Cushing's syndrome

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Cushing's syndrome
Classification & external resources
Cortisol
ICD-10 E24.
ICD-9 255.0
DiseasesDB 3242
MedlinePlus 000410
eMedicine med/485 

Cushing's syndrome or hypercortisolism or hyperadrenocorticism is an endocrine disorder caused by high levels of cortisol in the blood. Cortisol is released from the adrenal gland in response to ACTH being released from the pituitary gland in the brain. High levels of cortisol can also be induced by the administration of drugs. Cushings disease, or more properly termed secondary hyperadrenocortcism, is very similar to Cushing's syndrome in that all physiologic manifestations of the conditions are the same. Both diseases are characterized by elevated levels of cortisol in the blood, but the cause of elevated cortisol differs between the diseases. Cushing's disease specifically refers to a tumor in the pituitary gland that stimulates excessive release of cortisol from the adrenal gland by releasing large amounts of ACTH. It was discovered by American physician, surgeon and endocrinologist Harvey Cushing (1869-1939) and reported by him in 1932.

Cushing's syndrome is also a relatively common condition in domestic dogs in which causes are the same as the syndrome in humans, and in horses, where it leads to a long, tightly curled coat which does not shed and leads to weight loss and laminitis.

Contents

[edit] Signs and symptoms

Symptoms include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity), a round face often referred to as a "moon face", excess sweating, telangiectasia (dilation of capillaries), thinning of the skin (which causes easy bruising) and other mucous membranes, purple or red striae (also caused by thinning of the skin) on the trunk, buttocks, arms, legs or breasts, proximal muscle weakness (hips, shoulders), and hirsutism (facial male-pattern hair growth). A common sign is the growth of fat pads along the collar bone and on the back of the neck (known as a buffalo hump). The excess cortisol may also affect other endocrine systems and cause, for example, reduced libido, impotence, amenorrhoea and infertility. Patients frequently suffer various psychological disturbances, ranging from euphoria to frank psychosis. Depression and anxiety, including panic attacks, are common.

Other signs include persistent hypertension (due to the aldosterone-like effects) and insulin resistance, leading to hyperglycemia (high blood sugars) which can lead to diabetes mellitus. Untreated Cushing's syndrome can lead to heart disease and increased mortality. Cushing's syndrome due to excess ACTH may also result in hyperpigmentation of the skin, due to its ability to stimulate melanocyte receptors.

[edit] Diagnosis

When Cushing's is suspected, a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH levels) and 24-hour urinary measurement for cortisol have equal detection rates (Raff & Findling 2003). Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, low ACTH and high cortisol would be indicative of Cushing's syndrome because dexamethasone inhibited the release of ACTH from the pituitary gland. High ACTH and high cortisol would be indicative of Cushing's disease because pituitary adenomas are immune to negative feedback inhibition from elevated cortisol levels. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late night levels of salivary cortisol are high in Cushingoid patients. Other pituitary hormones may need to be determined, and performing physical examination directed for any visual field defect may be necessary if a pituitary lesion is suspected (which may compress the optic chiasm causing typical bitemporal hemianopia).

When these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of an adrenal or pituitary adenoma. These should be performed when other tests are positive, to decrease likelihood of incidentalomas (incidental discovery of harmless lesions in both organs). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Very rarely, determining the cortisol levels in various veins in the body by venous catheterisation working towards the pituitary (petrosal sinus sampling) is necessary.

[edit] Pathophysiology

A textbook example of endocrinology is the pituitary adrenal axis, which also involves the hypothalamus. Both the hypothalamus and the pituitary gland are in the brain. The hypothalamus releases CRH (corticotropin-releasing hormone), which stimulates the pituitary gland to release ACTH (adrenalcorticotropin hormone). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exhibit negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Strictly, Cushing's syndrome refers to excess cortisol of any etiology. One of the most common causes of Cushings syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low. Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a pituitary gland adenoma. This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because a tumor in the pituitary is unresponsive to negative feedback from high cortisol levels.

[edit] Treatment

If an adrenal adenoma is identified it may be removed by surgery. Pituitary ACTH producing adenoma should be removed after diagnosis. Regardless of the adenoma's location, most patients will require steroid replacement postoperatively at least in the interim as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed replacement with hydrocortisone or prednisolone is imperative.

In those patients not suitable for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy.

Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome (Nelson et al 1960).

In iatrogenic Cushing's, dose adjustment may be sufficient or it may be necessary to change to another type of immunosuppresive medication.

[edit] Epidemiology

Iatrogenic Cushing's syndrome (caused by treatment with corticosteroids) is the most common form of Cushing's syndrome. Endogenous (i.e. non-iatrogenic) Cushing's syndrome is relatively rare.

Incidence of causes of Cushing's syndrome per million person-years:

  • Cushing's disease: 10
  • Primary adrenal: 3
  • Ectopic ACTH: 1.4

[edit] Hyperadrenocorticism in companion animals

Hyperadrenocorticism is a common endocrinopathy in domestic dogs and domestic ferrets. Most cases in both species are caused by hyperplasia of the adrenal cortex in response to pituitary dysfunction. Hyperadrenocorticism in companion animals is usually treated with long term drug therapy. In dogs, treatment is accomplished with trilostane or with mitotane. Dogs with pituitary-dependent Cushing's syndrome may be treated by radiation therapy directed against a pituitary adenoma. Dogs productive adrenal tumors may be treated by adrenalectomy.

[edit] See also


[edit] References

  • Cushing HW. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;50:137-195.
  • Nelson DH, Meakin JW, Thorn GW. ACTH-producing tumors following adrenalectomy for Cushing's syndrome. Ann Intern Med 1960;52:560–569. PMID 14426442.
  • Raff H, Findling JW. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med 2003;138:980-91. PMID 12809455.

[edit] External links

v • d • e
Endocrine pathology: endocrine diseases (E00-35)

thyroid Hypothyroidism (Iodine deficiency, Cretinism, Congenital hypothyroidism, Goitre) - Hyperthyroidism (Graves-Basedow disease, Toxic multinodular goitre) - Thyroiditis (De Quervain's thyroiditis, Hashimoto's thyroiditis)
pancreas Diabetes mellitus (type 1, type 2, coma, angiopathy, ketoacidosis, nephropathy, neuropathy, retinopathy) - Zollinger-Ellison syndrome
parathyroid Hypoparathyroidism (Pseudohypoparathyroidism) - Hyperparathyroidism (Primary hyperparathyroidism, Secondary hyperparathyroidism, Tertiary hyperparathyroidism)
pituitary hyperfunction (Acromegaly, Hyperprolactinaemia, Syndrome of inappropriate antidiuretic hormone) - Hypopituitarism (Sheehan's syndrome, Kallmann syndrome, Simmonds' disease, Growth hormone deficiency) - Diabetes insipidus - Hypothalamic-pituitary dysfunction
adrenal Cushing's syndrome (Nelson's syndrome, Pseudo-Cushing's syndrome) - Congenital adrenal hyperplasia (due to 21-hydroxylase deficiency) - Hyperaldosteronism (Conn syndrome, Bartter syndrome) - Adrenal insufficiency (Addison's disease) - Hypoaldosteronism
gonads Polycystic ovary syndrome - 5-alpha-reductase deficiency - Hypogonadism - Delayed puberty - Precocious puberty
other Autoimmune polyendocrine syndrome - Carcinoid syndrome - Laron syndrome - Psychogenic dwarfism - Androgen insensitivity syndrome - Progeria

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