E J Ross, D C Linch
Cushing's syndrome--killing disease: discriminatory value of signs and symptoms aiding early diagnosis.
Lancet. 1982 Sep 18;2(8299):646-9.
Abstract/Text
Massimo Terzolo, Giuseppe Reimondo, Silvia Bovio, Alberto Angeli
Subclinical Cushing's syndrome.
Pituitary. 2004;7(4):217-23. doi: 10.1007/s11102-005-4024-6.
Abstract/Text
Clinically inapparent adrenal masses, or adrenal incidentalomas, are discovered inadvertently in the course of workup or treatment of unrelated disorders. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50% of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner, that is not fully restrained by pituitary feed-back, in 5 to 20% of cases depending on study protocols and diagnostic criteria. A number of different alterations in the endocrine tests aimed to assess the function of the hypothalamic-pituitary-adrenal axis has been demonstrated in such patients. This heterogeneous condition has been termed as subclinical Cushing's syndrome, a definition that is more accurate than preclinical Cushing's syndrome since the evolution towards clinically overt hypercortisolism does occur rarely, if ever. The criteria for qualifying subclinical cortisol excess are controversial and we presently do not have sufficient evidence to define a gold standard for the diagnosis of subclinical Cushing's syndrome. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipoproteinemia has been described in patients with subclinical Cushing's syndrome; however, there is not evidence-based demonstration of its long-term complications and, consequently, the management of this condition is largely empirical. Either adrenalectomy or careful observation associated with treatment of metabolic syndrome has been suggested as treatment options because data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenomas.
Rossella Libè, Chiara Dall'Asta, Laura Barbetta, Andrea Baccarelli, Paolo Beck-Peccoz, Bruno Ambrosi
Long-term follow-up study of patients with adrenal incidentalomas.
Eur J Endocrinol. 2002 Oct;147(4):489-94.
Abstract/Text
BACKGROUND: The incidence of adrenal incidentalomas has sharply increased in recent decades and concurrent subtle endocrine abnormalities, or even subclinical conditions, have been identified. Nonetheless, data concerning possible changes in adrenal size and/or hormonal pattern during follow-up are still inadequate.
OBJECTIVE: To evaluate long-term morphological and functional evolution of adrenal incidentalomas after initial diagnosis and to identify possible risk factors for hormonal hyperactivity and mass enlargement.
PATIENTS: Sixty-four patients (34-79 years) were followed-up for 12-120 months (median 25.5 months). Initial computerized tomography scan showed a unilateral mass in 51 patients and bilateral lesions in 13 patients. Average mass diameter at diagnosis was 2.5+/-0.1 cm (range 1.0-4.0). Twelve patients had subclinical Cushing's syndrome, 41 had mild hormonal alterations, and 11 had normal adrenal function at baseline. All patients were investigated by morphological and functional evaluation 6 and 12 months after diagnosis, and then at 1-year intervals.
RESULTS: During follow-up, a mass size increase >/=1 cm was observed in 13 patients, and 18 developed further subtle endocrine alterations. Cumulative risk of developing endocrine abnormalities was 17% at 1 year, 29% at 2 years, and 47% at 5 years. The risk was higher in the first 2 years of follow-up if the initial tumor diameter was >or=3 cm. Overall, cumulative risk of mass enlargement was 6% at 1 year, 14% at 2 years, and 29% at 5 years, and it was greater in patients with normal adrenal function than in those with subtle hormonal abnormalities (P<0.05). One female subject showed a mass enlargement after 6 months of follow-up and was eventually diagnosed with non-Hodgkin's lymphoma.
CONCLUSIONS: Patients with an adrenal incidentaloma are at risk for tumor growth and development of hormonal alterations. The risk of adrenal malignancy, although not elevated, also indicates the need for long-term follow-up.
Bogdan Catargi, Vincent Rigalleau, Agathe Poussin, Nathalie Ronci-Chaix, Veronique Bex, Vincent Vergnot, Henri Gin, Patrick Roger, Antoine Tabarin
Occult Cushing's syndrome in type-2 diabetes.
J Clin Endocrinol Metab. 2003 Dec;88(12):5808-13. doi: 10.1210/jc.2003-030254.
Abstract/Text
Subclinical Cushing's syndrome (SCS) caused by adrenal incidentalomas is frequently associated with overweight and insulin resistance. Metabolic syndrome X may therefore be a clue to the presence of CS. However, the incidence of CS in this situation remains unknown. We have conducted a prospective study to evaluate the prevalence of occult CS in overweight, type-2 diabetic patients devoided of specific clinical symptoms of CS. Two hundred overweight, type-2 diabetic patients, consecutively referred for poor metabolic control (HbA(1C) > 8%), were studied as inpatients. A first screening step was performed with the 1-mg overnight dexamethasone suppression test (DST) using a revised criterion for cortisol suppression (60 nmol/liter) to maximize the sensitivity of the procedure. A second confirmatory step of biochemical investigations (midnight plasma cortisol concentration, plasma cortisol circadian rhythm, morning plasma ACTH concentration, 24-h urinary free cortisol, and 4-mg i.v. DST) was performed in patients with impaired 1-mg DST. A third step of imaging studies was performed according to the results of second-step investigations. Fifty-two patients had impaired 1-mg DST. Among these, 47 were further evaluated. Thirty were considered as false positives of the 1-mg DST, whereas 17 displayed at least one additional biological abnormality of the hypothalamic-pituitary-adrenal axis. Definitive occult CS was identified in four patients (2% of the whole series) with Cushing's disease (n = 3) and surgically proven adrenal adenoma (n = 1). Definitive diagnosis remains to be established in seven additional patients (3.5%) with mild occult CS associated with unsuppressed plasma ACTH concentrations and a unilateral adrenal tumor of 10-29 mm in size showing prevalent uptake at radiocholesterol scintigraphy. In conclusion, a relatively high prevalence of occult CS was found in our study. Further studies are needed to evaluate the impact of the cure of occult CS on obesity and diabetes mellitus in these patients. Such studies might provide a rationale for systematic screening of occult CS in this population.
Iacopo Chiodini, Maria Lucia Mascia, Silvana Muscarella, Claudia Battista, Salvatore Minisola, Maura Arosio, Stefano Angelo Santini, Giuseppe Guglielmi, Vincenzo Carnevale, Alfredo Scillitani
Subclinical hypercortisolism among outpatients referred for osteoporosis.
Ann Intern Med. 2007 Oct 16;147(8):541-8.
Abstract/Text
BACKGROUND: Hypercortisolism is known to cause osteoporosis.
OBJECTIVE: To evaluate the prevalence of subclinical hypercortisolism in participants referred for evaluation of osteoporosis.
DESIGN: Cross-sectional study.
SETTING: Two community hospitals and research institutes in Italy.
PATIENTS: 219 patients without clinically overt hypercortisolism or other secondary causes of osteoporosis who were referred for evaluation of osteoporosis between January 2005 and December 2005.
MEASUREMENTS: Bone mineral density was measured by using dual-energy x-ray absorptiometry, and hypercortisolism was assessed with serum cortisol levels after a dexamethasone suppression test. Also measured were 24-hour urinary free cortisol levels and midnight plasma cortisol levels.
RESULTS: Seven of 65 patients with T-scores of 2.5 or less and vertebral fractures had subclinical hypercortisolism (prevalence, 10.8% [95% CI, 3.23% to 18.31%]). This prevalence was 4.8% (CI, 1.32% to 8.20%) among patients with osteoporosis. In multivariable analyses adjusted for age, sex, and body mass index, a positive dexamethasone suppression test result was associated with the presence of osteoporosis (odds ratio, 3.37 [CI, 1.78 to 6.43]; P < 0.001) and vertebral fractures (odds ratio, 1.70 [CI, 1.04 to 2.79]; P = 0.035).
LIMITATIONS: The study was conducted in a referral setting; its findings may not apply to the general population.
CONCLUSIONS: Subclinical hypercortisolism may be more common than is generally recognized in patients with osteoporosis in whom secondary causes of osteoporosis have been excluded.
J Lindholm, S Juul, J O Jørgensen, J Astrup, P Bjerre, U Feldt-Rasmussen, C Hagen, J Jørgensen, M Kosteljanetz, L Kristensen, P Laurberg, K Schmidt, J Weeke
Incidence and late prognosis of cushing's syndrome: a population-based study.
J Clin Endocrinol Metab. 2001 Jan;86(1):117-23.
Abstract/Text
The main purpose was to assess the incidence and late outcome of Cushing's syndrome, particularly in Cushing's disease. Information for all patients diagnosed with Cushing's syndrome during an 11-yr period in Denmark was retrieved. The incidence was 1.2-1.7/million.yr (Cushing's disease), 0.6/million.yr (adrenal adenoma) and 0.2/million.yr (adrenal carcinoma). Other types of Cushing's syndrome were rare. In 139 patients with nonmalignant disease, 11.1% had died during follow-up (median, 8.1 yr; range, 3.1-14.0), yielding a standard mortality ratio (SMR) of 3.68 [95% confidence interval (CI), 2.34-5.33]. The SMR was partly attributable to an increased mortality within the first year after diagnosis. Eight patients died before treatment could be undertaken. The prognosis in patients with malignant disease was very poor. Patients in whom more than 5 yr had elapsed since initial surgery were studied separately, including a questionnaire on their perceived quality of health. In 45 patients with Cushing's disease who had been cured through transsphenoidal neurosurgery, only 1 had died (SMR, 0.31; CI, 0.01-1.72) compared with 6 of 20 patients with persistent hypercortisolism after initial neurosurgery (SMR, 5.06; CI, 1.86-11.0). In patients with adrenal adenoma, SMR was 3.95 (CI, 0.81-11.5). The perceived quality of health was significantly impaired only in patients with Cushing's disease and appeared independent of disease control or presence of hypopituitarism. It is concluded that 1) Cushing's syndrome is rare and is associated with increased mortality, in patients with no concurrent malignancy also; 2) the excess mortality was mainly observed during the first year of disease; and 3) the impaired quality of health in long-term survivors of Cushing's disease is not fully explained.
Mohamed B Elamin, M Hassan Murad, Rebecca Mullan, Dana Erickson, Katherine Harris, Sarah Nadeem, Robert Ennis, Patricia J Erwin, Victor M Montori
Accuracy of diagnostic tests for Cushing's syndrome: a systematic review and metaanalyses.
J Clin Endocrinol Metab. 2008 May;93(5):1553-62. doi: 10.1210/jc.2008-0139. Epub 2008 Mar 11.
Abstract/Text
CONTEXT: The diagnosis of Cushing's syndrome (CS) requires the use of tests of unregulated hypercortisolism that have unclear accuracy.
OBJECTIVE: Our objective was to summarize evidence on the accuracy of common tests for diagnosing CS.
DATA SOURCES: We searched electronic databases (MEDLINE, EMBASE, Web of Science, Scopus, and citation search for key articles) from 1975 through September 2007 and sought additional references from experts.
STUDY SELECTION: Eligible studies reported on the accuracy of urinary free cortisol (UFC), dexamethasone suppression test (DST), and midnight cortisol assays vs. reference standard in patients suspected of CS.
DATA EXTRACTION: Reviewers working in duplicate and independently extracted study characteristics and quality and data to estimate the likelihood ratio (LR) and the 95% confidence interval (CI) for each result.
DATA SYNTHESIS: We found 27 eligible studies, with a high prevalence [794 (9.2%) of 8631 patients had CS] and severity of CS. The tests had similar accuracy: UFC (n = 14 studies; LR+ 10.6, CI 5.5-20.5; LR- 0.16, CI 0.08-0.33), salivary midnight cortisol (n = 4; LR+ 8.8, CI 3.5-21.8; LR- 0.07, CI 0-1.2), and the 1-mg overnight DST (n = 14; LR+ 16.4, CI 9.3-28.8; LR- 0.06, CI 0.03-0.14). Combined testing strategies (e.g. a positive result in both UFC and 1-mg overnight DST) had similar diagnostic accuracy (n = 3; LR+ 15.4, CI 0.7-358; LR- 0.11, CI 0.007-1.57).
CONCLUSIONS: Commonly used tests to diagnose CS appear highly accurate in referral practices with samples enriched with patients with CS. Their performance in usual clinical practice remains unclear.
Katherine Samaras, Sarah Pett, Andrew Gowers, Marilyn McMurchie, David A Cooper
Iatrogenic Cushing's syndrome with osteoporosis and secondary adrenal failure in human immunodeficiency virus-infected patients receiving inhaled corticosteroids and ritonavir-boosted protease inhibitors: six cases.
J Clin Endocrinol Metab. 2005 Jul;90(7):4394-8. doi: 10.1210/jc.2005-0036. Epub 2005 Mar 8.
Abstract/Text
Ritonavir, a protease inhibitor (PI), is a potent inhibitor of cytochrome P450 3A4. This pharmacological effect, even at low doses (
Smita K Baid, Ninet Sinaii, Matt Wade, Domenica Rubino, Lynnette K Nieman
Radioimmunoassay and tandem mass spectrometry measurement of bedtime salivary cortisol levels: a comparison of assays to establish hypercortisolism.
J Clin Endocrinol Metab. 2007 Aug;92(8):3102-7. doi: 10.1210/jc.2006-2861. Epub 2007 Jun 5.
Abstract/Text
CONTEXT: Although bedtime salivary cortisol measurement has been proposed as the optimal screening test for the diagnosis of Cushing's syndrome, its performance using commercially available assays has not been widely evaluated.
OBJECTIVE: Our objective was to compare RIA and tandem mass spectrometry (LC-MS/MS) measurement of salivary cortisol in obese subjects and healthy volunteers.
DESIGN AND SETTING: We conducted a cross-sectional prospective study of outpatients.
SUBJECTS AND METHODS: We studied 261 obese subjects (186 female) with at least two additional features of Cushing's syndrome and 60 healthy volunteers (30 female). Subjects provided split bedtime salivary samples for cortisol measurement by commercially available RIA and LC-MS/MS. Results were considered normal or abnormal based on the laboratory reference range. Subjects with abnormal results underwent evaluation for Cushing's syndrome.
RESULTS: In paired samples, RIA gave a lower specificity than LC-MS/MS in obese subjects (86 vs. 94%, P = 0.008) but not healthy volunteers (86 vs. 82%, P = 0.71). Among subjects with at least one abnormal result, both values were abnormal in 44% (confidence interval 26-62%) of obese and 75% (confidence interval 33-96%) of healthy volunteers. In obese subjects, salivary cortisol concentrations were less than 4.0 to 643 ng/dl (<0.11-17.7 nmol/liter; normal, < or =100 ng/dl, 2.80 nmol/liter) by LC-MS/MS and less than 50 to 2800 ng/dl (1.4-77.3 nmol/liter; normal, < or =170 ng/dl, 4.7 nmol/liter) by RIA. Cushing's syndrome was not diagnosed in any subject.
CONCLUSION: Salivary cortisol levels should not be used as the sole test to diagnose Cushing's syndrome if laboratory-provided reference ranges are used for diagnostic interpretation.
一般社団法人日本内分泌学会．日本ステロイドホルモン学会．厚生労働科学研究費補助金政策研究事業「副腎ホルモン産生異常に関する調査研究」班より．「日本内分泌学会臨床重要課題 潜在性クッシング症候群（下垂体性と副腎）の診断基準の作成．「副腎性サブクリニカルクッシング症候群 新診断基準」の作成と解説．2017年.
Giorgio Arnaldi, Tatiana Mancini, Barbara Polenta, Marco Boscaro
Cardiovascular risk in Cushing's syndrome.
Pituitary. 2004;7(4):253-6. doi: 10.1007/s11102-005-1172-7.
Abstract/Text
Chronic cortisol hypersecretion causes central obesity, hypertension, insulin resistance, dyslipidemia, protrombotic state, manifestations which form a metabolic syndrome in all patients with Cushing's syndrome. These associated abnormalities determine an increased cardiovascular risk not only during the active phase of the disease but also long after the "biomedical remission". Clinical management of these patients should be particularly careful in identifying global cardiovascular risk. Considering that remission from hypercortisolism is often difficult to achieve care and control of all cardiovascular risk factors should be one of the primary goals during the follow up of these patients. Extending the indications of the recent consensus on Cushing's syndrome, we suggest to carry out an OGTT to avoid underestimation of diabetes mellitus, an echocardiography and Doppler ultrasonography of the epiaortic vessels in all patients at diagnosis and during follow-up.
B Swearingen, B M Biller, F G Barker, L Katznelson, S Grinspoon, A Klibanski, N T Zervas
Long-term mortality after transsphenoidal surgery for Cushing disease.
Ann Intern Med. 1999 May 18;130(10):821-4.
Abstract/Text
BACKGROUND: Untreated Cushing disease historically has a high mortality rate, but the long-term survival of patients with Cushing disease after transsphenoidal surgery has not been reported.
OBJECTIVE: To determine long-term mortality rate in patients who are treated for Cushing disease with current management techniques.
DESIGN: Retrospective case series.
SETTING: Tertiary care center.
PATIENTS: 161 patients (32 men and 129 women; mean age, 38 years) who were treated for Cushing disease between 1978 and 1996.
INTERVENTION: Transsphenoidal adenomectomy and as-needed adjunctive therapy.
MEASUREMENT: Record review with follow-up interview.
RESULTS: The cure rate for patients with microadenomas who had no previous therapy was 90% (123 of 137). No perioperative deaths occurred (0 of 193 procedures [95% CI, 0.0% to 1.9%]). Follow-up data (mean, 8.7 years) were obtained for 99% of patients (159 of 161). Six patients died. The 5- and 10-year survival rates were 99% (CI, 97% to 100%) and 93% (CI, 88% to 99%), respectively. Survival was similar to that seen in an age- and sex-matched sample that was based on U.S. population data (standardized mortality ratio, 0.98 [CI, 0.44 to 2.2]; P > 0.2).
CONCLUSION: Survival of patients treated for Cushing disease with current management techniques between 1978 and 1996 was better than the poor survival historically associated with this disorder.
A Colao, R Pivonello, S Spiezia, A Faggiano, D Ferone, M Filippella, P Marzullo, G Cerbone, M Siciliani, G Lombardi
Persistence of increased cardiovascular risk in patients with Cushing's disease after five years of successful cure.
J Clin Endocrinol Metab. 1999 Aug;84(8):2664-72. doi: 10.1210/jcem.84.8.5896.
Abstract/Text
Patients with Cushing's disease (CD) mainly die because of cardiovascular accidents. The aim of this study was to evaluate whether patients with CD still have increased cardiovascular risk and suffer from premature atherosclerosis once cured. Fifteen patients cured from CD for a long term period (5 yr), 30 sex-and age-matched controls, and 30 body mass index (BMI)-matched controls were included in this study. BMI; waist to hip ratio (WHR); systolic (SBP) and diastolic (DBP) blood pressures; serum total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol; serum triglycerides, fibrinogen, and lipoprotein(a) levels; prothrombin time; activated partial thromboplastine time; and basal and glucose load-stimulated insulin and glucose levels were measured in patients and controls. By echo-Doppler ultrasonography, the intima media thickness (IMT), systolic and diastolic media-media distances, blood systolic (SPV) and diastolic (DPV) peak velocity, systolic (SLD) and diastolic (DLD) lumen diameter, and distensibility coefficient (DC) were measured at both common carotid arteries where the presence, size, and location of atherosclerotic plaques were also evaluated. Compared with a sex- and age-matched control population, CD patients had BMI (P < 0.001), WHR (P < 0.001), SBP (P < 0.005), DBP (P < 0.05), fasting glucose (P < 0.001) and insulin (P < 0.05), glucose load-stimulated glucose and insulin levels (P < 0.05), total cholesterol (P < 0.05), LDL cholesterol (P < 0.01), fibrinogen (P < 0.01), and lipoprotein(a) (P < 0.05) levels higher and HDL cholesterol levels (P < 0.05) lower than controls. At ultrasonography, in the patients, IMT (P < 0.05), SPV (P < 0.05) and DPV (P < 0.001) were significantly increased whereas SLD (P < 0.001), DLD (P < 0.001), and DC (P < 0.05) were significantly decreased compared to controls. In addition, CD patients had higher WHR (P < 0.05), DBP (P < 0.05), glucose load-stimulated glucose and insulin levels (P < 0.05), and fibrinogen levels (P < 0.01) and lower HDL cholesterol (P < 0.05) levels than BMI-matched controls. At ultrasonography, increased common carotid arteries IMT (P < 0.05) and DPV (P < 0.05) and decreased DLD (P < 0.05) and DC (P < 0.05) were measured in patients compared to those in BMI-matched controls. Atherosclerotic plaques were found in 26.7% of patients, in none of the sex- and age-matched controls, and in 3.3% of the BMI-matched controls. In CD patients, a significant correlation was found between both WHR and fasting serum insulin levels and DBP (r = 0.52 and r = 0.55; P < 0.05), triglycerides levels (r = 0.56 and r = 0.77; P < 0.05), and IMT (r = 0.64 and r = 0.56; P < 0.05). Right (r = -0.70; P < 0.005) and left (r = -0.65; P < 0.01) DC were inversely correlated to the duration of CD in the patient group. At the multiple regression analysis, WHR was the best predictor of fasting insulin levels (beta = 0.77; P < 0.05), and vice versa, fasting insulin level was the best predictor of WHR (beta = 1.20; P < 0.05). In conclusion, patients cured from CD for a long term period have a high prevalence of atherosclerosis and maintain increased several cardiovascular risk factors of the active disease, probably due to a residual abdominal obesity and/or insulin resistance syndrome.
