Low catestatin as a risk factor for cardiovascular disease - assessment in patients with adrenal incidentalomas.

Background: Catestatin (Cts) is a peptide derived from proteolytic cleavage of chromogranin A, which exhibits cardioprotective and anti-inflammatory properties. Cts has been proposed as a potential biomarker for cardiovascular (CV) disease. Objectives: examining Cts in patients with incidentally discovered adrenocortical adenomas (AI), and its associations with CV risk factors and blood pressure (BP). Materials and methods: In this cross-sectional study, 64 AI patients without overt CV disease other than primary hypertension were recruited along with 24 age-, sex-, and body-mass-index (BMI)-matched controls with normal adrenal morphology. Laboratory, 24-h ambulatory BP monitoring, echocardiography, and common carotid artery sonography examinations were performed. Results: Unadjusted Cts was higher in AI patients (median 6.5, interquartile range: 4.9-37 ng/ml) versus controls (4.5 (3.5 - 28)), p=0.048, however, the difference was insignificant after adjusting for confounding variables. Cts was lower in subjects with metabolic syndrome than in those without it (5.2 (3.9- 6.9) vs. 25.7 (5.8-115) ng/ml, p<0.01), and in men compared to women (4.9 (4-7.4) ng/ml vs. 7 (4.8-100), p=0.015). AI patients in the lower half of Cts levels compared to those in the upper had a higher prevalence of hypertension (OR 0.15, 95% CI: 0.041-0.5, p<0.001) and metabolic syndrome (OR 0.15, 95% CI 0.041-0.5, p<0.001). In AI patients Cts correlated positively with high-density lipoprotein cholesterol (Spearman's r=0.31), negatively with BMI (r=-0.31), and 10-year atherosclerotic CV disease risk (r=-0.42). Conclusions: Our data indicate associations between CV risk factors and Cts. More clinical research is needed to apply serum Cts as a biomarker.

Assessment of subclinical cardiovascular alterations in nonfunctioning adrenal incidentalomas.

BACKGROUND: Adrenal incidentalomas have been associated with increased cardiovascular risk and have a prevalence as high as 10%. This study aims to evaluate carotid- intima media thickness (CIMT), left ventricular mass, and epicardial adipose tissue thickness in nonfunctioning adrenal incidentaloma patients and compare their results with healthy controls. METHODS: Patients who were referred to the endocrinology clinic for adrenal incidentaloma between 2014 and 2019 were assessed with 1 mg dexamethasone suppression test, 24-h urine metanephrines and normetanephrines, plasma aldosterone to renin ratio. Age and gender-matched subjects without an adrenal mass formed the control group. Left ventricular mass, epicardial adipose tissue thickness, and CIMT of both groups were measured. RESULTS: A total of 41 adrenal incidentaloma patients (21 female, 52.5%) and 40 healthy controls (19 female, 46.3%) were included in the study. Patients with adrenal incidentalomas had increased CIMT. No differences were observed in left ventricle mass or epicardial adipose tissue thickness. There was no correlation between CIMT and adenoma size or serum cortisol (p = 0.2 and p = 0.6, respectively). There was a statistically significant correlation between CIMT and age (p = 0.016, r = 0.295). HBA1c (p = 0.001) and age (p = 0.05) were independently associated with CIMT in regression analysis. DISCUSSION: Adrenal incidentaloma patients need to be monitored for cardiac dysfunction. CIMT may be used to evaluate adrenal incidentaloma patients for early cardiovascular risk.

A Modern Assessment of Cancer Risk in Adrenal Incidentalomas: Analysis of 2219 Patients.

OBJECTIVE: The aim of this study was to analyze the incidence of and risk factors for adrenocortical carcinoma (ACC) in adrenal incidentaloma (AI). SUMMARY OF BACKGROUND DATA: AI guidelines are based on data obtained with old-generation imaging and predominantly use tumor size to stratify risk for ACC. There is a need to analyze the incidence and risk factors from a contemporary series. METHODS: This is a retrospective review of 2219 AIs that were either surgically removed or nonoperatively monitored for ≥12 months between 2000 and 2017. Multivariate logistic regression was performed to define risk factors. ROC curves constructed to determine optimal size and attenuation cut-offs for ACC. RESULTS: 16.8% of AIs underwent upfront surgery and rest initial nonoperative management. Of conservatively managed patients, an additional 7.7% subsequently required adrenalectomy. Overall, ACC incidence in AI was 1.7%. ACC rates by size were 0.1%, 2.4%, and 19.5% for AIs of <4, 4 to 6, and >6 cm, respectively. The optimal size cut-off for ACC in AI was 4.6 cm. ACC risks by Hounsfield density were 0%, 0.5%, and 6.3% for lesions of <10, 10 to 20, and >20 HU, with an optimal cut-off of 20 HU to diagnose ACC. 15.5% of all AIs and 19.2% of ACCs were hormonally active. Male sex, large tumor size, high Hounsfield density, and >0.6 cm/year growth were independent risk factors for ACC. CONCLUSION: This contemporary analysis demonstrates that ACC risk per size in AI is less than previously reported. Given these findings, modern management of AIs should not be based just on size, but a combination of thorough hormonal evaluation and imaging characteristics.

Frequency of masked hypertension in patients with nonfunctioning adrenal incidentalomas with normal and high normal blood pressure.

OBJECTIVES: Nonfunctioning adrenal incidentalomas (NFAIs) are associated with increased cardiovascular risk, but the frequency of masked hypertension (MH) is uncertain in these patients. This study aimed to evaluate the prevalence of MH by ambulatory blood pressure monitoring in patients with NFAIs. METHODS: The study included a total of 85 individuals: 43 patients with NFAIs and 42 controls of similar age, gender, BMI, smoking, and diabetes. The office BP and ABPM parameters of the NFAI and controls were measured. Biochemical, hormonal, and radiological data were obtained retrospectively in the NFAI group. RESULTS: There were no statistically significant difference between the NFAI and control groups in relation to the office SBP (134.4 ± 37.2 mmHg vs 133.1 ± 35.8 mmHg, p = 0.273) and office DBP (87.4 ± 14.5 mmHg vs 86.8 ± 13.7 mmHg, p = 0.318). Besides, normal (28% vs 28.6%, p = 0.176) and high normal blood pressure (72% vs 71.4%, p = 0.332) rates were similar. The prevalence of MH was significantly higher in patients with NFAI than in controls (25.5% vs 9.5%, p = 0.037). MH was significantly associated with diabetes odds ratio (OR) = 2.07, p = 0.044, office SBP (OR = 1.41, p = 0.046), smoking (OR = 1.46, p = 0.031), BMI (OR = 1.17, p = 0.037), and morning cortisol (OR = 1.21, p = 0.039). CONCLUSION: The prevalence of MH in the NFAI patient's was higher than in the control group. Patients with NFAI with high normal blood pressure should be evaluated for MH.

IS BIOCHEMICAL ASSESSMENT OF PHEOCHROMOCYTOMA NECESSARY IN ADRENAL INCIDENTALOMAS WITH MAGNETIC RESONANCE IMAGING FEATURES NOT SUGGESTIVE OF PHEOCHROMOCYTOMA?

OBJECTIVE: Currently, it is unclear whether pheochromocytomas can be ruled out based on low intensity on T2-weighted sequences and signal loss on out-of-phase magnetic resonance imaging (MRI) sequences. Hence, in this study, we investigated whether biochemical screening for pheochromocytoma in patients with adrenal incidentalomas (AIs) showing MRI features not suggesting pheochromocytoma would prove beneficial. METHODS: We performed MRI for 300 AIs in 278 consecutive patients. All patients were screened for pheochromocytoma with plasma metanephrine and normetanephrine. Patients with high plasma levels of metanephrine and/or normetanephrine were also assessed for pheochromocytoma by urinary metanephrines. RESULTS: Hyperintensity was detected on T2-weighted MRI sequences in 28 (9.3%) of the 300 AIs. Among these 28 incidentalomas, pheochromocytoma was diagnosed in 13 (46.4%) of the cases by histopathologic analysis. Hyperintensity on T2-weighted MRI was significantly higher in pheochromocytomas compared to the remaining AIs (P<.001). All 13 pheochromocytomas were characterized by hyperintensity on T2-weighted sequences and the absence of signal loss on out-of-phase MRI sequences. Pheochromocytoma was not detected in any of the 272 AIs that appeared hypointense or isointense on T2-weighted MRI sequences or in the 250 cases with signal loss on out-of-phase sequences. CONCLUSION: The results of this study suggest that AIs that appear hypointense or isointense on T2-weighted MRI sequences and those with signal loss on out-of-phase sequences may not require routine biochemical screening for pheochromocytoma. Further studies including a higher number of pheochromocytomas are required to confirm our results.

Screening for adrenal-endocrine hypertension: overview of accuracy and cost-effectiveness.

Formal studies have not been performed to assess the cost-effectiveness of screening strategies for endocrine causes of hypertension. However, an understanding of the diagnostic accuracy of available screening tests and the clinical settings where disease identification will lead to improved health outcomes form the basis for a cost-effective strategy. Primary aldosteronism screening should be selective and restricted to settings where knowledge of the diagnosis has the greatest chance of improving health outcomes. Pheochromocytoma is rare; however, because it is a potentially fatal disease, screening strategies should err on the side of not missing the diagnosis, especially in high-risk clinical settings.

Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink?

OBJECTIVE: To assess the performance of current clinical recommendations for the evaluation of an adrenal incidentaloma. DESIGN AND METHODS LITERATURE REVIEW: Electronic databases (Pubmed, Ovid and citation searches from key articles) from 1980 to 2008 were searched. Eligible studies were those deemed most applicable to the clinical scenario of a patient referred to an endocrinologist for assessment of an incidentally detected adrenal mass. Surgical series, histopathological series and oncological series were reviewed and most were excluded. RESULTS: The prevalence of functional and malignant lesions presenting as adrenal incidentaloma was similar to that quoted in most reviews, other than a lower incidence of adrenal carcinoma (1.9 vs 4.7%) and metastases (0.7 vs 2.3%). The development of functionality or malignancy during follow-up was rare (<1% becoming functional and 0.2% becoming malignant). During follow-up, false-positive rates of the recommended investigations are typically 50 times greater than true positive rates. The average recommended computed tomography (CT) scan follow-up exposes each patient to 23 mSv of ionising radiation, equating to a 1 in 430 to 2170 chance of causing fatal cancer. This is similar to the chance of developing adrenal malignancy during 3-year follow-up of adrenal incidentaloma. CONCLUSION: Current recommendations for evaluation of adrenal incidentaloma are likely to result in significant costs, both financial and emotional, due to high false-positive rates. The dose of radiation involved in currently recommended CT scan follow-up confers a risk of fatal cancer that is similar to the risk of the adrenal becoming malignant. This argues for a review of current guidelines.

Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation?

BACKGROUND: According to previous studies, around 15% of patients with an apparently sporadic pheochromocytoma and a negative family history had a hereditary disease. This high frequency together with the financial support provided to reference laboratories of molecular genetics by the French government led to a nearly systematic screening in each patient with a pheochromocytoma. OBJECTIVE: To check the efficiency of systematic genetic screening in patients with apparently sporadic pheochromocytoma, by analysing the 6 years experience of a multidisciplinary team in this field. METHODS: One hundred patients with a pheochromocytoma-only phenotype and no family history were included. Patients with extra-adrenal tumours were excluded. Prevalence of hereditary forms was determined and analyzed according to age at onset, sex. Cost of the genetic analysis was calculated. RESULTS: A germline mutation in one of the five susceptibility genes (VHL, RET, SDHD, SDHC, SDHB) was identified in eight patients (8%) with an age of onset between 13 and 57 years. Among them, six had a bilateral pheochromocytoma and only two had a unilateral tumour. If the guidelines for genetic screening were age of onset less than 50 or bilateral pheochromocytoma, no patients with a hereditary tumour would be missed and a 24% cost reduction would be achieved. CONCLUSIONS: According to these data, a genetic predisposition test for hereditary pheochromocytoma seems not recommended in patients with a unilateral adrenal tumour diagnosed after 50 in the absence of familial, clinical, biological or imaging features for a familial disease.

Incidence of pheochromocytoma in trauma patients during the management of unrelated illness: a retrospective review.

BACKGROUND: Over the last two decades the rate of detection of asymptomatic adrenal masses has increased as a result of the widespread use of abdominal imaging modalities. Incidental pheochromocytoma discovered during the management of an unrelated illness is a rare presentation of these tumors. They can occur in patients treated for multiple trauma with no history of prior arterial hypertension. METHODS: From January 1995 to December 2005 a total of 45 patients underwent adrenalectomy for incidentaloma. Of these, a pheochromocytoma was detected in 13 patients (29%) seen for an unrelated condition, 3 were in trauma patients. Nine men and 4 women with a mean age 44.5 years (range 21-67) underwent adrenalectomy for incidental pheochromocytoma. RESULTS: Less than half (6 patients, 46%), and one of the trauma patients had a history of arterial hypertension. Preoperative hormonal studies revealed a pheochromocytoma in 11 patients with incidentalomas. One patient had normal preoperative catecholamines levels. Laparoscopic transabdominal adrenalectomy was attempted in 10 patients with one conversion to open surgery in the case of paraganglioma and one for injury to the left renal vein. Three patients underwent open adrenalectomy. Mean surgery time of trauma patients was 167 (range, 130-235) min. Intraoperative instability (systolic pressure >200 mmHg) requiring nitroprusside and/or labetalol, was observed in 7 patients (54%). There was no postoperative morbidity or mortality. Over the last 10 years, 23% of the pheochromocytomas found incidentally were in trauma patients. CONCLUSION: Incidentally discovered adrenal masses need to be investigated for pheochromocytoma. This holds specially true for trauma patients who may be put in serious jeopardy should they need surgery for their injuries.

[Assessment and treatment of incidentally discovered adrenal tumors]. / Valutazione e trattamento degli incidentalomi del surrene.

An incidentally discovered adrenal mass involves two main questions: the first is the evaluation of the hormonal activity of incidentalomas, that by definition are considered clinically silent. The second problem is to establish preoperatively the biologic behaviour of the masses, whether they are benign or malignant. An essential endocrinological screening of these masses includes the 24 hour urine VMA determination, serum potassium level, and a 1 mg overnight dexamethasone suppression test. Furthermore, the recent observation of a possible partial deficit of 21-hydroxylase suggests the advantage of 17-hydroxyprogesterone dosage after ACTH stimulation. At present no biochemical or radiologic markers can reliably distinguish benign from malignant masses. For this reason the association of imaging study with scintigraphy seems to be helpful, providing "concordant" or "discordant" patterns with CT images. As regard to therapeutic indications, the resection of all hypersecretive masses, proved malignant or increased in diameter tumors is suggested. As regards to biochemically silent lesions, the tumor size has been deemed to be the most helpful determinant of the nature although controversy remains over the size cutoff below which the masses can safely be presumed to be benign and therefore observed. The threshold to proceed surgically has been based on the perceived risk of cancer balanced against the operative risk. However it seems reasonable to recommend excision or surgical exploration for hormonally silent tumors greater than 3 cm, particularly in younger patients. According to personal opinion the laparoscopic approach might represent the gold standard in the treatment of incidentally discovered adrenal masses.