Approach

The most important decision in the diagnosis of Cushing syndrome is deciding which patients need to begin a diagnostic evaluation. With the growing epidemic of obesity and metabolic syndrome (central obesity with hypertension and insulin resistance), many patients have a Cushingoid phenotype, but most do not have Cushing syndrome.

Important considerations include female sex, as women have a higher proportion of Cushing syndrome, unexplained hypertension (particularly in young patients), new onset of glucose intolerance or diabetes, unexplained weight gain, unexplained fractures (due to premature osteoporosis), hirsutism, menstrual irregularities, and unexplained proximal muscle weakness. Cushing syndrome creates a hypercoagulable state and is associated with an increased risk of venous thromboembolic disease, such as deep vein thrombosis and pulmonary embolism.[1]​​

History

All patients with suspected Cushing syndrome should have a complete history to exclude the use of oral, injectable, inhaled, or topical glucocorticoids manifesting as iatrogenic disease. At a minimum, patients with the following conditions should go on to be screened:[19][20]

  • Features unusual for age (i.e., osteoporosis or hypertension in young patients)

  • Less-usual features, such as unexplained psychiatric symptoms (including depression)

  • Unexplained nephrolithiasis

  • Multiple or progressive symptoms

  • Polycystic ovary syndrome

  • Pituitary adenomas

  • Adrenal adenomas

Physical

Clinical features suggesting Cushing syndrome include:

  • Progressive proximal muscle weakness

  • Bruising without obvious trauma

  • Facial plethora or rounding

  • Violaceous striae

  • Supraclavicular fat pad

  • Dorsocervical fat pad.

Children exhibiting weight gain with decreased linear growth velocity should also be considered. In addition, many patients have increased frequency of acne on the face, back, and chest.

Rapid virilisation in females (rapid-onset or increased hirsutism, voice deepening, and clitoral enlargement) in the setting of cortisol excess suggest adrenal carcinoma, which is associated with a 50% to 60% chance of Cushing syndrome.[5]

Initial biochemical testing

One of the following three high-sensitivity tests, or a combination, should be used as a first-line diagnostic test in patients with suspected Cushing syndrome:[19][21][22]

  • Late-night salivary cortisol

  • Overnight 1 mg dexamethasone suppression testing

  • 24-hour urinary free cortisol

The 48-hour 2 mg dexamethasone suppression test is rarely used in isolation but can be used in combination with other tests. Although all of the included diagnostic tests are highly sensitive and specific, dexamethasone suppression testing was found to be the most sensitive while 24-hour urinary free cortisol was less sensitive.[23]

Confirmation of biochemical testing

To increase diagnostic accuracy, the initial high-sensitivity test should be repeated.[19] For example, late-night salivary cortisol samples should be obtained on two separate nights.[24][25][26] Similarly, at least two 24-hour urinary free cortisol samples should be collected.[27] Alternatively, a second high-sensitivity test may be performed: for example, supplementing a late-night salivary cortisol test with a 24-hour urinary free cortisol measurement.[28] Testing of late-night salivary cortisol is more accurate at initial diagnosis, but late-night salivary cortisol can frequently be normal in patients with recurrent/persistent disease after pituitary surgery, requiring more samples for testing.[29]

Patients with initial normal biochemical testing are unlikely to have Cushing syndrome. If signs or symptoms progress, or intermittent Cushing syndrome is suspected, repeat biochemical testing can be performed after 6 months or at a time when cortisol hypersecretion is assumed.[19]

Patients with any abnormal initial biochemical testing require further investigation and referral to an endocrinologist should be considered. Before proceeding with any further evaluation, physiological causes of hypercortisolism should be excluded. These conditions include: psychiatric disorders including depression, alcohol use disorder, physical stress, malnutrition, pregnancy, and perhaps class III obesity (BMI 40 or above) or metabolic syndrome.[21][30][31][32] Urine pregnancy testing should be considered to exclude pregnancy, and glucose testing may reveal concomitant glucose intolerance or diabetes.

If multiple additional tests are abnormal, the patient has Cushing syndrome and differential diagnostic testing should be undertaken.

Algorithm for diagnosis of Cushing syndrome Opens in new window[21]

Initial differential diagnostic testing

Once hypercortisolism has been established, further testing is done to determine the aetiology.

Morning plasma adrenocorticotrophic hormone (ACTH) is the test of choice for differentiating ACTH-dependent from ACTH-independent Cushing syndrome (when interpreting values, note that assays differ between different laboratories).[1][2][33]​

  • Unsuppressed ACTH levels (>4 picomol/L [>20 picograms/mL]) suggest ACTH-dependent Cushing syndrome.

  • Suppressed/low ACTH levels (<2 picomol/L [<10 picograms/mL]) suggest ACTH-independent Cushing syndrome.

In patients with ACTH levels in the intermediate range, measurement of dehydroepiandrosteronesulphate may be considered. Dehydroepiandrosterone sulphate is ACTH-stimulated, therefore low-normal or suppressed dehydroepiandrosterone sulphate concentrations indicate an adrenal cause (ACTH-independent Cushing syndrome).[1]​ Greatly elevated dehydroepiandrosterone sulfate levels are suggestive of adrenocortical carcinoma, but are neither sensitive nor specific.[34]

Further differential diagnostic testing

ACTH-dependent Cushing syndrome - differentiating between ACTH-secreting pituitary adenomas (Cushing's disease) and ectopic ACTH-secreting tumours.

In patients with established ACTH-dependent Cushing syndrome, pituitary/sellar magnetic resonance imaging (MRI) is performed to detect an ACTH-secreting pituitary adenoma. A spoiled-gradient echo 3D T1 sequence has been shown to have higher sensitivity than dynamic MRI for detecting and localising pituitary micro-adenomas in patients with Cushing syndrome.[35]

Patients with ACTH-dependent Cushing syndrome and an adenoma ≥10 mm on MRI should proceed to treatment. Some clinicians prefer additional biochemical confirmation with high-dose dexamethasone suppression testing before initiating surgical therapy.[36]​ The use of high-dose dexamethasone suppression testing is an area of debate because of its variable sensitivity and specificity.[37]

Patients with adenomas 6-9 mm on MRI should undergo inferior petrosal sinus sampling (IPSS) to confirm the diagnosis.[21]​ Patients without definitive lesions on MRI should also undergo IPSS.[1][2][38]​​ Approximately 40% to 50% of patients with Cushing's disease will not have visible lesions on pituitary/sellar MRI.[1]​ Because of the potential risk to patient, IPSS should preferably be carried out in a specialised centre.[21]​ IPSS is the only test with sufficient diagnostic accuracy to differentiate Cushing's disease from ectopic ACTH production.[39]​ Patients with an IPSS central/peripheral gradient >2:1 or 3:1 after corticotrophin-releasing hormone (CRH) stimulation have Cushing's disease and can undergo therapy. Patients without an IPSS central/peripheral gradient >2:1 or 3:1 after CRH stimulation should be investigated for ectopic ACTH secretion.[38]​ This evaluation generally includes computed tomography (CT) scanning of the chest, abdomen, and pelvis to look for a tumour secreting ACTH. The most common tumours that secrete ACTH are bronchial or thymic carcinoids. Other neuroendocrine tumours include islet cell and medullary thyroid cancer.[2]​ An MRI of the chest may be helpful in selected cases; other imaging modalities such as fluorodeoxyglucose positron emission tomography (FDG-PET), gallium-68 dotatate positron emission tomography (PET)/CT, 18F-DOPA PET/CT, and octreotide scanning may be considered in some patients.[40][41][42][43][44][45]​​ Note that 18F-DOPA PET/CT is not currently widely available and is not approved in the US.

ACTH-independent Cushing syndrome

In patients with established ACTH-independent Cushing syndrome, imaging of the adrenal glands using CT is performed to identify adrenal pathology causing hypercortisolism, such as an adenoma.[1][33]​​​ Several adrenal abnormalities can produce excess cortisol; however, unilateral adrenal adenoma is the most common cause of ACTH-independent Cushing syndrome.[1]

Adrenal protocol CT is recommended to differentiate adenomas from adrenal carcinoma (unenhanced CT followed by contrast-enhanced CT as indicated).[33]​ Adrenal adenomas typically have attenuation less than 10 Hounsfield units (HU) on unenhanced CT and rapid contrast washout on contrast-enhanced CT scans. Adrenocortical carcinoma has attenuation more than 10 HU on unenhanced CT scans and delayed contrast washout.[1][2]​​ Additional evaluation recommended for suspected adrenal carcinoma includes FDG-PET/CT, chest CT with or without contrast, abdomen/pelvis CT or MRI scans with contrast.[18][33]​​

Primary bilateral macronodular adrenal hyperplasia is characterised by nodules with an appearance like bunches of grapes in both adrenal glands on adrenal CT.[2]​ Adrenal glands may appear normal on adrenal CT in patients with micronodular adrenal hyperplasia, or may appear slightly hyperplastic with micronodules, usually smaller than 6 mm in diameter.[2]

Mild autonomous cortisol secretion (previously known as subclinical Cushing syndrome)

These patients have an incidentally discovered adrenal adenoma producing mildly excessive cortisol, but do not have signs or symptoms of Cushing syndrome. Mild cortisol excess requires a specialised approach and may be more difficult to diagnose as a function of the inherent nature of the disease.[46][47][48]​​​​ In patients with incidentally discovered adrenal nodules without clinical features of Cushing syndrome, use the 1 mg dexamethasone suppression test as the initial diagnostic test because urinary free cortisol and late-night salivary cortisol have a lower sensitivity in these patients.​[22][47]​​[49][50]​​​​​ European guidelines also suggest considering a second careful clinical evaluation to check for overlooked signs or symptoms of Cushing syndrome and confirming ACTH independency with morning plasma ACTH.[47]​ Screening for comorbidities that may be attributable to mild cortisol excess (type 2 diabetes, hypertension, dyslipidaemia) is also recommended, to guide management.[47]

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