Cushing's syndrome resident survival guide: Difference between revisions

Latest revision as of 13:30, 20 August 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mydah Sajid, MD [2]

Overview

Cushing’s syndrome is characterized by elevated circulating levels of glucocorticoid (i.e. cortisol) in blood. It presents with a wide range of clinical spectrum ranging from mild to severe. The clinical symptoms are characterized by central obesity, facial edema, buffalo hump, proximal myopathy, hypertension, hyperglycemia, mood changes, skin thinning, abdominal striae, and easy bruising. The physician should aim to diagnose the cause of Cushing’s syndrome and treat it accordingly. This section provides a short and straight to the point overview of the Cushing's syndrome.

Causes

Life Threatening Causes

Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated.

Does not include any known cause.

Common Causes

Iatrogenic or factitious Cushing's syndrome due to administration of exogenous glucocorticoids.
Cushing's disease (due to excess secretion of Adrenocorticotropic hormone from anterior pituitary).
Paraneoplastic: due to ectopic secretion of ACTH (includes, small cell lung cancer, benign carcinoid tumors, Ewing's sarcoma). ^[1]^[2]^[3]
Ectopic secretion of Corticotropin-releasing hormone (CRH).
Adenoma and carcinoma in the adrenal cortex
Primary pigmented nodular adrenocortical disease (PPNAD)^[4]
Bilateral macronodular adrenal hyperplasia (BMAH)^[5]

Diagnosis

Shown below is an algorithm summarizing the diagnosis of Cushing's syndrome according to the Endocrine Society clinical guidelines.^[6]^[7]^[8]^[9]^[10]^[11]^[12]^[13]

Symptoms suggestive of Cushing’s syndrome:

Osteoporosis unusual for the age
Refractory hypertension
Facial edema resulting in Moon-like face
Central obesity
Proximal muscle weakness
Abdominal striae
Easy bruising
Menstrual abnormalities: oligomenorrhea
Mood disorders, depression
Hirtuism

Take a detailed history of the patient including medication history. Rule out the use of any exogenous topical, oral, parenteral, or inhaled glucocorticoid and synthetic progesterone.

Perform any two of the following three laboratory investigations:

Measure late-night levels of salivary cortisol (twice)
Measure 24 hours urinary free cortisol (UFC) excretion (twice)
Perform low-dose (1mg) overnight dexamethasone suppression test (DST)

Two of the following abnormal results:

Elevated levels of late-night salivary cortisol
24 hours UFC threefold greater than the upper reference range.
Early morning (8 am) sample having serum cortisol 1.8 mcg/dL or higher after overnight DST

Any one abnormal result

High suspicion for Cushing's syndrome

Low suspicion for Cushing's syndrome

Measure late night plasma ACTH levels

Refer to endocrinologist

Low value plasma ACTH <5 pg/mL

Indeterminate values of plasma ACTH between 5 to 20 pg/mL

High value plasma ACTH >20 pg/mL

CRH or desmopressin stimulation test

No ACTH response

+ ACTH response

ACTH independent Cushing's syndrome

ACTH dependent Cushing's syndrome

CT scan/ MRI of adrenal glands to look for adrenal tumors or hyperplasia.

Perform both tests:

CRH or desmopressin stimulation test
High dose (8mg) overnight DST

Adequate suppresion of early morning serum cortisol (with levels less than 5 mcg/dL) and stimulation with CRH

Negative or equivocal response

MRI of the pituitary

Tumor >6mm

Tumor <6mm or no mass lesion

Cushing's disease

Perform Inferior petrosal sinus sampling.

Central step-up

No Central step-up

Ectopic ACTH production

Treatment

Shown below is an algorithm summarizing the treatment of Cushing's syndrome according the the Endocrine Society clinical practice guidelines.^[14]^[15]^[16]

The treatment depends upon the underlying etiology

Cushing's disease

Paraneoplastic Cushing's syndrome

ACTH-independent Cushing's syndrome

Transsphenoidal surgery: Treatment of choice in patients with pituitary adenoma with distinct margins.

Resectable tumor

Nonresectable tumor

Adrenal adenoma

Bilateral adrenal hyperplasia

Pituitary irradiation carried out in patients with:

Failure to resect tumor completely by surgery.
The location of the tumor cannot be determined.
The patient wishes to conceive in the future.

Resection of the primary tumor

Medical therapy:

Inhibit the synthesis of adrenocortical enzymes: ketoconazole, metyrapone, and etomidate.

Inhibits the secretion of ACTH from the ectopic site: Octreotide

Inhibits hyperglycemia secondary to hypercortisolism: Mifepristone

Unilateral adrenalectomy

Bilateral adrenalectomy

Bilateral adrenalectomy is performed in patients with severe refractory hypercortisolism despite surgical and radiation therapy.

Do's

In ACTH-independent Cushing’s syndrome, glucocorticoid therapy should be given to patients post-operatively due to suppression of the hypothalamic-pituitary axis. Patients with medication-induced Cushing’s syndrome should taper the dose of glucocorticoid instead of sudden withdrawal of the medications.
Thromboprophylaxis should be initiated preoperatively in patients with Cushing’s syndrome^[14]. There is a hypercoagulable state in patients with Cushing’s syndrome due to impaired fibrinolysis and activation of the coagulation cascade. These patients have an increased risk of developing deep venous thrombosis compared to the normal patient population^[17].
Rebound thymic hyperplasia can occur in patients whose hypercortisolism is controlled. On the chest imaging, it is seen as a mass in the anterior mediastinum and can be misinterpreted as tumor recurrence, or metastasis^[18].

Don'ts

The 24 hours urinary free cortisol measurement should not be used for diagnosis in subclinical hypercortisolism (mild hypercortisolism in adrenal incidentaloma) as it can yield false-negative results^[6]. False-positive results are present in patients with physiological hypercortisolism (patients with a polycystic ovarian syndrome or major depressive disorder)^[19]^[20]. High fluid intake can result in an increased fraction of excretion of free cortisol yielding false-positive results.^[21]
MRI is not a cost-effective diagnostic test. CT scan of the abdomen and adrenal glands is preferred as an imaging test to localize adrenal adenoma or carcinoma compared to MRI. On the Ct scan adrenal carcinoma has a bigger size along with hemorrhage, necrosis and calcification in the lesion^[22].

References

↑ White A, Ray DW, Talbot A, Abraham P, Thody AJ, Bevan JS (2000). "Cushing's syndrome due to phaeochromocytoma secreting the precursors of adrenocorticotropin". J Clin Endocrinol Metab. 85 (12): 4771–5. doi:10.1210/jcem.85.12.7047. PMID 11134141.
↑ More J, Young J, Reznik Y, Raverot G, Borson-Chazot F, Rohmer V; et al. (2011). "Ectopic ACTH syndrome in children and adolescents". J Clin Endocrinol Metab. 96 (5): 1213–22. doi:10.1210/jc.2010-2276. PMID 21346064.
↑ Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK (2005). "Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health". J Clin Endocrinol Metab. 90 (8): 4955–62. doi:10.1210/jc.2004-2527. PMID 15914534.
↑ Larsen JL, Cathey WJ, Odell WD (1986). "Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing's syndrome. Case report and review of the literature". Am J Med. 80 (5): 976–84. doi:10.1016/0002-9343(86)90648-0. PMID 3010718.
↑ Lacroix A, Ndiaye N, Tremblay J, Hamet P (2001). "Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome". Endocr Rev. 22 (1): 75–110. doi:10.1210/edrv.22.1.0420. PMID 11159817.
↑ ^6.0 ^6.1 Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM; et al. (2008). "The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 93 (5): 1526–40. doi:10.1210/jc.2008-0125. PMC 2386281. PMID 18334580.
↑ Lacroix A, Feelders RA, Stratakis CA, Nieman LK (2015). "Cushing's syndrome". Lancet. 386 (9996): 913–27. doi:10.1016/S0140-6736(14)61375-1. PMID 26004339.
↑ Weber SL (1997). "Cushing'S syndrome attributable to topical use of lotrisone". Endocr Pract. 3 (3): 140–4. doi:10.4158/EP.3.3.140. PMID 15251475.
↑ Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP; et al. (2003). "Diagnosis and complications of Cushing's syndrome: a consensus statement". J Clin Endocrinol Metab. 88 (12): 5593–602. doi:10.1210/jc.2003-030871. PMID 14671138.
↑ LIDDLE GW (1960). "Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome". J Clin Endocrinol Metab. 20: 1539–60. doi:10.1210/jcem-20-12-1539. PMID 13761950.
↑ Crapo L (1979). "Cushing's syndrome: a review of diagnostic tests". Metabolism. 28 (9): 955–77. doi:10.1016/0026-0495(79)90097-0. PMID 225638.
↑ Doppman JL, Oldfield E, Krudy AG, Chrousos GP, Schulte HM, Schaaf M; et al. (1984). "Petrosal sinus sampling for Cushing syndrome: anatomical and technical considerations. Work in progress". Radiology. 150 (1): 99–103. doi:10.1148/radiology.150.1.6316418. PMID 6316418.
↑ Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH (1994). "Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population". Ann Intern Med. 120 (10): 817–20. doi:10.7326/0003-4819-120-10-199405150-00001. PMID 8154641.
↑ ^14.0 ^14.1 Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO; et al. (2015). "Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 100 (8): 2807–31. doi:10.1210/jc.2015-1818. PMC 4525003. PMID 26222757.
↑ Chow JT, Thompson GB, Grant CS, Farley DR, Richards ML, Young WF (2008). "Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience". Clin Endocrinol (Oxf). 68 (4): 513–9. doi:10.1111/j.1365-2265.2007.03082.x. PMID 17970770.
↑ Aniszewski JP, Young WF, Thompson GB, Grant CS, van Heerden JA (2001). "Cushing syndrome due to ectopic adrenocorticotropic hormone secretion". World J Surg. 25 (7): 934–40. doi:10.1007/s00268-001-0032-5. PMID 11572035.
↑ Van Zaane B, Nur E, Squizzato A, Dekkers OM, Twickler MT, Fliers E; et al. (2009). "Hypercoagulable state in Cushing's syndrome: a systematic review". J Clin Endocrinol Metab. 94 (8): 2743–50. doi:10.1210/jc.2009-0290. PMID 19454584.
↑ Tabarin A, Catargi B, Chanson P, Hieronimus S, Corcuff JB, Laurent F; et al. (1995). "Pseudo-tumours of the thymus after correction of hypercortisolism in patients with ectopic ACTH syndrome: a report of five cases". Clin Endocrinol (Oxf). 42 (2): 207–13. doi:10.1111/j.1365-2265.1995.tb01865.x. PMID 7704966.
↑ Cizza G, Nieman LK, Doppman JL, Passaro MD, Czerwiec FS, Chrousos GP; et al. (1996). "Factitious Cushing syndrome". J Clin Endocrinol Metab. 81 (10): 3573–7. doi:10.1210/jcem.81.10.8855803. PMID 8855803.
↑ Carroll BJ, Curtis GC, Davies BM, Mendels J, Sugerman AA (1976). "Urinary free cortisol excretion in depression". Psychol Med. 6 (1): 43–50. doi:10.1017/s0033291700007480. PMID 935296.
↑ Mericq MV, Cutler GB (1998). "High fluid intake increases urine free cortisol excretion in normal subjects". J Clin Endocrinol Metab. 83 (2): 682–4. doi:10.1210/jcem.83.2.4555. PMID 9467592.
↑ Blake MA, Kalra MK, Sweeney AT, Lucey BC, Maher MM, Sahani DV; et al. (2006). "Distinguishing benign from malignant adrenal masses: multi-detector row CT protocol with 10-minute delay". Radiology. 238 (2): 578–85. doi:10.1148/radiol.2382041514. PMID 16371582.

Template:WikiDoc Sources

[pmid11134141-1] White A, Ray DW, Talbot A, Abraham P, Thody AJ, Bevan JS (2000). "Cushing's syndrome due to phaeochromocytoma secreting the precursors of adrenocorticotropin". J Clin Endocrinol Metab. 85 (12): 4771–5. doi:10.1210/jcem.85.12.7047. PMID 11134141.

[pmid21346064-2] More J, Young J, Reznik Y, Raverot G, Borson-Chazot F, Rohmer V; et al. (2011). "Ectopic ACTH syndrome in children and adolescents". J Clin Endocrinol Metab. 96 (5): 1213–22. doi:10.1210/jc.2010-2276. PMID 21346064.

[pmid15914534-3] Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK (2005). "Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health". J Clin Endocrinol Metab. 90 (8): 4955–62. doi:10.1210/jc.2004-2527. PMID 15914534.

[pmid3010718-4] Larsen JL, Cathey WJ, Odell WD (1986). "Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing's syndrome. Case report and review of the literature". Am J Med. 80 (5): 976–84. doi:10.1016/0002-9343(86)90648-0. PMID 3010718.

[pmid11159817-5] Lacroix A, Ndiaye N, Tremblay J, Hamet P (2001). "Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome". Endocr Rev. 22 (1): 75–110. doi:10.1210/edrv.22.1.0420. PMID 11159817.

[pmid18334580-6] 6.0 ^6.1 Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM; et al. (2008). "The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 93 (5): 1526–40. doi:10.1210/jc.2008-0125. PMC 2386281. PMID 18334580.

[pmid26004339-7] Lacroix A, Feelders RA, Stratakis CA, Nieman LK (2015). "Cushing's syndrome". Lancet. 386 (9996): 913–27. doi:10.1016/S0140-6736(14)61375-1. PMID 26004339.

[pmid15251475-8] Weber SL (1997). "Cushing'S syndrome attributable to topical use of lotrisone". Endocr Pract. 3 (3): 140–4. doi:10.4158/EP.3.3.140. PMID 15251475.

[pmid14671138-9] Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP; et al. (2003). "Diagnosis and complications of Cushing's syndrome: a consensus statement". J Clin Endocrinol Metab. 88 (12): 5593–602. doi:10.1210/jc.2003-030871. PMID 14671138.

[pmid13761950-10] LIDDLE GW (1960). "Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome". J Clin Endocrinol Metab. 20: 1539–60. doi:10.1210/jcem-20-12-1539. PMID 13761950.

[pmid225638-11] Crapo L (1979). "Cushing's syndrome: a review of diagnostic tests". Metabolism. 28 (9): 955–77. doi:10.1016/0026-0495(79)90097-0. PMID 225638.

[pmid6316418-12] Doppman JL, Oldfield E, Krudy AG, Chrousos GP, Schulte HM, Schaaf M; et al. (1984). "Petrosal sinus sampling for Cushing syndrome: anatomical and technical considerations. Work in progress". Radiology. 150 (1): 99–103. doi:10.1148/radiology.150.1.6316418. PMID 6316418.

[pmid8154641-13] Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH (1994). "Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population". Ann Intern Med. 120 (10): 817–20. doi:10.7326/0003-4819-120-10-199405150-00001. PMID 8154641.

[pmid26222757-14] 14.0 ^14.1 Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO; et al. (2015). "Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 100 (8): 2807–31. doi:10.1210/jc.2015-1818. PMC 4525003. PMID 26222757.

[pmid17970770-15] Chow JT, Thompson GB, Grant CS, Farley DR, Richards ML, Young WF (2008). "Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience". Clin Endocrinol (Oxf). 68 (4): 513–9. doi:10.1111/j.1365-2265.2007.03082.x. PMID 17970770.

[pmid11572035-16] Aniszewski JP, Young WF, Thompson GB, Grant CS, van Heerden JA (2001). "Cushing syndrome due to ectopic adrenocorticotropic hormone secretion". World J Surg. 25 (7): 934–40. doi:10.1007/s00268-001-0032-5. PMID 11572035.

[pmid19454584-17] Van Zaane B, Nur E, Squizzato A, Dekkers OM, Twickler MT, Fliers E; et al. (2009). "Hypercoagulable state in Cushing's syndrome: a systematic review". J Clin Endocrinol Metab. 94 (8): 2743–50. doi:10.1210/jc.2009-0290. PMID 19454584.

[pmid7704966-18] Tabarin A, Catargi B, Chanson P, Hieronimus S, Corcuff JB, Laurent F; et al. (1995). "Pseudo-tumours of the thymus after correction of hypercortisolism in patients with ectopic ACTH syndrome: a report of five cases". Clin Endocrinol (Oxf). 42 (2): 207–13. doi:10.1111/j.1365-2265.1995.tb01865.x. PMID 7704966.

[pmid8855803-19] Cizza G, Nieman LK, Doppman JL, Passaro MD, Czerwiec FS, Chrousos GP; et al. (1996). "Factitious Cushing syndrome". J Clin Endocrinol Metab. 81 (10): 3573–7. doi:10.1210/jcem.81.10.8855803. PMID 8855803.

[pmid935296-20] Carroll BJ, Curtis GC, Davies BM, Mendels J, Sugerman AA (1976). "Urinary free cortisol excretion in depression". Psychol Med. 6 (1): 43–50. doi:10.1017/s0033291700007480. PMID 935296.

[pmid9467592-21] Mericq MV, Cutler GB (1998). "High fluid intake increases urine free cortisol excretion in normal subjects". J Clin Endocrinol Metab. 83 (2): 682–4. doi:10.1210/jcem.83.2.4555. PMID 9467592.

[pmid16371582-22] Blake MA, Kalra MK, Sweeney AT, Lucey BC, Maher MM, Sahani DV; et al. (2006). "Distinguishing benign from malignant adrenal masses: multi-detector row CT protocol with 10-minute delay". Radiology. 238 (2): 578–85. doi:10.1148/radiol.2382041514. PMID 16371582.

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@@ Line 2: / Line 2: @@
 {{Resident survival guide project}}
-{{WikiDoc CMG}}; {{AE}}
+{{WikiDoc CMG}}; {{AE}} {{MSJ}}
 ==Overview==
-This section provides a short and straight to the point overview of the disease or symptom.  The first sentence of the overview must contain the name of the disease.
+[[Cushing’s syndrome]] is characterized by elevated circulating levels of [[glucocorticoid]] (i.e. [[cortisol]]) in [[blood]]. It presents with a wide range of clinical spectrum ranging from mild to severe. The clinical symptoms are characterized by central [[obesity]], facial [[edema]], buffalo hump, proximal [[myopathy]], [[hypertension]], [[hyperglycemia]], mood changes, skin thinning, abdominal [[striae]], and easy [[Bruise|bruising]]. The [[physician]] should aim to diagnose the cause of [[Cushing’s syndrome]] and treat it accordingly. This section provides a short and straight to the point overview of the [[Cushing's syndrome]].
 ==Causes==
 ===Life Threatening Causes===
-Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.
+Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated.
-* [[Life threatening cause 1]]
+* Does not include any known cause.
-* [[Life threatening cause 2]]
-* [[Life threatening cause 3]]
 ===Common Causes===
-* [[Common cause 1]]
+* Iatrogenic or factitious [[Cushing's syndrome]] due to administration of exogenous [[glucocorticoids]].
-* [[Common cause 2]]
+*[[Cushing's disease]] (due to excess secretion of [[Adrenocorticotropic hormone]] from [[anterior pituitary]]).
-* [[Common cause 3]]
+* Paraneoplastic: due to ectopic secretion of ACTH (includes, [[small cell  lung cancer]], benign [[Carcinoid syndrome|carcinoid tumor]]<nowiki/>s, [[Ewing's sarcoma]]). <ref name="pmid11134141">{{cite journal| author=White A, Ray DW, Talbot A, Abraham P, Thody AJ, Bevan JS| title=Cushing's syndrome due to phaeochromocytoma secreting the precursors of adrenocorticotropin. | journal=J Clin Endocrinol Metab | year= 2000 | volume= 85 | issue= 12 | pages= 4771-5 | pmid=11134141 | doi=10.1210/jcem.85.12.7047 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11134141  }} </ref><ref name="pmid21346064">{{cite journal| author=More J, Young J, Reznik Y, Raverot G, Borson-Chazot F, Rohmer V | display-authors=etal| title=Ectopic ACTH syndrome in children and adolescents. | journal=J Clin Endocrinol Metab | year= 2011 | volume= 96 | issue= 5 | pages= 1213-22 | pmid=21346064 | doi=10.1210/jc.2010-2276 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21346064  }} </ref><ref name="pmid15914534">{{cite journal| author=Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK| title=Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health. | journal=J Clin Endocrinol Metab | year= 2005 | volume= 90 | issue= 8 | pages= 4955-62 | pmid=15914534 | doi=10.1210/jc.2004-2527 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15914534  }} </ref>
-* [[Common cause 4]]
+* Ectopic secretion of [[Corticotropin-releasing hormone]] (CRH).
-* [[Common cause 5]]
+*[[Adenoma]] and [[carcinoma]] in the [[adrenal cortex]]
+* Primary pigmented nodular adrenocortical disease (PPNAD)<ref name="pmid3010718">{{cite journal| author=Larsen JL, Cathey WJ, Odell WD| title=Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing's syndrome. Case report and review of the literature. | journal=Am J Med | year= 1986 | volume= 80 | issue= 5 | pages= 976-84 | pmid=3010718 | doi=10.1016/0002-9343(86)90648-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3010718  }} </ref>
+* Bilateral macronodular adrenal hyperplasia (BMAH)<ref name="pmid11159817">{{cite journal| author=Lacroix A, Ndiaye N, Tremblay J, Hamet P| title=Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome. | journal=Endocr Rev | year= 2001 | volume= 22 | issue= 1 | pages= 75-110 | pmid=11159817 | doi=10.1210/edrv.22.1.0420 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11159817  }} </ref>
 ==Diagnosis==
-Shown below is an algorithm summarizing the diagnosis of [[Cushing's syndrome]] according to the [Endocrine Society] clinical guidelines.
+Shown below is an algorithm summarizing the diagnosis of [[Cushing's syndrome]] according to the [[Endocrine Society]] clinical guidelines.<ref name="pmid18334580">{{cite journal| author=Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM | display-authors=etal| title=The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. | journal=J Clin Endocrinol Metab | year= 2008 | volume= 93 | issue= 5 | pages= 1526-40 | pmid=18334580 | doi=10.1210/jc.2008-0125 | pmc=2386281 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18334580  }} </ref><ref name="pmid26004339">{{cite journal| author=Lacroix A, Feelders RA, Stratakis CA, Nieman LK| title=Cushing's syndrome. | journal=Lancet | year= 2015 | volume= 386 | issue= 9996 | pages= 913-27 | pmid=26004339 | doi=10.1016/S0140-6736(14)61375-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26004339  }} </ref><ref name="pmid15251475">{{cite journal| author=Weber SL| title=Cushing'S syndrome attributable to topical use of lotrisone. | journal=Endocr Pract | year= 1997 | volume= 3 | issue= 3 | pages= 140-4 | pmid=15251475 | doi=10.4158/EP.3.3.140 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15251475  }} </ref><ref name="pmid14671138">{{cite journal| author=Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP | display-authors=etal| title=Diagnosis and complications of Cushing's syndrome: a consensus statement. | journal=J Clin Endocrinol Metab | year= 2003 | volume= 88 | issue= 12 | pages= 5593-602 | pmid=14671138 | doi=10.1210/jc.2003-030871 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14671138  }} </ref><ref name="pmid13761950">{{cite journal| author=LIDDLE GW| title=Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome. | journal=J Clin Endocrinol Metab | year= 1960 | volume= 20 | issue=  | pages= 1539-60 | pmid=13761950 | doi=10.1210/jcem-20-12-1539 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13761950  }} </ref><ref name="pmid225638">{{cite journal| author=Crapo L| title=Cushing's syndrome: a review of diagnostic tests. | journal=Metabolism | year= 1979 | volume= 28 | issue= 9 | pages= 955-77 | pmid=225638 | doi=10.1016/0026-0495(79)90097-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=225638  }} </ref><ref name="pmid6316418">{{cite journal| author=Doppman JL, Oldfield E, Krudy AG, Chrousos GP, Schulte HM, Schaaf M | display-authors=etal| title=Petrosal sinus sampling for Cushing syndrome: anatomical and technical considerations. Work in progress. | journal=Radiology | year= 1984 | volume= 150 | issue= 1 | pages= 99-103 | pmid=6316418 | doi=10.1148/radiology.150.1.6316418 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6316418  }} </ref><ref name="pmid8154641">{{cite journal| author=Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH| title=Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. | journal=Ann Intern Med | year= 1994 | volume= 120 | issue= 10 | pages= 817-20 | pmid=8154641 | doi=10.7326/0003-4819-120-10-199405150-00001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8154641  }} </ref>
 {{familytree/start |summary=PE diagnosis Algorithm.}}
-{{familytree | | | | A01 | | | A01= <div style="float: center; text-align: left;"> Symptoms suggestive of Cushing’s syndrome:
+{{familytree | | | | A01 | | | A01= <div style="float: center; text-align: left;"> Symptoms suggestive of [[Cushing’s syndrome]]:
-* Osteoporosis unusual for the age
+* [[Osteoporosis]] unusual for the age
-* Refractory hypertension
+* Refractory [[hypertension]]
-* Facial edema resulting in Moon-like face
+* Facial [[edema]] resulting in Moon-like face
-* Central obesity
+* Central [[obesity]]
 * Proximal muscle weakness
-* Abdominal striae
+* Abdominal [[striae]]
-* Easy bruising
+* Easy [[bruising]]
-* Menstrual abnormalities: oligomenorrhea
+* Menstrual abnormalities: [[oligomenorrhea]]
-* Mood disorders, depression
+* [[Mood disorder|Mood disorders]], [[depression]]
-* Hirtuism }}
+* [[Hirtuism]] }}
 {{familytree | | | | |!| | | | }}
-{{familytree | | | | B01 | | | B01= Take a detailed history of the patient including medication history. Rule out the use of any exogenous topical, oral, parenteral, or inhaled glucocorticoid and synthetic progesterone. }}
+{{familytree | | | | B01 | | | B01= Take a detailed history of the patient including medication history. Rule out the use of any exogenous topical, oral, parenteral, or inhaled [[glucocorticoid]] and synthetic [[progesterone]]. }}
 {{familytree | | | | |!| | | | }}
 {{familytree | | | | C01 | | | C01= <div style="float: center; text-align: left;"> Perform any two of the following three laboratory investigations:
-* Measure late-night levels of salivary cortisol (twice)
+* Measure late-night levels of salivary [[cortisol]] (twice)
-* Measure 24 hours urinary free cortisol (UFC) excretion (twice)
+* Measure 24 hours urinary free [[cortisol]] (UFC) excretion (twice)
-* Perform low-dose (1mg) overnight dexamethasone suppression test (DST)}}
+* Perform low-dose (1mg) overnight [[dexamethasone suppression test]] (DST)}}
-{{familytree | | |,|-|^|-|-|.| }}
+{{familytree | | | |,|-|^|-|-|.| }}
-{{familytree | | D01 | | |D02 | D01= <div style="float: center; text-align: left;"> Two of the following abnormal results:
+{{familytree | | | D01 | | |D02 | D01= <div style="float: center; text-align: left;"> Two of the following abnormal results:
-* Elevated levels of late-night salivary cortisol
+* Elevated levels of late-night salivary [[cortisol]]
 * 24 hours UFC threefold greater than the upper reference range.
 * Early morning (8 am) sample having serum cortisol 1.8 mcg/dL or higher after overnight DST| D02= Any one abnormal result }}
-{{familytree | | |!| | | | |!| | }}
+{{familytree | | | |!| | | | |!| | }}
-{{familytree | | E01 | | | E02 | E01= High suspicion for Cushing's syndrome | E02= Low suspicion for Cushing syndrome }}
+{{familytree | | | E01 | | | E02 | E01= High suspicion for [[Cushing's syndrome]] | E02= Low suspicion for [[Cushing's syndrome]] }}
-{{familytree | | |!| | | | |!| | }}
+{{familytree | | | |!| | | | |!| | }}
-{{familytree | |  F01| | | |F02| F01= Measure late night plasma ACTH levels | F02= Refer to endocrinologist }}
+{{familytree | | | F01 | | | F02 | F01= Measure late night plasma ACTH levels | F02= Refer to endocrinologist }}
-{{familytree |,|-|-|+|-|-|.| | | }}
+{{familytree |,|-|-|-|+|-|-|-|.| }}
-{{familytree |G01|G02| |G03| | G01= Low value plasma ACTH <5 pg/mL | G02= Indeterminate values of plasma ACTH between 5 to 20 pg/mL | G03= High value plasma ACTH >20 pg/mL }}
+{{familytree |G01| |G02| |G03| | G01= Low value plasma ACTH <5 pg/mL | G02= Indeterminate values of plasma ACTH between 5 to 20 pg/mL | G03= High value plasma ACTH >20 pg/mL }}
+{{familytree |!| | | |!| | | | | |!| }}
+{{familytree |!| | |H01| | | | |!| H01= CRH or desmopressin stimulation test }}
+{{familytree |!| |,|-|^|-|.| | | |!| }}
+{{familytree |!| |I01| |I02| |!| I01= No ACTH response | I02= + ACTH response }}
+{{familytree |!| | |!| | |!| | | |!| }}
+{{familytree |!| | |!| | |!| | | |!| }}
+{{familytree |J01|'| | |`|-|-|-|J02| J01= ACTH independent [[Cushing's syndrome]] | J02= ACTH dependent [[Cushing's syndrome]] }}
+{{familytree |!| | | | | | | | | |!| }}
+{{familytree |K01| | | | | | | |K02| K01= CT scan/ MRI of [[Adrenal gland|adrenal glands]] to look for adrenal tumors or [[hyperplasia]]. | K02= <div style="float: center; text-align: left;"> Perform both tests:
+* CRH or desmopressin stimulation test
+* High dose (8mg) overnight DST }}
+{{familytree | | | | | | | |,|-|-|^|-|-|.| }}
+{{familytree | | | | | | | |L01| | | |L02| L01= Adequate suppresion of early morning serum [[cortisol]] (with levels less than 5 mcg/dL) and stimulation with CRH | L02= Negative or equivocal response }}
+{{familytree | | | | | | | |!| | | | | | |!| }}
+{{familytree | | | | | | | |M01| | | | |!| M01= MRI of the [[Pituitary gland|pituitary]] }}
+{{familytree | | | | |,|-|-|^|-|.| | | | |!| }}
+{{familytree | | | | |N01| | |N02| | |!| | N01= Tumor >6mm | N02= Tumor <6mm or no mass lesion }}
+{{familytree | | | | |!| | | | |!| | | | |!| | }}
+{{familytree | | | | |O01| | |`|-|-|-|-|O02| O01= [[Cushing's disease]] | O02= Perform  [[Inferior petrosal sinus]] sampling. }}
+{{familytree | | | | |!| | | | | | |,|-|-|^|-|.| | }}
+{{familytree | | | | |!| | | | | | |!| | | | |!| | }}
+{{familytree | | | | |`|-|-|-|-|-|P01| | | |P02| P01= Central step-up | P02= No Central step-up }}
+{{familytree | | | | | | | | | | | | | | | | |!| | }}
+{{familytree | | | | | | | | | | | | | | | | |Q01| Q01= Ectopic ACTH production }}
 {{familytree/end}}
 ==Treatment==
-Shown below is an algorithm summarizing the treatment of <nowiki>[[disease name]]</nowiki> according the the [...] guidelines.
+Shown below is an algorithm summarizing the treatment of [[Cushing's syndrome]] according the the Endocrine Society clinical practice guidelines.<ref name="pmid26222757">{{cite journal| author=Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO | display-authors=etal| title=Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. | journal=J Clin Endocrinol Metab | year= 2015 | volume= 100 | issue= 8 | pages= 2807-31 | pmid=26222757 | doi=10.1210/jc.2015-1818 | pmc=4525003 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26222757  }} </ref><ref name="pmid17970770">{{cite journal| author=Chow JT, Thompson GB, Grant CS, Farley DR, Richards ML, Young WF| title=Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience. | journal=Clin Endocrinol (Oxf) | year= 2008 | volume= 68 | issue= 4 | pages= 513-9 | pmid=17970770 | doi=10.1111/j.1365-2265.2007.03082.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17970770  }} </ref><ref name="pmid11572035">{{cite journal| author=Aniszewski JP, Young WF, Thompson GB, Grant CS, van Heerden JA| title=Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. | journal=World J Surg | year= 2001 | volume= 25 | issue= 7 | pages= 934-40 | pmid=11572035 | doi=10.1007/s00268-001-0032-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11572035  }} </ref>
-{{familytree/start |summary=PE diagnosis Algorithm.}}
+{{familytree/start}}
-{{familytree | | | | | | | | A01 |A01= }}
+{{familytree | | | | | | | | | A01 | | | | | |A01= The treatment depends upon the underlying etiology }}
-{{familytree | | | | |,|-|-|-|^|-|-|-|-|.| | | }}
+{{familytree | | |,|-|-|-|-|-|-|+|-|-|-|-|-|-|-|-|.| }}
-{{familytree | | | B01 | | | | | | | | B02 | | |B01= |B02= }}
+{{familytree | | B01 | | | | | B02 | | | | | | | B03 |B01= [[Cushing's disease]] |B02= Paraneoplastic [[Cushing's syndrome]] |B03= ACTH-independent [[Cushing's syndrome]] }}
-{{familytree | | | |!| | | | | | | | | |!| }}
+{{familytree | |!| | | | |,|-|^|-|-|.| | | |,|-|^|-|-|.| }}
-{{familytree | | | C01 | | | | | | | | |!| |C01= }}
+{{familytree | |C01| | |C02| | |C03| |C04| | |C05| | C01= Transsphenoidal surgery: Treatment of choice in patients with [[pituitary]] [[adenoma]] with distinct margins. | C02= Resectable [[tumor]] | C03= Nonresectable [[tumor]] | C04= Adrenal [[adenoma]] | C05= Bilateral adrenal [[hyperplasia]] }}
-{{familytree | |,|-|^|.| | | | | | | | |!| }}
+{{familytree | |!| | | | |!| | | | |!| | | |!| | | | |!| }}
-{{familytree | D01 | | D02 | | | | | | D03 |D01= |D02= |D03= }}
+{{familytree |D01| | | |D02| | |D03| |D04| | |D05| D01= <div style="float: left; text-align: left;">  [[Pituitary]] irradiation carried out in patients with:
-{{familytree | |!| | | | | | | | | |,|-|^|.| }}
+* Failure to resect [[tumor]] completely by surgery.
-{{familytree | E01 | | | | | | | E02 | | | E03 |E01= |E02= |E03= }}
+* The location of the [[tumor]] cannot be determined.
-{{familytree | | | | | | | | | | |!| | | | |!| }}
+* The patient wishes to conceive in the future. | D02= Resection of the primary [[tumor]] | D03= <div style="float: left; text-align: left;">  Medical therapy:
-{{familytree | | | | | | | | | | F01 | | | F02 |F01= |F02= }}
+* Inhibit the synthesis of adrenocortical enzymes: [[ketoconazole]], [[metyrapone]], and [[etomidate]].
+* Inhibits the secretion of ACTH from the ectopic site: [[Octreotide]]
+* Inhibits hyperglycemia secondary to hypercortisolism: [[Mifepristone]] | D04= Unilateral [[adrenalectomy]] | D05= Bilateral [[adrenalectomy]] }}
+{{familytree | |!| | | | | | | | | | | | | | }}
+{{familytree |E01| | | | | | | | | | | | | | E01= Bilateral [[adrenalectomy]] is performed in patients with severe refractory hypercortisolism despite surgical and radiation therapy. }}
 {{familytree/end}}
 ==Do's==
-* The content in this section is in bullet points.
+* In ACTH-independent [[Cushing's syndrome|Cushing’s syndrome]], [[glucocorticoid]] therapy should be given to patients post-operatively due to suppression of the hypothalamic-pituitary axis. Patients with medication-induced [[Cushing's syndrome|Cushing’s syndrome]] should taper the dose of [[glucocorticoid]] instead of sudden withdrawal of the medications.
+* Thromboprophylaxis should be initiated preoperatively in patients with [[Cushing's syndrome|Cushing’s syndrome]]<ref name="pmid26222757">{{cite journal| author=Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO | display-authors=etal| title=Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. | journal=J Clin Endocrinol Metab | year= 2015 | volume= 100 | issue= 8 | pages= 2807-31 | pmid=26222757 | doi=10.1210/jc.2015-1818 | pmc=4525003 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26222757  }} </ref>. There is a hypercoagulable state in patients with [[Cushing's syndrome|Cushing’s syndrome]] due to impaired fibrinolysis and activation of the [[Coagulation|coagulation cascade]]. These patients have an increased risk of developing [[Deep vein thrombosis|deep venous thrombosis]] compared to the normal [[patient]] population<ref name="pmid19454584">{{cite journal| author=Van Zaane B, Nur E, Squizzato A, Dekkers OM, Twickler MT, Fliers E | display-authors=etal| title=Hypercoagulable state in Cushing's syndrome: a systematic review. | journal=J Clin Endocrinol Metab | year= 2009 | volume= 94 | issue= 8 | pages= 2743-50 | pmid=19454584 | doi=10.1210/jc.2009-0290 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19454584  }} </ref>.
+* Rebound thymic [[hyperplasia]] can occur in [[Patient|patients]] whose [[Cushing's syndrome|hypercortisolism]] is controlled.  On the [[chest]] imaging, it is seen as a mass in the anterior [[mediastinum]] and can be misinterpreted as [[tumor]] recurrence, or [[metastasis]]<ref name="pmid7704966">{{cite journal| author=Tabarin A, Catargi B, Chanson P, Hieronimus S, Corcuff JB, Laurent F | display-authors=etal| title=Pseudo-tumours of the thymus after correction of hypercortisolism in patients with ectopic ACTH syndrome: a report of five cases. | journal=Clin Endocrinol (Oxf) | year= 1995 | volume= 42 | issue= 2 | pages= 207-13 | pmid=7704966 | doi=10.1111/j.1365-2265.1995.tb01865.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7704966  }} </ref>.
 ==Don'ts==
-* The content in this section is in bullet points.
+* The 24 hours urinary free [[cortisol]] measurement should not be used for diagnosis in subclinical [[Cushing's syndrome|hypercortisolism]] (mild [[Cushing's syndrome|hypercortisolism]] in adrenal [[incidentaloma]]) as it can yield false-negative results<ref name="pmid18334580">{{cite journal| author=Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM | display-authors=etal| title=The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. | journal=J Clin Endocrinol Metab | year= 2008 | volume= 93 | issue= 5 | pages= 1526-40 | pmid=18334580 | doi=10.1210/jc.2008-0125 | pmc=2386281 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18334580  }} </ref>. False-positive results are present in patients with physiological [[Cushing's syndrome|hypercortisolism]] (patients with a [[Polycystic ovary syndrome|polycystic ovarian syndrome]] or [[Clinical depression|major depressive disorder]])<ref name="pmid8855803">{{cite journal| author=Cizza G, Nieman LK, Doppman JL, Passaro MD, Czerwiec FS, Chrousos GP | display-authors=etal| title=Factitious Cushing syndrome. | journal=J Clin Endocrinol Metab | year= 1996 | volume= 81 | issue= 10 | pages= 3573-7 | pmid=8855803 | doi=10.1210/jcem.81.10.8855803 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8855803  }} </ref><ref name="pmid935296">{{cite journal| author=Carroll BJ, Curtis GC, Davies BM, Mendels J, Sugerman AA| title=Urinary free cortisol excretion in depression. | journal=Psychol Med | year= 1976 | volume= 6 | issue= 1 | pages= 43-50 | pmid=935296 | doi=10.1017/s0033291700007480 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=935296  }} </ref>. High fluid intake can result in an increased fraction of excretion of free [[cortisol]] yielding false-positive results.<ref name="pmid9467592">{{cite journal| author=Mericq MV, Cutler GB| title=High fluid intake increases urine free cortisol excretion in normal subjects. | journal=J Clin Endocrinol Metab | year= 1998 | volume= 83 | issue= 2 | pages= 682-4 | pmid=9467592 | doi=10.1210/jcem.83.2.4555 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9467592  }} </ref>
+* MRI is not a cost-effective diagnostic test. CT scan of the [[abdomen]] and [[Adrenal gland|adrenal glands]] is preferred as an imaging test to localize adrenal [[adenoma]] or [[carcinoma]] compared to MRI. On the Ct scan adrenal carcinoma has a bigger size along with hemorrhage, necrosis and calcification in the lesion<ref name="pmid16371582">{{cite journal| author=Blake MA, Kalra MK, Sweeney AT, Lucey BC, Maher MM, Sahani DV | display-authors=etal| title=Distinguishing benign from malignant adrenal masses: multi-detector row CT protocol with 10-minute delay. | journal=Radiology | year= 2006 | volume= 238 | issue= 2 | pages= 578-85 | pmid=16371582 | doi=10.1148/radiol.2382041514 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16371582  }} </ref>.
 ==References==