High prevalence of frailty in patients with adrenal adenomas and adrenocortical hormone excess: a cross-sectional multi-centre study with prospective enrolment.

OBJECTIVE: Frailty, characterized by multi-system decline, increases vulnerability to adverse health outcomes and can be measured using Frailty Index (FI). We aimed to assess the prevalence of frailty in patients with adrenal disorders (based on hormonal sub-type) and examine association between FI and performance-based measures of physical function. DESIGN: Multi-centre, cross-sectional study (March 2019-August 2022). METHODS: Adult patients with adrenal disorders (non-functioning adrenal adenomas [NFA], mild autonomous cortisol secretion [MACS], Cushing syndrome [CS], primary aldosteronism [PA]) and referent subjects without adrenal disorders completed a questionnaire encompassing 47 health variables (comorbidities, symptoms, daily living activities). FI was calculated as the average score of all variables and frailty defined as FI ≥ 0.25. Physical function was assessed with hand grip, timed up-and-go test, chair rising test, 6-minute walk test, and gait speed. RESULTS: Compared to referent subjects (n = 89), patients with adrenal disorders (n = 520) showed increased age, sex, and body mass index-adjusted prevalence of frailty (CS [odds ratio-OR 19.2, 95% confidence interval-CI 6.7-70], MACS [OR 12.5, 95% CI 4.8-42.9], PA [OR 8.4, 95% CI 2.9-30.4], NFA [OR 4.5, 95% CI 1.7-15.9]). Prevalence of frailty was similar to referent subjects when post-dexamethasone cortisol was <28 nmol/L and was higher when post-dexamethasone cortisol was 28-50 nmol/L (OR 4.6, 95% CI 1.7-16.5). FI correlated with all measures of physical function (P < .001). CONCLUSIONS: Whilst frailty prevalence was highest in patients with adrenocortical hormone excess, even patients with NFA demonstrated an increased prevalence compared to the referent population. Future longitudinal studies are needed to evaluate the impact of various management strategies on frailty.

Current approach of primary bilateral adrenal hyperplasia.

PURPOSE OF REVIEW: To discuss the most recent findings on the pathophysiology, the genetic and molecular causes of primary bilateral adrenal hyperplasia (PBAH). The diagnostic approach of patients with PBAH will also be presented in detail with an emphasis on the emerging diagnostic tools and finally, the treatment of PBAH will be discussed with an emphasis on the newest surgical and medical treatment approaches. RECENT FINDINGS: PBAH is a highly heterogeneous condition mostly detected incidentally on abdominal imaging. Based on the size of the nodules, PBAH is subdivided into primary bilateral macronodular adrenal hyperplasia (PBMAH) and micronodular adrenal hyperplasia. A substantial proportion of patients with PBMAH harbor a germline mutation of the armadillo repeat containing 5 tumor suppression gene and therefore genetic testing is strongly recommended. Measurements of plasma or urinary multisteroid profiles show promising results in that PBMAH has a distinctive plasma steroid fingerprint that can help in diagnosis and subtyping of PBMAH. Finally, although surgery is the mainstay of treatment of patients with PBAH, medical therapy is increasingly emerging as an alternative option. SUMMARY: PBAH is a poorly studied and therefore a challenging disease to diagnose and treat. Hopefully with these newest diagnostic and therapeutic tools, a more comprehensive approach will be adopted.

Outcomes of Initial Management Strategies in Patients With Autoimmune Lymphocytic Hypophysitis: A Systematic Review and Meta-analysis.

CONTEXT: Lymphocytic hypophysitis (LyHy) is characterized by inflammation of the pituitary and or neuroinfundibulum and is uncommon. Treatment options include observation, high-dose glucocorticoids (HD-GCs) or surgery. Optimal first-line management strategy, however, remains unknown. OBJECTIVE: This work aimed to assess response to first-line treatment options (observation, HD-GCs, or surgery) of clinically relevant outcomes (symptomatic, hormonal, and radiographic improvement) among patients with LyHy. METHODS: A systematic review was conducted in 6 databases through 2020. Meta-analysis was conducted when feasible using a random-effects model. RESULTS: We included 33 studies reporting on 591 patients (423 women, 72%) with LyHy. Improvement/resolution of anterior pituitary dysfunction was highest when HD-GCs was first-line treatment. Surgery was associated with the greatest proportion of patients who had regression on imaging. Subgroup analysis comparing HD-GCs to observation showed the odds of anterior pituitary hormone recovery (OR 3.41; 95% CI, 1.68-6.94) or radiographic regression (OR 3.13; 95% CI, 1.54-6.36) were higher with HD-GCs, but so was the need for additional forms of treatment (OR 4.37; 95% CI, 1.70-11.22). No statistically significant difference was seen in recovery of diabetes insipidus (OR 0.9; 95% CI, 0.26-3.10). Certainty in these estimates was very low. CONCLUSION: Observation and use of HD-GCs both are successful first-line management strategies in LyHy. Although use of HD-GCs was associated with increased recovery of anterior pituitary hormone deficit, it also was associated with greater likelihood of additional treatment after withdrawal. Optimal dosing and duration of HD-GCs remains unknown.

Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.

BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Adipose Tissue Inflammation Is Not Related to Adipose Insulin Resistance in Humans.

The role of adipose tissue (AT) inflammation in AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression, and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC50). We studied 86 volunteers with normal weight or obesity at baseline and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong positive relationship between IC50 and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC50 and abdominal AT inflammatory markers CD68, CD14, CD206 ATM/100 adipocytes, senescent cells, IL-6, and TNF-α mRNA were not significant after adjustment for FCS. A 10% weight loss significantly reduced IC50; however, there was no reduction in adipose ATM content, senescent cells, or cytokine gene expression. Our study suggests that commonly used markers of AT inflammation are not causally linked to AT insulin resistance, whereas FCS is a strong predictor of AT insulin resistance with respect to lipolysis.

The Diagnostic, Prognostic and Therapeutic Role of miRNAs in Adrenocortical Carcinoma: A Systematic Review.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis and a high rate of recurrence and mortality. Therapeutic options are limited. In some cases, the distinction of ACCs from benign adrenal neoplasms with the existing widely available pathological and histopathological tools is difficult. Thus, new biomarkers have been tested. We conducted a review of the recent literature on the advances of the diagnostic, prognostic and therapeutic role of miRNAs on ACC patients. More than 10 miRNAs validated by multiple studies were found to present a diagnostic and prognostic role for ACC patients, from which miR-483-5p and miR-195 were the most frequently met biomarkers. In particular, upregulation of miR-483-5p and downregulation of miR-195 were the most commonly validated molecular alterations. Unfortunately, data on the therapeutic role of miRNA are still scarce and limited mainly at the experimental level. Thus, the role of miRNA regulation in ACC remains an area of active research.

Abnormal body composition in patients with adrenal adenomas.

OBJECTIVE: Increased visceral fat and sarcopenia are cardiovascular risk factors that may explain increased cardiovascular morbidity and frailty in patients with adrenal adenomas. Our objective was to compare body composition measurement of patients with adrenal adenomas to referent subjects without adrenal disease. DESIGN: Cross-sectional study, 2014-2018. METHODS: Participants were adults with nonfunctioning adrenal tumor (NFAT), mild autonomous cortisol secretion (MACS), and Cushing syndrome (CS) and age, sex, and BMI 1:1 matched referent subjects without adrenal disorders. Main outcome measures were body composition measurements calculated from abdominal CT imaging. Intra-abdominal adipose tissue and muscle mass measurements were performed at the third lumbar spine level. RESULTS: Of 227 patients with adrenal adenomas, 20 were diagnosed with CS, 76 with MACS, and 131 with NFAT. Median age was 56 years (range: 18-89), and 67% were women. When compared to referent subjects, patients with CS, MACS, and NFAT demonstrated a higher visceral fat (odds ratio (OR): 2.2 (95% CI: 0.9-6.5), 2.0 (1.3-3.2), and 1.8 (1.2-2.7) and a lower skeletal muscle area (OR: 0.01 (95% CI: 0-0.09), 0.31 (0.18-0.49), and 0.3 (1.2-2.7)) respectively. For every 1 µg/dL cortisol increase after overnight dexamethasone, visceral fat/muscle area ratio increased by 2.3 (P = 0.02) and mean total skeletal muscle area decreased by 2.2 cm2 (P = 0.03). CONCLUSION: Patients with adrenal adenomas demonstrate a lower muscle mass and a higher proportion of visceral fat when compared to referent subjects, including patients with NFAT. Even a subtle abnormality in cortisol secretion may impact health of patients with adenomas.

Categorisation of patients based on immune profiles: a new approach to identifying candidates for response to checkpoint inhibitors.

OBJECTIVES: Inhibitors to the checkpoint proteins cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are becoming widely used in cancer treatment. However, a lack of understanding of the patient response to treatment limits accurate identification of potential responders to immunotherapy. METHODS: In this study, we assessed the expression of PD-1 and CTLA-4 on 19 leucocyte populations in the peripheral blood of 74 cancer patients. A reference data set for PD-1 and CTLA-4 was established for 40 healthy volunteers to determine the normal expression patterns for these checkpoint proteins. RESULTS: Unsupervised hierarchical clustering found four immune profiles shared across the solid tumor types, while chronic lymphocytic leukaemia patients had an immune profile largely unique to them. Furthermore, we measured these leucocyte populations on an additional cohort of 16 cancer patients receiving the PD-1 inhibitor pembrolizumab in order to identify differences between responders and non-responders, as well as compared to healthy volunteers (n = 20). We observed that cancer patients had pre-treatment PD-1 and CTLA-4 expression on their leucocyte populations at different levels compared to healthy volunteers and identified two leucocyte populations positive for CTLA-4 that had not been previously described. We found higher levels of PD-1+ CD3+ CD4- CD8- cells in patients with progressive disease and have identified it as a potential biomarker of response, as well as identifying other significant differences in phenotypes between responders and non-responders. CONCLUSION: These results are suggestive that categorisation of patients based on immune profiles may differentiate responders from non-responders to immunotherapy for solid tumors.

Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study.

BACKGROUND: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. METHODS: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU. FINDINGS: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2-23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9-82·0] vs 64·0% [61·4-66.4]) while maintaining sensitivity (99·0% [94·4-100·0] vs 100·0% [96·3-100·0]; PPV 19·7%, 16·3-23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6-41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2-84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4-100·0). INTERPRETATION: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours. FUNDING: European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Immune Checkpoint Inhibitor-Induced Thyroiditis Is Associated with Increased Intrathyroidal T Lymphocyte Subpopulations.

Background: Immune checkpoint inhibitors (ICIs) frequently cause thyroid dysfunction but their underlying mechanism remains unclear. We have previously demonstrated increased circulating natural killer (NK) cells and human leukocyte antigen (HLA)-DR surface expression on inflammatory intermediate CD14+CD16+ monocytes in programmed cell death protein-1 (PD-1) inhibitor-treated patients. This study characterizes intrathyroidal and circulating immune cells and class II HLA in ICI-induced thyroiditis. Methods: This is a single-center prospective cohort study of 10 patients with ICI-induced thyroiditis by flow cytometry of thyroid fine needle aspirates (n = 9) and peripheral blood (n = 7) as compared with healthy thyroid samples (n = 5) and healthy volunteer blood samples (n = 44); HLA class II was tested in n = 9. Results: ICI-induced thyroiditis samples demonstrated overall increased T lymphocytes (61.3% vs. 20.1%, p = 0.00006), CD4-CD8- T lymphocytes (1.9% vs. 0.7%, p = 0.006), and, as a percent of T lymphocytes, increased CD8+T lymphocytes (38.6% vs. 25.7%; p = 0.0259) as compared with healthy thyroid samples. PD-1 inhibitor-induced thyroiditis had increased CD4+PD1+ T lymphocytes (40.4% vs. 0.8%; p = 0.021) and CD8+PD1+ T lymphocytes (28.8% vs. 1.5%; p = 0.038) in the thyroid compared with the blood. Circulating NK cells, certain T lymphocytes (CD4+CD8+, CD4-CD8- T, gamma-delta), and intermediate monocytes were increased in ICI-induced thyroiditis. Six patients typed as HLA-DR4-DR53 and three as HLA-DR15. Conclusions: ICI-induced thyroiditis is a T lymphocyte-mediated process with intra-thyroidal predominance of CD8+ and CD4-CD8- T lymphocytes. The HLA haplotypes may be involved but need further evaluation. These findings expand the limited understanding of ICI-induced thyroiditis, which could be further translated to guide immunomodulatory therapies for advanced thyroid cancer.

Adrenal Imaging in Patients with Endocrine Hypertension.

Hypertension is one of the commonest chronic diseases contributing to cardiovascular disease. Idiopathic (primary) hypertension accounts for approximately 85% of the diagnosed cases, and 15% of hypertensive patients have other contributing conditions leading to elevated blood pressure (secondary hypertension). Endocrine hypertension is a common secondary cause of hypertension. The most common causes of endocrine hypertension are excess production of mineralocorticoids (ie, primary hyperaldosteronism), glucocorticoids (Cushing syndrome), and catecholamines (pheochromocytoma). After biochemical confirmation of hormonal excess, appropriate use of imaging modalities, both functional and anatomic, should occur for the diagnostic workup of these patients and for location of the source of hormonal excess.

Assessment of The Bethesda System for Reporting Thyroid Cytopathology.

OBJECTIVES: Long-term follow-up is important for determining performance characteristics of thyroid fine-needle aspiration (FNA). METHODS: Histologic or 3 or more years of clinical follow-up was used to calculate performance characteristics of thyroid FNA before and after implementation of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) classification was also investigated. RESULTS: Follow-up was obtained for 1,277/1,134 and 1,616/1,393 aspirates/patients (median clinical follow-up, 9.9 and 4.4 years, pre- and post-TBSRTC, respectively). Nondiagnostic, suspicious for follicular neoplasm, and suspicious for malignancy (SFM) diagnoses decreased and benign diagnoses increased post-TBSRTC, while atypical rate remained less than 1%. Negative predictive value for benign nodules and positive predictive value (PPV) for SFM increased significantly. Eleven nodules were reclassified as NIFTP, slightly decreasing PPV/risk of malignancy (ROM). CONCLUSIONS: Appropriate ROM for thyroid FNA can be achieved through application of TBSRTC terminology with minimal use of atypical category.

Natural History of Adrenal Incidentalomas With and Without Mild Autonomous Cortisol Excess: A Systematic Review and Meta-analysis.

Background: Adrenal incidentalomas are mostly benign nonfunctioning adrenal tumors (NFATs) or adenomas causing mild autonomous cortisol excess (MACE), but their natural history is unclear. Purpose: To summarize the follow-up data of adults with NFAT or MACE to determine the proportions of tumor growth, malignant transformation, and incident changes in hormone function; the prevalence of incident cardiometabolic comorbid conditions; and mortality. Data Sources: MEDLINE, Embase, Cochrane, and Scopus (January 1990 to February 2019) and bibliographies of identified articles, without language restriction. Study Selection: Studies that included 20 or more conservatively managed patients with NFAT or MACE and reported outcomes at baseline and after at least 12 months of follow-up. Data Extraction: Pairs of reviewers extracted outcomes and assessed methodological quality. Data Synthesis: Thirty-two studies reported outcomes of 4121 patients with NFAT or MACE, 61.5% of whom were women; the mean age was 60.2 years, and mean follow-up was 50.2 months. Mean tumor growth was 2 mm over 52.8 months. Clinically significant tumor enlargement (≥10 mm) occurred in 2.5% of patients, and none developed adrenal cancer. Clinically overt hormone excess was unlikely to develop (<0.1%) in patients with NFAT or MACE. Only 4.3% of patients with NFAT developed MACE, and preexisting MACE was unlikely to resolve (<0.1%). Hypertension, obesity, dyslipidemia, and type 2 diabetes were highly prevalent (60.0%, 42.0%, 33.7%, and 18.1% of patients, respectively) and were more likely to develop and worsen in MACE than NFAT. New cardiovascular events were more prevalent in MACE (15.5%) than NFAT (6.4%). Mortality was 11.2% and was similar between NFAT and MACE. Limitation: Evidence was scarce, and definitions of MACE and comorbid conditions were heterogeneous. Conclusion: During follow-up, NFAT and MACE do not show clinically relevant changes in size or hormonal function, but they may carry an increased risk for cardiometabolic comorbid conditions. Primary Funding Source: None.

Modern Management of Mild Autonomous Cortisol Secretion.

Incidentally discovered adrenal tumors are reported in ~ 5% of adults undergoing cross-sectional imaging. Mild autonomous cortisol secretion (MACS) from the adrenal mass is demonstrated in 5-48% of patients with adrenal tumors. The diagnosis of MACS represents a challenge due to limitations of the currently used diagnostic tests, differences in the definitions of the clinically relevant MACS, and heterogeneity in an individual's susceptibility to abnormal cortisol secretion from the adrenal mass. Patients with MACS present with increased risk of cardiovascular risk factors, cardiovascular events, metabolic bone disease, and mortality. Adrenalectomy improves or reverses MACS-associated comorbidities in selected patients. The current review will address diagnostic and management challenges in the care of patients with MACS, discuss data on emerging biomarkers, and suggest future directions in the field of MACS.

Adrenal biopsy: performance and use.

The widespread use of cross-sectioning abdominal imaging in recent years has led to the increased detection of adrenal masses. In each case, determining whether a newly identified adrenal mass is benign or malignant is essential for management, but can be challenging. A significant proportion of adrenal lesions remain indeterminate after initial evaluation due to limitations of current imaging modalities. Adrenal biopsy can be considered for further diagnostic workup in select cases, particularly in patients with an active or previously diagnosed extra-adrenal malignancy. In this review, we describe the various types of image-guided adrenal biopsy, including percutaneous and endoscopic techniques, highlight the utility of adrenal biopsy in various clinical scenarios, and, examine the diagnostic performance and adverse event rate of the procedure. Finally, we outline a suggested algorithm for the use of adrenal biopsy in the evaluation of an adrenal mass.

Mitochondrial dysfunction in affected skin and increased mitochondrial DNA in serum from patients with psoriasis.

Psoriasis is characterized by keratinocyte proliferation and chronic inflammation, but the pathogenesis is still unclear. Dysregulated mitochondria (mt) could lead to reduced apoptosis and extracellular secretion of mtDNA, acting as "innate pathogen" triggering inflammation. Serum was obtained from healthy volunteers and psoriatic patients. Mitochondrial DNA was extracted from the serum and amplified with quantitative PCR (qPCR). Punch biopsies were obtained from lesional and non-lesional psoriatic skin (10 cm apart) and from healthy volunteers, were placed in RNA later and were stored at -80°C until RNA was extracted and cDNA was synthesized; gene expression of uncoupling protein 2 (UCP2), Dynamin-related protein 1 (Drp1) and calcineurin, involved in the regulation of mitochondria function, was detected with qPCR. Mitochondrial DNA was significantly increased (7s, P = 0.0496 and Cytochrome B, CytB, P = 0.0403) in the serum of psoriatic patients (n = 63) as compared to controls (n = 27). Gene expression was significantly reduced for UCP2 (P = 0.0218), Drp1 (P = 0.0001) and calcineurin (P = 0.0001) in lesional psoriatic skin, as compared to non-lesional or control skin. Increased serum extracellular mtDNA in psoriatic patients and decreased expression of mitochondrial regulatory proteins in psoriatic skin suggest increased inflammation and reduced keratinocyte apoptosis, respectively. Inhibitors of mtDNA secretion and/or UCP2 stimulants may be potential treatment options.

Clinical, Biochemical, and Radiological Characteristics of a Single-Center Retrospective Cohort of 705 Large Adrenal Tumors.

OBJECTIVE: To characterize large adrenal tumors (≥4 cm in diameter) and to identify features associated with malignancy. PATIENTS AND METHODS: We investigated the clinical, biochemical, and imaging characteristics in a large retrospective single-center cohort of patients with adrenal tumors of 4 cm or more in diameter during the period of January 1, 2000, through December 31, 2014. RESULTS: Of 4085 patients with adrenal tumors, 705 (17%) had adrenal masses measuring 4 cm or more in diameter; of these, 373 (53%) were women, with a median age of 59 years (range, 18-91 years) and median tumor size of 5.2 cm (range, 4.0-24.4 cm). Underlying diagnoses were adrenocortical adenomas (n=216 [31%]), pheochromocytomas (n=158 [22%]), other benign adrenal tumors (n=116 [16%]), adrenocortical carcinomas (n=88 [13%]), and other malignant tumors (n=127 [18%]). Compared with benign tumors, malignant tumors were less frequently diagnosed incidentally (45.5% vs 86.7%), were larger (7 cm [range, 4-24.4 cm] vs 5 cm [range, 4-20 cm]), and had higher unenhanced computed tomographic (CT) attenuation (34.5 Hounsfield units [HU] [range, 14.1-75.5 HU] vs 11.5 HU [range, -110 to 71.3 HU]; P<.001). On multivariate analysis, older age at diagnosis, male sex, nonincidental mode of discovery, larger tumor size, and higher unenhanced CT attenuation were all found to be statistically significant predictors of malignancy. CONCLUSION: The prevalence of malignancy in patients with adrenal tumors of 4 cm or more in diameter was 31%. Older age, male sex, nonincidental mode of discovery, larger tumor size, and higher unenhanced CT attenuation were associated with an increased risk for malignancy. Clinical context should guide management in patients with adrenal tumors of 4 cm or more in diameter.

Diagnostic performance of unenhanced computed tomography and 18 F-fluorodeoxyglucose positron emission tomography in indeterminate adrenal tumours.

OBJECTIVE: Evidence on the diagnostic performance of adrenal imaging is limited. We aimed to assess the diagnostic performance of unenhanced computed tomography (CT) and 18 F-fluorodeoxyglucose (18 FDG) positron emission tomography (PET)/CT imaging in a high-risk population for adrenal malignancy using an optimal reference standard. DESIGN: Retrospective cohort study. METHODS: Imaging studies of patients with adrenal nodules who underwent adrenal biopsy and/or adrenalectomy between 1994 and 2014 were reviewed and compared to the reference standard of histology. Eighty % of patients presented with known or suspected extra-adrenal malignancy. RESULTS: Unenhanced abdominal CT was performed in 353 patients with adrenal lesions; median size was 3 (0.7-15) cm and median radiodensity was 33 (-21-78) Hounsfield units (HU). Radiodensity of >10 HU diagnosed malignancy with a sensitivity of 100%, specificity of 33%, positive predictive value (PPV) of 72% and negative predictive value (NPV) of 100%. 18 FDG-PET/CT was performed in 89 patients; median tumour size was 2.1 (0.7-9.2) cm. Maximum standardized uptake (SUV max) was higher in malignant lesions when compared to benign lesions (median=10 [2.3-29.4] vs 3.7 [1.4-24.5], respectively, P<.0001). Similarly, median SUV max lesion to SUV max liver ratio (ALR) in malignant lesions was higher than in benign lesions (median=3 [0.74-13.4] vs 1.2 [0.5-6.6], respectively, P<.0001). 18 FDG-PET/CT ALR >1.8 diagnosed malignancy with a sensitivity of 87%, specificity of 84%, PPV of 85% and NPV of 86%. CONCLUSION: Noncontract CT radiodensity of ≤10 HU excludes malignancy even in a high-risk population. For indeterminate adrenal lesions, given a superior specificity, 18 FDG-PET/CT could be considered as a second stage imaging study.

Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas.

CONTEXT: Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. OBJECTIVE: To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. DESIGN: Retrospective cohort study. PATIENTS: Twenty-five patients with overt Cushing's syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE) and 32 patients with a nonfunctioning adrenal tumour (NFAT) were included. METHODS: Medical records were reviewed, and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). RESULTS: In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P < .001) and by 0.3 (P < .001); however, these measurements were decreased by 0.04 (P = .007) and 0.2 (P = .01), respectively, in patients with MACE. Total muscle mass was decreased by -10 cm2 (P = .02) in patients with overt CS compared to patients with NFAT. Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28 nmol/L cortisol increase there was a 0.008 increase in V/T (P < .001), 0.02 increase in the V/S fat ratio (P < .001) and a 1.2 cm2 decrease in mean total muscle mass (P = .002). CONCLUSIONS: The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas.

ENDOSCOPIC ULTRASOUND-GUIDED FINE-NEEDLE ASPIRATION IN THE DIAGNOSIS OF ADRENAL METASTASIS IN A HIGH-RISK POPULATION.

OBJECTIVE: While the left adrenal gland is readily accessible via endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), data regarding the utility of EUS-FNA in the diagnosis of adrenal lesions remain limited. We aimed to ( 1) describe the clinical context, adverse event rate, and diagnostic performance of EUS-FNA, and ( 2) compare the safety profile and diagnostic accuracy of EUS-FNA with percutaneous adrenal biopsy. METHODS: Single-center, retrospective cohort study. Medical records of patients who underwent adrenal EUS-FNA from 2005-2016 were reviewed. Biopsy outcomes were evaluated using a predefined reference standard. Results were compared to patients who underwent percutaneous biopsy (n = 419; 1994-2014) at the same institution. RESULTS: A total of 121 patients underwent EUS-FNA of 122 adrenal lesions (left [n = 121]; right [n = 1]; mean lesion size, 1.8 cm). Cytology was positive for malignancy in 35 (29%), suspicious for malignancy in 1 (1%), atypical in 1 (1%), negative for malignancy in 81 (66%), and nondiagnostic in 4 (3%). No adverse events were reported. EUS-FNA diagnosed metastasis with a sensitivity of 100%, specificity of 97.4%, positive predictive value of 91.7%, and negative predictive value of 100%. When compared to percutaneous biopsy, lesion size (1.8 cm vs. 3.7 cm; P<.001) and biopsy site (99% vs. 62% left adrenal; P<.001) were significantly different. EUS-FNA adverse event rate was lower than percutaneous biopsy (0% vs. 4%; P = .024), but nondiagnostic rates were similar (3.3% vs. 4.8%; P = .48). CONCLUSION: EUS-FNA is a sensitive technique to sample adrenal lesions in patients at high risk for adrenal metastasis with fewer adverse events compared to percutaneous biopsy. ABBREVIATIONS: CI = confidence interval CT = computed tomography EUS-FNA = endoscopic ultrasound-guided fine-needle aspiration NPV = negative predictive value PPV = positive predictive value TUS = transabdominal ultra-sound.