Cushing disease is an endocrine disorder characterized by increased adrenocorticotropic hormone (ACTH) production from the anterior pituitary, leading to excess cortisol release from the adrenal glands. Most often, this caused by a pituitary microadenoma (less than 5mm), or as the result of excess production of corticotropin-releasing hormone (CRH) from the hypothalamus. Symptoms include generalized weakness, high blood pressure, diabetes mellitus, menstrual irregularities, or psychiatric changes. Physical manifestations of excess cortisol levels include moon facies, buffalo hump, easy bruising, abdominal striae, obesity, facial plethora, and hirsutism.
A key feature is that many patients with Cushing disease do not present with bitemporal hemianopsia, and the reason is that the majority of lesions are pituitary microadenomas.
Patients with Cushing's disease almost always have a pituitary adenoma, often not evident by imaging. However, rare cases may result from diffuse corticotroph hyperplasia, even in the absence of ectopic secretion of corticotropin-releasing hormone (CRH). The tumors are usually microadenomas (less than 5 mm in size); only about 5 to 10 percent are macroadenomas. Macroadenomas are more likely to produce abnormally high ACTH concentrations when compared to microadenomas (83 versus 45 percent). Several genetic mutations are responsible for these adenomas, the most common mutation is USP8 (ubiquitin specific peptidase 8). These mutations lead to abnormal expression of growth factors, which act with ACTH to increase the level of cortisol.
Cushing disease is the second most common cause of Cushing syndrome, the first cause being the exogenous steroids. The average incidence of new cases is about 2.4 cases per million people per year. This disease often is diagnosed 3 to 6 years after the onset of the illness. The peak incidence of Cushing disease is in women between the ages of 50 and 60 years. The prevalence of hypertension and abnormalities of glucose metabolism are major predictors of morbidity and mortality in untreated cases of the disease. The mortality rate of Cushing disease is estimated to be about 10% to 11%.
The frequency of ACTH production remains the same, but the normal circadian rhythm is lost. The increased plasma ACTH causes bilateral adrenal hyperplasia and consequent increase in the production of cortisol. Therefore, the normal circadian rhythm of cortisol is also lost.
Cortisol functions primarily as a glucocorticoid; however, in high concentrations, cortisol also can exhibit mineralocorticoid activity, leading to hypertension and hypokalemia through the renin-angiotensin-aldosterone system (RAAS). The RAAS hormone system is involved in the regulation of plasma-sodium concentration and arterial blood pressure, which can indirectly lead to hypokalemia.
Histologically, the pituitary adenomas that secrete ACTH are usually basophilic on H&E staining and are strongly positive with periodic acid-Schiff (PAS) staining. The cytoplasm is granular, and the nucleus is large, with a prominent nucleolus and coarse chromatin.
Patients with hypercortisolism present with weight gain (50%), hypertension, easy bruising, striae, acne, flushing, poor wound healing, lower limb edema, fatigue, impaired glucose tolerance, osteoporosis, hyperpigmentation of the skin, mood and memory changes, amenorrhea, hirsutism, decreased sexual drive, or frequent infections. Clinical manifestations vary widely among patients; thus, a high index of clinical suspicion must be maintained to correctly make this diagnosis.
On presentation, more than half of the patients with Cushing disease have a microadenoma with a diameter of less than 5 mm. Of these, only 10% are large enough to cause a mass effect on the cerebral tissue to affect the structure of the sellar region. Therefore, most cases of ACTH-secreting pituitary adenomas are found after suspicion of excess cortisol and androgen production.
Biochemical diagnostic tests to confirm hypercortisolism include salivary and blood serum cortisol testing, 24-hour urinary-free cortisol testing, and low-dose overnight dexamethasone suppression testing. The late-night or midnight salivary cortisol test recently has been gaining support due to its ease of administration. This test measures free-circulating cortisol and has both a sensitivity and specificity of 95% to 98%. The urinary-free cortisol test measures the excess cortisol excreted by the kidneys into the urine. Results that are three times higher than normal cortisol levels, along with another abnormal test, are considered to be attributable to Cushing syndrome. This test needs to be repeated three times to exclude any normal periods of hypercortisolism. The specificity of this test is 81%. The high false-positive rate can be caused by pseudo-Cushingoid states, which include stress, obesity, alcoholism, pregnancy, sleep apnea, polycystic ovary syndrome, familial glucocorticoid resistance, and hyperthyroidism.
The low-dose dexamethasone suppression tests (DSTs) are standard screening tests to differentiate patients with CS of any cause from patients who do not have Cushing Syndrome (CS).
The overnight 1 mg DST consists of administration of 1 mg of dexamethasone at 11 PM to midnight, and measurement of serum cortisol at 8 AM the next morning. A cortisol level of less than 50 nmol/L is considered a normal response.
In 2 mg DST, dexamethasone 0.5 mg is administered by mouth at six-hour intervals for 48 hours. The serum cortisol level is measured 6 hours after the last dose of dexamethasone is given. Similar to 1 mg DST, a cortisol level of less than 50 nmol/L is considered a normal response. The sensitivity and specificity of this test are 100% and 88%, respectively, with a positive predictive value of 92% and a negative predictive value of 89%. The low dose DSTs cannot be used as a sole criterion for the diagnosis of CS. At least one other test should be utilized to establish or exclude the diagnosis. Moreover, drugs that alter the concentration of corticosteroid-binding globulin (CBG) may result in false tests. For instance, oral contraceptive pills and other estrogens can raise CBG, resulting in false-positive DSTs. Hence, they should be discontinued six weeks before performing these tests, or other tests should be performed.
Two or more positive initial screening tests in a patient with a high pretest probability of Cushing disease confirm the biochemical diagnosis of Cushing syndrome. Once Cushing syndrome has been diagnosed, the first step toward finding the cause is by measuring a baseline plasma ACTH level. A level consistently greater than 3.3 pmol/L is classified as corticotropin-dependent. To differentiate Cushing disease from ectopic corticotropin syndrome, a corticotropin-releasing hormone (CRH) test is needed. In a patient with Cushing disease, the administered CRH stimulates the release of additional corticotropin, resulting in an elevated plasma corticotropin level. The sensitivity of the CRH test for detecting Cushing disease is 93% when plasma levels are measured at fifteen and thirty minutes. Alternatively, a high-dose 48-hour dexamethasone suppression test or pituitary magnetic resonance imaging (MRI) can be used.
For high-dose 48-hour dexamethasone suppression testing, a plasma cortisol level above 50 nmol/L (measured 48-hours after either administration of dexamethasone 2 mg by mouth every 6 hours for 48 hours, or 48-hours after one dose of 8 mg is given) is indicative of Cushing disease. This test has an 8% false-negative rate.
Pituitary MRI may show the ACTH secreting tumor if present. However, MRI fails to detect a tumor in 40% of patients with Cushing disease. The average size of the tumor that was detected on MRI was about 6 mm.
The most accurate test used to differentiate a pituitary adenoma from ectopic or adrenal Cushing syndrome is inferior petrosal sinus sampling. This invasive method measures the difference in the level of ACTH found in the inferior petrosal sinus (where the pituitary gland drains) as compared to the periphery. A basal central to peripheral ratio of over 3:1 when CRH is administered confirms the diagnosis of Cushing disease. This test is considered the gold standard in diagnosing Cushing disease because it has a sensitivity and specificity of nearly 94%. Still, it is rarely used in clinical practice due to its high cost, invasiveness, rare but serious complications, and required expertise to administer.
If a primary ACTH secreting tumor is found, first-line treatment is surgical resection of the adenoma via trans-sphenoidal surgery (TSS). This can either be conducted via an endonasal or sublabial approach, depending on surgeon preferences. The probability of successful resection is higher in patients when the tumor can be identified during the initial surgery. Overall, remission rates after TSS are in the range of 65% to 90% for microadenomas and less than 65% for macroadenomas. Patients with persistent disease after initial surgery frequently undergo repeat pituitary surgery despite a lower success rate and increased risk for pituitary insufficiency. The most common complications of this procedure include diabetes insipidus (15%), fluid and electrolyte abnormalities (12.5%), and neurological deficits (5.6%). Patients over age 64 have a higher incidence of adverse outcomes.
Alternatively, pituitary radiation therapy can be used after an unsuccessful TSS. External-beam pituitary radiotherapy is most effective in pediatric patients, with cure rates in this population as high as 80% to 88%. The most common complication from this treatment is hypopituitarism, causing growth hormone deficiency. This complication has been reported in 36% to 68% of patients.
Lastly, bilateral adrenalectomy can be used to provide an immediate reduction of cortisol levels in patients with Cushing disease. However, these patients will then require lifelong administration of glucocorticoid and mineralocorticoid replacement therapy. A major complication of this treatment is Nelson syndrome, which is the development of ACTH secreting macroadenomas post-bilateral adrenalectomy. The incidence is between 8% to 29% and is diagnosed with an average of 15 years post-bilateral adrenalectomy.
Post-treatment testing with 24-hour urine and blood samples are used to detect the level of cortisol. The disappearance of the response to the desmopressin test after surgery may suggest complete removal of the tumor and, therefore, a lower possibility of recurrence. Recurrence of hypercortisolemia occurs in about a third of patients after initial treatment of Cushing disease. Therefore, lifelong monitoring is required. Late-night salivary cortisol appears to be the best predictor of recurrence.
The differential diagnosis for Cushing disease includes Cushing syndrome, ectopic ACTH secretion, exogenous corticosteroid use, pseudo-Cushing syndrome or physiological hypercortisolism.
Without treatment, Cushing disease is ultimately fatal. The mortality is due to the excess production of glucocorticoids, which can lead to many medical problems, including impairment in immune function. For patients who undergo surgery, life long treatment with glucocorticoids is necessary.
Medical therapy has been gaining popularity in the treatment of pituitary tumors quite recently. Although surgery is still considered the first-line treatment, pharmacological therapy can be used to control the associated hormonal imbalances. These medical therapies either target the central inhibition of ACTH secretion, adrenal inhibition of steroidogenesis, or glucocorticoid-receptor blockade. Centrally acting agents include pasireotide and cabergoline. Adrenal steroidogenesis inhibitors include ketoconazole, metyrapone, etomidate, mitotane, and osilodrostat. Lastly, mifepristone can be used as a glucocorticoid-receptor blocker. Currently, although regulatory authorities have approved several pharmaceutical treatments, their use remains limited due to high cost and associated side effects.
Cushing disease is a rare pituitary gland disorder that is best managed by an interprofessional team that includes a neurosurgeon, radiation consultant, endocrinologist, radiologist, primary care provider, nurse practitioner, and an internist. These patients are prone to several complications, including peptic ulcer disease, weight gain, osteoporosis, diabetes, depressed immune system, and hypertension. Hence they have to be closely monitored.
Large pituitary lesions usually require resection, but small lesions may be treated with medications. These patients need life long follow up with regular monitoring of cortisol levels. Recurrence of disease is not uncommon and too much or too little cortisol can be life-threatening. The pharmacist must emphasize to the patient the importance of medication compliance. In addition, the patient must be urged to wear a Medical Alert bracelet that can inform other clinicians about their health status. Patients need life long follow up. Close communication between the clinicians is vital to prevent complications and improve outcomes.
The prognosis for most patients is somewhat guarded. (Level V)
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