Update on the diagnosis of the pheochromocytoma | Hipertensión y Riesgo Vascular

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A. Rx de tórax y TC de tórax: infiltrados alveolares difusos bilaterales de predomino hiliar, así como derrame pleural bilateral y focos de vidrio deslustrado-engrosamiento de septos compatibles con edema agudo de pulmón. B. TC de abdomen: masa suprarrenal izquierda de gran tamaño (feocromocitoma). C. Cateterismo cardiaco con arterias coronarias normales. D. TC de cráneo: pérdida de diferenciación corticosubcortical y edema parietooccipital, troncoencefálico y cerebeloso sugestivos de áreas de isquemia-PRESS. CASO 2. A. Rx tórax y TC de tórax con contraste iv. Corte axial y coronal: cardiomegalia, infiltrados alveolares difusos bilaterales de predomino hiliar, así como derrame pleural bilateral compatibles con edema agudo de pulmón. En cortes superiores de abdomen se visualiza masa suprarrenal izquierda de gran tamaño (feocromocitoma). B. PET-TC DOPA. Captación del radiotrazador en la masa suprarrenal izquierda descrita previamente. C. CardioRM 4 cámaras: dilatación biventricular compatible con miocardiopatía dilatada. D. RM de abdomen corte axial y gammagrafía con MIBG: ausencia de lesión suprarrenal izquierda y ausencia de captación de la misma tras la intervención quirúrgica (adrenalectomía izquierda)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M.J. Vallejo Herrera, V. Vallejo Herrera, V. Márquez Pérez, F. Serrano Puche, I. Vegas Vegas" "autores" => array:5 [ 0 => array:2 [ "nombre" => "M.J." "apellidos" => "Vallejo Herrera" ] 1 => array:2 [ "nombre" => "V." "apellidos" => "Vallejo Herrera" ] 2 => array:2 [ "nombre" => "V." "apellidos" => "Márquez Pérez" ] 3 => array:2 [ "nombre" => "F." "apellidos" => "Serrano Puche" ] 4 => array:2 [ "nombre" => "I." "apellidos" => "Vegas Vegas" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1889183724000722?idApp=UINPBA00004N" "url" => "/18891837/unassign/S1889183724000722/v1_202405210419/es/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Update on the diagnosis of the pheochromocytoma" "tieneTextoCompleto" => true "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "E. Achote, O.F. Arroyo Ripoll, M. Araujo-Castro" "autores" => array:3 [ 0 => array:3 [ "nombre" => "E." "apellidos" => "Achote" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "O.F." "apellidos" => "Arroyo Ripoll" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:4 [ "nombre" => "M." "apellidos" => "Araujo-Castro" "email" => array:1 [ 0 => "marta.araujo@salud.madrid.org" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Endocrinología y Nutrición, Hospital Universitario Ramón y Cajal, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Endocrinología Clínica y Metabolismo, Universidad de Antioquia, Medellín, Colombia" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actualización en el diagnóstico del feocromocitoma" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1820 "Ancho" => 3296 "Tamanyo" => 290568 ] ] "descripcion" => array:1 [ "en" => "Molecular pathways involved in the tumorigenesis of pheochromocytomas and paragangliomas." ] ] ] "textoCompleto" => "IntroductionPheochromocytomas are neuroendocrine tumours that originate in the sympathetic adrenomedullary chromaffin tissue, resulting in their location in the adrenal gland, while paragangliomas (PGLs) derive from extra-adrenal sympathetic and parasympathetic chromaffin tissue.<a class="elsevierStyleCrossRef" href="#bib0175">1</a>Around 70% of pheochromocytomas/PGLs can occur in one of three molecular clusters that have different phenotypes, clinical behaviour and radiological characteristics.<a class="elsevierStyleCrossRef" href="#bib0180">2</a> Those of the group 1 are related to the Krebs cycle/VHL/EPAS1 (pseudohypoxia) that tend to be noradrenergic and with a high risk of metastasis and recurrence, those of the group 2 are usually adrenergic with episodic symptoms, less aggressive and are related to kinase signalling and those of the group 3 are closely associated with Wnt signalling and usually have an aggressive behaviour.<a class="elsevierStyleCrossRef" href="#bib0180">2</a> The diagnosis requires confirmation of catecholamine excess and the location of the tumour.<a class="elsevierStyleCrossRef" href="#bib0185">3</a> Although surgical resection is the treatment of choice,<a class="elsevierStyleCrossRef" href="#bib0190">4</a> as a general rule, presurgical treatment with α and β adrenergic blockade is recommended in order to prevent intraoperative hypertensive crises and other haemodynamic complications.<a class="elsevierStyleCrossRefs" href="#bib0195">5,6</a>Biochemical diagnosis is established based on the index of suspicion. In the case of a low index of suspicion, the measurement of 24-h urine metanephrines is the test of choice, whilst if suspicion is high, it is recommended to determine plasma metanephrine.<a class="elsevierStyleCrossRef" href="#bib0200">6</a> Once the excessive production of adrenal catecholamines is confirmed, the next step is to request a localisation study, being the abdominal computed tomography (CT) with contrast the test of choice. Subsequently, the functional diagnosis using nuclear medicine tests will be individualised based on the anatomical and genetic characteristics of the tumour.<a class="elsevierStyleCrossRef" href="#bib0205">7</a>In this paper, we offer a detailed review of the recommended diagnostic plan in patients with suspected pheochromocytoma, including biochemical, radiological, genetic and nuclear medicine tests.DiagnosisThe first diagnostic step consists of the biochemical demonstration of excess catecholamine secretion. The next step is the localisation study. Nuclear medicine tests are useful for initial tumour staging, as well as for detecting lesions not located by conventional imaging modalities. Once the diagnosis is confirmed, it is recommended to request a genetic study for all patients (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0210">8</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Biochemical diagnosisCatecholamines and metabolitesThe initial step in suspecting a pheochromocytoma is to biochemically confirm the excess of catecholamines and/or their metabolites. Catecholamines (noradrenaline, adrenaline and dopamine) and their metabolites (normetanephrine, metanephrines and 3-methoxytyramine) can be quantified in plasma samples. Catecholamines, metanephrines (total, fractionated, free) and vanillylmandelic acid are measured in 24-h urine. Free metanephrines can also be determined in salivary samples. There is a wide variety of methods available for their determination, and among them, high-performance liquid chromatography (HPLC) is one of the most sensitive and specific methods (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0240">14</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Measurement of plasma or urinary catecholamines is not recommended as screening tests due to the insignificant or episodic secretion of amines in a significant proportion of patients with pheochromocytoma. Free metanephrines, especially plasma ones, have a higher diagnostic accuracy (sensitivity [SE] 97.9% and specificity [SP] 94.2%) than urinary and salivary ones (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0215">9–13</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Since pheochromocytoma is a low-prevalence entity, which leads to low pre-test probability, false positives (FP) are common. In cases of low suspicion, it is recommended to use the determination of catecholamines and fractionated metanephrines in 24-h urine (SE 98% and specificity SP 98%) for screening, combined with the measurement of urinary creatinine to ensure adequate collection. The cut-off points will depend on the reference value of each assay. If the index of clinical suspicion is high (family history, genetic syndrome, previously resected pheochromocytoma, adrenal incidentaloma with radiological characteristics suggestive of pheochromocytoma), it is recommended to measure fractionated metanephrines in plasma.<a class="elsevierStyleCrossRefs" href="#bib0220">10,14</a> Normal plasma fractionated metanephrines exclude the diagnosis of pheochromocytoma except in patients with early preclinical disease and in those patients with strictly dopamine-secreting neoplasms.False positivesMultiple factors, whether pharmacological, physiological, dietary or pathological, may lead to FP in the determination of catecholamines and their metabolites:Pharmacological interactionsDrugs that are believed to increase catecholamine or metabolite levels should be discontinued at least 2 weeks before the hormonal determination. One of the most common interfering medications are tricyclic antidepressants, including cyclobenzaprine (although they do not show FP in plasma normetanephrine tests). High-performance liquid chromatography with mass spectrometry (HPLC–MS) has the advantage of providing less drug interaction, as it only shows interaction with MDMA (3,4-methylenedioxymethamphetamine) and midodrine, which can increase urinary levels of NMN and MN, respectively. Analytical interferences are usually associated with the use of spectrophotometric and fluorometric methods and less frequently with the use of the high-performance liquid chromatography with electrochemistry (HPLC–EC). The main drugs that can increase the levels of catecholamines and their metabolites are tricyclic antidepressants, levodopa, methyldopa, adrenergic receptor agonists (labetalol, sotalol, phenylephrine, mirtazapine, yohimbine, mianserin, venlafaxine), amphetamines, acetaminophen, buspirone, prochlorperazine, reserpine, ethanol, amoxicillin, rifampicin, sulfasalazine and methenamine.<a class="elsevierStyleCrossRef" href="#bib0245">15</a><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010">a.Changes to posture</li></ul>The sensitivity of plasma metanephrines decreases in the sitting position from 95% to 89%, which leads to an increase in the FP rate (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0250">16</a><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0015">b.Sympathoadrenal activation</li></ul>Severe acute and chronic pathologies can lead to sympathoadrenal activation as a homeostatic response mechanism, which leads to an increase in catecholamines and metabolites. In the case of hypertensive crises, left ventricular failure, multiorgan failure or shock and suspected pheochromocytoma as a cause, it is unlikely that biochemical tests will be interpretable, with imaging studies being recommended to reach a diagnosis in these cases.<a class="elsevierStyleCrossRef" href="#bib0200">6</a>Chronic kidney disease deserves special mention, since it produces FP due to analytical interference and increased sympathetic activity. In this situation, measurement of free metanephrines in plasma by prolonged supine HPLC–MS is preferred. In patients on haemodialysis, the measurement should be performed at the end of dialysis and shunt. Measurement of deconjugated metanephrines should be avoided because they are up to 12 times higher in chronic kidney disease.<a class="elsevierStyleCrossRef" href="#bib0255">17</a>Panic attacks and stressors such as vigorous exercise, cold environment, acute emotional stress (venipuncture, stressful days at work) can also activate the sympathoadrenal system and should therefore be avoided before sampling.<a class="elsevierStyleCrossRef" href="#bib0245">15</a><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0020">c.Diet</li></ul>Foods that can affect catecholamine and metabolite levels usually have a negligible impact. Caffeine and tobacco can increase catecholamine secretion.<a class="elsevierStyleCrossRef" href="#bib0245">15</a> Diet may cause an increase in dopamine and its associated metabolites if products containing l-dopa, dopamine and tyramine are consumed, such as bananas, pineapple or nuts, among others.<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0025">-Clonidine suppression test</li></ul>Clonidine is an α2 adrenergic agonist that inhibits noradrenaline secretion in healthy patients, but does not inhibit it in patients with pheochromocytoma. Therefore, it is useful to distinguish FP results from endogenous noradrenaline hypersecretion. A recent prospective study confirmed the usefulness of the clonidine suppression test with a sensitivity of 85% and specificity of 100%.<a class="elsevierStyleCrossRefs" href="#bib0260">18,19</a>This test is not recommended in the case of an isolated elevation of metanephrine because this is not influenced by the administration of clonidine as it does not influence the metabolism of the adrenal medulla.<a class="elsevierStyleCrossRefs" href="#bib0205">7,19</a><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0030">-Chromogranin A</li></ul>Its diagnostic accuracy is lower than that of plasma and urinary metanephrines, resulting in the non-provision of additional value to the diagnosis of pheochromocytoma. However, it can be useful in cases of non-functioning pheochromocytoma (with normal metanephrine levels), for post-surgical follow-up.<a class="elsevierStyleCrossRef" href="#bib0270">20</a>Differential diagnosisDifferential diagnosis of pheochromocytoma includes a wide spectrum of pathologies that, through an adequate clinical history and the support of specific tests, can be mostly excluded from the beginning. Among the main pathologies, the following stand out<a class="elsevierStyleCrossRef" href="#bib0205">7</a>:<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0035">1.Endocrine causes: hypoglycaemia, primary hypogonadism (menopausal syndrome), carbohydrate intolerance, thyrotoxicosis, pancreatic neuroendocrine tumours (e.g. insulinomas).</li><li class="elsevierStyleListItem" id="lsti0040">2.Cardiovascular causes: angina, paroxysmal cardiac arrhythmia, vascular deconditioning, pulmonary oedema, renovascular disease, labile essential hypertension, orthostatic hypotension, syncope (e.g. vasovagal reaction).</li><li class="elsevierStyleListItem" id="lsti0045">3.Psychological causes: intense anxiety and panic disorders, provoked seizures (e.g. drugs, Valsalva manoeuvre), hyperventilation, somatisation disorder.</li><li class="elsevierStyleListItem" id="lsti0050">4.Pharmacological causes: adrenergic inhibitor withdrawal, combination of MAOIs and decongestants, consumption of sympathomimetic drugs, chlorpropamide-alcohol, vancomycin (red man syndrome).</li><li class="elsevierStyleListItem" id="lsti0055">5.Neurological causes: stroke migraine headache, diencephalic epilepsy (autonomic crises), cerebrovascular insufficiency, autonomic neuropathy, postural orthostatic tachycardia syndrome.</li><li class="elsevierStyleListItem" id="lsti0060">6.Other causes: recurrent idiopathic anaphylaxis, unexplained flushing attacks, mastocytosis, carcinoid syndrome.</li></ul>Diagnosis by imagingAnatomic diagnosisThe initial imaging test of choice is abdominal computed tomography (CT) with contrast, since 95% of pheochromocytoma cases are found in this location.<a class="elsevierStyleCrossRef" href="#bib0270">20</a> Its sensitivity ranges between 98% and 100%, allowing the detection of tumours up to 5mm with good spatial resolution. However, its specificity is 70% due to the high prevalence of incidentalomas. Attenuation greater than 10HU (Hounsfield Units) and a delay in contrast washout (less than 50% at 10min) are highly suggestive features of pheochromocytoma.<a class="elsevierStyleCrossRef" href="#bib0275">21</a>Magnetic resonance imaging (MRI) is more sensitive for detecting extra-adrenal (15%), residual, recurrent and metastatic tumours, with a sensitivity of 90–95%.<a class="elsevierStyleCrossRef" href="#bib0270">20</a> MRI is the test of choice in patients with allergy to iodinated contrast, in situations that restrict exposure to radiation (children, pregnant women) and in people with germline mutations. Pheochromocytoma is a highly vascularised tumour, therefore, hyperintensity can be observed in the T2 sequence; in addition to enhancement of the lesion after administration of gadolinium.<a class="elsevierStyleCrossRefs" href="#bib0275">21,22</a> If CT and MRI do not identify tumour lesions in the abdomen and pelvis, the chest and neck should be inspected.Functional diagnosisThese imaging modalities use molecular tracers targeting catecholamine synthesis, storage, and secretion pathways, cellular receptors, or cellular metabolic activity. They are useful for confirming the diagnosis, staging the disease, selecting targeted radionuclide therapy, and assessing response. They may be valuable in cases where the anatomic diagnosis is negative, in doubtful lesions, and in patients with a high probability of metastatic or extra-adrenal disease (tumours larger than 5cm, pathogenic variants in SDHB, norepinephrine-secreting tumours).<a class="elsevierStyleCrossRefs" href="#bib0280">22,23</a>Meta-iodobenzylguanidine (I123MIBG) scintigraphyMeta-iodobenzylguanidine is an analogue of guanethidine and norepinephrine, which is stored and concentrated in the neurosecretory granules of adrenergic neurons and chromaffin cells of the adrenal medulla. It has a SE of 83–100%, a SP of 95–100%, and a detection rate of 74% (95% CI, 46–92%). Because the sensitivity is less than 50% in patients with the SDHB mutation, its diagnostic use is not recommended in these cases.<a class="elsevierStyleCrossRef" href="#bib0290">24</a>It interacts mainly with antihypertensive drugs (reserpine, labetalol, calcium channel blockers), sympathomimetic agents (phenylephrine, ephedrine, phenylpropanolamine), cocaine, tricyclic antidepressants (amitriptyline, imipramine and their derivatives) and phenothiazines, which can cause a decrease in the uptake of the radionucleotide.<a class="elsevierStyleCrossRef" href="#bib0280">22</a>Fluorodeoxyglucose positron emission tomography (FDG-PET)Fluorodeoxyglucose is a glucose analogue that is incorporated intracellularly through GLUT-1 receptors and is phosphorylated by hexokinase. This phosphorylation allows its accumulation in proportion to the rate of cellular glycolysis, since it is not metabolised until it loses its radioactivity.<a class="elsevierStyleCrossRef" href="#bib0280">22</a> In the detection of metastatic disease, it has a SE of 83% and a SP of 74%, with a detection rate of 38% (95% CI, 20–59%).<a class="elsevierStyleCrossRef" href="#bib0290">24</a>It is influenced by glucose metabolism, which in turn is affected by intake, nutritional status, and the presence of diabetes mellitus, as well as by certain medications, including corticosteroids, valproate, carbamazepine, phenytoin, phenobarbital, and catecholamines. Co-administration of colony-stimulating factors increases uptake in the spleen and bone marrow.<a class="elsevierStyleCrossRef" href="#bib0280">22</a>Underlying mutations in SDHx show a more avid uptake of 18-fluorodeoxyglucose.18F-DOPA positron emission tomography (18F-DOPA PET/CT)Fluorodopa (18F-DOPA) is an analogue of the aromatic amino acid l-DOPA that enters the amino acid transporter system, where it is metabolised to 18 F-fluorodopamine by the action of the enzyme l-DOPA decarboxylase and is stored in neurosecretory vesicles. It has a sensitivity of 79% and a specificity of 95%, with a detection rate of 80% (95% CI, 69–88%).<a class="elsevierStyleCrossRef" href="#bib0290">24</a>It presents some drug interactions: amino acid decarboxylase inhibitors such as carbidopa and COMT inhibitors such as entacapone or nitecapone may increase the bioavailability of 18F-DOPA. Haloperidol and monoamine oxidase inhibitors promote the accumulation of 18F-DOPA in the brain, while reserpine may empty the contents of intraneuronal vesicles, thus preventing the retention of 18F-DOPA in the brain. Glucagon may inhibit the beta cell of the pancreas, decreasing the ability to decarboxylate 18F-DOPA. Due to very limited uptake in the adrenals, 18F-DOPA may detect pheochromocytomas and small PGLs. Furthermore, it has a very high sensitivity for detecting SDHB-negative PPGLs, with a sensitivity of 93%, compared to SDHB-positive PPGLs, which is 20%.<a class="elsevierStyleCrossRef" href="#bib0280">22</a>Positron emission tomography with peptidesThese are somatostatin receptor agonists (SSTRs) and there are three main ligands: DOTATOC (DOTA-Tyr3-octreotide or edotreotide), DOTATATE (DOTA-Tyr3-octreotate or oxodothreotine), and DOTANOC (DOTA-Nal3-octreotide). These agents have a detection rate of 93% (95% CI, 91–95%).<a class="elsevierStyleCrossRef" href="#bib0290">24</a>Corticosteroids can induce downregulation of SSTR2. The use of functional imaging with radionucleotides should be individualised for each patient, depending on their clinical and genetic context, as recommended by the European Association of Nuclear Medicine (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRef" href="#bib0295">25</a><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Genetic testingForty per cent of pheochromocytomas and PGLs are associated with some genetic alteration. For this reason, the current recommendation is to request genetic testing in all patients with pheochromocytomas and PGLs.<a class="elsevierStyleCrossRef" href="#bib0200">6</a> More than 70% of hereditary PPGLs present mutations, both germline (40%) and somatic (70%). The Cancer Genome Atlas programme has identified four main pathways involved in tumorigenesis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<a class="elsevierStyleCrossRef" href="#bib0300">26</a><a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> provides an overview of the genetic and biochemical diversity of these tumours, which is crucial to understand their development mechanisms and to direct personalised therapies.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>The main genetic syndromes associated with pheochromocytoma/PGLs are multiple endocrine neoplasia type 2, VonHippel Lindau disease, neurofibromatosis type 1 and familial paraganglioma syndromes<a class="elsevierStyleCrossRef" href="#bib0305">27</a> (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Cardiac evaluationCatecholamine-induced cardiomyopathy, which includes variants such as dilated cardiomyopathy, Takotsubo cardiomyopathy (both classic and reverse), hypertrophic obstructive cardiomyopathy and myocarditis, is a condition of great clinical importance that we must consider in patients with pheochromocytomas.<a class="elsevierStyleCrossRef" href="#bib0310">28</a> Its diagnosis is often delayed, especially when it presents atypically.<a class="elsevierStyleCrossRef" href="#bib0315">29</a> Sometimes adrenergic crises induced by pheochromocytoma cause cardiovascular manifestations that can cause multiorgan failure or as an acute coronary syndrome, leading to a fatal outcome.<a class="elsevierStyleCrossRefs" href="#bib0320">30,31</a> The prevalence of history of cardiovascular pathology is variable in different series, but for example in the Argentine registry of pheochromocytomas it was reported that 7.6% of patients had a history of cardiovascular disease,<a class="elsevierStyleCrossRef" href="#bib0330">32</a> while in the Spanish registry it was reported in 14.2% of patients.<a class="elsevierStyleCrossRef" href="#bib0335">33</a> Early diagnosis is essential to prevent irreversible cardiac remodelling. It has been reported that after resection of pheochromocytoma, 96% of patients show an improvement in their ejection fraction, compared with those who did not undergo surgery. Of the latter, 33% experienced mortality and 11% required a heart transplant.<a class="elsevierStyleCrossRef" href="#bib0340">34</a>Since excess catecholamines may increase postoperative complications, a preoperative cardiological evaluation is recommended in all patients. This should include an electrocardiogram and a transthoracic echocardiogram, particularly in patients with long-standing arterial hypertension.<a class="elsevierStyleCrossRef" href="#bib0270">20</a>ConclusionsPheochromocytoma is a rare tumour, often of delayed diagnosis. Its diagnosis is based on confirming the excessive production of catecholamines and locating the adrenal tumour. The measurement of catecholamines and their metabolites can be made difficult by pharmacological interferences, diet, and conditions that increase sympathoadrenergic activity. Once the excess of catecholamines is confirmed, the next step is to locate the tumour by CT or MRI. If these studies are negative, functional tests may be necessary to confirm the diagnosis. Genetic testing is essential since 40% of pheochromocytomas are hereditary. An initial cardiological study with electrocardiogram and transthoracic echocardiogram is recommended to preoperatively identify catecholamine-induced cardiomyopathy, in order to optimise presurgical treatment to avoid complications during and after surgery.Ethics committee statementNot applicable.FundingThere was no funding for this research.Informed consent statementNot applicable.Conflict of interestsThe authors have no conflict of interest to declare in this paper." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres2269491" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1892216" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2269492" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1892217" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Diagnosis" "secciones" => array:1 [ 0 => array:3 [ "identificador" => "sec0015" "titulo" => "Biochemical diagnosis" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0095" "titulo" => "Catecholamines and metabolites" ] ] ] ] ] 6 => array:3 [ "identificador" => "sec0020" "titulo" => "False positives" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Pharmacological interactions" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Differential diagnosis" ] 2 => array:3 [ "identificador" => "sec0035" "titulo" => "Diagnosis by imaging" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0100" "titulo" => "Anatomic diagnosis" ] 1 => array:3 [ "identificador" => "sec0105" "titulo" => "Functional diagnosis" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Meta-iodobenzylguanidine (IMIBG) scintigraphy" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Fluorodeoxyglucose positron emission tomography (FDG-PET)" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "18F-DOPA positron emission tomography (18F-DOPA PET/CT)" ] ] ] ] ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "Positron emission tomography with peptides" ] 4 => array:2 [ "identificador" => "sec0060" "titulo" => "Genetic testing" ] 5 => array:2 [ "identificador" => "sec0065" "titulo" => "Cardiac evaluation" ] ] ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Ethics committee statement" ] 9 => array:2 [ "identificador" => "sec0080" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0085" "titulo" => "Informed consent statement" ] 11 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interests" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2024-08-08" "fechaAceptado" => "2024-08-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1892216" "palabras" => array:5 [ 0 => "Pheochromocytoma" 1 => "Metanephrines" 2 => "Hypertension" 3 => "Genetic study" 4 => "Clonidine test" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1892217" "palabras" => array:5 [ 0 => "Feocromocitoma" 1 => "Metanefrinas" 2 => "Hipertensión" 3 => "Estudio genético" 4 => "Test de clonidina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Pheochromocytoma is a rare neuroendocrine tumour that develops from chromaffin cells in the adrenal medulla and is characterised by the excessive production of catecholamines and their metabolites. Diagnostic confirmation is performed by detecting elevated levels of catecholamines and/or their metabolites in plasma or 24-h urine. In the case of moderate elevations of normetanephrine, the clonidine suppression test may be useful to differentiate between endogenous hypersecretion and false positive results. Once the biochemical diagnosis is performed, the tumour localisation is carried out using imaging techniques and sometimes with nuclear medicine imaging tests. Furthermore, in all patients with pheochromocytomas it is recommended to perform a genetic study to identify hereditary disorders that may be present in more than 30% of cases and to perform a cardiological evaluation to rule out the presence of cardiovascular involvement secondary to the catecholamine hypersecretion." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El feocromocitoma es un tumor neuroendocrino poco frecuente que se desarrolla a partir de células cromafines de la médula suprarrenal y que se caracteriza por la producción excesiva de catecolaminas y sus metabolitos. La confirmación diagnóstica se realiza mediante la detección de niveles elevados de catecolaminas y/o sus metabolitos en plasma y/o en orina de 24horas. En caso de elevaciones moderadas de normetanefrina, la prueba de supresión con clonidina puede ser de utilidad para diferenciar entre hipersecreción endógena y falsos positivos. Una vez realizado el diagnóstico bioquímico, la localización del tumor se lleva a cabo mediante técnicas de imagen y, en ocasiones, con pruebas de medicina nuclear. Además, en todos los pacientes se recomienda realizar un estudio genético para identificar trastornos hereditarios que pueden estar presentes en más del 30% de los casos y realizar una evaluación cardiológica para descartar la presencia de afectación cardiovascular secundaria al exceso de secreción de catecolaminas." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1525 "Ancho" => 3337 "Tamanyo" => 259866 ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithm for suspected pheochromocytoma. IE: isolated elevation, NMN: normetanephrine, MN: metanephrine, MOT: methoxytyramine, PPGL: pheochromocytoma–paraganglioma, ULN: upper limit of normal. *In CT more than 10UH or delayed washout of contrast of less than 50% at 10min. **Consider false positives due to pharmacological interferences, adequate sample collection technique, type of assay, acute and chronic diseases, fasting state (if isolated elevation of methoxytyramine)." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1820 "Ancho" => 3296 "Tamanyo" => 290568 ] ] "descripcion" => array:1 [ "en" => "Molecular pathways involved in the tumorigenesis of pheochromocytomas and paragangliomas." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "HPLC: high-performance liquid chromatography; IA: immunoassay; SE: sensitivity, SP: specificity, AUC: area under the curve, RAT: range of accuracy of the test (for prevalence ranges between .0 and 1), NPV: negative predictive value, PPV: positive predictive value, n.e: not evaluated." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Tests \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">SE \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">SP \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">AUC \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">RAT \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">NPV \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PPV</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">n \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">(%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">(%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">(Partial)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">(%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">(0.5%)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">(5%)<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">(0.5%)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">(5%)<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HPLC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">93 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.947 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">93–94 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.e. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.e. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">91 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">93 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.911 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">91–93 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.e. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.e. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Supine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">95<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">95<a class="elsevierStyleCrossRef" href="#tblfn0025">e</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.942 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">95–95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.9997 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.9972 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.0872 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.5000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Seated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">89<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.913 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">89–94 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.9994 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.9939 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.0694 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.4384 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Urine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">93 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90<a class="elsevierStyleCrossRef" href="#tblfn0025">e</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.932 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90–93 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.9996 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.9959 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.0446 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.3286 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3686358.png" ] ] ] "notaPie" => array:5 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "For more details see methods." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Prevalence of F/PG among hypertensive subjects (.2–.6%)." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "Prevalence of F/PG among subjects with incidentaloma." ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "Supine vs sitting p<.02." ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "Supine vs 24h urine p<.03. Translated into Spanish from Därr et al." ] ] ] "descripcion" => array:1 [ "en" => "Diagnostic accuracy of biochemical tests in the diagnosis of pheochromocytoma." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "HPLC–MS: high-performance liquid chromatography with mass spectrometry, NMN: normetanephrine, MN: metanephrine, MOT: methoxytyramine, DCs: deconjugated, vanillylmandelic acid." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Test \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HPLC–MS</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sensitivity \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Specificity \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plasma</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Noradrenaline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">87.4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72.2% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dopamine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77.4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">84.4% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Free NMN and MN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">96.6% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94.9% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Free NMN, MN and MOT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">97.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94.2% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AVM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">81.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62.2% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Urine</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Norepinephrine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">97.1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dopamine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">97.1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NMN and MN DCs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">92.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">92.8% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NMN, MN and MOT DCs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">92.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">92.1% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NMN and free MN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">92.9% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94.5% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NMN, MN and free MOT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">93.4% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AVM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66.7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">92.3% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Saliva</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NMN and free MN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">89% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">87% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3686360.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Sensitivity and specificity of the catecholamines and metanephrines according to the type of sample using HPLC–MS as the measurement method." ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "PGL: paragangliomas; SDHx: succinate dehydrogenase." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">First line \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Second line \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Third line<a class="elsevierStyleCrossRef" href="#tblfn0030">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sporadic pheochromocytomas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18F-FDOPA or 123I-MIBG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">68Ga-SSA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18F-FDOPA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Head and neck PGLs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">68Ga-SSA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18F-FDOPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">111In-SSA/99mTc-SSA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hereditary pheochromocytoma (except SDHx) NF1/RET/VHL/MAX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18F-FDOPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">123I-MIBG or 68Ga-SSA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18F-FDG \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multifocal extra-adrenal involvement and/or metastasis with or without SDHx \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">68Ga-SSA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">With SDHD: 18F-FDGWithout SDHD: 18F-FDOPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18F-FDG y 123I-MIBG o18F-FDG and 111In-SSA/99mTc-SSA \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3686357.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "a" "nota" => "If 18F-FDOPA and 68Ga-SSA are not possible." ] ] ] "descripcion" => array:1 [ "en" => "Proposed clinical algorithm for the use of functional imaging in case of PPGL recommended by the European Association of Nuclear Medicine." ] ] 5 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AD: autosomal dominant, PGL: paraganglioma, NET: neuroendocrine tumours, NMN: normetanephrines, NM: metanephrine, PNMT: phenylethanolamine N-methyltransferase; TH: tyrosine hydroxylase, NA: not applicable." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Von Hippel-Lindau syndrome \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MEN-2 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MEN-2B \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Neurofibromatosis type 1 \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prevalence \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 out of every 35,000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 out of every 200.000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 out of every 350,001 out of every 2000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peak age (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35–40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inheritance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AD \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VHL tumour suppressor gene \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Extracellular domain of RET protein (85% at codon 634, particularly p.Cys634Arg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intracellular domain of RET protein (95% methionine to threonine missense change in exon 16 (p.Met918Thr) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NF1 tumour suppressor gene \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chromosome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chromosome 3p25-26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chromosome 10q11.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chromosome 10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chromosome 17q11.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Penetrance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.1–7.7%$ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical characteristics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bilateral pheochromocytoma, mediastinal, abdominal, pelvic, neck and skull base PGL, hemangioblastoma, retinal angioma, clear cell renal cell carcinoma, pancreatic NETs, middle ear endolymphatic sac tumours, serous cystadenomas of the pancreas, papillary cystadenomas of the epididymis and broad ligament. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Medullary thyroid cancer (100%), pheochromocytoma (50%), primary hyperparathyroidism 20%, lichenoid cutaneous amyloidosis 5%, Hischprung disease (rare) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Medullary thyroid cancer (100%), pheochromocytoma (50%), mucocutaneous neuromas (70–100%), marfanoid habitus 100%, myelinated corneal nerves (100%), intestinal ganglioneuromas (60–90%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neurofibromas, multiple café-au-lait spots, axillary and inguinal freckles, iris hamartomas (Lisch nodules), bone abnormalities, central nervous system gliomas, pheochromocytoma and paraganglioma 3%, macrocephaly and cognitive deficits. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical phenotype \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bilateral and asynchronous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increased incidence of symptomatic paroxysmal hypertension \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Solitary or bilateral benign pheochromocytomas or a periadrenal abdominal PGL. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biochemical phenotype \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Noradrenergic with elevated NMN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lower expression of PNMT and TH adrenergic with elevated MN higher expression of PNMT and TH with higher concentration of catecholamines and metabolites \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3686359.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical, biochemical and genetic characteristics of syndromic disorders associated with pheochromocytoma." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib0175" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "O. 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Update on the diagnosis of the pheochromocytoma

Actualización en el diagnóstico del feocromocitoma

E. Achotea, O.F. Arroyo Ripollb, M. Araujo-Castroa,c,

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marta.araujo@salud.madrid.org

Corresponding author.

a Servicio de Endocrinología y Nutrición, Hospital Universitario Ramón y Cajal, Madrid, Spain

b Servicio de Endocrinología Clínica y Metabolismo, Universidad de Antioquia, Medellín, Colombia

c Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

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    "titulo" => "Update on the diagnosis of the pheochromocytoma"
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        "titulo" => "Actualizaci&#243;n en el diagn&#243;stico del feocromocitoma"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Molecular pathways involved in the tumorigenesis of pheochromocytomas and paragangliomas&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pheochromocytomas are neuroendocrine tumours that originate in the sympathetic adrenomedullary chromaffin tissue&#44; resulting in their location in the adrenal gland&#44; while paragangliomas &#40;PGLs&#41; derive from extra-adrenal sympathetic and parasympathetic chromaffin tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Around 70&#37; of pheochromocytomas&#47;PGLs can occur in one of three molecular clusters that have different phenotypes&#44; clinical behaviour and radiological characteristics&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a> Those of the group 1 are related to the Krebs cycle&#47;VHL&#47;EPAS1 &#40;pseudohypoxia&#41; that tend to be noradrenergic and with a high risk of metastasis and recurrence&#44; those of the group 2 are usually adrenergic with episodic symptoms&#44; less aggressive and are related to kinase signalling and those of the group 3 are closely associated with Wnt signalling and usually have an aggressive behaviour&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a> The diagnosis requires confirmation of catecholamine excess and the location of the tumour&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> Although surgical resection is the treatment of choice&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">4</span></a> as a general rule&#44; presurgical treatment with &#945; and &#946; adrenergic blockade is recommended in order to prevent intraoperative hypertensive crises and other haemodynamic complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Biochemical diagnosis is established based on the index of suspicion&#46; In the case of a low index of suspicion&#44; the measurement of 24-h urine metanephrines is the test of choice&#44; whilst if suspicion is high&#44; it is recommended to determine plasma metanephrine&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> Once the excessive production of adrenal catecholamines is confirmed&#44; the next step is to request a localisation study&#44; being the abdominal computed tomography &#40;CT&#41; with contrast the test of choice&#46; Subsequently&#44; the functional diagnosis using nuclear medicine tests will be individualised based on the anatomical and genetic characteristics of the tumour&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In this paper&#44; we offer a detailed review of the recommended diagnostic plan in patients with suspected pheochromocytoma&#44; including biochemical&#44; radiological&#44; genetic and nuclear medicine tests&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Diagnosis</span><p id="par0025" class="elsevierStylePara elsevierViewall">The first diagnostic step consists of the biochemical demonstration of excess catecholamine secretion&#46; The next step is the localisation study&#46; Nuclear medicine tests are useful for initial tumour staging&#44; as well as for detecting lesions not located by conventional imaging modalities&#46; Once the diagnosis is confirmed&#44; it is recommended to request a genetic study for all patients &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Biochemical diagnosis</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Catecholamines and metabolites</span><p id="par0035" class="elsevierStylePara elsevierViewall">The initial step in suspecting a pheochromocytoma is to biochemically confirm the excess of catecholamines and&#47;or their metabolites&#46; Catecholamines &#40;noradrenaline&#44; adrenaline and dopamine&#41; and their metabolites &#40;normetanephrine&#44; metanephrines and 3-methoxytyramine&#41; can be quantified in plasma samples&#46; Catecholamines&#44; metanephrines &#40;total&#44; fractionated&#44; free&#41; and vanillylmandelic acid are measured in 24-h urine&#46; Free metanephrines can also be determined in salivary samples&#46; There is a wide variety of methods available for their determination&#44; and among them&#44; high-performance liquid chromatography &#40;HPLC&#41; is one of the most sensitive and specific methods &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Measurement of plasma or urinary catecholamines is not recommended as screening tests due to the insignificant or episodic secretion of amines in a significant proportion of patients with pheochromocytoma&#46; Free metanephrines&#44; especially plasma ones&#44; have a higher diagnostic accuracy &#40;sensitivity &#91;SE&#93; 97&#46;9&#37; and specificity &#91;SP&#93; 94&#46;2&#37;&#41; than urinary and salivary ones &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">9&#8211;13</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Since pheochromocytoma is a low-prevalence entity&#44; which leads to low pre-test probability&#44; false positives &#40;FP&#41; are common&#46; In cases of low suspicion&#44; it is recommended to use the determination of catecholamines and fractionated metanephrines in 24-h urine &#40;SE 98&#37; and specificity SP 98&#37;&#41; for screening&#44; combined with the measurement of urinary creatinine to ensure adequate collection&#46; The cut-off points will depend on the reference value of each assay&#46; If the index of clinical suspicion is high &#40;family history&#44; genetic syndrome&#44; previously resected pheochromocytoma&#44; adrenal incidentaloma with radiological characteristics suggestive of pheochromocytoma&#41;&#44; it is recommended to measure fractionated metanephrines in plasma&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">10&#44;14</span></a> Normal plasma fractionated metanephrines exclude the diagnosis of pheochromocytoma except in patients with early preclinical disease and in those patients with strictly dopamine-secreting neoplasms&#46;</p></span></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">False positives</span><p id="par0055" class="elsevierStylePara elsevierViewall">Multiple factors&#44; whether pharmacological&#44; physiological&#44; dietary or pathological&#44; may lead to FP in the determination of catecholamines and their metabolites&#58;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pharmacological interactions</span><p id="par0060" class="elsevierStylePara elsevierViewall">Drugs that are believed to increase catecholamine or metabolite levels should be discontinued at least 2 weeks before the hormonal determination&#46; One of the most common interfering medications are tricyclic antidepressants&#44; including cyclobenzaprine &#40;although they do not show FP in plasma normetanephrine tests&#41;&#46; High-performance liquid chromatography with mass spectrometry &#40;HPLC&#8211;MS&#41; has the advantage of providing less drug interaction&#44; as it only shows interaction with MDMA &#40;3&#44;4-methylenedioxymethamphetamine&#41; and midodrine&#44; which can increase urinary levels of NMN and MN&#44; respectively&#46; Analytical interferences are usually associated with the use of spectrophotometric and fluorometric methods and less frequently with the use of the high-performance liquid chromatography with electrochemistry &#40;HPLC&#8211;EC&#41;&#46; The main drugs that can increase the levels of catecholamines and their metabolites are tricyclic antidepressants&#44; levodopa&#44; methyldopa&#44; adrenergic receptor agonists &#40;labetalol&#44; sotalol&#44; phenylephrine&#44; mirtazapine&#44; yohimbine&#44; mianserin&#44; venlafaxine&#41;&#44; amphetamines&#44; acetaminophen&#44; buspirone&#44; prochlorperazine&#44; reserpine&#44; ethanol&#44; amoxicillin&#44; rifampicin&#44; sulfasalazine and methenamine&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">a&#46;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Changes to posture</p></li></ul></p><p id="par0070" class="elsevierStylePara elsevierViewall">The sensitivity of plasma metanephrines decreases in the sitting position from 95&#37; to 89&#37;&#44; which leads to an increase in the FP rate &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">b&#46;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Sympathoadrenal activation</p></li></ul></p><p id="par0080" class="elsevierStylePara elsevierViewall">Severe acute and chronic pathologies can lead to sympathoadrenal activation as a homeostatic response mechanism&#44; which leads to an increase in catecholamines and metabolites&#46; In the case of hypertensive crises&#44; left ventricular failure&#44; multiorgan failure or shock and suspected pheochromocytoma as a cause&#44; it is unlikely that biochemical tests will be interpretable&#44; with imaging studies being recommended to reach a diagnosis in these cases&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Chronic kidney disease deserves special mention&#44; since it produces FP due to analytical interference and increased sympathetic activity&#46; In this situation&#44; measurement of free metanephrines in plasma by prolonged supine HPLC&#8211;MS is preferred&#46; In patients on haemodialysis&#44; the measurement should be performed at the end of dialysis and shunt&#46; Measurement of deconjugated metanephrines should be avoided because they are up to 12 times higher in chronic kidney disease&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">17</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Panic attacks and stressors such as vigorous exercise&#44; cold environment&#44; acute emotional stress &#40;venipuncture&#44; stressful days at work&#41; can also activate the sympathoadrenal system and should therefore be avoided before sampling&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">c&#46;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Diet</p></li></ul></p><p id="par0100" class="elsevierStylePara elsevierViewall">Foods that can affect catecholamine and metabolite levels usually have a negligible impact&#46; Caffeine and tobacco can increase catecholamine secretion&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a> Diet may cause an increase in dopamine and its associated metabolites if products containing <span class="elsevierStyleSmallCaps">l</span>-dopa&#44; dopamine and tyramine are consumed&#44; such as bananas&#44; pineapple or nuts&#44; among others&#46;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0105" class="elsevierStylePara elsevierViewall">Clonidine suppression test</p></li></ul></p><p id="par0110" class="elsevierStylePara elsevierViewall">Clonidine is an &#945;2 adrenergic agonist that inhibits noradrenaline secretion in healthy patients&#44; but does not inhibit it in patients with pheochromocytoma&#46; Therefore&#44; it is useful to distinguish FP results from endogenous noradrenaline hypersecretion&#46; A recent prospective study confirmed the usefulness of the clonidine suppression test with a sensitivity of 85&#37; and specificity of 100&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">18&#44;19</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">This test is not recommended in the case of an isolated elevation of metanephrine because this is not influenced by the administration of clonidine as it does not influence the metabolism of the adrenal medulla&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">7&#44;19</span></a><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0120" class="elsevierStylePara elsevierViewall">Chromogranin A</p></li></ul></p><p id="par0125" class="elsevierStylePara elsevierViewall">Its diagnostic accuracy is lower than that of plasma and urinary metanephrines&#44; resulting in the non-provision of additional value to the diagnosis of pheochromocytoma&#46; However&#44; it can be useful in cases of non-functioning pheochromocytoma &#40;with normal metanephrine levels&#41;&#44; for post-surgical follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Differential diagnosis</span><p id="par0130" class="elsevierStylePara elsevierViewall">Differential diagnosis of pheochromocytoma includes a wide spectrum of pathologies that&#44; through an adequate clinical history and the support of specific tests&#44; can be mostly excluded from the beginning&#46; Among the main pathologies&#44; the following stand out<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">7</span></a>&#58;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">1&#46;</span><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Endocrine causes&#58;</span> hypoglycaemia&#44; primary hypogonadism &#40;menopausal syndrome&#41;&#44; carbohydrate intolerance&#44; thyrotoxicosis&#44; pancreatic neuroendocrine tumours &#40;e&#46;g&#46; insulinomas&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">2&#46;</span><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Cardiovascular causes&#58;</span> angina&#44; paroxysmal cardiac arrhythmia&#44; vascular deconditioning&#44; pulmonary oedema&#44; renovascular disease&#44; labile essential hypertension&#44; orthostatic hypotension&#44; syncope &#40;e&#46;g&#46; vasovagal reaction&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">3&#46;</span><p id="par0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Psychological causes&#58;</span> intense anxiety and panic disorders&#44; provoked seizures &#40;e&#46;g&#46; drugs&#44; Valsalva manoeuvre&#41;&#44; hyperventilation&#44; somatisation disorder&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">4&#46;</span><p id="par0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Pharmacological causes&#58;</span> adrenergic inhibitor withdrawal&#44; combination of MAOIs and decongestants&#44; consumption of sympathomimetic drugs&#44; chlorpropamide-alcohol&#44; vancomycin &#40;red man syndrome&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">5&#46;</span><p id="par0155" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Neurological causes&#58;</span> stroke migraine headache&#44; diencephalic epilepsy &#40;autonomic crises&#41;&#44; cerebrovascular insufficiency&#44; autonomic neuropathy&#44; postural orthostatic tachycardia syndrome&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">6&#46;</span><p id="par0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Other causes&#58;</span> recurrent idiopathic anaphylaxis&#44; unexplained flushing attacks&#44; mastocytosis&#44; carcinoid syndrome&#46;</p></li></ul></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Diagnosis by imaging</span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Anatomic diagnosis</span><p id="par0175" class="elsevierStylePara elsevierViewall">The initial imaging test of choice is abdominal computed tomography &#40;CT&#41; with contrast&#44; since 95&#37; of pheochromocytoma cases are found in this location&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> Its sensitivity ranges between 98&#37; and 100&#37;&#44; allowing the detection of tumours up to 5<span class="elsevierStyleHsp" style=""></span>mm with good spatial resolution&#46; However&#44; its specificity is 70&#37; due to the high prevalence of incidentalomas&#46; Attenuation greater than 10<span class="elsevierStyleHsp" style=""></span>HU &#40;Hounsfield Units&#41; and a delay in contrast washout &#40;less than 50&#37; at 10<span class="elsevierStyleHsp" style=""></span>min&#41; are highly suggestive features of pheochromocytoma&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Magnetic resonance imaging &#40;MRI&#41; is more sensitive for detecting extra-adrenal &#40;15&#37;&#41;&#44; residual&#44; recurrent and metastatic tumours&#44; with a sensitivity of 90&#8211;95&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> MRI is the test of choice in patients with allergy to iodinated contrast&#44; in situations that restrict exposure to radiation &#40;children&#44; pregnant women&#41; and in people with germline mutations&#46; Pheochromocytoma is a highly vascularised tumour&#44; therefore&#44; hyperintensity can be observed in the T2 sequence&#59; in addition to enhancement of the lesion after administration of gadolinium&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">21&#44;22</span></a> If CT and MRI do not identify tumour lesions in the abdomen and pelvis&#44; the chest and neck should be inspected&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Functional diagnosis</span><p id="par0195" class="elsevierStylePara elsevierViewall">These imaging modalities use molecular tracers targeting catecholamine synthesis&#44; storage&#44; and secretion pathways&#44; cellular receptors&#44; or cellular metabolic activity&#46; They are useful for confirming the diagnosis&#44; staging the disease&#44; selecting targeted radionuclide therapy&#44; and assessing response&#46; They may be valuable in cases where the anatomic diagnosis is negative&#44; in doubtful lesions&#44; and in patients with a high probability of metastatic or extra-adrenal disease &#40;tumours larger than 5<span class="elsevierStyleHsp" style=""></span>cm&#44; pathogenic variants in <span class="elsevierStyleItalic">SDHB</span>&#44; norepinephrine-secreting tumours&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">22&#44;23</span></a></p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Meta-iodobenzylguanidine &#40;I<span class="elsevierStyleSup">123</span>MIBG&#41; scintigraphy</span><p id="par0200" class="elsevierStylePara elsevierViewall">Meta-iodobenzylguanidine is an analogue of guanethidine and norepinephrine&#44; which is stored and concentrated in the neurosecretory granules of adrenergic neurons and chromaffin cells of the adrenal medulla&#46; It has a SE of 83&#8211;100&#37;&#44; a SP of 95&#8211;100&#37;&#44; and a detection rate of 74&#37; &#40;95&#37; CI&#44; 46&#8211;92&#37;&#41;&#46; Because the sensitivity is less than 50&#37; in patients with the <span class="elsevierStyleItalic">SDHB</span> mutation&#44; its diagnostic use is not recommended in these cases&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">It interacts mainly with antihypertensive drugs &#40;reserpine&#44; labetalol&#44; calcium channel blockers&#41;&#44; sympathomimetic agents &#40;phenylephrine&#44; ephedrine&#44; phenylpropanolamine&#41;&#44; cocaine&#44; tricyclic antidepressants &#40;amitriptyline&#44; imipramine and their derivatives&#41; and phenothiazines&#44; which can cause a decrease in the uptake of the radionucleotide&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Fluorodeoxyglucose positron emission tomography &#40;FDG-PET&#41;</span><p id="par0210" class="elsevierStylePara elsevierViewall">Fluorodeoxyglucose is a glucose analogue that is incorporated intracellularly through GLUT-1 receptors and is phosphorylated by hexokinase&#46; This phosphorylation allows its accumulation in proportion to the rate of cellular glycolysis&#44; since it is not metabolised until it loses its radioactivity&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> In the detection of metastatic disease&#44; it has a SE of 83&#37; and a SP of 74&#37;&#44; with a detection rate of 38&#37; &#40;95&#37; CI&#44; 20&#8211;59&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">It is influenced by glucose metabolism&#44; which in turn is affected by intake&#44; nutritional status&#44; and the presence of diabetes mellitus&#44; as well as by certain medications&#44; including corticosteroids&#44; valproate&#44; carbamazepine&#44; phenytoin&#44; phenobarbital&#44; and catecholamines&#46; Co-administration of colony-stimulating factors increases uptake in the spleen and bone marrow&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Underlying mutations in <span class="elsevierStyleItalic">SDHx</span> show a more avid uptake of 18-fluorodeoxyglucose&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">18F-DOPA positron emission tomography &#40;18F-DOPA PET&#47;CT&#41;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Fluorodopa &#40;18F-DOPA&#41; is an analogue of the aromatic amino acid <span class="elsevierStyleSmallCaps">l</span>-DOPA that enters the amino acid transporter system&#44; where it is metabolised to 18 F-fluorodopamine by the action of the enzyme <span class="elsevierStyleSmallCaps">l</span>-DOPA decarboxylase and is stored in neurosecretory vesicles&#46; It has a sensitivity of 79&#37; and a specificity of 95&#37;&#44; with a detection rate of 80&#37; &#40;95&#37; CI&#44; 69&#8211;88&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">It presents some drug interactions&#58; amino acid decarboxylase inhibitors such as carbidopa and COMT inhibitors such as entacapone or nitecapone may increase the bioavailability of 18F-DOPA&#46; Haloperidol and monoamine oxidase inhibitors promote the accumulation of 18F-DOPA in the brain&#44; while reserpine may empty the contents of intraneuronal vesicles&#44; thus preventing the retention of 18F-DOPA in the brain&#46; Glucagon may inhibit the beta cell of the pancreas&#44; decreasing the ability to decarboxylate 18F-DOPA&#46; Due to very limited uptake in the adrenals&#44; 18F-DOPA may detect pheochromocytomas and small PGLs&#46; Furthermore&#44; it has a very high sensitivity for detecting <span class="elsevierStyleItalic">SDHB</span>-negative PPGLs&#44; with a sensitivity of 93&#37;&#44; compared to <span class="elsevierStyleItalic">SDHB</span>-positive PPGLs&#44; which is 20&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a></p></span></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Positron emission tomography with peptides</span><p id="par0235" class="elsevierStylePara elsevierViewall">These are somatostatin receptor agonists &#40;SSTRs&#41; and there are three main ligands&#58; DOTATOC &#40;DOTA-Tyr3-octreotide or edotreotide&#41;&#44; DOTATATE &#40;DOTA-Tyr3-octreotate or oxodothreotine&#41;&#44; and DOTANOC &#40;DOTA-Nal3-octreotide&#41;&#46; These agents have a detection rate of 93&#37; &#40;95&#37; CI&#44; 91&#8211;95&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">24</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Corticosteroids can induce downregulation of SSTR2&#46; The use of functional imaging with radionucleotides should be individualised for each patient&#44; depending on their clinical and genetic context&#44; as recommended by the European Association of Nuclear Medicine &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">25</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Genetic testing</span><p id="par0245" class="elsevierStylePara elsevierViewall">Forty per cent of pheochromocytomas and PGLs are associated with some genetic alteration&#46; For this reason&#44; the current recommendation is to request genetic testing in all patients with pheochromocytomas and PGLs&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">6</span></a> More than 70&#37; of hereditary PPGLs present mutations&#44; both germline &#40;40&#37;&#41; and somatic &#40;70&#37;&#41;&#46; The Cancer Genome Atlas programme has identified four main pathways involved in tumorigenesis &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a><a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> provides an overview of the genetic and biochemical diversity of these tumours&#44; which is crucial to understand their development mechanisms and to direct personalised therapies&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0250" class="elsevierStylePara elsevierViewall">The main genetic syndromes associated with pheochromocytoma&#47;PGLs are multiple endocrine neoplasia type 2&#44; VonHippel Lindau disease&#44; neurofibromatosis type 1 and familial paraganglioma syndromes<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Cardiac evaluation</span><p id="par0255" class="elsevierStylePara elsevierViewall">Catecholamine-induced cardiomyopathy&#44; which includes variants such as dilated cardiomyopathy&#44; Takotsubo cardiomyopathy &#40;both classic and reverse&#41;&#44; hypertrophic obstructive cardiomyopathy and myocarditis&#44; is a condition of great clinical importance that we must consider in patients with pheochromocytomas&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> Its diagnosis is often delayed&#44; especially when it presents atypically&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> Sometimes adrenergic crises induced by pheochromocytoma cause cardiovascular manifestations that can cause multiorgan failure or as an acute coronary syndrome&#44; leading to a fatal outcome&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">30&#44;31</span></a> The prevalence of history of cardiovascular pathology is variable in different series&#44; but for example in the Argentine registry of pheochromocytomas it was reported that 7&#46;6&#37; of patients had a history of cardiovascular disease&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">32</span></a> while in the Spanish registry it was reported in 14&#46;2&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a> Early diagnosis is essential to prevent irreversible cardiac remodelling&#46; It has been reported that after resection of pheochromocytoma&#44; 96&#37; of patients show an improvement in their ejection fraction&#44; compared with those who did not undergo surgery&#46; Of the latter&#44; 33&#37; experienced mortality and 11&#37; required a heart transplant&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">34</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">Since excess catecholamines may increase postoperative complications&#44; a preoperative cardiological evaluation is recommended in all patients&#46; This should include an electrocardiogram and a transthoracic echocardiogram&#44; particularly in patients with long-standing arterial hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a></p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusions</span><p id="par0265" class="elsevierStylePara elsevierViewall">Pheochromocytoma is a rare tumour&#44; often of delayed diagnosis&#46; Its diagnosis is based on confirming the excessive production of catecholamines and locating the adrenal tumour&#46; The measurement of catecholamines and their metabolites can be made difficult by pharmacological interferences&#44; diet&#44; and conditions that increase sympathoadrenergic activity&#46; Once the excess of catecholamines is confirmed&#44; the next step is to locate the tumour by CT or MRI&#46; If these studies are negative&#44; functional tests may be necessary to confirm the diagnosis&#46; Genetic testing is essential since 40&#37; of pheochromocytomas are hereditary&#46; An initial cardiological study with electrocardiogram and transthoracic echocardiogram is recommended to preoperatively identify catecholamine-induced cardiomyopathy&#44; in order to optimise presurgical treatment to avoid complications during and after surgery&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Ethics committee statement</span><p id="par0270" class="elsevierStylePara elsevierViewall">Not applicable&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Funding</span><p id="par0275" class="elsevierStylePara elsevierViewall">There was no funding for this research&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Informed consent statement</span><p id="par0280" class="elsevierStylePara elsevierViewall">Not applicable&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interests</span><p id="par0285" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare in this paper&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pheochromocytoma is a rare neuroendocrine tumour that develops from chromaffin cells in the adrenal medulla and is characterised by the excessive production of catecholamines and their metabolites&#46; Diagnostic confirmation is performed by detecting elevated levels of catecholamines and&#47;or their metabolites in plasma or 24-h urine&#46; In the case of moderate elevations of normetanephrine&#44; the clonidine suppression test may be useful to differentiate between endogenous hypersecretion and false positive results&#46; Once the biochemical diagnosis is performed&#44; the tumour localisation is carried out using imaging techniques and sometimes with nuclear medicine imaging tests&#46; Furthermore&#44; in all patients with pheochromocytomas it is recommended to perform a genetic study to identify hereditary disorders that may be present in more than 30&#37; of cases and to perform a cardiological evaluation to rule out the presence of cardiovascular involvement secondary to the catecholamine hypersecretion&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El feocromocitoma es un tumor neuroendocrino poco frecuente que se desarrolla a partir de c&#233;lulas cromafines de la m&#233;dula suprarrenal y que se caracteriza por la producci&#243;n excesiva de catecolaminas y sus metabolitos&#46; La confirmaci&#243;n diagn&#243;stica se realiza mediante la detecci&#243;n de niveles elevados de catecolaminas y&#47;o sus metabolitos en plasma y&#47;o en orina de 24<span class="elsevierStyleHsp" style=""></span>horas&#46; En caso de elevaciones moderadas de normetanefrina&#44; la prueba de supresi&#243;n con clonidina puede ser de utilidad para diferenciar entre hipersecreci&#243;n end&#243;gena y falsos positivos&#46; Una vez realizado el diagn&#243;stico bioqu&#237;mico&#44; la localizaci&#243;n del tumor se lleva a cabo mediante t&#233;cnicas de imagen y&#44; en ocasiones&#44; con pruebas de medicina nuclear&#46; Adem&#225;s&#44; en todos los pacientes se recomienda realizar un estudio gen&#233;tico para identificar trastornos hereditarios que pueden estar presentes en m&#225;s del 30&#37; de los casos y realizar una evaluaci&#243;n cardiol&#243;gica para descartar la presencia de afectaci&#243;n cardiovascular secundaria al exceso de secreci&#243;n de catecolaminas&#46;</p></span>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Diagnostic algorithm for suspected pheochromocytoma&#46; IE&#58; isolated elevation&#44; NMN&#58; normetanephrine&#44; MN&#58; metanephrine&#44; MOT&#58; methoxytyramine&#44; PPGL&#58; pheochromocytoma&#8211;paraganglioma&#44; ULN&#58; upper limit of normal&#46; &#42;In CT more than 10<span class="elsevierStyleHsp" style=""></span>UH or delayed washout of contrast of less than 50&#37; at 10<span class="elsevierStyleHsp" style=""></span>min&#46; &#42;&#42;Consider false positives due to pharmacological interferences&#44; adequate sample collection technique&#44; type of assay&#44; acute and chronic diseases&#44; fasting state &#40;if isolated elevation of methoxytyramine&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">HPLC&#8211;MS&#58; high-performance liquid chromatography with mass spectrometry&#44; NMN&#58; normetanephrine&#44; MN&#58; metanephrine&#44; MOT&#58; methoxytyramine&#44; DCs&#58; deconjugated&#44; vanillylmandelic acid&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Specificity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">87&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dopamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">77&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Free NMN&#44; MN and MOT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">97&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>AVM&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">81&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#46;2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Urine</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Norepinephrine&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">97&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dopamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NMN and MN DCs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NMN&#44; MN and MOT DCs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&#46;1&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NMN and free MN&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NMN&#44; MN and free MOT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>AVM&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&#46;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">92&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NMN and free MN&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">89&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">PGL&#58; paragangliomas&#59; <span class="elsevierStyleItalic">SDHx&#58; succinate dehydrogenase</span>&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleSup">68</span>Ga-SSA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">18</span>F-FDOPA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Head and neck PGLs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleSup"><span class="elsevierStyleBold">68</span></span><span class="elsevierStyleBold">Ga-SSA</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleSup">18</span>F-FDOPA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">111</span>In-SSA&#47;<span class="elsevierStyleSup">99</span>mTc-SSA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hereditary pheochromocytoma &#40;except <span class="elsevierStyleItalic">SDHx</span>&#41; <span class="elsevierStyleItalic">NF1&#47;RET&#47;VHL&#47;MAX</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">18</span>F-FDOPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">123</span>I-MIBG or <span class="elsevierStyleSup">68</span>Ga-SSA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">18</span>F-FDG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multifocal extra-adrenal involvement and&#47;or metastasis with or without <span class="elsevierStyleItalic">SDHx</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">68</span>Ga-SSA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">With SDHD&#58; <span class="elsevierStyleSup">18</span>F-FDGWithout SDHD&#58; <span class="elsevierStyleSup">18</span>F-FDOPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSup">18</span>F-FDG y <span class="elsevierStyleSup">123</span>I-MIBG o<span class="elsevierStyleSup">18</span>F-FDG and <span class="elsevierStyleSup">111</span>In-SSA&#47;<span class="elsevierStyleSup">99</span>mTc-SSA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab3686357.png"
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            0 => array:3 [
              "identificador" => "tblfn0030"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0035">If <span class="elsevierStyleSup">18</span>F-FDOPA and <span class="elsevierStyleSup">68</span>Ga-SSA are not possible&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Proposed clinical algorithm for the use of functional imaging in case of PPGL recommended by the European Association of Nuclear Medicine&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">AD&#58; autosomal dominant&#44; PGL&#58; paraganglioma&#44; NET&#58; neuroendocrine tumours&#44; NMN&#58; normetanephrines&#44; NM&#58; metanephrine&#44; PNMT&#58; phenylethanolamine N-methyltransferase&#59; TH&#58; tyrosine hydroxylase&#44; NA&#58; not applicable&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Von Hippel-Lindau syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MEN-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MEN-2B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Neurofibromatosis type 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prevalence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 out of every 35&#44;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 out of every 200&#46;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 out of every 350&#44;001 out of every 2000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Peak age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35&#8211;40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inheritance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VHL tumour suppressor gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Extracellular domain of RET protein &#40;85&#37; at codon 634&#44; particularly p&#46;Cys634Arg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intracellular domain of RET protein &#40;95&#37; methionine to threonine missense change in exon 16 &#40;p&#46;Met918Thr&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NF1 tumour suppressor gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chromosome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chromosome 3p25-26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chromosome 10q11&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chromosome 10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chromosome 17q11&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Penetrance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1&#8211;7&#46;7&#37;&#36;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clinical characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bilateral pheochromocytoma&#44; mediastinal&#44; abdominal&#44; pelvic&#44; neck and skull base PGL&#44; hemangioblastoma&#44; retinal angioma&#44; clear cell renal cell carcinoma&#44; pancreatic NETs&#44; middle ear endolymphatic sac tumours&#44; serous cystadenomas of the pancreas&#44; papillary cystadenomas of the epididymis and broad ligament&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Medullary thyroid cancer &#40;100&#37;&#41;&#44; pheochromocytoma &#40;50&#37;&#41;&#44; primary hyperparathyroidism 20&#37;&#44; lichenoid cutaneous amyloidosis 5&#37;&#44; Hischprung disease &#40;rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Medullary thyroid cancer &#40;100&#37;&#41;&#44; pheochromocytoma &#40;50&#37;&#41;&#44; mucocutaneous neuromas &#40;70&#8211;100&#37;&#41;&#44; marfanoid habitus 100&#37;&#44; myelinated corneal nerves &#40;100&#37;&#41;&#44; intestinal ganglioneuromas &#40;60&#8211;90&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neurofibromas&#44; multiple caf&#233;-au-lait spots&#44; axillary and inguinal freckles&#44; iris hamartomas &#40;Lisch nodules&#41;&#44; bone abnormalities&#44; central nervous system gliomas&#44; pheochromocytoma and paraganglioma 3&#37;&#44; macrocephaly and cognitive deficits&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clinical phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bilateral and asynchronous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increased incidence of symptomatic paroxysmal hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Solitary or bilateral benign pheochromocytomas or a periadrenal abdominal PGL&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Biochemical phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Noradrenergic with elevated NMN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower expression of PNMT and TH adrenergic with elevated MN higher expression of PNMT and TH with higher concentration of catecholamines and metabolites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Clinical&#44; biochemical and genetic characteristics of syndromic disorders associated with pheochromocytoma&#46;</p>"
        ]
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    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
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Article information

ISSN: 18891837
Original language: English

DOI:10.1016/j.hipert.2024.08.001

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