Cushing’s syndrome occurs as a result of increased endogenous or exogenous steroids. The diagnosis is considered when the classic clinical features are recognised. There are several causes of Cushing’s syndrome, but Cushing’s disease specifically refers to an ACTH-secreting pituitary tumour, leading to bilateral adrenal hyperplasia and excess cortisol secretion. Systematic biochemical evaluation is essential to accurately confirm the presence of Cushing’s syndrome and determine the source of excess steroid. Cushing’s syndrome can be a challenging condition both in terms of diagnosis and treatment.
Cushing’s syndrome is characterised by the development of central obesity, a dorso-cervical fat pad and increased roundness of the face. Patients often have a flushed appearance (plethoric) and complain of thin skin, easy bruising and proximal myopathy (Figure 4.1). Patients may present with hypertension, premature osteoporosis and diabetes mellitus. Left untreated, Cushing’s syndrome is associated with significant morbidity and has a 5-year mortality approaching 50%.
Biochemical screening tests
Before considering the differential diagnosis, it is important to confirm that true Cushing’s syndrome is present with the use of biochemical screening tests. Alcoholism and severe depression cause patients to look Cushingoid (pseudo-Cushing’s) but screening tests will usually be normal. Twenty-hour hour urine free cortisol (UFC), low dose dexamethasone suppression test (LDDST) and the overnight dexamethasone suppression test (DST) are used as screening tests. Twenty-four hour UFC levels will typically be elevated, and there is failure to suppress cortisol to <50 nmol/L after LDDST or overnight DST. The LDDST is more specific and sensitive than the overnight DST (Figure 4.1). Most recently, late night salivary cortisol has emerged as a convenient outpatient screening test, whereby patients with Cushing’s syndrome fail to demonstrate the expected nocturnal fall in cortisol levels.
Once Cushing’s syndrome has been confirmed, further assessment is needed to determine the cause (Figure 4.1). Cushing’s disease is more common than ectopic ACTH and has a higher prevalence in females. Hypokalaemia, a history of smoking and weight loss are suggestive of ectopic ACTH resulting from lung cancer or another malignancy. Significant and accelerated hirsutism suggests an adrenal tumour.
Imaging can lead to misleading information, because pituitary tumours may be too small to be seen on MRI, and‘incidentalomas’ of the adrenal and pituitary are common. Therefore, biochemical assessment should be performed before imaging.
If ACTH is low, an adrenal tumour is likely and adrenal imaging is indicated (CT or MRI). If ACTH is normal or high, Cushing’s disease or ectopic ACTH should be considered.
CRH and high dose DST
CRH injection causes an exaggerated rise in ACTH and cortisol in patients with Cushing’s disease, with a flat response observed in ectopic ACTH (CRH test). The high dose DST leads to some degree of cortisol suppression in Cushing’s disease but not in ectopic ACTH, although this test has largely been superseded by inferior petrosal sinus sampling (IPSS).
Imaging and inferior petrosal sinus sampling
If biochemical tests suggest Cushing’s disease, an MRI of the pituitary should be performed. If there is no clear pituitary lesion on MRI, IPSS can help to confirm central ACTH secretion by showing a clear gradient between central and peripheral ACTH levels after CRH injection. In suspected ectopic ACTH, a whole body CT scan, with or without PET imaging, may reveal a carcinoma.
If an adrenal tumour is found, laparoscopic adrenalectomy is the treatment of choice. In ectopic ACTH, appropriate treatment of the underlying malignancy and medical control of cortisol levels are needed. In Cushing’s disease, trans-sphenoidal removal of the pituitary adenoma is indicated.
Metyrapone blocks cortisol production and may improve symptoms. Other medical approaches include ketoconazole and pasireotide (a somatostatin analogue), which can be effective in some patients. Medical treatment can be used pre-operatively if symptoms are severe, or there is uncontrolled hypokalaemia, diabetes and hypertension.
In large pituitary tumours, and those invading the cavernous sinus, external beam or stereotactic radiotherapy may be required. Bilateral adrenalectomy can be performed to normalise cortisol status in Cushing’s disease, although uncontrolled negative feedback can lead to uncontrolled residual pituitary tumour growth. In some cases, this has an aggressive course and may be associated with extreme pigmentation due to very high ACTH levels, with headache and cranial nerve palsies (Nelson’s syndrome).
Follow-up and monitoring
For Cushing’s disease, an early postoperative cortisol level of <50 nmol/L suggests biochemical remission. Positive confirmation of ACTH immunostaining of the tumour is helpful to confirm the correct diagnosis. Low cortisol levels result from ACTH suppression in the remaining normal corticotroph cells due to exposure to previously high corticosteroid levels. Hydrocortisone replacement may be needed for several years until the hypothalamic–pituitary–adrenal (HPA) axis recovers. Patients with Cushing’s disease sh ng-term follow-up to ensure there is no recurrence.