Plasma Normetanephrine Research Articles

PSAT027 An Incidentally-Discovered Retro-Cardiac Paraganglioma Presenting as NSTEMI

Abstract Introduction/Background Paragangliomas are rare tumors arising from extra-adrenal chromaffin tissue (1,2). The majority of paragangliomas occur in the head and neck, with the heart representing an uncommon site (3). We present a rare case of a patient who was incidentally found to have a hypersecretory retro-cardiac paraganglioma. Clinical Case A 72-year-old woman with a history of hypertension, hyperlipidemia, migraines, and prior cerebrovascular accident presented to the Emergency Department with sudden, substernal, pleuritic chest pain. She described weeks of a "fluttering sensation" in the chest with one episode of syncope. She denied shortness of breath or diaphoresis. Vitals were normal and EKG did not demonstrate ischemia. Troponin uptrended and the patient was admitted due to concern for non-ST-elevation myocardial infarction (NSTEMI). She promptly underwent cardiac catheterization which revealed non-obstructive coronaries and a left atrial mass with blood supply from the right coronary artery and the left circumflex artery. Cardiac MRI demonstrated an extracardiac, interpericardial 42×24×37 mm mass below the left atrium without aggressive features, and delayed homogenous enhancement with dynamic perfusion, suggestive of a paraganglioma. Biochemical evaluation demonstrated elevated free plasma normetanephrines of 5.5 nmol/L (normal: < 0.90 nmol/L) and normal free plasma metanephrines. Chromogranin-A was elevated at 454 ng/ml (normal: <93 ng/ml). 24-hour urine total urine metanephrines were markedly elevated at 1438 mcg/24h (normal: 180-646 mcg/24h) with mainly urine normetanephrines of 1390 mcg/24h (normal: 148-560 mcg/24h). The patient's TSH, free T4, and total T3 were normal. PET/CT scan was negative for metastatic disease. The patient denied a family history of paraganglioma or pheochromocytoma. She was seen in follow-up with Cardiac Surgery, who felt the resection would be technically difficult, but that there were no other alternatives. The patient's procedure was postponed due to a COVID-19 surge and patient was begun on alpha- and beta-blockade, instead of pure alpha-blockade with phenoxybenzamine, in view of her recent history of NSTEMI. Conclusion We present a rare case of an incidentally-found cardiac mass, discovered during cardiac catheterization, with biochemical and radiographic evaluations concerning for a retro-atrial paraganglioma. Cardiac paragangliomas can present with a range of symptoms, from hypertension to different obstructive symptoms, including ischemia, depending on the tumor's location. The secretory activity of cardiac paragangliomas can also vary; the literature reports that about 31% are biochemically active (2). Though rare, our case highlights the importance of understanding the atypical presentation and evaluation of cardiac paragangliomas.

PMON42 A unique case of Norepinephrine secreting Head and Neck Paraganglioma

Abstract Introduction Head and neck Paragangliomas (HNPGLs) are rare, slow growing neuroendocrine tumors arising from parasympathetic and sympathetic paraganglia in the head and neck region. Traditionally, HNPGLs were presumed to be rarely secretory compared to thoracoabdominal sympathetic PGLs(<5%) and most of them are thought to be identified due to compressive symptoms or incidentally on imaging performed for screening in genetically predisposed individuals. However, most recent evidence has suggested that >10% of HNPGLs can be secretory although data has also shown that typically catecholamines. Case Presentation A 55-year-old man presented to the emergency room with worsening headaches, right sided neck pain and dizziness. Physical examination revealed multiple cranial neuropathies including right facial weakness with ipsilateral lagophthalmos, tongue atrophy, dystonic and atrophic sternocleidomastoid muscle, and vagal deficit. Blood pressure was markedly elevated at 227/108 mmHg. Computed tomography scan of head and neck revealed a large bony destructive lesion involving the right skull base measuring 9.0×7.0 cm, with involvement cervical vertebral bodies, as well as ventriculomegaly suggestive of obstructive hydrocephalus with mass effect on the brain stem and cerebellum. History revealed knowledge of this skull base mass for 13 years. Initially the mass was 3.2 cm in the largest dimension with elevated 24-hour urine normetanephrine 1113 mcg/day, Ref: 50-650 mcg/day and dopamine 667 mcg/day Ref: 60-440 mcg/day. He didn't seek further medical care at that time due to his family's opposition to traditional medicine. Magnetic resonance imaging upon this admission revealed 9.0×6.0×5.5 cm expansile, hypervascular, destructive mass at the right skull base with pronounced mass effect and brainstem compression with significant narrowing at the foramen magnum. 24-hour urine normetanephrines were significantly elevated at 4229 mcg/day, ref: 114-865 mcg/day, as well as elevated plasma Normetanephrine at 11.58 nmol/L, ref: 0.00-0.89 nmol/L, and urine Dopamine 10,071 mcg/day, ref: 71-485 mcg/day. Antihypertensive treatment was initiated with alpha blockade followed by additional beta blockade. After multidisciplinary discussion, the decision was made to pursue external radiation therapy given the considerable risk associated with the surgery due to location and vascularity. Genetic testing is pending at the time of abstract submission. Conclusion Recent evidence has suggested that >10% HNPGLs can be secretory as opposed to previous assumption that they are rarely secretory. Norepinephrine is the most common catecholamine secreted by HNPGL and dopamine is very rare. We present a unique case of HNPGL when surgery was deferred for more than a decade due to opposition to traditional medicine resulting in a large norepinephrine and dopamine secreting tumor (10 times the upper limit of normal) and multiple compressive cranial neuropathies. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP032 Case Series: Prazosin in the Preoperative Management of Pheochromocytoma and Paraganglioma

Abstract Background Prazosin is a competitive alpha-1 adrenoreceptor antagonist. It is an ideal agent for preoperative blockade in neuroendocrine tumors compared to more commonly used agents such as phenoxybenzamine, a non-selective alpha blocker or doxazosin a longer acting alpha-1 blocker. Its affinity for alpha-1 receptors lessens the risk for systemic side effects while its short half-life and a relatively short duration of action of about 10-24 hours decreases the risk for intra and post-operative hypotension. Case 1 38 year old male was found to have resistant hypertension during routine follow up visit. Work up for secondary causes of hypertension revealed plasma metanephrines 5.1nmol/L, normetanephrine 6.7nmol/L, epinephrine 5990pg/mL, norepinephrine 15318 pg/mL, with 24 hour urine epinephrine 1329ug/24hr and norepinephrine 3115ug/24hr. Imaging findings shows 4.8cm right adrenal mass consistent with Pheochromocytoma. He was started on Prazosin titrated up to a dose of 5mg TID and labetalol 200mg TID to a goal systolic BP <130 mmHg. A right laparoscopic adrenalectomy was done and intraoperatively, he remained hemodynamically stable with no vasopressor or antihypertensive requirement. His blood pressure normalized immediately post op and did not require further antihypertensives for the rest of his hospitalization. Case 2 62 year old female was found to have an incidental 4.7cm left adrenal mass after a routine surveillance for pulmonary nodule. Biochemical data showed plasma metanephrines 14nmol/L, normetanephrine 3nmol/L, epinephrine 2719pg/mL, norepinephrine 701pg/mL, and chromogranin A 3507ng/m with a 24 hour urine epinephrine 938uh/24hr, consistent with Pheochromocytoma. The patient was started on Prazosin, titrated up to a maximum tolerated dose of 2mg TID before symptomatic hypotension occurred. Labetalol 100mg BID was later added. She underwent a left laparoscopic adrenalectomy but required Clevidipine drip and IV pushes of norepinephrine PRN intraoperatively for low blood pressure. However, she was taken off antihypertensives immediately post-op, and did not have any hypotensive episodes events thereafter. Case 3 50 year old female presented for left sided chest pain where a CT angiogram was done and incidentally found a para-aortic mass measuring 2.7×1.6×2.3cm in the organ of Zuckerlandl. Biochemical findings showed plasma normetanephrine 5.6nmol/L, norepinephrine 4564pg/mL, and chromogranin A 440ng/mL, consistent with a Paraganglioma. She was started on Prazosin titrated up to 6mg TID, labetalol 100mg TID and amlodipine 10mg daily to reach goal systolic blood pressure and heart rate. She underwent an open resection where there were no hypotensive events intraoperatively but did require Clevidipine drip for hypertension. Immediately post-op her BP normalized, the drip was discontinued, and she did not have any post-op hypotensive events. Conclusion This case series highlights the advantages of short acting alpha-1 blockade in the preoperative management of neuroendocrine tumors. All three patients did not have any post-operative hypotension and had an uncomplicated post-op course. Presentation: No date and time listed

ODP020 A Challenging Case of Poorly Differentiated Carcinoma with Neuroendocrine Differentiation and Adrenal Mass

Abstract Background Neuroendocrine tumors (NETs) account for about 0.5% of all newly diagnosed malignancies. The most frequent primary sites are the gastrointestinal tract or pancreatic (62%-67%) and the lung (22%-27%). All poorly differentiated NETs have a Ki-67 index of greater than 20% and WHO grade of 3. The determination of the site of origin can be challenging in widely metastatic poorly differentiated NETs. Clinical Case A 51-year man with a history of hypertension and type 2 diabetes mellitus presented with angioedema while on lisinopril for years. Apart from a month's history of bilateral flank pain, he denied diarrhea, flushing, stridor, or shortness of breath. CT abdomen showed an 8.2×8. 0×7.9 cm right adrenal mass with a few punctate calcifications, hepatomegaly with multiple liver metastases, multiple retroperitoneal, hepatoduodenal, retrocrural adenopathy, and T4 metastatic lesion. CT chest showed bulky mediastinal and supraclavicular lymph nodes with trachea narrowing. All those lesions were FDG avid on PET/CT scan. Core biopsy of right supraclavicular lymph node revealed a poorly differentiated carcinoma with neuroendocrine differentiation and high proliferative index (25-50%). On cell block, it was negative for (AE1/AE3 (-), CAM5.2 (-), CK7, CK20, vimentin, desmin, CEA, EMA, CD45, CD20, and TTF-1 but positive for CK903 (focal +), synaptophysin (+), chromogranin (+), calretinin (focally +), inhibin (focally +). Based on the immunohistochemical stain, it was concluded as a metastatic small cell carcinoma of unknown origin. He was treated with carboplatin, etoposide, and atezolizumab and received 5 cycles. Endocrine was consulted two months after his initial presentation. Urine normetanephrine was > 4-fold elevated. Blood pressure was controlled on Doxazosin at 4 mg bid. The 10 gene-panel for hereditary pheochromocytoma and Paraganglioma (PGL) was negative. There was a progression of mediastinal adenopathy while on treatment with narrowing of proximal intrathoracic trachea requiring elective tracheostomy. Based on imaging findings and elevated normetanephrine, we believe he has metastatic pheochromocytoma and PGL. His chemo regimen was switched to Cyclophosphamide, Vincristine, and Dacarbazine (CVD). He finished 8 cycles of CVD with an overall reduction in the size of lymph nodes (both above and below the diaphragm) and right adrenal mass. His plasma normetanephrine level was also significantly improved. Presentation: No date and time listed

PSAT011 Biochemically Silent Pheochromocytoma in an Asymptomatic Patient with a Unilateral Lipid Poor Adrenal Adenoma

Abstract Introduction Pheochromocytomas are rare catecholamine-secreting tumors arising from the adrenal medulla, which can occur in asymptomatic patients. Diagnosis is primarily through biochemical evidence of catecholamine over secretion, however, in rare cases catecholamine levels are within normal limits. These are known as "biochemically silent" pheochromocytoma. The lack of biochemical evidence makes diagnosis particularly challenging in cases presenting as adrenal incidentalomas. We present a patient with a left adrenal incidentaloma, initially identified 10 years ago which has been slowly growing and gradually becoming biochemically active. This case illustrates how radiologic findings can alert providers to the presence of pheochromocytoma and the importance of not immediately attributing mild biochemical abnormalities to medications. Case A 50-year-old Caucasian female presented to the clinic for evaluation of a left adrenal incidentaloma discovered 10 years ago. Past medical history is significant for hypothyroidism, dyslipidemia, anxiety and depression. Patient had undergone surveillance of the adrenal nodule both radiographically and biochemically since its discovery. First available imaging is a CT Abdomen/Pelvis in 2016 that noted a 1.7cm left adrenal nodule with unenhanced attenuation value of 25.6 HU. Most recent CT Abdomen/Pelvis in June 2021 reported a 2.6cm mixed density enhancing left adrenal gland nodule with less apparent macroscopic fat, concerning for a lipid poor adenoma. Biochemical work up done previously was reported to be non-functional. In 2018, elevated 24-hr urine normetanephrine of 859mcg/24h (88-649mcg/24h) and elevated 24-hr urine total metanephrines of 955mcg/24h (182-739mcg/24h) were noted. No intervention was done at that time. In August 2021, elevated plasma normetanephrine of 308.6 pg/ml (0-136.8pg/ml), elevated urine 24hr norepinephrine of 165mcg/24h (0-135mcg/24h), and elevated urine 24 hr urine normetanephrine of 1015mcg/24h (131-612mcg/24h) were noted. Rest of the biochemical work up was negative for hyperaldosteronism, hypercortisolemia and hyperandrogenemia. Although elevations were noted in the above values, they were <2 fold and the patient was also taking Effexor which can falsely elevate the normetanephrine levels. However, given the increasing size of the lipid poor adenoma, the patient was referred for endocrine surgery evaluation. She was preoperatively placed on doxazosin and underwent laparoscopic surgical removal. Pathology was consistent with a 2.4cm pheochromocytoma. Postoperatively, plasma metanephrines and normetanephrines were within normal limits. Subjectively, patient reports improvement of her hot flashes, insomnia and anxiety. Conclusion This case emphasizes the importance of surveillance for a lipid poor adrenal nodule. Providers should have a high level of suspicion for pheochromocytoma in patients with a lipid poor adenoma even if they are biochemically silent. A knowledge of medications causing falsely elevated catecholamine levels is necessary, however, these should be considered along with other clinical and radiological findings. Early diagnosis is important, if pheochromocytoma remains unrecognized it can lead to high morbidity and mortality. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Quantitative analysis of catecholamines and their metabolites in 491 patients with adrenal tumors: a retrospective single-center cohort study.

Adrenal tumors, including benign cortical adenoma (BCA) and pheochromocytoma (PCC) or paraganglioma (PGL), have been more frequently detected during imaging examinations in recent years. However, the associated clinical or laboratory characteristics, especially on the Chinese population, still need to be investigated. We conducted a retrospective analysis of 491 patients pathologically diagnosed with adrenal tumors, from Jan 19, 2018 to Dec 17, 2019, at a tertiary referral hospital in Wuhan of China. Our findings including 247 (50.3%) BCA cases, and 92 (18.7) PCC/PGL cases and other cases. Both the clinical and laboratory parameters were reviewed and analyzed. Compared with other adrenal tumors, PCC/PGL showed larger tumor diameters and more frequently located on the right side, and were with higher levels of urinary catecholoamines and plasma metanephrines, especially for the 24h urinary vanilmandelic acid (VMA) and plasma normetanephrine (NMN). The optimal diagnostic thresholds were 29.40 ug/24h for VMA (sensitivity, 85%; specificity, 91%) and 0.63nmol/L for NMN (sensitivity, 91%; specificity, 92%). The 24h urinary VMA and plasma NMN also shared abilities to differentiate between different tumor laterality and different tumor size in PCC/PGL cases. In addition, compared with the other benign tumors, BCA were smaller in diameters (20 vs 35mm, p < 0.001), and seemed to be lower in levels of plasma epinephrine, dopamine and serum ACTH. 24h Urinary catecholoamines and plasma metanephrines, especially for the 24h urinary VMA and plasma MNM, showed higher diagnostic efficacies for PCC/PGL, and were tightly associated with the tumor laterality and tumor size.

Comparison of plasma metanephrines in patients with cyanotic and acyanotic congenital heart disease.

The co-occurrence of cyanotic congenital heart disease (CCHD) and PHEO/PGL has been reported, but the role of the hypoxic environment in the pathogenesis of PHEO/PGL remains unclear. Our aim was to compare plasma metanephrine and normetanephrine levels between patients with CCHD and patients with acyanotic congenital heart disease (ACCHD). We performed a cross-sectional study in a prospective cohort of 44 patients with congenital heart disease (CHD) (31 (70.5%) females) with a median age of 37.5 (31.0-55.6) years at the time of evaluation. Thirty-two (73%) patients had CCHD and 12 (27%) patients had ACCHD. Morning blood samples for plasma determination of metanephrine and normetanephrine were collected. Plasma normetanephrine levels were significantly higher in patients with CCHD compared to ACCHD (p = 0.002). Ten (31.3%) patients with CCHD had plasma normetanephrine levels elevated above the reference range, while all ACCHD patients had normal levels. Patients with lower oxygen saturation and higher proBNP had significantly higher normetanephrine levels (ρ = -0.444, p = 0.003 and ρ = 0.449, p = 0.002, respectively). No chromaffin cell tumors were detected. Increased plasma normetanephrine levels in patients with CCHD can be explained by the effect of hypoxia. Future research is needed to better understand the impact of chronic hypoxia in CCHD on increased sympathetic outflow, hyperplastic response of chromaffin tissue, and the role of somatic mutations in CCHD-PHEO/PGL pathogenesis related to hypoxia.

Role of Plasma Metanephrines in Predicting Cardiovascular and Cerebrovascular Events in Patients With Essential Hypertension

Abstract Background To investigate the role of plasma metanephrines (MN) and normetanephrines (NMN), in predicting cardiovascular events in essential hypertensive patients. Methods This was a retrospective analysis of 688 hospitalized patients diagnosed with essential hypertension at the Beijing Anzhen hospital from October 2016 to August 2018, with a median (interquartile range) follow-up time of 24 (20–29) months. The primary endpoint was defined as all-cause death and/or readmission for cardiovascular or cerebrovascular events. Patients were divided into event (n = 57) and nonevent (n = 631) groups. High-performance liquid chromatography–tandem mass spectrometry was used to determine plasma MN and NMN levels. According to the cutoff value of plasma NMN from receiver operating characteristic analysis, patients were further divided into NMN ≤125.75 ng/l and NMN &amp;gt;125.75 ng/l groups. The effects of NMN on the prognosis of hypertensive patients were evaluated using Kaplan–Meier curves and multivariate Cox regression analysis. Results The plasma NMN levels of the event group were higher than those of the nonevent group [110.0 (74.0–135.0) vs. 88.5 (62.0–119.5) ng/l, P = 0.004]. The incidence of the primary endpoint event in NMN ≤125.75 ng/l and NMN &amp;gt;125.75 ng/l groups was 6.0% and 15.8%, respectively. Kaplan–Meier analysis showed that patients with higher baseline NMN levels were more likely to experience adverse events (P &amp;lt; 0.001). Cox regression analysis showed that patients in NMN &amp;gt;125.75 ng/l group had over twofold higher risk of the primary endpoint event than those in NMN ≤125.75 ng/l group (HR = 2.11, 95% CI 1.15–3.84, P = 0.015). Conclusions Elevated plasma NMN levels are associated with higher risk of cardiovascular and cerebrovascular events in patients with essential hypertension.

Bladder Paraganglioma Presenting as Post-Micturition Syncope.

A 22-year-old woman presented with a 12-year history of intensifying paroxysms of anxiety, palpitations and recurrent syncope following micturition. The patient was referred to endocrinology upon discovery of hypertension. An extended family history revealed metastatic phaeochromocytoma and paraganglioma in two grand-uncles. Clinical examination revealed hypertension, with a mean 24-hour ambulatory blood pressure of 150/100 mmHg. Supine plasma normetanephrines were markedly elevated with a raised 3-methoxytyramine, while plasma metanephrines were normal. Computed tomography identified a 4.4 cm mass at the right inferolateral margin of the bladder wall. Scintigraphic imaging confirmed unifocal bladder lesion uptake with no additional metastatic lesions. Following pre-operative alpha blockade, the patient underwent a partial cystectomy. Histology confirmed a paraganglioma, and SDHB staining was lost in neoplastic cells consistent with an SDHB-related paraganglioma. Plasma normetanephrine, 3-methoxytyramine and blood pressure returned to normal postoperatively. Genetic screening identified a germline heterozygous SDHB gene variant c.723C>G. Bladder paragangliomas are a rare but important differential to consider when investigating post-micturition syncope. An extended family history should be sought and suspicion for a genetic cause should be raised, especially when the condition presents at a young age. This is the first reported case describing phaeochromocytoma or paraganglioma with the SDHB gene variant c.723C>G.LEARNING POINTSBladder paragangliomas are a rare neuroendocrine tumour which should be considered when assessing patients with haematuria and hypertension, headache, palpitations, sweating and facial pallor with micturition.This case highlights the importance of a thorough clinical history with an extended family history and examination in the setting of micturition syncope, which can rarely occur with bladder paraganglioma.Young age at presentation, a family history of phaeochromocytoma and paraganglioma (PPGL), unusual paraganglioma location, mutifocality and aggressive disease should raise the suspicion for a genetic predisposition to PPGL.

Preanalytical Considerations and Outpatient Versus Inpatient Tests of Plasma Metanephrines to Diagnose Pheochromocytoma.

Sampling of blood in the supine position for diagnosis of pheochromocytoma and paraganglioma (PPGL) results in lower rates of false positives for plasma normetanephrine than seated sampling. It is unclear how inpatient vs outpatient testing and other preanalytical factors impact false positives. We aimed to identify preanalytical precautions to minimize false-positive results for plasma metanephrines. Impacts of different blood sampling conditions on plasma metanephrines were evaluated, including outpatient vs inpatient testing, sampling of blood in semi- vs fully recumbent positions, use of cannulae vs direct venipuncture, and differences in outside temperature. A total of 3147 patients at 10 tertiary referral centers were tested for PPGL, including 278 with and 2869 without tumors. Rates of false-positive results were analyzed. Outpatient rather than inpatient sampling resulted in 44% higher plasma concentrations and a 3.4-fold increase in false-positive results for normetanephrine. Low temperature, a semi-recumbent position, and direct venipuncture also resulted in significantly higher plasma concentrations and rates of false-positive results for plasma normetanephrine than alternative sampling conditions, although with less impact than outpatient sampling. Higher concentrations and rates of false-positive results for plasma normetanephrine with low compared with warm temperatures were only apparent for outpatient sampling. Preanalytical factors were without impact on plasma metanephrines in patients with PPGL. Although inpatient blood sampling is largely impractical for screening patients with suspected PPGL, other preanalytical precautions (eg, cannulae, warm testing conditions) may be useful. Inpatient sampling may be reserved for follow-up of patients with difficult to distinguish true- from false-positive results.

Bilateral adrenal uptake of 123I MIBG scintigraphy with mild catecholamine elevation, the diagnostic dilemma, and its characteristics

Cases in which bilateral adrenal 123I-Metaiodobenzylguanidine (123I-MIBG) scintigraphy accumulation is sometimes shown, with mildly elevated catecholamine (CA) or metanephrine (MN) levels (within 3 times the upper reference limit) are diagnostic dilemmas. We experienced 3 cases of adrenal incidentalomas with this dilemma in the differential diagnosis. The clinical diagnosis was subclinical Cushing's syndrome in 2 cases, and primary aldosteronism in 1. Despite suspected CA excess in clinical symptoms and imaging findings, the pathological findings of all these tumors were revealed to be cytochrome P450 family 11 subfamily B member 1 (CYP11B1) positive adrenocortical adenomas. Interestingly, adrenal medullary hyperplasia (AMH) was detected in the adrenal parenchyma of all those backgrounds. To clarify the clinical features of such cases, a cross-sectional study was conducted at the Kobe University Hospital from 2014 to 2020. One-hundred sixty-four patients who had undergone 123I-MIBG scintigraphy were recruited. Among them, 10 patients (6.1%) met the above criteria, including the presented 3 cases. Plasma adrenaline, noradrenaline, urinary metanephrine, and normetanephrine had values of 0.05 ± 0.05 ng/mL, 0.63 ± 0.32 ng/mL, 0.22 ± 0.05 mg/day, and 0.35 ± 0.16 mg/day, respectively. Nine cases were complicated with hypertension, and symptoms related to CA excess were observed. Half of them (5 cases) including presented 3 cases had unilateral adrenal tumors. These suggest that in cases of bilateral adrenal uptake on 123I-MIBG, AMH needs to be considered. Adrenocortical adenomas may be associated with AMH and further larger investigation is needed for this pathology.

Improved Diagnostic Accuracy of Clonidine Suppression Testing Using an Age-Related Cutoff for Plasma Normetanephrine.

Moderately elevated plasma normetanephrine (NMN) levels are frequent among patients with suspected pheochromocytoma and paraganglioma (PPGL). Clonidine suppression testing (CST) is recommended to distinguish patients with from those without PPGL. We aimed at evaluating the diagnostic outcome of CST in patients with moderate NMN elevations. Data from patients participating in the PMT study (Prospective Monoamine-Producing Tumor) and the ENSAT (European Network for the Study of Adrenal Tumours) registry in 6 European reference centers were analyzed retrospectively. Eighty-nine patients with suspected PPGL and moderate NMN elevations upon screening were included. During follow-up, PPGL was confirmed in 16 and excluded in 73 cases. Plasma NMN was measured by liquid chromatography tandem mass spectrometry before and 180 minutes after oral clonidine. Receiver operating characteristic analysis was performed to identify optimal cutoffs. If published diagnostic criteria for CST (ie, NMN ≥112 ng/L and NMN suppression <40%) were applied, a sensitivity of 88% (CI, 61%-98%) and a specificity of 97% (CI, 90%-100%) were observed. An improved cutoff for plasma NMN 180 minutes after clonidine was established at 80% of the age-related upper limit of normal, resulting in a sensitivity of 94% and a specificity of 97%. False-negative CST results occurred in 2 patients with small PPGL. This study, involving one of the largest cohorts of patients with suspected PPGL and moderately elevated NMN, confirmed the diagnostic accuracy of CST. The application of an adapted cutoff further improved sensitivity.

T166 Evaluation of plasma free metanephrine and normetanephrine laboratory request forms

T166 Evaluation of plasma free metanephrine and normetanephrine laboratory request forms

Determinants of disease-specific survival in patients with and without metastatic pheochromocytoma and paraganglioma

BackgroundPheochromocytomas and paragangliomas (PPGLs) have a heterogeneous prognosis, the basis of which remains unclear. We, therefore, assessed disease-specific survival (DSS) and potential predictors of progressive disease in patients with PPGLs and head/neck paragangliomas (HNPGLs) according to the presence or absence of metastases. MethodsThis retrospective study included 582 patients with PPGLs and 57 with HNPGLs. DSS was assessed according to age, location and size of tumours, recurrent/metastatic disease, genetics, plasma metanephrines and methoxytyramine. ResultsAmong all patients with PPGLs, multivariable analysis indicated that apart from older age (HR = 5.4, CI = 2.93–10.29, P < 0.0001) and presence of metastases (HR = 4.8, CI = 2.41–9.94, P < 0.0001), shorter DSS was also associated with extra-adrenal tumour location (HR = 2.6, CI = 1.32–5.23, P = 0.0007) and higher plasma methoxytyramine (HR = 1.8, CI = 1.11–2.85, P = 0.0170) and normetanephrine (HR = 1.8, CI = 1.12–2.91, P = 0.0160). Among patients with HNPGLs, those with metastases presented with longer DSS compared to patients with metastatic PPGLs (33.4 versus 20.2 years, P < 0.0001) and only plasma methoxytyramine (HR = 13, CI = 1.35–148, P = 0.0380) was an independent predictor of DSS. For patients with metastatic PPGLs, multivariable analysis revealed that apart from older age (HR = 6.2, CI = 3.20–12.20, P < 0.0001), shorter DSS was associated with the presence of synchronous metastases (HR = 4.9, CI = 2.78–8.80, P < 0.0001), higher plasma methoxytyramine (HR = 2.4, CI = 1.44–4.14, P = 0.0010) and extensive metastatic burden (HR = 2.1, CI = 1.07–3.79, P = 0.0290). ConclusionsDSS among patients with PPGLs/HNPGLs relates to several presentations of the disease that may provide prognostic markers. In particular, the independent associations of higher methoxytyramine with shorter DSS in patients with HNPGLs and metastatic PPGLs suggest the utility of this biomarker to guide individualized management and follow-up strategies in affected patients.

Systemic inflammation and sympathetic activation in gestational diabetes mellitus with obstructive sleep apnea

BackgroundAlthough some evidence suggests an association between obstructive sleep apnea (OSA) and gestational diabetes mellitus (GDM), its consequences still remain largely unknown. We sought to determine whether OSA is associated with higher inflammation and sympathetic levels in GDM, and to relate them with insulin resistance and perinatal outcomes.MethodsOSA was identified by polysomnography and defined as an apnea–hypopnea index of ≥ 5 h−1. Plasma cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-10), metanephrine, and normetanephrine were determined by immunoassays.ResultsWe included 17 patients with GDM and OSA and 34 without OSA. Women with GDM and OSA had higher normetanephrine concentrations [81 IQR (59–134) vs. 68 (51–81) pg/mL]. No differences in the inflammatory profile were found, while IL-1β was higher in patients with mean nocturnal oxyhemoglobin saturation ≤ 94%. We found positive correlations between increased sympathetic activation and IL-1β, with obstructive apneas, while time in REM showed an inverse relationship with IL-1β and metanephrine. Furthermore, IL-10 was inversely related with time in sleep stages 1–2, and with the arousal index, and it was positively related with time in slow-wave sleep. Significant correlations were also found between IL-1β and insulin resistance. There were no significant differences in neonatal characteristics; however, we found inverse relationships between IL-10 and birth weight (BW), and percentile of BW.ConclusionsOSA increased sympathetic activity, and IL-1β concentration was higher in patients with GDM with lower nocturnal oxygenation, all of which were related with obstructive events, and time in REM. Moreover, IL-1β was related with insulin resistance, and IL-10 inversely correlated with neonatal BW.

Head/neck paragangliomas: focus on tumor location, mutational status and plasma methoxytyramine.

Head and neck paragangliomas (HNPGLs) are tumors of parasympathetic origin that occur at variable locations and are often secondary to germline mutations in succinate dehydrogenase (SDH) subunit genes. Occasionally, these tumors produce catecholamines. Here, we assessed whether different locations of HNPGLs relate to the presence of SDHx mutations, catecholamine production and other presentations. In this multicenter study, we collected clinical and biochemical data from 244 patients with HNPGLs and 71 patients without HNPGLs. We clarified that jugulotympanic HNPGLs have distinct features. In particular, 88% of jugulotympanic HNPGLs arose in women, among whom only 24% occurred due to SDHx mutations compared to 55% in men. Jugulotympanic HNPGLs were also rarely bilateral, were of a smaller size and were less often metastatic compared to carotid body and vagal HNPGLs. Furthermore, we showed that plasma concentrations of methoxytyramine (MTY) were higher (P < 0.0001) in patients with HNPGL than without HNPGL, whereas plasma normetanephrine did not differ. Only 3.7% of patients showed strong increases in plasma normetanephrine. Plasma MTY was positively related to tumor size but did not relate to the presence of SDHx mutations or tumor location. Our findings confirm that increases in plasma MTY represent the main catecholamine-related biochemical feature of patients with HNPGLs. We expect that more sensitive analytical methods will make biochemical testing of HNPGLs more practical in the future and enable more than the current 30% of patients to be identified with dopamine-producing HNPGLs. The sex-dependent differences in the development of HNPGLs may have relevance to the diagnosis, management and outcomes of these tumors.

SUSPECTED PHEOCHROMOCYTOMA PRECIPITATING TAKOTSUBO CARDIOMYOPATHY

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Takotsubo cardiomyopathy (TCM) is characterized by transient systolic dysfunction resulting in hallmark apical ballooning/hypokinesis without the presence of coronary artery disease.1 The pathophysiology entails extreme stress, which generates a sudden and massive surge of catecholamines which then markedly deranges cardiac contractility.1 One source of the catecholamine surge is pheochromocytoma: a catecholamine secreting tumor of the chromaffin cells.2 We present the case of patient who presents with both TCM and a suspected pheochromocytoma. CASE PRESENTATION: A 56-year-old female with history of both STEMI and NSTEMI presented with chest pain, nausea, vomiting, and lightheadedness. Blood pressure was 197/119 mmHg on admission. Cardiac enzymes were normal, however ECG demonstrated new lateral ST elevations in V4-V6. TTE showed apical and anterolateral akinesis with a markedly reduced EF of 18%. Nitroglycerin infusion was initiated, and patient was transferred emergently for cardiac catheterization. Patent coronary vessels were found, no intervention was performed, and medical management was pursued. Echocardiographic and catheterization findings were consistent with TCM. Further chart review showed multiple similar prior episodes plus a prior CT scan which demonstrated a 2 cm adrenal mass. Given clinical suspicion, workup for pheochromocytoma was initiated. Plasma and spot-urine metanephrines, plus spot-urine normetanephrines and 24-hour urine metanephrines were within normal limits. Plasma normetanephrines, 24-hour urine normetanephrines, epinephrine, norepinephrine, and dopamine were elevated at 731.7 pg/mL, 1538 ug/24 hours, 83 pg/mL, 4213 pg/mL, and 1020 pg/mL respectively.The patient's blood pressure was eventually controlled with oral medications. She was initiated on goal-directed medical therapy for her newly reduced EF and discharged home with endocrinology follow-up. DISCUSSION: Detection of pheochromocytoma is elusive and largely depends on elevated catecholamines in urine or blood samples via 24-hour collection. The difficulty lies in the fact that the secretion is intermittent. Measurement of VMA in urine can be done yet despite a high specificity (95%) there is a low sensitivity (64%).3 Pheochromocytoma can result in mass catecholamine release with systemic manifestations, affecting cardiac contractility. CONCLUSIONS: Our patient presented with TCM from a suspected pheochromocytoma. This diagnosis was reached via a combination of echocardiographic imaging showing apical and anterolateral akinesis, not consistent with any single coronary distribution, a clean coronary catheterization, and several lab panels demonstrating elevated levels of catecholamines/metanephrines in both the blood and urine. REFERENCE #1: Ahmad SA, Brito D, Khalid N, Ibrahim MA. Takotsubo Cardiomyopathy. In: StatPearls. StatPearls Publishing; 2020. Accessed November 13, 2020. http://www.ncbi.nlm.nih.gov/books/NBK430798/ REFERENCE #2: Y-Hassan S. Recurrent takotsubo syndrome triggered by undiagnosed pheochromocytoma. International Journal of Cardiology. 2015;187:369-371. doi:10.1016/j.ijcard.2015.03.220 REFERENCE #3: Vora KS, Shah VR. Diagnosis of pheochromocytoma. J Anaesthesiol Clin Pharmacol. 2012;28(2):274-276. doi:10.4103/0970-9185.94931 DISCLOSURES: No relevant relationships by James Gubitosa, source=Web Response No relevant relationships by Shivam Kaushik, source=Web Response

Plasma catecholamine levels in the acute and subacute stages of takotsubo syndrome: Results from the Stockholm myocardial infarction with normal coronaries 2 study.

AimsIt is well‐accepted that takotsubo syndrome (TS) is characterized by a massive surge of plasma catecholamines despite lack of solid evidence. The objective of this study was to examine the hypothesis of a massive catecholamine elevation in TS by studying plasma‐free catecholamine metabolites in patients participating in the Stockholm myocardial infarction (MI) with normal coronaries 2 (SMINC‐2) study where TS constituted more than one third of the patients.Methods and resultsThe patients included in the SMINC‐2 study were classified, according to cardiac magnetic resonance (CMR) imaging findings (148 patients), which was performed at a median of 3 days after hospital admission. Plasma‐free catecholamine metabolites; metanephrine, normetanephrine, and methoxy‐tyramine were measured on day 2–4 after admission. Catecholamine metabolite levels were available in 125 patients. One hundred and ten (88%) of the 125 patients included in SMINC‐2 study, and 38 (86.4%) of the 44 patients with TS had completely normal plasma metanephrine and normetanephrine levels. All patients had normal plasma methoxy‐tyramine levels. Fourteen (11.2%) of the 125 patients included in SMINC‐2 study, and 5 (11.6%) of the 43 patients with TS had mild elevations (approximately 1.2 times the upper normal limits) of either plasma metanephrine or normetanephrine. One patient with pheochromocytoma‐triggered TS had marked elevation of plasma metanephrine and mild elevation of plasma normetanephrine. There were no significant differences between the number or degree of catecholamine metabolite elevations between the different groups of patients with CMR imaging diagnosis included in SMINC‐2 study.ConclusionThere was no evidence of massive catecholamine elevations in the acute and subacute stages of TS apart from one patient with pheochromocytoma‐induced TS. Most of the TS patients had normal catecholamine metabolites indicating that blood‐borne catecholamines do not play a direct role in the pathogenesis of TS.

Addition of 3-methoxytyramine or chromogranin A to plasma free metanephrines as the initial test for pheochromocytoma and paraganglioma: Which is the best diagnostic strategy.

Measurements of plasma free metanephrines (MNs), including MN and normetanephrine, provide high sensitivity and specificity for the diagnosis of pheochromocytoma and paraganglioma (PPGL). 3-Methoxytyramine (3-MT) and chromogranin A (CgA) may allow the detection of dopamine-producing or biochemically silent PPGL. The aim of this study was to evaluate whether measurements of plasma 3-MT or CgA as a supplement of plasma MNs offer a better diagnostic strategy for initial testing of PPGL. We enroled 125 patients who underwent surgery from 2015 to 2016 for our study and identified 33 patients with PPGL and 92 patients with non-PPGL masses. The levels of plasma free MNs and 3-MT were measured for all 125 patients using liquid chromatography-tandem mass spectrometry. Plasma CgA concentrations were determined using a radioimmunoassay. To evaluate the diagnostic performance of plasma free MNs, 3-MT and CgA, sensitivity and specificity were determined, and receiver operating characteristic curves were constructed. We found that combining 3-MT and MNs increased the diagnostic sensitivity from 93.9% (95% confidence interval [CI]: 78.4%-98.9%) to 97.0% (95% CI: 82.5%-99.8%). In contrast, addition of plasma CgA test reduced the diagnostic specificity significantly from 91.3% (95% CI: 83.1%-95.9%) to 75.0% (95% CI: 64.7%-83.2%). Here, we demonstrated that 3-MT represents a valuable supplementary test to plasma MNs, which can further enhance the sensitivity of the assay, while plasma CgA added no additional diagnostic value to MNs due to the lowered diagnostic specificity.

A FAMILY WITH HEREDITARY PARAGANGLIOMA SECONDARY TO SDHD MUTATION

INTRODUCTIONA third of pheochromocytoma and paraganglioma (PPGL) tumours are part of a hereditary syndrome. Hereditary PPGL shows autosomal dominant inheritance with variable penetrance. Genetic testing is recommended in all patients diagnosed with PPGL regardless of age at presentation and family history. SDHD is the most frequently mutated gene in head and neck PGLs and associated tumours have low malignancy rate. This gene is maternally imprinted with silencing of the maternal allele, thus, the risk of developing paragangliomas is limited to offsprings who inherit the pathogenic variant from their father. Paternally inherited pathogenic variants are highly penetrant by age 50. We describe a family with hereditary paraganglioma due to mutation in the SDHD gene. RESULTSThe index patient is a 23 year-old female who was diagnosed to have bilateral adrenal pheochromocytoma with carotid and cardiac paragangliomas. Genetic screening revealed that she has SDHD mutation. Further family history revealed that 2 out of 3 paternal aunts have carotid paragangliomas. Her father, youngest of 5 siblings, paternal uncle and grandfather passed away at age 42, 40, 39 years old, respectively, due to severe headache and possible haemorrhagic stroke. Six other family members underwent genetic screening as well. Five family members were positive for SDHD mutation. These include the index patient’s elder sister, 3 paternal aunts (2 with carotid paragangliomas) and one male cousin. CONCLUSIONGenetic testing for family members of patients with hereditary paragangliomas is recommended after thorough genetic counselling. Genetic testing for firstand second-degree relatives is recommended for SDHDrelated paraganglioma. Healthy asymptomatic carriers for the gene mutation should undergo clinical assessment, plasma and/or urine metanephrines and normetanephrines and a combination of whole-body MRI (head and neck, abdominal and pelvic) and PET-CT imaging at initial screening. Thereafter, recommendations for long-term surveillance include annual clinical and biochemical evaluation along with whole body MRI repeated every 2-3 years.