Cushing's syndrome

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When a doctor suspects a patient may have Cushing’s syndrome they will do one of several possible screening tests. If the screening test indicates the patient may have Cushing’s syndrome, other tests will be carried out.

Screening tests

  • A 24-hour urine test. A positive test is when the urine contains more cortisol than normal. The reliability of the test depends on the patient performing an accurate 24 hour urine collection.
  • An overnight dexamethasone test. Whilst at home, at 11pm the patient takes a 1mg dexamethasone tablet. Blood for cortisol measurement is taken the following morning at 9 am. In a normal person the dexamethasone (a synthetic cortisol-like drug) will cause the blood cortisol concentration to be below normal in the morning (cortisol concentration will be supressed). In Cushing’s disease this suppression is not seen and the cortisol levels are high.
  • Low dose Dexamethasone test. The overnight suppression test described above is a simplified version of the official low dose dexamethasone test. This version however may also be used especially if the results of the overnight dexamethasone test are inconclusive. In this test the patient has to take eight doses of 0.5 mg consecutively at 9 a.m., 3 p.m., 9 p.m. and 3 a.m. for a period of 48 hours before returning for a blood test to check cortisol levels. Again in a normal person the levels should be suppressed after taking the dexamethasone.
  • Dexamethasone suppressed corticotropin-releasing hormone (CRH) test: This test is a variation of the low-dose dexamethasone suppression test described above. 0.5mgs of dexamethasone is taken as mentioned but then IV CRH is given 2 hours after 48 hours. Serum cortisol is then measured 15 minutes after. Corticosteroid levels are measured 15 minutes after CRH administration. This is a very reliable test for Cushing’s Syndrome, but may only be available in specialist centres.
  • Cortisol measurements at 9am and midnight. Normally, cortisol levels within the bloodstream are higher in the morning (peak at 9am) and lower at midnight. In a patient with Cushing’s syndrome the midnight cortisol may also be high. This test is usually reserved for patients who are already in hospital as the blood needs to be taken from an indwelling cannula. ACTH may also be measured on the 9am blood sample. It may also be tested on a saliva sample which is more convenient than a blood sample.

There are several reasons, such as drugs, anxiety and obesity, why the test may not be entirely reliable and the doctor may need to carry out further tests. If a screening test is positive further tests are carried out to determine the cause of Cushing’s syndrome.

Further tests to determine the cause of Cushing’s Syndrome

  • ACTH. ACTH production is pulsatile with a peak at 8-9am. Blood samples for ACTH measurement must therefore be collected at this time of day. If the cortisol levels are high but ACTH levels are low Cushing’s syndrome is due to too much cortisol from an adrenal tumour or ingestion of synthetic steroids. This is because the body has a feedback mechanism whereby excess cortisol will switch off further production by lowering the production of ACTH. Therefore low levels indicate that the excess cortisol is not coming from overproduction of ACTH. A CT scan or MRI scan of the abdomen may follow to rule out any adrenal pathology causing the excess cortisol secretion. Conversely if the ACTH levels are high this usually means that there is excess ACTH production somewhere either by a pituitary tumour, excess CRH or a tumour elsewhere producing ACTH.
  • Extended dexamethasone test/High dose dexamethasone test. If ACTH levels are high it may be due to a pituitary tumour or a tumour elsewhere in the body. This test is used to distinguish excess ACTH production from either an ectopic tumour or from a pituitary tumour. Dexamethasone is given at different doses, four times a day, over four days. In a healthy person, dexamethasone will suppress ACTH secretion and hence cortisol secretion. Ectopic ACTH production will not normally suppress as much with high doses of dexamethasone whereas ACTH from a pituitary tumour usually does.
  • CRH test. CRH is given to test for pituitary ACTH deficiency and to differentiate between pituitary and ectopic source of ACTH in Cushings. This test may be performed at the time of inferior petrosal sinus sampling ( see below). A blood sample for ACTH and cortisol level is taken and then an injection of CRH is given 15 minutes later. Blood samples for ACTH and cortisol levels are taken again at 5, 15, 30, 45 and 60 minutes after the injection. In a normal person ACTH shows a maximum increase at 10-30 minutes and for cortisol a maximum increase at 30-60 minutes. Patients with pituitary Cushings show an increase in ACTH of at least 35-50% to CRH. This is much less than a normal person where the increase in ACTH is around 400%. Patients with Cushing’s syndrome, due to an adrenal tumour or ectopic ACTH production, show little or no increase in ACTH or cortisol.
  • Inferior petrosal sinus sampling (IPSS). This is an in depth procedure in which adrenocorticotropic hormone (ACTH) levels are determined in the veins that drain from the pituitary gland and are compared with the ACTH levels in the bloodstream. It is used to determine whether the raised ACTH levels causing Cushing’s Syndrome are due to an ectopic source or from a pituitary tumour. IPSS can also be used to establish on which side of the pituitary gland the tumour is located.

Non-laboratory tests

  • Computed tomography (CT) scan. This is used to examine the pituitary, adrenal glands and other parts of the body for tumours.
  • Magnetic Resonance Imaging (MRI). This is used to examine the pituitary and adrenal glands for tumours.

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