Cushing's disease

Syndrome of glucocorticoid steroid excess, secondary to corticotroph adenoma of the pituitary gland. The diagnosis is confirmed with failure of cortisol suppression on a low dose dexamethasone suppression test, elevated ACTH and with an elevated midnight cortisol.

Initial clinical assessment

If the history and examination give only a low clinical suspicion of Cushing's and the initial screen is negative - explain results, reassure and discharge the patient. Endocrine society guidance suggests an initial screen may comprise either urinary free cortisol, late night salivary cortisol, a low dose or overnight dexamethasone suppression test depending on the centre. In our centre, 2 urinary collections and an out patient low dose dexamethasone suppression test are used. 

If the clinical suspicion remains high or the initial biochemical screen is positive, proceed to further investigation. The guidance above suggests a second of these tests and or a midnight serum cortisol or dexamethasone-CRH test be performed at this stage followed by formal assessment of the cause of the Cushing's if this second test is also abnormal. In our centre, we usually proceed to hospital admission for this stage, followed by localising studies. Recent guidelines give more detail on the procedures for screening and confirming the diagnosis of Cushing's.

If the clinical suspicion is high but the tests are negative recheck the medication history in case the clinical features are secondary to exogenous steroid use. It is also valid to wait and reassess the patient with a suggestive clinical assessment but normal biochemistry after 6 months to determine whether their condition has progressed, or to assess for cyclical disease.

In our centre, the following tests are performed prior to hospital admission:

Low dose dexamethasone suppression test,

Baseline 9am pituitary function including ACTH, cortisol, insulin-like growth factor-I, luteinising hormone, follicule stimulating hormone, thyroid stimulating hormone, free thyroxine, estrodiol/testosterone, sex hormone binding globulin and prolactin,

Adrenal androgen profile including testosterone, androstenedione, dehydroepiandrosterone and 17 hydroxyprogesterone.

Exogenous steroid use confirmed

Cushing's syndrome due to long term steroid use may be difficult to manage. Where possible, the causative agents should be slowly withdrawn under supervision. However, as the dose is reduced it is important to assess for axis recovery, usually with a 9am cortisol. If this is below 100nmol/l the axis clearly remains suppressed. Patients with levels between 100-500nmol/l  should undergo a Synacthen test to confirm whether they are safe to continue weaning off treatment.

Where there is evidence of on going adrenal suppression, low dose hydrocortisone (10mg, 5mg and 5mg) may be started, to protect the patient from hypoadrenalism while the causative drug is reduced and stopped. If the axis appears normal, the causative drug can be stopped safely.

Complications of Cushing's for example osteoporosis, hypertension, skin damage and glucose intolerance may all occur with exogenous steroid use, and so these patients also require aggressive screening and treatment.

Confirm diagnosis

In order to confirm the diagnosis of Cushing’s syndrome, most patients will require hospital admission to complete a sleeping midnight cortisol, and supervised low dose dexamethasone suppression test (for cortisol in all patients and also for androgens if the patient is virilised).

Imaging and localising studies

Arrange a chest radiograph, dynamic MRI scan of the pituitary, and CT scan of the chest and adrenals at diagnosis in all cases.

Further investigations

Assessment of circadian rhythm with a cortisol day curve is useful as an indicator of initial disease severity, though this is not a diagnostic test, and should only be performed after biochemical confirmation of diagnosis.

A high dose dexamethasone suppression test is also used by some units to help differentiate between pituitary and ectopic sources of ACTH in Cushing’s syndrome.

Corticotrophin releasing hormone test is similarly used only in selected cases only. Where pituitary disease is suspected, it is usefully combined with petrosal sampling.

Pituitary dependent Cushing's confirmed


Review all results at a multidisciplinary meeting

Typical indicators are raised UFCs, detectable midnight cortisol as well as partial suppression with dexamethasone, and detectable or elevated ACTH.

Pituitary MRI may or may not be obviously abnormal.


Inferior petrosal sinus sampling with simultaneous CRH testing

Selective venous catheterisation of the petrosal sinuses allows simultaneous sampling of central and peripheral blood to compare ACTH levels. A central to peripheral gradient above 4:1 confirms a central, i.e. pituitary, source of ACTH. 

An ACTH response to CRH testing further supports a suspicion of pituitary disease. In one large series, a bilateral IPS: peripheral ratio of >2, obtained 5 minutes after CRH stimulation has a sensitivity of 97% and specificity of 100% in diagnosing Cushing's disease. Sampling of both sinuses simultaneously also provides evidence of disease lateralisation prior to planning surgery: a ratio of >1.4 at 5 minutes post CRH has a sensitivity of 83% in correctly laterising the adenoma in this large series. 


Start medical treatment

Patients should be prepared medically prior to surgery to optimise the safety of the procedure. Typically metyrapone 500-750mg daily in divided doses is used.

Warn patient of the symptoms of hypoadrenalism, for example nausea and dizziness at the start of treatment, and offer supply of dexamethasone for emergency use. A "block and replace" regmine of high dose metyrapone with low dose dexamethasone may be used in some cases where it is difficult to titrate up the metyrapone without causing symptomatic hypoadrenalism. 

Reassess cortisol levels with 'metyrapone day curve' at three days. Arrange weekly monitoring of liver function during treatment. 

Patients with very severe disease not controlled by metyrapone may require the addition of ketoconazole. Patients unfit for surgery may continue long term medical treatment, though this requires long term monitoring. 

A new multireceptor ligand somatostain analog Pasireotide has also recently been licensed as a specific pituitary directed therapy for patients unsuitable for or not cured by surgery. This appears to control biochemical and local disease, although carries with it an increased risk of diabetes. 


Aim for medical optimisation for six weeks prior to surgery

Medical treatment aims to control cortisol excess to approximate mean serum levels of 250-300nmol/l, control blood pressure and ensure good diabetes control if indicated, prior to surgery.


Surgery

Trans-sphenoidal surgery is the standard treatment for pituitary disease.

Cushing's syndrome due to ectopic ACTH confirmed


Review all results at a multidisciplinary meeting

Typical indicators are raised UFCs and detectable midnight cortisol, as well as lack of suppression with dexamethasone, elevated basal ACTH levels, no response to corticotrophin releasing hormone testing and no central to peripheral gradient on inferior petrosal sinus sampling. 


Review CT chest and adrenals

Ectopic ACTH secretion is most commonly from a bronchial tumour.


Further localising studies

Consider total body imaging with octreotide scan/MIBG scan, followed by cross sectional imaging, for example MRI of any suspicious areas. 

Consider selective venous catheterisation of suspicious areas for measurements of ACTH.


Start medical treatment

Patients should be prepared medically prior to surgery to optimise the safety of the procedure. Typically metyrapone 500-750mg daily in divided doses is used.

Warn patient of the symptoms of hypoadrenalism, for example nausea and dizziness at the start of treatment, and offer supply of dexamethasone for emergency use. 

Reassess cortisol levels with 'metyrapone day curve' at three days. Arrange weekly monitoring of liver function during treatment.

Arrange weekly monitoring of liver function during treatment. If control is not acheived, consider adding ketoconazole, or further increasing the dose in a block and replace regime. In exceptional cases, or for adrenal cancer, consider use of mitotane, with intensive monitoring.


Aim for medical optimisation for six weeks prior to surgery

Medical treatment aims to control cortisol excess to approximate mean serum levels of 250-300nmol/l, control blood pressure, and ensure good diabetes control if indicated, prior to surgery. 


Surgery

Ideally, Cushing's syndrome due to ectopic ACTH should be treated by resection of the tumour after medical optimisation.


Consider bilateral adrenalectomy

If the source of ACTH is not identified, initial management is usually to continue long term medical treatment until the source becomes apparent.

Long term use of adrenolytic therapy may be poorly tolerated however, and safe long term control can also be achieved with bilateral adrenalectomy, which should also be considered in all cases. 

Lifelong follow up remains necessary post adrenalectomy, with periodic surveillance imaging and biochemical assessments until source is identified.

Adrenal Cushing's confirmed


Review all results at a multidisciplinary meeting

Typical indicators are raised UFCs, and detectable midnight cortisol as well as undetectable or low ACTH levels and no response to high or low dose dexamethasone suppression testing. 

Adrenal androgens may also be elevated but will not suppress with dexamethasone.


Review CT adrenals and consider MRI if necessary

Adrenal tumours are usually easily identified on CT, and their imaging characteristics and size are useful indicators of malignant potential - low Hounsfield units and small size are predictive of benign curable disease.


Start medical treatment

Patients should be prepared medically prior to surgery to optimise the safety of the procedure. Typically metyrapone 500-750mg daily in divided doses is used.

Warn patient of the symptoms of hypoadrenalism, for example nausea and dizziness at the start of treatment, and offer supply of dexamethasone for emergency use. 

Reassess cortisol levels with 'metyrapone day curve' at three days.

Arrange weekly monitoring of liver function during treatment. If control not achieved, consider adding or substituting with ketoconazole. In exceptional cases and adrenal cancer, consider use of mitotane with intensive monitoring.


Aim for medical optimisation for six weeks prior to surgery

Control of cortisol excess to approximate mean of 250-300nmol/l, good control of blood pressure with other agents if necessary, ensure good diabetes control if indicated.


Adrenalectomy

Refer to specialist MDT for surgical resection after six weeks medical optimisation.

Not cured


Continue medical treatment with six monthly assessment

Satisfactory control is evidenced by clinical response and a mean serum cortisol, during a circadian rhythm, of 250-300nmol/l.

2xUFC within the normal range is an alternative reflection of adequate biochemical control while awaiting definitive treatment.

Bone densitometry should be assessed in such patients. Calcium and vitamin D should be considered in all patients, and further treatments for osteoporosis discussed.


Re-assessment for recurrent or persistent disease

This requires 2x24hr UFC, 9am pre-dose cortisol and ACTH and LDDST for cortisol only.


Re-assessment for development of Nelson's syndrome

To detect and monitor Nelson's syndrome, ACTH should be checked both before and 120 minutes post hydrocortisone dose in patients who have undergone bilateral adrenalectomy. Rising ACTH alone does not indicate the development of Nelson's syndrome, but mandates repeat pituitary MRI scanning.


Further treatments

Consider further medical treatment, for example with pasireotide, or repeat surgery, adrenalectomy, or conventional radiotherapy if patients are not cured. 

Following radiotherapy, further surgery or radiosurgery can be considered in exceptional cases.


Post adrenalectomy assessments

Patients on steroid replacement therapy require a pre-dose 9am cortisol as well as a ACTH and rennin assessments prior to, and 120 minutes after, their hydrocortisone and fludrocortisone doses to guide replacement therapy and monitor for Nelson’s syndrome or emergence of an adrenal remnant.


Long term follow up

Check pre-dose cortisol level and ACTH prior to first follow up assessment.

Assess control at three, six and 12 months post treatment, and then usually on an annual basis long term.

Formally reassess for disease recurrence or re-emergence of normal hypothalomo-pituitary-adrenal axis with 9am cortisol, midnight cortisol, low dose dexamethasone suppression testing and 2xUFCS, at least every six months initially, or whenever their pre dose serum cortisol becomes detectable.

Ensure cardiovascular and bone health are assessed long term.

Also ensure that pitutary function is reassessed annually in all patients post pituitary surgery, with dynamic function testing at least every two years following radiotherapy.

Clinically cured


Cure is defined by a post operative 9am cortisol <50nmol/l

Patients with a low 9am cortisol post operatively, will need to commence hydrocortisone replacement therapy typically with 10mg on waking, 5mg at five hours and 5mg at nine hours, adjusted according to symptoms and hydrocortisone day curve as necessary. 

Unfortunately, though an undetectable post op cortisol is prognostically favourable, it does not guarantee long term cure, and so even patients clinically in remission require ongoing reassessments. 


Long term follow up

Check pre-dose cortisol level and ACTH prior to every follow up assessment.

Assess control at three, six and 12 months post treatment, and then usually on an annual basis long term. 

Formally reassess for disease recurrence or re-emergence of normal hypothalomo-pituitary-adrenal axis with pre-dose 9am cortisol, midnight cortisol, low dose dexamethasone suppression testing and 2xUFCS, at least every six months initially, or whenever their pre-dose serum cortisol becomes detectable.

Ensure cardiovascular and bone health are assessed long term.

Also ensure that pitutary function is re-assessed annually in all patients post pituitary surgery, with dynamic function testing at least every two years following radiotherapy.