Diagnosis of Cushing's Syndrome
Patients may be treated for several years for the symptoms of Cushing's syndrome before being correctly diagnosed. The clinical suspicion of Cushing's arises from clinical signs such as thin skin, bruising, hypertension, 'buffalo hump', plethora, moon face, purple striae, and proximal myopathy. This clinical suspicion needs confirmation by biochemical tests, but subclinical cases and those with an incidentally found adrenal mass will need screening as well.
The main steps in the diagnosis are:
- confirmation of raised blood cortisol
- the cause of this cortisol excess must be established
- any tumours must be localised.
1. Confirmation of raised blood cortisol
Fig.1: Loss of diurnal variation in Cushing's syndromeThere are several screening tests for hypercortisolism: the 24-hour urinary free cortisol, the overnight low-dose dexamethasone suppression test and a late-night salivary cortisol.
Low-dose dexamethasone suppression test is the best screening test, with 95% sensitivity, which takes advantage of the normal diurnal variation in plasma cortisol levels.
In Cushing's syndrome this variation is lost (Fig. 1). Patients are given 1mg of dexamethasone at 2300 hours and then have a 9 am cortisol level measured the next day. Normally this level would be suppressed by the dexamethasone, but the cortisol level is not suppressed in Cushing's syndrome.
Like all tests there are potential pitfalls however, with up to 30% false positives in for example, elderly or depressed patients, and those taking certain drugs, particularly anti-epileptics, oral contraceptives and oestrogen.
24-hour urinary cortisol estimation is a direct measurement of circulating free or biologically active cortisol. Any excess cortisol in the circulation is excreted in the urine as free cortisol. The 24-hour urine collection may need to be repeated several times to overcome the possibility of intermittent hypercortisolism, but a normal level pretty much excludes the diagnosis.
Late-night salivary cortisol is measured at around 10pm-midnight. Normally levels would be extremely low at that time, but Cushings patients lose the diurnal drop and have elevated levels instead.
2. Establishing the cause of the raised cortisol
A variety of tests are used to determine whether the cortisol excess is caused by:
- Over-production by the adrenal gland (ACTH-independent Cushing's)
- Over-stimulation of the adrenal gland by pituitary ACTH (ACTH-dependent Cushing's)
- Over-stimulation of the adrenal gland by ectopic ACTH (ACTH-dependent Cushing's)
These are summarised in the algorithm below (Fig. 2):
Fig.2: Algorithm for investigating suspected Cushing's syndrome
Plasma ACTH levels
These are used to distinguish between primary and secondary disease. ACTH is very low in primary Cushing's syndrome as the over-active adrenal, autonomously producing cortisol, inhibits ACTH production from the pituitary. In secondary disease it is the elevated production of ACTH from the pituitary that is stimulating the adrenal glands to produce excess cortisol. ACTH levels are therefore high in this situation.
High-dose dexamethasone test
This is used to demonstrate the presence of an ectopic source of ACTH or an adrenal tumour. The principle is that high doses of dexamethasone will suppress cortisol production in pituitary-dependent Cushing's disease but will not suppress either an autonomous adrenal tumour or an ectopic source of ACTH.
CRH Stimulation Test
Fig.3: CRH stimulation testThis test can be used to distinguish between pituitary-dependent Cushing's and an ectopic source of ACTH.
Corticotrophin releasing hormone (CRH) is administered intravenously and the cortisol response monitored. Normally there is a rise in both ACTH and cortisol.
In pituitary-dependent Cushing's patients however, the response is exaggerated, and in ectopic ACTH syndrome there will be no response (Fig. 3).
3. Localisation of the tumour
Abdominal CT & MRI scans
Adrenal adenomas and carcinomas tend to be large (>2cm and >6cm in diameter respectively). They therefore readily show up on CT or MRI, although there appears to be little difference on the image between benign and malignant lesions (Fig. 4).
Fig.4: CT scan of Cushing's tumour in the right adrenal gland (arrowed)Pituitary MRI
MRI is the best modality for imaging the pituitary. An isolated 6mm or greater pituitary lesion is almost diagnostic of Cushing's disease. But it is important to remember that up to 40% of patients with proven Cushing's disease have normal pituitary MRI scans and up to 10% of the normal population will have pituitary incidental lesions (but usually less than 5mm in size). Thus it is important that images are tallied with other test results.
Inferior petrosal venous sampling
When pituitary MRI has been equivocal bilateral selective inferior petrosal sinus venous sampling will distinguish between pituitary and non-pituitary sources of ACTH causing Cushing's syndrome. The principle of the test is to sample the blood from the petrosal sinuses draining the pituitary gland, to compare the levels of ACTH with those found in the peripheral blood.
A petrosal : peripheral ratio of > 2, indicating excess ACTH from the pituitary, is necessary to diagnose Cushing's disease with confidence. Accuracy can be improved using CRH stimulation to exaggerate the difference.
Chest CT scan
When an ectopic source of ACTH is suspected a thin-cut CT scan of the chest and abdomen is the ideal way of detecting primary tumours, such as bronchial carcinoid tumours, with a high detection rate.
Octreotide scan
This is where octreotide (an analogue of somatostatin), labelled with a radioactive isotope is injected into the bloodstream. ACTH secreting tumours often have somatostatin receptors on their surface, so that the radiolabelled analogue will bind to the tumour cells. X-ray imaging then allows the tumour to be visualised before surgery.
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