Endocrinology
Question 26 of 180
A 45 year old woman presents to the Emergency Department with abdominal pain. She is hypotensive and hypoglycaemic. She has a past medical history of Addison's disease. What is the most common cause of Addison's disease in the UK?
Answer:
Causes of Addison's disease:- Tuberculosis (commonest cause worldwide)
- Autoimmune disease (commonest cause in developed countries)
- Rarer causes:
- Adrenal metastases
- Adrenal haemorrhage
- Infection such as histoplasmosis, cryptococcosis, cytomegalovirus, and HIV
- Amyloidosis and haemochromatosis
- Congenital adrenal hyperplasia
- Bilateral adrenalectomy
- Congenital or neonatal primary adrenal insufficiency
- Genetic causes, particularly adrenoleukodystrophy
Addison's Disease and Other Adrenal Disorders
Endocrinology / Oncology & Palliative Care
Last Updated: 6th September 2022
Addison’s disease (primary adrenal insufficiency) is a result of destruction of the adrenal cortex resulting in reduced production of glucocorticoids (such as cortisol), mineralocorticoids (such as aldosterone) and adrenal androgens (such as dehydroepiandrosterone). The absence of cortisol leads to increased production of adrenocorticotropic hormone (ACTH) because negative feedback to the pituitary gland is reduced.
Causes
- Tuberculosis (commonest cause worldwide)
- Autoimmune disease (commonest cause in developed countries)
- Rarer causes:
- Adrenal metastases
- Adrenal haemorrhage
- Infection such as histoplasmosis, cryptococcosis, cytomegalovirus, and HIV
- Amyloidosis and haemochromatosis
- Congenital adrenal hyperplasia
- Bilateral adrenalectomy
- Congenital or neonatal primary adrenal insufficiency
- Genetic causes, particularly adrenoleukodystrophy
Clinical features
Diagnosis of Addison's disease is often delayed because symptoms are non-specific, common, and overlap with many other conditions.
Clinical features of Addison's disease:
- Fatigue
- Hyperpigmentation (due to increased pituitary adrenocorticotropic hormone)
- Gastrointestinal symptoms — weight loss; loss of appetite and premature satiety; nausea and vomiting; abdominal pain; cravings for salt, soy sauce, or liquorice
- Musculoskeletal symptoms — muscle weakness and cramps; joint pains
- Cardiovascular symptoms — postural dizziness due to hypotension (blood pressure decrease of 20 mmHg between sitting and standing measurements)
- Other symptoms — headache, low-grade fever, increased thirst or urination, loss of axillary or pubic hair in women, delayed puberty in children
A person with Addison's disease may present with a sudden crisis precipitated by intercurrent infection or stress. The adrenal glands cannot supply the extra corticosteroids needed to cope with the stress, and life-threatening symptoms develop. Features include hypotension, hypoglycaemia, acute abdominal pain, low-grade fever, and vomiting. Even if the person is young and otherwise fit, adrenal crisis may result in severe dehydration, hypovolaemic shock, altered consciousness, seizures, stroke, or cardiac arrest.
Investigations
- Serum cortisol level
- Serum cortisol less than 100 nanomol/L - adrenal insufficiency is highly likely and patients should be admitted to hospital for further investigation
- Serum cortisol 100–500 nanomol/L - patient should be referred to endocrinologist for further investigations including a Synacthen test
- Urea and electrolytes
- Hyponatraemia is present in 90% and hyperkalaemia in 65% of people with established Addison's disease
- Adrenocorticotropic hormone stimulation (Synacthen®) test
- A normal response to the ACTH stimulation test is an increase in the serum cortisol level
- Adrenocorticotropic hormone (ACTH) levels
- Serum ACTH levels are high in Addison's disease (primary adrenal insufficiency) but are low in secondary adrenal insufficiency
- Plasma renin and aldosterone levels
- Renin levels are typically high and aldosterone levels low in Addison's disease. In secondary adrenal insufficiency, the renin-angiotensin system can function normally
- Autoantibody levels
- Adrenal cortex autoantibodies or antibodies against 21-hydroxylase are present in more than 80% of people with recent-onset autoimmune adrenalitis
- Imaging
- Computed tomography (CT) or magnetic resonance imaging (MRI) is not usually required if autoimmune adrenalitis is likely, but it may be requested if tuberculosis or other infection, haemorrhage, infiltration, or neoplastic disease is suspected
Management
- Routine hormone replacement:
- Glucocorticoid replacement — hydrocortisone is usually used, but longer-acting glucocorticoids, such as prednisolone and dexamethasone, are sometimes used to avoid the peaks and troughs which may occur with hydrocortisone. The daily adult dosage of hydrocortisone is usually 15–30 mg in divided doses. Dosage depends on body weight, metabolism, and absorption.
- Mineralocorticoid replacement — fludrocortisone, which has 125 times the mineralocorticoid action of hydrocortisone, is usually used. The daily adult dosage of fludrocortisone is usually 50–300 micrograms. Dosage depends on metabolism and exercise levels.
- Androgen replacement — dehydroepiandrosterone (DHEA) is an androgen made in the adrenal cortex; therefore, levels are decreased in Addison's disease. DHEA replacement is not routinely prescribed in the UK.
- Self-care advice - patients should be made aware of:
- The need for lifelong glucocorticoid replacement treatment and the potentially life-threatening complications which may arise with inadequate glucocorticoid replacement, especially at times of illness and physical stress.
- How to adjust their replacement steroid medication during periods of illness (including fever), injury, or strenuous exercise.
- How to recognise the symptoms of an adrenal crisis and how to give intramuscular hydrocortisone in an emergency (a family member should also know how to do this).
- The need to make the team responsible for their care aware that they may need extra glucocorticoid replacement if they are undergoing a procedure such as surgery, dental treatment, or endoscopy.
- The importance of carrying emergency information on their person, for example MedicAlert® identification, steroid treatment card or emergency crisis letter.
- Addisonian crisis:
- Give the person hydrocortisone intramuscularly or intravenously (if not already self-administered) and stabilise with an intravenous saline infusion.
- The dose of hydrocortisone depends on the person's age.
- Adults: 100 mg.
- Children 6 years of age or older: 50 mg to 100 mg (use clinical judgement depending on the age and size of the child).
- Children 1–5 years of age: 50 mg.
- Infants up to 1 year of age: 25 mg.
- Emergency administration of fludrocortisone is not required because high-dose hydrocortisone has a mineralocorticoid effect.
Other causes of adrenal insufficiency
- Secondary adrenal insufficiency occurs when pituitary ACTH production is insufficient; this leads to adrenal atrophy. Causes include intracranial disorders, such as pituitary tumour, subarachnoid haemorrhage, and traumatic brain injury.
- Tertiary adrenal insufficiency results from disruption to the production of corticotropin-releasing hormone from the hypothalamus, which affects ACTH production from the anterior pituitary.
Other adrenal disorders
- Primary hyperaldosteronism (Conn's syndrome)
- In primary hyperaldosteronism (PA), aldosterone production exceeds the body's requirements and is relatively autonomous with regard to its normal chronic regulator, the renin-angiotensin II system. This results in excessive sodium reabsorption via amiloride-sensitive epithelial sodium channels within the distal nephron, leading to hypertension and suppression of renin-angiotensin II. Urinary loss of potassium and hydrogen ions, exchanged for sodium at the distal nephron, may result in hypokalaemia and metabolic alkalosis if severe and prolonged.
- The aldosterone/renin ratio is the most reliable available screening test, being more specific than renin measurement (levels of which are almost always suppressed) and more sensitive than plasma potassium or aldosterone measurement. Fludrocortisone suppression testing, in which the aldosterone response during 4 days' administration of oral fludrocortisone and oral salt loading is determined, is widely regarded as being the most reliable means of confirming or excluding PA.
- Approximately 30% have unilateral forms correctable by unilateral laparoscopic adrenalectomy, and 70% have bilateral forms in which hypertension responds well to aldosterone antagonist medicines.
- Phaeochromocytoma
- A tumour arising from catecholamine-producing chromaffin cells of the adrenal medulla that classically presents with headaches, diaphoresis, and palpitations in the setting of paroxysmal hypertension. Symptoms are usually episodic and tend to progress as the tumour grows. The majority of these tumours are benign. About 80% to 90% arise in the adrenal gland; the remainder being extra-adrenal in origin and most commonly found in the head and neck. These tumours mostly develop sporadically. Up to 40% of cases are a manifestation of a hereditary syndrome, such as multiple endocrine neoplasia type 2 or Von Hippel-Lindau syndrome.
- Diagnosed by increased levels of urine and serum catecholamines, metanephrines, and normetanephrines. After biochemical evidence has been confirmed, anatomical localisation should begin with imaging modalities such as CT or MRI of the abdomen and pelvis. All patients with pheochromocytomas should undergo genetic testing to identify potential hereditary tumour disorders that would necessitate more detailed evaluation and follow-up.
- Treatment includes medical therapy for hypertension (phenoxybenzamine, phentolamine, alpha-blockers) and surgical excision of tumour (open or laparoscopic adrenalectomy). For unresectable tumours, alternative approaches include chemotherapy or radiopharmaceuticals.
- Cushing’s syndrome (see separate article)
- Cushing syndrome is the clinical manifestation of pathological hypercortisolism from any cause. Patients often display weight gain with central obesity, facial rounding and plethora, proximal muscle weakness, and thinning of the skin. They also develop metabolic complications including diabetes mellitus, dyslipidaemia, metabolic bone disease, and hypertension. Cushing syndrome can be caused by adrenocorticotrophic hormone (ACTH)-secreting pituitary tumours (termed Cushing's disease), by autonomous adrenal cortisol overproduction, and, rarely, by ectopic ACTH-secreting tumours.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
