Cushing’s disease/Cushing syndrome


Hypercortisolism leading to obesity, diabetes, hypertension, hypogonadism, proximal muscle weakness and emotional lability.

Cushing syndrome results from prolonged elevated plasma cortisol levels due to either exogenous steroid use, or to excess endogenous cortisol production.

The most common cause of Cushing’s syndrome is exogenous glucocorticoid use from any administration route, including topical, or inhaled glucocorticoids.

Among patients with Cushing’s syndrome from excess endogenous production of cortisol, Cushing’s disease is the underlying cause in approximately 60 to 70% of patients, independent adrenal production of cortisol in 20 to 30% of patients, and ectopic paraneoplastic neuroendocrine tumors that secrete corticotropin, are the underlying cause in about 6 to 10% of patients.

Unilateral, adrenal adenoma, or carcinoma and bilateral micronodular or macro nodular adrenal hyperplasia are the most common causes of Cushing’s syndrome due to corticotropin independent, adrenal gland production of cortisol.

Endogenous pathological hypercortisolism incidents ranges from about 2 to 3 per million people to eight per million people annually.

The most common cause of endogenous Cushing syndrome is Cushing’s disease in which a benign pituitary adenoma oversecretes corticotropin.

Cushing disease is caused by corticotropin secreting pituitary adenoma is the typically benign and arise from an expansion of corticotroph cells in the anterior pituitary gland.

Patients with corticotropinomas present with Cushing disease, characterized by central adiposity, facial rounding, plethora in 72 to 90% of cases, hypertension in 60% of cases, dyslipidemia in 70% of cases, diabetes in 40%, hypogonadism in 75%, proximal muscle weakness in 60% of cases, reddish, purple striae, osteoporosis 60% of cases, and nephrolithiasis 20 to 50% of cases.

Cognitive dysfunction and psychiatric manifestations, such as anxiety, depression, insomnia, and psychosis occur in approximately 50% of patients.

Patients with Cushing’s disease have recurrent infections, edema, acne, alopecia, hypokalemia and decreased linear growth in children, commonly.

Approximately 90% of microadenomas are less than 10 mm in diameter.

Macroadenomas 10 mm or greater account for 10% of corticotroph adenomas.

Cushing syndrome from excess endogenous cortisol production may also be caused by a benign or malignant adrenal tumor that secretes cortisol or by a benign or malignant non-pituitary corticotropin secreting tumor.

Less than 1% of people with Cushing’s syndrome have a tumor that secretes corticotropin releasing hormone.

Elevated cortisol causes: hyperglycemia, abnormal protein catabolism, immunosuppression, neurocognitive changes, bone disorders, such as osteoporosis, and mood disorders, such as depression.

Weight gain, hypertension, and hypokalemia are  non-specific features of Cushing syndrome.

Easy, bruising, purple striae and facial plethora, arebcommon features that are more specific to Cushing syndrome.

Because many of the symptoms of Cushing syndrome are nonspecific diagnosis of Cushing syndrome may take 3 years and for Cushing disease even longer.

Pituitary and adrenal adenomas that cause endogenous Cushing syndrome affect women approximately 3 to 4 times more commonly than men.

ACTH values greater than 15 to 20 pg/mL are consistent with ACTH-dependent Cushing’s syndrome.

Pituitary MRI with gadolinium should be performed in all patients with ACTH-dependent Cushing’s syndrome.

Cushing’s disease due to pituitary macroadenoma is uncommon and accounts for fewer than 4% to 10% of cases.

Corticotropin secreting corticotroph adenomas account for up to 15% of pituitary tumors with an incidence of 1.6 cases per 1 million persons and are typically small, approximately 6 mm in diameter and are 5 to 10 times as common in women as in men.

Most cases of Cushing’s disease are the result of microadenomas, particularly tumors smaller than 6 mm, which are difficult to identify on imaging studies.

Corticotroph adenomas account for approximately 70% of cases of Cushing’s syndrome with iatrogenic hypercortisolism, ectopic corticotropin or corticotropin releasing hormone production and cortisol producing adrenal lesions accounting for the rest.

Adrenal sources of Cushing syndrome include unilateral, cortisol, producing adenomas, which are benign and originate in the Zona, fasciculata of the adrenal cortex.

When clinical, biochemical, and radiologic studies are discordant or equivocal, bilateral inferior petrosal sinus sampling should be performed. To increase diagnostic acumen.

Cushing’s syndrome due to endogenous cortisol hyperproduction is very rare, and overlapping clinically with more common diseases such as diabetes, obesity, and polycystic ovarian syndrome.

Because Cushing’s syndrome is potentially curable, the diagnosis should be pursued in all patients whose clinical course suggests endogenous hypercortisolism.

Associated with poor quality of life, mobility, increased mortality.

Clinical presentation varies, in part, related to the extent in duration of cortisol excess.

Clinical and laboratory features overlap with many other medical processes, and very few patients have classic presentation of moon facies, weight gain, dorsocervical pads, purple striae, hirsutism, acne, thin skin, fragility fractures, muscle weakness, and hypertension.

Proximal muscle weakness, increased fat in the abdomen, torso and face and wide purple striae suggest marked hypercortisolism.

Facial fullness, increase in dorsocervical fat pad and striae may be absent in the ectopic corticotropin syndrome since these changes take weeks to months to develop because the syndrome may develop too rapidly.

Patients often referred to a dermatologist for red facial skin, poor wound healing, and striae.

Majority of patients have abnormal glucose tolerance.

Patients present with depression, psychosis, and susceptibility to infections.

Edema and hypokalemic alkylosis occur in the minority of cases.

Approximately 70% of patients present with hypokalemia in ectopic corticotropin syndrome and is related to the degree of hypercortisolemia present.

Results from prolonged and inappropriate exposure to elevated levels of circulating free glucocorticoids.

Most common causes are from use of excessive exogenous glucocorticoids including oral, parenteral, topical or inhaled corticosteroids.

Patients with obesity, metabolic syndrome, polycystic ovary syndrome, uncontrolled diabetes, and eating disorders, such as anorexia nervosa may have mild increases in plasma cortisol.

These conditions increase hypothalamic corticotropin releasing hormone secretion, which stimulates pituitary corticotropin secretion and adrenal cortical cortisol secretion resulting in pseudoCushing syndrome.

An elevated plasma, cortisol level alone is insufficient to diagnose Cushing syndrome.

The disorder may be indolent or clinically florid, with a high mortality rate if inadequately managed.

Patients with poorly controlled disease have a five-fold excess mortality.

In a study involving 502 patients, the overall mortality ratio was 2.5 with 133 observed deaths versus 54 expected deaths with cardiovascular disease accounting for most of the excess deaths.

Incidence 0.7-2.4 per million population per year.

Incidence in obese patients with type II diabetes is higher at 2-5% range.

More common in women than men.

Divided into corticotropin dependent and corticotropin independent types.

Corticotropin dependent types: Cushing’s disease, Ectopic corticotropin syndrome, Unknown source of corticotropin.

Corticotropin secretion from the pituitary causing Cushing’s disease accounts for approximately 70% of endogenous cases, while adrenal tumors and ectopic production of corticotropin each account for approximately 15% of cases (Nieman LK).

Cushing’s disease refers to hypercortisolism due to a corticotropin secreting pituitary tumor.

Corticotropin independent types: Adrenal adenoma, Adrenal carcinoma, Macronodular hyperplasia, Primary pigmented nodular adrenal disease, McCune Albright syndrome.

Confirmation of the diagnosis requires demonstration of hypercortiolism, with measurement of 24 hour urinary cortisol excretion, or measurement of midnight salivary cortisol levels, or both.

Diagnosis can be challenging as approximately 40% of corticotropin secreting corticotroph tumors are not visible on imaging and at least 10% of persons in the general population have small, clinically silent microadenomas.

CD may be over diagnosed, especially since clinical features of hypercortisolism may overlap with more common disorders including obesity, hypertension, glucose intolerance, and osteoporosis.

Mortality increased in Cushing’s syndrome, especially in the pituitary form.

The diagnosis is established on the basis of clinical features of hypercortisolism coupled with reproducible evidence of failure to suppress plasma cortisol at a.m. 8 AM to a level below one point micrograms per deciliter after the administration of 1 mg of dexamethasone at 11 PM, with elevated 24 hour urinary free cortisol levels and midnight salivary cortisol values.

Basal corticotropin levels are usually inappropriately high and suppress ability of corticotropin by glucocorticoids may distinguish a pituitary tumor from an ectopic source.

The 1 mg dexamethasone suppression test can demonstrate the autonomous production of cortisol.

A corticotropin level of more than 20 pg per milliliter with hypercortisolism suggests corticotropin dependency, and a level below five pg per milliliter suggests an adrenal source.

MRI of the brain can identify pituitary tumors approximately 60% of the time when corticotropin dependency is established.

Venous sampling from the inferior petrosal sinus can differentiate between Cushing’s disease and ectopic production of corticotropin:-Cushing’s disease is the most likely diagnosis if the sinus-to-peripheral vein ratio of plasma corticotropin is at least 2:1 before or at least 3:1 after injection of corticotropin-releasing hormone during sampling from the inferior petrosal sinus.

When CD develops in an accelerated pattern adrenocortical cancer is a consideration while adrenal hyperplasia and nodular adrenocortical disease associated disease is more gradual in onset.

Ectopic production of corticotropin is suggested if 8 mg of dexamethasone does not suppress the plasma cortisol level.

Ectopic Cushing syndrome is predominantly, caused by lung, mediastinal, pancreas, and medullary thyroid neuroendocrine tumors that secrete corticotropin.

The source of the neuroendocrine tumor is undetected a presentation in approximately 80 to 90% of patients, and may remain so for years.

Treatment is transsphenoidal microsurgery of the pituitary adenoma.

Transsphenoidal surgery is a primary therapy for pituitary adenoma with a remission rates of 65-90%.

More radical surgery office the potential for total adenoma resection, but complication rates are higher and pituitary damage is more likely with total resection.

Relapse rates from transsphenoidal surgery occurs in up to 30% of patients.

Success rate for pituitary adenomas is 90%, 65% for macroadenomas and 38% for recurrent or persistent disease.

Gamma knife radiation to the pituitary gland is effective in 63% to 83% of patients.

Radiotherapy may control the disease, but efficacy is delayed for several years and approximately 30% of patients have a relapse.

Failure of transphenoidal surgery secondary to macroadenoma or hyperplasia can lead to reoperation, use of adrenolytic medical agents, radiation therapy to the pituitary gland or adrenalectomy.

Radiation therapy is administered by delivering photons or protons to the pituitary tumor.

Radiation can be delivered in a single fraction for smaller tumors that are far from the optic chasm.

Radiation therapy is second or third line therapy in patients with pituitary adenomas that occur after surgery.

Bilateral laparoscopic adrenalectomy preferred treatment in patients who fail transphenoidal pituitary surgery.

Adrenalectomy may immediately reverse hypercortisolism: lifelong replacement of adrenal hormones is challenging.

Adrenalectomy patients are at risk for adrenal crisis and Nelson’s syndrome.

Adrenal targeted medical therapy may provide clinical improvements.

Adrenal steroidogenesis inhibitors block hypercortisolemia but do not target the pituitary tumor.

Ketocanazole is an antifungal agent that normalizes urinary free cortisol levels in 50% of patients.

Natural history of untreated disease is a 5-year mortality of 50%.

Cancer associated Cushing’s synfrome usually develops rapidly and is associated with extreme elevations of corticotropin and severe hypercortisolemia.

Medical management for hypercortisolemia includes use of metyrapone and ketocanazole.

Corticotroph adenomas express somatostatin receptors, predominantly subtype 5, and activation of this subtype inhibits corticotropin secretion.

Pasireotide is a somatostatin analogue that targets 4 of 5 somatstatin receptors, with the highest affinity for subtype 5.

Pasireotide significantly decreases cortosol levels in patients with Cushing’s disease from pituitary corticotropin secreting pituitary adenomas (Colao A et al).

Pasireotide (Signifor) is approved for Cushing’s Disease, and is an injection for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.

The approval is based on data from PASPORT-CUSHINGS, a large randomized Phase 3 study evaluating medical treatment in patients with Cushing’s disease: found that a decrease in mean urinary-free cortisol, the key measure of biochemical control of the disease, was sustained during the treatment period in most patients with a subset of patients reaching normal levels, and that certain clinical manifestations of Cushing’s disease tended to improve.

Injections are available in 0.3mg/mL, 0.6mg/mL, and 0.9mg/mL dosage strengths.

Metyrapone controls urinary free cortisol levels in about 50% of patients, and accumulated steroid precursors may cause acne, hirsutism, hypertension, and hypokalemia.

Mitotane, is it adrenolytic agent and used mainly for adrenal carcinoma.

Mifespristone is a glucocorticoid receptor antagonist approved for the treatment of hyperglycemia associated with Cushing’s disease in patients in whom surgery has failed who are not surgical candidate.

Mifepristone blocks the action of cortisol, corticotropin,and urinary free cortisol levels are increased: adrenal failure, hypokalemia an excessive vaginal bleeding limit its use.

Patients with Cushing’s disease in long-term remission have elevated risks of stroke, venous thromboembolism,  sepsis and increased all cause mortality when compare with the general population, as well as increased cardiovascular mortality.

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