4th April 2024

Adrenal Disorders

Addison’s Disease

Pathophysiology

Addison’s disease, or primary adrenal insufficiency, is a rare condition whereby the adrenal glands are not able to secrete enough adrenocortical hormones to sustain normal bodily functions. It is usually an autoimmune condition where the individual’s immune system destroys healthy adrenal tissue. In normal health, these hormones – mainly cortisol, aldosterone and dehydroepiandrosterone (DHEA) – are vital in maintaining various balances within the body as well as responding to acute demands placed on the body in day-to-day life.

An understanding of the role of each of these hormones is useful in recognising the symptoms and signs in a patient presenting with Addison’s disease (see Table 1).

In addition to the symptoms and signs elicited directly from the hormone deficiencies, the adrenal gland’s place within the hypothalamic-pituitary-adrenal axis results in the classical sign of Addison’s disease: hyperpigmentation. This is because the low levels of adrenal hormones (specifically cortisol) are detected and lead to increased secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland via a negative feedback loop. The pituitary gland continues to secrete more and more ACTH in an attempt to stimulate the damaged adrenal gland. The high levels of ACTH have a stimulant effect on melanocytes to produce melanin, leading to hyperpigmented or ‘bronzed’ skin.

The onset of Addison’s disease is usually prolonged over several months of gradually progressive symptoms. In rare cases, the initial presentation may be an Addisonian crisis, where the levels of adrenal hormones (mainly cortisol) are so low as to be life-threatening. Addisonian crisis presents more commonly in patients with established Addison’s disease who experience an acute physiological stress, e.g., infection or abrupt removal of steroids.  Patients will commonly have reduced GCS, be hypotensive and have significant electrolyte disturbances.

Diagnosis

The signs and symptoms of Addison’s disease can be vague but a detailed history and examination, as well as simple blood tests such as urea and electrolytes, can raise suspicion. Some findings which are indicative of Addison’s disease include:

• Hyponatraemia and hyperkalaemia (due to low aldosterone levels)
• Hypoglycaemia (due to low cortisol)
• Uraemia
• Normocytic anaemia

If Addison’s disease is suspected a morning cortisol level should be taken and further investigations depending on the result:

• <83 nmol/L is highly suggestive of adrenal insufficiency
• >497 nmol/L makes adrenal insufficiency highly unlikely
• 83-497 nmol/L warrants further testing to determine if there is adrenal insufficiency

The diagnostic test for Addison’s disease is an ACTH suppression test, also called the short Synacthen test. This involves measuring baseline serum cortisol followed by administration of synthetic ACTH (Synacthen) to the patient after which cortisol levels are rechecked at 30- and 60-minute intervals. In an individual with healthy adrenal tissue, administration of ACTH will lead to a rise in cortisol but in Addison’s disease, the adrenal glands will not be able to mount a response. Cortisol levels below 497 nmol/L after synthetic ACTH indicate probable adrenal insufficiency and these patients will require further evaluation by an endocrinologist to confirm the diagnosis.

Management

This consists of glucocorticoid and mineralocorticoid replacement with hydrocortisone and fludrocortisone, respectively. During times of stress e.g., infection or surgery, there will be greater physiological demand for cortisol and patients should be educated to double their glucocorticoid dose. Medical alert bracelets detailing Addison’s disease can be helpful in ensuring prompt treatment is administered in the event of an Addisonian crisis.

Management of the Addisonian crisis involves replacing cortisol with IV hydrocortisone. Further treatment may involve fluid resuscitation, blood glucose control, optimisation of blood pressure and replacement of electrolytes and adrenal hormones. This may require admission to an intensive care unit and care must be taken to avoid rapid fluid shifts as patients are likely to be hyponatremic on presentation.

References

• Adrenal cortex and Cushing’s syndrome & Addison’s disease (adrenal insufficiency). Oxford handbook of clinical medicine. 9ᵗʰ edition
• Addison’s disease. BMJ Best Practice. Last reviewed 17ᵗʰ Jan 2022

Cushing’s Syndrome

Pathophysiology

Cushing’s syndrome is caused by an excess of glucocorticoid within the body. The most common cause is exogenous administration in patients on long term steroid tablets but less commonly, the syndrome can be due to excess ACTH or cortisol release from tumours.

Cushing’s disease is the most common non-iatrogenic cause of Cushing’s syndrome. It is caused by an ACTH secreting pituitary tumour which leads to bilateral adrenal hyperplasia. Certain cancers, including small cell lung cancers and carcinoid tumours can also secrete ACTH. In rare cases, cortisol is secreted directly from adrenal adenomas.

Clinical manifestations

Cushing’s syndrome affects multiple body systems shown in the image below.

Image Source: Wikimedia Commons (2015). Cushing’s Syndrome, Licensed under a creative commons licence. Available for free at: https://en.wikipedia.org/wiki/Cushing%27s_syndrome (Accessed: 6 February 2024).

Diagnosis

Numerous other conditions can present similarly to Cushing’s syndrome and it is important to exclude differentials such as metabolic syndrome; alcohol excess, pregnancy and physiological stress, before making a diagnosis. Medication history is important as chronic steroid use makes a diagnosis of Cushing’s syndrome more likely. Blood glucose should be monitored as Cushing’s syndrome can lead to glucose intolerance and diabetes.

Initial investigations include measurement of cortisol levels. This has diurnal variation with a morning peak and nadir at midnight. Measurements are checked at night when levels are lowest and the sample can be from saliva or a blood test.

Dexamethasone suppression tests are performed to confirm the diagnosis. This involves giving the patient 1mg of dexamethasone at 11pm and then testing their cortisol level at 8am the following morning. In a person without Cushing’s syndrome, the dexamethasone should inhibit further cortisol release due to the negative feedback loop on the hypothalamus-pituitary-adrenal axis, but this feedback loop is suppressed in Cushing’s syndrome. A positive result is indicated by a morning cortisol of >50 nanomols/L (it is worth noting that in some causes of Cushing’s syndrome, such as Cushing’s disease, a drop in cortisol is seen in response to high doses of dexamethasone).  Following confirmation of Cushing’s syndrome, checking ACTH levels can differentiate between ACTH-dependent and ACTH-independent causes. High ACTH levels indicate ACTH dependent causes of Cushing’s syndrome. This includes pituitary tumour (Cushing’s disease) and ectopic ACTH producing tumours. In ACTH independent causes (adrenal adenoma/bilateral adrenal hyperplasia), ACTH levels will be low.

If exogenous steroids are excluded as a cause but initial investigations still suggest Cushing’s syndrome then imaging including CT TAP and pituitary MRI are required to try and find the source of a possible ACTH or cortisol secreting tumour.

Management

In most cases where exogenous steroids are the cause there should be a discussion regarding risk-benefit of continuing them. If discontinuing steroids, they should be tapered gradually as abrupt cessation can precipitate adrenal insufficiency.

In cases where tumours are the cause of the syndrome surgical removal is the mainstay of treatment. Pituitary adenomas are usually removed through transsphenoidal surgery. If there is mild disease or if the patient is not fit for surgery or, if surgery has failed, then medical options include somatostatin analogues such as pasireotide.

References

• Cushing’s syndrome. BMJ Best Practice. Last reviewed 24 Jan 2022
• Adrenal cortex and Cushing’s syndrome. Oxford handbook of clinical medicine 9ᵗʰ edition
• Image taken from Wikipedia: Cushing’s Syndrome. Last edited 13ᵗʰ June 2022. Available at: https://en.wikipedia.org/wiki/Cushing%27s_syndrome

Phaeochromocytoma

Pathophysiology

A phaeochromocytoma is a rare tumour of the chromaffin cells within the adrenal medulla that produces excessive secretions of catecholamines e.g., adrenaline and noradrenaline. The 10% rule is used to describe the aetiology: 10% are malignant, 10% are extra-adrenal, 10% are bilateral and 10% are familial. From this, we can understand that most phaeochromocytomas are benign, sporadic tumours within one adrenal gland.

Clinical manifestations

The symptoms of a phaeochromocytoma occur due to the excess catecholamine levels and include headaches, diaphoresis, palpitations and hypertension. These symptoms generally occur in distinct episodes coinciding with the pulsatile release of catecholamines from the tumour.

Diagnosis

There is no definitive test for phaeochromocytomas but the initial approach in a patient with symptoms suggestive of it should be to measure catecholamine levels. This can be done through a blood test but catecholamine levels in the blood can be raised for a variety of reasons e.g., stress, and aren’t very specific for pheochromocytomas. Testing 24-hour urine collections for catecholamine levels is a much more specific test.

In a minority of patients, plasma or urine catecholamine levels may yield false-positive results. This may be because catecholamine levels in these individuals are always raised e.g., poor renal excretory function. In this cohort of patients, a clonidine suppression test can be used. Clonidine acts on adrenoreceptors at nerve terminals to decrease adrenaline release. However, a phaeochromocytoma will release adrenaline independently of this system and so adrenaline levels remain raised despite the administration of clonidine.

If there is biochemical evidence of a phaeochromocytoma, or if suspicion remains high despite negative tests, imaging such as CT or MRI of the adrenal glands are needed to confirm the diagnosis.

Management

Management is based around medically treating the effects of the tumour, particularly hypertension, followed by surgical resection. Some patients may present in hypertensive crises (SBP >250 mmHg) and will require urgent admission and medical management to reduce their blood pressure. This is usually achieved using phentolamine or nitroprusside.

Prior to surgery, steps must be taken to suppress the sympathetic system and stop the patient going into a hypertensive crisis. This is achieved through alpha blockers e.g., phenoxybenzamine or doxazosin, and then beta blockers if needed. Surgical excision of the affected adrenal gland is the main approach and is curative in 85% of cases. In the rare cases of malignant phaeochromocytoma, treatment is based around surgery followed by chemotherapy.

References

• Phaeochromocytoma. BMJ Best Practice. Last reviewed 24 Jan 2022
• Phaeochromocytoma. Oxford Clinical Handbook. 9ᵗʰ edition
• Medullary thyroid cancer. National Cancer Institute. Available at: https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-endocrine-tumor/medullary-thyroid-cancer

Hyperaldosteronism

Background

Hyperaldosteronism can be defined as excess levels of aldosterone in the blood, causing hypertension and hypokalaemia. Other symptoms commonly seen in patients with hyperaldosteronism include polyuria, lethargy and difficulty concentrating.  Most cases of hyperaldosteronism are primarily due to excess aldosterone being secreted from the adrenal gland. 70% of cases of primary hyperaldosteronism (PA) are caused by bilateral adrenal hyperplasia while 30% are due to aldosterone producing tumours within the adrenal gland (Conn’s syndrome).

Secondary hyperaldosteronism is much rarer and is caused by reduced renal perfusion e.g., renal artery stenosis. The decreased perfusion causes raised renin levels and subsequently raised aldosterone levels. Secondary hyperaldosteronism, therefore, indirectly leads to raised aldosterone levels. Management is based around treating the underlying cause.

Approximately 5% of cases of hypertension are caused by hyperaldosteronism and, therefore, newly hypertensive patients with risk factors or signs suggestive of hyperaldosteronism e.g., being relatively young, should be screened for PA.

Diagnosis and management

Checking the aldosterone/renin ratio is the main screening tool and is raised in patients with PA.

Management depends on the cause. Bilateral adrenal hyperplasia is managed medically with selective aldosterone antagonists, e.g., spironolactone. Conn’s syndrome is definitively treated with an adrenalectomy of the affected gland with four weeks of medical treatment prior to surgery.

References

• Hyperaldosteronism. Oxford Clinical Handbook 9ᵗʰ edition
• Primary hyperaldosteronism. BMJ Best Practice

Adrenal Tumours

Background

Adrenal tumours are excess growth of tissue within one or more of the adrenal glands. These tumours are often benign and are found incidentally on imaging. Others can be non-cancerous hormone secreting tumours e.g., the aldosterone secreting tumours seen in Conn’s syndrome. Some tumours are cancerous but unlikely to spread, e.g., phaeochromocytoma. However, adrenal metastases from cancers that started elsewhere in the body include lung cancer, kidney cancer and malignant melanoma.

Tumour types

Phaeochromocytomas are nearly always benign adrenal tumours that secrete excess catecholamines, e.g., adrenaline and noradrenaline. Symptoms include headaches, palpitations and diaphoresis. The tumour is unresponsive to the negative feedback loop of the hypothalamic-pituitary-adrenal axis. Diagnosis is through measuring catecholamine levels and treatment is based around surgical removal of the tumour.

Conn’s syndrome is caused by solitary aldosterone-secreting tumours that present with symptoms of hyperaldosteronism: polydipsia, polyuria, and weakness. Definitive treatment is laparoscopic surgery to remove the affected gland preceded by four weeks of medical management to control BP.

Adrenocortical carcinomas are very rare tumours that start in the adrenal cortex. Around two thirds secrete adrenal hormones such as cortisol and aldosterone. They are sometimes linked with rare genetic disorders such as Li Fraumeni syndrome and MEN type 1.

Neuroblastomas are tumours derived from neural tissue and most often present in children under five years old. The adrenal glands are one of the most common sites for the cancer to originate from and presentation is often with an abdominal mass.

References

• Adrenal gland tumours. Last reviewed 2ⁿᵈ Dec 2021. Available at: Adrenal gland tumours | Cancer Research UK
• What is neuroblastoma? Last reviewed 23ʳᵈ Feb 2021. Available at: What is neuroblastoma? | Cancer Research UK

Congenital Adrenal Hyperplasia

Pathophysiology

Congenital adrenal hyperplasia (CAH) is a genetic condition that presents with prepubertal excessive male characteristics in infants or children. The condition is caused by enzyme deficiencies, with a deficiency of 21-hydroxylase responsible for 90% of cases. The deficiencies lead to inadequate production of cortisol, leading to increased levels of ACTH and cortisol precursor hormones. In infants, the condition presents with failure to thrive, and later in childhood with precocious puberty, short stature, atypical genitalia, irregular menses and hirsutism in females.

Diagnosis and management

In children suspected of having CAH, diagnosis is confirmed through genetic testing and measuring levels of cortisol precursor hormones, in particular 17-hydroxyprogesterone. Treatment is based around steroid replacement in the majority of cases and surgery e.g., vaginoplasty, in a minority of girls.

References

• Congenital adrenal hyperplasia. BMJ Best Practice. Last updated: 24ᵗʰ Aug 2021
• Disorders of sexual development. Oxford handbook of clinical specialities. 10ᵗʰ edition