Addison's disease refers to the autoimmune destruction of the adrenal glands. It is the most common cause of primary adrenal insufficiency (PAI) (primary hypoadrenalism) in the UK and Western world, accounting for 90% of cases of PAI. Despite being the most common cause of PAI, Addison’s and PAI are both rare.
🦴 🏃♀️ Anatomy and physiology
The adrenal (suprarenal) glands are paired endocrine glands that sit on top of the kidneys. It can be divided into 2 parts - the cortex and the medulla.
The cortex can be subdivided into 3 layers:
- Zona glomerulosa - produces and secretes mineralocorticoids such as aldosterone.
- Zona fasciculata - produces and secretes corticosteroids such as cortisol. It also secretes a small amount of androgens.
- Zona reticularis - produces and secretes androgens such as dehydroepiandrosterone (DHEA). It also secretes a small amount of corticosteroids.
Let’s discuss these zones in more depth:
This is the outermost layer. It is responsible for the secretion of mineralocorticoid hormones such as aldosterone. These are vital for fluid balance through the uptake of sodium ions and secretion of potassium ions (via the Na+/K+ATPase and ENaC) in the collecting duct of the renal tubule.
💡 Conn’s syndrome is a benign tumour of the zona glomerulosa which leads to primary hyperaldosteronism and causes hypertension.
This is the middle layer of the adrenal cortex. It is responsible for the secretion of glucocorticoid hormones such as cortisol. These hormones are responsible for the regulation of glucose metabolism and the stress response.
Glucocorticoids are released in a diurnal pattern as increased secretion occurs in the morning and less at night time.
💡 Cushing’s disease is caused by a pituitary adenoma that leads to Cushing syndrome (hypercortisolism).
This is the innermost layer that sits above the adrenal medulla. It is the site of androgen precursor production, such as dehydroepiandrosterone (DHEA) and androstenedione. These are transported to the gonads for conversion to testosterone or oestrogen. They are responsible for the development of sexual characteristics during puberty.
💡 Congenital adrenal hyperplasia (CAH) may result in excessive testosterone and virilisation of female babies.
Pathophysiology
PAI is most commonly caused by destruction of the adrenal cortex. This is known as Addison’s disease. Addison’s is most commonly caused by autoimmune destruction of the adrenal cortex (90% of cases). The antibodies implicated are most commonly anti-21-hydroxylase antibodies (present in 80%-90% of individuals).
Around 40% of cases of Addison’s occur in isolation, with solely the adrenal gland being affected. The other 60% of cases are associated with other endocrine disorders with an autoimmune aetiology (such as Hashimoto’s thyroiditis Grave’s disease, type 1 diabetes mellitus) and autoimmune polyendocrine syndrome. Furthermore, patients with Addison’s are more likely to develop other autoimmune diseases such as rheumatoid arthritis, coeliac disease and Crohn’s disease.
⭐️ In countries endemic to tuberculosis, TB remains a significant cause of PAI.
Other causes of PAI include:
- Infection - meningococcal infection (leads to Waterhouse-Friderichsen syndrome, also known as haemorrhagic adrenalitis), systemic fungal infections, haeomphilus influenzae, cytomegalovirus and HIV.
- Infiltration - such as amyloidosis, haemochromatosis, sarcoidosis.
- Iatrogenic - after bilateral adrenalectomy, adrenal haemorrhage (after anticoagulation), immune checkpoint inhibitors, drugs that inhibit cortisol (such as antifungals).
- Malignancy - bilateral adrenal tumours or metastatic tumours.
- Genetic disorders - congenital adrenal hyperplasia (the most common cause of PAI in children) and adrenoleukodystrophy.
Approximately 2/3rds of patients with Addison’s disease have a type of APS. There are 2 types of APS:
APS type 1:
Most commonly is autosomal recessive and presents in childhood. It is also known as APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) as it commonly presents with a triad of Addison’s disease, hypoparathyroidism and chronic candidiasis).
APS type 2:
APS type 2 is more common and does not follow a simple Mendelian inheritance pattern. Instead it occurs due to more complex polygenic traits. It most commonly involves Addison’s disease and thyroid disease or type 1 diabetes mellitus.
Both forms of APS are associated with premature ovarian insufficiency, vitiligo, pernicious anaemia, and hypoparathyroidism.
Secondary and tertiary adrenal insufficiency is more common. These are termed central adrenal insufficiencies (CAI).
- Secondary adrenal insufficiency (SAI) - occurs due to reduced pituitary production of adrenal corticotrophic hormone (ACTH). This occurs with pituitary tumours, traumatic brain injury, haemorrhage.
- Tertiary adrenal insufficiency (TAI) - occurs due to reduced hypothalamic production of corticotropin-releasing hormone. This occurs with long-term corticosteroid use, tumours, radiotherapy or surgery.
⚠️ Risk factors
- Female sex - >90% of patients with PAI are women.
- Hypercoagulability - such as in antiphospholipid syndrome, sepsis, and heparin-induced thrombocytopenia (paradoxically leads to development of a hypercoagulable state despite “thrombocytopenia” in the name). These can lead to DIC and microvascular compromise which causes bilateral adrenal haemorrhage.
- Autoimmunity
- Tuberculosis
- Fungal infections
- Infiltrative disorders
- Malignancy
😷 Presentation
The features of Addison’s disease derive from the decreased production of the steroids produced by the adrenal gland. Around 90% of the adrenal cortex needs to be destroyed to result in the clinical manifestation of adrenal insufficiency. Most patients remain asymptomatic until the cortisol demands are more than normal, such as in times of stress, trauma or infection.
- Hypoaldosteronism:
- Hypotension
- Salt craving
- Hyponatraemia & hyperkalaemia - normally, aldosterone allows for reabsorption of sodium through expression of the ENaC channels. The Na+/K+ATPase is dependent on the gradient created by the ENaC for the excretion of potassium ions. As sodium is not reabsorbed (hence the hyponatraemia), potassium is not excreted (hence the hyperkalaemia). Hyponatraemia is present in around 70–80% and hyperkalaemia in 30–40% of people with Addison's disease.
- Hypocortisolism:
- Weight loss, anorexia
- Fatigue, lethargy, depression
- Muscle aches
- Weakness
- GI complaints (such a nausea, vomiting, diarrhoea)
- Sugar cravings
- Postural hypotension
- Hyponatraemia - because usually glucocrticoids inhibit ADH secretion, thus preventing excessive water retention. In this case, ADH is not suppressed and there is excessive fluid retention & dilution of blood, thus a dilutional hyponatraemia.
- Hypoglycaemia, because usually glucocorticoids inhibit peripheral glucose utilisation and increase gluconeogenesis.
- Hypoandrogenism:
- Loss of libido
- Loss of pubic and axillary hair
- Impaired spermatogenesis
- Low levels of DHEA-S
- Hyperpigmentation - of areas not exposed to sunlight, such as palmar creases, mucous membranes in the mouth etc. This is because ACTH derives from proopiomelanocortin (POMC). When POMC is broken down to produce ACTH, melanocyte-stimulating-hormone (MSH) is also produced. Elevated levels of MSH results in excessive melanin production.
- Prolonged neonatal jaundice
- Failure to thrive
- Delayed puberty
Addisonian crisis may include the same features of adulthood, in addition to hypoglycaemia.
A person with Addison's disease may present with a sudden crisis precipitated by illness or other stress. This may be sepsis, surgery, adrenal haemorrhage or withdrawal of steroids. If an Addisonian crisis is suspected, one should initiate management urgently. Failure to do so may result in the patient deteriorating and it is fatal if untreated.
- Hypotension
- Hypovolaemic shock
- Acute abdominal pain
- Uncontrollable vomiting
- Reduced consciousness
- Hypoglycaemia (more so in children)
🧰 Management:
- IV fluids - to manage the hypotension. 1L of normal saline can be infused over 30-60 minutes.
- Dextrose may be used if the patient is hypoglycaemic.
- IM/IV hydrocortisone (100mg) - this should be repeated every 6 hours until the patient is stable. This may then be converted into an oral replacement of hydrocortisone after 24 hours. This high dose should be tapered down to the maintenance dose over the subsequent 3-4 days.
Other than the presentations mentioned above, Addison's should be considered in people who come with:
- Hypothyroidism symptoms that worsen after starting thyroxine
- Type 1 diabetes mellitus with recurrent unexplained hypoglycaemic episodes.
- Other autoimmune conditions
- Hyponatraemia and hyperkalaemia on blood biochemistry
🔍 Investigations
💡 Addison’s disease should only be investigated if there is no impending Addisonian crisis. If crisis is suspected based on clinical suspicion then urgent treatment should be initiated. Children with suspected Addison’s disease should be referred urgently to the paediatrician.
- Serum cortisol - taken between 8am-9am.
- <100nmol/L → admit to hospital.
- 100-500nmol/L → refer to endocrinology for further investigating with Synacthen testing.
- Individuals who work shifts and cannot provide an early morning cortisol sample.
- Individuals who are on long-term corticosteroids.
- Individuals on oestrogen (such as contraceptives or HRT) as oestrogen increases the production of cortisol-binding globulin from the liver and this increases serum cortisol levels.
- Pregnant women
- Urea and electrolytes - may show hyponatraemia and hyperkalaemia. However, normal results do not exclude the diagnosis. Mild or moderate hypercalcaemia may be seen (although this is rare). Urea and creatinine levels may be elevate due to volume depletion.
- Blood glucose - may be borderline or low.
One should seek specialist advice from an endocrinologist if it is difficult to obtain a serum cortisol level, for example in:
Other blood tests may include:
- FBC - anaemia
- LFTs - elevated.
- TSH - elevated.
These should be performed in secondary care.
- 🏆 Synacthen test - this is the confirmatory test for Addison’s disease. The test involves obtaining a serum cortisol prior to administering 250mcg of tetracosactide (synthetic ACTH) (given IV or IM). Serum cortisol levels are then assessed 30 minutes after.
- Normal adrenal function will elicit a rise in cortisol levels >500-550nmol/L after 30-60 minutes.
- Adrenal insufficiency would elicit a serum cortisol level <500nmol/L.
Additional tests that can be done in secondary include:
- Anti-21-hydroxylase antibodies - present in >80% of Addisonian patients.
- Serum ACTH - these are elevated in primary adrenal insufficiency and low in secondary adrenal insufficiency.
- Plasma renin and aldosterone - renin is elevated and aldosterone is low.
- Serum DHEA-S- low.
- CT or MRI scan - not needed if autoimmune adrenalitis is likely. However, if an alternative aetiology is suspected it may be helpful (such as TB, haemorrhage, malignancy).
🧰 Management
Management for Addison’s needs to be started by an endocrinologist, after which a GP may continue the treatment protocols. Essentially, the management involves replacement of hormones that are no longer being produced. Glucocorticoid and mineralocorticoid replacement is essential, however, androgen replacement is not done routinely in the UK.
- Glucocorticoid replacement:
- Hydrocortisone - this is most commonly used. A 15-25mg daily dose is usually given (dependent on patient factors). This is broken up into either 2 or 3 doses throughout the day (to mimic the natural cycle of cortisol release from the body). 3 divided doses are preferred as 2 divided doses cause more variability in the cortisol levels. In children, the daily dose is dependent on body surface area (8-10mg/m²) and should be divided into 3 or 4 daily doses.
- Prednisolone - an alternative option that is less frequently used.
⚠️ If taking steroids equivalent to 20mg of prednisolone (80mg of hydrocortisone) then they should be given the seasonal influenza vaccine and pneumococcal vaccine.
- Mineralocorticoid replacement:
- Fludrocortisone - 50-200mcg (dependent on patient factors). However, this is higher in children as their requirement is much higher. The dosage may be increased in higher temperatures and humidity. Salt supplementation may also be needed in these situations and in children too.
Androgen replacement:
- Dehydroepiandrosterone (DHEA) - although not routinely prescribed in the UK, it may be prescribed sometimes (such as in patients with persistent fatigue).
Patients with Addison’s disease should be educated on circumstances when their corticosteroid dose should be increased (such as during periods of illness or strenuous exercise).
Let’s discuss some of the guidance provided by NICE:
- Illness or injury:
- Moderate illness (such as fever >37.5ºC, illness requiring antibiotics or bedrest) - double dose.
- Severe nausea - 20mg of hydrocortisone + oral rehydration solution.
- Severe illness (such as vomiting, persistent diarrhoea) or trauma - emergency injection and seek medical advice.
- Exercise:
- Strenuous exercise (such as marathon) - increase dose up to double dose.
- Gentle exercise (such as walking) - no adjustment needed.
- Sports with risk of injury - ensure someone is trained to administer emergency injection.
- Fasting:
- Risk assessment is needed with the team. It is also important to understand sick day rules (such as terminating or abstaining from fasting).
- Ensure they have an emergency injection pack and knows how to administer it.
- Procedures:
- Minor surgical or dental procedures - extra oral dose (1 hour ahead of the procedure) and another after the procedure.
- Major operations - managed in the hospital.
- Over-replacement - may result in Cushing syndrome with hypertension, thin skin, striae, easy bruising, hyperglycaemia, osteoporosis.
- Under-replacement - may result in Addison’s symptoms such as fatigue, postural hypotension, nausea, weight loss, hyperpigmentation, salt craving.
Secondary adrenal insufficiency is characterised by a dysfunction at the level of the pituitary gland, resulting in decreased production of adrenocorticotropic hormone (ACTH. n secondary adrenal insufficiency, the adrenal glands are structurally intact, but they do not receive the appropriate signals from the pituitary gland or hypothalamus to produce cortisol.
Secondary adrenal insufficiency can occur due to:
- Congenital disorders
- Fracture of the base of the skull
- Pituitary or hypothalamic surgery or neoplasms in the pituitary/hypothalamus
- Infiltration or infection of the brain
- Deficiency of corticotropin-releasing hormone (CRH)
Tertiary adrenal insufficiency involves a dysfunction of the hypothalamus → decreased CRH production.
- The most common cause is sudden discontinuation of chronic glucocorticoid therapy.
- Rarer causes include hypothalamic dysfunction (e.g., due to trauma, mass, haemorrhage, or anorexia): low CRH → low ACTH → low cortisol release.