Pitfalls in the Diagnosis and Management of Cushing's Syndrome

Vivek Bansal, MD; Nadine El Asmar, MD; Warren R. Selman, MD; Baha M. Arafah, MD


Neurosurg Focus. 2015;38(2):e4 

In This Article

Abstract and Introduction


Despite many recent advances, the management of patients with Cushing's disease continues to be challenging. Cushing's syndrome is a complex metabolic disorder that is a result of excess glucocorticoids. Excluding the exogenous causes, adrenocorticotropic hormone–secreting pituitary adenomas account for nearly 70% of all cases of Cushing's syndrome. The suspicion, diagnosis, and differential diagnosis require a logical systematic approach with attention paid to key details at each investigational step. A diagnosis of endogenous Cushing's syndrome is usually suspected in patients with clinical symptoms and confirmed by using multiple biochemical tests. Each of the biochemical tests used to establish the diagnosis has limitations that need to be considered for proper interpretation. Although some tests determine the total daily urinary excretion of cortisol, many others rely on measurements of serum cortisol at baseline and after stimulation (e.g., after corticotropin-releasing hormone) or suppression (e.g., dexamethasone) with agents that influence the hypothalamic-pituitary-adrenal axis. Other tests (e.g., measurements of late-night salivary cortisol concentration) rely on alterations in the diurnal rhythm of cortisol secretion. Because more than 90% of the cortisol in the circulation is protein bound, any alteration in the binding proteins (transcortin and albumin) will automatically influence the measured level and confound the interpretation of stimulation and suppression data, which are the basis for establishing the diagnosis of Cushing's syndrome. Although measuring late-night salivary cortisol seems to be an excellent initial test for hypercortisolism, it may be confounded by poor sampling methods and contamination. Measurements of 24-hour urinary free-cortisol excretion could be misleading in the presence of some pathological and physiological conditions. Dexamethasone suppression tests can be affected by illnesses that alter the absorption of the drug (e.g., malabsorption, celiac disease) and by the concurrent use of medications that interfere with its metabolism (e.g., inducers and inhibitors of the P450 enzyme system). In this review, the authors aim to review the pitfalls commonly encountered in the workup of patients suspected to have hypercortisolism. The optimal diagnosis and therapy for patients with Cushing's disease require the thorough and close coordination and involvement of all members of the management team.


Cushing's syndrome refers to a state of hypercortisolism (endogenous or exogenous) regardless of its etiology. Cushing's disease defines a state of hypercortisolism caused by an adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma. These tumors represent approximately 10%–12% of all pituitary adenomas and are seen predominantly in women, with a female-tomale ratio of 8:1 and a peak incidence in the 3rd to 4th decades of life. ACTH-secreting pituitary adenomas represent the most common cause of endogenous hypercortisolism, accounting for nearly 70% of all cases of Cushing's syndrome.[5] Whereas most of these tumors are generally benign, some are more invasive than other pituitary adenomas. Although most patients with ACTH-secreting adenomas present with small tumors that may not even be evident on MRI, some have invasive macroadenomas. In addition to signs and symptoms of hypercortisolism, the clinical manifestations in these patients include signs of mechanical effects of the macroadenoma on surrounding structures. Such effects include headaches, visual symptoms, and impairment of normal pituitary function.[5]

Even though the clinical, biochemical, and imaging characteristics of patients with Cushing's disease have been well appreciated for decades, the diagnosis and management of this disease are often challenging.[10,20,36] Patients with Cushing's disease exhibit an increased mortality rate and increased morbidity secondary to chronic hypercortisolism.[44] Deleterious effects of hypercortisolism include hypertension, obesity, osteoporosis, fractures, impaired immune function and wound healing, and glucose intolerance and diabetes.[5,6,36,44] The high morbidity and mortality rates in those with this disease make it imperative to optimize the management of such patients.

Although patients with various illnesses may have cushingoid features, some features that should raise concern for true Cushing's syndrome include proximal muscle weakness, multiple ecchymosis, prominent supraclavicular fat pads, violaceous striae, hypokalemia, unexplained osteoporosis, new-onset hypertension, and diabetes mellitus.[10,44] These clinical manifestations are observed in most patients with hypercortisolism. The known common causes of hypercortisolism are listed in Table 1, with the most common being oral, intraarticular, intramuscular, inhalational, or topical administration of exogenous glucocorticoids used for the treatment of various illnesses.

Once the diagnosis of Cushing's syndrome is clinically suspected, it should be confirmed or satisfactorily ruled out because of its association with increased risks of morbidity and mortality. The following 3 approaches are used to screen for hypercortisolism: assessment of cortisol secretion in a 24-hour period, documentation of the loss of normal diurnal variation in cortisol secretion (late-night salivary cortisol), and documentation of a loss of feedback inhibition of cortisol on the hypothalamic-pituitary-adrenal (HPA) axis (dexamethasone suppression testing). It is not unusual to require multiple tests to make the diagnosis. In this article, we review the pitfalls encountered in establishing the diagnosis of hypercortisolism in general and that of Cushing's disease in particular and emphasize the limitations in interpreting the tests and biochemical and imaging studies commonly used.