SUBCLINICAL CUSHING'S SYNDROME

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Classical overt Cushing's syndrome, the consequence of longstanding excess of circulating glucocorticoids, is characterized by typical signs and symptoms of hypercortisolism, such as plethora, a moon face, buffalo hump, and central obesity, easy bruising, deep purple striae, proximal muscle weakness, menstrual irregularities, acne, hirsutism, osteoporosis, and glucose intolerance. Classic Cushing's syndrome is a rare disease with an estimated incidence of 1 case per 500,000 persons.32 With the routine use of imaging techniques such as ultrasound and CT, adrenal masses are being detected with increased frequency.21 A substantial percentage of these incidentally detected adrenal tumors are hormonally active, with as many as 20% of the tumors producing glucocorticoids. Generally, autonomous glucocorticoid production without specific signs and symptoms of Cushing's syndrome is termed subclinical or preclinical Cushing's syndrome. It is assumed that glucocorticoid production in these patients is insufficient to cause a clinically recognizable syndrome. Preclinical or subclinical Cushing's syndrome was first described by Charbonnel and co-workers11 in 1981 and has become the focus of a steadily increasing number of studies.* The terms preclinical and subclinical Cushing's syndrome have often been used interchangeably in the literature; however, subclinical Cushing's syndrome relates to a biochemical abnormality that most likely will not become clinically manifest, whereas preclinical Cushing's syndrome implicates a general progression to overt Cushing's syndrome. Long-term prospective studies evaluating the outcome of patients with this condition are lacking. The progression to overt Cushing's syndrome seems to occur in a low percentage of patients5; therefore, the term subclinical Cushing's syndrome better describes the metabolic consequences of this condition and is used throughout this article.

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EPIDEMIOLOGY

The prevalence of classic overt Cushing's syndrome in the general population is not known with certainty.32 Approximately 85% of cases are adrenocorticotropic hormone (ACTH)–dependent, mainly as a result of pituitary-dependent Cushing's syndrome (Cushing's disease). ACTH-independent, adrenal Cushing's syndrome accounts for 15% of all cases of Cushing's syndrome, with 50% of these cases caused by adrenal adenomas and carcinomas, respectively, whereas bilateral adrenal disease is extremely rare.

CLINICAL PRESENTATION

By definition, no clinical signs or symptoms of Cushing's syndrome should be present in patients with incidentally detected adrenal tumors; however, more detailed questioning and careful second physical examination may reveal subtle evidence of hormone excess (e.g., recent weight gain, skin atrophy, increased facial fullness) (Fig. 1). Arterial hypertension and obesity are significantly more prevalent in patients with incidentally detected adrenal masses than in the general population.

BIOCHEMICAL EVALUATION

The rationale for screening patients with adrenal incidentalomas for the presence of subclinical Cushing's syndrome is twofold. First, early detection of subclinical Cushing's syndrome holds the potential of early prevention of disease. Second, subclinical Cushing's syndrome must be ruled out in every patient with adrenal incidentaloma scheduled for unilateral adrenalectomy because a postoperative adrenal crisis (in some cases, with fatal outcome20, 25 has been reported in patients with

ADRENAL SCINTIGRAPHY

Visualization of the adrenal mass by means of 131I-norcholesterol scintigraphy has been advocated by several groups to screen for subclinical Cushing's syndrome.21 The rationale of this approach is based on the observation that significant glucocorticoid production by the tumor will lead to unilateral tracer uptake, whereas the contralateral adrenal will be scintigraphically silent owing to atrophy. Moreover, adrenal scintigraphy seems to allow a differentiation between benign and malignant

PROSPECTIVE STUDIES AND THERAPEUTIC CONSIDERATIONS

As a general rule, hormonally active incidentally detected adrenal masses are surgically removed to prevent serious morbidity.12, 19, 21, 24, 25, 29, 31 This strategy is undisputed for aldosterone-producing adrenal tumors and pheochromocytoma31; however, it remains doubtful whether patients with subclinical Cushing's syndrome benefit from adrenal surgery because the progression from subclinical disease to overt Cushing's syndrome occurs in a minority of cases. Long-term follow-up studies of

SUMMARY

Classic Cushing's syndrome is a rare disease with an estimated incidence of 1 case per 100,000 persons. With routine use of imaging techniques such as ultrasound and CT, adrenal masses are being detected with increased frequency. A substantial percentage of these incidentalomas are hormonally active, with 5% to 20% of the tumors producing glucocorticoids.

Autonomous glucocorticoid production without specific signs and symptoms of Cushing's syndrome is termed subclinical Cushing's syndrome. With

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    Address reprint requests to Martin Reincke, MD, Medical Department, University of Freiburg, Hugstetter-Strasse 55, D-79106 Freiburg, Germany, e-mail: [email protected]

    *

    Medical Department, University of Freiburg, Freiburg, Germany

    *

    References 1, 2, 5, 6, 7, 8, 10, 12, 13, 16, 19, 20, 24, 25, 26, 27, 29, 30, 31, and 34, 35, 36, 37.

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