Cushing’s syndrome

Cushing’s syndrome is the term used to describe the clinical state of increased free circulating glucocorticoid. It occurs most often following the therapeutic administration of synthetic steroids. All the spontaneous forms of the disease are rare.

Causes of Cushing’s syndrome:

ACTH-dependent disease:

• Pituitary-dependent (Cushing’s disease)
• Ectopic ACTH-producing tumours
• ACTH administration

Non-ACTH-dependent causes:

• Adrenal adenomas
• Adrenal carcinomas
• Glucocorticoid administration

Others:

• Alcohol-induced pseudo-Cushing’s syndrome

Clinical features:

• Centripetal obesity
• Amenorrhoea/oligomenorrhoea
• Thin skin/easy bruising
• Hair growth/acne
• Growth arrest in children
• Polyuria/polydipsia
• Moon face
• Buffalo hump (interscapular fat pad)
• HT
• Poor wound healing
• Osteoporosis
• Oedema poor libido

Diagnosis:

There are 2 phases to the investigation:

1. Confirmation of the presence or absence of Cushing’s syndrome
2. Differential diagnosis of its cause (e.g. pituitary, adrenal or ectopic)

Confirmation of Cushing’s syndrome:

Confirmation rests on demonstrating inappropriate cortisol secretion, NOT suppressed by exogenous glucocorticoids.

24-hour urinary free cortisol measurements:

• Repeatedly normal values (corrected for body mass) render the diagnosis most unlikely

48-hour low-dose dexamethasone test:

Normal individuals suppress plasma cortisol to <50nmol/L

Patients with Cushing’s syndrome fail to show complete suppression of plasma or urinary cortisol levels

Circadian rhythm:

• After 48 hours in hospital, cortisol samples are taken at 0900h and 2400h (without warning the patient).
• Normal subjects show a pronounced circadian variation
• Those with Cushing’s syndrome have high midnight cortisol levels (>100nmol/L), though the 0900h value may be normal

Differential diagnosis of the cause:

This can be very difficult. Biochemical and radiological procedures for diagnosis include:

Adrenal CT or MRI scans:

• Adrenal adenomas and carcinomas are relatively large and always detectable by CT scan
• Carcinomas are distinguished by:
• Irregular outline
• Large size
• Signs of infiltration/metastases

Pituitary MRI:

• Of less value than the adrenal scans
• Many adenomas are not seen (as they are so small)

Plasma potassium levels:

• All diuretics must be stopped
• Hypokalaemia is common with ectopic ACTH secretion

High-dose dexamethasone test:

• Failure of significant plasma cortisol suppression suggests an ectopic source of ACTH or an adrenal tumour

Plasma ACTH levels:

• Low or undetectable ACTH levels (<10ng/L) on 2 or more occasions are a reliable indicator of non-ACTH-dependent disease

CRF test:

• An exaggerated ACTH and cortisol response to exogenous CRF (with or without vasopressin) suggests pituitary-dependent Cushing’s disease, as ectopic sources rarely respond

CXR:

• This is mandatory to demonstrate a carcinoma of the bronchus or a bronchial carcinoid
• Lesions may be very small – whole lung and mediastinal CT scanning should be performed

Drug treatment of Cushing’s syndrome:

• The usual drug is metyrapone (an 11Β-hydroxylase inhibitor)
• Given in doses of 750mg-4g daily TID or QID
• Plasma cortisol should be monitored, aiming to reduce the mean level during the day to 150-300nmol/L (equivalent to normal production rates)

Ketoconazole and aminoglutethamide are sometimes used.

Treatment of Cushing’s disease:

Trans-sphenoidal removal of the tumour:

• Treatment of choice
• Selective adenomectomy nearly always leaves the patient ACTH-deficient postoperatively (this is considered a good prognostic sign)

External pituitary irradiation:

• Very slow
• Only effective in 50-60% of patients
• Children respond better (80% being cured)

Medical therapy to reduce ACTH:

• E.g. Bromocriptine
• Rarely effective

Bilateral adrenalectomy:

• An option of last resort
• May be performed laparoscopically

Treatment of other causes:

Adrenal adenomas:

• Should be resected after achievement of clinical remission with metyrapone or Ketoconazole
• Contralateral adrenal suppression may last for years

Adrenal carcinomas:

• Highly aggressive with a poor prognosis
• In general, if there are no widespread metastases, tumour bulk should be reduced surgically

Ectopic ACTH-secreting tumours:

• Should be removed if possible
• Otherwise, chemotherapy/radiotherapy should be used, depending on the tumour