Description
Cushing’s syndrome is a complex endocrine disorder characterised by the persistent elevation of cortisol levels, often resulting from the chronic exposure to excessive glucocorticoids. This excess can originate endogenously, often due to overactive adrenal glands or pituitary adenomas, as seen in adrenal-based Cushing’s and Cushing’s disease, respectively. Alternatively, the disorder can be triggered exogenously through prolonged intake of glucocorticoid medications. There’s also the rare ectopic ACTH syndrome, where non-pituitary tumours produce the adrenocorticotropic hormone (ACTH), driving cortisol overproduction. Regardless of the cause, this consistent hypercortisolism leads to a wide array of symptoms and physical alterations that comprise the clinical presentation of Cushing’s syndrome.
Pathogenesis
Cushing’s syndrome can be caused by:
- Pituitary adenomas producing excessive ACTH, leading to adrenal hyperplasia and increased cortisol production (Cushing’s disease)
- Ectopic production of ACTH by non-pituitary tumours such as small cell lung carcinoma (ectopic ACTH syndrome)
- Adrenal tumours or hyperplasia independently producing cortisol
- Chronic administration of exogenous glucocorticoids (based on the type, dose, and duration of treatment) – oral and injectable corticosteroids have a higher risk with chronic use of higher doses, compared to inhaled, topical, nasal, and intra-articular corticosteroids.
Epidemiology, Risk Factors & Associations
- Incidence of Cushing’s syndrome: 0.7-2.4 cases per million people per year (overall incidence), and 10 cases per million per year for endogenous Cushing’s.
- Females are affected 3 times more often than males.
- Most common cause is the administration of exogenous glucocorticoids.
- Endogenous Cushing’s most commonly caused by Cushing’s disease (70%).
Clinical Features
Classic symptoms and signs include:
- Central obesity with buffalo hump and moon face: Excess cortisol stimulates adipocyte differentiation and fatty acid mobilisation, preferentially depositing fat in central and cervical areas.
- Thin skin, easy bruising, and purplish striae on the abdomen: Elevated cortisol levels inhibit collagen formation, resulting in weakened skin and blood vessels. The striae result from rapid weight gain and skin stretching.
- Muscle wasting and weakness: Cortisol induces proteolysis, leading to muscle protein breakdown and subsequent muscle wasting and weakness.
- Hirsutism and menstrual irregularities in women: High cortisol can disrupt the normal balance of sex hormones, leading to increased androgen production and its associated features.
- Osteoporosis: Chronic hypercortisolism can accelerate bone resorption and impair bone formation, leading to osteoporosis.
- Hypertension: Excess cortisol enhances vascular reactivity to vasoconstrictors and increases fluid retention, raising blood pressure.
- Diabetes: Cortisol-induced insulin resistance and impaired glucose tolerance can lead to diabetes.
Complications
- Cardiovascular disease
- Thromboembolic events
- Infections
- Psychiatric disturbances
Subtypes
Cushing’s syndrome can be categorised based on the source of cortisol overproduction:
- Cushing’s Disease (70 – 80% of cases): Most common cause of Cushing’s syndrome. Caused by an adenoma (benign tumour) of the pituitary gland that produces excess ACTH, leading to increased cortisol production by the adrenal glands. More common in women and typically presents in the third to fifth decades of life.
- Ectopic ACTH Syndrome (10%): Caused by non-pituitary tumours that produce ACTH. These tumours can be benign or malignant and are most often located in the lungs (e.g., small cell lung carcinoma or carcinoid tumours), thymus, or pancreas (pancreatic neuroendocrine tumour).
- Adrenal-based Cushing’s (10 – 15%): Caused by an adenoma, carcinoma, or hyperplasia of the adrenal gland itself, leading to the overproduction of cortisol.
- Exogenous Cushing’s: Caused by chronic exposure to glucocorticoids, often due to medication use (e.g., prednisone or dexamethasone). Can occur at any age with symptoms often resolving once the glucocorticoids are discontinued, though this must be done carefully to avoid adrenal insufficiency.
Pathological Features
Histopathology
- In pituitary-based disease, a pituitary adenoma may be identified.
- In adrenal-based disease, adenomas, carcinomas or nodular hyperplasia may be seen.
Biochemistry
- Elevated cortisol levels
- Elevated ACTH in pituitary and ectopic Cushing’s syndrome
- Suppressed ACTH in adrenal and exogenous Cushing’s syndrome
Radiological Features
CT
- Demonstrates adrenal adenomas or hyperplasia in adrenal Cushing’s syndrome.
- May show bilateral adrenal enlargement in cases of ACTH-dependent Cushing’s syndrome.
- Pituitary adenoma (Cushing’s Disease): Pituitary adenomas can be seen as a well-defined, enhancing lesion in the sella turcica. However, many are microadenomas (<1 cm) and may not be seen.
- Ectopic ACTH syndrome: The source of ectopic ACTH can often be identified using CT. Chest CT may identify lung tumours, and abdominal CT can identify other potential sources such as pancreatic neuroendocrine tumours.
- Adrenal adenoma or carcinoma: Adrenal adenomas usually present as small (<4 cm), well-defined, low-attenuation lesions on CT. Adrenal carcinomas are typically larger, irregular, and may demonstrate local invasion or metastasis.
- Exogenous Cushing’s: CT of the adrenal glands may show bilateral adrenal atrophy due to suppression of ACTH from the chronic exogenous glucocorticoid use.
MRI
- Preferred for suspected Cushing’s disease.
- Pituitary adenoma (Cushing’s Disease): On MRI, pituitary adenomas (microadenomas (less than 10 mm) or macroadenomas (more than 10 mm)) may show as hypointense on T1-weighted images and variable intensity on T2-weighted images. They typically enhance after contrast administration.
- Ectopic ACTH syndrome: MRI can be helpful in further characterising lesions identified on CT.
- Adrenal adenoma or carcinoma: Adrenal adenomas are typically hypointense on out-of-phase T2-weighted images compared to in-phase images due to their lipid content. Carcinomas may appear heterogeneous due to areas of necrosis or haemorrhage.
- Exogenous Cushing’s: As with CT, chronic exogenous glucocorticoid use may result in bilateral adrenal atrophy visible on MRI.
Octreotide Scans
- Used to identify source of ectopic ACTH production.
- Octreotide, a synthetic somatostatin analogue, binds to somatostatin receptors on neuroendocrine tumour cells.
- After being labelled with a radioactive tracer (usually Indium-111), it allows for the visualisation of these tumours through gamma camera imaging.
- Not all ACTH-secreting tumours will show. Negative results do not completely exclude the condition.
Differential Diagnosis
- Pseudo-Cushing’s Syndrome: This condition can mimic the signs and symptoms of Cushing’s syndrome. It is often related to obesity, depression, alcoholism or high estrogen states. These individuals often have normal cortisol rhythm and suppression on dexamethasone testing.
- Polycystic Ovary Syndrome (PCOS): PCOS can also mimic some features of Cushing’s syndrome, such as hirsutism, menstrual irregularities and obesity. However, the presence of polycystic ovaries on ultrasound and other hormonal imbalances can help differentiate PCOS.
- Metabolic Syndrome: This condition is associated with obesity, insulin resistance, dyslipidemia, and hypertension, which can overlap with some manifestations of Cushing’s syndrome. However, metabolic syndrome does not typically present with the specific signs of cortisol excess, such as thinning skin or easy bruising.
- Adrenal Incidentaloma: This refers to an unexpected adrenal mass detected on imaging done for other reasons. These need to be evaluated for hormonal activity. A non-functional adenoma may be managed with surveillance imaging, while a functional adenoma producing excess cortisol would be a cause of Cushing’s syndrome.
Management
- Surgical removal of the source of excess cortisol is the treatment of choice.
- Pharmacotherapy is an option for patients who cannot undergo surgery.
- Refer to endocrinology for management of hypercortisolism and its complications.