Plasma Normetanephrine Levels Research Articles

PS-BPR03-4: STAGED RESECTION OF SUSPECTED BILATERAL PHAEOCHROMOCYTOMA IN A PATIENT WITH END-STAGE KIDNEY DISEASE ON HAEMODIALYSIS

Objective: Phaeochromocytoma is a rare finding in the dialysis population. The usual complexities of its management are complicated by diagnostic considerations of anuria and catecholamine variability in relation to dialysis, as well as reduced margins of error in perioperative fluid balance. To date, available case reports detailing management of phaeochromocytoma in dialysis patients have described unilateral lesions. We describe the management of a haemodialysis patient with resistant hypertension secondary to suspected bilateral phaeochromocytoma, to undergo staged surgical resection. We report on the surgical outcomes of the initial staged resection as well as the effect of dialysis timing (pre- and post-dialysis) on laboratory plasma metanephrine measurements. Design and Methods: Case Report A 73-year-old male on home haemodialysis presents with resistant hypertension. He has a background of end-stage kidney disease (ESKD) secondary to hypertensive nephrosclerosis, vascular disease, and Type 2 diabetes mellitus. CT imaging performed for back pain incidentally revealed contrast-enhancing lesions in the left and right adrenal glands, measuring 5.5 cm and 1.4 cm respectively (Figure 1A). PET-CT demonstrated FDG-avid lesions in bilateral adrenal glands with marked activity on PET Gallium Dotatate study, consistent with neuroendocrine tumours (Figure 1B). In the context of resistant hypertension, these were favoured to represent phaeochromocytomas. Plasma normetanephrine levels were consistent with this diagnosis at 6,600pmol/L (Ref < 1,079pmol/L). Blood pressure was not adequately controlled with the original anti-hypertensive regimen (irbesartan, lercanidipine, atenolol, and prazosin), with systolic values of 170–210mmHg, and was altered in the work-up for surgical resection of the lesions. Maximum alpha-receptor blockade was achieved with high-dose phenoxybenzamine (300 mg/day), and a beta-blocker (propranolol) and calcium-channel blocker (nifedipine) were added to attain pre-operative systolic blood pressures of 140–160mmHg with expected postural falls. Preoperative fluid status was adjusted via haemodialysis ultrafiltration, balancing the risks of intraoperative hypotension with anaesthetic considerations of potential pulmonary oedema. Results: The patient underwent laparoscopic resection with initial removal of the left adrenal lesion (Figure 1C), confirmed on histopathology to be phaeochromocytoma (Figure 1D). Blood pressures intraoperatively were maintained with minimal vasopressor support, and postoperatively with no support, consistent with expected outcomes in a staged resection of suspected bilateral phaeochromocytomas. A right adrenalectomy is planned in two months. Conclusion: This is the first reported case of suspected bilateral phaeochromocytoma in an ESKD patient on haemodialysis, and highlights the associated complexities of diagnosis and management. We demonstrate staged resection of bilateral lesions can be a safe approach in this high-risk population.

LBSAT65 Search For A Duplicitous Pheochromocytoma

Abstract Introduction Pheochromocytomas are discovered during work up of adrenal incidentalomas and can be biochemically and clinically silent. We present a case of a patient who presented with typical "adrenergic spells" suggestive of pheochromocytoma but negative biochemical testing and non-confirmatory imaging findings. Case Report 39-year-old male presented with 4 weeks history of episodes of throbbing headaches, palpitations, sweating. He was found to be hypertensive, blood pressure of 220/110 mm Hg. Losartan was initiated, but symptoms persisted. Work-up for endocrine causes of hypertension revealed normal plasma renin activity 1.123 ng/ml/hr (0.167 to 5.380) and undetectable aldosterone level <1 ng/dl (0. 0-3. 0), mildly elevated random plasma normetanephrine 270 pg/ml (0-210), normal plasma metanephrines 49 pg/ml (0-88). Low-dose dexamethasone suppression test showed unsuppressed morning cortisol of 2.1ug/dl, undetectable ACTH <5 pg/ml, dexamethasone level 486 ng/dl. 24 urinary cortisol and 2 midnight salivary cortisol samples failed to confirm the diagnosis. 24-hr urine studies showed mildly elevated 24-hr normetanephrine 735 ug/24 hr (156-729), normal 24-hr metanephrines 197 ug/L (58-276), normal 24 hr epinephrine and dopamine levels. Repeat testing revealed normal plasma metanephrines levels and mildly elevated plasma normetanephrine levels 287 pg/ml (less than twice above the upper limit of normal). Dopamine and Chromogranin A levels were undetectable. Abdominal CT showed 2 cm round soft tissue density 42HU in right adrenal gland. Left adrenal gland contained 3 nodules measuring 11, 15 and 16 mm–all with density <10HU. MRI findings for the 2.2 cm right adrenal nodule was without significant drop in signal intensity on the in and out of phase sequences appearing moderately T2 hyperintense and T1 hypointense. Differential included atypical/fat poor adenoma, pheochromocytoma, or metastasis. On GA 68 Dotatate PET-CT this 2.2cm adrenal nodule had minimal to low radiotracer uptake. Since a pheochromocytoma could not be ruled out, patient was started on alpha blockade. Preoperative genetic testing was negative for common mutations associated with pheochromocytoma/paraganglioma syndromes. Patient underwent laparoscopic right adrenalectomy. Histopathology report confirmed 2.8 cm pheochromocytoma with a low PASS (2/20) and low GAPP score. Conclusion and Discussion Patients with borderline nor metanephrine elevations represent a diagnostic and therapeutic dilemma. The patient presented with adrenergic paroxysms strongly suggestive of underlying pheochromocytoma. Labs and imaging were not typical for pheochromocytoma and were indeterminate. Given strong clinical suspicion for a pheochromocytoma, we decided to proceed with adrenalectomy after pre-treatment with alpha blockers. Final histopathologic report confirmed the diagnosis of pheochromocytoma. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

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.

Incidence, risk factors and clinical significance of postoperative haemodynamic instability after adrenalectomy for phaeochromocytoma.

Due to risk of haemodynamic instability (HDI), it has been recommended that patients undergoing adrenalectomy for phaeochromocytoma should be monitored in an intensive care facility. The aim of this study was to evaluate the incidence, risk factors and outcomes of postoperative HDI in these patients. Retrospective cohort study of 46 consecutive patients who underwent open (OA, N=26) or laparoscopic (LA, N=20) adrenalectomy for phaeochromocytoma at a single centre [2007-2017]. HDI was defined as systolic BP >200 or <90 mmHg, heart rate >120 or <50 bpm or vasopressor therapy within 24 hours. Risk factors for intraoperative and postoperative HDI were evaluated by univariable and multivariable analyses. Intraoperative hypertension occurred in 25/42 patients (60%). Preoperative plasma normetanephrine levels ≥3,500 pmol/L were significantly associated with intraoperative hypertension on multivariable analysis [odds ratio (OR) 42; 95% CI: 4-429; P=0.002). Postoperative hypotension occurred in 21/45 patients (47%), and 13 (29%) required vasopressor therapy. Preoperative beta-blockade therapy was the only independent risk factor for postoperative hypotension on multivariable analysis (OR 4.0; 95% CI: 1.2-13.9, P=0.029). No patients (0/9) with tumours <5 cm treated by LA needed postoperative vasopressor therapy, compared to 39% (7/18) treated by OA (P=0.059). Complications developed in 9 patients (20%), and were less likely in those with intraoperative hypertension (8% vs. 41%; P=0.019). There was one postoperative death. Preoperative beta-blockade therapy is an independent risk factor for postoperative HDI after adrenalectomy for phaeochromocytoma. Patients who undergo laparoscopic adrenalectomy (LA) for phaeochromocytomas <5 cm are unlikely to need postoperative vasopressor therapy, and may not require intensive care monitoring.

Performance of plasma free metanephrines in diagnosis of pheochromocytomas and paragangliomas in the population of Asturias

IntroductionPheochromocytoma and paraganglioma are uncommon tumours whose best known symptoms include high blood pressure, palpitations, headache, and sweating. Clinical identification is not easy, however, and requires biochemical tests that allow for early diagnosis, including measurement of metanephrines levels. The aim of this study was to assess the diagnostic performance of plasma free metanephrines (PMETs) and to verify the transferability of the reference values used. MethodsPMETs levels were measured by liquid chromatography coupled to tandem mass spectrometry. Other biochemical tests evaluated (plasma catecholamine, urine metanephrine, catecholamine and vanilmandelic acid levels) were performed by liquid chromatography with electrochemical detection. Requests of these tests from 01/09/2015 to 31/10/2017 were reviewed, and both the reference values (document EP28-A3c) and the parameters of biological variation (Fraser method) for PMETs were estimated. ResultsThe study sample consisted of 1279 patients (61.3% females) aged 0–90 years, including 19 with pheochromocytoma/paraganglioma. Tests requested included: PMETs (n=662), catecholamines (n=589), metanephrines (n=586), and vanilmandelic acid (n=513) in urine, and plasma catecholamines (n=228). Tests with higher sensitivity were urinary fractionated metanephrines (91.7%) and PMETs (82.4%). When performance was compared in patients with both tests (n=243), they detected the same number of tumours (90.9%), but PMETs showed greater specificity (93.5% vs. 88.8%). Plasma normetanephrine levels showed a significant association with age (rho=0.19, p<0.0001). ConclusionPMETs and urinary fractionated metanephrines are the biochemical tests with better performance in diagnosis of pheochromocytomas/paragangliomas.

Rendimiento de las metanefrinas libres plasmáticas en el diagnóstico de los feocromocitomas y paragangliomas en la población asturiana

IntroductionPheochromocytoma and paraganglioma are uncommon tumors whose best known symptoms include high blood pressure, palpitations, headache, and sweating. Clinical identification is not easy, however, and requires biochemical tests that allow for early diagnosis, including measurement of metanephrines levels. The aim of this study was to assess the diagnostic performance of plasma free metanephrines (PMETs) and to verify the transferability of the reference values used. MethodsPMETs levels were measured by liquid chromatography coupled to tandem mass spectrometry. Other biochemical tests evaluated (plasma catecholamine, urine metanephrine, catecholamine and vanilmandelic acid levels) were performed by liquid chromatography with electrochemical detection. Requests of these tests from 01/09/2015 to 31/10/2017 were reviewed, and both the reference values (document EP28-A3c) and the parameters of biological variation (Fraser method) for PMETs were estimated. ResultsThe study sample consisted of 1,279 patients (61.3% females) aged 0-90 years, including 19 with pheochromocytoma/paraganglioma. Tests requested included: PMETs (n=662), catecholamines (n=589), metanephrines (n=586), and vanilmandelic acid (n=513) in urine, and plasma catecholamines (n=228). Tests with higher sensitivity were urinary fractionated metanephrines (91.7%) and PMETs (82.4%). When performance was compared in patients with both tests (n=243), they detected the same number of tumors (90.9%), but PMETs showed greater specificity (93.5% vs 88.8%). Plasma normetanephrine levels showed a significant association with age (rho=0.19, P<.0001). ConclusionPMETs and urinary fractionated metanephrines are the biochemical tests with better performance in diagnosis of pheochromocytomas/paragangliomas.

Exogenous Tryptophan Promotes Cutaneous Wound Healing of Chronically Stressed Mice through Inhibition of TNF-α and IDO Activation.

Stress prolongs the inflammatory response compromising the dermal reconstruction and wound closure. Acute stress-induced inflammation increases indoleamine 2, 3-dioxygenase-stimulated tryptophan catabolism. To investigate the role of indoleamine 2, 3-dioxygenase expression and tryptophan administration in adverse effects of stress on cutaneous wound healing, mice were submitted to chronic restraint stress and treated with tryptophan daily until euthanasia. Excisional lesions were created on each mouse and 5 or 7 days later, the lesions were analyzed. In addition, murine skin fibroblasts were exposed to elevated epinephrine levels plus tryptophan, and fibroblast activity was evaluated. Tryptophan administration reversed the reduction of the plasma tryptophan levels and the increase in the plasma normetanephrine levels induced by stress 5 and 7 days after wounding. Five days after wounding, stress-induced increase in the protein levels of tumor necrosis factor-α and indoleamine 2, 3-dioxygenase, and this was inhibited by tryptophan. Stress-induced increase in the lipid peroxidation and the amount of the neutrophils, macrophages and T cells number was reversed by tryptophan 5 days after wounding. Tryptophan administration inhibited the reduction of myofibroblast density, collagen deposition, re-epithelialization and wound contraction induced by stress 5 days after wounding. In dermal fibroblast culture, the tryptophan administration increased the cell migration and AKT phosphorylation in cells treated with high epinephrine levels. In conclusion, tryptophan-induced reduction of inflammatory response and indoleamine 2, 3-dioxygenase expression may have accelerated cutaneous wound healing of chronically stressed mice.

Abstract 8811: Pheochromocytoma Cardiomyopathy: The Extreme Effect of Catecholamines on the Heart

A previously healthy 19-year-old man was admitted with nausea, vomiting and labile blood pressures after several months of headaches and palpitations. Though normotensive on presentation, his blood pressure rose to 240/160 mmHg after administration of IV metoclopramide. He then developed dyspnea, acute pulmonary edema, and became hypotensive. Echocardiogram revealed an LV ejection fraction of 10% without cavity dilation. Coronary angiography revealed no coronary artery disease, and ventriculography revealed no regional wall motion abnormalities or apical ballooning. Given the concern for myocarditis, an RV endomyocardial biopsy was performed, which revealed necrotic myocytes, but no inflammatory infiltrate. CT scan of the abdomen revealed a 4.0 x 3.5 cm mass within the right adrenal gland and plasma normetanephrine levels were markedly elevated at 28.8 nmol/L. In the context of a presumptive diagnosis of pheochromocytoma complicated by catecholaminergic cardiomyopathy, plans were made for surgical resection of the tumor following alpha-adrenergic blockade. Continued hypotension prompted urgent implantation of a percutaneous ventricular assist device (pVAD). With pVAD support, hemodynamics improved over 2 weeks, serial echocardiograms showed improvement in LV ejection fraction to 60%, and laparoscopic removal of the adrenal mass was safely undertaken. Pathology confirmed a pheochromocytoma. Pheochromocytoma-induced cardiogenic shock is a rare syndrome described after adrenergic storm triggered by mechanical compression, tumor hemorrhage, or administration of dopaminergic agonists, such as metoclopromide in this case. The pathophysiology of acute myocardial stunning during catecholamine surge remains unclear. Postulated mechanisms include coronary vasospasm, direct toxic effects of catecholamines on cardiomyocytes, and a newly proposed hypothesis of Gi-receptor-coupled catecholamine signaling (stimulus trafficking). Our patient illustrates that the inhibitory effects of catecholamine excess on myocardial function may be reversible with early clinical recognition, aggressive hemodynamic support, appropriate pre-operative preparation, and surgical resection by a specialized team.

Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives

Nicotinamide and catecholamines are both degraded by S-adenosylmethionine-dependent methylation. Whether excess nicotinamide affects the degradation of catecholamines is unknown. The aim of this study was to investigate the effect of nicotinamide on the methylation status of the body and methylation-mediated catecholamine degradation in both normotensives and hypertensives. The study was conducted in 19 normotensives and 27 hypertensives, using a nicotinamide-loading test (100 mg orally). Plasma nicotinamide, N(1)-methylnicotinamide, homocysteine (Hcy), betaine, norepinephrine, epinephrine, normetanephrine and metanephrine levels before and 5 h after nicotinamide loading were measured. Compared with normotensives, hypertensives had higher baseline (fasting) levels of plasma nicotinamide, Hcy and norepinephrine, but lower levels of plasma normetanephrine, a methylated norepinephrine derivative. Nicotinamide loading induced a significant increase in the levels of plasma N(1)-methylnicotinamide and norepinephrine, and a significant decrease in the levels of O-methylated epinephrine (metanephrine) and betaine, a major methyl donor, in both hypertensives and normotensives. Moreover, nicotinamide-loading significantly increased plasma Hcy levels, but decreased plasma normetanephrine levels in normotensives. The baseline levels of plasma epinephrine in hypertensives were similar to those of normotensives, but the post-nicotinamide-loading levels of plasma epinephrine in hypertensives were higher than those of normotensives. This study demonstrated that excess nicotinamide might deplete the labile methyl pool, increase Hcy generation and inhibit catecholamine degradation. It also revealed that hypertensives had an abnormal methylation pattern, characterized by elevated fasting plasma levels of unmethylated substrates, nicotinamide, Hcy and norepinephrine. Therefore, it seems likely that high nicotinamide intake may be involved in the pathogenesis of Hcy-related cardiovascular disease.

Plasma free metanephrines in healthy cats, cats with non-adrenal disease and a cat with suspected phaeochromocytoma

Phaeochromocytomas are catecholamine-secreting tumours of the adrenal glands and are rare in cats. Plasma metanephrine levels are widely considered the diagnostic test of choice for phaeochromocytoma in people but have not been investigated in cats. In this study plasma free normetanephrine and metanephrine levels were measured using high-pressure liquid chromatography in healthy cats, sick cats with non-adrenal disease and in a cat with a suspected phaeochromocytoma. Plasma normetanephrine was significantly higher in sick cats with non-adrenal disease compared to healthy cats (P<0.05) and markedly higher in the cat with a suspected phaeochromocytoma when compared to either group. Plasma metanephrine was not significantly different in any of the groups. This study establishes a first-line guide reference range for plasma metanephrine and normetanephrine levels in healthy cats and cats with non-adrenal disease. These results provide rationale for further studies to establish the use of plasma normetanephrine levels as a potential diagnostic test for phaeochromocytoma in the cat.

Malignant paraganglioma associated with succinate dehydrogenase subunit B in an 8-year-old child: the age of first screening?

Several studies have shown that patients with succinate dehydrogenase subunit B (SDHB) mutations have a very high risk for developing malignant paragangliomas. However, there is no consensus of what age screening for paragangliomas should start. We report a case of an 8-year-old white girl with a 3-year history of catecholamine excess-related complaints who was diagnosed with a malignant SDHB-associated mediastinal paraganglioma. The patient presented with intermittent sweating, headache, nausea, vomiting, fatigue and weight loss that had been present since she was 5 years of age. A large posterior mediastinal mass measuring 6.4 cm x 3.1 cm x 4.6 cm was discovered on computed tomography (CT) and magnetic resonance imaging (MRI). Laboratory data included an elevated level of urine normetanephrine of 45,400 microg/g creatinine (upper reference limit 718 microg/g) and elevated level of plasma normetanephrine of 62.4 nmol/l (upper reference limit <0.90 nmol/l). She was diagnosed with a thoracic paraganglioma and subsequently underwent surgical removal of the tumor and two lymph nodes. Histopathologic examination confirmed metastatic paraganglioma. Postoperatively, her blood pressure normalized and plasma normetanephrine levels remained normal. Our patient first presented with paraganglioma-associated signs and symptoms at the young age of 5 years. This case clearly illustrates the need for increased vigilance and screening for paragangliomas in families with SDHB at a younger age than previously thought.