Cushing‘s syndrome
D E F I N I T I ON
Syndrome associatedwith chronic inappropriate elevation of free circulating
cortisol.
AET IOLOGY
ACTH-dependent (80%)
. Excess ACTH secreted from a pituitary adenoma: Cushing’s disease (80%).
. ACTH secreted from an ectopic source, e.g. small-cell lung carcinomas, pulmonary
carcinoid tumours (20%).
ACTH-independent (20%)
. Excess cortisol secreted from a benign adrenal adenoma (60%).
. Excess cortisol secreted from an adrenal carcinoma (40%).
Rare: ACTH-independent micro- or macronodular adrenal hyperplasia1.
E P IDEMI OLOGY
Incidence reported as 2–4/1000000 per year, but may be more
common. Endogenous Cushing’s syndrome is more common in females. Peak incidence
is 20–40 years.
H ISTORY
Increasing weight and fatigue. Muscle weakness, myalgia, thin skin, easy
bruising, poor wound healing, fractures (resulting from osteoporosis).
Hirsutism, acne, frontal balding. Oligo- or amenorrhoea, depression or psychosis.
EXAMI N A T ION
Facial fullness, facial plethora, interscapular fat pad.
Proximal muscle weakness, thin skin, bruises.
Central obesity, pink/purple striae on abdomen, breast, thighs.
Kyphosis (due to vertebral fracture). Poorly healing wounds.
Hirsutism, acne, frontal balding.
Hypertension. Ankle oedema (salt and water retention as a result of mineralocorticoid effect
of excess cortisol).
Pigmentation in ACTH-dependent cases.
(Signs in italic are more discriminatory)
I N V E S T IGATIONS
Must only be performed in patients with a high pre-test probability.
Blood: Non-specific changes include hypokalaemia (particularly in ectopic Cushing’s), "
glucose.
Initial high-sensitivity tests:
Urinary free cortisol (two or three 24 h urine collections). Late-night salivary cortisol. Overnight
dexamethasone suppression test. Low dose dexamethasone suppression test (LDDST).
LDDST involves giving 0.5mg dexamethasone orally every 6 h for 48 h. In Cushing’s
syndrome, serum cortisol measured 48 h after the first dose of dexamethasone fails to
suppress below 50nmol/L.
Tests to determine the underlying cause:
ACTH-independent (adrenal adenoma/carcinoma): # Plasma ACTH. CT or MRI of adrenals.
ACTH-dependent (pituitary adenoma): " Plasma ACTH. Pituitary MRI. High-dose dexamethasone
suppression test (largely abandoned in centres where inferior petrosal sinus
sampling is available). Inferior petrosal sinus sampling: Central: peripheral ratio of venous
ACTH > 2:1 (or >3:1 after CRH administration) in Cushing’s disease.
ACTH-dependent (ectopic):
If lung cancer is suspected: CXR, sputum cytology, bronchoscopy, CT scan. Radiolabelled
octreotide scans to detect carcinoid tumours as they express somatostatin receptors.
MANAGEMENT
In iatrogenic cases, discontinue administration, lower steroid dose or use
an alternative steroid-sparing agent if possible.
Medical: Pre-operative or if unfit for surgery. Inhibition of cortisol synthesis with metyrapone
or ketoconazole. Treat osteoporosis and provide physiotherapy for muscle weakness.
Surgical:
Pituitary adenomas: Trans-sphenoidal adenoma resection (hydrocortisone replaced until
pituitary function recovers).
Adrenal adenoma/carcinoma: Surgical removal of tumour (plus adjuvant therapy with
mitotane for adrenal carcinoma).
Ectopic ACTH production: Treatment is directed at the tumour.
Radiotherapy: In those who are not cured and have persistent hypercortisolaemia after transsphenoidal
resection of the tumour. Stereotactic radiotherapy provides less irradiation to
surrounding tissues.
In refractory cases of Cushing’s disease, bilateral adrenalectomy may be performed.
COM P L IC A T I ONS
Diabetes, osteoporosis, hypertension. Pre-disposition to infections.
Complications of surgery: CSF leakage, meningitis, sphenoid sinusitis, hypopituitarism.
Complications of radiotherapy: Hypopituitarism, radionecrosis, small " risk of second
intracranial tumours and stroke.
Bilateral adrenalectomy may rarely be complicated by development of Nelson’s syndrome
(locally aggressive pituitary tumour causing skin pigmentation due to excessive ACTH
secretion).
PROGNOSIS
In the untreated, 5-year survival rate is 50%. Depression usually persists for
many years following successful treatment.
1 Micronodular adrenal hyperplasia may be isolated or occur as part of Carney’s complex (autosomal
dominant syndrome characterized by spotty skin pigmentation, endocrine tumours and myxomas of the
skin, heart, breast). Three responsible genes have so far been identified: PRKAR1A, PDE11A, and MYH8.
Macronodular adrenal hyperplasia: Ectopic adrenal expression of G protein coupled receptors or "
expression/activity of some eutopic receptors. McCune–Albright syndrome is a rare variant caused by
activating mutations of the a-subunit of stimulatory G protein. It is characterized by cafe au lait spots,
polyostotic fibrous dysplasia, precocious puberty and other endocrine disorders. Surgical bilateral adrenalectomy
is used in patients with micronodular adrenal hyperplasia and most patients with macronodular
adrenal hyperplasia.
ENDOCRINOLOGY
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