Cushing's syndrome

The clinical syndrome of glucocorticoid excess. This may be caused by exogenous steroid use, ACTH independent adrenal disease, or ectopic ACTH. The diagnosis Cushing's disease specifically refers to Cushing's caused by ACTH secreting tumours of the pituitary gland.

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.

Confirm diagnosis

In order to confirm the diagnosis of Cushing’s syndrome, most patients will require hospital admission. 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) should be performed.

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. Pitutiary incidental lesions are common and so a biochemical picture suggestive of pitutiary disease will require inferior petrosal sinus sampling to confirm this. Conversely, discreet adrenal nodules may be seen in patients in whom a clear diagnosis of pitutiary dependant disease has been established. For this reason, we advocate imaging in all patients after biochemical confirmation of Cushing's.

Further investigations

If the patient has obvious Cushing's clinically, fails to suppress their cortisol on low dose dexamethasone suppression testing, has a low or undetectable ACTH, a normal MRI pituitary and an obvious adrenal lesion (with or without elevated androgens) the diagnosis of adrenal Cushing's is obvious. Assessment of circadian rhythm with a cortisol day curve may be used as an indicator of initial disease severity, and as a baseline to compare biochemical control on medical treatment. However, with adrenal disease, the expectation is of complete surgical cure so this may not be considered necessary.

A high dose dexamethasone suppression test is used by some units to help differentiate between pituitary and ectopic sources of ACTH in difficult Cushing’s syndrome. Corticotrophin releasing hormone test is similarly used in selected cases only. These tests are generally not required in the assessment of adrenal Cushing's.

Pituitary dependent Cushing's confirmed


Review all results at a multidisciplinary meeting

Typical indicators of pituitary disease are raised urinary free cortisols, detectable midnight serum cortisol as well as partial suppression of serum cortisol with dexamethasone, and a detectable or elevated serum 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 urinary free cortisol levels and detectable midnight cortisol, as well as a lack of suppression with dexamethasone, elevated basal ACTH levels, no response to CRH 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

If the source of the ectopic ACTH is not obvious, consider total body imaging with octreotide or MIBG scan, followed by cross sectional imaging, for example MRI of any suspicious areas. 

Consider performing selective venous catheterisation of suspicious areas for measurements of ACTH to confirm disease localisation.


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 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, it is usual 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. 

Life long 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 urinary free cortisol levels 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 an approximate mean serum level of 250-300nmol/l, good control of blood pressure with other agents if necessary, and optimisation of diabetes control should all be acheived during this period.


Adrenalectomy

Refer to a specialist adrenal or urological multidisciplinary team for consideration of laparascopic surgical resection after six weeks medical optimisation. Stop all adrenolytic therapy, and give 100mg hydrocortisone im on induction of anaesthesia and continue 6 hourly until the patient can eat and drink. Revert to oral hydrocortisone 20mg tds until the patient is clinically well (48h), then reduce to 10mg waking, 5mg at midday and 5mg early evening. This should be continued until the patient has been reassessed for hypothalamopituitary adrenal axis recovery, though this may take many months. 

Clinically cured


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

An undetectable 9am cortisol the morning after surgery confirms cure and is useful in patients with ACTH dependant disease. After adrenalectomy, cure and adrenal suppression is the norm, and so this is unecessary. These patients should be started empirically on hydrocortisone replacement therapy: 100mg im 6 hourly during anaesthesia, reverting to high dose oral replacement of 20mg tds for the first few days after surgery, reverting to standard low dose replacement therapy: typically 10mg on waking, 5mg at five hours and 5mg at nine hours, once they are well. This should then be adjusted according to symptoms and hydrocortisone day curve, and reassessment of hypothalamo-pituitary-adrenal axis recovery as necessary. 


Long term follow up

Check pre hydrocortisone dose cortisol and ACTH levels prior to all follow up assessments.

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 hypothalomic pituitary adrenal axis with 9am cortisol, midnight cortisol, low dose dexamethasone suppression testing and 2x urinary free cortisols. Reassess at least every six months initially, or whenever their pre dose serum cortisol becomes detectable.

Ensure cardiovascular and bone health are assessed long term.

Not cured


Continue medical treatment with six monthly assessment

Adrenal Cushing's should be cured after adrenalectomy. Non cure immediately following surgery should lead to review of the patient's results - did they actually have bilateral adrenal disease or was it in fact ACTH dependant?

Also, review the histology carefully, as late recurrence may indicate that the patient actually had adrenocortical carcinoma. Satisfactory biochemical control is evidenced by clinical response and a mean serum cortisol, during a circadian rhythm, of 250-300nmol/l. However, if the patient has adrenocortical carcinoma, they should be started on mitotane and considered for an oncological clinical trial.

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


Reassessment for recurrent or persistent disease

This requires two urinary free cortisols, a 9am pre-dose cortisol and ACTH, and a low dose dexamethasone suppresssion test for cortisol. This should be performed every six months initially, and at least annually long term.


Further treatments

Consider repeat surgery to remove the adrenal remnant in the non-cured patient with unilateral adrenal disease, or bilateral adrenalectomy if the histology and review of the clinical case suggests bilateral ACTH independant disease eg primary pigmented nodular adrenal hyperplasia or Carney complex.


Post adrenalectomy assessments

Patients on steroid replacement therapy require a pre dose 9am cortisol before each visit. They also require an ACTH and renin assessment prior to, and 120 minutes after, their hydrocortisone and fludrocortisone doses to guide replacement therapy and monitor for the development of Nelson’s syndrome or the 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 urinary free cortisols. Reassess at least every six months initially, or whenever their pre dose serum cortisol becomes detectable.

Patients with previous pituitary surgery or radiotherapy need to be monitored for the development of anterior pituitary failure. All patients require that cardiovascular risks and bone health are assessed long term.

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.