Cushing's syndrome overview

# Overview
Cushing's Syndrome is an  endocrine disorder caused by high levels of cortisol in the blood from a variety of causes, including primary pituitary adenoma (known as Cushing's disease), primary adrenal hyperplasia or neoplasia, ectopic ACTH production (e.g., from a small cell lung cancer), and iatrogenic (steroid use).  Cushing's syndrome was first identified by Dr. Harvey Cushing (an American physician, surgeon, and endocrinologist) in 1932 as a polyglandular disorder. It was later named as Cushing's syndrome. Normally, cortisol is released from the adrenal gland in response to ACTH being released from the pituitary gland. Both Cushing's syndrome and Cushing's disease are characterized by elevated levels of cortisol in the blood, but the cause of elevated cortisol differs between the two. Cushing's disease specifically refers to a tumor in the pituitary gland that stimulates the excessive release of cortisol from the adrenal gland by releasing large amounts of ACTH. In Cushing's disease, ACTH levels do not respond to negative feedback from the high levels of cortisol. Cushing's disease is particularly common in females. Annually, there are around 25 new cases per million people worldwide. Common risk factors in the development of Cushing's disease are female gender and genetic factors. Symptoms of Cushing's syndrome 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", excessive sweating, insomnia, reduced libido, impotence, amenorrhea, infertility and psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety. Cushing's syndrome may progress to develop amenorrhoea, infertility, and psychological disturbances. If left untreated, patients with Cushing's syndrome may progress to develop diabetes, cardiovascular and psychiatric complications. The prognosis depends on the severity of the disease. When Cushing's is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level) or a 24-hour urinary measurement for cortisol offer equal detection rates. 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, high cortisol would be indicative of Cushing's syndrome. 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 hormone levels may need to be ascertained. CT scan of the adrenal gland is performed to detect the presence of the adrenal adenoma and the cause of ectopic ACTH. CT scan is preferred over MRI in these cases. MRI of the pituitary gland is performed to detect the presence of the pituitary adenoma. The medications usually used for the treatment of Cushing's syndrome are Pasireotide, Cabergoline, Ketoconazole, and Metyrapone. The choice of medical therapy should be individualized. It is guided by drug efficacy, side effects, individual patient factors, and cost. If an adrenal adenoma is identified it may be removed by either laparoscopic or open adrenalectomy. An ACTH-secreting corticotrophic pituitary 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.

# Historical Perspective
Cushing's syndrome was first identified by Dr. Harvey Cushing (an American physician, surgeon, and endocrinologist) in 1932 as a polyglandular disorder. It was later named as Cushing's syndrome.

# Classification
Cushing's syndrome may be classified according to the source of cortisol into four subtypes; Endogenous, exogenous, familial Cushing's Syndrome, and pseudo-Cushings syndrome.

# Pathophysiology
Both the hypothalamus and the pituitary gland are part of the brain. The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release corticotropin (ACTH). 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 exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Strictly, Cushing's syndrome refers to excess cortisol due to any etiology. One of the causes of Cushing's 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 corticotropic ] 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 causes the pituitary to be unresponsive to negative feedback from high cortisol levels. Cortisol can also exhibit mineralocorticoid activity in high concentrations, causing worsening of hypertension and  hypokalemia (common in ectopic ACTH secretion).

# Causes
Cushings syndrome occurs when the body is exposed to high levels of corticosteroids for a long period of time. Many people develop Cushings syndrome because they take glucocorticoids, (steroid hormones that are chemically similar to naturally produced cortisol) such as prednisone for asthma, rheumatoid arthritis, lupus, and other inflammatory diseases. Glucocorticoids are also used to suppress the immune system after transplantation to keep the body from rejecting the new organ or tissue. Other people may develop Cushings syndrome as a result of excessive cortisol production due to adrenal or extra-adrenal causes.

# Differentiating (Disease name) from other Conditions
Cushing's syndrome must be differentiated from other diseases that cause hypertension, obesity, and hyperandrogenism, such as metabolic syndrome X and pseudo-Cushing's syndrome.

# Epidemiology and Demographics
Cushing's disease is particularly common in females. Annually, there are around 25 new cases per million people worldwide.

# Risk Factors
Common risk factors in the development of Cushing's disease are female gender and genetic factors.

# Screening
There is insufficient evidence to recommend routine screening for Cushing's syndrome.

# Natural History, Complications and Prognosis
Cushing's disease may present initially as rapid weight gain, a round face often referred to as a "moon face", and insomnia. It may progress to amenorrhoea, infertility, and psychological disturbances. If left untreated, patients with Cushing's syndrome may develop diabetes, cardiovascular and psychiatric complications. The prognosis depends on the severity of the disease.

# Diagnosis

## History and Symptoms
Symptoms of Cushing's syndrome include  rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity), a round face also known as a "moon face", excessive sweating, insomnia, reduced libido, impotence, amenorrhea, infertility and psychological disturbances, ranging from euphoria to psychosis and may also include depression and anxiety.

## Physical Examination
Patients with Cushing's syndrome usually appear obese. Physical examination of patients with Cushing's syndrome is remarkable for moon-like faces, easy bruising, purple skin stria, and hirsutism.

## Laboratory Findings
When Cushing's disease is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level) or a 24-hour urinary measurement of cortisol may be used for detection. 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, high cortisol would be indicative of Cushing's syndrome. 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 hormone levels may also need to be ascertained.

## Electrocardiogram
There are no electrocardiogram findings associated with Cushing's syndrome.

## Chest X Ray
AnX-Ray may be helpful to identify the causes of ectopic ACTH in Cushing's syndrome such as lung carcinoma, bronchial carcinoid, and thymic carcinoid.

## CT
CT scan of the adrenal gland is performed to detect the presence of the adrenal adenoma and the cause of ectopic ACTH. CT scan is preferred over MRI in these cases.

## MRI
MRI of the pituitary gland is performed to detect the presence of the pituitary adenoma.

## Echocardiography or Ultrasound
There are no electrocardiography or ultrasound findings associated with Cushing's disease.

## Other Imaging Findings
Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary.

# Treatment

## Medical Therapy
The medications usually used for the treatment of Cushing's syndrome are pasireotide, cabergoline, ketoconazole, and metyrapone. The choice of medical therapy should be individualized. It is guided by drug efficacy, side effects, individual patient factors, and cost.

## Surgery
If an adrenal adenoma is identified, it may be removed by either laparoscopic or open adrenalectomy. An ACTH-secreting corticotropic pituitary 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. If both adrenals are removed, replacement with hydrocortisone or prednisolone is imperative.

## Primary prevention
There are no primary preventive measures available for Cushing's syndrome.

## Secondary prevention
There are no secondary preventive measures available for Cushing's syndrome.