Cushing's Syndrome

A 40-year-old woman presents with weight gain, a "moon face," and purple stretch marks on her abdomen. She also reports easy bruising, muscle weakness, and high blood pressure. Laboratory tests reveal hyperglycaemia and a loss of the normal diurnal variation of cortisol secretion.

Pathophysiology

Cushing's syndrome is caused by prolonged exposure to elevated levels of cortisol. This can be due to various causes, but the ultimate effect is the same: cortisol excess disrupts carbohydrate, lipid, and protein metabolism, leading to a wide range of clinical manifestations.

• Increased gluconeogenesis and reduced glucose uptake contribute to hyperglycaemia and an increased risk of developing diabetes.
• Protein catabolism leads to muscle wasting, weakness, and thin skin with easy bruising.
• Altered fat distribution results in central obesity, a "moon face," and a "buffalo hump."
• Mineralocorticoid effects of cortisol can contribute to hypertension and hypokalaemia.

Aetiology

Cushing's syndrome can be classified as exogenous or endogenous, depending on the source of excess cortisol.

Exogenous Cushing's Syndrome

This is the most common cause overall and is caused by prolonged use of exogenous glucocorticoids, such as prednisolone or dexamethasone.

Endogenous Cushing's Syndrome

Endogenous Cushing's syndrome is much less common and arises from within the body. It can be further divided into ACTH-dependent and ACTH-independent causes.

• ACTH-dependent Cushing's Syndrome:
  • Cushing's disease: This refers specifically to excess cortisol production due to an ACTH-secreting pituitary adenoma. It is the most common endogenous cause, accounting for around 75% of cases. These adenomas are usually small (microadenomas).
  • Ectopic ACTH secretion: This occurs when a non-pituitary tumour secretes ACTH, leading to increased cortisol production by the adrenal glands. Small cell lung cancer and bronchial carcinoids are common culprits.
• ACTH-independent Cushing's Syndrome:
  • Adrenal adenomas: Benign tumours of the adrenal cortex can autonomously produce cortisol, leading to Cushing's syndrome. They are typically unilateral and account for about 10% of endogenous cases.
  • Adrenal carcinomas: Malignant adrenal tumours can also secrete cortisol. They are less common than adenomas and often present with more rapid symptom development and features of virilisation due to co-secretion of androgens.
  • Micronodular adrenal dysplasia: Very rare

Epidemiology & Risk Factors

Exogenous Cushing's syndrome is more common than endogenous Cushing's syndrome.

Endogenous Cushing's syndrome has an annual incidence of approximately 2 per million.

Risk factors for endogenous Cushing's syndrome include:

• Female sex: Endogenous Cushing's syndrome is more common in women, with a female-to-male ratio ranging from 3:1 to 15:1.
• Age: The typical age of onset is between 20 and 50 years.
• Genetic predisposition: Certain genetic syndromes, such as Carney complex and McCune-Albright syndrome, are associated with an increased risk of developing Cushing's syndrome due to adrenal tumours.

Clinical Features

The clinical presentation of Cushing's syndrome is diverse, but some key features are highly suggestive of the diagnosis. The mnemonic "CUSHINGOID" can be helpful in remembering these features:

• Cataracts
• Ulcers (peptic ulcers)
• Skin (striae, bruising, thinning, ulcers)
• Hirsutism, hypertension
• Infections (due to immunosuppression)
• Necrosis (e.g. avascular necrosis of the femoral head)
• Glycosuria
• Obesity, osteoporosis
• Immunosuppression
• Diabetes

Other common clinical features include:

• Weight gain: Particularly central obesity with a prominent abdomen.
• Moon face: A rounded, full face with facial plethora.
• Buffalo hump: A fatty deposit between the shoulders.
• Proximal myopathy: Muscle weakness, particularly in the shoulders and hips, leading to difficulty climbing stairs or rising from a chair.
• Thin skin and easy bruising: Due to protein catabolism and impaired collagen synthesis.
• Purple striae: Wide, purplish stretch marks, typically on the abdomen, breasts, and thighs.
• Hirsutism and acne: Due to increased androgen production.
• Menstrual irregularities: Amenorrhea or oligomenorrhea.
• Psychological disturbances: Depression, anxiety, irritability, and even psychosis can occur.

Investigations

Confirming Hypercortisolism

The first step in diagnosing Cushing's syndrome is to confirm the presence of hypercortisolism. Several tests can be used, and it's generally recommended to use at least two different tests to confirm the diagnosis.

• 24-hour urinary free cortisol: This measures the amount of cortisol excreted in the urine over a 24-hour period. An elevated level is suggestive of Cushing's syndrome. However, false positives can occur in obese patients, athletes, and those under stress.
• Overnight dexamethasone suppression test: This involves taking a low dose of dexamethasone at night and measuring cortisol levels the following morning. In healthy individuals, cortisol levels should be suppressed by dexamethasone. Failure to suppress cortisol suggests Cushing's syndrome. However, false positives can occur in patients with depression, obesity, alcohol excess, and those taking medications that induce liver enzymes.
• Late-night salivary cortisol: This measures cortisol levels in saliva collected late at night. Cortisol levels should be low at night in healthy individuals. An elevated level suggests Cushing's syndrome.
• 48-hour low-dose dexamethasone suppression test: This is similar to the overnight test but involves taking dexamethasone for two days and measuring cortisol levels at the end of the test.

Localising the Source of Excess Cortisol

Once hypercortisolism is confirmed, the next step is to determine the source of excess cortisol.

• 9am Plasma ACTH levels:
  • Suppressed ACTH: This suggests an ACTH-independent cause, such as an adrenal tumour.  CT or MRI of the adrenal glands should be performed to locate the tumour.
  • Elevated or normal ACTH: This indicates an ACTH-dependent cause, such as Cushing's disease or ectopic ACTH secretion. Further tests are needed to differentiate between these two possibilities.
• High-dose dexamethasone suppression test: This involves taking a higher dose of dexamethasone for two days and measuring cortisol levels.
  • Suppression of cortisol: Suggests Cushing's disease, but not if the pituitary adenoma is large (macroadenoma).
  • No suppression of cortisol: Suggests ectopic ACTH secretion or an adrenal tumour.
• CRH stimulation test: if dexamethasone stimulation test is inconclusive, this involves administering CRH intravenously and measuring cortisol levels.
  • Exaggerated cortisol rise: Supports a pituitary cause (Cushing's disease).
  • No cortisol rise: Suggests ectopic ACTH secretion or an adrenal tumour.
• Inferior petrosal sinus sampling (IPSS): This is a specialised test that involves collecting blood samples from the veins draining the pituitary gland and comparing ACTH levels with those in peripheral blood. A high gradient of ACTH in the petrosal sinus suggests Cushing's disease. IPSS is considered the gold standard for differentiating Cushing's disease from ectopic ACTH production.
• Imaging studies:
  • Pituitary MRI: Can detect pituitary adenomas in Cushing's disease, but small microadenomas may be missed.
  • Chest and abdominal CT: Used to locate ectopic ACTH-secreting tumours.

Management

The management of Cushing's syndrome depends on the underlying cause.

Lifestyle Modifications

Lifestyle modifications, such as weight loss and exercise, can help improve some symptoms, particularly insulin resistance and hypertension. However, they are not a cure for Cushing's syndrome.

Medical Management

Medical therapy may be used to control cortisol levels while awaiting definitive treatment or in cases where surgery is not feasible. Medications used include:

• Metyrapone and ketoconazole: These drugs inhibit cortisol synthesis and can be used to lower cortisol levels.
• Other medications: Fluconazole, mitotane, and etomidate are other options for reducing cortisol production.

Surgical Management

Surgery is the primary treatment for most cases of endogenous Cushing's syndrome.

• Cushing's disease: Trans-sphenoidal surgery to remove the pituitary adenoma is the treatment of choice.
• Adrenal adenoma or carcinoma: Adrenalectomy (removal of the affected adrenal gland) is the definitive treatment. Adrenalectomy is usually curative for adenomas but is less successful in cases of carcinoma.
• Ectopic ACTH secretion: If the tumour is localised and resectable, surgical removal is the preferred treatment.

Post-Surgical Management

• Hormone replacement: Patients who undergo bilateral adrenalectomy require lifelong glucocorticoid and mineralocorticoid replacement therapy, similar to the management of Addison's disease.
• Monitoring for recurrence: Regular follow-up with an endocrinologist is essential to monitor for recurrence of Cushing's syndrome, particularly after surgery.

Complications & Prognosis

Untreated Cushing's syndrome is associated with significant morbidity and mortality.  Complications include:

• Cardiovascular disease: Hypertension, atherosclerosis, heart failure, and stroke.
• Diabetes mellitus: Due to persistent hyperglycaemia.
• Osteoporosis: Increased bone resorption leads to weakened bones and an increased risk of fractures.
• Infections: Immunosuppression increases susceptibility to infections.
• Psychiatric disorders: Depression, anxiety, and psychosis.
• Venous thromboembolism: Patients with Cushing's syndrome have an increased risk of blood clots.

The prognosis for Cushing's syndrome depends on the underlying cause and the timeliness of diagnosis and treatment. With appropriate treatment, many patients can experience significant improvement in their symptoms and quality of life.  However, some complications, such as osteoporosis and diabetes, may persist even after successful treatment of the underlying cause.