Cushing syndrome

Cushing syndrome is a syndrome that refers to the issues derived from hypercortisolism. It can split into endogenous and exogenous types depending on the source of cortisol.

The most common causes of Cushing are prolonged glucocorticoid therapy (exogenous Cushing syndrome) and pituitary adenoma (Cushing’s disease - the most common cause of endogenous Cushing syndrome).

🏃‍♀️ Physiology

Cortisol is a glucocorticoid made by the zona fasciculata of the adrenal cortex (the middle layer). It is secreted in response to adrenocorticotrophic hormone (ACTH) which is released in a pulsátiles manner in relation to the circadian rhythm. Cortisol levels are highest in the morning and lowest at night, the opposite of melatonin.

Let’s recap the hypothalamic-pituitary-adrenal (HPA) axis:

A stimulus (such as stress) causes increased secretion of corticotropin-releasing hormone (CRH) from the hypothalamus. CRH acts on the corticotrophic cells in the anterior pituitary. These corticotrophic cells secrete ACTH into the blood stream. This ACTH travels to the adrenal cortex and stimulates the production of the cortisol from the zona fasciculata.

So what are the effects of cortisol?

• Metabolic effects - cortisol aims to provide energy to the body through the mobilisation of energy reserves. It achieves this through:
• Gluconeogenesis
• Glycogen synthesis
• Protein catabolism and lipolysis
• Increasing appetite
• Insulin resistance
• Immune effects - cortisol has anti-inflammatory effects and immunosuppressive effects. This is through suppression of lymphocytes and reduction of neutrophil migration.
• Impaired wound healing - as mentioned it can reduce the inflammatory cells migrating to the wound site. It also inhibits fibroblasts and reduces collagen synthesis which also impairs wound healing.
• Pain sensitivity modulation - anti-inflammatory effects along with dampening of algesic signalling leads to interference of pain transmission in acute settings. However, chronic exposure to steroids may lead to exacerbation of pain which may result in chronic pain syndromes.
• Stress response - cortisol is the stres hormone and helps cope with stres by increasing the heart rate and blood pressure, by enhancing the sympathetic response, suppressing non-essential functions in times of stress (digestion, growth, reproduction) and suppressing the immune system.
• Increased blood pressure - as mentioned, cortisol may enhance sympathetic activity and may also enhance the catecholamine response. It also may exhibit a mineralocorticoid effect to activate the RAAS. This is because cortisol is usually coverted to cortisone (the inactive form) through 11β-hydroxysteroid dehydrogenase. Cortisone is unable to bind to the mineralocorticoid receptor. However, if cortisol levels are too high, 11β-hydroxysteroid dehydrogenase becomes saturated. This allows cortisol to bind to the mineralocorticoid receptor which increases water and sodium retention as well as potassium and hydrogen ion excretion. This leads to hypertension and hypokalaemia.
• Mood changes - chronic activation of the stress response may lead to anxiety and irritability. Serotonin and dopamine systems are also affected by cortisol which may disrupt their balances and may contribute to depression. The hippocampus is also affected which impairs cognition. Disruptions to the cortisol rhythm may also affect the melatonin levels in the body and this may lead to insomnia which too can contribute to mood disturbances, irritability, fatigue.

Pathophysiology

Cushing syndrome occurs when there is an excessive amount of cortisol in the body (hypertcortisolism). This cortisol may be produced by the body itself (endogenous Cushing syndrome) or it may be obtained through glucocorticoid medication (exogenous Cushing syndrome). Let’s discuss both in more depth:

Exogenous Cushing syndrome:

⭐️ This is the most common cause of Cushing syndrome overall.

Prolonged glucocorticoid therapy leads to hypercortisolism. Increased levels of cortisol lead to reduced ACTH release. Over time this leads to bilateral adrenal atrophy. This means that the levels of the minerals normally secreted from the adrenals are reduced (such as aldosterone → hypoaldosteronism, and androgens → hypoandrogenism). So, when high-dose glucocorticosteroids are stopped, patients can develop adrenal insufficiency despite a clinical phenotype of Cushing's.

Endogenous Cushing syndrome:

Cortisol may be produces endogenously in excessive amounts due to overproduction of the hormones along the HPA axis. This includes cortisol itself (primary), ACTH (secondary) or CRH (tertiary):

• Primary hypercortisolism (ACTH-independent Cushing syndrome):

In primary hypercortisolism, there is autonomous overproduction of cortisol by a pathological adrenal gland. This causes ACTH suppression → atrophy of the other adrenal gland. Causes include:

1. Adrenal adenoma - accounts for 10% of cases endogenous Cushing.
2. Bilateral macronodular adrenal hyperplasia
3. Adrenal carcinomas - rare.
4. Carney complex (CNC)- an autosomal dominantly inherited disorder that affects the integumentary, endocrine, cardiovascular, and central nervous systems. Endocrine-wise, it involves numerous small, autonomously functioning adrenal nodules which can lead to primary pigmented nodular adrenocortical disease (PPNAD).
• Secondary hypercortisolism (ACTH-dependent Cushing syndrome):

Secondary hypercortisolism refers to the overproduction of ACTH.

1. Pituitary adenoma (Cushing's disease) - Cushing’s disease is the most common cause of endogenous hypercortisolism, accounting for 70-80% of cases. In Cushing disease, there is a pituitary adenoma leading to elevated ACTH → bilateral adrenal gland hyperplasia → increased cortisol.
2. Ectopic ACTH production - ectopic secretion of ACTH is usually from neuroendocrine tumours and paraneoplastic syndromes. Carcinomas involved in this include:
• Small cell lung cancer - the most common, because SCLC arises from neuroendocrine cells (Kulchitsky cells/ APUD cells) that release ectopic ACTH.
• Renal cell carcinoma
• Pancreatic carcinoma - ACTH-producing neuroendocrine tumour (NET) of the pancreas is rare.
• Bronchial carcinoid carcinoma - a rare lung cancer also arising from Kulchitsky cells that produce ACTH.
• Phaeochromocytoma - very rarely, phaeochromocytoma can be ACTH-secreting causing secondary endogenous hypercortisolism.

It is important to note that these patients often present atypically, skipping the usual features of Cushing, and presenting with hypertension & hypokalaemia

• Tertiary hypercortisolism:

This refers to excessive CRH release which leads to hypercortisolism, but is extremely rare and hence not discussed here.

😷 Presentation

• Secondary hypertension - this is present in ∼90% of cases.
• Increased susceptibility to infections - due to immunosuppression.
• Peptic ulcer disease - as cortisol inhibits phospholipase A2, this inhibiting the production of arachidonic acid, which would go through COX1 or COX2 pathways to form prostaglandins that are protective of the GI mucosal lining (specificially PGE2).
• Cataracts - specifically, posterior subcapsular cataracts. This is due to glucocorticoid-induced changes to the lens of the eye and lens protein metabolism. It also predisposes one to diabetes and hypertension which increase the risk for cataract development.

• Skin changes:
• Thin, easily bruisable skin 
• Stretch marks - classically purple abdominal striae known as violaceous striae. This is due to rapid weight gain coupled with dermal thinning and decreased collagen synthesis.
• Hirsutism - due to excessive androgens through stimulation of the zona reticulata, peripheral conversion in adipose tissue, and ovarian production of androgens.
• Acne - as androgens increase sebaceous gland activity. There is also increased skin sensitivity and inflammation. Hyper insulin anemia also stimulates sebum production and increases inflammation in the skin.
• Hyperpigmentation - in areas that are not exposed to the sun - due to the overproduction of melanin, as melanocyte stimulating hormone (MSH) is also stimulated by ACTH. It is only present in secondary hypercortisolism and not primary hypercortisolism.
• Facial flushing (facial plethora)
• Delayed wound healing

• Musculoskeletal effects:
• Osteopenia, osteoporosis, pathological fractures, avascular necrosis of the femoral head - due to the inhibition of calcitriol by cortisol. Osteoclast activity is increased while osteoblasts are suppressed. Cushing also leads to impaired blood supply to bone through vasoconstriction and endothelial dysfunction → AVN.
• Muscle atrophy/weakness - usually proximal muscles. This is because cortisol leads to protein metabolism and degradation.
• Neuropsychological effects:
• Depression
• Anxiety and irritability
• Lethargy and fatigue
• Sleep disturbance
• Memory deficits
• Psychosis
• Endocrine and metabolic effects:
• Mild polyuria - in cases of severe hyperglycaemia due to insulin resistance that arises from diabetogenic effects of cortisol and other glucocorticoids. Polyuria occurs as a result of osmotic diuresis when glucose levels cross the proximal tubular reabsorption threshold of 180 mg/dL.
• Dyslipidaemia - as increases in cortisol cortisol result increased lipolysis.
• Weight gain - characterised by central obesity, moon face, dorsocervical fat pad (buffalo hump at the base of the neck) - due to relocation of body fat from the body periphery to the body centre.
• In males: decreased libido
• In females: decreased libido, virilization (masculinization), and/or irregular/absent menstrual cycles

In children: growth delay

🔍 Investigations

Initial investigations include:

• Urine pregnancy test - as pregnancy can be a cause of pseudo-Cushing's, it needs to be excluded before further evaluation in all women of childbearing age
• Serum glucose - elevated.
• U&Es - hypokalaemia may be seen.
• Blood gas - metabolic alkalosis.

There are 3 tests we can consider as first-line options:

• 🥇 Late-night salivary cortisol - samples are collected by saturating a collection swab with saliva or by passively drooling into a collection tube between 11pm and midnight. Normally, cortisol levels are lowest at midnight. In patients with hypercortisolism, the cortisol level does not drop as low at midnight because of the loss of the circadian rhythm. 2 measurements are required.
• 🥇24-hr urinary free cortisol - >50mcg/24 hours is positive. This can be considered as first-line for everyone except patients with renal failure. 2 measurements are required.
• 🥇 Low-dose overnight dexamethasone suppression test - this be a first-line test in any patient with suspected Cushing syndrome, except those taking medications affecting dexamethasone metabolism (phenytoin, carbamazepine, rifampicin, and cimetidine). The low-dose test is considered a screening test for Cushing syndrome as it is the most sensitive first-line test.

1 mg of dexamethasone is administered between 11 pm - 12 am, and serum cortisol is measured the following morning between 8-9 am. A normal result is that the cortisol level is suppressed. A supportive diagnostic result is those who do not have their morning spike suppressed (elevated cortisol - >1.8mcg/dL).

There is a variation of the low-dose test, the low dose 48-hour test which is used in suspected Cushing’s syndrome. For the low-dose 48-hour test, 0.5 mg dexamethasone is taken every 6 hours for 8 doses, starting at 9 am on the first day. Cortisol is checked at 9 am on day 1 (before the first dose) and 9 am on day 3 (after the last dose). A normal result is that the cortisol level on day 3 is suppressed. Failure of the dexamethasone to suppress the day 3 cortisol (>1.8 micrograms/dL) could indicate Cushing syndrome.

💡 General rule of thumb is that a diagnosis of Cushing syndrome is made when at least 2 of the first-line tests are positive.

Once a diagnosis is confirmed, we should perform localisation testing to identify the cause of hypercortisolism:

• 🥇 Early morning and midnight plasma ACTH and cortisol levels - if ACTH is suppressed then this indicates a non-ACTH dependent cause such as an adrenal adenoma.
• High-dose dexamethasone suppression test - it is done in the same manner as the low dose 48-hour test, except now the dose is high enough (2mg) to suppress the Cushing syndrome caused by a pituitary adenoma (Cushing’s disease), but not when it is caused by an adrenal adenoma or ectopic ACTH.

• CRH stimulation - this can help localise the source as either pituitary or adrenal/ectopic:
• Pituitary - cortisol rises.
• Adrenal/ectopic - no change in cortisol.
• Inferior petrosal sinus sampling (IPSS) can be done in patients with confirmed ACTH-dependent Cushing syndrome, when a pituitary adenoma could not be confirmed on MRI. Blood is sampled peripherally and in the inferior petrosal sinuses simultaneously:
• If the blood in the petrosal sinuses has a concentration of ACTH greater than 2x of that in the peripheral blood at baseline or greater than 3x after stimulation with CRH, the source of the hypercortisolism is pituitary ACTH secretion.
• If the ACTH ratio does not reach this threshold, ectopic ACTH secretion is likely
• Imaging - may be done to identify a tumour:
• MRI brain for a pituitary adenoma (done with gadolinium enhancement)
• CT chest for small cell lung cancer
• CT abdomen for adrenal tumours

Management