Dr Jonathan Newell-Price
University of Sheffield

In 1912, Harvey Cushing described a patient with diabetes mellitus (high blood sugar), hypertension, extra weight, thinning of the skin, loss of menstrual cycle, loss of hair on scalp and Osteoporosis. This was the result of too much Cortisol being produced by the body. Other symptoms of Cushing's include weakness, difficulty standing up, excess facial hair and bruising. It can be extremely difficult for GPs to diagnose this condition.

The quoted incidence of Cushing's is one in 200,000 but it is probably more common. There are no environmental triggers and it is not believed to be hereditary. Although it is rare in children, some as young as six have been diagnosed. Children with Cushing's may suffer from growth problems. In adults, the average age of diagnosis is 30-40 years. Far more women suffer from Cushing's but it is not known why. Once cured, recurrence is unusual.

70% of Cushing's cases are caused by a Pituitary tumour. This tumour produces adrenocorticotrophin, otherwise known as ACTH, which causes the Adrenal glands to make cortisol. In 10% of cases the ACTH comes from elsewhere in the body, e.g. a lung tumour. The remaining 20% of cases are caused by an adrenal gland tumour, which produces too much cortisol.

There are several tests to diagnose Cushing's. The best tests are low-dose dexamethasone suppression tests and testing blood cortisol levels at midnight. The 24-hour urinary cortisol test indicates when cortisol levels are high. This can be indicative of Cushing's but if the cortisol results are normal it may indicate cyclical Cushing's, where the cortisol levels fluctuate over a long period of time.

Inferior petrosal sinus sampling is the best test to decide if ACTH is coming from a pituitary tumour or elsewhere. This test can be unpleasant but is 97% effective. Adrenal tumours are easier to diagnose.

Treatment

Surgery can remove the pitutary tumour and control excess cortisol production. Radiotherapy may also be necessary. Adrenal surgery for adrenal tumours will control excess cortisol. If pituitary surgery is not fully successful for pituitary Cushing's, removal of the adrenal glands can be performed by laparoscopic (keyhole) surgery. Radiotherapy on the Pituitary gland is still advisable. Nelsons's syndrome (darkening of the skin) can occur after an Adrenalectomy due to high levels of ACTH.

In anything but mild cases, drug therapy is used to control cortisol before adrenal surgery. Some patients experience dizziness whilst taking such drugs, as a result of the drop in cortisol levels. This medication therefore requires careful monitoring.

The ideal outcome of pituitary surgery, (usually transsphenoidal), is the cure of Cushing's with no radiotherapy and no pituitary hormone replacement. There is a 60% cure rate, which is still a long way from perfect. Radiotherapy has two separate ideal outcomes: to prevent regrowth of large tumours, and if the case of an active tumour, to control cortisol levels. Radiotherapy should stop cells growing and as the cells grow at a slow rate the radiotherapy can take at least three years to take effect. Conventional radiotherapy involves 25 small doses, which can be inconvenient and time-consuming but effective.

High focused radiotherapy such as Gamma Knife/Linac is a highly accurate one-day treatment. It is not appropriate for all tumour types but may be quicker for treatment of Cushing's disease and Acromegaly, although this is not yet proven. Research to develop statistics to compare modern radiotherapy techniques with conventional methods is in progress. Even 5-10 years afte radiotherapy, some patients may need to start pituitary hormone replacement therapy.

After surgery, patients often need to take Hydrocortisone to mimic the typical cortisol levels produced during the day, with a higher dosage in the morning than at night. The total daily dosage of 20 mg is a general guideline depending on the patient's weight, but patients should seek guidance from their consultant.

All Cushing's patients receive continuous long-term monitoring at their endocrine clinic, which includes blood tests (for hormones), monitoring blood pressure, bone density scans (DEXA) and MRI scans. Life-long follow-up is recommended due to the increased risk of osteoporosis, high blood pressure, diabetes mellitus, asthma and depression.