Dipartimento di Scienze Cliniche e Biologiche, Medicina Interna I, Università di Torino, 10043 Orbassano (TO), Italy
Address all correspondence and requests for reprints to: Alberto Angeli, M.D., Dipartimento di Scienze Cliniche e Biologiche, A.S.O. San Luigi, Regione Gonzole 10, 10043 Orbassano, Italy. E-mail: alberto.angeli{at}unito.it.
In the heyday of high-tech medicine, the incidental discovery of an adrenal mass is a frequent event because of the routine use of sophisticated imaging techniques. A clinically inapparent adrenal mass that is discovered serendipitously, in the course of diagnostic evaluation or follow-up of unrelated disorders, is commonly known as adrenal incidentaloma (1). Adrenal incidentaloma is an "umbrella" term that is pertinent to many pathologies sharing the same way of discovery. Because of the great heterogeneity, what has been called a disease of modern technology (2) is actually a cluster of diseases. Certainly, the adrenal incidentaloma is a public health challenge because these tumors are currently being detected in millions of people worldwide and their number is expected to grow in aging populations that have access to ever-improving radiological techniques (1, 2, 3).
In recent years, significant new information has helped to clarify uncertainties and controversies about the risk that the various types of adrenal incidentaloma present to patients (1, 4, 5, 6). An adrenal incidentaloma that is found to be a primary or secondary adrenal malignancy, or pheochromocytoma as well, can significantly affect a patients health (7, 8, 9). However, it is presently unclear whether or not there is potential harm to the health of patients who bear an incidental cortical adenoma (8, 9, 10). This dilemma, which is addressed by Tauchmanovà et al. (11) in this issue of JCEM, is at the heart of the clinical problem of the adrenal incidentaloma. In fact, the management of a clinically inapparent adrenal adenoma, whether by laboratory testing is hormonally active or not, may have a great deal to do with cardiovascular prevention and health promotion.
Cortical adenoma is the most frequent tumor among adrenal incidentalomas (1). It is often associated with subtle, possibly transient, autonomous glucocorticoid hypersecretion. Therefore, inapparent cortical adenoma may cause a particular endocrine disorder, subclinical Cushings syndrome. A logical assumption is that patients with such adenomas suffer, at least to some extent, from the detrimental effects of sustained cortisol excess (7, 8, 12). Accordingly, the identification of patients with subclinical Cushings syndrome may provide an opportunity for presymptomatic treatment of a notoriously dangerous disease. To support convincingly this view on a population basis, however, it is mandatory to resolve diagnostic criteria for subclinical Cushings syndrome, to assess the probability and size of risk for an adverse outcome, to set strategies of monitoring, and to select appropriate treatments in terms of attainable benefits, risk of iatrogenic complications, and monetary costs (10). Each of these steps is fraught with difficulties.
By definition, patients with subclinical Cushings syndrome lack the overt physical stigmata of Cushings syndrome. Diagnosis comes to light after a detailed biochemical workup (7, 12, 13) and may be corroborated in vivo by iodocholesterol scintigraphy (1, 5, 14). Standard biochemical tests for overt Cushings syndrome, however, are likely to be less accurate in a population presenting with no reliable clinical clues (2, 10). Thus, there is a gray area of results that often hampers unambiguous interpretation of the data. Therefore, it is hardly surprising that the criteria for qualifying the state of subclinical glucocorticoid excess are controversial (2, 8, 12). Various endocrine algorithms with disparate assumptions can be found in many different studies (5, 6, 7, 8, 9, 12, 13, 15).
The study by Tauchmanovà et al. (11) gives us an additional example of current inconsistency on how to define subclinical Cushings syndrome. The authors followed the criteria developed by the Italian Study Group on Adrenal Tumors, requiring the demonstration of at least two abnormalities in the hypothalamic-pituitary-adrenal axis (6); however, there were some inconsistencies such as using the 2-d low-dose dexamethasone test instead of the 1-mg overnight test. Whatever the test used, we do not know the significance of a subtle biochemical diagnosis. We do know that autonomous cortisol output by an adrenal adenoma is variable over the course of time and continuously distributed among different patients; thus, it is difficult to demonstrate whether or not a patient meets criteria for subclinical Cushings syndrome.
Notwithstanding uncertainty regarding the definition of subclinical Cushings syndrome, there is no doubt that many patients with clinically inapparent adrenal adenoma can be exposed to cortisol excess. End organ complications of this biochemical diagnosis would add strength to the concept of cortisol excess in these patients. The study by Tauchmanovà et al. (11) adds new evidence that subclinical Cushings syndrome does predispose to atherosclerosis and relevant cardiovascular complications. It was found that 28 of 126 subjects with adrenal incidentaloma, who met criteria for subclinical Cushings syndrome, sustained an adverse cardiovascular and metabolic risk compared with controls matched for gender, age, and body mass index (11). They had higher systolic and diastolic blood pressure and an increased waist to hip ratio. In addition, they had increased scores in the homeostasis model assessment, which provides a surrogate index of insulin resistance (16), higher triglyceride, total and low-density lipoprotein cholesterol and fibrinogen levels, and an exceedingly high prevalence of impaired glucose tolerance (IGT) or diabetes mellitus (11). The impact of these abnormalities on the vascular system was documented by significant changes in carotid intimal-medial thickness. Not surprisingly, evidence of impaired cardiac function was found in about half of the patients (11).
A constellation of clinical and biochemical characteristics, which usually coexist and are associated with insulin resistance, is referred to as the "metabolic syndrome" or "syndrome X." They include abdominal (central) obesity, dyslipidemia with low high-density lipoprotein cholesterol and high triglyceride levels, with or without raised low-density lipoprotein cholesterol levels, hyperuricemia, hypertension, hypercoagulability, and various degrees of glucose intolerance, ranging from fasting normoglycemia with hyperinsulinemia to clinically overt type 2 diabetes mellitus (17, 18). Traits are all also recognized as independent risk factors for atherosclerosis and cardiovascular complications. Overall, the metabolic syndrome is associated with increased cardiovascular mortality (19).
Several studies support a pathogenetic role for cortisol in the metabolic syndrome. Cortisol counteracts the action of insulin at multiple sites (20, 21, 22) and increases hepatic gluconeogenetic efficiency (23). It promotes abdominal fat distribution (22, 24), enhances activity of the sympathetic nervous system (22), and has complex effects on vascular tone that promote endothelial dysfunction, hypercoagulability, and arterial hypertension (25).
The results of the study by Tauchmanovà et al. (11) confirm and extend previous data. In an uncontrolled study, Fernandez-Real et al. (26) found a remarkably high prevalence of IGT or unknown diabetes among patients with nonfunctioning adrenal tumors, whereas Garrapa et al. (27) found increased visceral fat mass along with IGT and hyperinsulinemia in an analogous cohort of patients. They reported that the degree of metabolic and body fat alterations were intermediate between that of controls and patients with overt Cushings syndrome (27). We have demonstrated also that nonobese, normoglycemic patients with incidental adrenal adenoma have elevated blood pressure, reduced insulin sensitivity, and frequent occurrence of glucose intolerance compared with matched controls. Interestingly, such alterations were not restricted to patients with subclinical Cushings syndrome, but they were more pronounced than in patients without this diagnosis. Obviously, the degree of hyperinsulinemia was even greater in patients with overt Cushings syndrome (28). To summarize, complementary results from different studies support the view that cortisol secretion by incidental adrenal adenomas demonstrates a spectrum of intensity; hence, the metabolic effects are likely to vary accordingly.
Caveats are needed for a meaningful appraisal of data that are consistent with current knowledge. To some extent, the data could be influenced by referral bias. We are faced with the challenge to match accurately the many factors that contribute to insulin resistance and the metabolic syndrome. A causal link between hypercortisolism and insulin resistance is, indeed, the most plausible explanation for the observed abnormalities, but an alternative hypothesis that adrenal incidentaloma may itself be an unrecognized manifestation of the metabolic syndrome can be formulated (29). From the clinical viewpoint, however, the most relevant application of available data concerns the advantages of a systematic assessment of cardiovascular risk in patients bearing incidentally discovered adrenal adenoma. Awareness is increasing that even a modest and inapparent cortisol excess may eventually be harmful to individuals who express other (genetically determined or acquired) risk factors, and cortisol excess may play an important role in accelerating the appearance of insulin resistance and vascular deterioration.
Evidence of increased morbidity and mortality in patients with clinically inapparent adrenal adenoma, with or without subclinical Cushings syndrome, is presently lacking, even if it is held that the metabolic syndrome carries with it an adverse prognosis (18, 19). In this era of evidence-based medicine, the long-term complications of incidentally discovered adrenal adenomas remain virtually unknown, and, consequently, the management of such tumors is largely empirical. The (scarce) available data suggest that the great majority of patients with adrenal incidentaloma remain asymptomatic throughout life (12, 30), but the existing follow-up studies have focused almost exclusively on imaging and endocrine testing. The aims of such studies have been to identify adenomas that are growing (how many, how much) and to identify patients with subclinical Cushings syndrome who will eventually develop an overt syndrome. Little, if any, attention has been paid to the longitudinal assessment of metabolic and cardiovascular complications. Clearly, prospective studies should address the incidence of disease-specific and all-cause events and mortality. Such studies will require a multi-institutional international collaboration due to the low frequency of disease-specific outcomes.
Preliminary data suggest that adrenalectomy may ameliorate the vascular risk profile of patients with subclinical Cushings syndrome (11, 12, 31). Even if these data were confirmed in larger series, it is unlikely that surgery will be the first choice of treatment for such patients. As mentioned previously, autonomous cortisol secretion by the tumor and its attendant detrimental effects, if any, vary greatly across different individuals. Moreover, if our aim is to prevent metabolic disease and cardiovascular events, the performance of surgery in terms of risk, cost, and outcome should be compared with the other possible interventions, including lifestyle changes and pharmacological approach. An optimal preventive measure should be harmless for patients, but this is not the case with adrenalectomy, even when performed by laparoscopic or retroperitoneoscopic techniques. Indeed, in skilled hands, laparoscopic adrenalectomy has relatively little morbidity and minimal (but not zero) mortality, yet specific experience is critical, and there is a learning curve (32). Thus, surgery on more people has the potential to cause more complications.
With the present knowledge, it is wise to elect to operate on those patients with subclinical Cushings syndrome who have by history a progressively rising vascular risk and a metabolic syndrome resistant to medical interventions. The time course of the attendant disturbances is important for the surgical choice because it is held that established complications of overt Cushings syndrome do not fully resolve after successful surgery (33). Patients who are not candidates to surgery (plausibly the majority) should be enrolled in a program of regular and careful follow-up to detect, treat, and control central obesity, hypertension, glucose intolerance, dyslipidemia, and other manifestations of the metabolic syndrome. This conceptual framework also serves for advising either lifestyle changes or more aggressive treatments with drugs that have been demonstrated to be protective for metabolic and cardiovascular complications as well (18, 19, 34).
Acknowledgments
Footnotes
This work was supported in part by a MURST grant (fondi "ex-40%").
Abbreviation: IGT, Impaired glucose tolerance.
Received September 12, 2002.
Accepted September 17, 2002.
References