Continuing Education Activity

Cushing disease is an endocrine disorder characterized by excessive adrenocorticotropic hormone (ACTH) production by the anterior pituitary, which leads to the release of an excess of cortisol from the adrenal glands. This activity explains the evaluation and treatment of Cushing disease and the role of the interprofessional team in managing patients with this condition.

Objectives:

• Identify the etiology of Cushing disease.

• Assess the actions of ACTH in the pathophysiology of Cushing disease.

• Evaluate the physical exam findings associated with Cushing disease.

• Communicate some interprofessional team strategies that can improve increase collaborative care and improve patient outcomes.

Introduction

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.[1] A pituitary adenoma often causes this, or it results from excess production of corticotropin-releasing hormone (CRH) from the hypothalamus.[2] Symptoms of the disease include generalized weakness, high blood pressure, diabetes mellitus, menstrual irregularities, or psychiatric changes.[1] Physical manifestations of excess cortisol levels include moon facies, buffalo hump, easy bruising, abdominal striae, obesity, facial plethora, and hirsutism (see Image. Cushing Syndrome).[2] A key feature is that many patients with Cushing disease do not present with bitemporal hemianopsia because most lesions are pituitary microadenomas (less than 10mm in size).

Etiology

Patients with Cushing disease almost always have a pituitary adenoma, often not evident by imaging. However, rare cases may result from diffuse corticotroph cell hyperplasia, even without ectopic secretion of CRH. The tumors are usually microadenomas (less than 10 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).[3][4] Several genetic mutations are responsible for these adenomas.[5] 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 cortisol levels.[6]

Epidemiology

Cushing disease is the second most commonly seen cause of Cushing syndrome, the first cause being the exogenous use of steroids. The average incidence of new cases is about 2.4 per million people annually.[2] This disease is often diagnosed 3 to 6 years after the onset of the illness. The peak incidence of Cushing disease is in women between 50 and 60 years old.[2] The prevalence of hypertension and the abnormalities of glucose metabolism are major predictors of morbidity and mortality in untreated cases of the disease.[2] The mortality rate of Cushing disease is estimated to be about 10% to 11%.[2]

Pathophysiology

In Cushing disease, the frequency of ACTH production remains the same, but the normal circadian rhythm is lost. The increased plasma ACTH causes bilateral adrenal hyperplasia and a consequent increase in the production of cortisol. Therefore, the normal circadian rhythm of cortisol is also lost.[7] Cortisol functions primarily as a glucocorticoid; however, in high concentrations, cortisol can also exhibit mineralocorticoid activity, leading to hypertension and hypokalemia through the renin-angiotensin-aldosterone system.[1] The renin-angiotensin-aldosterone system hormone system regulates plasma sodium concentrations as well as arterial blood pressure, which can indirectly lead to hypokalemia.[1]

Histopathology

Histologically, the pituitary adenomas that secrete ACTH are usually basophilic on hematoxylin and eosin staining and strongly positive with periodic acid-Schiff staining. The cytoplasm is granular, and the nucleus is large, with a prominent nucleolus and coarse chromatin.

History and Physical

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 diagnose this correctly.[8] See Image. The Hypothalamic-Pituitary-Adrenal Axis. Although uncommon, large pituitary tumors (macroadenomas) can also present with mass effects on surrounding structures.[8] These cases may present with decreased peripheral vision or headaches.[9]

Evaluation

On presentation, more than half of the patients with Cushing disease have a microadenoma with a diameter of less than 5 mm.[10] Of these, only 10% are large enough to cause a mass effect on the cerebral tissue to affect the structure of the sellar region.[10] Therefore, most cases of ACTH-secreting pituitary adenomas are found after suspicion of excess cortisol and androgen production.[11] 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.[12][13] Late-night or midnight salivary cortisol tests have recently gained support due to their ease of administration.[14] This test measures free-circulating cortisol with a sensitivity and specificity of 95% to 98%. The urinary-free cortisol test measures the excess cortisol excreted by the kidneys into the urine.[15] Results three times higher than normal free cortisol levels and another abnormal test are attributable to Cushing syndrome.[15] This test must be repeated three times to exclude any normal periods of hypercortisolism. The specificity of this test is 81%. Pseudo-Cushingoid states, including stress, obesity, alcoholism, depression, pregnancy, sleep apnea, polycystic ovary syndrome, familial glucocorticoid resistance, and hyperthyroidism, can cause a high false-positive rate.[12]

The low-dose dexamethasone, 1 or 2mg, suppression tests (DSTs) are standard screening tests to differentiate patients with CS of any cause from patients who do not have Cushing Syndrome (CS).[16] The overnight 1 mg DST consists of administering 1 mg of dexamethasone from 11 PM to midnight and measuring the serum cortisol at 8 AM the next morning. A cortisol level of less than 1.8 mcg/dL (or 50 nmol/L) is considered a normal response.[16] 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. Like 1 mg DST, a cortisol level of less than 1.8 mcg/dL is a normal response. This test's sensitivity and specificity are 100% and 88%, respectively, with a positive predictive value of 92% and a negative predictive value of 89%.[15] Low-dose DSTs cannot be used as the sole criterion for diagnosing CS. At least one other test should be utilized to establish or exclude the diagnosis. Moreover, drugs that alter corticosteroid-binding globulin concentration may result in false test results. For instance, oral contraceptive pills and other estrogens can raise corticosteroid-binding globulin, resulting in false-positive DSTs. Hence, they should be discontinued six weeks before performing these tests, or other tests should be performed.[16]

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.[12][17] Once Cushing syndrome has been diagnosed, the first step toward finding the cause is measuring a baseline plasma ACTH level.[15] A level consistently greater than 3.3 pmol/L is classified as corticotropin-dependent.[15] A CRH test is needed to differentiate Cushing disease from ectopic corticotropin syndrome.[15] In a patient with Cushing disease, the administered CRH stimulates additional corticotropin release, resulting in an elevated plasma corticotropin level.[15] The sensitivity of the CRH test for detecting Cushing disease is 93% when plasma levels are measured at fifteen and thirty minutes.[15] Alternatively, a high-dose 48-hour dexamethasone suppression test or pituitary magnetic resonance imaging (MRI) can be used.[15]

For the high-dose, 48-hour dexamethasone suppression test, a plasma cortisol level above 1.8 mcg/dL (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.[2] This test has an 8% false-negative rate.[2] A 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 detected on MRI was about 6 mm.[10] Inferior petrosal sinus sampling is The most accurate test to differentiate a pituitary adenoma from ectopic or adrenal Cushing syndrome.[12][18] This invasive method measures the difference in ACTH level found in the inferior petrosal sinus (where the pituitary gland drains) compared to the periphery.[12][18] A basal central, peripheral ratio of over 3:1 when CRH is administered confirms the diagnosis of Cushing disease.[18] 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 the required special expertise to perform.

Treatment / Management

If a primary ACTH-secreting tumor is found, the first-line treatment is surgical resection of the adenoma via trans-sphenoidal surgery (TSS).[15][19] Depending on surgeon preferences, This can be conducted via an endonasal or sublabial approach.[20] The probability of successful resection is higher when the tumor can be identified during the initial surgery. Overall, remission rates after TSS are 65% to 90% for microadenomas and less than 65% for macroadenomas.[15][21] 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%).[20][5] Patients over age 64 have a higher incidence of adverse outcomes.[22]

Alternatively, pituitary radiation therapy can be used after an unsuccessful TSS.[15][23] External-beam pituitary radiotherapy is most effective in pediatric patients, with cure rates as high as 80% to 88% in this population.[24] The most common complication from this treatment is hypopituitarism, causing growth hormone deficiency. This complication has been reported in 36% to 68% of patients.[24] Lastly, bilateral adrenalectomy can be used to provide an immediate reduction of cortisol levels in patients with Cushing disease. However, these patients then require lifelong administration of glucocorticoid and mineralocorticoid replacement therapy.[25] A major complication of this treatment is Nelson syndrome, which is the development of ACTH-secreting macroadenomas post-bilateral adrenalectomy.[2] The incidence is between 8% to 29%, and is diagnosed with an average of 15 years post-bilateral adrenalectomy.[2]

Post-treatment testing with 24-hour urine and blood samples is used to detect the level of cortisol.[15] 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.[26] Recurrence of hypercortisolemia occurs in about a third of patients after initial treatment of Cushing disease.[24][27] Therefore, lifelong monitoring is required.[27] Late-night salivary cortisol appears to be the best predictor of recurrence.[28][29] In recurrent or remnant Cushing disease, pharmacological therapy can control the associated hormonal imbalances.[30] These medical therapies target the central inhibition of ACTH secretion, the adrenal inhibition of steroidogenesis, or the glucocorticoid-receptor blockade. 

Centrally acting agents, including pasireotide and cabergoline, have been shown to control Cushing disease in 35-40% of the cases.[31][32] The pasireotide therapy also helped with tumor volume reductions, with over 40% of patients showing over 20% tumor reduction. The pasireotide use has become much better tolerated and accepted by patients when administered IM once monthly. This medication can cause or worsen hyperglycemia, and it should be used with caution in patients with diabetes who might require adjustment of their antidiabetic medications.[33][34] Cabergoline has also been shown to help Cushing disease patients normalize lab results and shrink tumors. The dosage of the medication needs to be uptitrated and that increases the risk of side effects and complications, like impulse control disorders and heart valve problems.[31][35]

Adrenal steroidogenesis inhibitors include ketoconazole, metyrapone, etomidate, mitotane, and osilodrostat. Ketoconazole, the most commonly prescribed medication for Cushing, has shown lab normalization in over 60% of cases lasting over 24 months. Its use is limited by hepatotoxicity, which presents in 10-20% of the treated patients, but it is easily reversible after reducing the dose or stopping the medication in the majority of those patients.[36][37] Metyrapone use has limited availability through special orders to the manufacturing company, while the etomidate is only used in rare cases where patients are hospitalized and awaiting further treatment. Mitotane is kept for use in persistent Cushing disease, mostly in cases of adrenal cancer. Osilodrostat is the most recently approved treatment for Cushing disease in the US and Europe after studies showed that it was very well tolerated and helped 86% of patients to normalize lab results.[38][39]

Lastly, mifepristone can be used as a glucocorticoid-receptor blocker. It has been shown to normalize several symptoms and signs of Cushing's disease, including hyperglycemia, in over 60% of patients in recent studies. The cortisol levels remain high, so this test cannot be used to monitor its adrenal effect. However, better clinical presentation is needed to diagnose adrenal insufficiency and treat patients with appropriate cortisol replacement therapy. This medication also causes irregular vaginal bleeding in female patients due to the anti-progesterone effect. Close monitoring of other hormone levels, like the thyroid, must also be done regularly.[40][41] Other medications, like retinoic acid and silibinin, have shown some promising results but its use is limited by high cost and side effects, but more studies are conducted and further results are expected in the near future.[11]

Differential Diagnosis

The differential diagnosis for Cushing disease includes Cushing syndrome, ectopic ACTH secretion, exogenous corticosteroid use, pseudo-Cushing syndrome, or physiologic hypercortisolism.[16]

Prognosis

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 cardiovascular problems and impairment in immune function.[42] For patients who undergo surgery, lifelong treatment with glucocorticoids is necessary.[43]

Complications

Complications of untreated Cushing disease include:

• Osteoporosis, which can lead to pathological fractures, often appears in the foot bones and ribs.
• Hypertension
• Type 2 diabetes mellitus
• Infections resulting from an impaired immune response
• Reduced muscle mass
• Depression and other psychological problems

Deterrence and Patient Education

Patients need to understand that often Cushing disease is secondary to another pathophysiology and that they must comply with the treatment regimen for both conditions to help alleviate their disease.

Pearls and Other Issues

Medical therapy has been gaining popularity in the treatment of pituitary tumors quite recently. Although surgery is still considered the first-line treatment, the variety of medications studied in Cushing disease offer further treatment options for patients who are not good surgical candidates or who have remnant disease after surgery.

Enhancing Healthcare Team Outcomes

Cushing disease is a rare pituitary gland disorder best managed by an interprofessional team that includes a neurosurgeon, radiation consultant, endocrinologist, radiologist, primary care provider, nursing staff, internist, and pharmacist. 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. The interprofessional approach drives improved outcomes by connecting aspects of all pathophysiology present with valuable input from all disciplines. Large pituitary lesions usually require resection, but small lesions may be treated with medications. These patients need lifelong 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.[44] The pharmacist must emphasize to the patient the importance of medication compliance. The patient must also be urged to wear a medical alert bracelet to inform other clinicians about their health status. Patients need lifelong follow-up. Close communication between the clinicians is vital to prevent complications and improve outcomes. The prognosis for a lot of patients may be guarded.[45]