SECRETARIA DE SEGURIDAD SOCIAL Resolución Nº 7/2010

Christopher Lattimer

Cushing’s syndrome was first described in 1932 by Harvey Cushing. He discovered eight patients with similar symptoms and signs. Six of these patients had basophil adenomas of the pituitary gland and they were later classified as having Cushing’s disease. Women predominate with Cushing’s disease (8:1) with a peak incidence in the second or third decade. The primary lesion is a basophil adenoma of the pituitary gland, which secretes excess levels of ACTH. This hormone acts upon the zona fasciculata of the adrenal cortex to stimulate an over-production of cortisol, which is responsible for the features of the disease.

Clinical features

These are all secondary to chronically elevated levels of circulating cortisol. Excess levels of cortisol can be produced in a number of ways but their effects on metabolism are similar. The clinical features can be divided into anatomical and metabolic. They comprise of truncal obesity, buffalo hump, plethoric moon face, proximal muscle wasting, skin atrophy, poor wound healing, osteoporosis, acne, excessive bruising, impotence, and growth retardation in children. Patients are usually hypertensive, accounting for 0.2% of newly diagnosed hypertensives with a 5-year survival, if untreated, of 50%. Diabetes, and psychiatric disturbances like depression, insomnia or overt psychosis can also be precipitated. Fatal complications include cerebral thrombosis and myocardial infarction, which are the commonest causes of death. Female patients may suffer from hirsutism, greasy skin, amenorrhoea and infertility. Cushingoid striae are purple. They can thus be distinguished from the white striae of simple obesity.

Aetiology

Cushing’s syndrome is usually caused by excessive steroid administration. Primary Cushing’s can be classified into ACTH dependent (pituitary or ectopic) or ACTH independent.

1. Ectopic ACTH (10%). This can be secreted by an oat cell carcinoma of the lung or a

bronchial carcinoid (ectopic ACTH syndrome). It presents with a rapid onset of symptoms and is more common in men (2:1) and in the fourth to fifth decade.

2. Exogenous ACTH. This can be administered therapeutically in excess.

3. Adrenal cortisol (20%). Both benign and malignant tumours of the adrenal gland can

secrete a variety of inappropriate glucocorticoids and corticosteroids. These occur more commonly in women (adenoma 3:1, carcinoma 2:1) in the third and fourth decades. The condition of nodular adrenal hyperplasia (NAH) occurs at around 18 years of age. It is characterized by the presence of multiple adrenal nodules up to 3 mm in diameter. In this condition, an excess of cortisol is produced with ACTH suppression.

4. Exogenous cortisol. The commonest cause of Cushing’s syndrome is iatrogenic, the

therapeutic administration of corticosteroids for conditions like rheumatoid arthritis, autoimmune diseases and chronic inflammatory disorders.

5. Cushing’s disease (70%). Pituitary (ACTH)-dependent Cushing’s is caused by a

pituitary adenoma or microadenoma (<1 cm) which is nearly always benign.

Investigations itions

The aim of the investigations is firstly to establish the presence of hypercortisolism, secondly to determine its origin and finally to image the suspected organ involved.

1. Diagnosis. Hypercortisolism is determined by an elevated plasma cortisol and loss of

the diurnal variation. Two tests are routinely used: the dexamethasone suppression test and the urinary-free cortisol. One mg of dexamethasone given at 11 pm suppresses the adrenal axis and in normal subjects cortisol levels the following morning will be low. No suppression will occur in those with Cushing’s syndrome. A 24-hour urinary collection measuring cortisol gives an integrated measure of plasma-free cortisol. Cortisol is protein bound in normal individuals with a very low urinary excretion. If creatinine levels are concurrently measured the cortisol: creatinine ratio can be calculated and used instead of the long collection period required to estimate urinary excretion. False positive values can occur in alcohol abuse, obesity and depression. If diagnosis is still questioned midnight and morning cortisol levels are taken to assess if the normal cortisol diurnal ratio is intact (normally 1:4). A level of less than 1:2 is diagnostic. The level at 6:00 a.m. is normally higher than the 6:00 p.m. dip (a level less than 5 µg/dl is normal). All patients with non-pituitary Cushing’s syndrome should exhibit resistance to suppression with a low-dose dexamethasone suppression test (0.5 mg is given every 6 hours for 2 days) by maintaining their hypercortisol state. Diurnal salivary cortisol estimations reflect plasma values and may also aid diagnosis.

2. Origin. It is often difficult to distinguish between pituitary-dependent Cushing’s

disease and ectopic ACTH production. The high-dose dexamethasone suppression test (2 mg is given every 6 hours for 2 days) may help to further localize the problem. Cushing’s disease rarely produces the grossly elevated levels that are seen in ectopic ACTH syndrome. In pituitary Cushing’s syndrome hypercortisolism is suppressed with this level of dexamethasone but hormone production continues with the hypercortisolism of adrenal or ectopic origin. Measurement of ACTH levels with a

radioimmunoassay should distinguish an ectopic ACTH source from hypercortisolism of adrenal origin, because in the latter condition ACTH levels are low. Adrenal carcinomas secrete a variety of adrenal steroids (unlike adrenal adenomas) and a high level of DHEA-S (a specific adrenal androgen) is diagnostic. A chest radiograph or better still, a chest CT, should never be forgotten.

3. Adrenal imaging. A selenium-75-selenomethylcholesterol scintigram images the

adrenal glands. Bilateral increased uptake is indicative of excess ACTH stimulation, whereas asymmetrical uptake is more indicative of nodular adrenal hyperplasia. Lateralized uptake is pathognomonic of an adrenal adenoma. Adrenal carcinoma often shows poor uptake and the cortisol it produces suppresses the contralateral gland resulting in bilateral non-visualization. Furthermore, compared to that of benign disease, the hormone profiles of adrenal malignancy demonstrate increased levels of a large variety of steroid metabolic by-products. CT and MRI may be used in a

complementary fashion to image the adrenal glands. Somatostatin analogue or PET scanning is occasionally of value. These investigations often allow a ‘histological’ diagnosis to be inferred in the majority of patients.

4. Pituitary imaging. In Cushing’s disease, 10% of patients have tumours large enough to

cause an enlarged sella on plain skull X-rays. Only half of the patients with pituitary microadenomas, however, have lesions visualized on a CT scan, which makes the confirmation of Cushing’s disease difficult. MRI scanning is the preferable imaging modality, however, it may not identify tumours of less than 10 mm and 25% of the population have non-functioning micropituitary adenomas. If a chest radiograph or whole body CT fails to show evidence of an ectopic ACTH source in lung, pancreas or mediastinum, bilateral selective petrosal venous sampling for ACTH can confirm excess pituitary ACTH production. This is a difficult, but invaluable, technique only carried out at specialist centres.

Treatment

The treatment of Cushing’s disease in patients where a pituitary microadenoma has been identified is carried out with a trans-sphenoidal microsurgical dissection and excision of the adenoma. Ninety per cent of patients are cured in this way, however long-term studies have demonstrated recurrence rates up to 50%. Surgical complications include corticotropin, thyroid-stimulating hormone or gonadotropin deficiencies as well as permanent or transient diabetes insipidus and anosmia. In patients demonstrating suprasellar tumour extension, direct excision together with hypophysectomy is associated with early recurrence of Cushing’s disease of over 50%. In these patients, bilateral adrenalectomy is indicated with autotransplantation of 8 g of sliced adrenal into the rectus abdominis muscle. This prevents dependence on glucocorticoid and mineralocorticoid replacement, preserves reproductive function and prevents Nelson’s syndrome. The major disadvantage to autotransplantation is that exogenous steroids may not be required and any residual pituitary lesion will be freed from steroid inhibition and encouraged to expand. External pituitary irradiation or interstitial radiotherapy can be administered as adjuvant therapy and primary therapy. The latter is especially indicated in children. Complete adrenal blockade can be achieved with Metyrapone which acts by

inhibiting the conversion of 11-deoxycortisol to cortisol. It can be used as a poor alternative to surgery in Cushing’s syndrome and has prophylactic value prior to surgery. Bilateral adrenalectomy is indicated:

• following unsuccessful pituitary surgery or if such surgery is impossible; • in patients with rapidly progressive and severe hypercortisolism; • in palliative treatment for ectopic corticotropin syndrome.

Replacement steroid therapy is required following adrenalectomy, and prophylactic antibiotics are helpful to prevent the wound infections cushingoid patients are prone to developing. Wound sutures should be left undisturbed for several more days than for normal patients. Adrenalectomy is now possible using endoscopic approaches.

Nelson’s syndrome

In 1960, Nelson described a syndrome of hyperpigmentation, pituitary enlargement and ACTH elevation in patients following bilateral adrenalectomy for pituitary-dependent Cushing’s disease. The hyper-pigmentation is due to the increased levels of ACTH and melanocyte-stimulating hormone (MSH). Treatment involves prophylactic pituitary irradiation at the time of adrenalectomy. If the syndrome becomes established (this occurs in 30% of patients), hypophysectomy or pituitary irradiation is indicated.

Further reading

Farndon JR, Dunn JM. Adrenal tumours. Recent Advances in Surgery, 1992; 15:55–68. Lucarotti M, Farndon JR. Cushing’s syndrome. Current Practice in Surgery, 1993; 5:172–177. Wheeler MH. The adrenal glands. The New Aird’s Companion in Surgical Studies, 1992; 44:1215–

1232.

Related topics of interest Adrenal tumours (p. 13); Renal tumours (p. 280).