​Kembara Xtra - Medicine - Cushing Disease and Cushing Syndrome

​Kembara Xtra - Medicine - Cushing Disease and Cushing Syndrome 
Introduction 

Excessive glucocorticoid exposure can be caused by exogenous sources, such as steroid medicines, or, less typically, by endogenous sources, such as the pituitary gland, adrenal glands, pulmonary tissue, and so on. This is what is known as Cushing syndrome.
Glucocorticoid excess is the hallmark symptom of Cushing illness, which is caused by an overabundance of adrenocorticotropic hormone (ACTH) release from a pituitary tumor.
● System(s) affected: endocrine/metabolic, musculoskeletal, skin/exocrine, cardiovascular; neuropsychiatric 

Considerations Relating to Children

Cushing disease accounts for approximately 75% of all instances of Cushing syndrome in children older than 7 years. Cushing syndrome affects a small percentage of infants and children.
– Cushing disease, which is caused by an adenoma that produces ACTH in the pituitary gland, can occasionally be the first sign of multiple endocrine neoplasia (MEN) type 1 in young patients.
Adenoma, cancer, or bilateral hyperplasia of the adrenal glands are the most common causes of Cushing syndrome in children younger than seven years old.
Lack of growth and weight gain is the symptom that presents itself most frequently in patients.

Important Information Regarding Pregnancy The risk of developing the condition is increased during pregnancy, and normal pregnancy causes cortisol levels to rise.

Epidemiology (Incidence and Prevalence) 

Incidence
Endogenous causes of Cushing syndrome are uncommon in the United States, with approximately 8 instances reported for every million inhabitants.
Prevalence
2–5% prevalence found in diabetics with obesity and hypertension (HTN) who have difficulty maintaining their blood sugar levels.

Causes and effects: etiology and pathophysiology 

 Exogenous: The use of glucocorticoids for an extended period of time (most typically seen in patients with chronic conditions such as asthma, chronic obstructive pulmonary disease, etc.) 
80–85% of hypercortisolism is caused by endogenous glucocorticoid release, which is dependent on endogenous ACTH.
 75% of cases of Cushing illness are caused by ACTH-secreting pituitary tumors.
 Endogenous ACTH– independent hypercortisolism: 15–20% of cases
○ Adrenal adenoma
○ Adrenal carcinoma
In children and adolescents: adrenal hyperplasia due to McCune-Albright syndrome, with an average age of 1.2 years; adrenocortical tumors, with an average age of 4.5 years; ectopic ACTH syndrome, with an average age of 10.1 years; primary pigmented nodular adrenocortical disease, with an average age of 13.0 years; cushing disease, with an average age of 14.1 years
Pituitary-dependent Cushing syndrome during pregnancy resulting from adrenal causes
– ACTH-independent adrenal hyperplasia
Genetics
● MEN

Activating somatic mutations of the USP8 (ubiquitin-specific protease 8) gene are found in a large proportion of cases of Cushing disease. Carney complex is an inherited multiple neoplasia syndrome. McCune-Albright syndrome is caused by a mutation of the GNAS1 gene. Familial isolated pituitary adenomas are caused by mutations in the aryl hydrocarbon receptor–interacting protein gene. There is a correlation between the presence of the USP8 mutation in pituitary tumors and a greater risk of tumor recurrence following transsphenoidal surgery.

factors of danger 
An extended course of corticosteroid treatment

Preventative Steps and Precautions 

When it is in your power, stay away from corticosteroids.

Conditions That Often Occur Together 
Psychiatric problems, diabetes, high blood pressure, hypokalemia, infections, dyslipidemia, osteoporosis, and a lack of physical fitness are some of the conditions that are associated with obesity.

Providing Some Background Information Increase in weight: 95% Decrease in libido: 90%
● Menstrual irregularity: 80%
 Depression and emotional lability: between fifty and eighty percent
● Easy bruising: 95%
● Diabetes or glucose intolerance: 90%
In cases with ectopic ACTH syndrome, particularly those involving paraneoplastic syndrome, the classic symptoms may not be present.
In addition to its catabolic effects, hypercortisolemia frequently causes hypokalemia.

The Patient's Clinical Examination 

 Obesity (often central): 95% of patients
Plethora of facial hair: 90%

Moon face (facial adiposity): 90% of people have it.
● Thin skin: 85%
● HTN: 75%

● Hirsutism: 75%
Weakness in the proximal muscles: 90 %
Acne Increased adipose tissue in the neck and trunk, supraclavicular fat pads, and buffalo hump Purple striae on the skin Skeletal growth retardation in children (epiphyseal plates remain open): 70–80% of the time

Differential Diagnosis Obesity Type 2 diabetes mellitus (T2DM) Hypertension Metabolic syndrome X Polycystic ovarian disease Pseudo-Cushing (e.g., drunkenness, severe serious depression, physical stress) 

Results From the Laboratory Initial Examinations (lab, imaging)
In accordance with the standards of the Endocrine Society, testing for Cushing syndrome should include the following: - Multiple increasing signs characteristic of Cushing disease despite the presence of an adrenal incidentaloma
- Unusual characteristics for their age, such as early osteoporosis and high blood pressure
– Abnormal growth and increased weight in children – Screening tests performed in laboratories – Abnormal growth
Cushing syndrome should not be confused with pseudo-Cushing syndrome, which can be caused by conditions such as obesity, drunkenness, or depression.
The late-night salivary cortisol test, the 24-hour urine free cortisol (UFC) test, and the low-dose dexamethasone suppression test are the ones that are utilized the most frequently.
Cortisol levels can change throughout the course of a single day, and a single urine free cortisol or salivary cortisol reading taken late at night may not accurately reflect the whole amount of cortisol exposure.

 The Endocrine Society Guidelines suggest a biochemical diagnosis based on one of the following three approaches:  Determining the 24-hour urinary free cortisol level while determining the daily cortisol excretion:
Get at least two different readings to rule out the possibility of having intermittent hypercortisolism.
Concomitant 24-hour urine creatinine excretion should be measured to check sufficiency of collection because results may be inaccurately low if renal impairment (glomerular filtration rate (GFR) of less than 60 mL/min) is present.
Sensitivity and specificity, taken as a whole, range from 90–97% and 85–99%, respectively. 
Due to the possibility of obtaining false-positive results, you should avoid consuming an excessive amount of water.
Documenting the lack of the diurnal fluctuation in salivary cortisol levels late at night:

 Obtain a minimum of two different measurements.
The release of cortisol is at its maximum in the morning and at its lowest between the hours of 11 PM and midnight.
There is a possibility that licorice, chewing tobacco, and oral gels containing steroids will produce false-positive results. Those who work night shifts or suffer from oral disorders that leave them with inadequate saliva may have tests that produce false-negative findings.
The lowest possible level of serum cortisol is maintained in patients with pseudo-Cushing, but this is not the case in patients with Cushing disease.
Both the sensitivity and specificity range from greater than 90 to 95%.
Documenting the loss of feedback inhibition of cortisol on the hypothalamic-pituitary-adrenal (HPA) axis: testing for suppressive effects of modest doses of dexamethasone: 
One milligram of dexamethasone is administered between the hours of 11 p.m. and midnight, and the next morning's fasting plasma cortisol levels are tested between 8 and 9 a.m.
Having a serum cortisol level that is lower than 1.8 ng/dL rules out Cushing syndrome, but the specificity of this test is restricted.
The test of choice for determining whether or not a patient has subclinical Cushing syndrome (people who have a slight elevation in cortisol but no other obvious indications of hormonal excess; monitor these patients for possible development). 
The presence of pseudo-Cushing states (depression, obesity, and other similar conditions), hepatic or renal disease, or any substance that activates cytochrome P450 enzymes can lead to an inaccurate test result.
It is possible that determining the simultaneous level of dexamethasone will be helpful.
— Additional diagnostic procedures that can be performed
Plasma cortisol samples were taken at midnight while the subject was awake on three separate occasions. A blood cortisol level that is greater than 7.5 g/dL in the evening has a sensitivity of 99% and a specificity of 100%. Cushing syndrome is indicated when serum cortisol levels remain persistently raised; the nadir of serum cortisol levels is maintained in obese patients, but not in Cushing patients.
 Although not a reliable procedure, measuring corticotropin-releasing hormone (CRH) following dexamethasone may be used to differentiate between pseudo-Cushing and Cushing syndrome. 
A referral to an endocrinologist for additional testing is beneficial in determining the origin of Cushing syndrome if it has been determined that the individual does not have pseudo-Cushing or physiologic hypercortisolism.

 Tests to determine localization: After it has been established that the patient has Cushing syndrome: – Morning ACTH levels:
 ACTH-independent Cushing syndrome at a concentration of less than 10 pg/mL
 ACTH-dependent Cushing syndrome at a concentration of more than 20 pg/mL
The CRH stimulation test is advised at concentrations between 10 and 20 pg/mL for distinguishing between the two types.
High-dosage suppression test: an oral dose of 8 milligrams of dexamethasone is administered at 11 o'clock at night, and the cortisol level is measured at 8 o'clock in the morning the following day.
– Before taking dexamethasone for the first time in the morning, a baseline test of cortisol is taken at eight in the morning.
If the blood cortisol level is reduced to less than fifty percent of its baseline value, this is suggestive of a pituitary source of ACTH as opposed to primary adrenal illness or ectopic ACTH. The sensitivity of this test is 95%, while the specificity is 100%.
– Cortisol levels can also be assessed at eight in the morning, following administration of eight milligrams of dexamethasone the night before. Cortisol levels below 5 ng/dL are characteristic of Cushing illness.
Fake cases of Cushing syndrome are quite uncommon. Take into consideration the possibility that the hormonal lab results are discordant with the normal adrenal findings on imaging.
Imaging - It is important to rule out the possibility of adrenal and pituitary incidentalomas before beginning any imaging procedures related to the Cushing syndrome.
Dotatate PET/CT is a high-resolution diagnostic technique that is highly useful in finding cancers overlooked by other means of imaging (2). Its sensitivity is between 90 and 91%, making it one of the most accurate imaging methods available.
In spite of traditional body imaging and other modalities of nuclear imaging such as scintigraphy/SPECT, there is a possibility that up to 19% of ectopic ACTH-secreting tumors will go undetected.
o Octreotide scintigraphy to search for an ACTH-secreting tumor that may be occult
a pituitary MRI scan should be performed on all patients with ACTH-dependent hypercortisolism. a chest CT scan should be performed if there is a suspicion of ectopic ACTH secretion. an abdominal CT scan should be performed if there is a suspicion of adrenal illness.

Warning: Certain medications, including those used to treat epilepsy, progesterone, oral contraceptives, rifampin, and spironolactone, have the potential to provide a false-positive result on a dexamethasone suppression test.
During the initial screening of pregnant women (or women using birth control pills), it is suggested that UFC be administered rather than dexamethasone. Only a UFC that is more than three times the normal upper limit when measured in the second or third trimester raises the possibility of Cushing syndrome.

Diagnostic Methods and Other Procedures

Testing for associated findings, such as thyroid function, type 2 diabetes, and osteoporosis, can be helpful. Other associated findings include: polycystic ovarian syndrome/hyperandrogenism; oligomenorrhea/hypogonadism; hypercoagulable state/venous thromboembolism; metastases from malignant tumors; atrial fibrillation; hypokalemia; growth hormone reduction; and hypercoagulable state/hypercoagulable state.

Management 

After determining what caused the condition, the most effective treatment is a surgical resection of the affected area.

Medication 

 Medical therapy is typically useless for long-term treatment; pituitary irradiation, on the other hand, is utilized either as a preparatory treatment before surgery or as an adjuvant treatment after surgery. Metyrapone, ketoconazole, and mitotane all work by blocking the synthesis and secretion of cortisol in the adrenal gland directly. This has the effect of lowering cortisol levels. The administration of glucocorticoid replacement medication is frequently necessary.

Metyrapone is known for having a quick onset of action, with the lowest of cortisol levels following a single dose occurring within two hours. Mitotane causes a chemical adrenalectomy by inhibiting the enzymes in the adrenal gland that are responsible for steroidogenesis. Because it accumulates in adipose tissue, it has a long half-life. Inhibition of adrenal enzymes by ketoconazole causes cortisol levels to drop to their lowest point in two to three days.
Etomidate administered intravenously works well to reduce cortisol levels immediately in patients with severe Cushing syndrome because it inhibits the manufacture of adrenal corticosteroids.
Mifepristone is a powerful glucocorticoid receptor antagonist, and the Food and Drug Administration (FDA) has given it the green light to treat hyperglycemia in people with endogenous Cushing syndrome who also have type 2 diabetes or glucose intolerance as a result of hypercortisolism and for whom surgery has not been successful (or who are not candidates for surgery).
The use of pasireotide, which is a somatostatin receptor ligand, has been authorized for the treatment of Cushing disease in cases when surgery is either unable to be performed or does not work. One of the most prevalent and important negative side effects is hyperglycemia.

Osilodrostat, which is an inhibitor of CYP11B1 and CYP11B2, can prevent steroidogenesis from occurring. In terms of its ability to inhibit cortisol synthesis, it is on par with metyrapone and more effective than ketoconazole.

Agents that target the pituitary tumor, such as retinoic acid, silibinin (an inhibitor of heat shock protein that is overexpressed in Cushing disease tumors), and roscovitine (an inhibitor of cyclin-dependent kinase), have the potential to be useful in the treatment of Cushing illness.


Procedures Involving Surgery Transsphenoidal surgery:
- Remission rates for the primary treatment of Cushing illness vary from 95 to 90%
— Surgical removal of the ectopic tumor that was generating ACTH
Surgery on the adrenal glands
Surgery is the recommended course of treatment for patients who suffer from hormonally active, unilateral adrenal adenomas. When it comes to cortisol-secreting tumors with minor symptoms, the decision to have surgery is made on an individual basis.
– A bilateral adrenalectomy is typically indicated for patients who have been diagnosed with nodular hyperplasia.
– When treating patients who have Cushing disease, a bilateral laparoscopic adrenalectomy is an option that may be considered if the condition is still present after pituitary surgery and radiotherapy. Replacement of glucocorticoids and mineralocorticoids must be done throughout the rest of the patient's life. Because of the potential for teratogenic effects of other drugs, it is recommended for women of childbearing age. In individuals with unmanageable ACTH-dependent hypercortisolism, synchronous bilateral adrenalectomy is an effective and safe treatment option. If cancer is suspected, further diagnostic investigations and/or adrenalectomy may be necessary.

 Radiotherapy and stereotactic radiosurgery (SRS) is the secondline treatment for persistent hypercortisolism after surgery. Additionally, this treatment modality has become the method of choice for small adenoma tumors in the sellar and parasellar regions.
- Traditional radiation therapy for patients who have big tumors or cancers that are located in close proximity to the optic nerve.
a potential increased risk of hypopituitarism when undergoing radiation therapy.

Continuous Care Education regarding diet and regular weight monitoring, early treatment of illnesses, and the management of emotional lability


In most cases, a chronic course with cyclical exacerbations and only infrequent remissions is anticipated. 
The risk of recurrence for adrenal tumors is twenty percent.
ectopic hormone production and poor prognosis due to small cell carcinoma of the lung.
A fall in cortisol levels after surgery is a predictor of how well the patient will recover.
Some individuals may require supraphysiologic steroid replacement after surgery, which should be weaned off over the course of many months.

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