Adrenal insufficiency: a review

Endocrine emergencies are commonly encountered by both primary care and prehospital clinicians, with diabetic presentations such as hypoglycaemia or hyperglycaemia considered routine (Savage et al, 2004). While most clinicians will feel comfortable in managing a diabetic emergency, other endocrine emergencies are more complex to manage because of both the rarity of presentations and a lack of reliable diagnostic and management tools available in the prehospital setting (Savage et al, 2004).

Of relevance to paramedic practice is that adrenal crisis is one of the two endocrine emergencies in which a patient may be pharmacologically stabilised under the UK ambulance services clinical practice guidelines (Association of Ambulance Chief Executives (AACE), 2019).

The mortality rate of established episodes of adrenal crisis is approximately 0.5–2%; however deaths are often preventable, and occur in relatively young patients because of delayed or insufficient steroid replacement (Amrein et al, 2018).

Adrenal insufficiency is a chronic endocrine disorder and precursor to adrenal crisis, and is generally managed collaboratively by primary care physicians and endocrinologists (Iqbal et al, 2019).

Responding to increasing pressures within both general practice and emergency departments, paramedic practice has evolved to work in a ‘see and treat’ model of care in which long-term conditions are increasingly encountered (Heaney et al, 2020). The transformation in prehospital care follows recommendations initially outlined in the Bradley report (Department of Health and Social Care, 2005) and aligns with objectives of the NHS England (2014) Five Year Forward View.

As a result of these recommendations, there has been an expansion in specialist and advanced paramedic roles within UK ambulance service trusts. Both are characterised by additional tertiary education, diagnostic adjuncts (such as point-of-care testing) and patient group directives (AACE, 2011), with non-medical prescribing available to advanced paramedics upon completion of the course (College of Paramedics, 2018).

Alongside this expanded role, knowledge of common endocrine conditions not covered in traditional undergraduate paramedic education becomes more relevant and appropriate for review.

Giving the unpredictable nature and changing model of prehospital care, it is pertinent to understand paramedics' role in both recognising and signposting adrenal insufficiency, as well as recognising and managing a potentially fatal crisis.

Case study

A 21-year-old woman called 999 for an emergency ambulance complaining of dizziness, nausea, vomiting and mild abdominal discomfort. An advanced paramedic was dispatched to assess the patient with the overarching aim of providing care in the community.

The patient reported a 24-hour history of gastrointestinal (GI) symptoms, including diarrhoea and vomiting, and had been intermittently feeling ‘feverish’ since onset. She denied chest pain, headache, loss of consciousness, respiratory distress, symptoms of GI bleeding and urinary complaints. A medical history revealed a diagnosis of Addison's disease which was well controlled with hydrocortisone. However, because of vomiting, she was unable to tolerate oral hydrocortisone and had therefore became acutely unwell.

Physical examination revealed a relatively thin young woman with pale and dry mucosal membranes and hyperpigmentation on her hands and face. Her initial observations are presented in Table 1. Additional diagnostic adjuncts available to the attending clinician, including human chorionic gonadotropin tests and urinalysis, were not used as the patient was presenting as clinically unstable.

Table 1. Clinical observations of a patient presenting in adrenal crisis
Table 1. Clinical observations of a patient presenting in adrenal crisis
Glasgow Coma Scale score 15/15
Heart rate 130
Blood pressure 75/40
Respiratory rate 22
Oxygen saturation 98%
Temperature 37.5°C

A clinical impression of adrenal crisis was made. Following UK ambulance service clinical guidance on hydrocortisone (AACE, 2019), an intravenous (IV) cannula was inserted, and both 100mg hydrocortisone and a 500 ml bolus of normal saline were administered. The patient made some improvement, and was transported to the nearest hospital with prenotification to the receiving emergency department team.

Physiology of the adrenal gland

The adrenal glands are located on the superior medial aspect of each kidney. They comprise the adrenal cortex and adrenal medulla, which produce steroids and catecholamines respectively. The adrenal cortex specifically produces glucocorticoids such as cortisol, mineralocorticoids including aldosterone and gonadocoticoids (androgen hormones and oestrogen). The adrenal medulla produces catecholamines, namely adrenaline, noradrenaline and small amounts of dopamine (Idrose, 2016).

Expanding on the roles of the adrenal steroids, cortisol can be thought of as the ‘stress hormone’ of the body, being released in response to stress while also facilitating the functioning of the body under states of increased stress (Puar et al, 2016). In the current context, stress can be considered as physiological, with non-exhaustive causes including allergic reactions, infections, surgery and trauma, as well as having psychological and emotional triggers. Cortisol release potentiates catecholamine release from the adrenal medulla and has a direct effect on cardiovascular function, immune system suppression and metabolism through increasing gluconeogenesis and decreasing peripheral glucose uptake (Baranowski et al, 2018).

Aldosterone is regulated by the renin-angiotensin-aldosterone system and plasma potassium concentration. Its primary function is maintenance of sodium and potassium plasma concentration and regulating extracellular volume, which helps to maintain blood pressure (Wagner, 2014).

Finally, gonadocorticoid oestrogen and androgen hormones promote the development of sex characteristics; however, androgens are primarily produced in the testes in men and those produced in the adrenal gland are less responsible for sexual function (Baranowski et al, 2018).

What is adrenal insufficiency?

Adrenal insufficiency is a chronic disorder of the adrenal glands, arising when production of vital hormones and catecholamines is inadequate (Pituitary Foundation, 2009). Ordinarily, a person can live a healthy, active life with steroid replacement.

A patient may present symptomatically with features of adrenal insufficiency that do not meet the severity of illness associated with adrenal crisis (Amrein et al, 2018). Symptoms of both adrenal insufficiency and adrenal crisis are similar; the key difference is the maintenance of cardiovascular function in adrenal insufficiency. Adrenal insufficiency may become symptomatic before diagnosis or where not appropriately managed but may also be a precursor to adrenal crisis, and therefore can be treated along the same management path to avoid further deterioration (Rushworth et al, 2019).

Why does it occur?

Healthy adrenal glands secrete cortisol in stressful situations in an attempt to maintain normal homeostasis, particularly affecting the cardiovascular, immune and metabolic systems (Idrose, 2016). Adrenal insufficiency arises when there is a relative or complete deficiency in cortisol because of underlying disease or autoimmune destruction of the adrenal glands and therefore an inability to increase endogenous cortisol levels (Amrein et al, 2018).

A crisis occurs when there is a lapse in essential medication, either purposeful or because of illness, or a stressful trigger overwhelms the body's normal defence mechanism, requiring additional administration of exogenous glucocorticoids such as hydrocortisone, regardless of a patient's daily steroid intake (Puar et al, 2016). Cortisol has a half-life of 90 minutes so deficiency can occur within hours of cortisol deprivation (Katzung et al, 2012; Rushworth et al, 2019).

The primary change occurring in cortisol deficiency is the loss of inflammatory suppression, where self-regulation of immune response is impaired, giving rise to symptoms of anorexia, fever, malaise and myalgia. Concomitantly, there is loss of catecholamine-mediated cardiovascular function causing vasodilation, hypotension and compensatory tachycardia. Finally, there is a reduction of gluconeogenesis so hypoglycaemia ensues (Rushworth et al, 2019).

Deficiency in aldosterone, the primary mineralocorticoid, exacerbates adrenal crisis through sodium and water loss as well as potassium retention, both worsening hypotension while giving rise to electrolyte derangement such as hyponatraemia and hyperkalemia (Puar et al, 2016).


Adrenal insufficiency results from primary, secondary or glucocorticoid-induced adrenal insufficiency depending on the underlying condition (Table 2) (Puar et al, 2016). The most common cause of insufficiency is primary autoimmune destruction of the adrenal gland (up to 90% of cases); however, the growing number of chronically unwell patients requiring long-term steroid use are increasingly contributing to the manifestation of adrenal insufficiency (Bornstein et al, 2016).

Table 2. Causes of adrenal insufficiency
Table 2. Causes of adrenal insufficiency
Primary insufficiency: Addison's disease Destruction of the adrenal cortex, usually autoimmune in nature
  • Infections: tuberculosis, systemic fungal infections, AIDS
  • Metastasis
  • Congenital adrenal hyperplasia
  • Adrenomyeloneuropathy/adrenoleukodystrophy
  • Bilateral adrenal haemorrhage
  • Bilateral adrenalectomy
Secondary insufficiency Less common, usually involves a decrease in secretion of adrenocorticotropic hormone secretion, reducing cortisol production. Aldosterone and sex hormone levels are preserved
  • Pituitary or metastatic tumour
  • Other tumours
  • Pituitary surgery or radiation
  • Lymphocytic hypophysitis
  • Head trauma
  • Pituitary apoplexy/Sheehan's syndrome
  • Pituitary infiltration (sarcoidosis, histiocytosis)
Glucocorticoid-induced adrenal insufficiency Long-term exogenous glucocorticoid use such as inhaled corticosteroids or prednisolone

Adrenal crisis may arise in a patient with a history of primary, secondary or glucocorticoid-induced adrenal insufficiency. It is often precipitated by: events such as emotional distress; some types of chemotherapy and immunotherapy; infections (commonly gastroenteritis since vomiting and diarrhoea impair absorption of oral medication); major trauma; strenuous exercise; surgery; and viral illnesses in children. Non-adherence to daily medication is particularly relevant in illnesses in which the daily dose is high (3–5mg of prednisone or the equivalent per day), since sudden discontinuation can be a precipitant (Rushworth et al, 2019).

Clinical features

Diagnosis of adrenal insufficiency is considered one of the most difficult in primary care, as symptoms are often vague and non-specific, relying on the practitioner having a high level of clinical judgement and suspicion (Makin et al, 2019).

Symptoms of adrenal insufficiency include persisting abdominal discomfort, anxiety, depression, lethargy, fatigue, nausea and vomiting, postural dizziness and weight loss (Bornstein et al, 2016). Because symptoms are ambiguous, patients with undiagnosed primary adrenal insufficiency are often misdiagnosed and treated for mental health illnesses such as anorexia or depression (Mankin et al, 2019). Signs of chronic adrenal insufficiency may be present and found on physical examination; these include hyperpigmentation or vitiligo in palmar creases, mucosa, axillae and face as well as anorexia (Charmandari et al, 2014).

Identification of adrenal crisis involves taking a pragmatic approach of using physiological parameters in the setting of known adrenal insufficiency and clinical assessment (Rushworth et al, 2019). Central to its identification is a sharp fall in blood pressure, with the patient presenting with systolic blood pressure <100mmHg or >20mmHg lower than their usual level (Rushworth et al, 2019). In crisis, the patient may present with abdominal pain (sometimes mimicking peritonitis or with an acute abdomen), extreme lethargy, nausea and vomiting, syncope and weakness (Puar et al, 2016; Rushworth et al, 2019). Physical signs can include altered consciousness, hypoglycaemia, hypotension and compensatory tachycardia (Bornstein et al, 2016; Puar et al, 2016).

Identification in pre-adolescent children is challenging, so the defining symptoms are broadened to include a notable deterioration in cardiovascular status (hypotension or tachycardia relative to age) or marked electrolyte disturbance not attributed to other disease. Children may also present with failure to thrive or delayed adolescence (Bornstein et al, 2016).

Regardless of age, the patient's condition will generally improve within 1–2 hours of parenteral glucocorticoid administration. When clinical features do not substantially improve, the clinician should consider alternate diagnoses such as sepsis (Rushworth et al, 2019).

Point-of-care testing

While point-of-care testing (POCT) is not routinely available to paramedics, some UK ambulance services have begun to incorporate this diagnostic tool into the advanced paramedic scope of practice (Heaney et al, 2020). POCT may be useful in a patient presenting with adrenal insufficiency but is likely to be inappropriate in adrenal crisis as treating this is time critical.

Regardless of illness severity, both adrenal insufficiency and adrenal crisis have common derangements (Table 3). Hyponatraemia, hyperkalemia and hypoglycaemia are common findings, with the first two abnormalities arising from aldosterone deficiency, and the last from metabolism imbalance (Puar et al, 2016).

Table 3. Common electrolyte derangements in adrenal insufficiency and adrenal crisis
Table 3. Common electrolyte derangements in adrenal insufficiency and adrenal crisis
Pathology Defined serum concentration
Hyponatraemia <138mmol/l
Hyperkalaemia >4.5 mmol/l
Hypoglycaemia <3.9mmol/l

Considering these electrolyte derangements, it may be appropriate to initiate POCT where patients are clinically symptomatic and testing is available to the attending clinician. Pending the results of POCT, a practitioner may refer a clinically stable patient to their GP to prompt further investigation in secondary care. Alternatively, where electrolyte derangement is profound, a practitioner may be able to arrange medical admission to the receiving hospital for review and management.

Management and pharmacology

Patients complaining of persistent and non-specific signs and symptoms of adrenal insufficiency as outlined above should be told to contact their GP for further investigation (Wass et al, 2013). Failure to thrive or delayed adolescence in children should also prompt referral to the GP (Bornstein et al, 2016).

Investigations in primary care include taking a serum cortisol level, ideally between 8am and 9am because of diurnal changes in cortisol levels, along with electrolyte and blood glucose testing (Wass et al, 2013). Upon confirmation of cortisol deficiency, a patient would then be referred to secondary care to either an endocrinologist or paediatrician for further investigation.

Investigations in secondary care may involve an adrenocorticotropic hormone stimulation test, which has a high sensitivity to Addison's disease and also helps differentiate between primary and secondary causes of insufficiency (Wass et al, 2013). Plasma renin and aldosterone levels would also likely be taken, with renin being high and aldosterone being low in Addison's disease (Wass et al, 2013).

Following diagnosis, the Endocrine Society's clinical practice guidelines recommend starting oral steroids: hydrocortisone in 2–3 divided daily doses of up to 30 mg, increased in times of physiological stress; or prednisolone for those whose compliance is expected to be poor (Bornstein et al, 2016). Additionally, in patients with primary adrenal insufficiency, it is recommended that a replacement mineralocorticoid, most commonly fludrocortisone, is also taken (Bornstein et al, 2016).

Exploring the pharmacology, hydrocortisone is a glucocorticoid replacement and the pharmacological preparation of endogenous cortisol (Katzung et al, 2012). It is responsible for restoring the actions of cortisol in deprived states. Its mechanism of actions include: restoration of vascular and bronchial smooth muscle relaxation; stimulation of gluconeogenesis and glycogen synthesis; increase in serum glucose levels; and dramatic reduction in inflammatory mediators (Katzung et al, 2012). While hydrocortisone has some mineralocorticoid activity, it must be supplemented with a salt-retaining medication such as fludrocortisone to help maintain blood pressure, plasma renin activity and electrolyte balance.

The above pharmacological agents replace the deficient endogenous glucocorticoid and mineralocorticoid hormones to allow normal daily functioning of people with adrenal insufficiency. It is important, however, that the patient is educated on what to do when they become unwell and how to recognise crisis. As with other long-term medical conditions, ‘sick day rules’ apply to patients diagnosed with adrenal insufficiency (Table 4) (Bornstein et al, 2016).

Table 4. Sick day rules
Table 4. Sick day rules
Sick day rule 1 Double the routine oral glucocorticoid dose when the patient experiences fever or illness, when they require antibiotics for an infection or before a small outpatient procedure
Sick day rule 2 Inject a glucocorticoid preparation intramuscularly or intravenously in case of severe illness, trauma, persistent vomiting, when fasting for a procedure or during surgical intervention

In the prehospital setting, adrenal crisis is managed by as per the hydrocortisone drug guideline in the UK ambulance clinical practice guidelines (AACE, 2019) with hydrocortisone administered as single dose in a range of 25mg–100mg depending on age. It is given parenterally through slow IV administration, or by intraosseous flush or intramuscularly where IV access is not possible. It is indicated for patients in both established adrenal crisis and steroid-dependent patients who have become critically unwell to prevent impending adrenal crisis.

If in doubt, it is more appropriate to administer hydrocortisone than to wait (AACE, 2019). Patients presenting with adrenal crisis should be rapidly transported to the nearest emergency department with resuscitation facilities and a pre-alert should be placed.

Paramedics need to be aware of both sick day rules and potential for deterioration when managing a patient with adrenal insufficiency in the community. With these rules in mind, the patient should be advised to increase oral glucocorticoid dose for the duration of illness and availability of parenteral glucocorticoid at the patient's home should be assessed. It is prudent to leave strict safety netting advice, and consider alerting the patient's GP to current illness so they can monitor the patient's condition.


Adrenal insufficiency is difficult to diagnose and can lead to a potentially fatal crisis. While the primary cause of adrenal insufficiency is autoimmune in nature, an increasing number of chronically unwell patients on long-term steroids are contributing to adrenal insufficiency and crisis.

Traditionally, adrenal insufficiency has not been considered as a differential diagnosis in prehospital setting but the changing model of care in paramedic practice sees clinicians encountering chronic conditions more frequently. Patients presenting with vague symptoms of adrenal insufficiency should be referred to their GP and POCT should be considered where available. Sick day rules should be followed when managing acute injury or illness in the community.

Adrenal crisis is life threatening and should be promptly managed as per the UK ambulance clinical practice hydrocortisone guideline (AACE, 2019), with rapid transport and pre-alert to the receiving hospital.

Key points

  • Adrenal crisis is an endocrine emergency that paramedics are increasingly likely to encounter because their roles have expanded
  • Adrenal insufficiency and crisis describe the scale of an endocrine disorder involving the adrenal glands in which there is insufficient production of vital hormones (glucocorticoids, mineralocorticoids and gonadocoticoids) and catecholamines
  • Diagnosis and management of adrenal insufficiency are challenging due to vague patient symptoms sometimes correlating with an alternate pathology
  • Both adrenal insufficiency and crisis present with symptoms of malaise, abdominal discomfort, nausea, vomiting and fever; the key differential when identifying adrenal crisis is presence of cardiovascular compromise
  • Patients presenting with persisting symptoms of adrenal insufficiency without diagnosis should be referred to their general practitioner for further investigation. Adrenal crisis, however, is a life-threatening emergency and early identification and administration of hydrocortisone is key to successful patient outcome

CPD Reflection Questions

  • What is your understanding of adrenal insufficiency and how it differentiates from adrenal crisis?’
  • What signs and symptoms could I become aware of to help identify adrenal insufficiency? How would knowledge of these signs and symptoms change my practice?
  • How can I incorporate sick day rules into my practice? What specific advice could I be giving?

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