Free Metanephrines Research Articles

Differential Responses of Urinary Epinephrine and Norepinephrine to 24-h Shift-Work Stressor in Physicians.

Multiple stressors, including 24-h-shifts characterise the working environment of physicians, influencing well-being, health and performance. We aimed to evaluate the effect of the stressor 24-h-shift on the adrenal medullary and sympathoneural system in physicians with the hypothesis that shift work might have different impacts on both systems. Twenty-two physicians collected two 12-h-urine samples (“daytime” and “nighttime”) during a 24-h shift (“on-duty”) and on a free weekend (“off-duty”), respectively. Urinary excretion rates per m2 body surface area were assessed for the catecholamines epinephrine, norepinephrine and their respective free O-methylated metabolites metanephrine and normetanephrine by LC-MS/MS-analysis. The stressor provoked differential responses of epinephrine and norepinephrine. Epinephrine excretion rates showed significant increases from off to on duty. The largest proportional change (off-duty to on-duty) for epinephrine was observed for nighttime (205%), the increase for daytime was 84%. An increase in norepinephrine from off to on duty was only visible for nighttime collections. For the catecholamine metabolites, normetanephrine paralleled norepinephrine and exhibited an increase in excretion from off to on duty during nighttime collections of 53% whereas there was no change during daytime collections (3%). In conclusion: Whilst the 24-h-shift-work stressor in physicians activates the sympatho-adrenomedullary system, represented by epinephrine, the sympathoneural response through norepinephrine reflects mainly an ambulatory position during working hours.

Left Ventricular Structural and Functional Alterations in Patients With Pheochromocytoma/Paraganglioma Before and After Surgery

ObjectivesThis study sought to evaluate left ventricular (LV) structure and function in pheochromocytoma and paraganglioma (PPGL) patients before and after curative surgery. BackgroundData on catecholamine-induced effects on LV structure and function in patients with PPGL are limited and conflicting. MethodsThe study evaluated 81 consecutive patients with a PPGL, among whom 66 were evaluated 12 months after tumor removal. Fifty patients matched for age, sex, hypertension presence, and blood pressure (BP) levels served as a control group (non-PPGL group). Echocardiography was employed to assess the LV mass index (LVMI), systolic function including speckle tracking echocardiography, and diastolic function. ResultsPatients with PPGL were characterized by higher LVMI (median 103 [interquartile range (IQR): 88 to 132] g/m2 vs. median 94 [IQR: 74 to 106] g/m2; p = 0.006) and frequency of LV hypertrophy (44.4% vs. 24.0%; p = 0.018) compared with the non-PPGL group. Patients with PPGLs were characterized by lower global longitudinal strain (GLS) and early diastolic mitral annular velocity compared with patients in the non-PPGL group (median –17.2% [IQR: 15.6% to 18.9%] vs. median –19.3% [IQR: 17.7% to 20.6%]; p < 0.001; and median 11.1 [IQR: 8.3 to 13.0] cm/s vs. median 12.3 [IQR: 10.6 to 14.6] cm/s; p = 0.018, respectively). Presence of LV hypertrophy and GLS were independently associated with plasma free metanephrine concentrations. In operated patients, there were lower frequencies of LV hypertrophy (39.4% vs. 22.7%; p = 0.003), LVMI (median 98 [IQR: 85 to 115] g/m2 vs. median 90 [IQR: 76 to 109] g/m2; p < 0.001), and the ratio of transmitral early diastolic velocity to early diastolic mitral annular velocity (median 6.8 [IQR: 5.5 to 8.6] vs. median 6.0 [IQR: 5.0 to 7.6]; p = 0.005) but higher values for GLS (median –17.4 [IQR: –15.8 to 19.1] vs. median −18.5 [IQR: –17.1 to 20.1] p < 0.001) after compared with before surgery. ConclusionsCatecholamine excess in patients with PPGLs can lead not only to LV hypertrophy, but also to impairment of systolic LV function and subclinical alterations of diastolic LV function, independently of BP levels. These structural and functional changes are reversible after surgical intervention.

Clinical profile of pheochromocytoma and paraganglioma with normal plasma free metanephrines

Plasma free metanephrines (MNs) have been widely used as an initial test for pheochromocytoma and paraganglioma (PPGL). PPGL without MNs elevation has been reported on rare occasions. The objective of this study was to analyze the clinical profile of sporadic PPGL patients with normal MNs. In the study, 104 patients with sporadic PPGL diagnosed by histopathology in Peking University First Hospital from March 2015 to January 2020 were enrolled. All the patients had plasma MNs result, of whom, eight (7.69%) were with normal MNs. The reasons for their medical visits, clinical manifestations, the levels of plasma free MNs, 3-methoxytyramine (3-MT), catecholamines and chromogranin A (CgA), and the imaging findings were documented. Their preoperative diagnosis, perioperative medical management, and intraoperative blood pressure were analyzed. All the data mentioned above were compared with the MNs elevated group. The postoperative follow-up for MNs normal patients were applied. For the eight PPGL patients with normal plasma MNs, the most common clinical symptoms were sweating (3/8), abdominal and back pain (3/8), headache (2/8), palpitations (2/8), and fatigue (2/8). There were no significant differences in plasma free 3-MT and catecholamines' diagnostic positive rate between the MNs normal group and MNs elevated group, but the rate for plasma CgA was significantly decreased in the MNs normal group (2/5 vs. 41/43, P=0.005). No significant difference was found for the incidence of typical findings by enhanced CT between the two groups. In these eight MNs normal patients, six were diagnosed with PPGL by the previous history of PPGL, typical symptoms and CT findings, or elevation of 3-MT, CgA levels or positive results of PET-CT; two patients were misdiagnosed as nonfunctioning adenoma or primary aldosteronism. All these MNs normal patients underwent preoperative management with alpha adrenergic receptor blockers, of whom, one had an average intraoperative arterial pressure < 60 mmHg during surgery. The median follow-up time for the eight patients was 1.5 (0.5－4.5) years. No evidence of new tumors was found on the enhanced CT scans. Two MNs normal patients' plasma 3-MT and (or) CgA decreased to normal. For patients with adrenal or retroperitoneal tumors, typical symptoms or a previous history of PPGL, normal plasma MNs is not a sufficient exclusion for PPGL. Plasma 3-MT, catecholamine, CgA results and the imaging findings are helpful for the diagnosis of PPGL. We recommend patients with suspected MNs normal PPGL take alpha adrenergic receptor blockers as preoperative blockade, but should avoid overdose. Postoperative follow-up for patients with normal MNs should focus on the positive biochemical markers before surgery.

Detection of spot urinary free metanephrines and 3-methoxytyramine with internal reference correction for the diagnosis of pheochromocytomas and paragangliomas

Detection of normetanephrine (NMN), metanephrine (MN) and 3-methoxytyramine (3-MT) could be used to diagnose pheochromocytomas and paragangliomas (PPGLs). The accuracy for the diagnosis of PPGLs is only 6% by virtue of the classic symptom triad. In addition, false-positive results were found using plasma free MNs as biomarkers. Spot urinary free metanephrines (MNs) presented high specificity for PPGLs diagnosis in our previous work by HPLC with the electrochemical detection. Whereas, MNs and creatinine (Cr) need to be detected separately. A simple and specific method was urgently needed for the diagnosis of PPGLs.Here, we established a new HPLC method for spot urinary free MNs and 3-MT by the fluorescence detection and Cr by the ultraviolet detection simultaneously. It was worth mentioning that Cr for the virtue of being fairly constant in a given subject was used as an internal reference correction to eliminate the effect of spot urine volume for the diagnosis of PPGLs.Thirty-seven patients with PPGLs and 164 control subjects were detected by the established method and the peak area ratios of MNs and 3-MT to Cr were used innovatively for the diagnosis of PPGLs. The results showed acceptable precisions and recoveries. The sensitivities of the method were 94.6%, 91.9% and 86.5% and the specificities were 96.3%, 93.9% and 82.3%, respectively by the peak area of NMN/Cr, MN/Cr and 3-MT/Cr for the diagnosis. The established method provides a promising way for simple, rapid and accurate diagnosis of PPGLs.

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

A Series of Two Patients With Cardiac Paragangliomas

The objective of this report is to present 2 cases of cardiac paragangliomas (PGLs), and to outline the presentation, management, and associated genetic mutations. Case 1, a 38-year-old female, presented with a 12-month history of paroxysmal palpitations, headaches, and weight loss. Her investigations included plasma free metanephrines and urinary metanephrines, 68-gallium DOTATATE positron emission tomography/computed tomography, and cardiac imaging. Case 2, a 28-year-old male, presented with a hypertensive crisis and abdominal pain on a background of hypertension. Given his abdominal pain, he was investigated with an abdominal computed tomography (CT) scan, followed by plasma free meta-nephrines and urinary metanephrines, echocardiogram, and 123-iodine meta-iodobenzylguanidine single-photon emission CT. Case 1 had an elevated plasma normetadrenaline of 6,750 pmol/L (reference range is <900 pmol/L) and 3-methoxytyramine of 1,845 pmol/L (reference range is <110 pmol/L). 68-gallium DOTATATE positron emission tomography/computed tomography showed an avid cardiac lesion. The lesion was resected, and histopathology confirmed PGL. Genetic studies revealed an SDHC gene mutation. For case 2, abdominal CT revealed a para-spinal mass. Workup for this lesion revealed elevated normetadrenaline of 56,000 pmol/L (reference range is <900 pmol/L). An echocardiogram, arranged for investigation of hypertension, showed an additional cardiac mass. A 123-iodine meta-iodobenzylguanidine single-photon emission CT scan confirmed that both masses were functioning. The lesions were successfully excised. He was found to have an SDHB gene mutation. Both patients had long-standing symptoms secondary to catecholamine excess, thus it is important to promptly screen patients with unexplained hypertension or paroxysmal symptoms of palpitations, headaches, and diaphoresis with plasma free metanephrines or urinary metanephrines. All patients with PGLs should be offered genetic testing due to the high incidence of genetic mutations.

In Matrix Derivatization Combined with LC-MS/MS Results in Ultrasensitive Quantification of Plasma Free Metanephrines and Catecholamines.

Plasma-free metanephrines and catecholamines are essential markers in the biochemical diagnosis and follow-up of neuroendocrine tumors and inborn errors of metabolism. However, their low circulating concentrations (in the nanomolar range) and poor fragmentation characteristics hinder facile simultaneous quantification by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Here, we present a sensitive and simple matrix derivatization procedure using propionic anhydride that enables simultaneous quantification of unconjugated l-DOPA, catecholamines, and metanephrines in plasma by LC-MS/MS. Dilution of propionic anhydride 1:4 (v/v) in acetonitrile in combination with 50 μL of plasma resulted in the highest mass spectrometric response. In plasma, derivatization resulted in stable derivatives and increased sensitivity by a factor of 4–30 compared with a previous LC-MS/MS method for measuring plasma metanephrines in our laboratory. Furthermore, propionylation increased specificity, especially for 3-methoxytyramine, by preventing interference from antihypertensive medication (β-blockers). The method was validated according to international guidelines and correlated with a hydrophilic interaction LC-MS/MS method for measuring plasma metanephrines (R2 > 0.99) and high-performance liquid chromatography with an electrochemical detection method for measuring plasma catecholamines (R2 > 0.85). Reference intervals for l-DOPA, catecholamines, and metanephrines in n = 115 healthy individuals were established. Our work shows that analytes in the subnanomolar range in plasma can be derivatized in situ without any preceding sample extraction. The developed method shows improved sensitivity and selectivity over existing methods and enables simultaneous quantification of several classes of amines.

MON-907 Silent Presentation of Urinary Bladder Paraganglioma: A Case Report

Background: Paraganglioma is a rare extraadrenal, neuroendocrine tumor of the sympathetic or parasympathetic ganglia (1). Bladder paraganglioma accounts for 1% of all paragangliomas and 0.05% of all bladder tumors (1,2). Characteristic presentation of this tumor includes hypertensive crisis and postmicturition syncope (3). Clinical Case: 35 year old Middle Eastern man with no pertinent past medical history presented with gross hematuria associated with dysuria, purulent penile discharge, urinary frequency, suprapubic pain, and bilateral flank pain for eight months for which he was given a course of an unknown antibiotic in his home country. Social history revealed smoking half a pack of cigarettes/day for 7 years. Has no family history of cancer. On physical exam he had normal blood pressure with mild tenderness to palpation in suprapubic region. U/A was remarkable for hematuria. Patient was treated for UTI with a course ciprofloxacin without resolution of symptoms. Culture returned negative.CT abdomen/pelvis yielded an approximately 1.9 cm enhancing mural nodule involving the anterior aspect of the bladder. Free metanephrine, nor-metanephrine, plasma catecholamine, and urine vanillylmandelic acid were within normal limits. Cystoscopy and transurethral resection of the tumor (TURBT) was completed; a 5-6mm tumor was visualized and resected. Surgical pathology demonstrated tumor growth into the lamina propria and muscularis propria. Neoplastic cells in the sample were diffusely positive for synaptophysin and chromogranin. S100 protein immunostain highlighted sustentacular cells. The diagnosis of paraganglioma was made based on surgical pathology. Post TURP MRI yielded an approximately 1.7 x 0.9 cm transmural hypervascular enhancing mass lesion involving the anterior aspect of the bladder. Given transmural extension of the tumor, an open partial cystectomy was performed. The tumor was resected successfully with resolution of symptoms. Conclusion: This is an exceedingly rare example of a hormonally silent paraganglioma, mimicking the presentation of a UTI. This case may present the unique consideration of tobacco specific carcinogens as a potential risk factor for the development of bladder paraganglioma.

MON-LB034 A Severe Case of Pheochromocytoma Presenting as Classic Takotsubo’s Cardiomyopathy With Rapid Resolution

Background: Inverted Takotsubo’s cardiomyopathy requiring extra-corporeal membrane support (ECMO) with pheochromocytoma is well described. Classic Takotsubo’s cardiomyopathy, however, is rarely described in this setting. Clinical Case: A 50-year old woman with no previous comorbidities presented with pulmonary edema and cardiogenic shock. She required rapid escalation of vasopressor, inotrope, and intra-aortic balloon pump then ECMO with consideration of cardiac transplant. Initial echocardiogram showed an ejection fraction of 17%. Coronary angiography showed apical ballooning in keeping with classic Takotsubo’s cardiomyopathy. Abdominal ultrasound for transplant screening showed a 4.6 cm abdominal mass. Computed tomography confirmed a 4.6 cm mass with classic radiologic features of pheochromocytoma. Plasma free normetaphrine and metanephrine were elevated at 2.34 nmol/L and 0.25 nmol/L. A 24-hour urine collection included urine volume of 3500 ml, urine creatinine 7.2 mmol/day, elevated urine norepinephrine 1199 nmol/day, elevated urine epinephrine 888 nmol/day, and normal urine dopamine 335 nmol/day. Parathyroid hormone and calcitonin were normal at 0.4 pmol/L and 4.8 pmol/L, respectively. Plasma aldosterone was normal at 87 pmol/L and plasma renin normal at 3.5 ng/L. Doxazosin 1 mg daily was initiated and she had clinical improvement next day and came off ECMO. Her ejection fraction improved to 55% subsequent week. She had retroperitoneoscopic adrenalectomy two weeks later with full recovery. Conclusion: Classic Takotsubo’s cardiomyopathy is a possible presentation of pheochromocytoma with rapid resolution with alpha blockade.

SUN-182 Rare Case of Adrenocortical Carcinoma with Tumor Extension into the Inferior Venacava, Right Atrium and Right Ventricle

Introduction: Adrenocortical carcinoma is a rare and highly aggressive malignancy with an incidence rate of 1-2 per million population per year. It is an aggressive tumor with early metastasis to lungs, liver, bone and lymph nodes. Venous tumor thrombosis to inferior venacava (IVC), atrium or ventricle is rare and is considered as a tumor extension instead of metastatic disease, but with a poor prognostic outcome. Clinical Case: We present a rare case of adrenocortical carcinoma with tumor extension into the IVC, right atrium and right ventricle. A 62-year-old female with history of breast cancer on anastrozole presented to the clinic for a routine screening colonoscopy. Patient was noted to have uncontrolled hypertension before the procedure, so was sent to the ER. Upon further interviewing she complained of increasing abdominal distension, hirsutism, and bilateral lower extremity swelling over the past six months. CT abdomen revealed a large 10 x11 x13 cm heterogeneously enhancing mass arising above the right kidney, with extensive tumor extension into the IVC, right atrium and right ventricle. MRI too characterized a large mass in the right adrenal gland with tumor thrombus extension into the IVC, right atrium, and right ventricle. Hormonal studies demonstrated elevated cortisol, dehydroepiandrosterone-sulfate and testosterone levels. A 1 mg dexamethasone suppression test inadequately suppressed cortisol levels, consistent with Cushing’s syndrome due to endogenous over secretion of cortisol. Free plasma and urine metanephrine levels were normal. Plasma renin and aldosterone concentration were within normal limits. With the cooperation of a multidisciplinary team, patient underwent right adrenalectomy with removal of tumor thrombus from right atrium and right ventricle under cardiopulmonary bypass. Surgical pathology confirmed adrenocortical carcinoma. She was started on mitotane as adjuvant therapy. Patient was also noted to have a lung nodule with biopsy showing oncocytic neoplasm favoring metastasis from adrenal cortex. She did receive chemotherapy for the lung metastasis with decrease in the size of the nodule. Conclusion: Adrenal cortical carcinoma is a rare disease and the venous tumor thrombus to IVC, atrium and ventricle is even rarer and has a poor prognostic outcome. Complete tumor resection is the only curative approach with adjuvant therapies aiming to decrease the risk of recurrence only. Due to the aggressive nature of the tumor and quick development of metastasis, early diagnosis gives the best chance of resection and hence the greatest chances of survival.

SAT-229 Bilateral Pheochromocytoma as Incidental Finding in a Patient with Neurofibromatosis Type 1

Background.In contrast to other genetic syndromes associated with Pheochromocytoma and Paraganglioma (PPGL) in which yearly biochemical screening is recommended, in neurofibromatosis due to the low penetrance of these tumors, screening is only recommended when there is clinical suspicion1. Given that signs and symptoms of catecholamine excess are vague and non-specific, clinicians should keep a low threshold for biochemical testing in these patients.Clinical Case.70 year old female with Neurofibromatosis type 1 (NF-1) diagnosed at age 24, hypertension and atrial fibrillation, was referred to our institution after being found incidentally with bilateral adrenal nodules. She had a 2 year history of poorly controlled, labile hypertension. Treatment at the time of presentation included doxazosin, metoprolol, valsartan and hydralazine. She denied other symptoms of catecholamine excess.Further workup revealed elevated 24 hour urine normetanephrine at 2,530 mcg (ULN 500 mcg) and metanephrine at 1,325 mcg (ULN 290 mcg). Serum metanephrines were also elevated with free metanephrine of 1.6 nmol/L (ULN 0.5 nmol/L) and free normetanephrine of 4.1 nmol/L (ULN 0.9 nmol/L). Her biochemical metanephrine profile was consistent with pheochromocytomas in NF-1. MIBG uptake confirmed the presence of bilateral pheochromocytomas. She underwent a complete right adrenalectomy and a left cortical sparing adrenalectomy. Her adrenocortical function remains adequate. Post operatively while her blood pressures were no longer labile, she continued to require anti-hypertensive therapy.Conclusion.Patients who are at risk of developing pheochromocytomas and paragangliomas due to genetic syndromes or known germline mutations need ongoing clinical follow and biochemical testing for timely case detection. While in NF-1 pheochromocytomas are usually unilateral and present during early adulthood, they can present with bilateral disease and later in life2. During surgical treatment, even with unilateral disease, adrenocortical function should be preserved when possible3. Hypertension may persist despite complete surgical resection.

SAT-199 Diagnostic Dilemma: An Adrenal Incidentaloma in a Young Adult

Introduction:In an adult endocrine clinic, the majority of patients referred for evaluation of an adrenal incidentaloma are older than 30 years of age. It is important to be reminded that a patient may be diagnosed with an adrenal mass at any age but the etiology may vary depending on the age at presentation.Clinical case:An 18 year-old African American female with no significant past medical problems presented with a 2 month history of flank and abdominal pain associated with nausea and vomiting. An abdominal CT scan and a dedicated adrenal CT showed a right adrenal mass measuring 2.2 x 2.6 cm. The noncontrast Hounsfield units were 23, enhanced Hounsfield units 210, and delayed Hounsfield units 72. The calculated washout was 44%, not consistent with an adrenal adenoma. An MRI of the abdomen showed a 2.5 cm right adrenal nodule. The lesion did not demonstrate significant loss of signal between in and out of phase imaging, therefore the characteristics were not consistent with a lipid rich adenoma. Laboratory tests included an ACTH of 31 pg/mL (6-48 pg/mL), cortisol 8.7 ug/mL at 10:57 am (7-9 am 5.27-22.45 ug/mL), aldosterone 10.1 ng/dL (6-48 ng/dL), renin 2.2 ng/mL/hr (upright 0.5-4.0 ng/mL/hr), DHEA-sulfate 129 ug/dL (44-248 ug/dL), plasma free metanephrine 0.10 nmol/L (0.00-0.49 nmol/L), and plasma free normetaneprhine 0.41 nmol/L (0.00-0.89 nmol/L). The 24-hour urine norepinephrine, epinephrine, and metanephrine were all normal, however the 24-hour urine dopamine was elevated, 824 ug/24 hrs (52-480 ug/24 hrs). Subsequently, plasma dopamine, norepinephrine, and epinephrine were all within the reference range. The patient had a robotic-assisted right adrenalectomy removing a 5.7 x 3.5 x 1.7 cm gland, weighing 16.3 grams. The pathology demonstrated a ganglioneuroma within the right adrenal gland measuring 2.2 x 2.0 x 2.7 cm, negative for neuroblastoma or blastic components. Focal hemorrhage was noted, there was no tumor necrosis, and no mitotic figures were present. The tumor appeared to be encapsulated in the adrenal gland and the Ki-67 stain was negative in ganglioneuroma cells.Conclusion:Adrenal adenomas that appear as incidentalomas in young adulthood are extremely rare. Evaluating younger versus older adults found to harbor an adrenal “incidentaloma“ requires a unique approach for each age group, as the differential diagnosis varies widely. In our patient, the imaging was extremely concerning and diagnostic considerations included neuroblastoma, adrenocortical malignancy, pheochromocytoma, or ganglioneuroma. Adrenal ganglioneuromas are most frequently diagnosed in fourth and fifth decades of life. In younger adults ganglioneuromas are usually found in the retroperitoneum and posterior mediastinum. For our patient, surgical resection of the adrenal mass confirmed the pathologic diagnosis and provided definitive cure.

SAT-212 Management of VHL-Associated Pheochromocytoma in Pregnancy

Background: The appropriate treatment of pheochromocytoma during pregnancy is crucial because, while its incidence is rare (0.007%), it is associated with increased maternal and fetal mortality1. Clinical Case: A 32 year old Caucasian primigravida female presented with intrauterine pregnancy at 25 weeks for evaluation and management of a 9 mm left adrenal mass. The patient was previously diagnosed at age 10 with Von-Hippel Lindau (VHL) syndrome and genetic testing was positive for a VHL gene mutation (Type 2C VHL). At age 14, she underwent laparoscopic adrenalectomy to excise a right sided pheochromocytoma. At age 20, imaging revealed an enhancing left adrenal mass with imaging characteristics consistent with pheochromocytoma and with catecholaminergic labs that were normal or only mildy increased to 1.5 times upper normal range. Pre-partum the patient had been experiencing periodic episodes of headaches and palpitations. She reported experiencing baseline levels of palpitations and sweating with new onset of pre-syncope and hypotension during her pregnancy. Labs revealed normal serum levels of fractionated free metanephrines. Alpha adrenergic blockade, beta adrenergic blockade, and surgery were considered but deemed unnecessary as the patient was asymptomatic, imaging indicated the left adrenal mass was stable in size, and the patient wished to avoid lifelong adrenal replacement therapy. The patient’s blood pressure and heart rate were monitored closely throughout pregnancy and the use of alpha blockade or beta blockade was not needed. The patient had an uncomplicated induced delivery at 39 weeks. MRI with contrast of abdomen performed 10 months postpartum confirmed the presence of an enhancing 8 mm lesion on the inferior pole of the left adrenal gland with imaging characteristics again consistent with pheochromocytoma. Conclusion: This case demonstrates that a conservative approach of monitoring blood pressure and heart rate can be sufficient and appropriate for management of some patients with pheochromocytoma and VHL during pregnancy.Citation:1. ENDOCRINOLOGY IN PREGNANCY: Pheochromocytoma in pregnancy: case series and review of literature in: European Journal of Endocrinology Volume 177 Issue 2 (2017).

SAT-184 Silent Pheochromocytoma Complicated by Adrenal Insufficiency After Unilateral Adrenalectomy

Background: Adrenal insufficiency (AI) following unilateral adrenalectomy for pheochromocytoma (PCC) is an exceedingly rare occurrence described previously in 1 study in only 4 out of 13 patients with unilateral PCC. We discuss an unusual case of a patient with incidentally discovered PCC who underwent unilateral adrenalectomy and subsequently developed AI. Clinical Case: 61-year-old male in overall good health taking no medications presented with left flank and groin pain after a handlebar injury in a bicycle crash. CT angiogram Abdomen & Pelvis revealed a complex enhancing left adrenal mass with internal necrosis measuring 13 x 12 cm. He denied history of headaches, diaphoresis, chest pain or hypertensive crisis. He did endorse palpitations which had resolved with reduced caffeine intake. Labs showed plasma free metanephrine 3,295 pg/mL (ref range <57) and normetanephrine 68,472 pg/mL (<148), 24hr urine metanephrine 192,677 ug (52-341), 24hr urine normetanephrine 171,880 ug (88-444), 24hr urine vanillylmandelic acid (VMA) 182 mg (1.8-6.7), serum aldosterone 8.1 ng/dL (<39.2), serum free cortisol 0.47 ug/dL (0.07-0.93), 24hr urine cortisol 41.6 ug (<60), DHEA sulfate 37 ug/dL (42-290). He was started on phenoxybenzamine and underwent left adrenalectomy. Of note patient remained only minimally hypertensive with tumor manipulation intraoperatively. Pathology was consistent with PCC with no evidence of regional or distant metastases. Postop-labs showed plasma free metanephrine <25 pg/mL and normetanephrine 122 pg/mL. Calcitonin and parathyroid hormone levels were normal. Patient was evaluated in endocrinology clinic 4 weeks after surgery for complaint of severe fatigue, weight loss, anorexia and myalgias. Adrenocorticotropic hormone (ACTH) level was 31 pg/mL (7.2-63) with AM cortisol of 2.1 ug/dL (5-23) which increased to 7.4 ug/dL 1 hour after Cosyntoprin 250 mcg stimulation. He was started on prednisone 10 mg once daily with significant improvement in his symptoms. Conclusion: PCCs typically manifest as sustained or paroxysmal hypertension, episodic headaches, palpitations or diaphoresis. Our patient was found to have a PCC with strikingly elevated levels of catecholamines without typical signs and symptoms of PCC. To the best of our knowledge this is the 5th reported case where a patient developed AI after unilateral adrenalectomy for PCC. There are case reports describing PCCs which secrete both catecholamines and ACTH. However, our patient lacked clinical or biochemical evidence of hypercortisolism preoperatively and his tumor cells in path sample stained negative for ACTH. Other possible pathophysiologic mechanisms include ectopic corticotropin releasing factor production leading to subclinical Cushing syndrome (SCS). Clinicians should have a high suspicion for SCS in the setting of PCC to promptly diagnose and treat AI after unilateral adrenalectomy.

MON-LB44 Cushing’s Syndrome and Illegal Receptors

Case presentation: A 48-year-old female with HTN presented to the endocrinology clinic for the evaluation of incidental bilateral adrenal masses noted on chest CT for dyspnea workup. At the time of the presentation, she reported generalized fatigue, significant weight gain in the past year and shortness of breath. Her physical exam was remarkable for central obesity. Lab work showed elevated cortisol after 1 mg dexamethasone suppression test x 2 and elevated 24- hour urine cortisol. Plasma free metanephrine levels and aldosterone/ renin ratio were normal. MRI abdomen was done and showed bilateral adrenal masses (left: 5.6 cm, right: 3.2 cm). Patient was diagnosed with Cushing’s syndrome secondary to primary bilateral adrenal hyperplasia and was referred to endocrine surgery who recommended unilateral adrenalectomy. The decision was made to remove the larger left side adrenal mass. On post-operative day one her am cortisol decreased to 2.1 and she was started on hydrocortisone 20 mg in the morning and 10 mg in the evening. Discussion: Primary bilateral adrenal hyperplasia is a rare cause (< 2 %) of endogenous Cushing’s syndrome, usually occurs in a bimodal age distribution, in childhood and in the fifth- sixth decades. Presentation is variable with most patients having no symptoms or subclinical Cushing’s. The theory is the larger nodule size corelates with the higher cortisol production. Studies have shown between 60-70% of cases has aberrant ectopic hormone receptors which leads to increased cortisol production not only from ACTH but also from other ligands such as serotonin and vasopressin. Aberrant receptor testing examines whether cortisol or other steroid production increases in response to either physiologic or pharmacologic stimulus. Multiple genetic mutations have been associated, the most frequent is mutations in the Armadillo repeat- containing 5 gene identified in 2013. Treatment can either be medical or surgical. Medical therapy can be initiated if testing for an aberrant receptor is positive. In recent years there has been a trend towards doing unilateral adrenalectomy instead of bilateral, with initial remission of symptoms reported in about 84% of cases after unilateral adrenalectomy although there is a small risk of recurrence. Post operatively after unilateral adrenalectomy patients should be monitored for adrenal insufficiency. Our patient declined aberrant receptor testing and opted for surgery and is doing well post operatively. Conclusion: Primary bilateral adrenal hyperplasia is a rare cause of endogenous Cushing’s syndrome which can be treated either medically or surgically.

SAT-353 Familial Hyperparathyroidism - Due to a Rare Genetic Mutation

Introduction: Hyperparathyroidism occurs most commonly in middle age patients, predominantly in women. It can be caused by parathyroid adenoma, hyperplasia or parathyroid carcinoma. Genetic predisposition can be found in about 10% of primary hyperparathyroidism due to certain gene mutations. This case emphasizes the importance of taking a detailed family history when patients present with hyperparathyroidism at a young age, so that familial hyperparathyroidism, if present, can be detected and relatives screened.Clinical case: A 26 y.o. male presented with symptoms of fatigue and polydipsia for several years.He was noted to have a serum calcium of 12.4 mg/dL(8.5–10.5), with parathyroid hormone of213 pg/ml (15–65). He denied any history of kidney stones, fractures and no palpable neck masses. The patient’s family history was significant for his paternal half-sister who had parathyroidectomy for hyperparathyroidism at 20yrs old and paternal grandmother died of parathyroid cancer in her 50s. The patient’s father died of pancreatic cancer at 41yrs old. A neck ultrasound revealed a mass posterior to the left inferior thyroid. A Sestamibi parathyroid scan revealed a parathyroid adenoma at the posteroinferior aspect of the left hemithyroid. Labs for free metanephrines and normetanephrine, prolactin and gastrin levels were all normal.Due to his young age and the possibility of having familial hyperparathyroidism, he underwent bilateral neck exploration and parathyroidectomy, with removal of his left inferior, right superior, left superior parathyroid glands and left upper thymus. Surgical pathology revealed, hypercellular parathyroid tissue. Post operatively, his calcium and vitamin D remained within the normal range.Genetic studies revealed a mutation in the parafibromin gene - CDC73 (also called HRPT2), a tumor suppressor gene, which is on chromosome 1q25. The patient currently has 6 children ranging from age 5 months to 6 years. He was advised to have his children tested any time from age 7 years for the gene mutation.The patient has remained stable 4yrs post operatively, with normal calcium and PTH levels. He does not have any history of jaw tumor. He never had an ultrasound kidney done. He is being monitored with yearly lab tests. Conclusion: CDC73 gene mutation-associated disorders are inherited as an autosomal dominant fashion, with variable penetrance. This gene mutation can be found in conditions such as hyperparathyroidism jaw tumor, familial hyperparathyroidism and parathyroid cancer.Reference:1.CDC73-Related Disorders: Clinical Manifestations and Case Detection in Primary Hyperparathyroidism. J Clin Endocrinol Metab. 2017 Dec 1;102(12):4534–4540.

SAT-181 Pheochromocytoma Masquerading as Acute Coronary Syndrome. To Cath or Not to Cath?

BackgroundPheochromocytoma had been known as the “Great Mimic” as it can present with signs and symptoms consistent with numerous differentials [1]. Cardiac ischemia is one in particular which creates a diagnostic dilemma and poses significant risk for misdiagnosis.Clinical Case62-year-old female with recent onset hypertension and type II diabetes(HbA1C of 6.9%) presented to the ER with new episodes of nausea, vomiting, and substernal chest pain. During the preceding four months she also experienced episodic headaches, palpitations, and flushing.Initial vital signs were significant for blood pressure 157/81 mm Hg. Physical exam was unremarkable. An Electrocardiogram showed normal sinus rhythm with right axis deviation and ST segment depressions in the inferior leads II, III and aVF.Labs revealed a troponin peak at 2.95 (<0.04 ng/mL) and d-dimer of 403 (<400 ng/mL). Serum chemistry, TSH, and complete blood count were within normal limits. A CT Chest with angiography was negative for pulmonary emboli. However, it did note a heterogenous 7.6 cm right adrenal mass. At this juncture there was clinical concern for pheochromocytoma and serum free metanephrines was ordered.Prior to receiving medical treatment for her pheochromocytoma, she underwent cardiac catheterization which showed no evidence of coronary artery disease. The procedure was uncomplicated. However, post-procedurally she did develop worsening paroxysms and severe hypertensive episodes with heart rate up to 140 beats per minute and systolic blood pressure up to 220 mm Hg. She was subsequently started on alpha blockage with phenoxybenzamine 10mg twice daily to which she responded favorably. Her initial serum free metanephrine was 6087(< 57 pg/mL) and free normetanephrine 2489 (<148 pg/mL).ConclusionsThis case highlights the importance of maintaining a high index of suspicion for pheochromocytoma for all patients with acute chest pain and hypertension. Her untreated pheochromocytoma could have been fatal during or immediately after the cardiac catheterization. Given the suspicion for pheochromocytoma in this case, it would have been most appropriate to have begun alpha blockade after blood was drawn for metanephrines and before attempting any invasive procedures. Pheochromocytoma should be included in the differential diagnosis of acute coronary syndrome because it can mimic an ischemic episode.

MON-339 Secondary Hyperparathyroidism Due to Decrease 1 Alpha Hydroxylase Activity

•Our patient is a 63-year-old African American female with medical history significant for hypertension, class 1 obesity, osteoarthritis of knees who initially presented to the adult ambulatory clinic on 9/19/2013 with complaints of body aches and bone pain. Labs were remarkable for a serum calcium level of 9.8 mg/dl, serum phosphorous of 4.7 mg/dl, and serum parathyroid hormone level of 166 pg/ml (15-65 pg/ml), normal GFR and serum vitamin 25-OH D of 62. A DEXA scan was performed which showed mild osteopenia wof 1.0 (0.8-1.8), serum 1,25 - OH vitamin D of <8 pg/ml, normal alpha and beta carotene level, negative endomysial antibodies and normal magnesium level. A diagnosis of secondary hyperparathyroidism with unclear etiology was made. Same treatment was continued and a follow up in 3 months with repeat labs was advised. Repeat PTH went up to 281pg/ml but serum calcium and phosphate remained normal. Based on normal serum 25 OH vitamin D and low 1, 25 OH vitamin D, patient was started on calcitriol 0.25 mg daily. On next follow up in 3 months PTH decreased to 203pg/ml and 1, 25 OH vitamin D level normalized (35pg/ml). MEN was excluded with normal serum free metanephrine and gastrin levels. On subsequent visits DEXA scan normalized and PTH further trended downward to 101.7 pg/ml. Patient was discharged from endocrine clinic back to the PCP. • •Patient continued to follow up in adult medicine clinic but calcitriol fall off of patient’s medication list likely due to an error. Patient was off of calcitriol for 6 months but continue to take calcium vitamin D.PTH trended up to 186pg/ml and then to 350pg/ml. A referral to endocrinology was made again and a parathyroid sestamibi scan was obtained which did not reveal any abnormal uptake. Serum calcium, phosphate, magnesium and vitamin OH 25 vitamin D remained normal. •Patient was started back on calcitriol 0.5 mg daily and PTH again started to trend downward. The last PTH was down to 82 on March 20th 2019 with normal serum calcium, phosphate, magnesium and eGFR. The final diagnosis was secondary hyperparathyroidism due to decrease 1 alpha hydroxylase activityith a T score of −1.5 at left forearm. A diagnosis of primary hyperparathyroidism was made by the PCP and patient was started on calcium vitamin D and Fosamax and was referred to endocrinology for further evaluation. • •Further testing in the endocrine clinic revealed 24-hour urine calcium of 49 mg (100-300) and urine creatinine. This case report concludes that low 1-alpha hydroxylase activity should be considered as a cause of secondary hyperparathyroidism in a patient with normal GFR and 25-OH vitamin D level

SAT-LB306 A Case of Synchronous Non-Functioning Paraganglioma of the Urinary Bladder and Prostate Cancer

IntroductionThe bladder is an uncommon site for a paraganglioma, with only <1% of all paragangliomas occurring in the bladder. Management of non-functioning bladder paraganglioma is uncharted due to its rarity, and there is even less data for cases with synchronous malignancy. We found two case reports of synchronous paraganglioma and prostate cancer, only one in the bladder. Here we report a second case and discuss management.Clinical CaseA 72-year-old man with high risk prostate cancer, Grade group 5 on biopsy, was found to have a 1.2 x 1.6 cm bladder wall mass on staging CT scan. The transmural mass was only partially resectable via transurethral approach. Pathology unexpectedly revealed paraganglioma, confirmed by immunohistochemical stains for Synaptophysin, Chromogranin, and CD56.The patient had longstanding hypertension controlled on losartan and denied any symptoms of catecholamine excess. He had no family history of paraganglioma, pheochromocytoma, or related neoplastic syndrome. Plasma free metanephrine and normetanephrine levels were 57pg/mL (normal 57pg/mL) and 157pg/mL (normal 148pg/mL), respectively. Urinary studies were not performed due to stage 4 chronic kidney disease.Staging CT scan and bone scan did not show any other lesions. Even in cases of known distant metastases of paraganglioma, surgical resection of all tissue is recommended if possible. Thus, he underwent radical prostatectomy, bilateral pelvic lymphadenectomy and partial cystectomy. Prostate cancer was downgraded to Grade group 2, pT3aN0Mo and complete excision of the paraganglioma was confirmed.Evaluating for metastases and follow up are challenging in all paraganglioma cases, but especially non-functioning paragangliomas. Bladder paragangliomas carry a 10-15% risk of malignancy, but no separate data is reported for non-functioning ones. Histology scoring systems that are somewhat predictive in pheochromocytoma are less helpful in paragangliomas. Imaging is also challenging. CT, MRI, and a variety of functional imaging modalities have sensitivities for paraganglioma metastases in the range of 50 – 94% depending on location, functionality, and presence of germline mutation. For now, we recommend non-contrast CT with 18F-fluoro-2-deoxy-2-D-gluocse (FDG) PET. Though guidelines recommend annual biochemical surveillance, the usefulness in non-functioning paraganglioma is questionable.Genetic testing is recommended for all patients with paraganglioma. Succinate dehydrogenase B (SDHB) is most important given the propensity for metastases. Thus, we recommended the SDHx germline mutation package.Clinical LessonThis case is the second reported synchronous bladder paraganglioma and prostate cancer. It highlights the challenge, lack of data, and need for advancement in our knowledge for the best management of incidental, non-functioning, extra-adrenal paragangliomas.

Overnight/first-morning urine free metanephrines and methoxytyramine for diagnosis of pheochromocytoma and paraganglioma: is this an option?

Sympathoadrenal activity is decreased during overnight rest. This study assessed whether urinary-free normetanephrine, metanephrine and methoxytyramine in overnight/first-morning urine collections might offer an alternative to measurements in 24-h collections or plasma for diagnosis of pheochromocytoma and paraganglioma (PPGL). Prospective multicenter cross-sectional diagnostic study involving 706 patients tested for PPGL, in whom tumors were confirmed in 79 and excluded in 627 after follow-up. Another 335 age- and sex-matched volunteers were included for reference purposes. Catecholamines and their free O-methylated metabolites were measured in 24-h collections divided according to waking and sleeping hours and normalized to creatinine. Plasma metabolites from blood sampled after supine rest were measured for comparison. Urinary outputs of norepinephrine, normetanephrine, epinephrine and metanephrine in the reference population were respectively 50 (48-52)%, 35 (32-37)%, 76 (74-78)% and 15 (12-17)% lower following overnight than daytime collections. Patients in whom PPGLs were excluded showed 28 (26-30)% and 6 (3-9)% day-to-night falls in normetanephrine and metanephrine, while patients with PPGLs showed no significant day-to-night falls in metabolites. Urinary methoxytyramine was consistently unchanged from day to night. According to receiver-operating characteristic curves, diagnostic accuracy of metabolite measurements in overnight/first-morning urine samples did not differ from measurements in 24-h urine collections, but was lower for both than for plasma. Using optimized reference intervals, diagnostic specificity was higher for overnight than daytime collections at similar sensitivities. Measurements of urinary-free catecholamine metabolites in first-morning/overnight urine collections offer an alternative for diagnosis of PPGL to 24-h collections but remain less accurate than plasma measurements.