Cushing's syndrome

Source: Wikipedia, the free encyclopedia.
Cushing's syndrome
Other namesHypercortisolism, Itsenko-Cushing syndrome, hyperadrenocorticism
round face, often reddened due to facial plethora, fat lump between the shoulders, weak muscles, acne, fragile skin[2]
ComplicationsHigh blood pressure (hypertension), Type 2 diabetes, Frequent or unusual infections, Loss of muscle mass and strength, Bone loss (osteoporosis).[3]
Usual onset20–50 years[4]
CausesProlonged exposure to cortisol[4]
Diagnostic methodRequires a number of steps[5]
TreatmentBased on underlying cause[6]
PrognosisGenerally good with treatment[7]
Frequency2–3 per million people per year[8] (from 1/333,333 to 1/500,000 people)

Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to

chronic feeling of tiredness.[2]

Cushing's syndrome is caused by either excessive cortisol-like medication, such as

ACTH may be done.[5]

Most cases can be treated and cured.[7] If due to medications, these can often be slowly decreased if still required or slowly stopped.[6][15] If caused by a tumor, it may be treated by a combination of surgery, chemotherapy, and/or radiation.[6] If the pituitary was affected, other medications may be required to replace its lost function.[6] With treatment, life expectancy is usually normal.[7] Some, in whom surgery is unable to remove the entire tumor, have an increased risk of death.[16]

About two to three cases per million persons are caused overtly by a tumor.[8] It most commonly affects people who are 20 to 50 years of age.[4] Women are affected three times more often than men.[8] A mild degree of overproduction of cortisol without obvious symptoms, however, is more common.[17] Cushing's syndrome was first described by American neurosurgeon Harvey Cushing in 1932.[18] Cushing's syndrome may also occur in other animals including cats, dogs, and horses.[19][20]

Signs and symptoms

stria in a person with medication-induced Cushing's syndrome[1]
Features of Cushing syndrome including a round face, acne, reddish skin, central obesity, and poor muscle tone[22]

Symptoms include rapid

GnRH release.[23]

Many of the features of Cushing's are those seen in metabolic syndrome, including insulin resistance, hypertension, obesity, and elevated blood levels of triglycerides.[24]

Cognitive conditions, including memory and attention dysfunctions, as well as depression, are commonly associated with elevated cortisol,

anxiety disorders are also common.[26]

Other striking and distressing skin changes that may appear in Cushing's syndrome include facial acne, susceptibility to superficial fungus (dermatophyte and malassezia) infections, and the characteristic purplish, atrophic striae on the abdomen.[27]: 500 

Other signs include

gastrointestinal disturbances, opportunistic infections, and impaired wound healing related to cortisol's suppression of the immune and inflammatory responses. Osteoporosis is also an issue in Cushing's syndrome since osteoblast activity is inhibited. Additionally, Cushing's syndrome may cause sore and aching joints, particularly in the hip, shoulders, and lower back.[citation needed
]

Brain changes such as cerebral atrophy may occur.[28] This atrophy is associated with areas of high glucocorticoid receptor concentrations such as the hippocampus and correlates highly with psychopathological personality changes.[29][30][31][32]

Hyperpigmentation

Cushing's syndrome due to excess

β-lipotropin, and γ-lipotropin, which contain weak MSH function, can act on the melanocortin 1 receptor. A variant of Cushing's disease can be caused by ectopic, i.e. extra pituitary, ACTH production from, for example, a small-cell lung cancer.[33]

When Cushing's syndrome is caused by an increase of cortisol at the level of the adrenal glands (via an adenoma or hyperplasia), negative feedback ultimately reduces ACTH production in the pituitary. In these cases, ACTH levels remain low and no hyperpigmentation develops.[33]

Causes

Cushing's syndrome may result from any cause of increased glucocorticoid levels, whether due to medication or internal processes.[10][34] Some sources however do not consider the glucocorticoid medication-induced condition as "Cushing's syndrome" proper, instead using the term "Cushingoid" to describe the medication's side effects which mimic the endogenous condition.[35][34][36]

Cushing's disease is a specific type of Cushing's syndrome caused by a pituitary tumor leading to excessive production of

ACTH (adrenocorticotropic hormone). Excessive ACTH stimulates the adrenal cortex to produce high levels of cortisol, producing the disease state. While all Cushing's disease gives Cushing's syndrome, not all Cushing's syndrome is due to Cushing's disease.[37] Several possible causes of Cushing's syndrome are known including the taking of herbal supplements over-the-counter that do not list glucocorticoids in their ingredients.[38][39]

Exogenous

The most common cause of Cushing's syndrome is the use of prescribed glucocorticoids to treat other diseases (iatrogenic Cushing's syndrome). Glucocorticoids are used in treatment of a variety of disorders, including asthma and rheumatoid arthritis, and also used for immunosuppression after organ transplants. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility. Rarely, Cushing's syndrome can also be due to the use of medroxyprogesterone acetate.[40][41] In exogenous Cushing's, the adrenal glands may often gradually atrophy due to lack of stimulation by ACTH, the production of which is suppressed by glucocorticoid medication. Abruptly stopping the medication can thus result in acute and potentially life-threatening adrenal insufficiency and the dose must hence be slowly and carefully tapered off to allow internal cortisol production to pick up. In some cases, patients never recover sufficient levels of internal production and must continue taking glucocorticoids at physiological doses for life.[35][42]

Cushing's syndrome in childhood is especially rare and usually results from use of glucocorticoid medication.[43]

Endogenous

ACTH is released from the pituitary gland when necessary to stimulate the release of cortisol from the adrenal glands.[citation needed
]

Pseudo-Cushing's syndrome

Elevated levels of total cortisol can also be due to estrogen found in oral contraceptive pills that contain a mixture of estrogen and progesterone, leading to pseudo-Cushing's syndrome. Estrogen can cause an increase of cortisol-binding globulin and thereby cause the total cortisol level to be elevated. However, the total free cortisol, which is the active hormone in the body, as measured by a 24-hour urine collection for urinary free cortisol, is normal.[47]

Pathophysiology

The

ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on CRH in the hypothalamus, which decreases the amount of ACTH released from the anterior pituitary gland.[citation needed
]

Strictly, Cushing's syndrome refers to excess cortisol of any etiology (as syndrome means a group of symptoms). One of the causes of Cushing's syndrome is a cortisol-secreting adenoma in the cortex of the adrenal gland (primary hypercortisolism/hypercorticism). The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low.[citation needed]

Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism). This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because the tumor is unresponsive to negative feedback from high cortisol levels.[citation needed
]

When Cushing's syndrome is due to extra

ACTH it is known as ectopic Cushing syndrome.[48] This may be seen in a paraneoplastic syndrome
.

When Cushing's syndrome is suspected, either a

]

When any of these tests is positive,

incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Occasionally, determining the ACTH levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary. In many cases, the tumors causing Cushing's disease are less than 2 mm in size and difficult to detect using MRI or CT imaging. In one study of 261 patients with confirmed pituitary Cushing's disease, only 48% of pituitary lesions were identified using MRI prior to surgery.[50]

Plasma CRH levels are inadequate at diagnosis (with the possible exception of tumors secreting CRH) because of peripheral dilution and binding to CRHBP.[51]

Diagnosis

Diagnostic algorithm of suspected Cushing's syndrome:[52]
ACTH=adrenocorticotropic hormone.
CBG=corticosteroid-binding globulin.
CRH=corticotropin-releasing hormone.
DST=dexamethasone suppression test.
IPSS=inferior petrosal sinus sampling.
UFC=urinary free cortisol.
*There is consensus that all patients with lesions smaller than 6 mm in diameter should have IPSS and those with lesions of ≥10 mm do not need IPSS, but expert opinions differed for lesions 6–9 mm in diameter.
†This alternative option does not have clear consensus and needs further research, and this is indicated by darker boxes.
Green boxes indicate points to consider
Darker colors indicate less validated testing pathways.

Cushing's syndrome can be ascertained via a variety of tests which include the following:[53]

Treatment

Most cases of Cushingoid symptoms are caused by corticosteroid medications, such as those used for asthma, arthritis, eczema and other inflammatory conditions. Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication that causes the symptoms.[citation needed]

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

In those patients not suited for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy.[citation needed] Mifepristone is a powerful glucocorticoid type II receptor antagonist and, since it does not interfere with normal cortisol homeostasis type I receptor transmission, may be especially useful for treating the cognitive effects of Cushing's syndrome.[54] However, the medication faces considerable controversy due to its use as an abortifacient. In February 2012, the FDA approved mifepristone to control high blood sugar levels (hyperglycemia) in adult patients who are not candidates for surgery, or who did not respond to prior surgery, with the warning that mifepristone should never be used by pregnant women- although pregnancy is extremely rare during the course of Cushing's Syndrome[55][56][57] [58] In March 2020, Isturisa (osilodrostat) oral tablets a 11-beta-hydroxylase enzyme inhibitor was approved by FDA for treating those patients who cannot undergo pituitary surgery or for patients who underwent surgery but continue to have the disease.[59]

Management algorithm of Cushing's disease:[52]
DST=dexamethasone suppression test.
IPSS=inferior petrosal sinus sampling.
ACTH=adrenocorticotropic hormone.
*Pituitary surgery should be performed by an experienced surgeon.
†Absence of ACTH-staining adenoma.
‡See table 2 and panel 3 for considerations regarding selection of medical therapy.
§Lifelong monitoring for hypopituitarism and secondary neoplasia in the radiation field required.
¶On maximum tolerated dose of the drug.

Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol.[60] In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome.[61]

Epidemiology

Cushing's syndrome caused by treatment with corticosteroids is the most common form. Cushing's disease is rare; a Danish study found an incidence of less than one case per million people per year.[62] However, asymptomatic microadenomas (less than 10 mm in size) of the pituitary are found in about one in six individuals.[63]

About 0.9 to 1% of those with Cushing's syndrome have a tendency to develop venous thrombosis. Other factors such as surgery and obesity also increase the chance of getting thrombosis.[64]

See also

References

  1. ^
    PMID 22958272
    .
  2. ^ a b c d "What are the symptoms of Cushing's syndrome?". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
  3. ^ "Cushing syndrome". mayoclinic.org. Mayo Clinic. Retrieved June 5, 2022.
  4. ^ a b c d e f "Cushing's Syndrome". National Endocrine and Metabolic Diseases Information Service (NEMDIS). July 2008. Archived from the original on 10 February 2015. Retrieved 16 March 2015.
  5. ^ a b c d e f "How do health care providers diagnose Cushing's syndrome?". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
  6. ^ a b c d "What are the treatments for Cushing's syndrome?". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
  7. ^ a b c "Is there a cure for Cushing's syndrome?". 2012-11-30. Archived from the original on 27 March 2015. Retrieved 16 March 2015.
  8. ^ a b c d "How many people are affected by or at risk for Cushing's syndrome?". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
  9. from the original on 2017-09-08.
  10. ^ .
  11. .
  12. .
  13. ^ "What causes Cushing's syndrome?". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
  14. PMID 16378774
    .
  15. ^ "Cushing syndrome - Diagnosis and treatment - Mayo Clinic". www.mayoclinic.org. Retrieved 2019-04-21.
  16. PMID 22385888
    .
  17. .
  18. ^ "Cushing Syndrome: Condition Information". 2012-11-30. Archived from the original on 2 April 2015. Retrieved 16 March 2015.
  19. from the original on 2017-09-08.
  20. .
  21. ^ "Cushing syndrome". Mayo Clinic. March 28, 2013. Archived from the original on May 25, 2015. Retrieved 2015-05-25.
  22. PMID 20049152
    .
  23. .
  24. .
  25. .
  26. .
  27. .
  28. .
  29. .
  30. .
  31. .
  32. .
  33. ^ a b "Cushing's Syndrome". The Lecturio Medical Concept Library. Retrieved 11 July 2021.
  34. ^
    PMID 29261900
    . Retrieved 2019-04-20.
  35. ^ .
  36. .
  37. ^ Lynnette K. Nieman, Beverly M. K. Biller, James W. Findling, John Newell-Price, Martin O. Savage, Paul M. Stewart, Victor M. Montori, The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 93, Issue 5, 1 May 2008, Pages 1526–1540,
  38. ^ Research, Center for Drug Evaluation and (2022-10-31). "Public Notification: Artri King contains hidden drug ingredients". FDA.
  39. PMID 36447831
    .
  40. .
  41. .
  42. .
  43. .
  44. .
  45. .
  46. .
  47. .
  48. ^ Ectopic Cushing syndrome Archived 2013-10-02 at the Wayback Machine at A.D.A.M. Medical Encyclopedia, PubMedHealth, National Institute of Health
  49. S2CID 14930007
    .
  50. .
  51. .
  52. ^
    PMID 34687601.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  53. ^ "Cushing syndrome: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 16 March 2018.
  54. S2CID 3067889
    .
  55. .
  56. .
  57. .
  58. ^ "FDA approves mifepristone (Korlym*) for patients with endogenous Cushing' s syndrome". February 18, 2012. Archived from the original on September 9, 2012.
  59. ^ Office of the Commissioner (2020-03-24). "FDA Approves New Treatment for Adults with Cushing's Disease". FDA. Retrieved 2020-06-21.
  60. S2CID 34513590
    .
  61. .
  62. .
  63. .
  64. .

External links