Are You Confident of the Diagnosis?
What you should be alert for in the history
Cushing’s syndrome results from prolonged exposure to glucocorticoid excess and includes a wide variety of signs and symptoms. Depending on the duration and degree of glucocorticoid excess, the clinical manifestations may range from mild to florid.
Common symptoms or complaints include weight gain, muscle weakness, particularly proximally, easy bruising, excess hair (hirsutism), acne, stretch marks, and irregular menses. Less commonly patients may complain of headaches, increased skin pigmentation, and abdominal pain. If Cushing’s is suspected, one should inquire about polyuria, polydypsia, back pain or history of fractures, and exposure to exogenous glucocorticoids.
Characteristic findings on physical examination
On physical examination, the most common feature is central obesity, typically involving the face, neck (Figure 1), upper back otherwise known as a “buffalo hump” or dorsocervical fat pad, and finally in the supraclavicular fossae. Rarely exophthalmos may result from retroorbital fat deposition in roughly 5% of patients.
Multiple dermatologic manifestations occur including skin atrophy with loss of subcutaneous fat and connective tissue, resulting in fragility, easy bruisability, and poor wound healing. Thick purple striae, greater than 1cm in diameter, are characteristic of Cushing’s syndrome (Figure 2). As the fragile skin is stretched, the venous blood of the dermis becomes apparent and imparts the reddish-purple hue. Most commonly, striae are present on the abdomen and lower flanks, but they also may be seen on the breasts, upper thighs and arms, buttocks, hips and shoulders. While striae may be present in up to 70% of Cushing’s syndrome patients, hyperpigmentation is rare (less than 16% of patients).
As hyperpigmentation is the result of increased adrenocorticotropic hormone (ACTH) that is capable of binding to melanocyte-stimulating hormone receptors, it occurs only in those patients with the ectopic ACTH syndrome or less often in those with Cushing’s disease (pituitary overproduction of ACTH). Though the hyperpigmentation is generalized in some cases, it tends to be more prominent in light-exposed areas including face, neck, and back of hands, or areas subject to pressure or friction like elbows, knees, and waist. Acanthosis nigricans, due to insulin resistance, may be appreciated in the axillae and on the back of the neck. Cutaneous fungal infections such as tinea versicolor or onychomycosis may also be present.
Since the adrenal glands are the major source of androgens in women, they may demonstrate signs of androgen excess including hirsutism, primarily limited to the face, oily facial skin or acne, and thinning of scalp hair. Virilization, which manifests with voice deepening, a male body habitus and escutcheon, clitoral hypertrophy, and temporal balding is extremely rare in Cushing’s syndrome and is limited to those cases that are due to an adrenal carcinoma.
Other physical examination findings in Cushing’s syndrome include facial plethora and proximal muscle weakness and wasting. Several coexisting conditions including osteoporosis, accompanied by pathologic fractures, glucose intolerance, hypertension,and psychiatric illness are common in this population. An increased frequency of infections and thromboembolic events has also been reported.
Expected results of diagnostic studies
Once Cushing’s syndrome is suspected based upon history and physical examination and use of excess exogenous glucocorticoids excluded, initial biochemical testing should be done. Acceptable screening modalities include 24-hour urine collection for free cortisol, late-night salivary cortisol measurement, and overnight dexamethasone suppression testing. At least two measurements of urine or salivary cortisol should be obtained since the hypercortisolism may be variable. A 24-hour urinary cortisol excretion greater than 3 times the upper limit of normal is considered abnormal.
Interpretation of the late night salivary cortisol measurement depends upon assay-specific and age-specific normative values. Two options for dexamethasone suppression testing are available: the 1mg overnight test and the 2-day 2mg test. For the former, 1mg dexamethasone is administered at 2300h and serum cortisol is measured at 0800h the following morning. In the 2-day 2mg test, dexamethasone is administered in 0.5mg doses every 6 hours for 48 hours and the serum cortisol level is measured 6 hours after the last dose of dexamethasone. For both dexamethasone suppression tests, a serum cortisol greater than 1.8mcg/dL is considered an abnormal result.
Under the direction of an endocrinologist, individuals with abnormal results on two different screening tests will require complex additional testing to establish the cause of Cushing’s syndrome. These tests may include measurement of plasma ACTH concentration, high-dose dexamethasone suppression testing, pituitary and/or adrenal gland imaging, and petrosal sinus sampling when indicated.
The differential diagnosis for Cushing’s syndrome includes pseudo-Cushing’s, which encompasses several disorders that may be associated with hypercortisolism and therefore, similar clinical features. Examples of such conditions are severe obesity, chronic alcoholism, and severe major depressive disorder. A careful history can help to identify these conditions, and clinically, most patients with pseudo-Cushing’s will not have the cutaneous or muscular signs of Cushing’s syndrome.
Who is at Risk for Developing this Disease?
Individuals most at risk for developing Cushing’s syndrome are those who undergo prolonged exposure to medically prescribed corticosteroids. The incidence of exogenous Cushing’s increases with increased duration and dosage of glucocorticoid. One study with 799 patients on prednisone greater than 6 months’ duration found Cushingoid features in 2.7%, 4.3%, 15.8%, and 24.6% of patients on no glucocorticoids, less than 5mg prednisone daily, 5 to 7.5mg prednisone, and greater than 7.5mg prednisone respectively. Endogenous Cushing’s syndrome, which excludes the former iatrogenic cases, has a reported incidence of two to three cases per 1 million inhabitants per year in European population-based studies.
What is the Cause of the Disease?
The causes of Cushing’s syndrome are divided into two different groups: ACTH-dependent and ACTH-independent causes. The most common ACTH-dependent cause is Cushing’s disease, which is pituitary hypersecretion of ACTH from a corticotroph microadenoma in most cases. The increased plasma ACTH concentration results in bilateral adrenocortical hyperplasia, which in turn leads to cortisol hypersecretion. Other less common ACTH-dependent causes include ectopic secretion of ACTH by nonpituitary tumors, such as small-cell carcinomas of the lung and pulmonary, thymic, and pancreatic carcinoid tumors and ectopic secretion of corticotropin-releasing hormone (CRH).
Exogenous administration of glucocorticoids is the most common cause of Cushing’s syndrome overall and is the first of the ACTH-independent causes. The next major cause of Cushing’s syndrome in this category is primary hyperfunction of adrenocortical adenomas. The overly efficient adrenal adenoma produces excess cortisol, which in turn suppresses both CRH and ACTH secretion. Less commonly, adrenal carcinomas cause Cushing’s syndrome by the same mechanism; typically these carcinomas also produce adrenal androgens in excess
Very rare ACTH-independent causes include primary pigmented micronodular adrenocortical disease, which occurs in both sporadic and familial (Carney complex) forms, and bilateral ACTH-independent macronodular hyperplasia.
Systemic Implications and Complications
In the mid-20th century, Cushing’s syndrome was reported to have a 5-year survival of only 50%, with vascular and infectious complications causing the majority of deaths. However, since the development of modern-day treatments, one study reports a similar standard mortality ratio to an age-matched population without Cushing’s after cortisol levels were successfully normalized during 1 to 20 years of follow-up. On the other hand, if moderate hypercortisolism persists, studies demonstrate a 3.8- to 5.0-fold increase in standard mortality ratio compared with the general population.
Since Cushing’s syndrome has a propensity to progress and severe hypercortisolism is believed to be associated with worse outcomes, early recognition and treatment is of critical importance.
As previously discussed, many patients with Cushing’s syndrome will have coexistent systemic disorders such as glucose intolerance, hypertension, and osteoporosis. Following normalization of cortisol, glucose intolerance and hypertension will improve, though they may not completely resolve. Osteoporosis typically improves significantly during the 2 years after resolution of hypercortisolemia but may not completely normalize in all patients. Many of the physical symptoms and signs of Cushing’s syndrome gradually disappear over a 12-month period following effective treatment, plus psychiatric symptoms and health-related quality of life also tend to improve. Treatment options are summarized in the Table.
Treatment options are summarized in the Table 1.
|Medical Treatment||Surgical Procedures|
|Adrenal enzyme inhibitors-|
|Transsphenoidal pituitary surgery to excise the corticotroph adenoma|
|Excision of tumor secreting ectopic ACTH or CRH|
|Unilateral or bilateral total adrenalectomy|
Optimal Therapeutic Approach for this Disease
Treatment of Cushing’s syndrome is directed at the primary cause of the syndrome, but the common goal for each therapeutic option is normalization of cortisol.
The mainstay of treatment in iatrogenic Cushing’s is to stop exogenous glucocorticoid therapy; gradual withdrawal is most appropriate to avoid hypothalamic-pituitary adrenal insufficiency from chronic suppression of the endogenous axis.
Transsphenoidal pituitary surgery to remove the corticotroph adenoma is the treatment of choice for Cushing’s disease (pituitary ACTH hypersecretion). When a clearly circumscribed adenoma is not apparent at surgery, subtotal anterior pituitary resection may be performed. In such cases of subtotal hypophysectomy, patients are at high risk for subsequent hypopituitarism. The cure rate after transsphenoidal surgery among experienced neurosurgeons is roughly 70% to 80%.
Patients who do not achieve cure after transsphenoidal surgery for Cushing’s disease may undergo pituitary irradiation, including conventional and stereotactic techniques. Maximum benefit from irradiation may take up to 12 months.
For Cushing’s disease patients with persistent hypercortisolism despite transsphenoidal surgery, bilateral total adrenalectomy is an alternative to pituitary irradiation and is a definitive cure. Patients subsequently require lifelong daily glucocorticoid and mineralocorticoid replacement therapy.
The treatment of choice for the ectopic ACTH and CRH syndromes is surgical excision of the responsible tumor. As a result, the ACTH or CRH source is removed. In cases of metastatic tumor where surgical excision is not an option, medical adrenalectomy (see below) can be implemented.
Cushing’s syndrome due to cortisol hypersecretion by adrenal adenomas or carcinomas should be treated with unilateral adrenalectomy. Unfortunately, carcinomas recur in as many as 50% of cases after adrenalectomy; irradiation, chemotherapy, and medical adrenalectomy can be offered in such cases.
Bilateral adrenalectomy is recommended in most cases of ACTH-independent bilateral adrenal hyperplasia (both micronodular and macronodular). Patients subsequently require lifelong daily glucocorticoid and mineralocorticoid replacement therapy.
Individuals who are not surgical candidates for transsphenoidal pituitary surgery or adrenalectomy or who have persistent hypercortisolemia despite other definitive therapies can be considered for medical adrenalectomy. Multiple medications that inihibt enzymes in the cortisol synthetic pathway are available to achieve this. Mitotane, for example, given at a dose of 2 to 3gm daily, is effective as an adrenolytic. At some point patients receiving mitotane will become hypocortisolemic and therefore require glucocorticoid replacement.
Major side effects associated with mitotane include nausea, vomiting, and anorexia. Among the adrenal enzyme inhibitors, mitotane is first-line; however, alternative medications that can induce medical adrenalectomy are ketoconazole, metyrapone, and etomidate.
The natural progression of hypercortisolism and the significant morbidity/mortality associated with untreated hypercortisolism must be clearly explained to patients and their families. However, it should be emphasized that cortisol normalization can be achieved in the majority of patients through multiple available treatment modalities and is associated with clear reductions in morbidity and mortality.
Patients require close long-term follow-up after treatment aimed at cortisol normalization is completed. Assessment for remission may be done through measurement of 24-hour urine free cortisol, early morning ACTH and cortisol, and performance of a low-dose dexamethasone suppression test. The time intervals for such testing depend upon the mode of treatment used. Additionally, patients who have undergone subtotal hypophysectomy or pituitary irradiation will require periodic hormonal monitoring to detect hypopituitarism.
Unusual Clinical Scenarios to Consider in Patient Management
The vast majority of pituitary tumors responsible for Cushing’s disease are benign adenomas; however, in extremely rare cases a pituitary carcinoma may be the source of excess ACTH secretion. Pituitary carcinomas comprise only 0.1 to 0.2% of all pituitary tumors, and only a subset of these are ACTH-secreting. The prognosis for pituitary carcinomas is extremely poor; most are resistant to treatment and the mean survival is 4 years. Chemotherapy is an option but at best achieves only a temporary remission in a small number of patients.
What is the Evidence?
Biller, B, Grossman, A, Stewart, P, Melmed, S, Bertagna, X, Bertherat, J. “Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement”. J Clin Endocrinol Metab. vol. 93. 2008. pp. 2454-62. (This comprehensive consensus statement represents the collaborative effort of 32 experts in the field and provides a review of the first-line treatment options for Cushing's syndrome, as well as alternatives and options for persistent disease.)
Elamin, M, Murad, M, Mullan, R, Erickson, D, Harris, K, Nadeem, S. “Accuracy of diagnostic tests for Cushing's syndrome: a systematic review and meta-analyses”. J Clin Endocrinolo Metab. vol. 93. 2008. pp. 1553-62. (Meta-analysis of 27 studies that compare the accuracy of available Cushing's syndrome screening tests, including urine free cortisol, dexamethasone suppression test, and midnight cortisol assays. Results revealed similar accuracy for all three screening tests, as well as combined strategies.)
Findling, J, Raff, H. ” Diagnosis and differential diagnosis of Cushing's syndrome”. Endocrinol Metab Clin North Am. vol. 30. 2001. pp. 729-47. (An excellent review of the differential diagnosis and diagnostic process to consider during the work-up for Cushing's syndrome.)
Huscher, D, Thiele, K, Gromnica-Ihle, E, Hein, G, Demary, W, Dreher, R. ” Dose-related patterns of glucocorticoid-induced side effects”. Ann Rheum Dis. vol. 68. 2009. pp. 1119-24. (This study evaluated the frequency of self-reported health issues, including Cushingoid phenotype, associated with long-term (more than 6 months) glucocorticoid use at different doses compared with frequency in patients not on glucocorticoids.)
Newell-Price, J, Bertagna, X, Grossman, A, Nieman, L. ” Cushing's syndrome”. Lancet. vol. 367. 2006. pp. 1605-17. (Outstanding clinical review of the pathogenesis, clinical manifestations, approach to differential diagnosis, and finally management options for Cushing's syndrome.)
Nieman, L, Biller, B, Findling, J, Newell-Price, J, Savage, M, Stewart, P. “The diagnosis of Cushing's syndrome: an endocrine society clinical practice guideline”. J Clin Endocrinol Metab. vol. 93. 2008. pp. 1526-40. (The Endocrine Society's comprehensive evidence-based guideline detailing the stepwise approach necessary to accurately diagnose Cushing's syndrome.)
Orth, D. ” Medical progress: Cushing's syndrome”. N Engl J Med. vol. 332. 1995. pp. 791-803. (An excellent general overview of Cushing's syndrome, including detailed reviews of the pathophysiology, clinical manifestations, diagnostic work-up, and treatment options.)
Swearingen, B, Biller, B, Barker, F, Katznelson, L, Grinspoon, S, Klibanski, A. ” Long-term mortality after transsphenoidal surgery for cushing disease”. Ann Intern Med. vol. 130. 1999. pp. 821-4. (This study reviewed 161 patients with Cushing disease treated with transsphenoidal surgery between 1978-1996 to determine the long-term mortality rate.)
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