Clinical Significance of Pheochromocytoma Size on the Timing and Extent of Surgery.

INTRODUCTION: Elevated metanephrine and catecholamine levels 3-fold upper limit of normal (ULN) are diagnostic for pheochromocytoma. We sought to determine whether size correlates with biochemical activity or symptoms which could guide timing of surgery. METHODS: Data from consecutive patients undergoing adrenalectomy for pheochromocytoma at our institution over a 10-year period were retrospectively collected. These included maximal lesion diameter on preoperative imaging, plasma/urine metanephrine and/or catecholamine levels, demographic variables and presence of typical paroxysmal symptoms. Receiver operating characteristic curves were used to assess predictive accuracy. RESULTS: Sixty-three patients were included in the analysis (41 females and 22 males). Median age was 56 (43, 69) years. Due to various referring practices, 31 patients had documented 24-h urine metanephrine, 26 had 24-h urine catecholamine, and 52 had fractionated plasma metanephrine levels available for review. Values were converted to fold change compared to ULN and the maximum of all measured values was used for logistic regression. Median tumor size was 3.40 (2.25, 4.55) cm in greatest dimension. Tumor size at which pheochromocytoma produced > 3-fold ULN was ≥2.3 cm (AUC of 0.84). Biochemical activity increased with doubling tumor size (odds ratio = 8, P = 0.0004) or ≥ 1 cm increase in tumor size (odds ratio = 3.03, P = 0.001). 40 patients had paroxysmal symptoms, but there was no significant correlation between tumor size/biochemical activity and symptoms. CONCLUSIONS: In our study, tumor size directly correlated with the degree of biochemical activity and pheochromocytomas ≥2.3 cm produced levels 3 times ULN. These findings may allow clinicians to adjust timing of operative intervention.

Chromogranin A as a diagnostic marker of pheochromocytoma and paraganglioma: A systematic review and meta-analysis.

OBJECTIVES: This work aims to assess the diagnostic value of chromogranin A (CgA) in the laboratory diagnosis of neuroendocrine tumors classified as pheochromocytoma and paraganglioma (PPGL). METHODS: A comprehensive search was performed in PubMed, Embase, the Cochrane Library, and Web of Science databases to obtain relevant studies reporting the diagnostic accuracy of CgA in patients with PPGL. The search involved studies written in English between the time of library inception and May 1, 2023. We computed the pooled sensitivity, specificity, and diagnostic odds ratio (DOR). Additionally, the receiver operating characteristic curve and area under the curve (AUC) were determined. The heterogeneity was assessed using the Chi-square test and the I2 test. The subgroup analyses were performed to investigate the origins of heterogeneity. Stata 15.1 statistical software was used in all data analyses. RESULTS: This meta-analysis included 13 studies involving 1470 patients. CgA had a pooled diagnostic sensitivity of 0.86 (95% CI 0.81-0.91), a specificity of 0.90 (95% CI 0.81-0.95), and a DOR of 57 (95% CI 23-142). CgA had an AUC of 0.93. The studies did not reveal any threshold effect (r = -0.165; p > 0.05). The subgroup analyses revealed that the control group category and the detection method caused the overall heterogeneity. CONCLUSIONS: Our study suggests that CgA is a helpful PPGL biomarker. However, relying solely on CgA for diagnosis is not advisable. A comprehensive approach is essential for accurate diagnosis. Future large-scale research is needed to refine CgA's clinical application.

Expression Patterns of MOTS-c in Adrenal Tumors: Results from a Preliminary Study.

Adrenal tumors, such as adrenocortical carcinoma (ACC), adrenocortical adenoma (ACA), and pheochromocytoma (PCC) are complex diseases with unclear causes and treatments. Mitochondria and mitochondrial-derived peptides (MDPs) are crucial for cancer cell survival. The primary aim of this study was to analyze samples from different adrenal diseases, adrenocortical carcinoma, adrenocortical adenoma, and pheochromocytoma, and compare them with normal adrenal tissue to determine whether the expression levels of the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) gene and protein vary between different types of adrenal tumors compared to healthy controls using qPCR, ELISA, and IHC methods. Results showed decreased MOTS-c mRNA expression in all adrenal tumors compared to controls, while serum MOTS-c protein levels increased in ACA and PCC but not in ACC. The local distribution of MOTS-c protein in adrenal tissue was reduced in all tumors. Notably, MOTS-c protein expression declined with ACC progression (stages III and IV) but was unrelated to patient age or sex. Tumor size and testosterone levels positively correlated with MOTS-c mRNA but negatively with serum MOTS-c protein. Additionally, serum MOTS-c protein correlated positively with glucose, total cholesterol, HDL, LDL, and SHGB levels. These findings suggest disrupted expression of MOTS-c in the spectrum of adrenal diseases, which might be caused by mechanisms involving increased mitochondrial dysfunction and structural changes in the tissue associated with disease progression. This study provides a detailed examination of MOTS-c mRNA and protein in adrenal tumors, indicating the potential role of MDPs in tumor biology and progression.

Discrepancies in the Recommended Management of Adrenal Incidentalomas by Various Guidelines.

PURPOSE: Adrenal incidentalomas are being discovered with increasing frequency, and their discovery poses a challenge to clinicians. Despite the 2002 National Institutes of Health consensus statement, there are still discrepancies in the most recent guidelines from organizations representing endocrinology, endocrine surgery, urology and radiology. We review recent guidelines across the specialties involved in diagnosing and treating adrenal incidentalomas, and discuss points of agreement as well as controversy among guidelines. MATERIALS AND METHODS: PubMed®, Scopus®, Embase™ and Web of Science™ databases were searched systematically in November 2019 in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement to identify the most recently updated committee produced clinical guidelines in each of the 4 specialties. Five articles met the inclusion criteria. RESULTS: There is little debate among the reviewed guidelines as to the initial evaluation of an adrenal incidentaloma. All patients with a newly discovered adrenal incidentaloma should receive an unenhanced computerized tomogram and hormone screen. The most significant points of divergence among the guidelines regard reimaging an initially benign appearing mass, repeat hormone testing and management of an adrenal incidentaloma that is not easily characterized as benign or malignant on computerized tomography. The guidelines range from actively recommending against any repeat imaging and hormone screening to recommending a repeat scan as early as in 3 to 6 months and annual hormonal screening for several years. CONCLUSIONS: After reviewing the guidelines and the evidence used to support them we posit that best practices lie at their convergence and have presented our management recommendations on how to navigate the guidelines when they are discrepant.

Study of stability and interference for catecholamines and metanephrines, 3-methoxytyramine: key point of an accurate diagnosis for pheochromocytoma and paraganglioma.

BACKGROUND: Accurate diagnosis of pheochromocytoma and paraganglioma (PPGLs) is highly dependent on the detection of metanephrines and catecholamines. However, the systematic investigation on influencing factors including specimen (plasma or whole blood), anticoagulant, storage conditions, and interference factors need further confirmation. METHODS: Blood with heparin-lithium or EDTA-K2 were collected, stability of epinephrine (EPI), norepinephrine (NE), dopamine (DA), metanephrine (MN), normetanephrine (NMN), 3-methoxytyramine (3-MT) in whole blood and plasma at room temperature and 4 °C for different storage times, stability of plasma MN, NMN and 3-MT at -20 °C and -80 °C were investigated. Plasma with hemoglobin (1 g/L, 2 g/L, 3 g/L, 4 g/L, 6 g/L), TG (<5 mmol/L, 5-8 mmol/L, >8 mmol/L) were prepared. RESULTS: EPI, NE, DA were prone to degrade at room temperature, samples should be centrifuged at 4 °C. EPI and NE were stable in whole blood at 4 °C for 4 h and in plasma for 2 h. For MN, NMN, 3-MT, plasma can be stable at room temperature and 4 °C for at least 6 h, which is better than whole blood; there was no significant difference when stored at -20 °C and -80 °C for 7 days. Heparin-lithium had a slight advantage over EDTA-K2. EPI, NE, DA should not be performed when Hb > 1 g/L or TG > 5 mmol/L. MN, NMN, 3-MT should not be performed when Hb > 2 g/L, whereas TG had no interference. CONCLUSIONS: According to the actual clinical application scenario, this study provided a reliable basis for the accurate diagnosis of PPGLs.

Intrarenal hemodynamics and kidney function in pheochromocytoma and paraganglioma before and after surgical treatment.

PURPOSE: Current evidence regarding renal involvement in pheochromocytoma and paraganglioma (PPGL) is scant. More accurate diagnostic methods, such as renal Doppler ultrasound for intrarenal hemodynamic studies, may provide more detailed information on renal function. It might be postulated that renal function in PPGL patients might be altered by high blood pressure and excess secretion of catecholamines. The aim of this prospective study was to assess intrarenal blood flow parameters in PPGL patients included in the prospective monoamine-producing tumour (PMT) study and to evaluate the effects of normalisation of catecholamine production after surgical treatment on long-term renal function. MATERIALS AND METHODS: Seventy consecutive patients (aged 46.5 ± 14.0 years) with PPGL were included. Forty-eight patients from the PMT study cohort, matched for age, gender, blood pressure level and presence of hypertension, served as a control group. Renal artery doppler ultrasound spectral analysis included mean resistance index (RRI) and pulsatility index (PI). Forty-seven patients completed 12 months follow-up. RESULTS: There were no differences in renal parameters such as RRI, PI and kidney function between PPGL and non-PPGL patients as assessed by renal ultrasound, serum creatinine, eGFR and albumin excretion rate. No correlations between kidney function parameters, intrarenal doppler flow parameters and plasma catecholamines were observed in PPGL patients. At 12 months after surgery, no differences in creatinine level, eGFR, albumin excretion rate, RI and PI were found as compared to baseline results. CONCLUSIONS: In contrast to patients with other forms of secondary hypertension, our study did not show differences in intrarenal blood flow parameters and renal function between PPGL and non-PPGL subjects. Intrarenal hemodynamics and renal function did not change after normalisation of catecholamine levels by surgical treatment.

Blood sampling for metanephrines comparing venipuncture vs. indwelling intravenous cannula in healthy subjects.

Background To diagnose pheochromocytoma or sympathetic paraganglioma, guidelines recommend blood sampling after at least 30 min of supine rest and using an indwelling intravenous cannula is preferred. Although blood sampling by venipuncture is more convenient and cost-effective, it is unknown whether venipuncture affects plasma concentrations of free metanephrines (MNs). We therefore investigated whether there is a difference in plasma concentrations of free MNs collected by venipuncture or by an intravenous cannula. Methods We included 22 healthy participants (12 men and 10 women, median age 26 years). We collected blood using an indwelling cannula and venipuncture to determine plasma concentrations of free MNs and catecholamines, and calculated the median of the individually calculated absolute and relative differences. Results Plasma concentrations of free MN, normetanephrine (NMN) and epinephrine were higher with blood sampling using venipuncture compared to that when using an indwelling cannula. The median (interquartile range [IQR]) difference was MN 0.020 (-0.004 to 0.040) nmol/L, median percentage difference 20.5% (-2.4 to 35.2%), NMN 0.019 (-0.004 to 0.077) nmol/L, median percentage difference 4.6% (-1.1 to 25.4%) and epinephrine 0.022 (0.007-0.079) nmol/L, median percentage difference 24.9% (7.8-83.3%). When the two sampling conditions were compared, plasma-free 3-methoxytyramine (3-MT), norepinephrine and dopamine concentrations did not differ. Conclusions Blood sampling by venipuncture resulted in statistically significant higher concentrations of MN, NMN and epinephrine compared to sampling by means of an indwelling cannula. However, differences were small. For most patients it seems justifiable to collect blood via venipuncture.

Patients with pheochromocytoma exhibit low aldosterone renin ratio-preliminary reports.

BACKGROUND: Plasma renin activity (PRA) is generally increased in patients with pheochromocytoma (PCC) due to low circulating plasma volume and activation of ß-1 adrenergic receptor signaling. However, there has been no study on the aldosterone renin ratio (ARR) in patients with PCC. To elucidate the issue, this study aimed to determine the PRA, plasma aldosterone concentration (PAC), and ARR in patients with PCC and compare them with those in patients with subclinical Cushing's syndrome (SCS) and non-functioning adrenal adenoma (NFA). METHODS: In this retrospective single-center, cross-sectional study, 67 consecutive patients with adrenal tumors (PCC (n = 18), SCS (n = 18), and NFA (n = 31)) diagnosed at Kobe University Hospital between 2008 and 2014 were enrolled. RESULTS: PRA was significantly higher in patients with PCC than in those with SCS and NFA (2.1 (1.3 ~ 2.8) vs. 0.7 (0.5 ~ 1.8) and 0.9 (0.6 ~ 1.4) ng/mL/h; p = 0.018 and p = 0.025). Although PACs were comparable among the three groups, ARR was significantly lower in patients with PCC than in those with SCS and NFA (70.5 (45.5 ~ 79.5) vs. 156.0 (92.9 ~ 194.5) and 114.9 (90.1 ~ 153.4); p = 0.001 and p < 0.001). Receiver operating characteristic curve analysis demonstrated that, in differentiating PCC from NFA, PRA > 1.55 ng/mL/h showed a sensitivity of 70.0% and specificity of 80.6%. Interestingly, ARR < 95.4 showed a sensitivity of 83.3% and specificity of 86.7%, which were higher than those in PRA. CONCLUSIONS: ARR decreased in patients with PCC, which was a more sensitive marker than PRA. Further study is necessary to understand the usefulness of this convenient marker in the detection of PCC. TRIAL REGISTRATION: This study was not registered because of the retrospective analysis.

MicroRNA-210 May Be a Preoperative Biomarker of Malignant Pheochromocytomas and Paragangliomas.

BACKGROUND: Currently, no reliable predictive clinical or laboratory tests exist that can accurately distinguish between benign and malignant pheochromocytomas or paragangliomas (PPGLs). The aim of this study was to investigate if serum microRNA-210 (miR-210) levels could be a marker of malignancy in patients with PPGLs. METHODS: Preoperative serum from patients with PPGLs was collected on the day of surgery. Clinical demographics, germline mutation status, primary tumor size, postoperative biochemical response, and the development of malignant disease were prospectively collected. Total microRNA was extracted from preoperative serum samples, and miR-210 levels were measured by quantitative real-time reverse transcription-polymerase chain reaction and normalized to miR-16. Prognostic variables were compared using univariable and multivariable analyses. RESULTS: Of the 35 patients, 10 (29%) were diagnosed with malignant PPGLs and 25 patients (71%) were diagnosed with benign PPGLs (median follow-up 72.5 mo). Sixty-nine percent of patients had a pheochromocytoma (n = 24/35) compared with 31% of patients with paraganglioma (n = 11/35). The most common germline mutation was succinate dehydrogenase complex subunit B (SDHB) (n = 10). On univariable analysis, lower serum miR-210 expression level (2.3 ± 0.5 versus 3.1 ± 1.2, P = 0.013) and larger primary tumor size (6.7 ± 5.0 cm versus 4.1 ± 2.3 cm, P = 0.043) were significantly associated with malignant disease. No significant prognostic variables were found on multivariable analysis. CONCLUSIONS: In this pilot study, low serum miR-210 expression levels and large primary tumors were identified to be markers of PPGL malignancy on univariable analysis. Given the initial encouraging results in a small cohort, further investigation is warranted to determine if serum miR-210 levels are prognostic.

Pheochromocytoma as a Clinical Model of Peripheral Sympathetic Overdrive: Old and New Findings.

PURPOSE OF REVIEW: The present paper will review the results of experimental and clinical studies aimed at defining the functional behavior of the central and peripheral nervous system in adrenal pheochromocytoma. RECENT FINDINGS: The contribution of sympathetic neural influences to the development of high blood pressure values in pheochromocytoma is complex. Studies performed in experimental animal models have shown that hypertension and the concomitant high circulating levels of catecholamines can lead to inhibition of central sympathetic neural outflow by reflex mechanisms and direct stimulation of central adrenergic receptors, respectively. However, these studies have also shown that high circulating levels of catecholamines favor a downregulation of alpha- and beta-adrenergic receptors, lessening their response to endogenous and exogenous adrenergic stimulation. The present paper reviews results of human studies performed by our group and others on the behavior of the central and peripheral nervous system in human pheochromocytoma. We discuss data collected in patients with different levels of peripheral sympathetic drive, i.e., before and after surgical removal of the adrenal pheochromocytoma. In the presence of elevated plasma catecholamine level, such as that characterizing adrenal pheochromocytoma, microneurography shows that central sympathetic neural activity is normal or even inhibited. At the peripheral vascular level, pheochromocytoma is characterized by a reduced vascular reactivity to exogenous sympathetic stimulation but a normal response by the vessels to endogenous adrenergic stimulation.

A simple and robust liquid chromatography tandem mass spectrometry assay for determination of plasma free metanephrines and its application to routine clinical testing for diagnosis of pheochromocytoma.

Plasma free metanephrines (PFMs) have high sensitivity for detecting pheochromocytoma (PCC). Herein, we developed a simple and reliable liquid chromatography tandem mass spectrometry assay for PFMs determination in Chinese population. PFMs were enriched by SPE without requiring extract evaporation or the use of buffers containing nonvolatile salts. The analytes were analyzed in multiple reaction monitoring mode. Inter- and intra-assay precisions were ≤4.3% and ≤ 6.3%. The lower limits of quantification were 0.07 nmol/L for metanephrine and 0.06 nmol/L for normetanephrine. Recoveries of PFMs were in the range of 89.3-113%. The method was free from significant matrix effect, carryover and interference. Owing to its fast analysis time, more than 150 samples/day could be easily performed by a single operator. With the established reference intervals of PFMs in the Chinese population, this simple and robust LC-MS/MS method could be valuable for use in routine clinical laboratories. It is noted that the combined tests of PFMs with urinary catecholamines or urinary vanillylmandelic acid could improve specificity.

Ghrelin as a potential molecular marker of adrenal carcinogenesis: In vivo and in vitro evidence.

CONTEXT: Adrenal tumours belong to one of the most prevalent neoplasms. It is a heterogeneous group with different aetiology, clinical manifestation and prognosis. Its histopathologic diagnosis is difficult and identification of differentiation markers for tumorigenesis is extremely valuable for diagnosis. DESIGN: To assess ghrelin expression and the relationship among ghrelin, IGF2 and the clinicopathological characteristics of adrenal tumours. To investigate the influence of ghrelin on ACC cell line proliferation. MATERIALS AND METHODS: Expression of ghrelin and IGF2 in a total of 84 adrenal tissue samples (30 adenoma, 12 hyperplasia, 8 myelolipoma, 20 pheochromocytoma, 7 carcinoma and 7 unchanged adrenal glands) were estimated. Every operated patient from whom samples were obtained underwent clinicopathological analysis. All the parameters were compared among the groups examined and correlations between these were estimated. H295R cell line was incubated with ghrelin to assess its effect on proliferation and migration rate. RESULTS: The highest ghrelin expression was observed in carcinoma samples and the lowest in the control group. Ghrelin expression was 21 times higher in carcinoma (P = .017) and 2.4 times higher in adenoma (P = .029) compared with controls. There were no statistically significant differences between myelolipoma (P = .093) and pheochromocytoma (P = .204) relative to the control. Ghrelin level was significantly higher in carcinoma compared to adenoma (P = .049) samples. A positive correlation between ghrelin and IGF2 expression was observed only in myelolipoma (P = .001). Ghrelin at concentrations of 1 × 10-6  mol/L and 1 × 10-8  mol/L significantly stimulated proliferation and migration rate in the H295R cell line. CONCLUSION: Ghrelin appears to be an essential factor in driving adrenal tumours development.

A case of pheochromocytoma with a marked decrease in catecholamine levels after rupture in which a good outcome was achieved by elective surgery.

Changes in imaging findings and hormone levels before and after pheochromocytoma rupture, as well as detailed histopathology of resected tumors, have rarely been reported. A 52-year-old woman developed hypertension and diabetes mellitus in 2014, but despite treatment with antihypertensive and hypoglycemic drugs, good control was not achieved. On April 2, 2016, the patient started to have headaches and palpitations, and on April 6, she visited our hospital. Plain computed tomography (CT) of the abdomen showed a 4-cm, isodense mass in the left adrenal gland, and the patient was hospitalized for further examination. Because the patient had hypertension, tachycardia, and hyperglycemia on admission, therapies for those were started. Catecholamine levels were markedly elevated. However, after the patient developed left flank pain on Day 4, antihypertensive and insulin therapies were no longer required. Plain CT then showed heterogeneous high density areas in the left adrenal mass. On Day 7, 3 meta-iodobenzylguanidine scintigraphy showed no abnormal uptake. On Day 8, contrast CT showed low density areas within the left adrenal tumor and contrast enhancement of the tumor margins, and catecholamine levels were markedly decreased. Elective left adrenal tumor resection was performed on Day 49. The capsule of the resected tumor was ruptured. Histopathology showed widespread hemorrhagic necrosis and viable cell components in the tumor margins. Positive chromogranin A staining of the tumor cells confirmed a diagnosis of pheochromocytoma. This patient displayed remarkable changes in imaging findings and hormone levels before and after pheochromocytoma rupture. Pheochromocytoma rupture and hemorrhagic necrosis were confirmed histopathologically.

Fulminant adrenergic myocarditis complicated by pulmonary edema, cardiogenic shock and cardiac arrest.

Adrenergic myocarditis is an uncommon presentation of pheochromocytoma and extremely rare cause of de novo acute heart failure (AHF). We present a case of a 31-year-old Caucasian woman with a history of hypertension and recurrent occipital headaches who was admitted to the emergency department due to severe de novo AHF presenting as pulmonary edema and cardiogenic shock. During the hospital admission the patient experienced asystolic cardiac arrest and was successfully resuscitated, intubated, and mechanically ventilated. Bedside transthoracic echocardiography revealed severe diffuse left ventricular hypokinesis with ejection fraction (LVEF) of 10%. Coronary angiography disclosed normal epicardial coronary arteries. The diagnosis of fulminant myocarditis was based on clinical, laboratory and imaging findings including cardiac magnetic resonance imaging (cMRI) Lake Louise criteria. STIR-cMRI sequences revealed myocardial edema in the lateral, inferior and posterior walls of the left ventricle, whereas T1-weighted early contrast-enhanced sequences showed myocardial hyperemia and capillary leak. An ultrasound and computed tomographic scan of the abdomen disclosed a solid, heterogeneous mass (3.6×3.2×2.8-cm) in the right suprarenal area. Urinary and plasma catecholamines and metanephrines were markedly elevated. A pheochromocytoma was suspected and laparoscopic resection of the tumor was performed after pharmacological preparation with phenoxybenzamine. The histopathological findings were consistent with pheochromocytoma. Follow-up cMRI showed complete reversal of myocardial edema and hyperemia. At 12-month follow-up, the patient has remained asymptomatic and normotensive with no recurrence of cardiovascular symptoms.

Adrenal Vein Catecholamine Levels and Ratios: Reference Intervals Derived from Patients with Primary Aldosteronism.

Phaeochromocytoma localisation is generally reliably achieved with modern imaging techniques, particularly in sporadic cases. On occasion, however, there can be diagnostic doubt due to the presence of bilateral adrenal abnormalities, particularly in patients with mutations in genes predisposing them to the development of multiple phaeochromocytomas. In such cases, surgical intervention is ideally limited to large or functional lesions due to the long-term consequences associated with hypoadrenalism. Adrenal venous sampling (AVS) for catecholamines has been used in this situation to guide surgery, although there are few data available to support diagnostic thresholds. Retrospective analyses of AVS results from 2 centres were carried out. A total of 172 patients (88 men, 84 women) underwent AVS under cosyntropin stimulation for the diagnosis of established primary aldosteronism (PA) with measurement of adrenal and peripheral venous cortisol, aldosterone and catecholamines. Six patients (3 men, 3 women) with phaeochromocytoma underwent AVS for diagnostic purposes with subsequent histological confirmation. Reference intervals for the adrenal venous norepinephrine to epinephrine ratio were created from the PA group. Using the 97.5th centile (1.21 on the left, 1.04 on the right), the false negative rate in the phaeochromocytoma group was 0%. In conclusion, this study describes the largest dataset of adrenal venous catecholamine measurements and provides reference intervals in patients without phaeochromocytoma. This strengthens the certainty with which conclusions related to adrenal venous sampling for catecholamines can be drawn, acknowledging the procedure is not part of the routine diagnostic workup and is an adjunct for use only in difficult clinical cases.

Changes in Body Mass Index in Pheochromocytoma Patients Following Adrenalectomy.

Catecholamine excess from pheochromocytoma results in cardiovascular symptoms such as arterial hypertension and tachycardia and induces metabolic alterations including glucose intolerance and increase in resting metabolic rate. The objective of our study was to investigate the effect of surgical cure of pheochromocytoma on body-mass-index and the correlation of body-mass-index changes to preoperative endocrine parameters. Pheochromocytoma patients from the Munich ENSAT Registry were matched (1:2) for age and gender to patients from the German Conn's Registry, who had undergone surgery for aldosterone-producing-adenomas. Thereby, 43 pheochromocytoma patients (17 males/26 females) and 86 aldosterone-producing-adenoma patients were analyzed for body-mass-index, blood pressure, and catecholamine levels before and one year after adrenalectomy. Seventy-four percent of pheochromocytoma patients were hypertensive preoperatively and 48% one year postoperatively. Systolic blood pressure did not differ significantly in pre- and postoperative measurements whereas diastolic blood pressure was significantly reduced over time. Moreover, pheochromocytoma patients gained body weight (p<0.001) one year following adrenalectomy accompanied by significant increases in body-mass-index, whereas aldosterone-producing adenoma patients displayed a slight weight loss. Despite weight gain, diagnosis of diabetes mellitus dropped from 9 of 43 investigated pheochromocytoma patients at baseline to 4 at follow-up. A significant correlation between body-mass-index changes to the preoperative catecholamine levels was found only for urinary normetanephrines. These data suggest that normalization of chronic catecholamine excess by adrenalectomy is associated with an increase in body-mass-index, which is more pronounced in patients with high preoperative levels of urinary normetanephrines.

Excessive Catecholamine Secretion and the Activation of the Renin-Angiotensin-Aldosterone-System in Patients with Pheochromocytoma: A Single Center Experience and Overview of the Literature.

Catecholamines stimulate renin-secretion in the juxtaglomerular cells of the kidney and a number of case reports suggest an association between pheochromocytoma and activation of the RAAS. Therefore, it could be asked whether patients suffering from pheochromocytoma with high concentrations of circulating catecholamines present with oversecretion of renin and aldosterone. We identified twelve patients with excessive catecholamine secretion due to pheochromocytoma and compared them to a group of twelve patients with essential hypertension (EH) with regard to the activation of the renin-angiotensin-aldosterone-system (RAAS). The PubMed database was screened for studies that investigate the association between pheochromocytoma and activation of the RAAS. The plasma concentrations of metanephrines (19.9-fold) and normetanephrines (29.5-fold) were significantly higher in the pheochromocytoma group than in the EH group. Renin and aldosterone levels were 1.3-fold and 1.6-fold higher, respectively, as compared to the EH group, whereas the differences were not statistically significant. There was no significant correlation between plasma metanephrine or normetanephrine levels and the plasma renin concentration (rs=0.077, rs=0.049, respectively) in our patients. The data from our institution and from review of literature suggest that an association between pheochromocytoma in the context of high plasma catecholamine levels and activation of the RAAS is present. However, results have not been consistent. Thus, other causes of RAAS-activation should be considered also in the presence of pheochromocytoma or reinvestigation for aldosteronism should be offered to such patients after removal of the catecholamine-producing tumour.

ACCURACY OF PLASMA FREE METANEPHRINES IN THE DIAGNOSIS OF PHEOCHROMOCYTOMA AND PARAGANGLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVE: Various studies have validated plasma free metanephrines (MNs) as biomarkers for pheochromocytoma and paraganglioma (PPGL). This meta-analysis aimed to estimate the overall diagnostic accuracy of this biochemical test for PPGL. METHODS: We searched the PubMed, the Cochrane Library, Web of Science, Embase, Scopus, OvidSP, and ProQuest Dissertations & Theses databases from January 1, 1995 to December 2, 2016 and selected studies written in English that assessed plasma free MNs in the diagnosis of PPGL. Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) was used to evaluate the quality of the included studies. We calculated pooled sensitivities, specificities, positive and negative likelihood ratios, diagnostic odds ratios (DORs) and areas under curve (AUCs) with their 95% confidence intervals (95% CIs). Heterogeneity was assessed by I2. To identify the source of heterogeneity, we evaluated the threshold effect and performed a meta-regression. Deeks' funnel plot was selected for investigating any potential publication bias. RESULTS: Although the combination of metanephrine (MN) and normetanephrine (NMN) carried lower specificity (0.94, 95% CI 0.90-0.97) than NMN (0.97, 95% CI 0.92-0.99), NMN was generally more accurate than individual tests, with the highest AUC (0.99, 95% CI 0.97-0.99), DOR (443.35, 95% CI 216.9-906.23), and pooled sensitivity (0.97, 95% CI 0.94-0.98) values. Threshold effect and meta-regression analyses showed that different cut-offs, blood sampling positions, study types and test methods contributed to heterogeneity. CONCLUSION: This meta-analysis suggested an effective value for combined plasma free MNs for the diagnosis of PPGL, but testing for MNs requires more standardization using tightly regulated studies. ABBREVIATIONS: AUC = area under curve; CI = confidence interval; DOR = diagnostic odds ratio; EIA = enzyme immunoassay; LC-ECD = liquid chromatography-electrochemical detection; LC-MS/MS = liquid chromatography-tandem mass spectrometry; MN = metanephrine; NMN = normetaneprhine; PPGL = pheochromocytoma and paraganglioma; QUADAS-2 = Quality Assessment of Diagnostic Accuracy Studies 2.

[The application of captopril challenge test in the diagnosis of primary aldosteronism].

Objective: To evaluate the value of captopril challenge test (CCT) in the diagnosis of primary aldosteronism (PA). Methods: A total of 674 patients [(45.0±13.7) years, men 341, women 333] admitted to Peking Union Medical College Hospital from 2000 to 2015 were analyzed. Among them, 222 subjects were with essential hypertension (EH), 28 were with pheochromocytoma (PHEO), 246 were with idiopathic hyperaldosteronism (IHA) and 178 were with aldosterone producing adenoma (APA). All patients received CCT. 24 h urine sodium was measured in partial patients. Plasma renin activity (PRA), aldosterone (ALD) were detected. Results: Compared with EH [PRA: before 0.5(0.2, 0.9) µg·L(-1)·h(-1,) after 0.8(0.4, 1.5) µg·L(-1)·h(-1;) ALD: before (393±122) pmol/L, after (360±97) pmol/L] and PHEO [PRA: before 0.3(0.1, 0.9) µg·L(-1)·h(-1,) after 0.4(0.1, 1.6) µg·L(-1)·h(-1;) ALD: before (396±108) pmol/L, after (374±114) pmol/L], lower levels of PRA and higher levels of ALD before and after CCT were observed in PA patients [PRA: before 0.1 (0.1, 0.2) µg·L(-1)·h(-1,) after 0.1 (0.1, 0.2) µg·L(-1)·h(-1;) ALD: before (468±216) pmol/L; after (457±199) pmol/L]. After CCT, the suppression rate of ALD [2.8% (-8.8%, 15.4%) vs 6.6% (-4.3%, 17.6%)] and increasing rate of PRA [0(0, 50%) vs 50%(0, 200%)] in PA patients were lower than those in EH patients. The ALD/PRA ratio (ARR) were higher in PA than that in EH or PHEO patients. In the EH subjects, ALD levels of seated posture were higher than those of recumbent posture both before and after receiving captopril, but with no changes in ARR after CCT. No significant differences in ALD and ARR (before and after receiving captopril) were observed between seated and recumbent position in the PA group. The ARR after CCT tended to decrease in EH subjects with elevated urine-sodium compared with those with normal urine-sodium. No changes could be viewed in ALD and PRA levels between normal urine-sodium and elevated urine-sodium groups among APA, IHA and EH patients either before or after CCT. Among patients with APA, the ALD levels before CCT and the ARR after CCT were lower in the patients with AngiotensionⅡ(AngⅡ) reactive than those without. A ROC curve analysis suggested that the optimal cutoff value was 46.2 (ALD unit: ng/dl; PRA unit: µg·L(-1)·h(-1)) for ARR after challenge in diagnosing PA, with the sensitivity of 88.7% and specificity of 84.8%. Conclusions: ARR after 25 mg captopril had high sensitivity and specificity in diagnosis of PA with the cutoff of 46.2. Seated CCT could replace recumbent CCT as a more confirmatory test. The PRA increasing rate should be taken into consideration when diagnosis of PA.

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.