Cushing's Syndrome

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Contents

Introduction

Cushing's syndrome is an inappropriate, persistent elevation of circulating glucocorticoids. It has several causes.

Alcohol can produce a pseudoCushing syndrome due to inhibition of part of the steroid metabolic pathway.


Pathology

Exogenous corticosteoids are the cause of the majority of cases of Cushing's syndrome. Corticosteroids are effective immunosuppressive drugs and are employed to treat a variety of autoimmune conditions, as well as chronic obstructive pulmonary disease. The doses required to treat the disease are often sufficient to induce Cushing's syndrome. However, the exogenous corticosteroids suppress the release of ACTH by the pituitary gland and induce a marked reduction in the production of glucocorticoids by the adrenal cortex. If the steroid treatment is continued for more than a few days the absence of ACTH to nurture the adrenal cortex results in atrophy of the adrenal cortex. Although this atrophy is reversible if the exogenous corticosteroids are stopped, the adrenal cortex requires time to return to its original size. During this recovery period the patient is unable to produce sufficient endogenous corticosteroids and severe acute Addison's disease can result. In order to prevent this potentially serious complication, courses of corticosteroid treatment are slowly tapered to withdrawal so that the adrenal gland can recover.

The most common source of ectopic ACTH is a small cell carcinoma of the lung. Carcinoid tumours can also produce ACTH. Ectopic ACTH secretion accounts for 15-20% of cases of Cushing's syndrome.

Cushing's disease is the term given to a pituitary adenoma which secretes ACTH in an unregulated fashion. It tends to present in the third or fourth decade and has a male : female ratio of 1 : 3. There is bilateral secondary hyperplasia of the adrenal cortices. The co-existence of the terms Cushing's syndrome and Cushing's disease can be a source of confusion.

Adrenal adenomas and carcinomas each account for around 10% of cases of Cushing's syndrome. As with parathyroid neoplasms, the distinction between an adrenal adenoma and an adrenal carcinoma can be difficult in the absence of metastases. Various criteria have been suggested. Macroscopically, carcinomas tend to be larger than adenomas, with the latter usually weighing less than 50g. Adenomas are circumscribed and have a uniform yellow cut surface; carcinomas may be discernibly non-encapsulated and possess a variegated cut surface which features haemorrhage and necrosis. Local invasion may be visible. Adenomas tend to present between the ages of 30 and 40 years and are more common in women whereas carcinomas have their peak incidence later and exhibit no gender predilection (however these epidemiological features are of no diagnostic use in an individual patient).

Macronodular hyperplasia features multiple adrenal cortical nodules that are least 5mm in diameter. In some cases the hyperplasia is profound and the adrenal glands can weigh up to 200g.

A micronodular form of adrenal cortical hyperplasia also exists but tends not to be hormonally active.

Pigmented adrenal cortical hyperplasia is another rare cause of Cushing's syndrome in which the adrenal cortices display numerous darkly pigmented nodules that microscopically resemble the zona reticularis. In some cases it is part of an inherited disease, such as Carney's syndrome (lentigenes, atrial myxomas, mucocutaneous myxomas and blue naevi).

McCune-Albright syndrome is a rare inherited disorder in which there is a mutation in one of the G proteins that is linked to adenylate cyclase. This results in overactivity of the pituitary gland, thyroid, adrenal cortex and gonads, together with cutaneous pigmentation and fibrous dysplasia of the bones.


Clinical Features

Patients who have Cushing's syndrome manifest a characteristic physical appearance. There is weight gain which is distributed in the centre of the body. When this is combined with the muscle wasting that occurs due to glucocorticoid-driven protein catabolism the overall result is an obese torso and thin limbs which has been described as a 'lemon on sticks'. The 'buffalo hump' of Cushing's syndrome is caused by an accumulation of fat in the posterior neck and upper back.

The face is red (plethoric) with ruddy cheeks and is rounded due to fat deposition. This is referred to as a 'moon face' and is accompanied by hirsuitism. Acne may develop.

The inhibition of collagen synthesis in the skin produces thin skin which bruises easily and features red-purple striae on the abdomen.

Hypertension is common. This is caused by an excessive potentation of the action of the sympathetic nervous system on the caridovascular system and also by the amplification of the weak mineralocorticoid actions of glucocorticoids by their sheer weight of numbers.

The muscle wasting is sufficiently frequent to produce a myopathy and weakness. The weakness particularly affects the proximal muscles and can present as difficulty in climbing stairs.

The majority of patients have some form of psychiatric disturbance such as depression, lethargy or poor concentration. In some cases there can be paranoia or full psychosis.

Osteoporosis can result in chronic disease and has the attendant risk of pathological fractures.

Secondary diabetes mellitus can develop.

Amenorrhoea may occur.

Patients have an increased risk of infection due to the immunosuppressive effects of glucocorticoids.

In some patients there are alterations in the sex steroids and this can result in virilism and infertility. Virilism is particularly encountered in women who have Cushing's syndrome secondary to an adrenal cortical carcinoma.

The Cushing's syndrome may also demonstrate clinical features that are related to the underlying cause. This is particularly likely in pituitary tumours and small cell carcinoma of the lung (where the cachectic aspects of the carcinoma can produce a confusing clinical appearance).


Investigations

The diurnal variation in cortisol levels makes a single measurement of blood cortisol potentially unreliable in the diagnosis of Cushing's syndrome. However, blood cortisol is usually lowest at midnight, so this can be a good time to take the blood. Nevertheless, more robust evidence of an inappropriate elevation of cortisol levels is necessary and this is provided by the low dose dexamethasone suppression test.

Dexamethasone is a potent exogenous glucocorticoid. The normal response to a dose of dexamethasone is for the body to suppress the production of its own glucocorticoids and thus cortisol levels should fall. However, in Cushing's syndrome the glucocorticoid system is acting autonomously and this feedback control is lost.

The high dose dexamethasone test is employed once Cushing's syndrome has been diagnosed in order to determine if the cause of the syndrome is Cushing's disease itself. An ACTH-secreting pituitary adenoma may retain some sensitivity to circulating glucocorticoids and if a sufficiently large dose of dexamethasone is given this residual suppressibility may be exploited.

Levels of ACTH can be measured. They will be low or undetectable in cases of an adrenal tumour and adrenal hyperplasia but will be elevated in Cushing's disease and ectopic ACTH secretion.

As well as confirming the diagnosis, blood tests are important in the evaluation of some of the complications of Cushing's syndrome. Hypokalaemia is encountered in nearly all patients who have ectopic ACTH secretion yet curiously is found in only 10% of patients who have Cushing's disease. The blood glucose should also be measured.

Imaging of the adrenal and pituitary glands is necessary.


Treatment

An adrenal adenoma or carcinoma is treated by adrenalectomy. The contralateral adrenal gland will be severely suppressed and may require up to two years to recover its normal chipper demeanour.

Adrenal hyperplasia usually requires surgery.

Pituitary adenomas are treated by transphenoidal resection of the adenoma. Rarely it may be necessary to excise the adrenal glands instead. This may also be required in some cases of ectopic ACTH secretion.

Adrenal cortical function can be inhibited with the drug metyrapone but the role of this agent tends to be restricted to controlling the disease in preparation for surgery.

Untreated Cushing's syndrome has a 50% five year survival.