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Departments of Molecular and Clinical Endocrinology and Oncology (L.T., R.R., B.B., M.P., V.N., G.L.) and Internal Medicine (E.-A.P., S.F.), University Federico II, Naples, Italy
Address all correspondence and requests for reprints to: Dr. Libuse Tauchmanovà, Department of Molecular and Clinical Endocrinology and Oncology, University Federico II, Via S. Pansini n. 5, 801 31 Naples, Italy. E-mail: tauchman{at}unina.it.
Abstract
Subclinical Cushing’s syndrome (SCS) is increasingly being reported in incidentally discovered adrenal adenomas; its hallmark is mild autonomous cortisol hyperproduction without specific clinical signs of cortisol excess. Increased prevalence of hypertension, obesity, and impaired glucose tolerance have been described in SCS, but there is no specific study of the risk factors for cardiovascular diseases. In this cross-sectional study we assessed the cardiovascular profile in 28 consecutive SCS patients (19 women and 9 men; aged 56 ± 10.6 yr) compared with 100 controls matched for age, gender, and body mass index. Systolic (P < 0.001) and diastolic (P < 0.005) blood pressures were higher in patients, as were fasting glucose, insulin, total cholesterol, triglycerides (all P < 0.001), and fibrinogen (P < 0.05). Moreover, the insulin resistance index was increased in patients as was the waist to hip ratio and mean carotid artery intima-media thickness (all P < 0.001). Of the patients, 60.7% had arterial hypertension, 71.4% had lipid abnormalities, 28.6% had impaired glucose tolerance, 35.7% type 2 diabetes mellitus, and 53.6% had abnormalities in hemostatic parameters. Atherosclerotic plaques were more frequent in patients (P < 0.0001). Only 4 (14.3%) patients did not have multiple risk factors for cardiovascular events. Six (21.3%) had clinical evidence of cardiovascular disease; another 11 (39.3%) had cardiovascular abnormalities as revealed by ultrasound scanning of carotid arteries and/or electrocardiogram records. These results strongly suggest that an increased cardiovascular risk profile, similar to that described in overt Cushing’s syndrome, is present is SCS subjects. This finding supports the concept that chronic mild endogenous cortisol excess may have important systemic effects on the human body.
CONSEQUENT TO THE routine use of sophisticated diagnostic tools, subclinical endocrine diseases and their effects on the human body have become a matter of debate. Subclinical dysfunction of the thyroid has attracted most attention (1, 2), followed by subclinical Cushing’s syndrome (SCS) (3, 4), which has been increasingly reported in cases of adrenal tumors discovered incidentally by abdominal imaging procedures performed for unrelated reasons (4, 5, 6, 7). Although the diagnostic criteria adopted vary slightly (4, 5, 6, 7), SCS is defined as an autonomous cortisol (F) hyperproduction of mild entity not causing specific clinical signs, but detectable biochemically as derangements of the hypothalamic-pituitary-adrenal (HPA) axis function. We have adopted the diagnostic criteria suggested by the National Italian Group on Adrenal Tumors (6, 7): no clinical signs of hormone excess (i.e. truncal obesity, thin extremities with muscular hypotrophy, moon face, nuchal gibbous, and cutaneous purple striae) and at least two abnormalities in HPA axis function; a mandatory criterion was failure to suppress serum F to less than 83 nmol/liter (3 µg/dl) by a 2-mg dexamethasone (DXM) test, which has a high positive predictive value in diagnosing F excess (6, 8).
Overt Cushing’s syndrome is associated with complications such as high cardiovascular morbidity and bone loss; the morbidity related to the subclinical form is less clear. There are several reports of an increased incidence of several modifiable cardiovascular risk factors (9), including hypertension (4, 6, 7), obesity (4, 7), and impaired glucose tolerance (7, 10, 11), in adrenocortical incidental adenomas and SCS. Increased bone turnover and decreased mineral density have also been reported in SCS subjects by some investigators (12, 13, 14, 15), but not by others (16). It has been hypothesized that SCS first affects bone tissue (13).
We previously reported an elevated incidence of hypertension, obesity, impaired glucose tolerance, and abnormal lipid pattern in 12 SCS subjects (7, 11), which suggested an increased cardiovascular risk profile in these subjects. To our knowledge, the cardiovascular risk has not been systematically investigated in this clinical condition. The aim of this study was to assess the cardiovascular risk profile in a large group of SCS patients.
Subjects and Methods
Subjects
Among 126 subjects evaluated at the Department of Molecular and Clinical Endocrinology and Oncology, University Federico II (Naples, Italy) for incidentally discovered adrenal mass, 28 patients (9 men and 19 women; aged 26–72 yr; median age, 56.5) met the criteria of SCS (6, 7). All incidentalomas were discovered by abdominal ultrasound or computed tomography scans, performed for evaluation of such unrelated disorders as urinary tract infections, renal or biliary colic, or nonspecific abdominal pain or during a regular check-up. All patients enrolled in the study had incomplete inhibition of serum F levels after a low dose 2-mg DXM suppression test (orally, 0.5 mg four times a day for 2 d) and at least 1 other abnormality in the following parameters of HPA axis function: baseline serum F or plasma ACTH at 0800 h (mean of at least 2 samples taken on different days); 24-h excretion of urinary free F (UFF); daily average F, calculated as (F at 0800 h + F at 1600 h + F at 2400 h)/3; F at 2400 h/0800 h percent ratio expressing F circadian rhythm abnormalities, calculated as (F at 2400 h/F at 0800 h) x 100 (7). Abnormal values were those outside the range determined by the mean of the control group ± 2 SD. Twenty-four-hour urinary catecholamines and plasma renin activity to aldosterone ratio were within normal range in all patients, thereby excluding pheochromocytoma and aldosteronoma. Serum and urinary Na and K were normal in all patients, and there was no difference in serum Na and K between patients on and off antihypertensive treatment.
One hundred subjects matched for gender, body mean index (BMI), and age were enrolled as controls. They were from a group of consecutive patients referred to the Department of Internal Medicine for abdominal ultrasound examination for similar reasons as the group of patients (see above) and who were not found to be affected by any relevant disorder. No participant was receiving contraceptive or estrogen and progestin replacement therapy. The patients were evaluated off treatment for hyperlipidemia (most of them had been never treated, three patients underwent appropriate wash-out), and only calcium antagonists were administered as antihypertensive treatment during hospitalization; patients underwent appropriate wash-out for other treatments. No participant suffered from sleep disorders. Two patients and six control subjects smoked from two to nine cigarettes a day. All subjects entered the study after giving their informed consent, and the study was performed in accordance with the Second Declaration of Helsinki.
Comparison of the endocrine evaluations of patients and controls is shown in Table 1
. Although great individual variability was present among patients (Table 2), morning F (P < 0.0001), average daily F (P < 0.0001), F at 2400 h/0800 h percent ratio (P < 0.05), and UFF (P < 0.0001) were significantly higher, and morning ACTH levels were lower (P < 0.05) in patients than in controls. The post-DXM values of F and UFF were also significantly higher in patients (P < 0.0001 for both; Table 1). Moreover, 17 (61%) of patients had more than 2 abnormalities in HPA axis function.
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Clinical evaluation. BMI was calculated as kilograms per meter squared as weight/height squared. A BMI between 25 and 30 was considered overweight, whereas a BMI above 30 was considered obesity (17). Blood pressure and heart rate were measured by auscultation after 20 min resting in a supine position according to the recommendations of the American Heart Association (18). A complete physical examination was performed to exclude the presence of typical symptoms or signs of overt Cushing’s syndrome (7, 19). A standard 12-lead electrocardiogram was performed by standardized procedures. The waist to hip ratio (WHR) was determined as the ratio between the smallest circumference of the torso between the 12th rib and the iliac crest, and the maximal circumference of the hip at the extension of the buttocks. The patients were in an upright position with a relaxed abdomen, arms at sides, and feet joined.
In accordance with WHO criteria (20), hypertension was diagnosed when diastolic blood pressure was above 90 mm Hg and systolic pressure was above 140 mm Hg. In patients receiving antihypertensive treatment, diagnosis and evaluation of hypertension severity were determined from pretreatment values.
Biochemical evaluation. The following fasting concentrations were determined by standard procedures: glucose; insulin; triglycerides; total, high density lipoprotein (HDL), and low density lipoprotein (LDL) cholesterol; fibrinogen levels, activated partial thromboplastin time; and prothrombin time. Subjects without known diabetes mellitus at study entry also underwent the oral glucose tolerance test (OGTT; 75 g glucose diluted in 250 ml water), with the determination of plasma glucose and insulin levels at baseline and after 60, 120, and 180 min. Diabetes mellitus was diagnosed when fasting glucose levels exceeded 7.0 mmol/liter (126 mg/dl) or the glucose response at 120 min after the OGGT was 11.1 mmol/liter (200 mg/dl) or greater (21). Impaired glucose tolerance (IGT) was diagnosed when blood glucose levels were between 6.1 and 7.0 mmol/liter (110 and 126 mg/dl, respectively) at fasting and between 7.8 and 11.1 mmol/liter (140–200 mg/dl) after the OGTT (21).
Lipid metabolism abnormalities were diagnosed when total cholesterol was greater than 5.2 mmol/liter (200 mg/dl), LDL cholesterol was greater than 4.14 mmol/liter (160 mg/dl), HDL cholesterol was less than 0.9 mmol/liter (35 mg/dl), or triglycerides were more than 1.8 mmol/liter (160 mg/dl). The total/HDL cholesterol ratio, considered an additional marker of cardiovascular risk, was calculated and was considered abnormal if it was above 5 (22). In nondiabetic subjects and in diabetics not treated with insulin, the insulin resistance index was also assessed by the homeostasis model, calculated as follows (23): homeostasis model assessment of insulin resistance (HOMA IR) = FIRI x FPG/22.5, where FIRI is the fasting plasma insulin level (microunits per milliliter), and FPG is the fasting plasma glucose level (millimoles per liter). This index is highly correlated with the insulin resistance index assessed by the euglycemic-hyperinsulinemic clamp, which is the gold standard of insulin resistance (23, 24) and is widely adopted in clinical studies.
Ultrasound carotid artery evaluation. Echo-Doppler ultrasonography was carried out with a 10-MHz annular phased array transducer. Segments of right and left carotid arteries (common, proximal internal carotid arteries, and the bulb) were scanned longitudinally. Scanning was performed with the subject in the supine position after a 10-min rest. M mode images were taken for several cardiac cycles after achieving a satisfactory B mode image of all segments. The entire accessible carotid tree was examined in each subject. The site of greatest intimal-medial thickness (IMT) at baseline in the carotid artery far wall was located and scanned thoroughly from three angles: antero-lateral, lateral, and postero-lateral. Diastolic IMT was measured for 10 mm (less when not visible) in one angle for the far carotid wall. The means of three measurements for any value were calculated. The presence, size, and localization of plaques were evaluated at all segments considered. Measurements were always made by the same operator, who was unaware of the subjects he was evaluating; the images were stored on magnetic media and were analyzed later when the data for all subjects were available.
Changes in the cardiovascular risk profile after surgical treatment. As previously reported, only those SCS patients with a large tumor size (>3.5 cm), severe hypertension, or tumor growth were treated by unilateral adrenalectomy (7). The endocrine pattern normalized in all eight patients after surgical removal of the adrenal lesion. Patients were reevaluated at a median postoperative follow-up of 44 months (range, 24–72 months), and improvement in clinical and metabolic parameters was expressed as a percentage of the preoperative values. The postoperative values were always determined after recovery of F secretion by the remaining adrenal as previously described (7).
Assays
All hormone assays were performed in the same laboratory using commercially available kits. F, UFF, and insulin were tested by Immulite, solid phase chemiluminescent enzyme immunoassay (Diagnostics Products Corp., Los Angeles, CA); ACTH was tested by double antibody 125I RIA (Diagnostics Products Corp.). Other biochemical analytes were assayed in the same laboratory using standard methods.
Statistical analysis
Continuous variables are summarized as the mean ± SEM. Unpaired t test was used to compare the means between the groups of patients and controls and between two subgroups of patients divided by age. The nonparametric method (Mann-Whitney U test) was used when the results of the Wilk-Shapiro test were not consistent with the Gaussian distribution of the data (F, UFF in response to DXM). The 
2 test was used to compare binary variables between groups. The correlation was assessed using simple linear regression analysis and multiple linear regression analysis. Significance was retained for P < 0.05.
Results
Clinical evaluation
Six (21.4%) patients were overweight, and 9 (32.1%) were obese vs. 22 obese and 32 overweight control subjects. The WHR was higher in patients than in controls (P < 0.001). Diastolic and systolic arterial pressures were significantly higher in patients despite the antihypertensive treatment (Table 3). Heart rates were similar in the 2 groups. Considering patients individually, 17 of 28 (60.7%) patients had arterial hypertension, and it was poorly controlled in 8 (47%) despite multiple pharmacological treatment. Symptomatic cardiovascular disease was diagnosed in 7 (21.3%) patients; 5 patients (1, 3, 7, 8, and 23; 17.9%) had ischemic heart disease, and 2 patients (8 and 20; 7.14%) had symptomatic obstructive peripheral vascular disease (claudicatio intermittens). Left ventricular hypertrophy, abnormalities of the repolarization phase, and/or arrhythmia (supraventricular premature beats) were identified in another 8 (28.6%) nonsymptomatic patients by electrocardiogram. In summary, half the patients had evidence of cardiovascular system function impairment (Table 4).
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Fasting glucose and insulin levels were higher in patients (P < 0.0001 for both; Table 3
). The HOMA index was also higher in patients (P < 0.001). A condition of impaired glucose metabolism was present in 18 (64.3%) patients. Seven patients were already diabetic (type 2 diabetes mellitus) at study entry, 3 had been diagnosed as diabetic by the OGTT, and 4 of them had a positive family history for type 2 diabetes mellitus. IGT was found in 8 (28.6%) patients by the same test (Table 4). Triglycerides and total and LDL cholesterol (all P < 0.0001) were higher in patients than in controls as was the total/HDL cholesterol ratio (P < 0.0001). Lipid profile abnormalities were present in 20 (71.4%) patients; high cholesterol levels were found in 10 patients, combined hyperlipidemia (increased cholesterol and triglycerides levels) in 7, and high triglycerides values in 3. Abnormal total/HDL cholesterol was present in 18 patients. Fibrinogen levels were higher in patients (P < 0.0001), whereas prothrombin time and activated partial thromboplastin time were similar in the 2 groups. However, 15 patients (53.6%) had increased levels of at least 1 hemostatic parameter above the mean ± 2 SD of controls (Table 4); the most frequent abnormality was increased fibrinogen levels.
Ultrasound carotid arteries evaluation
Two subjects with symptomatic obstructive vascular disease were found to have significant stenosis (>50%) of the carotid, femoral, iliac, and popliteal arteries and were considered separately; their IMTs were 1.7 and 1.5 mm. The remaining 26 patients had higher mean carotid artery IMT values (P < 0.0001) than controls (Table 3). Well defined carotid wall atherosclerotic plaques were detected in 15 (53.6%) patients and in 10 controls (2 = 23.72; P < 0.0001). Plaques were prevalently fibrolipidic and fibrocalcific in 4 patients. Nine patients had plaques at the right carotid bifurcation, resulting in a maximum diameter of 30 mm and a thickness of 3.2 mm, whereas 6 patients had a plaque at the left internal carotid artery (maximal diameter, 24 mm; thickness, 2 mm). In summary, evidence of impaired vascular function was detected by carotid ultrasound scan and/or electrocardiogram records in 11 (39.3%) patients without clinical evidence of cardiovascular disease.
There was no significant correlation between the results of endocrine evaluation and any clinical or biochemical parameter; however, there was a mild, but significant, simple linear correlation between the HOMA IR index and carotid IMT (r = 0.78; P = 0.048). Furthermore, WHR was correlated to glucose levels (r = 0.59; P = 0.039) and to carotid IMT (r = 0.65; P = 0.043). No correlation was found with multiple regression analysis.
Changes in the cardiovascular risk profile after surgical treatment
As shown in Fig. 1, after surgery there was a significant decrease in BMI (P < 0.05), systolic (P < 0.001) and diastolic (P < 0.005) blood pressures, and fibrinogen levels (P < 0.005). A follow-up study of SCS patients, including those who did not undergo surgery, is ongoing.
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Chronic F excess has been implicated in central obesity, systemic arterial hypertension, IGT, insulin resistance, altered lipid profile, and hypercoagulability (19, 25, 26, 27, 28, 29, 30, 31, 32). Combined, these factors confer increased cardiovascular risk, determining a plurimetabolic X syndrome that does not completely regress after successful treatment of the active disease (27). Although it is well recognized that patients with overt Cushing’s syndrome are at increased risk for cardiovascular morbidity and mortality (19, 25, 26, 27, 28, 29, 30, 31), the effects of subclinical F excess on the cardiovascular system are unclear.
Incidental adrenal adenomas have variable F secretion rates and a degree of autonomous F production (11, 13). However, there is probably a continuum of F secretion abnormalities, and a diagnosis of SCS can be considered an arbitrary cut-off point that separates the subgroup affected by more severe abnormalities. Consequently, we discuss our results in the light of findings reported for patients with both SCS and adrenal incidental adenoma.
As found in an earlier study (33), the WHR was significantly higher in patients than in controls, although they were matched for BMI. The WHR is a reliable index of abdominal obesity and is more closely associated with increased cardiovascular risk than is general obesity (22, 34). Thus, an altered body fat distribution and increased visceral abdominal fat may be important in the development of the metabolic syndrome in patients with SCS.
Arterial hypertension was significantly more frequent in our patients than in a southern Italian population of similar age (22) and was poorly controlled by pharmacological treatment in 50% of patients. Arterial hypertension has been reported in 41% and 75% of SCS patients in a retrospective multicentric study (6) and in a prospective monocentric study (4), respectively. The discrepancies are probably due to differences in study design and to the relatively small number of patients in the latter study (4). The pathogenesis of hypertension related to F excess is probably multifactorial and is not completely understood (35); however, repeated observations of improved blood pressure control after successful treatment of mild hypercortisolism (4, 7) confirm the link between these two features.
The prevalence of IGT (64%) in our SCS patients is within the range reported for Cushing’s syndrome, i.e. between 39–90% (25, 29, 30, 31). A similar frequency (61% and 66%) was found in a monocentric and a multicentric study, respectively, in patients harboring incidental adrenal tumors (10). Type 2 diabetes mellitus was more frequent among our patients (10 of 28) than in patients with incidental adenomas and overt F excess (10–15%) (6, 10, 19, 29, 30, 31). We probably detected a higher frequency of diabetes mellitus because we used a fasting glucose cut-off of 126 mg/dl (21) compared with that of 140 mg/dl used in previous studies. Diabetes mellitus is characterized by poor glucose control in subjects with F excess, whereas glycemic control was greatly improved after successful treatment of hypercortisolism (36). Insulin levels and the HOMA IR index were significantly higher in our patients than in controls, suggesting enhanced insulin resistance; the latter has also been found in eight nonfunctioning adrenal adenomas based on steady state plasma glucose (32). Seventy-one percent of our patients had increased cholesterol and triglyceride levels and decreased HDL cholesterol levels, which are indicative of increased atherosclerotic risk.
Fibrogen levels were significantly higher in our SCS patients than in controls; 53.6% had abnormality of at least one hemostatic parameter vs. 42% of previously reported patients harboring adrenal incidentalomas (37). This feature is known to increase the risk of thromboembolic events in overt Cushing’s syndrome (27, 37, 38, 39).
Carotid IMT, a marker of systemic atherosclerosis (40), was significantly increased in SCS patients vs. controls. This suggests a higher prevalence of this condition in our patients, a concept supported by the increased frequency of atherosclerotic plaques. Experimental and clinical evidence obtained in animals and humans points to a link between F excess and atherosclerosis (39, 41, 42).
The lack of a correlation among clinical, biochemical, and endocrine parameters in the multiple regression analysis strongly suggests that the global cardiovascular risk in these patients is determined by synergy between different factors. Age does not seem to be a factor in the development of milder clinical manifestations of F excess (43). In fact, in our study as many as one third (9 of 28; 32.14%) of patients were 50 yr or younger, and clinical and biochemical features did not differ when the patients were divided according to age (
50 or >50 yr), except for higher fibrinogen levels in patients 50 yr or younger (360 ± 29 vs. 297 ± 11.79 mg/dl; P = 0.021).
Surgical treatment of F excess is currently reserved for patients with a large or growing adrenal tumoral mass and/or those with overt hormone excess, and SCS is not considered to belong to the latter category. However, arterial pressure control, lipid profile, fibrinogen levels, and glycemic control improved in our eight SCS patients treated by surgery. Similarly, hypertension, BMI, and glycemic control improved in seven of eight SCS surgically treated patients in a previous report (4). In addition, insulin resistance improved in surgically treated patients with adrenal incidentalomas (44). These very preliminary data suggest that cardiovascular risk factors decrease after the cessation of mild F excess. However, mortality was not increased in patients with incidental adrenal adenomas not treated by surgery (45, 46), but epidemiological studies of large numbers of patients and longer follow-up periods are required to compare the outcomes of surgically treated and untreated patients to verify the relationship among incidental adrenal adenomas, subclinical F excess, and cardiovascular morbidity/mortality.
In conclusion, in accordance with other studies (10, 33, 37, 47) multiple risk factors for cardiovascular events were found in all but four SCS patients (87.5%), and 64% of the patients had evidence of cardiovascular function impairment. The results of this study strongly suggest that an increased cardiovascular risk profile, similar to that described in overt Cushing’s syndrome, is present in SCS subjects. This finding supports the concept that chronic mild endogenous F excess may have important systemic effects on the human body. Surgical treatment induced a reduction of the cardiovascular risk profile.
Acknowledgments
We are indebted to Jean Ann Gilder for her help in editing the manuscript.
Footnotes
Presented at the 83rd Annual Meeting of The Endocrine Society, June 21, 2001, Denver, Colorado (OR 21-2).
Abbreviations: BMI, Body mass index; F, cortisol; DXM, dexamethasone; HDL, high density lipoprotein; HOMA IR, homeostasis model assessment of insulin resistance; HPA, hypothalamic-pituitary-adrenal; IGT, impaired glucose tolerance; IMT, intimal-medial thickness; LDL, low density lipoprotein; OGTT, oral glucose tolerance test; SCS, subclinical Cushing’s syndrome; UFF, urinary free cortisol; WHR, waist to hip ratio.
Received November 2, 2001.
Accepted June 28, 2002.
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G. D. Braunstein and for the National Institutes of Health State-of-the Management of the Clinically Inapparent Adrenal Mass Ann Intern Med, March 2, 2004; 140(5): 401 - 402. [Full Text] [PDF]
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J. W. Findling, H. Raff, and D. C. Aron The Low-Dose Dexamethasone Suppression Test: A Reevaluation in Patients with Cushing's Syndrome J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1222 - 1226. [Abstract] [Full Text] [PDF]
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 G. La Cava, A. Imperiale, C. Olianti, G. R. Gheri, C. Ladu, M. Mannelli, and A. Pupi SPECT Semiquantitative Analysis of Adrenocortical 131I-6{beta}-Iodomethyl-Norcholesterol Uptake to Discriminate Subclinical and Preclinical Functioning Adrenal Incidentaloma J. Nucl. Med., July 1, 2003; 44(7): 1057 - 1064. [Abstract] [Full Text] [PDF]
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A. Angeli and M. Terzolo Adrenal Incidentaloma--A Modern Disease with Old Complications J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4869 - 4871. [Full Text] [PDF]
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