Cushing syndrome

Cushing syndrome is an endocrine disorder caused by hypercortisolism, most commonly due to exogenous glucocorticoid administration (iatrogenic Cushing syndrome). Cushing syndrome can also be caused by endogenous overproduction of cortisol. Primary hypercortisolism is caused by autonomous overproduction of cortisol by the adrenal gland (e.g., due to an adrenal adenoma or carcinoma). Secondary hypercortisolism is the result of elevated adrenocorticotropic hormone (ACTH) due to overproduction by either a pituitary adenoma (Cushing disease) or ectopic, paraneoplastic foci (e.g., in patients with small cell lung cancer). Typical clinical features include central obesity, thin and easily bruisable skin, abdominal striae, secondary hypertension, hyperglycemia, and proximal muscle weakness. Prepubertal children with Cushing syndrome also commonly present with lack of height gain and excessive weight gain. Measurement of cortisol (urine free and/or late-night salivary cortisol) and/or the dexamethasone suppression test are used to diagnose hypercortisolism. Serum ACTH levels are used to differentiate between primary and secondary hypercortisolism. Depending on the suspected type of Cushing syndrome, additional studies may include imaging, further hormone testing, and bilateral sampling of the inferior petrosal sinus. The treatment of endogenous hypercortisolism primarily involves surgical removal of the source of excessive cortisol (e.g., adrenalectomy) or ACTH (e.g., transsphenoidal hypophysectomy) production. Pharmacological treatment aimed at normalizing cortisol levels (e.g., metyrapone) may be used in addition to surgical treatment or as second-line treatment if surgery is unsuccessful.

Exogenous (iatrogenic) Cushing syndrome

• Prolonged glucocorticoid therapy → hypercortisolism → decreased ACTH → bilateral adrenal atrophy
• Most common cause of hypercortisolism

Endogenous Cushing syndrome

While the term “Cushing syndrome” can be applied to any cause of hypercortisolism, “Cushing disease” refers specifically to secondary hypercortisolism that results from excessive production of ACTH by pituitary adenomas.

Secondary hypercortisolism is also called ACTH-dependent Cushing syndrome because hypercortisolism is the result of increased ACTH levels.

For additional features in children, see “Cushing syndrome in children.”

Skin [2]

• Thin, easily bruisable skin with ecchymoses
• Stretch marks (classically purple abdominal striae)
• Hirsutism
• Acne
• If secondary hypercortisolism: often hyperpigmentation (darkening of the skin due to an overproduction of melanin), especially in areas that are not normally exposed to the sun (e.g., palm creases, oral cavity)
  • Caused by excessive ACTH production because melanocyte-stimulating hormone (MSH) is cleaved from the same precursor as ACTH called proopiomelanocortin (POMC)
  • Not a feature of primary hypercortisolism
• Delayed wound healing
• Flushing of the face

Neuropsychological

• Anxiety, irritability
• Lethargy, fatigue
• Sleep disturbance
• Memory deficits
• Depression
• Psychosis

Musculoskeletal [2]

• Osteopenia, osteoporosis, pathological fractures, avascular necrosis of the femoral head
• Muscle atrophy/weakness

Endocrine and metabolic [3]

• Insulin resistance; → hyperglycemia (see “Diabetes mellitus”) → mild polyuria in the case of severe hyperglycemia
• Dyslipidemia
• Weight gain characterized by
  • Central obesity
  • Round face (sometimes called “moon facies”)
  • Dorsocervical fat pad
  • Supraclavicular fat pads
• ♂: Decreased libido, gynecomastia
• ♀: Decreased libido, virilization, and/or irregular menstrual cycles (e.g., amenorrhea)

Other features [1]

• Secondary hypertension (∼ 90% of cases)
• Increased susceptibility to infections (due to immunosuppression)
• Peptic ulcer disease
• Cataracts

“CUSHINGOID” is the acronym for side effects of corticosteroids: Cataracts, Ulcers, Striae/Skin thinning, Hypertension/Hirsutism/Hyperglycemia, Infections, Necrosis (of the femoral head), Glucose elevation, Osteoporosis/Obesity, Immunosuppression, Depression/Diabetes.

Patients with secondary hypercortisolism due to ectopic ACTH production may present with rapid onset of hypertension and hypokalemia without other typical features of Cushing syndrome.

Consider a diagnosis of hypercortisolism in patients who present with proximal muscle weakness, central obesity, thinning skin, weight gain, sleep disturbance, and/or depression.

Approach [1][4][5]

• Evaluate for clinical features of Cushing syndrome.
• Rule out exogenous Cushing syndrome caused by glucocorticoid administration.
• Obtain initial testing to confirm hypercortisolism; consult endocrinology if the diagnosis remains unclear.
• Refer to endocrinology for further diagnostics and treatment if hypercortisolism is confirmed.
• Identify the cause of hypercortisolism.
  • Consider nonneoplastic causes of endogenous hypercortisolism (pseudo-Cushing).
  • Determine if Cushing syndrome is ACTH-dependent.
  • Order further testing depending on the suspected type of Cushing syndrome.

Prolonged glucocorticoid therapy is the most common cause of hypercortisolism (exogenous Cushing syndrome); further testing is not required in these patients.

Routine laboratory studies [6]

Not required to establish the diagnosis, but if performed, may show the following typical findings:

• Hypernatremia, hypokalemia, metabolic alkalosis
• Hyperglycemia: due to stimulation of gluconeogenic enzymes (e.g., glucose-6-phosphatase) and inhibition of glucose uptake in peripheral tissue
• Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia)
• CBC: leukocytosis without left shift (predominantly neutrophilic), eosinopenia

Testing for hypercortisolism [2][3][4][5][7]

Any of the following tests can be used. The diagnosis is confirmed if at least two of the tests have abnormal results.

• Urine free cortisol ; [2]
  • Free cortisol is measured in a complete 24-hour urine collection.
  • Supportive finding: ↑ urine free cortisol [2][3]
• Low-dose dexamethasone suppression test
  • 1 mg of dexamethasone is administered between 11 pm and midnight and serum cortisol is measured the following morning between 8 and 9 am.
  • Supportive finding: ↑ early morning serum cortisol level (> 50 nmol/L) [5]
• Late-night salivary cortisol
  • A saliva sample is collected at the patient's usual bedtime.
  • Supportive finding: ↑ salivary cortisol (> 4 nmol/L) [5][8]
• Late-night serum cortisol: not routinely recommended as the initial test but can be used in patients with inconsistent results from previous tests
  • A serum sample is taken from the patient (awake or asleep).
  • Supportive finding: ↑ serum cortisol (> 210 nmol/L) [4]

Consult an endocrinologist for further evaluation if any of the findings above are present or if the results are negative despite a high pretest probability.

Identifying the cause [5]

Initial evaluation

1. Consider nonneoplastic and physiological causes of hypercortisolism based on clinical features and patient history (e.g., depression, heavy alcohol use, obesity) and in pregnant patients. [9]
2. Measure serum ACTH levels.
   • Low (< 5 pg/mL): Suspect primary hypercortisolism (ACTH-independent). [2][10]
   • Inappropriately normal OR elevated (> 20 pg/mL): Suspect secondary hypercortisolism (ACTH-dependent). [2][3][10]
3. Proceed based on the results.
   • If ACTH-independent hypercortisolism is suspected: Obtain adrenal MRI and/or CT.
     • Assess for an adrenal tumor (e.g., adrenal adenoma, carcinoma, hyperplasia).
     • The adrenal cortex contralateral to the tumor shows atrophy due to reduced ACTH stimulation.
   • If ACTH-dependent hypercortisolism is suspected: Obtain further testing.

Differentiating between Cushing syndrome and nonneoplastic-physiologic hypercortisolism can be very challenging. If there is any doubt, refer the patient to a specialized center.

Further testing in patients with ACTH-dependent hypercortisolism [2][5]

The goal is to differentiate between Cushing disease and ectopic ACTH production. A combination of tests is often necessary.

• Obtain a pituitary MRI to evaluate for Cushing disease (see also “Diagnostics” in “Pituitary adenoma”).
  • Pituitary adenoma > 10 mm confirms Cushing disease.
  • If there is no evidence of a pituitary adenoma or findings are unclear, obtain either: [5]
    • Bilateral sampling of the inferior petrosal sinus
    • Hormone testing in ACTH-dependent hypercortisolism
• If ectopic ACTH production is suspected: imaging to locate the ACTH-producing primary malignancy (e.g., SCLC, RCC, neuroendocrine tumor).
  • Multiple studies are often necessary. [10]
  • May include a thin-slice whole-body CT scan and functional imaging (e.g., PET scan)

Abdominal CT or MRI in a patient with Cushing disease will show bilateral hyperplasia of both the zona fasciculata and zona reticularis.

The results of these tests must always be considered in the clinical context, and a combination of tests is usually necessary. Hormone-secreting pituitary microadenomas cannot always be detected on imaging and, conversely, small endocrine-inactive tumors may be detected in healthy individuals, potentially leading to overdiagnosis.

In Cushing syndrome, only patients with Cushing disease remain (partially) susceptible to cortisol suppression (high-dose dexamethasone suppression test) and stimulation (CRH stimulation test).

The following section applies to endogenous Cushing syndrome. For patients with exogenous Cushing syndrome, consider lowering the dose of glucocorticoids or replacing them.

Approach [2][3][5][11]

• Manage with a multidisciplinary team including an endocrinologist.
• First-line treatment: tumor resection
• Second-line or adjunctive therapy: pharmacological treatment

Patients who develop adrenal insufficiency after surgery require lifelong glucocorticoid replacement therapy.

Enzyme inhibitors (e.g., metyrapone, ketoconazole) suppress cortisol synthesis, while glucocorticoid antagonists block the action of cortisol in peripheral tissues.

Supportive management [11]

• Educate patients about the disease, including the risk of recurrence and the increased risk for venous thromboembolism.
• Ensure vaccinations are up-to-date in accordance with the ACIP immunization schedule.
• Screen for and treat any common comorbidities (e.g., diabetes, hypertension, osteoporosis, psychiatric disorders).

First line: curative surgery [12]

Radiotherapy and/or chemotherapy may be indicated as part of the management of the causative tumor.

Surgical procedures

• Primary hypercortisolism: : unilateral or bilateral laparoscopic or open adrenalectomy for adrenocortical tumors
• Cushing disease: transsphenoidal hypophysectomy
• Ectopic ACTH production: tumor resection with node dissection, as appropriate

Follow-up

• Patients should receive lifelong monitoring for recurrence by a specialist.
• Glucocorticoid replacement therapy is often necessary after surgery.
  • Reevaluate 6–18 months after unilateral adrenalectomy or resection of ACTH-secreting tumors.
  • Lifelong glucocorticoid replacement therapy is required after bilateral adrenalectomy (see “Treatment” in “Adrenal insufficiency”).

Pharmacological treatment

Decisions about pharmacotherapy should be guided by an endocrinologist.

Bilateral adrenalectomy [11]

• Indications
  • Primary hypercortisolism caused by bilateral adrenal disease (recommended curative treatment)
  • Emergency treatment in severe ACTH-dependent hypercortisolism that cannot be controlled pharmacologically
  • Symptomatic treatment for metastatic or occult ectopic tumors
• Complication: Nelson syndrome (post adrenalectomy syndrome) [13]
  • Etiology: bilateral adrenalectomy in patients with a previously undetected pituitary adenoma
  • Pathophysiology: bilateral adrenalectomy → no endogenous cortisol production → no negative feedback from cortisol on the hypothalamus → ↑ CRH production → uncontrolled enlargement of preexisting but undetected ACTH-secreting pituitary adenoma → ↑ secretion of ACTH and MSH → manifestation of symptoms due to pituitary adenoma and ↑ MSH
  • Clinical features: headache, bitemporal hemianopia (mass effect), cutaneous hyperpigmentation
  • Diagnostics
    • High levels of β-MSH and ACTH
    • Pituitary adenoma on MRI confirms the diagnosis.
  • Treatment: surgery (e.g., transsphenoidal resection) and/or pituitary radiation therapy (e.g., if the tumor cannot be fully resected)

Etiology [5][14]

• Most common: exogenous glucocorticoid exposure [14]
• Less common: endogenous Cushing syndrome [5][14]
  • Children < 6 years: usually due to adrenal causes
  • Children ≥ 6 years: usually due to ACTH-secreting pituitary tumors

Clinical features [5][14][15]

• Clinical features of Cushing syndrome are similar in adults and children.
• Key findings specific to children include:
  • Lack of height gain combined with excessive weight gain
  • Atypical pubertal development (e.g., delayed gonadarche, advanced adrenarche)

Diagnosis [5][14]

Diagnostics for Cushing syndrome are similar in children and adults, with the following exceptions:

• Refer to a pediatric endocrinologist to differentiate ACTH-dependent causes from ACTH-independent causes.
• The following tests require adaptations for children: [15]
  • Dexamethasone suppression test: Lower doses may be required depending on weight.
  • Urinary free cortisol: Correct for body surface area.
• Consider genetic screening in children with any of the following: [5]
  • A family history of endocrine tumors
  • Clinical features suggesting a genetic syndrome

Management [5][14]

Refer all children to a multidisciplinary center with specialist expertise (e.g., pediatric endocrinology, neurosurgery). Management of Cushing syndrome is similar in children and adults, with the following exceptions:

• Ketoconazole (off-label) or metyrapone (off-label) is the preferred pharmacotherapy when indicated. [5]
• Growth hormone replacement is often necessary to optimize height.
  • Evaluate for growth hormone deficiency 3–6 months postoperatively. [5]
  • Replace growth hormone if deficiency is confirmed.