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{{CMG}}; {{AE}} {{Ammu}}
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{{SK}} MEN type 4; MEA type 4; Multiple endocrine neoplasms type 4; Multiple endocrine adenomatosis type 4
==Overview==


== Overview ==
'''Cushing's disease''' (also known as '''Cushing disease''', '''tertiary or secondary hypercortisolism''', '''tertiary or secondary hypercorticism''', '''Itsenko-Cushing disease''')<ref>[http://www.whonamedit.com/doctor.cfm/1520.html "Whonamedit - Nikolai Mikhailovich Itsenko"]. "Nikolai Mikhailovich Itsenko investigated neural infections, vegetative nervous system diseases and cerebral tumors. In 1926 he was the first one who described Itsenko-Cushing's disease, six years before Cushing."</ref><ref name="gozhenko">{{cite book|author=A.I. Gozhenko,  I.P. Gurkalova, W. Zukow, Z. Kwasnik, B. Mroczkowska |title =Pathology: Medical Student's Library|chapter =Trematoda|publisher =Radomska Szkola Wyžsza uk. Zubrzyckiego|year =2009|page=280|isbn =978-83-61047-18-6|url =http://books.google.com.ph/books?id=Pvk0MoLNjgYC&lpg=PA280&dq=Itsenko-Cushing's%20disease%20and%20Itsenko-Cushing's%20syndrome%5C&pg=PA280#v=onepage&q=Itsenko-Cushing's%20disease%20and%20Itsenko-Cushing's%20syndrome%5C&f=false}}</ref> is a cause of [[Cushing's syndrome]] characterised by increased secretion of [[adrenocorticotropic hormone]] (ACTH) from the [[anterior pituitary]] ('''secondary''' [[hypercortisolism]]). This is most often as a result of a pituitary [[adenoma]] (specifically pituitary basophilism) or due to excess production of hypothalamus CRH ([[Corticotropin releasing hormone]]) ('''tertiary''' hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing's syndrome,<ref name="cushing's" /> when excluding Cushing's syndrome from exogenously administered [[corticosteroid]]s.
Multiple endocrine neoplasia type 4 is a type of [[tumor]] that arises from [[endocrine]] cells of [[parathyroid]] gland and [[pituitary]] gland. Multiple endocrine neoplasia type 4 is part of the broad group of [[disease]]s called [[multiple endocrine neoplasia]]. Heterozygous [[mutation]] of ''Cdkn1b/CDKN1B'' [[gene]] on [[chromosome]] 12p13 is suspected to be the cause of multiple endocrine neoplasia type 4. Multiple endocrine neoplasia type 4 must be differentiated from other hereditary tumors such as [[medullary thyroid carcinoma]], C-cell hyperplasia, [[von Hippel Lindau syndrome]], familial hyperparathyroidism, [[acromegaly]], [[multiple endocrine neoplasia type 1]] (MEN 1), [[multiple endocrine neoplasia type 2a]], and [[multiple endocrine neoplasia type 2b]]. The most potent risk factor in the development of multiple endocrine neoplasia type 4 is family history. There is insufficient evidence to recommend routine screening for multiple endocrine neoplasia type 4. The most common symptoms of multiple endocrine neoplasia type 4 include [[lethargy]], [[constipation]], and [[headache]]. Transsphenoidal surgery is used for treating [[pituitary adenoma]] of multiple endocrine neoplasia type 4.


==Historical Perspective==
This should not be confused with [[Cushing's syndrome#Pathophysiology|ectopic Cushing syndrome]] or exogenous steroid use.<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001443/</ref>
* Historical background of multiple endocrine neoplasia type 4 is given in the table below.


<br>
== Signs and symptoms ==
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
 
|+'''''MEN IV Historical Background'''''
The symptoms of Cushing's disease are similar to those seen in other causes of [[Cushing's syndrome]].<ref>{{cite web|title=Cushing's Syndrome Information Page|url=http://www.ninds.nih.gov/disorders/cushings/cushings.htm|accessdate=August 26, 2013}}</ref>
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Years}}
Patients with Cushing's disease usually present with one or more signs and symptoms secondary to the presence of excess [[cortisol]] or [[ACTH]].<ref>{{cite journal|last=Kirk|first=Lawrence F., Jr |author2=Robert B. Hash |author3=Harold P. Katner |author4=Tom Jones |title=Cushing's Disease: Clinical Manifestations and Diagnostic Evaluation |journal=American Family Physician |date=September 2000|volume=62|page=1119; 1127|url=http://www.aafp.org/afp/2000/0901/p1119.html|accessdate=2013-08-26}}</ref>
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Scientist}}
Although uncommon, some patients with Cushing's disease have large pituitary tumors (macroadenomas). In addition to the severe hormonal effects related to increase blood cortisol levels, the large tumor can compress adjacent structures. {{citation needed|date=April 2013}} These tumors can compress the nerves that carry information from the eyes, causing a decrease in peripheral vision.{{citation needed|date=April 2013}} Glaucoma and cataracts also may occur in Cushing's syndrome. In children, the two main symptoms are obesity and decreased linear growth.<ref name="newell-price" />
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Contribution}}
 
|-
The clinical diagnosis must be based on the presence of one or more of the symptoms listed below, because the syndrome itself has no true pathognomonic signs or symptoms.{{citation needed|date=April 2013}} The most common symptoms seen in male patients are [[stretch marks|purple striae]], [[muscle atrophy]], [[osteoporosis]], and [[kidney stone]]s.<ref name="newell-price" />
! style="background: #DCDCDC;" |2006
 
! style="background: #F5F5F5;" |Pellegata
===Common symptoms===
| style="padding: 5px 5px; background: #F5F5F5;" |Reported a case study of a patient with [[multiple endocrine neoplasia type 1]] like features such as [[acromegaly]], [[pituitary tumor]], and primary [[hyperparathyroidism]]
Symptoms include:
|-
{|
! style="background: #DCDCDC;" |2007
| valign=top |
! style="background: #F5F5F5;" |Georgitsi
* weight gain
| style="padding: 5px 5px; background: #F5F5F5;" |Reported a case study of a female with small cell neuro endocrine tumor, [[pituitary adenoma]], and [[hyperparathyroidism]]
* high blood pressure <ref name="symptoms">{{cite journal|last=Wilson|first=P.J. |author2=Williams, J.R. |author3=Smee, R.I.|title=Cushing's disease: A single centre's experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy|journal=Journal of Clinical Neuroscience|year=2014|volume=21|issue=1|pages=100–106|pmid=24074805|url=http://www.ncbi.nlm.nih.gov/pubmed/24074805|doi=10.1016/j.jocn.2013.04.007}}</ref>
|-
* poor short-term memory
! style="background: #DCDCDC;" |2010
* irritability
! style="background: #F5F5F5;" |Molatore
* excess hair growth (women)<ref name="cushing's" />
| style="padding: 5px 5px; background: #F5F5F5;" |Reported a case study of a female with bronchial [[carcinoid]], [[pituitary adenoma]], [[parathyroid adenoma]], and papillary thyroid carcinoma
* Impaired immunological function <ref name="symptoms" />
|-
* red, ruddy face {{ns|35}}
! style="background: #DCDCDC;" |2012
| valign=top |
! style="background: #F5F5F5;" |Malanga
* extra fat around neck
| style="padding: 5px 5px; background: #F5F5F5;" |Reported a case study of a female with gastric [[carcinoid tumor]] and [[hyperparathyroidism]]
* [[moon face]]
|-
* fatigue
! style="background: #DCDCDC;" |2014
* red stretch marks
! style="background: #F5F5F5;" |Toneli
* poor concentration
| style="padding: 5px 5px; background: #F5F5F5;" |Reported a case study of a female with [[hyperparathyroidism]] and gastrointestinal [[neuroendocrine tumor]]
* irregular menstruation.<ref name="newell-price">{{cite journal|last=Newell-Price|first=J.|author2=Bertagna, X. |author3=Grossman, A.B. |author4= Nieman, L.K. |title=Cushing's syndrome|journal=The Lancet|year=2006|volume=367|issue=9522|pages=1605–1617|doi=10.1016/S0140-6736(08)61345-8|url=http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)68699-6/abstract|accessdate=30 January 2014}}</ref>
|}
|}


== Pathophysiology==
===Less common symptoms===
Multiple endocrine neoplasia type 4 is a rare genetic disease which is the latest addition to the family of multiple endocrine neoplasia. It is characterized by [[parathyroid adenoma]] and [[pituitary adenoma]].<ref name="pmid23933118">{{cite journal| author=Thakker RV| title=Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). | journal=Mol Cell Endocrinol | year= 2014 | volume= 386 | issue= 1-2 | pages= 2-15 | pmid=23933118 | doi=10.1016/j.mce.2013.08.002 | pmc=PMC4082531 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23933118  }} </ref>
The less-common symptoms include:
* [[insomnia]]
* recurrent infection
* thin skin and stretch marks <ref name="symptoms" />
* easy bruising
* weak bones {{ns|39}}
* [[acne]]
* balding (women)
* depression
* hip and shoulder weakness
* swelling of feet/legs
* [[diabetes mellitus]].<ref name="symptoms"/>


=== Genetics ===
==History==
* Multiple endocrine neoplasia type 4 is an [[autosomal dominant]] disorder caused by genetic [[mutation]] of ''Cdkn1b/CDKN1B'' gene.
In 1924, the Soviet neurologist Nikolai Mikhailovich Itsenko reported two patients with [[pituitary adenoma]]. The resulting excessive adrenocorticotropic hormone secretion led to the production of large amounts of [[cortisol]] by the [[adrenal glands]]. The disease associated with this increased secretion of cortisol was described by [[Harvey Cushing]] in 1932, after Cushing was presented with a unique case of the disease<ref>{{cite book|last=Laws Jr., E.R., Ezzat, S., Asa, S.L., Rio, L.M., Michel, L. & Knutzen, R.|title=Pituitary Disorders: Diagnosis and Management|year=2013|publisher=Wiley-blackwell|location=United Kingdom|isbn=978-0-470-67201-3|page=xiv}}</ref> In 1910, the American neurosurgeon [[Harvey Cushing]] (1869-1939) was presented with a case of a 23-year-old woman called Minnie G.. Minnie’s symptoms included painful [[obesity]], [[amenorrhea]], [[hypertrichosis]] (abnormal hair growth), underdevelopment of secondary sexual characteristics, [[hydrocephalus]] and cerebral tension.<ref name="cushing's">{{cite journal|last=Lanzino|first=Giuseppe|author2=Maartens, Niki F. |author3=Laws, Edward R. |title=Cushing's case XLV: Minnie G.|journal=Journal of Neurosurgery|year=2002|volume=97|issue=1|pages=231–234|accessdate=January 30, 2014|pmid=12134925|doi=10.3171/jns.2002.97.1.0231}}</ref> This combination of symptoms was not yet described by any medical disorder at the time.<ref name="cushing's" /> However, Cushing was confident that Minnie’s symptoms were due to dysfunction of the pituitary gland, and resembled those associated with an [[adrenal tumor]]. Given this conviction, and his knowledge of the three [[anterior pituitary]] cell types, Cushing hypothesized that if acidophil [[hyperpituitarism]] (excess secretion from the acidophil cells) caused [[acromegaly]], then an excess of [[basophil cell]]s must be involved in another pituitary disorder that involves sexual dysfunction ([[amenorrhea]] in females and [[erectile dysfunction]] in males) and could explain Minnie's symptoms.<ref name="cushing's" /> Experimental evidence and case reports by Cushing led to his publication in 1932 on pituitary basophilism as the cause of Cushing's disease. In this publication, the clinical symptoms of the disease, named after [[Harvey Cushing]], were described.<ref>{{cite journal|first=Harvey|last=Cushing|title=The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism)|journal=[[Bulletin of the Johns Hopkins Hospital]]|volume=50|pages=137–95|year=1932|pmc=2387613|pmid=19310569|issue=4}}</ref><ref>{{cite news|title=Dr. Cushing Dead; Brain Surgeon, 70. A Pioneer Who Won Fame as Founder of New School of Neuro-Surgery. Discovered Malady Affecting Pituitary dre. Was Noted Teacher and Author|url=http://select.nytimes.com/gst/abstract.html?res=F30915F73C5A177A93CAA9178BD95F4D8385F9|work=[[New York Times]]|date=8 October 1939|accessdate=2010-03-21}}</ref> Out of the 12 cases with [[hypercortisolism]] described in Cushing’s monograph on the pituitary body, 67% died within a few years after symptom presentation, whereas Minnie G. survived for more than 40 years after symptom presentation, despite the fact that she did not receive any treatments for a pituitary tumor.<ref name="cushing's" /> The prolonged survival led to the uniqueness of Minnie's case. The reason behind this survival remains a mystery, since an [[autopsy]] of Minnie was refused after her death.<ref name="cushing's" /> However, the most likely explanation, proposed by J. Aidan Carney and based on statistical evidence, was that the [[basophil]] [[adenoma]] Minnie might have harbored underwent partial [[infarction]], leading to symptom regression.<ref name="cushing's" /> The other hypothesis was that Minnie might have suffered from Primary Pigmented Nodular Adrenocortical Disease (PPNAD), which when associated with Cushing's syndrome ([[Carney complex]]) can infrequently cause spontaneous symptom regression of the latter.<ref name="cushing's" />
* The chromosome involved in the development of the disease is 12p13.
* A tumor supressor protein called p27Kip1 is encoded by ''Cdkn1b/CDKN1B'' gene germline mutation.
* The [[protein]] is derived from a cell cycle inhibitor [[p27 (gene)|''p27'']].
* The mechanism of action of the [[gene]] is to inhibit [[Cyclin-dependent kinase|cyclin/cyclin-dependent kinase]] complexes.
* Inhibition of [[Cyclin-dependent kinase|cyclin/cyclin-dependent kinase]] complexes causes cessation of cell cycle progression.<ref name="LeePellegata2013">{{cite journal|last1=Lee|first1=Misu|last2=Pellegata|first2=Natalia S.|title=Multiple Endocrine Neoplasia Type 4|volume=41|year=2013|pages=63–78|issn=0301-3073|doi=10.1159/000345670}}</ref>


=== Associated Conditions===
== Diagnosis ==
* Gastric [[carcinoid syndrome]]
Diagnosis is made first by diagnosing Cushing's Syndrome, which can be difficult to do clinically since the most characteristic symptoms only occur in a minority of patients.<ref name="nieman">{{cite journal|last=Nieman|first=L.K.|author2=Ilias, I.|title=Evaluation and treatment of Cushing’s syndrome|journal=The American Journal of Medicine|year=2005|volume=118|issue=12|pages=1340–1346|doi=10.1016/j.amjmed.2005.01.059|url=http://www.amjmed.com/article/S0002-9343(05)00160-9/abstract|accessdate=30 January 2014|pmid=16378774}}</ref> Some of the biochemical diagnostic tests used include [[saliva testing|salivary]] and blood serum cortisol testing, 24-hour urinary free cortisol (UFC) testing, the [[dexamethasone suppression test]] (DST), and bilateral [[inferior petrosal sinus sampling]] (BIPSS). No single test is perfect and multiple tests should always be used to achieve a proper diagnosis.<ref name="newell-price" /> Diagnosing Cushing's disease is a multidisciplinary process involving doctors, endocrinologists, radiologists, surgeons, and chemical pathologists.<ref name="newell-price" />
* [[Uterine fibroids]]
 
* [[Adrenal tumor|Adrenal mass]]
Once Cushing's syndrome has been diagnosed, the first step towards finding the cause is measuring plasma corticotropin concentrations. A concentration consistently below 1.1 pmol/L is classified as corticotropin-independent and does not lead to a diagnosis of Cushing's disease. In such cases, the next step is adrenal imaging with X-ray computed tomography|CT. If plasma corticotropin concentrations are consistently above 3.3 pmol/L, then corticotropin-dependent Cushing's syndrome is most likely. Any intermediate values need to be cautiously interpreted and a corticotropin-releasing hormone (CRH) test is advised in order to confirm corticotropin dependency. If corticotropin-dependent Cushing's syndrome is determined then the next step is to distinguish between Cushing's disease and ectopic corticotropin syndrome. This is done via a combination of techniques including CRH, high-dose DST, BIPSS, and pituitary [[Magnetic resonance imaging|MRI]].
* [[Zollinger-Ellison syndrome]]
 
* [[Gastrinoma]]
Two dexamethasone suppression tests (DSTs) are generally used, the overnight and 48-h DSTs.<ref name="newell-price" /> For both tests, a plasma cortisol level above 50 nmol/L is indicative of Cushing's disease.<ref name="newell-price" /> However, 3-8% of patients with Cushing's disease will test negative due to a retention of dexamethasone suppression abilities.<ref name="newell-price" /> For non-Cushing or healthy patients, the false-positive rate is 30%.<ref name="newell-price" /> The 48-h DST is advantageous since it is more specific and can be done by outpatients upon proper instruction.<ref name="newell-price" /> In the high-dose 48-h DST, 2&nbsp;mg of dexamethasone is given every 6 hours for 48 hours or a single dose of 8&nbsp;mg is given.<ref name="newell-price" /> This test is not needed if the 48-h low-dose DST has shown suppression of cortisol by over 30%.<ref name="newell-price" /> These tests are based on the glucocorticoid sensitivity of pituitary adenomas compared to non-pituitary tumors.<ref name="newell-price" />
* [[Acromegaly]]
 
* [[Cushing's syndrome]]
Administration of [[corticotropin releasing hormone]] (CRH) can differentiate this condition from ectopic ACTH secretion. In a patient with Cushing's disease, the tumor cells will be stimulated to release corticotropin and elevated plasma corticotropin levels will be detected.<ref name="newell-price" /> This rarely occurs with ectopic corticotropin syndrome and thus is quite useful for distinguishing between the two conditions.<ref name="newell-price" /> If ectopic, the plasma ACTH and [[cortisol]] levels should remain unchanged; if this is pituitary related, levels of both would rise. The CRH test uses recombinant human or ovine-sequence CRH, which is administered via a 100μg intravenous [[Bolus (medicine)|bolus]] dose. The sensitivity of the CRH test for detecting Cushing's disease is 93% when plasma levels are measured after fifteen and thirty minutes.<ref name="newell-price" /> However, this test is used only as a last resort due to its high cost and complexity.<ref name="nieman" />
* [[Neuroendocrine tumor]]s of [[cervix]]
 
A CT or MRI of the pituitary may also show the ACTH secreting tumor if present. However, in 40% of Cushing's disease patients MRI is unable to detect a tumor.<ref name="newell-price" /> In one study of 261 patients with confirmed pituitary Cushing's Disease, only 48% of pituitary lesions were identified using MRI prior to surgery. The average size of tumor, both those that were identified on MRI and those that were only discovered during surgery, was 6&nbsp;mm.<ref>Jagannathan, J. et al, [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945523/ Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease], ''Journal of Neurosurgery'', 25 September 2010, Retrieved 2014-01-27</ref>


==Causes==
A more accurate but invasive test used to differentiate pituitary from ectopic or adrenal Cushing's syndrome is [[inferior petrosal sinus sampling]].<ref>{{cite journal|last=Deipolyi|first=A|author2=Karaosmanoglu, A|author3=Habito, C|author4=Brannan, S|author5=Wicky, S|author6=Hirsch, J|author7=Oklu, R|title=The role of bilateral inferior petrosal sinus sampling in the diagnostic evaluation of Cushing disease.|journal=Diagnostic and interventional radiology (Ankara, Turkey)|date=2011-02-23|pmid=21348009|doi=10.4261/1305-3825.DIR.4279-11.0|volume=18|issue=1|pages=132–8}}</ref> A corticotropin gradient sample via BIPSS is required to confirm diagnosis when pituitary MRI imaging and biochemical diagnostic tests have been inconclusive.<ref name="newell-price" /> A basal central:peripheral ratio of over 3:1 when CRH is administered is indicative of Cushing’s disease.<ref name="newell-price" /> This test has been the gold standard for distinguishing between Cushing's disease and ectopic corticotropin syndrome.<ref name="newell-price" /> The BIPSS has a sensitivity and specificity of 94% for Cushing's disease but it is usually used as a last resort due to its invasiveness, rare but serious complications, and the expertise required to perform it.<ref name="nieman" />
* Heterozygous mutation of ''Cdkn1b/CDKN1B'' gene on chromosome 12p13 is suspected to be the cause of multiple endocrine neoplasia type 4.<ref name="pmid23652671">{{cite journal| author=Lee M, Pellegata NS| title=Multiple endocrine neoplasia type 4. | journal=Front Horm Res | year= 2013 | volume= 41 | issue= | pages= 63-78 | pmid=23652671 | doi=10.1159/000345670 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23652671  }} </ref>


==Differentiating Multiple endocrine neoplasia type 4 from other Diseases==
Another diagnostic test used is the urinary free cortisol (UFC) test, which measures the excess cortisol excreted by the kidneys into the urine. Results of 4x higher cortisol levels than normal are likely to be Cushing's disease.<ref name="newell-price" /><ref name="nieman" /> This test should be repeated three times in order to exclude any normally occurring periods of hypercortisolism.<ref name="nieman" /> The UFC test has a specificity of 81% and thus has a high rate of false-positives that are due to [[Pseudo-Cushing's syndrome|pseudo-Cushing states]], [[sleep apnea]], [[polycystic ovary syndrome]], familial glucocorticoid resistance, and [[hyperthyroidism]].<ref name="nieman" />
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align=center
|valign=top|
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Disease}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Definition}}
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |[[Multiple endocrine neoplasia type 1]] ([[MEN 1]])
| style="padding: 5px 5px; background: #F5F5F5;" |An [[autosomal dominant]] genetic disorder causing [[tumor]]s of [[parathyroid]], [[pancreas]], and [[pituitary gland]].
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |[[Multiple endocrine neoplasia type 2]]
| style="padding: 5px 5px; background: #F5F5F5;" |An [[autosomal dominant]] disorder characterized by [[medullary thyroid carcinoma]] (MTC), [[pheochromocytoma]], and primary [[hyperparathyroidism]].
|-
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |[[von Hippel-Lindau syndrome]]
| style="padding: 5px 5px; background: #F5F5F5;" |An [[autosomal dominant]] genetic disorder causing abnormal growth of [[blood vessel]]s in different parts of the [[body]].
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |[[Medullary thyroid carcinoma]]
| style="padding: 5px 5px; background: #F5F5F5;" |[[Medullary thyroid cancer]] (MTC) is a form of [[thyroid carcinoma]] which originates from the [[parafollicular cell]]s ([[C cell]]s), which produce the [[hormone]] [[calcitonin]].
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |C-cell hyperplasia
| style="padding: 5px 5px; background: #F5F5F5;" |C-cell hyperplasia is a form of [[thyroid]] disease which originates from the [[parafollicular cell]]s ([[C cell]]s), which produce the [[hormone]] [[calcitonin]].
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |Familial hyperparathyroidism
| style="padding: 5px 5px; background: #F5F5F5;" |A [[disorder]] due to excess production of [[parathyroid]] hormone characterized by  [[kidney stone]]s, [[hypercalcemia]], [[constipation]], [[peptic ulcer]]s, and [[depression]].
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |[[Acromegaly]]
| style="padding: 5px 5px; background: #F5F5F5;" |A rare syndrome due to excess [[growth hormone]] characterized by enlargement of the [[hand]]s, [[feet]], [[nose]], [[lip]]s, [[ear]]s, general thickening of the [[skin]], [[hypertrichosis]], [[hyperpigmentation]], [[hyperhidrosis]], and [[carpal tunnel syndrome]].
|-
| style="padding: 5px 5px; background: #F5F5F5;" colspan="2"|<small>Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). ''Mol Cell Endocrinol''. 2014;386(1-2):2-15.<ref name="pmid23933118">{{cite journal| author=Thakker RV| title=Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). | journal=Mol Cell Endocrinol | year= 2014 | volume= 386 | issue= 1-2 | pages= 2-15 | pmid=23933118 | doi=10.1016/j.mce.2013.08.002 | pmc=PMC4082531 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23933118  }} </ref> </small>
|}


== Epidemiology and Demographics ==
The late-night or midnight Saliva testing#Cortisol and melatonin aberrations|salivary cortisol test has been gaining support due to its ease of collection and stability at room temperature, therefore it can be assigned to outpatients.<ref name="newell-price" /> The test measures free circulating cortisol and has both a sensitivity and specificity of 95-98%.<ref name="newell-price" /><ref name="nieman" /> This test is especially useful for diagnosing children.<ref name="newell-price" />
* It is a very rare disease. So far only 12 index cases have been reported and the prevalence of the disease is estimated to be less than 1 in 100,000.


===Age===
== Treatment ==
* The age of onset of [[tumor]] is variable.
The first-line treatment of Cushing's disease is surgical resection of ACTH-secreting [[pituitary adenoma]]; this surgery involves removal of the tumor via transsphenoidal surgery (TSS).<ref>{{cite journal|last=Ding|first=Dale |author2=Robert M. Starke |author3=Jason P. Sheehan |title=Treatment paradigms for pituitary adenomas: defining the roles of radiosurgery and radiation therapy|journal=J Neurooncol|year=2013|doi=10.1007/s11060-013-1262-8|volume=117|pages=445–457}}</ref>
* [[Pituitary  tumor]]s are reported from 3rd decade.
There are two possible options for access to sphenoidal sinus including of endonosal approach (through the nostril) or sublabial approach (through an incision under the top lip); many factors such as the size of nostril, the size of the lesion, and the preferences of the surgeon cause the selection of one access route over the other.<ref>{{cite book|last=Laws|first=Edward R|title=Transsphenoidal Surgery|year=2010|publisher=Elsevier Inc.|url=http://www.expertconsultbook.com/expertconsult/ob/book.do?method=display&type=bookPage&decorator=none&eid=4-u1.0-B978-1-4160-0292-5..00017-6--s0080&isbn=978-1-4160-0292-5#lpState=opened&lpTab=contentsTab&content=4-u1.0-B978-1-4160-0292-5..00032-2%3Bfrom%3Dtoc%3Btype%3DbookPage%3Bisbn%3D978-1-4160-0292-5&search=none}}</ref>
* [[Parathyroid adenoma|Parathyroid tumor]]s are reported from 4th decade of life.
Some tumors do not contain a discrete border between tumor and pituitary gland; therefore, careful sectioning through pituitary gland may be required to identify the location of tumor.<ref name=TREATMENT>{{cite journal |vauthors=Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M |title=Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement.|journal=J Clin Endocrinol Metab|year=2008|volume=93|issue=7|pages=2454–2462|pmid=18413427|doi=10.1210/jc.2007-2734|pmc=3214276}}</ref> The probability of successful resection is higher in patients where the tumor was identified at initial surgery in compare to patients where no tumor was found initially; the overall remission rates in  patients with microadenomas undergoing TSS are in range of 65%-90%, and the remission rate in patients with macroadenomas are lower than 65%.<ref name=TREATMENT/> patients with persistent disease after initial surgery are treated with repeated pituitary surgery as soon as the active persistent disease is evident; however, reoperation has lower success rate and increases the risk of pituitary insufficiency.<ref name=TREATMENT/>


===Gender===
Pituitary [[radiation therapy]] is another option for treatment of postoperative persisting hypercortisolemia following unsuccessful [[transsphenoidal surgery]].<ref name=RT>{{cite journal|last=Storr|first=HL|author2=Plowman PN |author3=Carroll PV |author4=François I |author5=Krassas GE |author6=Afshar F |author7=Besser GM |author8=Grossman AB |author9=Savage MO.  |title=Clinical and Endocrine Responses to Pituitary Radiotherapy in Pediatric Cushing’s Disease: An Effective Second-Line Treatment|journal=J Clin Endocrinol Metab|year=2003|volume=88|issue=1|pages=34–37|doi=10.1210/jc.2002-021032}}</ref> External-beam pituitary RT is more effective treatment for pediatric CD in children with cure rates of 80%-88%. [[Hypopituitarism]] specifically [[growth hormone deficiency]] has been reported as the only most common late morbidity of this treatment; GHD has been reported in 36% and 68% of the patients undergoing post pituitary RT for Cushing's disease.<ref name=RT/>
* Females are more affected than males.


== Risk Factors ==
Bilateral adrenalectomy is another treatment which provides immediate reduction of cortisol level and control of hypercortisolism. However, it requires education of patients, because lifelong [[glucocorticoid]] and [[mineralocorticoid]] replacement therapy is needed for these patients. One of the major complications of this treatment is progression of Nelson's syndrome which is caused by enhance level of tumor growth and ACTH secretion post adrenalectomy in 8%-29% of patients with CD.<ref>{{cite journal|last=Gadelha|first=Mônica R. |author2=Leonardo Vieira Neto |title=Efficacy of medical treatment in Cushing's disease: a systematic review|journal=Clinical Endocrinology|year=2014|volume=80|pages=1–12|doi=10.1111/cen.12345}}</ref>
The most potent risk factor in the development of multiple endocrine neoplasia type 4 is family history of pituitary tumors and parathyroid tumors.
During post surgical recovery, patients collect 24-hour urine sample and blood sample for detecting the level of cortisol with the purpose of cure test; level of cortisol near the detection limit assay, corresponds to cure. Hormonal replacement such as [[steroid]] is given to patients because of steroid withdrawal. After the completion of collecting urine and blood samples, patients are asked to switch to  glucocorticoid such as [[prednisone]] to decrease symptoms associated with adrenal withdrawal.<ref>{{cite news|last=Fairfield|first=Wesley P.|title=Cushing's Disease after Successful Transsphenoidal Surgery - What to Expect and How to Manage|url=http://csrf.net/doctors-articles/recovery/cushings-disease-after-successful-transphenoidal-surgery-what-to-expect-and-how-to-manage/|accessdate=Jan 31, 2014|year=2003}}</ref>


== Natural History, Complications and Prognosis==
A study of 3,525 cases of TSS for Cushing's disease in the nationally representative
There is no established comments on the prognosis of multiple endocrine neoplasia type 4.
sample of US hospitals between 1993 and 2002 was conducted and revealed the following results: the in-hospital mortality rate was 0.7%; the complication rate was 42.1%. [[Diabetes insipidus]] (15%), fluid and [[electrolyte]] abnormalities (12.5%), and neurological deficits (5.6%) were the most common complications reported.  The analyses of the study show that complications were more likely in patients with pre-operative [[comorbidities]]. Patients older than 64 years were more likely to have an adverse outcome and prolonged hospital stay. Women were 0.3 times less likely to have adverse outcomes in comparison to men.<ref name="pmid17961019">{{cite journal|last=Patil|first=CG|author2=Lad, SP |author3=Harsh, GR |author4=Laws ER, Jr |author5=Boakye, M |title=National trends, complications, and outcomes following transsphenoidal surgery for Cushing's disease from 1993 to 2002.|journal=Neurosurgical focus|year=2007|volume=23|issue=3|pages=E7|pmid=17961019|doi=10.3171/foc.2007.23.3.9}}</ref>


== Diagnosis ==  
==Epidemiology==
There is no established criteria for the diagnosis of multiple endocrine neoplasia type 4.


=== Symptoms ===
Cases of Cushing's disease are rare, and few epidemiological data is available on the disease. An 18 year study conducted on the population of Vizcaya, Spain reported a 0.004% [[prevalence]] of Cushing's disease.<ref name=Epidemiology>{{cite journal|last=Etxabe|first=J.|author2=J. A. Vazquez|title=Morbidity and mortality in Cushing’s disease: an epidemiological approach|journal=Clinical endocrinology|year=1994|volume=40|issue=4|pages=479–484|accessdate=January 31, 2014|pmid=8187313|doi=10.1111/j.1365-2265.1994.tb02486.x}}</ref> The average [[incidence (epidemiology)|incidence]] of newly diagnosed cases was 2.4 cases per million inhabitants per year. The disease is often diagnosed  3–6 years after the onset of illness.<ref name=Epidemiology />
* [[Lethargy]]
Several studies have shown that Cushing's disease is more prevalent in women than men at a ratio of 3-6:1, respectively.<ref>{{cite journal|last=Boggan|first=J.E |author2=Tyrell, J.B |author3=Wilson C.B|title=Transsphenoidal microsurgical management of Cushing’s disease: report of 100 cases.|journal=Journal of neurosurgery|year=1983|volume=95|issue=2|pages=195–200|url=http://thejns.org/doi/abs/10.3171/jns.1983.59.2.0195|doi=10.3171/jns.1983.59.2.0195}}</ref><ref>{{cite journal|last=Howlet|first=T.A|author2=Perry L. |author3=Doniach I. |author4=Rees LH. |author5=Besser G.M |title=Diagnosis and management of ACTHdependent Cushing’s syndrome: comparison of the features in ectopic and pituitary ACTH production.|journal=Clinical endocrinology|year=1986|volume=24|issue=6|pages=699–713|pmid=3024870|url=http://www.ncbi.nlm.nih.gov/pubmed/3024870|accessdate=January 31, 2014 |doi=10.1111/j.1365-2265.1986.tb01667.x}}</ref> Moreover, most women affected were between the ages of 50 and 60 years.
* [[Depression]]
The prevalence of [[hypertension]], and abnormalities in [[glucose metabolism]] are major predictors of [[Case fatality rate|mortality]] and [[morbidity]] in untreated cases of the disease.<ref name=Epidemiology /> The mortality rate of Cushing's disease was reported to be 10-11%,<ref name=Epidemiology /><ref>{{cite journal|last=Lindholm|first=J. |author2=Juul, S. |author3=Jørgensen, J.O.L. |author4=Astrup, J. |author5=Bjerre, P. |author6=Feldt-Rasmussen, U. |author7=Hagen, C. |author8=Jørgensen, J. |author9=Kosteljanetz, M. |author10=Kristensen, L.Ø. |author11=Laurberg, P. |author12=Schmidt, K.  |author13=Weeke, J|title=Incidence and late prognosis of Cushing's syndrome: A population-based study|journal=Journal of Clinical Endocrinology and Metabolism|year=2001|volume=86|issue=1|pages=117–123|pmid=11231987|url=http://www.ncbi.nlm.nih.gov/pubmed/11231987|accessdate=January 31, 2014|doi=10.1210/jc.86.1.117}}</ref> with the majority of deaths due to vascular disease <ref name="symptoms" /><ref name=Epidemiology />  Women aged 45–70 years have a significantly higher mortality rate than men.<ref name=Epidemiology />
* [[Constipation]]
Moreover, the disease shows a progressive increase with time. Reasons for the trend are unknown, but better diagnostic tools, and a higher incidence rate are two possible explanations.<ref name=Epidemiology/>
* [[Headache]]


== Treatment ==
== See also ==
=== Surgery and Device Based Therapy ===
* [[Cushing's syndrome]]
* Transsphenoidal surgery is used for treating [[pituitary adenoma]] of multiple endocrine neoplasia type 4.
* [[Hyperpituitarism]]


==References==
==References==
{{Reflist|2}}
{{reflist|2}}
 
==External links==
* [http://www.aboutcushings.com/understanding-cushings-disease/causes-and-differences.jsp The difference between Cushing’s disease and other forms of Cushing’s syndrome]
* [http://pituitary.asn.au/Adults/ConditionsIntroduction/Cushingssyndrome.aspx Australian Pituitary Foundation]
* [http://csrf.net/ Cushing's Support & Research Foundation]
* [http://www.eje-online.org/content/early/2012/06/22/EJE-11-1095.full.pdf The burden of Cushing’s disease (CD): clinical and health-related quality of life aspects  (RA Feelders,  SJ Pulgar, A Kempel, and AM Pereira)]


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Cushing's disease (also known as Cushing disease, tertiary or secondary hypercortisolism, tertiary or secondary hypercorticism, Itsenko-Cushing disease)[1][2] is a cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (specifically pituitary basophilism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing's syndrome,[3] when excluding Cushing's syndrome from exogenously administered corticosteroids.

This should not be confused with ectopic Cushing syndrome or exogenous steroid use.[4]

Signs and symptoms

The symptoms of Cushing's disease are similar to those seen in other causes of Cushing's syndrome.[5] Patients with Cushing's disease usually present with one or more signs and symptoms secondary to the presence of excess cortisol or ACTH.[6] Although uncommon, some patients with Cushing's disease have large pituitary tumors (macroadenomas). In addition to the severe hormonal effects related to increase blood cortisol levels, the large tumor can compress adjacent structures. [citation needed] These tumors can compress the nerves that carry information from the eyes, causing a decrease in peripheral vision.[citation needed] Glaucoma and cataracts also may occur in Cushing's syndrome. In children, the two main symptoms are obesity and decreased linear growth.[7]

The clinical diagnosis must be based on the presence of one or more of the symptoms listed below, because the syndrome itself has no true pathognomonic signs or symptoms.[citation needed] The most common symptoms seen in male patients are purple striae, muscle atrophy, osteoporosis, and kidney stones.[7]

Common symptoms

Symptoms include:

  • weight gain
  • high blood pressure [8]
  • poor short-term memory
  • irritability
  • excess hair growth (women)[3]
  • Impaired immunological function [8]
  • red, ruddy face Template:Ns
  • extra fat around neck
  • moon face
  • fatigue
  • red stretch marks
  • poor concentration
  • irregular menstruation.[7]

Less common symptoms

The less-common symptoms include:

History

In 1924, the Soviet neurologist Nikolai Mikhailovich Itsenko reported two patients with pituitary adenoma. The resulting excessive adrenocorticotropic hormone secretion led to the production of large amounts of cortisol by the adrenal glands. The disease associated with this increased secretion of cortisol was described by Harvey Cushing in 1932, after Cushing was presented with a unique case of the disease[9] In 1910, the American neurosurgeon Harvey Cushing (1869-1939) was presented with a case of a 23-year-old woman called Minnie G.. Minnie’s symptoms included painful obesity, amenorrhea, hypertrichosis (abnormal hair growth), underdevelopment of secondary sexual characteristics, hydrocephalus and cerebral tension.[3] This combination of symptoms was not yet described by any medical disorder at the time.[3] However, Cushing was confident that Minnie’s symptoms were due to dysfunction of the pituitary gland, and resembled those associated with an adrenal tumor. Given this conviction, and his knowledge of the three anterior pituitary cell types, Cushing hypothesized that if acidophil hyperpituitarism (excess secretion from the acidophil cells) caused acromegaly, then an excess of basophil cells must be involved in another pituitary disorder that involves sexual dysfunction (amenorrhea in females and erectile dysfunction in males) and could explain Minnie's symptoms.[3] Experimental evidence and case reports by Cushing led to his publication in 1932 on pituitary basophilism as the cause of Cushing's disease. In this publication, the clinical symptoms of the disease, named after Harvey Cushing, were described.[10][11] Out of the 12 cases with hypercortisolism described in Cushing’s monograph on the pituitary body, 67% died within a few years after symptom presentation, whereas Minnie G. survived for more than 40 years after symptom presentation, despite the fact that she did not receive any treatments for a pituitary tumor.[3] The prolonged survival led to the uniqueness of Minnie's case. The reason behind this survival remains a mystery, since an autopsy of Minnie was refused after her death.[3] However, the most likely explanation, proposed by J. Aidan Carney and based on statistical evidence, was that the basophil adenoma Minnie might have harbored underwent partial infarction, leading to symptom regression.[3] The other hypothesis was that Minnie might have suffered from Primary Pigmented Nodular Adrenocortical Disease (PPNAD), which when associated with Cushing's syndrome (Carney complex) can infrequently cause spontaneous symptom regression of the latter.[3]

Diagnosis

Diagnosis is made first by diagnosing Cushing's Syndrome, which can be difficult to do clinically since the most characteristic symptoms only occur in a minority of patients.[12] Some of the biochemical diagnostic tests used include salivary and blood serum cortisol testing, 24-hour urinary free cortisol (UFC) testing, the dexamethasone suppression test (DST), and bilateral inferior petrosal sinus sampling (BIPSS). No single test is perfect and multiple tests should always be used to achieve a proper diagnosis.[7] Diagnosing Cushing's disease is a multidisciplinary process involving doctors, endocrinologists, radiologists, surgeons, and chemical pathologists.[7]

Once Cushing's syndrome has been diagnosed, the first step towards finding the cause is measuring plasma corticotropin concentrations. A concentration consistently below 1.1 pmol/L is classified as corticotropin-independent and does not lead to a diagnosis of Cushing's disease. In such cases, the next step is adrenal imaging with X-ray computed tomography|CT. If plasma corticotropin concentrations are consistently above 3.3 pmol/L, then corticotropin-dependent Cushing's syndrome is most likely. Any intermediate values need to be cautiously interpreted and a corticotropin-releasing hormone (CRH) test is advised in order to confirm corticotropin dependency. If corticotropin-dependent Cushing's syndrome is determined then the next step is to distinguish between Cushing's disease and ectopic corticotropin syndrome. This is done via a combination of techniques including CRH, high-dose DST, BIPSS, and pituitary MRI.

Two dexamethasone suppression tests (DSTs) are generally used, the overnight and 48-h DSTs.[7] For both tests, a plasma cortisol level above 50 nmol/L is indicative of Cushing's disease.[7] However, 3-8% of patients with Cushing's disease will test negative due to a retention of dexamethasone suppression abilities.[7] For non-Cushing or healthy patients, the false-positive rate is 30%.[7] The 48-h DST is advantageous since it is more specific and can be done by outpatients upon proper instruction.[7] In the high-dose 48-h DST, 2 mg of dexamethasone is given every 6 hours for 48 hours or a single dose of 8 mg is given.[7] This test is not needed if the 48-h low-dose DST has shown suppression of cortisol by over 30%.[7] These tests are based on the glucocorticoid sensitivity of pituitary adenomas compared to non-pituitary tumors.[7]

Administration of corticotropin releasing hormone (CRH) can differentiate this condition from ectopic ACTH secretion. In a patient with Cushing's disease, the tumor cells will be stimulated to release corticotropin and elevated plasma corticotropin levels will be detected.[7] This rarely occurs with ectopic corticotropin syndrome and thus is quite useful for distinguishing between the two conditions.[7] If ectopic, the plasma ACTH and cortisol levels should remain unchanged; if this is pituitary related, levels of both would rise. The CRH test uses recombinant human or ovine-sequence CRH, which is administered via a 100μg intravenous bolus dose. The sensitivity of the CRH test for detecting Cushing's disease is 93% when plasma levels are measured after fifteen and thirty minutes.[7] However, this test is used only as a last resort due to its high cost and complexity.[12]

A CT or MRI of the pituitary may also show the ACTH secreting tumor if present. However, in 40% of Cushing's disease patients MRI is unable to detect a tumor.[7] In one study of 261 patients with confirmed pituitary Cushing's Disease, only 48% of pituitary lesions were identified using MRI prior to surgery. The average size of tumor, both those that were identified on MRI and those that were only discovered during surgery, was 6 mm.[13]

A more accurate but invasive test used to differentiate pituitary from ectopic or adrenal Cushing's syndrome is inferior petrosal sinus sampling.[14] A corticotropin gradient sample via BIPSS is required to confirm diagnosis when pituitary MRI imaging and biochemical diagnostic tests have been inconclusive.[7] A basal central:peripheral ratio of over 3:1 when CRH is administered is indicative of Cushing’s disease.[7] This test has been the gold standard for distinguishing between Cushing's disease and ectopic corticotropin syndrome.[7] The BIPSS has a sensitivity and specificity of 94% for Cushing's disease but it is usually used as a last resort due to its invasiveness, rare but serious complications, and the expertise required to perform it.[12]

Another diagnostic test used is the urinary free cortisol (UFC) test, which measures the excess cortisol excreted by the kidneys into the urine. Results of 4x higher cortisol levels than normal are likely to be Cushing's disease.[7][12] This test should be repeated three times in order to exclude any normally occurring periods of hypercortisolism.[12] The UFC test has a specificity of 81% and thus has a high rate of false-positives that are due to pseudo-Cushing states, sleep apnea, polycystic ovary syndrome, familial glucocorticoid resistance, and hyperthyroidism.[12]

The late-night or midnight Saliva testing#Cortisol and melatonin aberrations|salivary cortisol test has been gaining support due to its ease of collection and stability at room temperature, therefore it can be assigned to outpatients.[7] The test measures free circulating cortisol and has both a sensitivity and specificity of 95-98%.[7][12] This test is especially useful for diagnosing children.[7]

Treatment

The first-line treatment of Cushing's disease is surgical resection of ACTH-secreting pituitary adenoma; this surgery involves removal of the tumor via transsphenoidal surgery (TSS).[15] There are two possible options for access to sphenoidal sinus including of endonosal approach (through the nostril) or sublabial approach (through an incision under the top lip); many factors such as the size of nostril, the size of the lesion, and the preferences of the surgeon cause the selection of one access route over the other.[16] Some tumors do not contain a discrete border between tumor and pituitary gland; therefore, careful sectioning through pituitary gland may be required to identify the location of tumor.[17] The probability of successful resection is higher in patients where the tumor was identified at initial surgery in compare to patients where no tumor was found initially; the overall remission rates in patients with microadenomas undergoing TSS are in range of 65%-90%, and the remission rate in patients with macroadenomas are lower than 65%.[17] patients with persistent disease after initial surgery are treated with repeated pituitary surgery as soon as the active persistent disease is evident; however, reoperation has lower success rate and increases the risk of pituitary insufficiency.[17]

Pituitary radiation therapy is another option for treatment of postoperative persisting hypercortisolemia following unsuccessful transsphenoidal surgery.[18] External-beam pituitary RT is more effective treatment for pediatric CD in children with cure rates of 80%-88%. Hypopituitarism specifically growth hormone deficiency has been reported as the only most common late morbidity of this treatment; GHD has been reported in 36% and 68% of the patients undergoing post pituitary RT for Cushing's disease.[18]

Bilateral adrenalectomy is another treatment which provides immediate reduction of cortisol level and control of hypercortisolism. However, it requires education of patients, because lifelong glucocorticoid and mineralocorticoid replacement therapy is needed for these patients. One of the major complications of this treatment is progression of Nelson's syndrome which is caused by enhance level of tumor growth and ACTH secretion post adrenalectomy in 8%-29% of patients with CD.[19]

During post surgical recovery, patients collect 24-hour urine sample and blood sample for detecting the level of cortisol with the purpose of cure test; level of cortisol near the detection limit assay, corresponds to cure. Hormonal replacement such as steroid is given to patients because of steroid withdrawal. After the completion of collecting urine and blood samples, patients are asked to switch to glucocorticoid such as prednisone to decrease symptoms associated with adrenal withdrawal.[20]

A study of 3,525 cases of TSS for Cushing's disease in the nationally representative sample of US hospitals between 1993 and 2002 was conducted and revealed the following results: the in-hospital mortality rate was 0.7%; the complication rate was 42.1%. Diabetes insipidus (15%), fluid and electrolyte abnormalities (12.5%), and neurological deficits (5.6%) were the most common complications reported. The analyses of the study show that complications were more likely in patients with pre-operative comorbidities. Patients older than 64 years were more likely to have an adverse outcome and prolonged hospital stay. Women were 0.3 times less likely to have adverse outcomes in comparison to men.[21]

Epidemiology

Cases of Cushing's disease are rare, and few epidemiological data is available on the disease. An 18 year study conducted on the population of Vizcaya, Spain reported a 0.004% prevalence of Cushing's disease.[22] The average incidence of newly diagnosed cases was 2.4 cases per million inhabitants per year. The disease is often diagnosed 3–6 years after the onset of illness.[22] Several studies have shown that Cushing's disease is more prevalent in women than men at a ratio of 3-6:1, respectively.[23][24] Moreover, most women affected were between the ages of 50 and 60 years. The prevalence of hypertension, and abnormalities in glucose metabolism are major predictors of mortality and morbidity in untreated cases of the disease.[22] The mortality rate of Cushing's disease was reported to be 10-11%,[22][25] with the majority of deaths due to vascular disease [8][22] Women aged 45–70 years have a significantly higher mortality rate than men.[22] Moreover, the disease shows a progressive increase with time. Reasons for the trend are unknown, but better diagnostic tools, and a higher incidence rate are two possible explanations.[22]

See also

References

  1. ↑ "Whonamedit - Nikolai Mikhailovich Itsenko". "Nikolai Mikhailovich Itsenko investigated neural infections, vegetative nervous system diseases and cerebral tumors. In 1926 he was the first one who described Itsenko-Cushing's disease, six years before Cushing."
  2. ↑ A.I. Gozhenko, I.P. Gurkalova, W. Zukow, Z. Kwasnik, B. Mroczkowska (2009). "Trematoda". Pathology: Medical Student's Library. Radomska Szkola Wyžsza uk. Zubrzyckiego. p. 280. ISBN 978-83-61047-18-6.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Lanzino, Giuseppe; Maartens, Niki F.; Laws, Edward R. (2002). "Cushing's case XLV: Minnie G.". Journal of Neurosurgery. 97 (1): 231–234. doi:10.3171/jns.2002.97.1.0231. PMID 12134925. |access-date= requires |url= (help)
  4. ↑ http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001443/
  5. ↑ "Cushing's Syndrome Information Page". Retrieved August 26, 2013.
  6. ↑ Kirk, Lawrence F., Jr; Robert B. Hash; Harold P. Katner; Tom Jones (September 2000). "Cushing's Disease: Clinical Manifestations and Diagnostic Evaluation". American Family Physician. 62: 1119; 1127. Retrieved 2013-08-26.
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 7.19 7.20 7.21 7.22 7.23 Newell-Price, J.; Bertagna, X.; Grossman, A.B.; Nieman, L.K. (2006). "Cushing's syndrome". The Lancet. 367 (9522): 1605–1617. doi:10.1016/S0140-6736(08)61345-8. Retrieved 30 January 2014.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Wilson, P.J.; Williams, J.R.; Smee, R.I. (2014). "Cushing's disease: A single centre's experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy". Journal of Clinical Neuroscience. 21 (1): 100–106. doi:10.1016/j.jocn.2013.04.007. PMID 24074805.
  9. ↑ Laws Jr., E.R., Ezzat, S., Asa, S.L., Rio, L.M., Michel, L. & Knutzen, R. (2013). Pituitary Disorders: Diagnosis and Management. United Kingdom: Wiley-blackwell. p. xiv. ISBN 978-0-470-67201-3.
  10. ↑ Cushing, Harvey (1932). "The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism)". Bulletin of the Johns Hopkins Hospital. 50 (4): 137–95. PMC 2387613. PMID 19310569.
  11. ↑ "Dr. Cushing Dead; Brain Surgeon, 70. A Pioneer Who Won Fame as Founder of New School of Neuro-Surgery. Discovered Malady Affecting Pituitary dre. Was Noted Teacher and Author". New York Times. 8 October 1939. Retrieved 2010-03-21.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 Nieman, L.K.; Ilias, I. (2005). "Evaluation and treatment of Cushing's syndrome". The American Journal of Medicine. 118 (12): 1340–1346. doi:10.1016/j.amjmed.2005.01.059. PMID 16378774. Retrieved 30 January 2014.
  13. ↑ Jagannathan, J. et al, Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease, Journal of Neurosurgery, 25 September 2010, Retrieved 2014-01-27
  14. ↑ Deipolyi, A; Karaosmanoglu, A; Habito, C; Brannan, S; Wicky, S; Hirsch, J; Oklu, R (2011-02-23). "The role of bilateral inferior petrosal sinus sampling in the diagnostic evaluation of Cushing disease". Diagnostic and interventional radiology (Ankara, Turkey). 18 (1): 132–8. doi:10.4261/1305-3825.DIR.4279-11.0. PMID 21348009.
  15. ↑ Ding, Dale; Robert M. Starke; Jason P. Sheehan (2013). "Treatment paradigms for pituitary adenomas: defining the roles of radiosurgery and radiation therapy". J Neurooncol. 117: 445–457. doi:10.1007/s11060-013-1262-8.
  16. ↑ Laws, Edward R (2010). Transsphenoidal Surgery. Elsevier Inc.
  17. ↑ 17.0 17.1 17.2 Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M (2008). "Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement". J Clin Endocrinol Metab. 93 (7): 2454–2462. doi:10.1210/jc.2007-2734. PMC 3214276. PMID 18413427.
  18. ↑ 18.0 18.1 Storr, HL; Plowman PN; Carroll PV; François I; Krassas GE; Afshar F; Besser GM; Grossman AB; Savage MO. (2003). "Clinical and Endocrine Responses to Pituitary Radiotherapy in Pediatric Cushing's Disease: An Effective Second-Line Treatment". J Clin Endocrinol Metab. 88 (1): 34–37. doi:10.1210/jc.2002-021032.
  19. ↑ Gadelha, Mônica R.; Leonardo Vieira Neto (2014). "Efficacy of medical treatment in Cushing's disease: a systematic review". Clinical Endocrinology. 80: 1–12. doi:10.1111/cen.12345.
  20. ↑ Fairfield, Wesley P. (2003). "Cushing's Disease after Successful Transsphenoidal Surgery - What to Expect and How to Manage". Retrieved Jan 31, 2014.
  21. ↑ Patil, CG; Lad, SP; Harsh, GR; Laws ER, Jr; Boakye, M (2007). "National trends, complications, and outcomes following transsphenoidal surgery for Cushing's disease from 1993 to 2002". Neurosurgical focus. 23 (3): E7. doi:10.3171/foc.2007.23.3.9. PMID 17961019.
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 Etxabe, J.; J. A. Vazquez (1994). "Morbidity and mortality in Cushing's disease: an epidemiological approach". Clinical endocrinology. 40 (4): 479–484. doi:10.1111/j.1365-2265.1994.tb02486.x. PMID 8187313. |access-date= requires |url= (help)
  23. ↑ Boggan, J.E; Tyrell, J.B; Wilson C.B (1983). "Transsphenoidal microsurgical management of Cushing's disease: report of 100 cases". Journal of neurosurgery. 95 (2): 195–200. doi:10.3171/jns.1983.59.2.0195.
  24. ↑ Howlet, T.A; Perry L.; Doniach I.; Rees LH.; Besser G.M (1986). "Diagnosis and management of ACTHdependent Cushing's syndrome: comparison of the features in ectopic and pituitary ACTH production". Clinical endocrinology. 24 (6): 699–713. doi:10.1111/j.1365-2265.1986.tb01667.x. PMID 3024870. Retrieved January 31, 2014.
  25. ↑ Lindholm, J.; Juul, S.; Jørgensen, J.O.L.; Astrup, J.; Bjerre, P.; Feldt-Rasmussen, U.; Hagen, C.; Jørgensen, J.; Kosteljanetz, M.; Kristensen, L.Ø.; Laurberg, P.; Schmidt, K.; Weeke, J (2001). "Incidence and late prognosis of Cushing's syndrome: A population-based study". Journal of Clinical Endocrinology and Metabolism. 86 (1): 117–123. doi:10.1210/jc.86.1.117. PMID 11231987. Retrieved January 31, 2014.

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