Plasma Metanephrines Research Articles

ODP042 Hereditary Pheochromocytoma with a Novel Mutation in the Succinate Dehydrogenase Subunit A gene

Abstract Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumorswith a diverse clinical presentation. Pathogenic variants in the genes encoding different subunits of the succinate dehydrogenaseenzyme complex that plays a central role in energy metabolism,have been linked to hereditary PPGL syndromes. Here wereport a rare case of hereditary pheochromocytoma with a novel mutation in the succinate dehydrogenase subunit A (SDHA) gene. A middle aged woman presented with left sided abdominal pain and was incidentally found to have bilateral adrenal lesions on abdominal imaging. She denied any symptoms of catecholamine excess but her plasma metanephrines level was elevated. Family history was significant for breast cancer in her motherand sister. Computed tomography (CT) scan of the abdomen showed bilateralbulky adrenal glands with a lesion in theleft adrenal gland. Magnetic resonance imaging (MRI) abdomen was performed for further characterization, the lesion measured approximately 2.8×2.6 cm with imaging characteristics suggestive of pheochromocytoma. Iodine-131 Metaiodobenzylguanidine (MIBG) whole body scan showed abnormal focal radiotracer uptake at the left adrenal gland, and she then underwentleft sided robotic adrenalectomy. Following surgery, the patient had symptomatic relief. Histopathology confirmed the diagnosis of pheochromocytoma measuring 2×2×1.5 cm with PASS (Pheochromocytoma of the Adrenal gland Scaled Score) score of 1/10, due to cellular monotony. Genetic testing revealed that she was positive for a pathogenic mutation in the SDHA gene consistent with the diagnosis of hereditary PPGL syndrome. Genetic testing was performed for the patient due to her presentation with bilateral adrenal masses and family history of cancers. Guidelines recommend genetic testing for patients with features that indicate a high likelihood of a hereditary cause for PPGL, including positive family history, syndromic features, and multifocal, bilateral, or metastatic disease. SDHA mutated PPGLs have diverse phenotypes and may be at high risk of metastasis. They are also associated with extra-adrenal tumors, include gastrointestinal stromal tumours (GIST), pituitary adenomas, papillary thyroid carcinoma, renal carcinoma and breast carcinoma. The detection of susceptibility genes for hereditary PPGL syndromes has key implications, for surveillance to detectextra-adrenal disease and recurrent tumors, as well as for consideration of genetic testing forfamily members. Presentation: No date and time listed

PSUN11 Outcomes of Nonselective or Selective Alpha-Adrenergic Antagonist for Preoperative Management of Intra-adrenal Pheochromocytoma

Abstract Background Pheochromocytoma is a rare neoplasm of the adrenal medulla that leads to catecholamine excess. Adrenalectomy is the standard management for operative candidates. Preoperative alpha-adrenergic antagonism has been traditionally performed with the non-selective irreversible agent phenoxybenzamine. Recently, use of this agent has been limited due to availability and cost. We sought to determine whether type of preoperative antihypertensive management with nonselective alpha-adrenergic antagonist or selective alpha-1 antagonist was associated with differences in patient outcomes for those undergoing adrenalectomy. Methods We performed a retrospective review of adult patients at a single institution undergoing index adrenalectomy for initial diagnosis of intra-adrenal pheochromocytoma from 2012 through 2021. Exclusion criteria were prior adrenalectomy and extra-adrenal pheochromocytoma or paraganglioma. Clinical and demographic factors were assessed. Our primary outcome was intraoperative hemodynamic stability, secondary outcomes were postoperative hemodynamic instability, and surgical complications. Data were analyzed using Chi-squared, Fisher's exact and Mann Whitney U tests. Results During the study period, 38 patients underwent index adrenalectomy for initial diagnosis of intra-adrenal pheochromocytoma. Patient age was a mean of 57.8 years (SD 13.6) with 14 male (37%) and 34 (90%) white. On preoperative cross-sectional imaging, the mean tumor size was 3.9cm (IQR 2.5–5.2) with 15 (40%) left sided, 21 (58%) right sided and 1 (3%) bilateral with 32 (87%) undergoing minimally invasive laparoscopic or robotic assisted adrenalectomy. The mean pre-contrast density on computed tomography imaging was 35.4 Hounsfield units (SD 15). Preoperative plasma metanephrines were mean 0.65 (SD 6.7), plasma normetanephrines 11.1 (SD 14.3). For preoperative pharmacologic therapy, 16 (42%) were on phenoxybenzamine, 21 (55%) selective alpha-1 antagonist, and 1 (3%) patient on both who was excluded from comparative analysis. Nine patients overall (24%) had preoperative hypertensive crisis with no difference between the groups. There was no difference between the groups for intraoperative hemodynamic instability with 6 (38%) in the phenoxybenzamine group and 10 (48%) in the selective alpha blockade group (p = 0.74) or postoperative hemodynamic instability with 5 (31%) compared with 9 (45%) respectively (p = 0.50). Groups were also similar with regard to age, sex, body mass index, comorbidities, preoperative catecholamine levels, American Society of Anesthesiologists Physical Status classification, minimally invasive or open surgery, tumor size, estimated surgical blood loss, and postoperative complications. Follow up duration was longer for the phenoxybenzamine group at 55 months (SD 35) compared with 21 months (SD 25) for the selective alpha blockade group (p = 0.003). Conclusions Use of preoperative alpha adrenergic antagonism selective alpha-1 antagonists showed similar outcomes intraoperative and postoperatively compared with irreversible nonselective alpha-adrenergic antagonists in this cohort. Use of selective alpha-1 antagonists should be considered when nonselective agents are not accessible. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP280 A Unique Case of Coexisting Paraganglioma, Primary Hypoaldosteronism and Primary Hyperparathyroidism in a Single Patient

Abstract Introduction To date, case reports have shown an association between paraganglioma and primary hyperaldosteronism, and primary hyperparathyroidism with primary aldosteronism, but not for all three of the aforementioned endocrinopathies combined. Clinical Case A 54-year-old woman with history of uncontrolled HTN, hypokalemia, DM2, CKD stage III, Takotsubo cardiomyopathy and primary hyperparathyroidism presented to the hospital with back pain. CT scan showed a 4.3 cm necrotic retroperitoneal mass. Due to her labile blood pressure, ranging from 194/102 mmHg to 106/60 mmHg, endocrinology was consulted for evaluation of secondary hypertension. Plasma normetanephrines were 3447 pg/mL (n ≤ 57 pg/mL), 24-hour urine normetanephrines 5954 mcg/24 hours (n 122-676 mcg/24 hours) and 24-hour urine norepinephrines 476 mcg/24 hours (n 15-100 mcg/24 hours). 24-hour urine cortisol and 24-hour urine metanephrines were within normal limits. Plasma aldosterone level and plasma renin activity (PRA) were 19 ng/dL and 0.78 ng/mL/h (n 0.25-5.82 ng/mL/h),. However, the patient was also taking spironolactone and telmisartan which interfered with results, and withdrawal of interfering medications was considered unsafe. 68Ga-DOTATATE PET/CT showed mild uptake in a left para-aortic mass. Genetic testing did not show pathogenic mutations of AP2S1, CASR, MEN1, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, TMEM127 or VHL genes. The patient was started on doxazosin and underwent successful removal of the left retroperitoneal mass consistent with paraganglioma. Six months later, surveillance testing showed normalization of fractionated plasma metanephrines and of 24-hour urine metanephrines. However, due to blood pressure of 152/100 mmHg and K of 2.8 mmol/L (n 3.5-4.7 mmol/L), concern was raised for primary hyperaldosteronism. After potassium repletion, labs showed plasma aldosterone of 37 ng/dL, PRA of 0.2 ng/mL/h (n 0.25-5.82 ng/mL/h) and ARR of 185 with potassium of 4.1 mmol/L (n 3.5-4.7 mmol/L) consistent with primary hyperaldosteronism. MRI of adrenal glands showed a left adrenal gland that was thickened and nodular but without discrete nodules > 1 cm. The patient was referred for adrenal vein sampling. Five years previously, the patient had been diagnosed with primary hyperparathyroidism, with PTH of 188.5 pg/mL (n 14-64 pg/dL), Calcium of 10.6 mg/dL (n 8.5-10.1 mg/dL) and GFR of 39. Pre-operative imaging with MRI neck had shown enlargement of two parathyroid glands. She had undergone two-gland parathyroidectomy with intraoperative PTH decrease of > 50% and normalization of calcium. However two weeks later, her PTH returned to pre-operative levels (with normal 25(OH)D) and continues to remains elevated. This has been attributed to underlying secondary hyperparathyroidism from her chronic kidney disease. Conclusion To our knowledge, this is a unique case of combined paraganglioma, primary hyperaldosteronism and primary hyperparathyroidism, as thorough literature review has not shown such a coexistence in the past. Presentation: No date and time listed

PSAT009 Cushing's Syndrome Developing 42 Years After Successful Treatment for Metastatic Adrenocortical Carcinoma

Abstract Introduction ACC is a rare malignancy with poor prognosis. ACC is associated with CS in about 10% of the cases. Herein we report a case of a patient with metastatic ACC who developed contralateral functional adrenal adenoma causing Cushing's syndrome 42 years later. Clinical Case A 72-year-old female presented for evaluation of right adrenal incidentaloma, measuring 4.4×3 cm, on CT abdomen and pelvis (CTAP), done as part of the evaluation for hip pain. In addition to the adrenal incidentaloma, a large left adnexal mass (8×7 cm) was also observed. Her past medical history was significant for left adrenal ACC diagnosed at the age of 30, The patient's initial presentation included virilization and menstrual abnormalities. Laboratory evaluation revealed hyperandrogenism and hypercortisolism. There was no evidence of metastatic disease, and the patient was managed surgically (total left adrenalectomy) with normalization of laboratory abnormalities and resolution of symptoms. Four years later, patient pulmonary metastasis were observed in a surveillance scan and the patient underwent wedge resection and chemotherapy. The patient did not have any evidence of recurrent disease thereafter. At the current presentation, there were no symptoms or signs of adrenal hormone excess. Hormonal workup revealed borderline elevation of plasma metanephrines, with normal 24 h urinary metanephrines and catecholamines. DHEA-S and testosterone levels, as well as other androgens, were normal. 1 mg dexamethasone suppression (DST) was abnormal, with cortisol of 5.5 mcg/dL 8 h after dexamethasone administration (normal <1.8 mcg/dL). High dose DST was repeatedly abnormal, with cortisol levels at 4.0 and 4.4 mcg/dL (normal <1.8 mcg/dL). AM cortisol was elevated, at 23.4 mcg/dL (normal 4-22 mcg/dL) with ACTH at 12 pg/mL (normal <45 pg/dL). 24 h urinary free cortisol (UFC) was repeatedly elevated at 123.2 and 83.8 mcg/d (normal <45.0 mcg/d). CA 125 was normal. As there are case reports of ectopic Cushing's syndrome related to ovarian malignancies, and the patient had a large adnexal mass, adrenal and ovarian vein sampling was performed. Cortisol levels were higher in the right adrenal vein compared to the periphery, and the gradient was normal for the left ovarian vein. The right ovary was not visualized, and it was not possible to catheterize the right ovarian vein. Whole body FDG scan revealed intermediate uptake by right adrenal mass and normal uptake by left adnexal mass. Based on these results, it was determined that the right adrenal was the source of excess cortisol, and the patient underwent laparoscopic right adrenalectomy. Pathology evaluation showed adrenal adenoma, without evidence of ACC. The patient was started on physiologic replacement doses of hydrocortisone and fludrocortisone. The patient has been doing very well clinically. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

OR29-3 High-specific-activity Iodine 131 Metaiodobenzylguanidine for the Treatment of Advanced Pheochromocytoma and Paraganglioma: A Real-world Study

Abstract Introduction Metastatic pheochromocytomas/paragangliomas (mPPGLs) are rare tumors with limited treatment options. High-specific-activity 131I-meta-iodobenzylguanidine (HSA 131I-MIBG) is the only approved therapy for mPPGLs. We summarized the efficacy and safety profile of HSA 131I-MIBG in patients with mPPGL. Methods This is a retrospective cohort study in patients with mPPGL treated with HSA 131I-MIBG on label at a tertiary cancer center. The primary endpoint was radiographic treatment response determined with CT/MRI according to RECIST v1.1 and 123 I-MIBG scan. Secondary endpoints were blood pressure changes and HSA 131I-MIBG related adverse events. We correlated responses with the genetic background as an exploratory endpoint. Results Twenty-four patients were treated including 15 men (62%). Median age at the time of treatment was 44 years (range 18–82). Twenty-three patients had distant metastases and one patient had an unresectable primary tumor. Seventeen patients (70%) had hormonally active tumors and 17 patients (70%) were on antihypertensive medications before HSA 131I-MIBG therapy [7 patients on alpha-blockers only and 10 on combination antihypertensive therapy]. Thirteen patients (54%) previously received antineoplastic treatment. Eleven patients (46%) received one dose of HSA 131−I-MIBG, the remaining received two doses. Median duration of follow-up was 15 months (range 2–52). In 23 evaluable patients, radiographic responses included: 2 complete responses (CR), 10 partial responses (PR), 8 stable diseases (SD), 2 mixed responses (MR), and 1 progressive disease (PD) yielding disease control rate (DCR) of 87%. Median time to response was 12.5 months (95% CI, 4.6 to 25.1). Radiographic responses in patients with sporadic disease were [6/11 SD, 3/11 PR, 1/11 MR, 1/11 PR], while the response in patients with a genetic mutation (SDHB, VHL, RET) was [2/12 CR, 7/12 PR, 2/12 SD, 1/12 MR]. In 17 hormonally active tumors, plasma metanephrines normalized in 3(18%), improved by 50% in 5(29%), increased in 4(24%), 4 patients (24%) had no repeat levels and one had stable levels. Blood pressure was evaluable in 22 (92%) patients. Blood pressure normalized in 9 patients (41%) leading to discontinuation of antihypertensive therapy. One patient had an improvement in the blood pressure leading to a reduction of antihypertensive medications. The most common adverse events were grade I/II nausea/vomiting and transient bone marrow suppression. One patient developed premature ovarian failure. Grade III/IV myelosuppression was seen in 3/24 (12%) patients. One patient had fatal pneumonitis, and one patient developed fatal gastrointestinal bleeding a month after treatment with unclear attribution to HSA 131 −I-MIBG. Conclusions In mPPGL, HSA 131I-MIBG is associated with high DCR regardless of underlying genetic mutation. Severe adverse events are infrequent but can be fatal. Presentation: Tuesday, June 14, 2022 10:15 a.m. - 10:30 a.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.

Pheochromocytoma recurrence in hereditary disease: does a cortical-sparing technique increase recurrence rate?

BackgroundPosterior retroperitoneoscopic adrenalectomy is an appealing approach for patients with hereditary pheochromocytoma and lends well to cortex preservation. We sought to examine pheochromocytoma recurrence in patients with hereditary pheochromocytoma in the era of posterior retroperitoneoscopic adrenalectomy and evaluate the predictors of recurrence. MethodsPatients with hereditary pheochromocytoma who underwent adrenalectomy for pheochromocytoma between 1995 and 2020 with biochemical cure and follow-up >1 year were identified. Recurrence was defined as plasma metanephrines above the upper limit of normal with radiographic evidence of disease in the ipsilateral adrenal bed. ResultsSeventy-eight hereditary pheochromocytoma patients (median age = 32.4 years; 60.3% women) underwent 114 adrenalectomies for pheochromocytoma. Of these patients, 40 had multiple endocrine neoplasia type 2A (51.3%), 10 had multiple endocrine neoplasia type B (12.8%), 17 had von Hippel-Lindau disease (21.8%), and 11 had neurofibromatosis type 1 (14.1%). Thirty-eight adrenalectomies (33.3%) were performed before the introduction of posterior retroperitoneoscopic adrenalectomy and 76 (66.7%) after. Cortical-sparing technique was performed in 62 (54.4%) adrenalectomies, with no difference in its use before and after posterior retroperitoneoscopic adrenalectomy introduction (P > .05). During a median follow-up of 80.7 months (interquartile range 43.4–151.2), 12 ipsilateral recurrences (10.5%) were identified. There was no difference in recurrence before and after the introduction of posterior retroperitoneoscopic adrenalectomy or by surgical technique or approach of the entire cohort (P > .05). Recurrence was more common in those with RET M918T mutation (23.5% vs 8.2%; P = .05). Patients with RET M918T mutations had a shorter recurrence-free survival (P = .013). On multivariate analysis, only RET M918T mutation was independently associated with an increased recurrence risk (hazard ratio = 4.30; 95% confidence interval, 1.26–14.66; P = .019). ConclusionThe introduction of posterior retroperitoneoscopic adrenalectomy did not influence the recurrence rate after adrenalectomy for hereditary pheochromocytoma patients. Patients with a RET M918T germline mutation are at increased risk for pheochromocytoma recurrence and may benefit from initial total adrenalectomy.

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.

PSIII-A-5 Blood Catecholamine Profiling of Transportation Stress in Goats Previously Habituated to Livestock Trailer

Abstract Long distance transportation can cause significant physiological changes in goats that can impact their wellbeing. This experiment was conducted to determine the effects of habituation to livestock trailer on plasma catecholamine profile in goats transported for long periods. A total of 168 intact male Spanish goats were separated into two treatment (TRT) groups and maintained on two different paddocks in a split-plot design. Concentrate supplement was fed to one group inside two livestock trailers (5.0 × 2.3 m each; habituated group, H), while the other group received the concentrate supplement, but not inside the trailers (non-habituated, NH). After 4 weeks of habituation period, goats were subjected to a 10-hour transportation stress in 4 replicates (n = 21 goats/replicate/TRT). Blood samples were collected prior to loading (Preload), 20 min after loading (0 h), and at 2, 4, 6, 8, and 10 h of transportation (Time) for catecholamine analysis using a sensitive, high-throughput GC-MS/MS method. Habituation did not have any significant effect on dopamine, norepinephrine, and normetanephrine concentrations, while there was a tendency for TRT effect (P &amp;lt; 0.1) on epinephrine, tyramine, and metanephrine concentrations. Phenyethylamine and 5-methoxytryptamine concentrations were significantly higher (P &amp;lt; 0.05) in the H group compared to the NH group, which may enhance emotional wellbeing and energy levels. While both dopamine and 5-methoxytryptamine concentrations decreased (P &amp;lt; 0.05) with transportation time, dopamine concentrations increased again at 10 h. Plasma metanephrine concentrations were 0.86, 0.85, 4.22, 3.68, 2.30, 2.05, 2.14 (SEM = 0.327) nM, respectively at Preload, 0, 2, 4, 6, 8, and 10 h, indicating that stress peaked during the initial hours and decreased thereafter. Interaction effects were not significant. Habituation to trailer may be beneficial in mood and energy stabilization in goats during long-distance transportation. Metanephrine concentrations may more accurately reflect stress levels in goats.

Abstract P119: Severe Paroxysmal Hypertension In Patient With Gastric Neuroendocrine Tumor Detected By PET Dotatate Imaging

Neuroendocrine tumors (NET) are rare neoplasms originating from neuroendocrine cells in the endocrine, gastrointestinal, or bronchopulmonary systems. When symptomatic, patients may present with paroxysmal HTN. A 51-year-old woman with CAD and prior CABG presented to the hospital with sudden onset headache and BP in the 200s/90s. Her physical exam was unremarkable. ECG showed new T wave inversions in leads V1 and V2 and high-sensitivity troponin was elevated at 1827 ng/L. CT angiography of her head and neck was normal. Her HTN improved with IV labetalol and pain control. We admitted her for BP control and secondary HTN evaluation. Initial lab findings were unremarkable (see table). A renal artery ultrasound showed no renal artery stenosis. CT of her chest, abdomen, and pelvis showed no evidence of NET. She continued to have paroxysms of severe HTN, initially controlled with IV medications, then transitioned to an oral four-drug regimen prior to discharge. Fractionated plasma metanephrines and catecholamines, and 24-hour urine fractional metanephrines were obtained (results pending at time of discharge).Follow up testing showed elevated urinary metanephrines and Chromogranin levels (see table), suggestive of NET. A Ga-68 PET-DOTATE scan showed a focus of increased activity in the anterior stomach. Endoscopy revealed a gastric body lesion, identified as grade 2, well-differentiated NET on biopsy. The patient underwent laparoscopic wedge gastrectomy with clear margins. Her headaches resolved, and BP improved. This case demonstrates the utility of Ga-68 PET DOTATE imaging in determining the presence of NET, not detected by CT images, as the reason for severe, paroxysmal HTN.

TH1.13 The Role of Metanephrines in the Diagnosis of Pheochromocytoma

Abstract Introduction Pheochromocytomas are rare neuroendocrine catecholamine-producing tumors that arise from either the adrenal medulla (PHEO) or extra-adrenal paraganglionic tissues (paraganglioma/PGLs). PHEO is responsible for about 0.01–0.1% of the cases of hypertension. Assessment of the plasma/urinary levels of metanephrines (catecholamines metabolites) is now considered the gold standard for the diagnosis of PHEOs. In this study, we aimed to investigate the role of the plasma and 24-hour urinary metanephrines levels in the diagnosis of PHEO/PGLs. Patients and Methods Retrospective review of 26 patients diagnosed with PHEO/PGLs. We measured the plasma/ 24-h urinary metanephrines. The data were compared with another set of 26 patients with other adrenal pathologies. The correlation coefficient between the tumor sizes and the plasma/24-hour urinary metanephrines levels was calculated. Results The mean tumor size was 4.88 ± 1.99 cm. The sensitivity and specificity of the plasma metanephrines were about 95.8% and 98%, respectively, while for 24-hour urinary metanephrines were about 83.3% and 98%, respectively. We found a strong positive relationship (r = 0.472, P = 0.05) between the tumor size and the summed plasma concentrations of metanephrines. The relation between the tumor diameter and summed 24-hour urinary metanephrine was potentially strong (r = 0.354, P = 0. 083). Conclusion Plasma/24-hour urinary metanephrines are of great value in the diagnosis PHEOs/ PGLs as they are continuously produced by the tumor. There are strong relations between the size of these tumors and the plasma and urinary concentration of these metabolites, which can help to predict the size of the tumor even before imaging.

EP-630 Pheochromocytoma Associated with SDHB Mutation: A case report

Abstract Introduction Pheochromocytomas and paragangliomas are rare neuroendocrine tumors arising from the chromaffin cells of the adrenal medulla or extra-adrenal tissues. 10% to 20% of tumors are detected before age 18 years. Approximately 10%–15% of pheochromocytoma and 20%–50% of paraganglioma are malignant. Up to 24% of the cases are familial where they may be associated with genetic syndromes like MEN 2, succinate dehydrogenase subunit B (SDHB) gene mutations and VHL syndrome. Germline mutations in SDHB gene increase the risk of PGLs/ PHEOs and RCC with 38%-83% risk of malignancy. We represent a rare case of pheochromocytoma associated with SDHB mutation in a child. Case presentation A 17-year old patient presented with repeated vomiting and hypertension. BMI was 14.4 kg/m2, BP was 140/112 mmgh, PR was127 peats/min. The rest of the clinical examination was unremarkable. Plasma and 24-hour urinary metanephrines levels were highly elevated together with Chromogranin A level. Abdominal CT and MRI scans revealed an enlarged right adrenal gland measuring approximately 45 mm, indenting but not invading the posterior aspect of the IVC. Management Treatment was initiated with α-blockers; (Doxazosin then phenoxybenzamine); followed by β-blockers. The patient underwent laparoscopic right adrenalectomy. The tumor was 50×30×30 mm and weighting 58g. The tumor was positive with chromogranin, and S100. The PASS score was 2. Genetic mutation was detected at SDGB (c.72+1G&amp;gt;A). Conclusion We recommend genetic testing for all suspecting cases of PHEO/PGLs to establish the appropriate follow-up plan.

Biochemical Diagnosis of Catecholamine-Producing Tumors of Childhood: Neuroblastoma, Pheochromocytoma and Paraganglioma.

Catecholamine-producing tumors of childhood include most notably neuroblastoma, but also pheochromocytoma and paraganglioma (PPGL). Diagnosis of the former depends largely on biopsy-dependent histopathology, but this is contraindicated in PPGL where diagnosis depends crucially on biochemical tests of catecholamine excess. Such tests retain some importance in neuroblastoma though continue to largely rely on measurements of homovanillic acid (HVA) and vanillylmandelic acid (VMA), which are no longer recommended for PPGL. For PPGL, urinary or plasma metanephrines are the recommended most accurate tests. Addition of methoxytyramine to the plasma panel is particularly useful to identify dopamine-producing tumors and combined with normetanephrine also shows superior diagnostic performance over HVA and VMA for neuroblastoma. While use of metanephrines and methoxytyramine for diagnosis of PPGL in adults is established, there are numerous pitfalls for use of these tests in children. The establishment of pediatric reference intervals is particularly difficult and complicated by dynamic changes in metabolites during childhood, especially in infants for both plasma and urinary measurements, and extending to adolescence for urinary measurements. Interpretation of test results is further complicated in children by difficulties in following recommended preanalytical precautions. Due to this, the slow growing nature of PPGL and neglected consideration of the tumors in childhood the true pediatric prevalence of PPGL is likely underappreciated. Earlier identification of disease, as facilitated by surveillance programs, may uncover the true prevalence and improve therapeutic outcomes of childhood PPGL. For neuroblastoma there remain considerable obstacles in moving from entrenched to more accurate tests of catecholamine excess.

A Case of Adrenal Pheochromocytoma Presenting with Anxiety

Pheochromocytoma is a rare, neuroendocrine tumor secreting catecholamine, arising from chromaffin cells of the adrenal medulla. Also, very rare cause of secondary hypertension in pediatric age, and however, it is important to suspect. Presentation of this tumor is highly variable but the most common pediatric cases being persistent hypertension, tachycardia, sweating, and headache. In addition, anxiety, weight loss and recurrent hypertension may also appear among the clinical manifestations of the disease. The diagnosis requires measurement of plasma metanephrines, with imaging studies performed for localization and identification of metastatic lesions. The definitive management of hypertension is surgical. We present a case with pheochromocytoma that was previously diagnosed as anxiety due to tachycardia associated with hypertension.

Pheochromocytoma in pregnancy - a rare but dangerous diagnosis.

Pheochromocytoma is a rare cause of hypertension in pregnancy. Unrecognized, it carries a great risk for both mother and the foetus. The main reason for missing the diagnosis is the misconception that any hypertension occurring in pregnancy is gestational hypertension or pre (eclampsia). As many as 90% of patients report one or more pheochromocytoma-related symptoms antenatally, but the diagnosis is made in 75% of patients, meaning that 3 out of 10 patients are diagnosed after childbirth or post-mortem. The symptoms are similar to other more common causes of hypertension in pregnancy, which presents a major diagnostic challenge. The diagnosis is based on determination of metanephrines in plasma or 24-hour urine. Magnetic resonance imaging (MRI) and ultrasound (US) are used to localize the tumour. If the diagnosis is made before the 24th week of pregnancy, laparoscopic removal of the tumour in the second trimester is recommended. If diagnosed later, the tumour could be removed during or after delivery. Preoperative preparation with alpha blockers is required to stabilize blood pressure. The decision on the mode of delivery depends on several factors, so an experienced multidisciplinary team is needed to minimize maternal and foetal mortality.

Phéochromocytomes et paragangliomes

AbstractPheochromocytomas and paragangliomas (PPGL) are very rare neuroendocrine tumors secreting catecholamine (epinephrine, norepinephrine, dopamine).This secretion is mainly paroxysmal, spontaneous or induced. It is responsible for a symptomatology with arterial hypertension associated to the triad headache-sweat-palpitations. Biological diagnosis of PPGL is based on the measurement of the metabolites of the catecholamines: metanephrine (metadrenalin) and normetanephrine (normetadrena- lin) respectively for epinephrine and norepinephrine, also called metanephrines (plurial). Their measurements are made on 24-hour urine collection for free (or unconjugated) and total (conjugated + free metanephrine, after acid hydrolysis) metanephrine measurement, or most recently, on blood sample for free plasma metanephrine measurement. Even though this last measurement is not yet reimbursed, it is the best tool for PPGL diagnosis with sensitivity and specificity upper than 95%. Nonetheless, there are still few false positive measurements because of analytical interferences (that have almost disappeared thanks to LC-MS/MS use), or because of pharmacological interferences, through the use of molecules interfering with catecholamines metabolism or drawing conditions leading to activation of sympathetic nervous system. Any treatment that could increase catecholamine concentrations has to be discontinued. Imaging (conventional and functional) is part of the follow up for slowly positive measurements and for tumor(s) localization.As most of the PPGL are hereditary diseases, the genetic diagnosis is also a huge part of their diagnosis.

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.

Adrenocortical Tumors and Pheochromocytoma/Paraganglioma Initially Mistaken as Neuroblastoma-Experiences From the GPOH-MET Registry.

In children and adolescents, neuroblastoma (NBL), pheochromocytoma (PCC), and adrenocortical tumors (ACT) can arise from the adrenal gland. It may be difficult to distinguish between these three entities including associated extra-adrenal tumors (paraganglioma, PGL). Precise discrimination, however, is of crucial importance for management. Biopsy in ACT or PCC is potentially harmful and should be avoided whenever possible. We herein report data on 10 children and adolescents with ACT and five with PCC/PGL, previously mistaken as NBL. Two patients with adrenocortical carcinoma died due to disease progression. Two (2/9, missing data in one patient) patients with a final diagnosis of ACT clearly presented with obvious clinical signs and symptoms of steroid hormone excess, while seven patients did not. Blood analyses indicated increased levels of steroid hormones in one additional patient; however, urinary steroid metabolome analysis was not performed in any patient. Two (2/10) patients underwent tumor biopsy, and in two others tumor rupture occurred intraoperatively. In 6/10 patients, ACT diagnosis was only established by a reference pediatric pathology laboratory. Four (4/5) patients with a final diagnosis of PCC/PGL presented with clinical signs and symptoms of catecholamine excess. Urine tests indicated possible catecholamine excess in two patients, while no testing was carried out in three patients. Measurements of plasma metanephrines were not performed in any patient. None of the five patients with PCC/PGL received adrenergic blockers before surgery. In four patients, PCC/PGL diagnosis was established by a local pathologist, and in one patient diagnosis was revised to PGL by a pediatric reference pathologist. Genetic testing, performed in three out of five patients with PCC/PGL, indicated pathogenic variants of PCC/PGL susceptibility genes. The differential diagnosis of adrenal neoplasias and associated extra-adrenal tumors in children and adolescents may be challenging, necessitating interdisciplinary and multidisciplinary efforts. In ambiguous and/or hormonally inactive cases through comprehensive biochemical testing, microscopical complete tumor resection by an experienced surgeon is vital to preventing poor outcome in children and adolescents with ACT and/or PCC/PGL. Finally, specimens need to be assessed by an experienced pediatric pathologist to establish diagnosis.