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cushing disease

Updated : February 15, 2024





Background

It is an endocrine disorder characterized by increased ACTH (adrenocorticotropic hormone) production by the anterior pituitary gland, resulting in excessive cortisol release from adrenal glands. Moon facies, easy bruising, buffalo hump, abdominal striae, facial plethora, hirsutism, and central obesity appear due to excess cortisol levels.

Symptoms include high blood pressure, generalized weakness, menstruation abnormalities, diabetes, and psychological disorders. This disease is also triggered by a pituitary microadenoma or excess corticotropin-releasing hormone from the hypothalamus.

Epidemiology

Exogenous steroids are the primary cause of Cushing syndrome. About 2.4 new cases are reported annually per million people. This disorder is often diagnosed three to six years after its onset. Women between 50 and 60 have the highest occurrence of Cushing disease.

Major risk factors for morbidity and mortality in untreated cases of the disease include the predominance of hypertension and irregularities in glucose metabolism. Cushing disease is estimated to have a 10%–11% mortality rate.

Anatomy

Pathophysiology

In addition to its primary role as a glucocorticoid, cortisol demonstrates mineralocorticoid activity at high concentrations, which can cause hypokalemia and hypertension via the RAAS (renin-angiotensin-aldosterone pathway). Hypokalemia results indirectly as the RAAS hormone system controls arterial blood pressure and plasma sodium concentration.

Although the frequency of ACTH synthesis stays constant, the usual circadian rhythm is disrupted. Increased plasma ACTH increases cortisol production and promotes bilateral adrenal hyperplasia. Hence the normal cortisol circadian rhythm is disrupted.

Etiology

A pituitary adenoma is present in Cushing disease patients. Lack of release of corticotropin-releasing hormone, a rare case of widespread corticotroph hyperplasia develops (CRH). In most cases, the tumors are microadenomas (less than 5 mm in size); approximately 5–10% are macroadenomas.

Compared to microadenomas, macroadenomas are more likely to have unusually high ACTH concentrations (83 vs. 45 %). Several genetic abnormalities cause these adenomas. USP8 is the most specific mutation (ubiquitin-specific peptidase 8). These mutations result in aberrant growth factor expression, which works with ACTH to raise cortisol levels.

Genetics

Prognostic Factors

Cushing’s disease is eventually fatal if untreated. The mortality is caused by the excess production of glucocorticoids, which can result in various health problems, including immune system dysfunction. Patients with surgical interventions require to take glucocorticoids for prolonged periods.

Clinical History

Physical Examination

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Medication

 

pasireotide

Initial SC:

0.6 - 0.9

mg

twice a day


Dose adjustment: Increase the dose in increments of 0.3 mg twice a day every 3 months depending on the normalization of urinary-free cortisol levels
Decrease the dose by 0.3 mg if an adverse reaction occurs
Maintenance dose SC: 0.3 to 0.9 mg twice a day
Initial IM: 10 mg once every 4 weeks
Dose adjustment: Monitor for 24-hour UFC levels, if not normalized increase the dose maximum up to 40 mg once every 4 weeks
Discontinue the therapy if adverse reactions occur
Do not administer missed dose 2 weeks prior to the next dose



Dose Adjustments

For Hepatotoxicity:
Moderate hepatotoxicity for IM dose: Initially 20 mg once every 4 weeks and maintain not more than 40 mg once every 4 weeks
Severe hepatic impairment for IM dose: Discontinue temporarily
Moderate hepatotoxicity for SC: initial 0.3 mg twice a day and maintain 0.6 mg twice a day
Severe hepatic impairment for SC dose: Discontinue temporarily

osilodrostat 

Initial dose
:

2

mg

Tablet

Orally 

twice a day


Titration:1 to 2mg twice a day initially, no more than two weeks
Maintenance dose:2-7mg twice a day
maximum dose-30mg



 
 

Media Gallary

References

https://www.ncbi.nlm.nih.gov/books/NBK448184/

cushing disease

Updated : February 15, 2024




It is an endocrine disorder characterized by increased ACTH (adrenocorticotropic hormone) production by the anterior pituitary gland, resulting in excessive cortisol release from adrenal glands. Moon facies, easy bruising, buffalo hump, abdominal striae, facial plethora, hirsutism, and central obesity appear due to excess cortisol levels.

Symptoms include high blood pressure, generalized weakness, menstruation abnormalities, diabetes, and psychological disorders. This disease is also triggered by a pituitary microadenoma or excess corticotropin-releasing hormone from the hypothalamus.

Exogenous steroids are the primary cause of Cushing syndrome. About 2.4 new cases are reported annually per million people. This disorder is often diagnosed three to six years after its onset. Women between 50 and 60 have the highest occurrence of Cushing disease.

Major risk factors for morbidity and mortality in untreated cases of the disease include the predominance of hypertension and irregularities in glucose metabolism. Cushing disease is estimated to have a 10%–11% mortality rate.

In addition to its primary role as a glucocorticoid, cortisol demonstrates mineralocorticoid activity at high concentrations, which can cause hypokalemia and hypertension via the RAAS (renin-angiotensin-aldosterone pathway). Hypokalemia results indirectly as the RAAS hormone system controls arterial blood pressure and plasma sodium concentration.

Although the frequency of ACTH synthesis stays constant, the usual circadian rhythm is disrupted. Increased plasma ACTH increases cortisol production and promotes bilateral adrenal hyperplasia. Hence the normal cortisol circadian rhythm is disrupted.

A pituitary adenoma is present in Cushing disease patients. Lack of release of corticotropin-releasing hormone, a rare case of widespread corticotroph hyperplasia develops (CRH). In most cases, the tumors are microadenomas (less than 5 mm in size); approximately 5–10% are macroadenomas.

Compared to microadenomas, macroadenomas are more likely to have unusually high ACTH concentrations (83 vs. 45 %). Several genetic abnormalities cause these adenomas. USP8 is the most specific mutation (ubiquitin-specific peptidase 8). These mutations result in aberrant growth factor expression, which works with ACTH to raise cortisol levels.

Cushing’s disease is eventually fatal if untreated. The mortality is caused by the excess production of glucocorticoids, which can result in various health problems, including immune system dysfunction. Patients with surgical interventions require to take glucocorticoids for prolonged periods.

pasireotide

Initial SC:

0.6 - 0.9

mg

twice a day


Dose adjustment: Increase the dose in increments of 0.3 mg twice a day every 3 months depending on the normalization of urinary-free cortisol levels
Decrease the dose by 0.3 mg if an adverse reaction occurs
Maintenance dose SC: 0.3 to 0.9 mg twice a day
Initial IM: 10 mg once every 4 weeks
Dose adjustment: Monitor for 24-hour UFC levels, if not normalized increase the dose maximum up to 40 mg once every 4 weeks
Discontinue the therapy if adverse reactions occur
Do not administer missed dose 2 weeks prior to the next dose



Dose Adjustments

For Hepatotoxicity:
Moderate hepatotoxicity for IM dose: Initially 20 mg once every 4 weeks and maintain not more than 40 mg once every 4 weeks
Severe hepatic impairment for IM dose: Discontinue temporarily
Moderate hepatotoxicity for SC: initial 0.3 mg twice a day and maintain 0.6 mg twice a day
Severe hepatic impairment for SC dose: Discontinue temporarily

osilodrostat 

Initial dose
:

2

mg

Tablet

Orally 

twice a day


Titration:1 to 2mg twice a day initially, no more than two weeks
Maintenance dose:2-7mg twice a day
maximum dose-30mg



https://www.ncbi.nlm.nih.gov/books/NBK448184/