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==Historical Perspective==
==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.
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==
==Classification==
Cushing's syndrome may be classified according to the source of cortisol into four subtypes; Endogenous, exogenous, familial Cushing's Syndrome, and pseudo-Cushing’s syndrome.
Cushing's syndrome may be classified according to the source of [[cortisol]] into four subtypes; [[Endogenous]], [[exogenous]], [[familial]] Cushing's Syndrome, and pseudo-Cushing’s syndrome.


==Pathophysiology==
==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 [[Adrenocorticotropic hormone|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 of 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 corticotrophic pituitary 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, worsening hypertension and which leads to [[hypokalemia]] (common in ectopic ACTH secretion).  
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 [[Adrenocorticotropic hormone|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 [[[pituitary]] [[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==
==Causes==
Cushing’s syndrome occurs when the body’s tissues are exposed to high levels of [[corticosteroids]] for a long period. Many people develop Cushing’s syndrome because they take [[glucocorticoids]], ([[steroid hormones]] that are chemically similar to naturally produced [[cortisol]]) such as [[prednisone]] for [[asthma]], [[Rheumatoid Arteritis|rheumatoid arthritis]], [[lupus]], and other [[inflammatory diseases]]. [[Glucocorticoid]]s are also used to suppress the [[immune system]] after [[transplantation]] to keep the body from rejecting the new organ or tissue. Other people develop Cushing’s syndrome because their bodies produce too much [[cortisol]] due to adrenal or extra-adrenal causes.
Cushing’s syndrome occurs when the body is exposed to high levels of [[corticosteroids]] for a long period of time. Many people develop Cushing’s syndrome because they take [[glucocorticoids]], ([[steroid hormones]] that are chemically similar to naturally produced [[cortisol]]) such as [[prednisone]] for [[asthma]], [[Rheumatoid Arteritis|rheumatoid arthritis]], [[lupus]], and other [[inflammatory diseases]]. [[Glucocorticoid]]s 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 Cushing’s syndrome as a result of excessive [[cortisol]] production due to [[adrenal]] or extra-[[adrenal]] causes.


==Differentiating (Disease name) from other Conditions==
==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]].
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==
==Epidemiology and Demographics==
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==Risk Factors==
==Risk Factors==
Common risk factors in the development of Cushing's disease are female gender and genetic factors.
Common risk factors in the development of Cushing's disease are female gender and [[genetic]] factors.
 
==Screening==
==Screening==
There is insufficient evidence to recommend routine screening for Cushing's syndrome.
There is insufficient evidence to recommend routine screening for Cushing's syndrome.
==Natural History, Complications and Prognosis==
==Natural History, Complications and Prognosis==
Cushing's disease can lead to  The symptoms of Cushing's syndrome usually start with rapid [[obesity|weight gain]], a [[round face]] often referred to as a "[[moon face]]", and [[insomnia]]. It may progress to develop [[amenorrhoea]], [[infertility|infertility,]] and [[Psychological|psychological disturbances]]. If left untreated, patients with Cushing's syndrome may progress to develop [[Diabetes mellitus|diabetes]], [[cardiovascular]] and [[Psychiatric|psychiatric complications]]. The prognosis depends on the severity of the disease.
Cushing's disease may present initially as rapid [[obesity|weight gain]], a [[round face]] often referred to as a "[[moon face]]", and [[insomnia]]. It may progress to [[amenorrhoea]], [[infertility|infertility,]] and [[Psychological|psychological disturbances]]. If left untreated, patients with Cushing's syndrome may develop [[Diabetes mellitus|diabetes]], [[cardiovascular]] and [[Psychiatric|psychiatric complications]]. The prognosis depends on the severity of the disease.


==Diagnosis==
==Diagnosis==
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===Laboratory Findings===
===Laboratory Findings===
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.
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===
===Electrocardiogram===
There are no electrocardiogram findings associated with Cushing's syndrome.
There are no electrocardiogram findings associated with Cushing's syndrome.
===Chest X Ray===
===Chest X Ray===
Chest X-Ray can help to identify the causes of ectopic ACTH in Cushing's syndrome such as [[lung carcinoma]], [[Carcinoid cancer|bronchial carcinoid]], and [[Carcinoid cancer|thymic carcinoid]].
An[[ X-Ray]] may be helpful to identify the causes of [[ectopic]] [[ACTH]] in Cushing's syndrome such as [[lung carcinoma]], [[Carcinoid cancer|bronchial carcinoid]], and [[Carcinoid cancer|thymic carcinoid]].


===CT===
===CT===
[[CT scan]] of the adrenal gland is performed to detect the presence of the [[adrenal adenoma]] and the cause of [[Ectopic ACTH Syndrome|ectopic ACTH]]. CT scan is preferred over MRI in these cases.
[[CT scan]] of the [[adrenal gland]] is performed to detect the presence of the [[adrenal adenoma]] and the cause of [[Ectopic ACTH Syndrome|ectopic ACTH]]. [[CT scan]] is preferred over [[MRI]] in these cases.


===MRI===
===MRI===
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===Echocardiography or Ultrasound===
===Echocardiography or Ultrasound===
There are no electrocardiography or ultrasound findings associated with Cushing's disease.
There are no [[electrocardiography]] or [[ultrasound]] findings associated with Cushing's disease.


===Other Imaging Findings===
===Other Imaging Findings===
[[Scintigraphy]] of the adrenal gland with iodocholesterol scan is occasionally necessary.
[[Scintigraphy]] of the [[adrenal gland]] with iodocholesterol scan is occasionally necessary.


==Treatment==
==Treatment==


===Medical Therapy===
===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.
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===
===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.
If an adrenal [[adenoma]] is identified, it may be removed by either [[laparoscopic]] or open [[adrenalectomy]]. An [[Adrenocorticotropic hormone|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]] [[Adrenocorticotropic hormone|ACTH]] and normal adrenal tissue does not recover immediately. If both [[Adrenal Gland|adrenals]] are removed, replacement with [[hydrocortisone]] or [[prednisolone]] is imperative.


===Primary prevention===
===Primary prevention===

Latest revision as of 19:38, 20 October 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

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 2–5 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-Cushing’s 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 [[[pituitary]] 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

Cushing’s syndrome occurs when the body is exposed to high levels of corticosteroids for a long period of time. Many people develop Cushing’s 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 Cushing’s 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 2–5 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.

References


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