Cushing’s Syndrome
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.
Clinical features
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%.
Investigation
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.
Differential diagnosis
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.
ACTH levels
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.
Management
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.
Medical treatment
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.
Additional treatment
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.
