Non-functioning Adrenal Incidentalomas Research Articles

A retrospective study on the association between urine metanephrines and cardiometabolic risk in patients with nonfunctioning adrenal incidentaloma

Several studies argued that cardiovascular evaluation of patients with nonfunctioning adrenal incidentaloma is of particular importance. Therefore, we aimed to evaluate the possibility of stratifying the cardiometabolic risk using metanephrine levels in this setting of patients. A retrospective cross-sectional study was designed, collecting data of metanephrine values in 828 patients with nonfunctioning adrenal incidentaloma, referred to our Division within the University of Turin between 2007 and 2021. The univariate analysis showed associations between urine metanephrines and cardiometabolic variables/parameters, particularly considering the noradrenaline metabolite. At the univariate regression, normetanephrine was associated with metabolic syndrome (OR = 1.13, p = 0.002), hypertensive cardiomyopathy (OR = 1.09, p = 0.026), microalbuminuria (OR = 1.14, p = 0.024), and eGFR < 60 mL/min/1.73 m2 (OR = 1.11, p = 0.013), while metanephrine was associated with microalbuminuria (OR = 1.50, p = 0.008). At multivariate regression, considering all major cardiovascular risk factors as possible confounders, normetanephrine retained a significant association with metabolic syndrome (OR = 1.10, p = 0.037). Moreover, metanephrine retained a significant association with the presence of microalbuminuria (OR = 1.66, p = 0.003). The present study showed a further role for metanephrines in the cardiovascular risk stratification of patients with nonfunctioning adrenal incidentaloma. Individuals with high levels of these indirect markers of sympathetic activity should be carefully monitored and may benefit from an aggressive treatment to reduce their additional cardiometabolic burden.

Characterisation of the urinary steroid profile of patients with nonfunctioning adrenal incidentalomas: A matched controlled cross-sectional study.

To identify alterations in steroid metabolism in patients with nonfunctioning adrenal incidentalomas (NFAIs) through the analysis of their urinary steroid profile (USP). Cross-sectional study with one study group (NFAIs, cortisol post dexamethasone suppression test [DST] ≤ 1.8 µg/dl [49.7 nmol/L]) and 2 control groups: patients with autonomous cortisol secretion (ACS group, cortisol post-DST > 1.8 µg/dl (49.7 nmol/L) and patients without adrenal tumours (healthy-adrenal group). Twenty-four-hoururine collections for USP measurement (total and free fraction of 51 24 h-urine specimens) were obtained from 73 participants (24 with NFAIs, 24 without AIs, and 25 with ACS). USP was determined by gas chromatography coupled to mass spectrometry. Patients of the three groups were matched according to sex, age (±5 years-old) and body mass index (±5 kg/m2 ). Compared to healthy-adrenal controls, patients with NFAIs had a lower excretion of androgen metabolites (230.5 ± 190.12 vs. 388.7 ± 328.58 µg/24 h, p = .046) and a higher excretion of urinary free cortisol (UFC) (54.3 ± 66.07 vs. 25.4 ± 11.16 µg/24 h, p = .038). UFC was above the reference range in 20.8% of patients in the NFAI, compared to 0% in the healthy-adrenal group (p = .018). Patients with ACS had a higher prevalence of hypertension, dyslipidemia, and diabetes than patients with NFAIs or the control group. A lower excretion of androgen metabolites (218.4 ± 204.24 vs. 231 ± 190 µg/24 h, p = .041) and a nonsignificant higher excretion of glucocorticoid metabolites (2129.6 ± 1195.96 vs. 1550.8 ± 810.03 µg/24 h, p = .180) was found in patients with ACS compared to patients with NFAIs. NFAIs seem to secrete a subtle, yet clinically relevant, excess of glucocorticoids. Future studies are needed to confirm our findings; and to identify metabolic alterations associated with an increased cardiometabolic risk.

A machine learning approach to distinguishing between non-functioning and autonomous cortisol secreting adrenal incidentaloma on magnetic resonance imaging using texture analysis.

To investigate the possibility of distinguishing between nonfunctioning adrenal incidentalomas (NFAI) and autonomous cortisol secreting adrenal incidentalomas (ACSAI) with a model created with magnetic resonance imaging (MRI)-based radiomics and clinical features. In this study, 100 adrenal lesions were evaluated. The lesions were segmented on unenhanced T1-weighted in-phase (IP) and opposed-phase (OP) as well as on T2-weighted (T2-W) 3Tesla MRIs. The LASSO regression model was used to select potential predictors from 108 texture features for each sequence. Subsequently, a combined radiomics score and clinical features were created and compared. A significant difference was found between median rad-scores for ACSAI and NFAI in training and test sets (p < 0.05 for all sequences). Multivariate logistic regression analysis revealed that the length of the tumor (OR = 1.09, p = 0.007) was an independent risk factor related to ACSAI. Multivariate logistic regression analysis was used for building clinical-radiomics (combined) models. The Op, IP, and IP plus T2-W model had a higher performance with area under curve (AUC) 0.758, 0.746, and 0.721 on the test dataset, respectively. ACSAI can be distinguished from NFAI with high accuracy on unenhanced MRI. Radiomics analysis and the model constructed by machine learning algorithms seem superior to another radiologic assessment method. The inclusion of chemical shift MRI and the length of the tumor in the radiomics model could increase the power of the test.

Adrenalectomy improves blood pressure control in nonfunctioning adrenal incidentalomas and glycemic and lipid control in patients with autonomous cortisol secretion

To compare the evolution of the cardiometabolic parameters in patients with nonfunctioning adrenal incidentalomas (NFAI) and autonomous cortisol secretion (ACS) who underwent adrenalectomy and those who were conservatively managed. A retrospective study of all patients with NFAI and ACS submitted to surgery or in follow-up in our center between January 2011-October 2020. NFAI was defined as an adrenal incidentaloma with cortisol post-dexamethasone suppression test (DST) ≤ 50 nmol/L and ACS as values >50 nmol/L without specific clinical signs of overt Cushing´s syndrome. A total of 486 patients with NFAI (16 in the surgical group and 470 in the control group) and 259 with ACS (42 in the surgical group and 217 in the control group) were included. At baseline, patients with ACS were older than those with NFAI (P = 0.010). After adjusting by age, patients with ACS had a higher prevalence of hypertension (adjusted OR = 1.9 [1.36-2.60]) and higher levels of fasting plasma glucose and HbA1c (adjusted β = 6.9 [2.05-11.83] and adjusted β = 0.4 [0.12-0.63]) than NFAI. During follow-up, ACS patients who underwent adrenalectomy had a greater decrease in glucose levels (-16.6 ± 45.07 vs. -1.0 ± 26.92 mg/dL, P = 0.035) and in triglycerides (-20.21 ± 55.97 vs. 1.3 ± 59.23 mg/dL, P = 0.029) than ACS patients conservatively managed. NFAI patients who underwent surgery experienced an improvement in systolic blood pressure compared to NFAI of the conservative group (-11.1 ± 15.94 vs 1.0 ± 17.54 mmHg, P = 0.009). The benefits of adrenalectomy in the cardiometabolic profile in adrenal incidentalomas are not limited only to the group of patients with ACS, an improvement in blood pressure control is also observed in NFAI patients after surgery.

A Proposal for Nomenclature Revision of Nonfunctioning Adrenal Incidentalomas as Adrenal Lesions of Undetermined Secretion of Adrenal Steroids (ALUSAS)

In this commentary we propose a change of the nomenclature of non-functioning adrenal incidentalomas (NFAI) to adrenal lesions of undetermined secretion of adrenal steroids (ALUSAS) since there are mounting evidence suggesting that a substantial proportion of so-called NFAIs do actually secrete steroids in excess. In fact, it is known that some NFAIs develop ACS over time. In the commentary we justify the change of term by summarizing the evidence that shows that NFAIs present a higher cardiometabolic risk than the general population, and the metabolomics studies in which an increase in cortisol metabolites is observed in patients with NFAI.

Association between cortisol/DHEA-S ratio and inflammatory indicators in patients with non-functioning adrenal incidentalomas

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

An observational retrospective study on the association of urine metanephrine levels with cardiometabolic risk in patients with nonfunctioning adrenal incidentaloma

An observational retrospective study on the association of urine metanephrine levels with cardiometabolic risk in patients with nonfunctioning adrenal incidentaloma

Clinical sexual dimorphism in patients with nonfunctioning adrenal incidentaloma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

NEW BIOMARKERS TO PREDICT CARDIOVASCULAR RISK IN PATIENTS WITH ADRENAL INCIDENTALOMA; IRISIN AND NESFATIN-1.

In our study, we aimed to investigate the levels of irisin, nesfatin-1 and the relationship between levels of these relatively new molecules with cardiometabolic risk markers; carotid intima-media thickness (CIMT), epicardial adipose tissue (EAT) thickness in patients with nonfunctional adrenal incidentaloma (NFAI). Patients with NFAI (n=59) and age, sex and body mass index-matched healthy control subjects (n=59) were enrolled in this study. Serum glucose, insulin, C-reactive protein (CRP), lipid, irisin and nesfatin-1 levels and echocardiographic CIMT and EAT thickness measurements were performed in patients and controls. The irisin level was 17.58 ± 4.38 pg/mL in the NFAI group, significantly higher (p<0.001) than 14.03 ± 4.03 pg/mL in the control group. Nesfatin-1 level was significantly lower in the NFAI group 194.98 ± 119.15 pg/mL ((p < 0.001)) versus 303.48 ± 200.78 pg/mL in the control group. A positive correlation was found between irisin and nesfatin-1 levels and CIMT and EAT thickness in the NFAI group. In our study, we found that irisin level was higher and nesfatin-1 level was lower in patients with NFAI, and both irisin and nesfatin-1 levels were associated with CIMT and EAT thickness in NFAI patients.

Assessment of subclinical cardiovascular alterations in nonfunctioning adrenal incidentalomas.

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. 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. 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. Adrenal incidentaloma patients need to be monitored for cardiac dysfunction. CIMT may be used to evaluate adrenal incidentaloma patients for early cardiovascular risk.

Predictors of Tumour Growth and Autonomous Cortisol Secretion Development during Follow-Up in Non-Functioning Adrenal Incidentalomas.

Purpose: To assess the risk of developing autonomous cortisol secretion (ACS) and tumour growth in non-functioning adrenal incidentalomas (NFAIs). Methods: Multicentre retrospective observational study of patients with NFAIs. ACS was defined as serum cortisol >1.8 µg/dL after 1 mg-dexamethasone suppression test (DST) without specific data on Cushing’s syndrome. Tumour growth was defined as an increase in maximum tumour diameter >20% from baseline; and of at least 5 mm. Results: Of 654 subjects with NFAIs included in the study, both tumour diameter and DST were re-evaluated during a follow-up longer than 12 months in 305 patients. After a median follow-up of 41.3 (IQR 24.7–63.1) months, 10.5% of NFAIs developed ACS. The risk for developing ACS was higher in patients with higher serum cortisol post-DST levels (HR 6.45 for each µg/dL, p = 0.001) at diagnosis. Significant tumour growth was observed in 5.2% of cases. The risk of tumour growth was higher in females (HR 10.7, p = 0.004). Conclusions: The frequency of re-evaluation with DST in NFAIs during the initial 5 years from diagnosis can probably be tailored to the serum cortisol post-DST level at presentation. Re-evaluation of NFAIs with imaging studies, on the other hand, seems unnecessary in most cases, particularly if the initial imaging demonstrates features specific to typical adenoma, given the low rate of significant tumour growth.

Plasma Steroid Profiling in Patients With Adrenal Incidentaloma.

Most patients with adrenal incidentaloma have nonfunctional lesions that do not require treatment, while others have functional or malignant tumors that require intervention. The plasma steroid metabolome may be useful to assess therapeutic need. This work aimed to establish the utility of plasma steroid profiling combined with metanephrines and adrenal tumor size for the differential diagnosis of patients with adrenal incidentaloma. This retrospective cross-sectional study, which took place at 7 European tertiary-care centers, comprised 577 patients with adrenal incidentaloma, including 19, 77, 65, 104 and 312 respective patients with adrenocortical carcinoma (ACC), pheochromocytoma (PHEO), primary aldosteronism (PA), autonomous cortisol secretion (ACS), and nonfunctional adrenal incidentaloma (NFAI). Mesaures of diagnostic performance were assessed (with [95% CIs]) for discriminating different subgroups of patients with adrenal incidentaloma. Patients with ACC were characterized by elevated plasma concentrations of 11-deoxycortisol, 11-deoxycorticosterone, 17-hydroxyprogesterone, androstenedione, and dehydroepiandrosterone-sulfate, whereas patients with PA had elevations of aldosterone, 18-oxocortisol, and 18-hydroxycortisol. A selection of those 8 steroids, combined with 3 others (cortisol, corticosterone, and dehydroepiandrosterone) and plasma metanephrines, proved optimal for identifying patients with ACC, PA, and PHEO at respective sensitivities of 83.3% (66.1%-100%), 90.8% (83.7%-97.8%), and 94.8% (89.8%-99.8%); and specificities of 98.0% (96.9%-99.2%), 92.0% (89.6%-94.3%), and 98.6% (97.6%-99.6%). With the addition of tumor size, discrimination improved further, particularly for ACC (100% [100%-100%] sensitivity, 99.5% [98.9%-100%] specificity). In contrast, discrimination of ACS and NFAI remained suboptimal (70%-71% sensitivity, 89%-90% specificity). Among patients with adrenal incidentaloma, the combination of plasma steroid metabolomics with routinely available plasma free metanephrines and data from imaging studies may facilitate the identification of almost all clinically relevant adrenal tumors.

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

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

Non-functioning adrenal incidentalomas may increase toxic metabolites.

Non-functioning adrenal incidentaloma (NFAI) is afrequent diagnosis with increasing radiological tests. The emerging shreds of evidence showed that they might have negative cardiometabolic effects. The study aimed to investigate whether the toxic metabolites, asymmetric dimethylarginine (ADMA) levels, were altered in NFAI patients. We included 43NFAI patients and 41controls with similar ages and body mass indices in the study. We compared plasma ADMA levels of both groups and noted the radiological features of NFAIs. The ADMA levels were significantly higher in NFAI patients than in the control group (307.04 ng/ml, range 81.89-577.7 ng/ml vs 192.54 ng/ml, range 70.61-440.26 ng/ml, p = 0.001). Nevertheless, we could not reach asignificant correlation between ADMA levels and mass size. The ADMA is known as atoxin and is increased in NFAI patients. NFAIs may not be innocent and may be considered apotential risk for the body. Further investigations were needed for more explanations.

P23-8 Multiple endocrine neoplasia type 2a syndrome: A tertiary care center experience in Pakistan

Multiple endocrine neoplasia type 2a (MEN-2a) is a rare autosomal dominant disorder. Available literature in the subcontinent is limited. Here we report a case series of MEN-2a patients from two families. This case series was conducted at Shaukat Khanum Memorial Cancer Hospital and Research Center. We included 2 families that fulfilled clinical criteria for MEN-2a. Five patients were clinically diagnosed with MEN-2a syndrome. Mean age at presentation was 22.4 yrs. All 5 patients had medullary thyroid cancer (MTC). Four patients had pheochromocytoma and 1 patient had a nonfunctioning adrenal incidentaloma. One patient had primary hyperparathyroidism (PHPT). All 5 patients underwent total thyroidectomy and 4 patients underwent adrenalectomy. One patient underwent neck exploration surgery for PHPT. Post treatment, 4 patients had resolution of MTC, 1 patient has calcitonin levels which remain high and is under investigation. All 4 patients had resolution of pheochromocytoma post surgery. Only one patient had all three manifestations of MEN-2a. None of the patients underwent genetic testing due to non-availability; therefore MEN-2a was diagnosed purely on clinical grounds. Both families were advised screening for MEN-2a syndrome of all first-degree family members. In this case series, age, clinical presentation and outcomes were like those reported in literature. In our practice we face various challenges such as logistics, lack of availability of genetic testing, financial constraints and poor follow up. Given the above limitations, would the management recommendations for family members of clinically diagnosed MEN-2a patients be the same as for patients who have had positive genetic testing, as international guidelines suggest measures like prophylactic thyroidectomies based on genetic testing. More studies are needed from the subcontinent so that recommendations for MEN 2-a can be made specific to this population.

Natural history of nonfunctioning adrenal incidentalomas: a 10-year longitudinal follow-up study.

Most data on the natural history of nonfunctioning adrenal incidentalomas (NFAI) are provided by follow-ups up to 5 years. We conducted a 10.5 (9.1–11.9)-year prospective follow-up study of NFAI in 67 participants (20 (29.9%) males, 47 (70.1%) females) of mean age 57.9 (52.3–63.9) years and BMI 27.42 (24.07–30.56) kg/m2). We also evaluated the associations between baseline BMI and changes of NFAIs’ characteristics at follow-up. Progression to mild autonomous cortisol excess (MACE) was observed in 15 (22 %) patients, with 14 of them having post overnight dexamethasone suppression test (ODST) cortisol between 50 and138 nmol/L and only one > 138 nmol/L. The progression rate was significantly higher in overweight and obese than in normal-weight subjects. Patients that developed MACE had a significantly higher baseline mean cortisol after 1 mg ODST. Tumor enlargement ≥10 mm occurred in 8.9% of patients. In comparison with reports of shorter observational periods, we observed a higher growth rate ≥ 10 mm and higher progression rate from NFAI to MACE, particularly in overweight and obese subjects. All tumors had persistent radiological characteristics typical for adrenal adenoma. We concluded that the duration of the follow-up period is an important factor in characterizing the natural history of NFAI. Higher baseline BMI and higher baseline cortisol after ODST might predict the long-term likelihood of progression in hormonal activity. The magnitudes of observed progressions in growth or hormonal activity were clinically insignificant. Our long-term follow-up, therefore, clearly supports the general view that a long-term monitoring of patients with NFAI is not necessary.

Assessment of glucolipid metabolism in patients with nonfunctional adrenal incidentaloma

Assessment of glucolipid metabolism in patients with nonfunctional adrenal incidentaloma

Risk of developing autonomous cortisol secretion and/or significant tumor growth in non-functioning adrenal incidentalomas during follow-up

Risk of developing autonomous cortisol secretion and/or significant tumor growth in non-functioning adrenal incidentalomas during follow-up

Nonfunctional adrenal adenomas and impaired glucose metabolism: a systematic review and meta-analysis.

Evidence on nonfunctioning adrenal incidentaloma's (NFAI) associated comorbidities and in particular, glucose disorders, is unclear in contrast to adrenal tumors with mild autonomous cortisol secretion. The current systematic review and meta-analysis aimed to assess the burden of impaired glucose metabolism including diabetes mellitus type 2 (T2DM), fasting blood glucose (FBG), and fasting blood insulin (FBI) levels in patients with NFAI and 1-mg overnight dexamethasone suppression test (ODST) ≤ 1.8 μg/dl across published studies. We searched PubMed, Cochrane, and Scopus databases for identifying studies published between 1956 and March 2021. Twenty-five studies met the selection criteria including prospective, retrospective, and case-control studies. Two reviewers independently extracted studies, participants' characteristics and outcome data in a total pooled sample of 1548 patients. Patients with NFAI had twofold [(odds ratio (OR) (95% confidence interval (CI)): 2.03 (1.39-2.98)] increased odds to present T2DM as well as higher FBG [weighted mean difference (WMD) (95% CI): 3.85 (1.96-5.74)] and homeostasis model assessment (HOMA) [WMD (95% CI): 0.68 (0.23-1.12)] with respect to controls. On the contrary, the WMD of FBI levels did not differ between the two groups. The incidence of T2DM in a subgroup analysis of patients with NFAI without glucose disorders at baseline was 6% [pooled incidence (95% CI): 0.06 (0.04-0.09)]. Patients with NFAI and 1-mg ODST ≤ 1.8 μg/dl presented higher odds of T2DM and higher levels of FBG and HOMA index than healthy controls.

Catecholamine-Producing Adrenal Schwannoma: A Rare Pheochromocytoma Imposter

Abstract Background:Adrenal schwannoma is a tumor of the adrenal medulla that poses a pre-operative diagnostic challenge due to its non-specific imaging findings and rarity. Even more uncommon are functional catecholamine-producing adrenal schwannomas (CPAS) that can lead to the clinical presentation of catecholamine excess. Here, we present a case of biochemically and histopathologically confirmed CPAS and provide a review of the existing cases in the literature. Clinical Case: A 43-year old woman with a history of hypertension was incidentally found to have a 4 cm left adrenal lesion. Computed tomography of the mass demonstrated indeterminate enhancement and washout characteristics. Upon evaluation, she had episodes of palpitations and fatigue without headache or flushing. Her medications were notable for metoprolol, vortioxetine, and lisdexamfetamine. Laboratory results were notable for elevated 24-hour urine metanephrine and normetanephrine of 551 mcg/24hr (normal: 58–203 mcg/24hr) and 927 mcg/24hr (normal: 88–649 mcg/24hr) respectively. Due to the possibility of pheochromocytoma, the patient elected for surgery and underwent laparoscopic left adrenalectomy after pre-treatment with an alpha-1-antagonist. Pathology demonstrated a 4.8 cm well-circumscribed tumor arising from the adrenal medulla that showed mostly hypercellular areas of spindled cells with wavy nuclei and focal nuclear palisading along with hypocellular areas with loose edematous stroma with focal areas of calcification and microcyst formation. IHC of the tumor cells was diffusely positive for S-100 and SOX-10, consistent with adrenal schwannoma. Laboratory results approximately 2 months post-operative on the same medications demonstrated normalization of 24-hour urine metanephrine and normetanephrine, confirming CPAS. A search of PubMed was performed using the search terms “adrenal schwannoma,” which returned 41 reports, of which 2 confirmed CPAS. Of the 3 cases, including ours, patients had a mean age of 44 years old and M:F ratio of 1:2. Each of the 3 tumors were left-sided with sizes ranging from 4.8 cm to 7.7 cm, which were all surgically removed. In the two previously published reports, the reported pre-operative laboratory markers were serum catecholamines and urine catecholamines, respectively, but neither compared levels to a reference range. In all cases, catecholamine levels normalized following surgical removal. Conclusion: Adrenal schwannoma is a rare entity in the differential diagnosis of non-functioning adrenal incidentaloma, but it should be considered for catecholamine-producing adrenal tumors as well. A summary of published cases suggests that these are typically large tumors with possible female predominance. This case is the first to document levels of catecholamine metabolite concentrations in CPAS.