Definition: 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 or ACTH . All the spontaneous forms of the syndrome are rare.

Causes of Cushing's Syndrome

Adrenal hyperplasia

-Secondary to pituitary ACTH overproduction -Pituitary-hypothalamic dysfunction -Pituitary ACTH-producing micro- or macroadenomas -Secondary to ACTH or CRH-producing non endocrine tumors (bronchogenic carcinoma, carcinoid of the thymus, pancreatic carcinoma, bronchial adenoma) Adrenal macronodular hyperplasia Adrenal micronodular dysplasia -Sporadic -Familial

Adrenal neoplasia

-Adenoma -Carcinoma Exogenous, iatrogenic causes -Prolonged use of glucocorticoids -Prolonged use of ACTH

Causes of Cushing's syndrome are usually subdivided into two groups:

increased circulating ACTH from the pituitary

(65% of cases), known as Cushing's disease, or from an 'ectopic', non-pituitary, ACTHproducing tumour else where in the body (10%) with consequential glucocorticoid excess. A primary excess of endogenous cortisol secretion (25% of spontaneous cases) by an adrenal tumour or nodular hyperplasia, with subsequent (physiological) suppression of ACTH.

Rare cases are due to aberrant expression of

receptors for other hormones (e.g. glucosedependant insulinotrophic peptide [GIP], LH or catecholamines) in adrenal cortical cells. A cushingoid appearance can be caused by excess alcohol consumption (pseudoCushing's syndrome) - the pathophysiology is poorly understood.

Clinical features :

The predominant clinical features of

Cushing's syndrome are those of glucocorticoid excess . Pigmentation occurs only with ACTHdependent causes. Impaired glucose tolerance or frank diabetes are common, especially in the ectopic ACTH syndrome. Hypokalaemia due to the mineralocorticoid activity of cortisol is common with ectopic ACTH secretion.

Sign or Symptom Typical habitus (centripetal obesity) Increased body weight Fatigability and weakness Hypertension (blood pressure > 150/90) Hirsutism Amenorrhea Broad violaceous cutaneous striae Personality changes Ecchymoses Proximal myopathy Edema Polyuria, polydipsia Hypertrophy of clitoris

Percent of Patients 97 94 87 82 80 77 67 66 65 62 62 23 19

Moon face and plethora

Cushing's syndrome with truncal obesity

Hirsutism with facial plethora

Buffalo hump appearance

Diagnosis :
There are two phases of 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 :

Most obese, hirsute, hypertensive patients do

not have Cushing's syndrome, and some cases of mild Cushing's have relatively subtle clinical signs. Confirmation rests on demonstrating inappropriate cortisol secretion, not suppressed by exogenous glucocorticoids: difficulties occur with obesity and depression where cortisol dynamics are often abnormal. Random cortisol measurements are of no value.

Investigations to confirm the diagnosis include:

48-hour low-dose dexamethasone test

Normal individuals suppress plasma cortisol to < 50 nmol/L. Patients with Cushing's syndrome fail to show complete suppression of plasma cortisol levels. This test is highly sensitive (> 97%). 24-hour urinary free cortisol measurements. This is simple, but less reliable - repeatedly normal values (corrected for body mass) render the diagnosis most unlikely, but some patients with Cushing's have normal values on some collections (approximately 10%).

Circadian rhythm.

-After 48 hours in hospital, cortisol samples are taken at 0900 h and 2400 h (without warning the patient). -Normal subjects show a pronounced circadian variation; those with Cushing's syndrome have high midnight cortisol levels (> 100 nmol/L), though the 0900 h value may be normal. Other tests. -There are frequent exceptions to the classic responses to diagnostic tests in Cushing's syndrome. If any clinical suspicion of Cushing's remains after preliminary tests then specialist investigations are still indicated, these may include insulin stress test, desmopressin stimulation test and CRH tests.

Test and protocol

Measure

Normal test result or positive suppression

Use and explanation

Dexamethasone (for Cushing's) Overnight Take 1 mg on going to bed at 2300 h 'Low-dose' 0.5 mg 6-hourly Eight doses from 0900 h on day 0 2 mg 6-hourly Eight doses from 0900 h on day 0 Plasma cortisol at 0900 h on days 0 and +2 Plasma cortisol at 0900 h on days 0 and +2 Plasma cortisol < 50 nmol/L on second sample Plasma cortisol on day +2 less than 50% of that on day 0 suggests pituitarydependent For diagnosis of Cushing's syndrome Differential diagnosis of Cushing's syndrome Pituitarydependent Plasma cortisol at 0900 h next morning Plasma cortisol < 100 nmol/L Outpatient screening test Some 'false positives'

'High-dose' used in differential diagnosis

Differential diagnosis of the cause

This can be extremely difficult since all causes can result in clinically identical Cushing's syndrome. The classical ectopic ACTH syndrome is distinguished by a short history, pigmentation and weight loss, hypokalaemia, clinical or chemical diabetes and plasma ACTH levels above 200 ng/L, but many ectopic tumours are benign and mimic pituitary disease closely both clinically and biochemically. Severe hirsutism/virilization suggests an adrenal tumour.

Biochemical and radiological procedures for diagnosis include:

Adrenal CT or MRI scan.

-Adrenal adenomas and carcinomas causing Cushing's syndrome are relatively large and always detectable by CT scan. -Carcinomas are distinguished by large size, irregular outline and signs of infiltration or metastases. -Bilateral adrenal hyperplasia may be seen in ACTH-dependent causes or in ACTHindependent nodular hyperplasia. Pituitary MRI. -A pituitary adenoma may be seen but the adenoma is often small and not visible in a significant proportion of cases.

Plasma potassium levels.

- 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 (< 10 ng/L) on two or more occasions are a reliable indicator of non-ACTH-dependent disease. CRH test. -An exaggerated ACTH and cortisol response to exogenous CRH suggests pituitary-dependent Cushing's disease, as ectopic sources rarely respond. Chest X-ray Is mandatory to look for a carcinoma of the bronchus or a bronchial carcinoid. Carcinoid lesions may be very small; if ectopic ACTH is suspected, whole-lung and mediastinal CT scanning should be performed.

Others: Bronchoscopy, cytology and regional arteriograms are occasionally necessary. Radiolabelled octreotide (111In octreotide) is occasionally helpful in locating ectopic ACTH sites.

prognosis

-Untreated Cushing's syndrome has a very bad prognosis. Causes of death -hypertension, myocardial infarction, infection and heart failure.

Treatment:
Whatever the underlying cause, cortisol hypersecretion should be controlled prior to surgery or radiotherapy. Choice of further treatment depends upon the cause. Cushing's disease (pituitary-dependent hyperadrenalism) -Trans-sphenoidal removal of the tumour is the treatment of choice. -Selective adenomectomy nearly always leaves the patient ACTH-deficient immediately postoperatively, and this is a good prognostic sign.

-External pituitary irradiation alone is slow acting, only effective in 50-60% even after prolonged follow-up and mainly used after failed pituitary surgery. Children, however, respond much better to radiotherapy, 80% being cured. -Medical therapy to reduce ACTH (e.g. bromocriptine) is rarely effective. -Bilateral adrenalectomy is an effective last resort if other measures fail to control the disease.

Adrenal carcinomas are highly aggressive and

the prognosis is poor. In general, if there are no widespread metastases, tumour bulk should be reduced surgically. The adrenolytic drug op'DDD (Mitotane) may inhibit growth of the tumour and prolong survival. Some would also give radiotherapy to the tumour bed after surgery.

Tumours secreting ACTH ectopically

should be removed if possible. Otherwise chemotherapy/radiotherapy may be used, depending on the tumour. Control of the Cushing's syndrome with metyrapone or ketoconazole is beneficial for symptoms, and bilateral adrenalectomy may be appropriate to give complete control of the Cushing's syndrome if prognosis from the tumour itself is reasonable.

Nelson's syndrome:
Nelson's syndrome is increased pigmentation

(because of high levels of ACTH) associated with an enlarging pituitary tumour, which occurs in about 20% of cases after bilateral adrenalectomy for Cushing's disease. The syndrome is rare now that adrenalectomy is an uncommon primary treatment, and its incidence may be reduced by pituitary radiotherapy soon after adrenalectomy. The Nelson's adenoma may be treated by pituitary surgery and/or radiotherapy .

Congenital adrenal hyperplasia (CAH):

Pathophysiology: This condition results from an autosomal recessive deficiency of an enzyme in the cortisol synthetic pathways. There are six major types, but most common is 21-hydroxylase deficiency which occurs in about 1 in 15 000 births and which has been shown to be due to defects on chromosome 6 . As a result, cortisol secretion is reduced and feedback leads to increased ACTH secretion to maintain adequate cortisol - leading to adrenal hyperplasia.

 Diversion of the steroid precursors into the

androgenic steroid pathways occurs. Thus, 17hydroxyprogesterone, androstenedione and testosterone levels are increased, leading to virilization. Aldosterone synthesis may be impaired with resultant salt wasting.

Clinical features:

If severe, this presents at birth with sexual

ambiguity or adrenal failure (collapse, hypotension, hypoglycaemia), sometimes with a salt-losing state (hypotension, hyponatraemia). In the female, clitoral hypertrophy, urogenital abnormalities and labioscrotal fusion are common, but the syndrome may be unrecognized in the male. Precocious puberty with hirsutism is a later presentation. Rare, milder cases only present in adult life, usually accompanied by primary amenorrhoea. Hirsutism developing before puberty is suggestive of CAH.

Investigations: 17-Hydroxyprogesterone levels are increased. Urinary pregnanetriol excretion is increased. Basal ACTH levels are raised. Treatment : Replacement of glucocorticoid activity, and mineralocorticoid activity if deficient, is as for primary hypoadrenalism .Correct dosage is often difficult to establish in the child but should ensure normal 17hydroxyprogesterone levels while allowing normal growth; excessive replacement leads to stunting of growth.

Uses and problems of therapeutic steroid therapy:

Apart from their use as therapeutic

replacement for endocrine deficiency states, synthetic glucocorticoids are widely used for many non-endocrine conditions . Short-term use (e.g. for acute asthma) carries only small risks of significant side-effects except for the simultaneous suppression of immune responses. The danger lies in their long-term use. In general, therapy for 3 weeks or less, or a dose of prednisolone less than 10 mg per day, will not result in significant long-term suppression of the normal adrenal axis.

 Long-term therapy with synthetic or natural

steroids will, in most respects, mimic endogenous Cushing's syndrome. Exceptions are the relative absence of hirsutism, acne, hypertension and severe sodium retention, as the common synthetic steroids have low androgenic and mineralocorticoid activity. Local and inhaled steroids rarely cause Cushing's syndrome, although they commonly cause adrenal suppression.

All patients receiving steroids should carry

a 'Steroid Card'. They should be made aware of the following points: I. Long-term steroid therapy must never be stopped suddenly. II.Doses should be reduced very gradually, with most being given in the morning at the time of withdrawal - this minimizes adrenal suppression. III.Doses need to be increased in times of serious inter-current illness (defined as presence of a fever), accident and stress. Double doses should be taken during these times.

Other physicians, anesthetists and dentists

must be told about steroid therapy. Patients should also be informed of potential side-effects and all this information should be documented in the clinical record. Regular supervision including, e.g. DXA scan.