferred.
It is also important to check TFTs as hyperthyroidism can increase the metabolism of cortisol and secondary hypothyroidism raises the possibility of secondary adrenal insufficiency.
Emergency Management
The main principle of treatment is to give the body the lifesaving steroid it can’t produce itself. Very large doses of hydrocortisone are used which also stimulates the mineralocorticoid/aldosterone receptor which more potently fixes the salt-water losing crisis & hypotension.
- Immediate administration of a steroid. The Society for Endocrinology recommends a bolus of 100mg IV (or IM Hydrocortisone if in the community)
- Aggressive rehydration with IV fluids to maintain blood pressure
- An infusion of 200mg of Hydrocortisone over the next 24 hours or 6 hourly administration of 50mg of hydrocortisone usually intramuscularly (or intravenously). Intramuscular steroids are preferred as with intravenous preparations the hydrocortisone wears off at around 4 hours which can lead to significant hypotension.
- Once recovered, with senior endocrinology input, the patient may then begin to taper their steroid dose
Non-Emergency Management
Patients are often started on replacement steroids that vary up to 20mg of hydrocortisone (10mg on waking, 5mg at midday, 5mg at 6pm) or 5mg of Prednisolone once daily. Further blood tests are done to assess whether this is the right dose for the patient and adjustments may be made. For those with aldosterone deficiency (primary adrenal insufficiency), fludrocortisone is additionally given to prevent the loss of salt & water.
In illness, steroid doses are usually doubled as per sick day rules. This could mean Prednisolone 5mg is doubled to 5mg BD or Hydrocortisone is doubled to 20mg, 10mg, 10mg. Patients on doses of Prednisolone exceeding 10mg rarely need to increase any further unless in need of emergency management as above for major illness or surgery.
Sick Day Rules
Adrenal Crises can be avoided through the following two simple rules:
- Patients with adrenal insufficiency should double their dose of steroids when they’re sick or anticipating stress. This will help them meet the increased cortisol demands of the illness or surgery.
- Patients who are suddenly unable to absorb their steroids – due to being Nil By Mouth, diarrhoea or vomiting – should be switched immediately to IV or IM alternatives.
Ensure that patients are provided with an emergency pack allowing them to self-administer hydrocortisone in an emergency, a steroid card and/or bracelet and finally the Society for Endocrinology “Steroid Sick Day Rules” leaflet providing them with detailed advice.
Steroids: Adrenal Suppression & Weaning
It is important to acknowledge that patients should not develop adrenal insufficiency unless on lower than the equivalent physiological requirements. In the well patient, this is 5mg Prednisolone, 0.5-0.75mg Dexamethasone, 20mg Hydrocortisone in divided doses and in the unwell patient as per sick day rules, it is approximately double this dose.
Given this, a patient on 100mg of Prednisolone could wean immediately to 5 or 10mg (depending on their physiological needs) from the perspective of adrenal insufficiency without a risk of an adrenal crisis. Of course, this wouldn’t be the case if undergoing major surgery or illness (see “Emergency Management” above) – typically the weaning regime is defined by the disease process for which the steroids are indicated. For example, slow weaning in asthma to reduce the risk of a flare.
After that though, it is difficult to know exactly which patients require a slow wean to allow time for the HPA axis to recover and hence this really requires discussion with the endocrine team. Often early morning cortisol measurement after steroid cessation can guide the degree of HPA recovery and non-emergency dosing (see above) can be used with regular assessments of cortisol with further weaning once recovery occurs. Hydrocortisone is often used when assessing this as its short duration of action means minimal steroid levels overnight providing time for the HPA axis to recover.
Further Reading
Written by Dr Glen Davies (SHO) with edits by Dr Akash Doshi (Endocrinology & Diabetes Registrar)
