“Subclinical Cushing’s syndrome” is not subclinical: improvement after adrenalectomy in 9 patients

doi:10.1016/j.surg.2007.10.001

Surgery

Volume 142, Issue 6, December 2007, Pages 900-905.e1

https://doi.org/10.1016/j.surg.2007.10.001 Get rights and content

Background

A subgroup of patients with adrenal cortisol hypersecretion fails to meet the biochemical criteria for Cushing’s syndrome. Appropriate therapy for this entity, subclinical Cushing’s syndrome (subclinical CS), is unclear. We examined outcomes for patients who underwent unilateral adrenalectomy for subclinical CS.

Methods

Between 2003 and 2006, all patients who underwent adrenalectomy for cortisol hypersecretion caused by an adrenal mass were examined. We analyzed biochemical, metabolic, and clinical outcomes.

Results

Overall, 24 patients underwent adrenalectomy for adrenal cortisol hypersecretion, of which 9 were found to have subclinical CS. Median serum cortisol was 2.0 μg/dL (range, 1.1–6.1) after 1-mg overnight dexamethasone suppression testing. Suspicious clinical findings on preoperative examination included skin bruising, unexplained weight gain, proximal muscle weakness, abnormal fat pads, skin thinning, fatigue, and facial plethora. During a median follow-up period of 5 months (range, 1–30 months), all 8 patients with easy bruising noted resolution postoperatively. Fatigue improved in 4 of 5 patients, muscle weakness in 6 of 8 patients, and weight in 7 of 9 patients, with a median body mass index change of –2.0 kg/m² (range, –7.1 to +0.5 kg/m²).

Conclusion

Adrenalectomy improves clinical and metabolic parameters for many patients with subclinical CS.

Section snippets

Methods

We reviewed retrospectively the records of patients who underwent adrenalectomy for hypercortisolism of adrenal origin over a 40-month period at the University of Texas Southwestern Medical Center. Patient complaints of recent unexpected weight gain and excessive fatigue, as well as clinicians’ assessment of easy bruising, proximal weakness, abnormal supraclavicular and dorsocervical fat pads, thin skin, and facial plethora, were extracted from clinic data. Patients with overt CS (defined as

Results

The mean age of the patients was 52.3 years (range, 35–80 years); all were Caucasian, and 8 of 9 were women. Median body mass index (BMI) preoperatively was 33 kg/m² (range, 25.2–41.2 kg/m²). Of the 9 patients, 8 had hypertension (all on medication) and 3 had type 2 diabetes. Mean adrenal mass diameter by CT was 3.1 cm (range, 0.6–5.2 cm). Laboratory, pathology, and imaging results are noted in Table II, Table III.

Three patients had bilateral lesions on CT and underwent adrenal vein sampling to

Discussion

The major finding of this study is that many patients with subclinical CS and adrenal masses improve considerably after adrenalectomy. Our study is the largest series of surgical outcomes reported in subclinical CS to date. Although the biochemical definition of subclinical CS is still unresolved, we have found that extensive biochemical testing, in conjunction with our clinical characterization (Table I), defines a subgroup that appear to benefit from adrenalectomy.

Subclinical CS seems to be

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To describe the approach to primary aldosteronism as a common disease.
The study methods involved are literature review and personal experience.
Primary aldosteronism is the most common form of endocrine hypertension, yet screening rates are abysmally low. Major reasons for low screening rates include misconceptions about the drug interference and limited access to adrenal vein sampling expertise for subtyping. The workup of primary aldosteronism is greatly simplified by considering the condition as a continuum with low-renin primary hypertension. Thus, the purpose of the evaluation is not a yes/no dichotomous diagnosis but rather a gauging of how likely the patient has a lateralized source and will benefit from unilateral adrenalectomy. This approach favors the selective rather than universal use of cross-sectional imaging and adrenal vein sampling but promotes the liberal use of mineralocorticoid-receptor antagonists.
The review will develop a practical approach to the patient using a series of questions with answers from the literature.
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Hypercortisolism may be considered as a continuum in terms of both hormonal and cardiometabolic abnormalities. It ranges from cases with “normal” hormonal profile and low to intermediate risk of comorbidity to florid cases with clear clinical and hormonal evidence of glucocorticoid excess and clearly increased cardiometabolic risk. Even in patients with nonfunctioning adrenal incidentaloma (NFAI), defined as adrenal incidentaloma with normal results on the currently available hormonal test for evaluation of hypercortisolism, cardiometabolic and mortality risk is higher than in the general population without adrenal lesions. Mild hypercortisolism or autonomous cortisol secretion (ACS) is a term used for patients with adrenal incidentaloma and pathological dexamethasone suppression test (DST) results, but without specific clinical signs of hypercortisolism. It is widely known that this condition is linked to higher prevalence of several cardiometabolic comorbidities, including diabetes, hypertension, osteoporosis and metabolic syndrome, than in patients with NFAI or without adrenal tumor. In case of overt Cushing's syndrome, cardiovascular risk is extremely high, and standard mortality ratio is high, cardiovascular disease being the leading cause of death. The present review summarizes the current evidence for a detrimental cardiometabolic profile in patients with possible (NFAI), probable (ACS) and certain hypercortisolism (overt Cushing's syndrome).
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The latter examples can take place in Congenital Adrenal Hyperplasia (CAH), as well as other inflammatory, psychiatric, and metabolic disorders [8,9]. Similarly, Cushing's disease and Addison's disease are both prominent adrenal disorders where clinical testing showcases clear signs of irregular levels of corticosteroids [10,11]. Circulating cortisol-cortisone can therefore function as biomarkers that allow for the detection and monitoring of chronic stresses, adrenal disorders, and more.
High-Performance Liquid Chromatography-Tandem Mass Spectrometry has emerged triumphant over the years as a reliable and high throughput clinical instrument to assess different metabolic irregularities. One of the latest applications of LC-MS/MS has been in the field of quantification of glucocorticoids, such as cortisol and cortisone from saliva, that can be an indicator of abnormalities such as Congenital Adrenal Hyperplasia (CAH), Cushing's Syndrome, and Addison's disease. We have developed and validated an LC-MS/MS-based assay for simultaneous detection of cortisol and cortisone in human saliva, which requires only 20 µL of sample, to measure cortisol across a 0.5 – 70 ng/mL range, and cortisone across a 1.2– 100 ng/mL range, respectively. The developed method exhibits linearity of R²>0.99, for both analytes, inclusive of both MRMs, and a percent coefficient of variation that is less than or equal to 20%. Using dilute-and-shoot for sample preparation, we have exhibited sample accuracy of 100±20 for the assay calibrators, and integrated Needle Wash Solvent Chemistry for minimal sample carryover, making it adaptable for crucial for potential diagnostic use. We have exhibited a method that is simplistic, specific, and highly automatable on liquid handling platforms, such as the JANUS® G3 Workstation. With our innovation, we have introduced a potential to test 81-unknown samples in singlicate within an on-deck plating time of fewer than four minutes. We performed additional verification studies, including an accelerated stability study and a freeze-thaw study showcasing the potential long-term usability of our proposed prototype kit. Overall, this work presents an optimized LC-MS/MS method with automated sample preparation that is ready to be utilized for cortisol-cortisone detection for clinical diagnostic contexts related to Cushing's Disease, among other adrenal and endocrine disorders.
Cardiovascular complications of mild autonomous cortisol secretion
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Therefore, it is not always easy to assess whether and to what extent these comorbidities are due to the cortisol excess. Taken together, the studies comparing surgical and conservative management of MACS patients have generally described a significant improvement of some cardiometabolic risk factors (in particular blood pressure, glycaemia and body weight) after adrenalectomy in about half of MACS patients [86–89]. In keeping with these data, a retrospective non-randomized study showed that in case of conservative treatment, blood pressure, glycaemia and cholesterol worsened (in 50, 37.5 and 50% of patients, respectively) more frequently than in surgically treated patients (0, 0 and 24%, respectively) [88].
Adrenal incidentalomas (AI) may be associated with a mild autonomous cortisol secretion (MACS) in up to one third of cases. There is growing evidence that MACS patients actually present increased risk of cardiovascular disease and higher mortality rate, driven by increased prevalence of known cardiovascular risk factors, as well as accelerated cardiovascular remodelling. Adrenalectomy seems to have cardiometabolic beneficial effects in MACS patients but their management is still a debated topic due to the lack of high-quality studies. Several studies suggested that so called “non-functioning” AI may be actually “functioning” with an associated increased cardiovascular risk. Although the individual cortisol sensitivity and peripheral activation have been recently suggested to play a role in influencing the cardiovascular risk even in apparently eucortisolemic patients, to date the degree of cortisol secretion, as mirrored by the cortisol levels after dexamethasone suppression test remains the best predictor of an increased cardiovascular risk in AI patients. However, whether or not the currently used cut-off set at 50 nmol/L for cortisol levels after dexamethasone suppression could be considered completely reliable in ruling out hypercortisolism remains unclear.
THE QUANTITATIVE RELATIONSHIP between AUTONOMOUS CORTISOL SECRETION, DYSGLYCEMIA and the METABOLIC SYNDROME
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In 2 small pilot studies, short-term treatment with the glucocorticoid receptor antagonist mifepristone demonstrated significant reductions in FPG and insulin resistance, measured by the homeostatic model assessment for insulin resistance (33,34). Several studies, including a small prospective trial, have demonstrated improvement in the glycemic burden, BP values, and body weight following surgical resection of an adrenal mass associated with ACS (35–40). The 2016 European society of endocrinology guidelines recommend an individualized approach for the management of patients with biochemical evidence of ACS and cortisol-related comorbidities (i.e., hypertension, type 2 diabetes, obesity, and osteoporosis) (3).
Objective: Autonomous cortisol secretion (ACS) is the most common endocrine abnormality in the evaluation of adrenal incidentalomas. The categorization of ACS is derived from a 1 mg dexamethasone suppression test (DST). Impaired DST is associated with several metabolic derangements. In this study we analyzed the association between post-DST cortisol level, analyzed as a continuous parameter, and indices of glycemic metabolism.
Methods: We prospectively collected data of 1,976 patients evaluated for adrenal incidentalomas in a large tertiary medical center between December 1, 2017, and August 31, 2019. Seventy-three patients completed the evaluation process. Post-DST cortisol levels were analyzed for correlation with various metabolic parameters, including fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) among the general cohort and for subgroups stratified by the number of metabolic syndrome (MS) criteria.
Results: Post-DST cortisol demonstrated a linear association with FPG and HbA1c across its entire cortisol range (R = 0.51 and 0.41, respectively; P≤.01). The association between post-DST cortisol and FPG was strengthened with an increased number of metabolic syndrome criteria. Patients with 4 MS criteria show a stronger association (R = 0.92) compared to patients with only a single criterion (R = 0.509). Furthermore, mean post-DST cortisol levels increased as the number of MS criteria accumulated.
Conclusion: Post-DST cortisol should be viewed as a continuous parameter in risk stratification algorithms for the development of MS and particularly dysglycemia.
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Objective: The objective of this Disease State Clinical Review is to provide clinicians with a practical approach to the evaluation of incidentally discovered adrenal masses.
Methods: A case-based clinical approach to the evaluation of adrenal masses is presented. Recommendations were developed using available prospective and randomized studies, cohort studies, cross-sectional studies, anecdotal observations, and expert opinions.
Results: Incidentally discovered adrenal masses are common. The approach to the patient with an adrenal mass should involve assessment of malignant potential via imaging characteristics and adrenal hormone excess via clinical and biochemical features. The roles of biopsy, surgical or medical therapy, and longitudinal surveillance are also important to consider and are influenced by case-specific factors. Inappropriate or inadequate evaluations may put patients at increased risk for developing preventable adverse cardiometabolic outcomes or cancer.
Conclusion: Incidentally discovered adrenal masses require a multimodal assessment that involves interpretation of multiple imaging characteristics, dynamic and static hormonal measurements, and a nuanced approach to considering interventional diagnostics, treatments, and longitudinal surveillance. Herein, we review these evaluations and provide a practical approach for clinicians.
Abbreviations: ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; DHEAS = dehydroepiandrosterone sulfate; HU = Hounsfield units; MRI = magnetic resonance imaging; UFC = urinary free cortisol

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American Association of Endocrine Surgeons“Subclinical Cushing’s syndrome” is not subclinical: improvement after adrenalectomy in 9 patients

Background

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Lancet

Lancet

Lancet

Metabolism

Endocrinol Metab Clin North Am

Endocrinol Metab Clin North Am

Morbidity and mortality in Cushing’s disease: an epidemiological approach

Clin Endocrinol

Occult Cushing’s syndrome in type-2 diabetes

J Clin Endocrinol Metab

Diagnosis and management of Cushing’s syndrome: results of an Italian multicentre studyStudy Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis

J Clin Endocrinol Metab

Urinary free cortisol and cortisone determined by high performance liquid chromatography in the diagnosis of Cushing’s syndrome

J Clin Endocrinol Metab

The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing’s syndrome

J Clin Endocrinol Metab

Evidence for the low dose dexamethasone suppression test to screen for Cushing’s syndrome—recommendations for a protocol for biochemistry laboratories

Ann Clin Biochem

American Association of Endocrine Surgeons
“Subclinical Cushing’s syndrome” is not subclinical: improvement after adrenalectomy in 9 patients