How is Cushing’s Disease diagnosed?
Diagnosing Cushing’s disease can be difficult. Not only are many of the symptoms common in other conditions but tumours in the pituitary causing Cushing’s disease are typically small. Furthermore, symptoms can also progress very slowly, making changes difficult to notice by patients and family.
No single test can be used to diagnose Cushing’s disease. A number of tests are needed, firstly to confirm that your cortisol levels are high (points 3-5 below), and then to identify the cause as originating from the pituitary or not (points 6-9 below). Sometimes additional tests may be needed to screen for other health conditions commonly occur with Cushing’s disease (points 10-11 below).
1. Medical History and Physical Examination
Your doctor will ask you questions about your health, symptoms and medical history, including if you take any medications or use supplements, have other health conditions and your family history. Examination is important to measure your weight, blood pressure and identify signs that might support a diagnosis of Cushing’s syndrome.
2. Blood tests
A blood test will be used to measure the levels of cortisol and ACTH in your blood. This blood test generally needs to be performed in the morning (before 9am) as in normal circumstances cortisol levels fall over the day. You may be asked to fast the night before. A small amount of blood is taken and sent to a laboratory for testing. The doctor may also be interested in measuring the levels of other pituitary hormones as well.
The results of your blood test cannot diagnose Cushing’s disease. Your doctor will note your hormones levels and interpret them with the results of other tests.
3. 24-hour urinary free cortisol test
This test measures the level of cortisol produced by your body over one full day. You will be provided with a urine collection jug and a larger container to collect all urine passed over a 24-hour period (1 full day). For the test, it is important to choose a day where you will be able to collect all your urine across the whole time. This is because an incomplete collection will make the test invalid, and the whole process will need to be repeated on another day.
The 24-hour period starts immediately after the first urination in the morning and continues until the same time the following day. Collect all urine in the collection jug and then add to the larger container, which should be kept refrigerated until taken back to the pathology centre. It is important not to drink excess fluids over the 24 hours of the collection as large urine volumes also make the test unreliable.
- High levels of urine cortisol may suggest Cushing’s syndrome. Other tests are needed to confirm Cushing’s syndrome and identify the cause.
- Normal levels of cortisol do not suggest Cushing’s syndrome, although this cannot rule out milder cases. Other tests or repeat testing may be required.
4. Midnight salivary cortisol test
In healthy people, cortisol levels rise in the morning and fall across the day, with the lowest levels seen around midnight. In people with Cushing’s disease, this daily rhythm can be lost. Measuring cortisol levels at midnight checks whether cortisol levels decrease through the night.
This test can be done at home. It involves taking a swab/sample of your saliva at midnight. It is important not to eat, drink, smoke or brush your teeth for 30 minutes before collecting the sample. For the collection, you should leave the swab in your mouth for 2 minutes or until it is soaked in saliva. To ensure accurate results, do not chew the swab or touch it with your hands.
- A high level of cortisol in the saliva may suggest Cushing’s syndrome. For some people, midnight cortisol levels can be high even with no Cushing’s syndrome e.g. shift workers.
- A low cortisol level in the night suggests a normal daily cortisol rhythm. Other tests or repeat testing may be required if clinical suspicion of Cushing’s syndrome is high.
5. Low dose dexamethasone suppression test
Dexamethasone is a medication that usually reduces cortisol levels in healthy people. Your doctor may organise this test to check whether your body can reduce cortisol production in response to this medication. This test is usually done overnight, but may also be done over 2 days. Sometimes the test needs to be done on a couple of occasions at different dexamethasone doses.
For the overnight low dose dexamethasone suppression test, 1mg of dexamethasone (in tablet form) is taken at home at around 11pm. The following morning at exactly 8am (9 hours after swallowing the dexamethasone), a blood sample will be taken to measure cortisol levels. You will need to attend a pathology centre or a medical clinic for this blood test, and it is a good idea to book in with the pathology lab for this test as the timing is very important.
For the two-day low dose dexamethasone test, a morning blood sample is taken to measure baseline cortisol and ACTH levels. A 0.5mg dexamethasone tablet is then taken exactly every 6 hours over the next 2 days. This includes late at night and early morning. After the two days, you will have another morning blood test to again measure cortisol and ACTH levels.
- No reduction in cortisol after dexamethasone may suggest Cushing’s syndrome.
- A low cortisol after dexamethasone suggests Cushing’s syndrome is not present, although cortisol can still be reduced with mild Cushing’s syndrome.
- Sometimes cortisol levels are influenced by other medications (e.g. oral contraceptives, anticonvulsants). It is important to let your doctor know about any other medications you are taking.
6. High-dose dexamethasone suppression test
High doses of dexamethasone usually suppress cortisol if the tumour producing the excess ACTH is located in the pituitary gland, but not if the tumour is located in other organs of the body.
This test can be done in three ways: dexamethasone can be given in tablet form as a single dose (oral) or given intravenously (into the vein). Less commonly, the dexamethasone is taken as a tablet over two days.
For the oral overnight dexamethasone suppression test, an 8mg dexamethasone dose is taken at home at around 11pm. A blood sample is then taken at a pathology centre at exactly 8:00am the following morning, to check cortisol levels.
The intravenous high dose dexamethasone suppression test is performed at a specialised endocrine testing centre as a day patient following an overnight fasting period. A high dose of dexamethasone will be administered through a cannula placed in a vein in the arm over a period of five hours. A blood sample will be collected through a cannula in the other arm every 30 minutes to measure your ACTH and cortisol levels.
The oral two-day high dose dexamethasone suppression test begins with a morning blood sample taken to measure cortisol and ACTH. A 2mg dose of dexamethasone is then taken exactly every 6 hours over the next 2 days. This includes late at night and early morning. After the two days, you will have another morning blood test to again measure cortisol and ACTH levels.
- Reduced cortisol levels after high dose dexamethasone suggest the tumour is located in the pituitary gland.
- No reduction in cortisol levels after high dose dexamethasone suggest the tumour is located elsewhere in the body.
7. CRH test
The corticotropin releasing hormone (CRH) test is sometimes used to help determine the source of high cortisol and ACTH levels.
In healthy people, ACTH production increases in response to a hormone called corticotropin releasing hormone (CRH). If the tumour causing excess ACTH is located in the pituitary gland, then ACTH levels will increase in response to CRH, whereas tumours outside of the pituitary usually don’t respond to CRH.
Before the test, you will have a cannula (thin tube) placed in a vein in your arm. This will be used to take blood samples and administer the CRH, avoiding the need for repeat needles.
Blood will be collected through the cannula to measure baseline ACTH and cortisol levels. CRH will then be administered through the cannula. Blood samples will then be collected every 15 minutes for up to 90 minutes to assess cortisol and ACTH.
- An increase in ACTH and cortisol after CRH suggests the tumour is located in the pituitary gland.
- No change in ACTH or cortisol levels suggests the tumour is located elsewhere in the body.
8. MRI scan
If the previous tests have confirmed Cushing’s syndrome (high cortisol levels) and suggest this is due to a pituitary tumour (Cushing’s disease), your doctor will send you for an MRI scan of the pituitary. Knowing the size and location of a tumour is important for planning treatment.
An MRI scan uses a magnetic field and radio waves to take pictures of parts of the body. Before having an MRI, you will usually change into a gown and remove any watches or other metallic objects. You might be given earplugs or headphones, as the MRI machine can be noisy. Some people with metal in their body (for example, some pacemakers, welding injuries with metallic foreign bodies in their eyes) cannot have an MRI.
Before the scan, the staff will put a cannula in a vein in your arm or hand so they can inject a contrast solution later during the scan. This dye helps to see the outline of the tumour against the normal pituitary tissue.
For the scan, you will lie on a platform that slides into the MRI machine. You will need to lie very still while inside the machine, as movement can blur the images. When inside the MRI machine, you will still be able to talk to the operator through an intercom system. The scan can take up to an hour.
After the initial scans, you will be moved out of the tunnel a little, so the contrast dye can be injected into the cannula in your hand/arm for a second set of scans. You may feel cold in your arm as the dye is injected. After the scan, you will be moved completely out of the tunnel. The cannula will then be removed, and the site bandaged.
- If you have a pituitary tumour, this may be seen on an MRI and its size and location assessed. This will help plan for treatment.
- In around 40% of people with Cushing’s disease however, the MRI does not show an obvious tumour because they can be very small. Further testing will be required to locate the source of the excess ACTH. These can include inferior petrosal sinus sampling (IPSS) and other imaging looking at other places in the body.
9. Inferior petrosal sinus sampling (IPSS)
This test checks whether the ACTH-producing tumour is in the pituitary gland. While this test may be done when the results of other tests are inconclusive, it can also be done when a small pituitary tumour is observed on MRI. This is because in the general population pituitary tumours that are non-functioning (i.e. not causing excess hormone production) are very common, and doctors don’t want to assume the tumour is the cause of the ACTH secretion.
The IPSS test measures ACTH in the veins that drain blood directly from the pituitary gland. These veins are called the inferior petrosal sinuses.
Before your test: The night before you go to hospital for this test, you will need to stop eating anything from after dinner right through until you have your test.
On the day of your test: You will go into the hospital and change into a hospital gown. A cannula (thin tube) will be placed into a vein in your arm. This avoids having repeat needles and is used to administer medications. You will be given pain relief but will be awake during the procedure. The test takes around 4 hours, including recovery time afterwards.
For this test, blood samples need to be collected from the left and right inferior petrosal sinuses. To access these sites, a thin catheter is inserted into a vein in the groin area and passed through the veins until it reaches the right position – which is observed using x-ray imaging. Blood samples will be collected from around the sinuses as well as your arm to measure baseline ACTH.
Corticotropin releasing hormone (CRH) is then administered through the cannula in your arm. This should cause ACTH levels to increase. Blood samples will be collected for around 15 minutes to monitor changes in ACTH.
The catheter will then be removed, and your groin bandaged. You will remain in recovery for around 2 hours. After the test, you should limit strenuous physical activity for two days.
- Higher ACTH levels after CRH in the blood samples taken from the inferior petrosal sinuses compared to the samples taken from the arm, strongly suggests that the tumour is located in the pituitary gland.
- Similar ACTH levels after CRH in both the arm and inferior petrosal blood samples suggests the tumour is located elsewhere in the body.
10. Vision test
Your doctor may organise to test your vision. This is because larger pituitary tumours can sometimes push on the nerves that connect the eye to the brain, called the optic nerve. This causes patchy or blurred vision, particularly at the far edges of your sight. Vision tests are most often conducted through eye specialists (an optometrist or ophthalmologist).
- If reduced vision is thought to be a result of the pituitary tumour then surgery will be needed more urgently to remove the tumour. You will require close monitoring of your vision by an optometrist or ophthalmologist.
- If you have normal vision, the tumour has not resulted in damage to the optic nerve. Sometimes a tumour can be close to the optic nerve but not yet cause any visual loss and your doctor may recommend regular monitoring of your vision by an optometrist or ophthalmologist.
11. Bone mineral density (BMD) test
Your doctor may test your bone mineral density. This is because Cushing’s disease can increase the risk of osteoporosis (thinning and weakening of the bones, resulting in an increased risk of fracture). The best way to test bone mineral density is using a DEXA scan (Dual Energy X-ray Absorptiometry scan).
This is a fairly quick (10-30 minutes) and painless imaging procedure with less radiation exposure than a chest x-ray. It involves lying fully clothed on a platform while a scanner passes over you to take pictures of your hip, spine and, sometimes, forearm.
Results are generally reported as a T score.
- T-scores above -1.0 indicate normal bone density.
- T scores between -1.0 and -2.5 indicate osteopaenia (slightly reduced bone density).
- T scores below -2.5 indicate osteoporosis (low bone density and increased risk of bone fractures).
Your doctor may recommend calcium and/or vitamin D supplements and potentially other medication to strengthen bones and reduce the risk of fractures. Treating Cushing’s disease may also stop further loss of bone density or even improve bone density.