Terzolo, M., Pia, A. and Reimondo, G. (2012), Subclinical Cushing’s syndrome: definition and management. Clinical Endocrinology, 76: 12–18. doi: 10.1111/j.1365-2265.2011.04253.x
Subclinical Cushing’s syndrome is an ill-defined endocrine disorder that may be observed in patients bearing an incidentally found adrenal adenoma. The concept of subclinical Cushing’s syndrome stands on the presence of ACTH-independent cortisol secretion by an adrenal adenoma, that is not fully restrained by pituitary feed-back. A hypercortisolemic state of usually minimal intensity may ensue and eventually cause harm to the patients in terms of metabolic and vascular diseases, and bone fractures. However, the natural history of subclinical Cushing’s syndrome remains largely unknown. The present review illustrates the currently used methods to ascertain the presence of subclinical Cushing’s syndrome and the surrounding controversy. The management of subclinical Cushing’s syndrome, that remains a highly debated issue, is also addressed and discussed. Most of the recommendations made in this chapter reflects the view and the clinical experience of the Authors and are not based on solid evidence.
Since the early nineties, the serendipitous detection of clinically inapparent adrenal adenomas has been associated with a state of subtle cortisol excess. First described in case reports, subclinical hypercortisolism was then appreciated as a frequent endocrine disorder, being detected in up to 15–20% of patients with adrenal incidentalomas.1,2 This condition was initially defined as ‘preclinical’ Cushing’s syndrome, but afterward the term ‘subclinical’ entered in use because it does not imply any assumption on the further development of a clinically overt syndrome. The National Institute of Health, State-of-the-Science Conference concluded that a more precise definition should be ‘subclinical autonomous glucocorticoid hypersecretion’ but this never gained widespread acceptance.3 The semantic quarrel underscores the uncertainties about subclinical Cushing’s syndrome that has still been recently labelled as a poorly defined entity.4 In this review, subclinical hypercortisolism and subclinical Cushing’s syndrome will be used synonymously.
Definition of subclinical Cushing’s syndrome
The concept of subclinical hypercortisolism
Subclinical Cushing’s syndrome is a common disorder assuming a frequency of up to 20% in patients harbouring incidentally discovered adrenal adenomas, which are found in approximately 4% of middle-age persons and in more than 10% of elderly population.3,5–7Ascertainment of subclinical Cushing’s syndrome should stand on three criteria: first, the patient bears an adrenal adenoma detected serendipitously without any previous suspect of adrenal disease; second, the patient does not present a clear Cushingoid phenotype; third, the endocrine work-up shows autonomous (ACTH-independent) cortisol secretion.8
As to the first point, the concept of subclinical hypercortisolism may apply also to patients bearing pituitary incidentalomas and patients who are on steroid replacement;8 however, discussion of these conditions is beyond the scope of this review.
The second criterion is elusive depending largely on individual clinical judgment and personal practice. The problem is that Cushing’s syndrome is actually a spectrum of clinical presentations that is hard to categorize, because of a continuous variability from the more severe phenotypes to the milder ones. The less-experienced physician may not recognize (mild) signs of hypercortisolism, such as facial fullness that can be identified only after a careful assessment of the patient’s photographic material. Thus, what is subclinical for a given physician may actually be obvious for another one. The patients with ‘true’ subclinical Cushing’s syndrome should present only clinical features that are less specific for cortisol excess and are of common observation in the context of the metabolic syndrome (i.e. central obesity, hypertension).
The third point suffers from the inadequacy of current tests to detect minimal cortisol excess. Studies may demonstrate that average results of a specific test are able to differentiate patients with adenomas secreting cortisol autonomously from patients with nonfunctioning adenomas. However, there is considerable overlap between the different categories and it is usually difficult to qualify an individual patient, unless his or her results fall in the extreme ends of distribution. In this context, cortisol secretion ranges from nonfunctioning adrenal adenomas, to adenomas producing cortisol in overt excess with a manifest clinical phenotype, with adenomas associated with minimal cortisol excess and subclinical Cushing’s lying between these extremes. Thus, there is no clear dichotomy between normal and abnormal cortisol secretion, and the process of setting thresholds associated with various outcomes is arbitrary, being related, either implicitly or explicitly, to personal preferences rather than solid evidence.3,8–10
In Table 1, we compared subclinical and mild Cushing’s syndrome; in general, patients with subclinical Cushing are older, more frequently of male gender and bearing an adrenal instead of pituitary adenoma when compared to patients with mild Cushing’s. These differences result from comparison of average data and are of limited help when evaluating an individual patient. The clinical presentation is somewhat different, because the condition is recognized serendipitously in one case and following clinical suspicion in the other, and the specific signs of cortisol excess11 should not be present in the subclinical variant. Having said this, we have to admit that it is difficult to set precise boundaries separating patients with a mild phenotype from patients with a nonspecific phenotype. Only personal experience and clinical experience may help differentiating, as an example, a slight facial fullness caused by mild cortisol excess from facial roundness associated with obesity. There is also a great overlap in the biochemical presentation, even if endocrine alterations are generally more consistent in mild Cushing’s syndrome where ACTH-independent disease is less frequent.
Table 1. Comparison of subclinical Cushing’s syndrome and mild Cushing’s syndrome.