Evolving Clinical Presentation and Assessment of Pheochromocytoma: A Review


Pheochromocytoma (PHEO) is a rare adrenomedullary tumor causing secondary hypertension, with an incidence of 0.1-0.6%.(1-5) These tumors can synthesize, metabolize, store, and secrete catecholamines and their metabolites. (6) A high index of clinical suspicion remains the pivotal point to initiate biochemical studies, particularly in those patients with certain patterns of spells, blood pressure elevations (paroxysmal or alternating with hypotension), drug-resistant hypertension, sudden palpitations with or without pallor, unexplained sweating particularly at night or in cold weather, unexplained hyperglycemia, and a hereditary predisposition for PHEO.(7-13)   

Although biochemical testing for PHEO is indicated for symptomatic patients as described above, it is also indicated for patients with incidentally found adrenal lesions or identified genetic predispositions or syndromic presentation pointing towards a high likelihood to develop PHEO (e.g. in patients with multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), mutations of the succinate dehydrogenase genes (SDHB, SDHD), and hypoxia-induced factor 2A (HIF2A)-related PHEO-polycythemia syndrome).(14-23) Only after PHEO is biochemically proven should imaging be performed. Current imaging modalities include anatomical (CT, MRI) and functional (molecular) imaging procedures using various radiopharmaceuticals, depending on the clinical situation. If a detailed clinical assessment together with well-thought and appropriate diagnostic approaches is not applied, consequences from improper or delayed diagnosis of PHEO almost always occur. This may lead to catastrophic consequences from sudden catecholamine release and their impact on cardiovascular and other systems, including lethal tachyarrhythmia, myocardial infarction, stroke, or death,24 and significant myocardial dysfunction persisting even after normalization of catecholamine levels postoperatively. (25)

During the last few years, enormous progress has been made in the diagnosis of PHEO.  These new discoveries include the inclusion of 3-methoxytyramine in the biochemical diagnosis,26-29 new reference values for seating and standing metanephrine levels, new reference values for children,11 metabolite profiling (metabolomics) and evaluation of relationships between metabotypes and genotypes,30 in vivo proton magnetic spectroscopy for the assessment of catecholamines and succinate, the use of new functional imaging modalities particularly somatostatin analogs radiolabeled with gallium-68 (68Ga-DOTA-SSA) 31 in the localization of PHEO, and finally the advancement in the identification and characterization of new susceptible genes related to disruption of HIF degradation, such as prolyl hydroxylase (PHD) and HIF mutations, 21,32 mutations in chromatin remodeling genes, e.g. MERTK, MET, and H3F3A, (33) and disruption in DNA copy numbers.(34) Also, new therapeutic approaches are on the horizon focusing on HIF-2 inhibitors, hypomethylating agents, and 177Lu-DOTATATE for peptide receptor radionuclide therapy (PRRT) and precision medicine approach. (35)

This review is undertaken to provide insight on the evolving clinicalpresentation of pheochromocytoma and to come up with diagnostic algorithms that will guide clinicians for early identification of the evolving clinical presentation and timely assessment of pheochromocytoma.


The Sympathoadrenal (SA) Cell Lineage And The Adrenal Medulla

The SA cells are a sub-lineage of the neural crest, giving rise to neuroendocrine chromaffin cells in the adrenal medulla and extra-adrenal neurons clinically called paraganglia.36 These SA derivatives have the common characteristics to synthesize, store, and release catecholamines. The migration of these cells is found along the sympathetic ganglia from the neck, mediastinum, and abdomen, down to the urinary system. The sympathetic neurons and chromaffin cells share the same progenitor in the neural crest. BMP-4 has shown to be the major induction factor for maturation of SA progenitor cells (Figure 1). (37) The differentiation of the SA cellular lineage to sympathetic neurons and chromaffin cells may be due to inherent environmental influence but remain unclear. However, it is during this phase of NC cells migration in the presence of established transcription factors (TFs) including MASH-1, Phox2a, Phox2b, Hand2, Gata2/3 and Insm1 that they acquire catecholaminergic features and phenotypes. (38-40) Other hypothetical suggested TFs are NOTCH-signaling, HAIRY1/2/3, and DELTA1, SERRATE, and NUMB, Inscuteable/dlg1. (40-41)

The temporal triggering events for specific chromaffin cells remain debatable due to lack of appropriate markers. The final target regions such as the adrenal medulla, paraganglia, and sympathetic ganglia have been demonstrated to be influenced by glucocorticoids (GCs). (42-44) The GC- signaling has shown to not originate specifically from adrenal cortex and even present in GC-deficient mice. Several crosstalk pathways between GC/GR signaling, GR/MAPK pathways, IGF-1, FGF-2, and NGF receptor trkA have been described (45-46) which is vital for chromaffin survival. GC signaling is likewise crucial in the induction of adrenaline synthesizing enzyme phenyl ethanolamine-N-methytransferase (PNMT), so that GC-deficient mice only produce noradrenaline. (46) In GC receptor knockout mice, chromaffin vesicles are intact and can still be identified by molecular markers such as neuropeptides, transporters, and chromogranin B. (47)


Catecholamine Synthesis And Metabolism: Physiologic Vs. Pathologic In Pheochromocytoma

The mother substance for catecholamine synthesis is amino acid L-tyrosine. Tyrosine is derived from the diet or synthesized from phenylalanine.  Synthesis starts at the rate-limiting step of conversion of tyrosine 3,4-dihydroxyphenylalanine (DOPA) by the enzyme tyrosine hydroxylase (TH) (Fig. 2A). (48) Conversion of DOPA to dopamine (DA) is catalyzed by aromatic L-amino acid decarboxylase (AADC). The DA formed in the cytoplasm by AADC is transported into vesicular storage granules. In dopaminergic neurons, DA is released without any further conversion to norepinephrine (NE), but in noradrenergic neurons and adrenal chromaffin cells DA is further converted to NE by dopamine b-hydroxylase (DBH). (16,49) The enzyme is present in vesicular storage granules, either bound to the vesicular membrane or present in the solute matrix core. In adrenomedullary cells NE stored in vesicular storage granules can leak into the cytosol where enzyme phenylethanolamine N-methyrltransferrase (PNMT) is exclusively present and converts NE to epinephrine (E). (16,50) The formed E is translocated back into chromaffin granules. (17)

Another major enzyme vital in the metabolism of cathecholamines is catechol-O-methytransferase (COMT) which is present both extra- and intramedullary for conversion of DA to methoxytyramine (MTY), NE to normetanephrine (NMN), and E to metanephrine (MN).51 Ninety percent of MN and 23% of NMN in the circulation come from this pathway. (51-52) Sympathetic nerves contain the enzyme monoamine oxidase (MAO) which deaminates NE to 3-4-dihydroxyphenylglycol (DHPG). DHPG is methylated by COMT to 3-methoxy-4-hydroxyphenylglycol (MHPG), which is converted by aldehyde dehydrogenase (AD) in the liver to the metabolite vanillylmandelic acid (VMA), an end product of catecholamine metabolism in human urine. (53-54) The O-methylated metabolites of NE, E and DA are continuously released from PHEO and become major parameters to assess tumoral activity. (27,55-59)

Apart from being excreted in the urine, the free metanephrines are also conjugated in the wall of gastrointestinal tract by the enzyme sulfotransferase family, cytosolic, 1A phenol-preferring member 3 (SULT1A3). (60) These sulfate-conjugated forms of metanephrines prolong their plasma half-lives 30x higher than the free forms. (61-62) Measurements of urine metanephrines utilize an acid hydrolysis step to convert the sulfate-conjugated metabolites to free forms. Thus, such measurements reflect the total metanephrines (Fig. 2B). (6)

In pheochromocytoma, there are elevations of catecholamines and their metabolites specific for locations of lesions (adrenomedullary and extra-adrenal), abnormal tumor enzymatic activity (increased normetanephrine, metanephrine, and methoxytyramine) and altered pathway mechanisms. (6)


Early Diagnosis Of Pheochromocytoma

The two major factors for increased morbidity and mortality in PHEO are delay in the diagnosis63 and late detection of metastasis. (25) Recent developments addressed these concerns, such as improved biochemical analytical procedures, (6) analysis and recognition of evolving clinical presentations, (13,64-66) and inclusion of methoxytyramine in the work-up of PHEO, (17,67)  improved imaging modalities, (67-68)  and correlation of biochemical and imaging profiles with phenotype and genotype of the patients. (11)


Improved Sample Preparation, Specific Reference Values And Advanced Laboratory Methods

Catecholamines are measured in plasma and urine in several forms - as unconjugated norepinephrine, epinephrine, and dopamine, or by their O-methylated metabolites- normetanephrine, metanephrine, and methoxytyramine.6 Research institutions and commercial laboratories in most countries do not ordinarily measure these hormones and, therefore, have to be sent out through courier. It is imperative that preparation, collection, handling, storage and packaging of these specimens must be done with utmost care, caution, and precision so as not to alter the true values of the hormones. (69)

Prior to sample analysis, various important factors must be assessed in order to avoid or minimize false-positive and false-negative results, thus yielding better diagnostic accuracy. These factors are- age, position of the patient during blood extraction, immediate dietary intake, and current medications. (Table 1). (6,11,70-73) Values of plasma catecholamines and metanephrines have shown to approximate tumoral activity if blood extraction is done in the supine position.69-70,74 Dietary restrictions for tyramine-rich diet (cheese, nuts, cereal, beer, wine) are made mainly for the measurement of 3-methoxytyramine (MTY), a dopamine metabolite, and blood sample must be collected after an overnight fast. (71)

Co-morbidites have been reported also to influence plasma and urine MN and NMN results, such as renal failure, stroke or intracerebral hemorrhage, decompensated congestive heart failure and obstructive sleep apnea. (75) Stabilization of co-morbidities is imperative to avoid false low (renal failure) or inadvertently high values (decompesated heart failure, stroke, obstructive sleep apnea). (Table 2)  Plasma metanephrine has shown to be least affected by these conditions. (75)

Diagnostic specificity and sensitivity of biochemical tests rely significantly on cut-offs of measured values of plasma catecholamines and their metabolites. (76) Recently, Eisenhofer and his group established age-adjusted cut-offs of reference intervals for plasma normetanephrine and optimized cut-offs for metanephrine, minimizing false positive results, increasing diagnostic specificity to 96.0%, with minimal loss in diagnostic sensitivity of 93.6%. (16,77) Plasma metanephrine, but not normetanephrine, was higher in men but reference interval did not differ.  Upper cut-offs of reference intervals for normetanephrine increased from 0.47 nmol/L in children to 1.05 nmol in subjects older than 60 years (Table 3, Table 4). (16,77)

Equally important is the significant progress in the development of catecholamine assay methodology.6 Although immunoassays remain useful for measuring metanephrines (78-79) underestimation of plasma concentrations of metanephrines and normetanephrines have been reported.80 Recently, liquid chromatography with electrochemical detection (LC-ECD) or coupled to tandem mass spectrometry (LC-MS/MS) are currently becoming the preferred methods with favoring more of the latter. (81-84) Aside from having superior accuracy and precision of catecholamine measurement with LC-ECD and LS-MS/MS, (80,82-83) they allow fractionated measurements of normetanephrine and metanephrine vs. colorimetric and fluorometric of total metanephrines (combined normetaphrine and metanephrine). Furthermore, there is additional and important advantage of capability to measure 3-methoxytyramine (MTY), (80) a biomarker which importance will be highlighted in subsequent discussion.

Metabolomics, a global metabolite profiling, is a new technology of functional genomics used for investigating metabolite changes associated with some gene mutations. LC-MS/MS, gas chromatography- mass spectrometry (GC-MS), (85) ultrahigh pressure liquid chromatography with tandem mass spectrometry (UPHPLC-MS/MS), (30) 1H nuclear magnetic resonance (NMR) spectroscopy (86) and recently, a new technique, so-called 1H high-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy87 have been employed with the advantages suited for small sample of tissues with no chemical extraction and manipulation. The modality showed promising usefulness in the clinical assessment specifically for SDHx-related tumors as a screening method and functional test for evaluating SDHx mutation of unknown pathogenicity. (87)


Evolving Clinical Presentation Of Pheochromocytoma

High index of suspicion remains the pivot point to initiate biochemical and imaging studies in patients suspected to have PHEO. The clinical presentation is defined by the biochemical secretory characteristic of the lesion, NE, EPI and their metabolites, (15-19) dictated by enzymatic profile of the tumor. (13) Basic knowledge on organ-specific role of adrenoceptors is necessary in order to understand responses to catecholamines which are magnified in patients with PHEO due to excess secretion of the hormones and their metabolites (Table 5).

Based on ligand studies and their agonists and antagonists, adrenoceptors are classified into adrenergic (α1, α2, β1, β2, β3) and dopamnergic recceptors (D1, D2) and their subtypes. Almost all tissues and organs of the body express these receptors.88 However, to date, there is no close relationship established between specific subtypes and signaling mechanisms. Each vascular structure may harbor mixtures of α1-adrenoceptor subtypes and may respond to the same stimuli at the same time. (89-91) On the other hand, the maximal b-mediated vasodilatation varies from vascular bed to vascular bed and depends on the tone of the tissue. (92-93)

Norepinephrine mainly signals α1, α2, and β1 receptors, while epinephrine mainly signals β1 and β2 receptors. Normally dopamine does not affect the adrenergic receptors, but with increased plasma concentrations, it can stimulate both α and β receptors. (13)

In general, alpha-1 receptors, mostly found in smooth muscle, peripheral arteries and veins cause vasoconstriction upon stimulation and increasing systemic pressure. In pheochromocytoma, manifestations include hypertension, headache, and pallor. Stimulation of α2-adrenergic receptors located on smooth muscles will result in arterial vasodilation and coronary vasoconstriction; in PHEO typical manifestations may include diaphoresis and orthostatic hypotension. Stimulation of β1-adrenergic receptors has a positive chronotrophic and inotropic effect in the heart and will also result in release of renin. In PHEO this can contribute to hypertension, palpitations, and tachycardia. Stimulation of β2-adrenergic receptors will induce vasodilation of muscular arteries, and some common effects in PHEO include constipation and nausea. β3-adrenergic receptors in adipocytes induces lipolysis and can cause weight loss in PHEO. (13,17,94)

Pourian and his group66 recently attempted to formulate the likelihood ratio (LR) of signs and symptoms to aid in PHEO diagnosis in the clinical setting. The most prevalent signs and symptoms were hypertension, headache, palpitation and diaphoresis. But based on their calculated LR, the significant symptoms that could aid in diagnosis were diaphoresis, palpitations, and headache alone, with the exclusion of hypertension.

The Sweden National Cancer Registry reported a 4x higher risk for mortality in PHEO compared to the general population with deaths occurring from acute hypertensive crisis. (63) Interestingly, Stolk et al., (65) have demonstrated that among PHEO vs. patients with essential hypertension, there is clearly a higher rate of cardiovascular (CV) events in PHEO excluding differences in hypertension and other CV risk factors. Recently, the literature have been showing case reports of young individuals in their 20's, unsuspected to harbor PHEO, presenting with dramatic CV events, with one succumbing to CV failure.95 Interestingly, CV anatomic and functional abnormalities reverse after adrenalectomy (Table 6). (95-96) This is similar to our case of 20-year old female diagnosed and operated for large malignant PHEO. Except for her hypertension of one year, she has no other risk factors for CVD. Her echocardiographic finding showed dyskinesia of the septum (Figure 3).

Early diagnosis of PHEO does not only resolve the catecholamine-induced cardiomyopathy with timely treatment but also the arterial stiffness. It has been shown that those PHEO patients whose diagnosis and treatment happened within 4 years from onset of hypertension do not require anti-hypertensive medications postoperatively as opposed to those whose onset of hypertension is 10 years or later from diagnosis and treatment. (97)  Interestingly, early diagnosis treated with mere unloading of the circulation with excess catecholamine by removing the dominant catecholamine-secreting lesion in patients with bilateral PHEO results into complete resolution of symptomatology, significant lowering to normalization of blood pressure, decrease in the number of antihypertensive medications, and better quality of life. (98-99)

It seems that the destructive effect of chronic hypercatecholaminemia happens insiduously if diagnosis of PHEO is overlooked, and dramatic CVD events and death occurs when there is sudden surge in the concentration of the hormones adding significant insult to a compromised cardiac function. This explosive cardiovascular picture of patients with PHEO may provide new insights in the paradigm shift in the clinical assessment of these patients. Research is warranted to demonstrate the value and cost-effectiveness of 2D echocardiogram, a test readily available, in the assessment and monitoring of patients with minimal or absent CVD risk factors and being suspected for PHEO but with vague clinical presentation and equivocal biochemical results. Cardiac MRI is worth doing in patients with severe clinical symptomatology of cardiac disease like dyspnea, orthopnea and chest pain and with evidence of myocardial damage in the ECG and elevated cardiac enzymes . (100)


Methoxytyramine: A Noble Biomarker For Early Diagnosis Of PHEO And Early Detection Of Metastasis

Until recently, the biggest challenge in the biochemical evaluation of PHEOs is those with minimal catecholamine secretion (101) or exclusively secreting dopamine (76) which often leads to delayed and missed diagnosis. These tumoral dopaminergic phenotype are also observed to be mostly extra-adrenal, metastatic, and associated with hereditary lesions.(17,26,77,102) The introduction of the measurement of plasma O-methylated dopamine metabolite, 3-methoxytyramine (MTY) made the evaluation of dopamine-producing PHEOs including their metastases possible and very useful, especially in those presenting with succinate dehydrogenase gene mutations. (17,26,77)

The measurement of 3-MTY discriminated two distinct groupings; 1) MEN2 and NF1 and 2) VHL and SDHx.77  Patients with VHL and SDH mutations harbor immature tumors and lack PNMT necessary for epinephrine secretion; therefore, they do not synthesize metanephrine (MN) but only normetanephrine (NMN) and/or 3- MTY. The best biomarker for SDH tumors is 3-MTY since this is produced only by these tumors. Since MEN2 and NF1 tumors secrete both NE and E, measurement of NMN and MN best distinguishes these two from VHL and SDH tumors.17,26 With combined measurements of NMN, MN and 3-MTY, patients with NF1 and MEN2 can be discriminated from those with VHL, SDHB and SDHD, and 3-MTY can discriminate SDHB and SDHD from VHL in 78% of cases.17,26 Gupta and his colleagues recently demonstrated that 50% of malignant PHEO have increased levels of both NM and 3-MTYgupta. (35)

PHEOs of the dopaminergic phenotype have generally been found to have reduced levels of the enzyme dopamine β-hydroxylase, which results in dopamine accumulation and a decreased production of norepinpephrine. (103-104) This finding may be due to proliferation of dedifferentiated progenitor cells giving rise to these tumors, as seen in patients with metastatic disease and with mutations in SDHB and SDHD.105 Patients with these mutations show increases in the levels of dopamine and methoxytyramine in addition to elevations in the level of normetanephrine. (77,106-107)

Biochemical secretory attributes of tumors using 3-MTY biomarker has been shown also to assist in deciphering location and metastasis. (26,77) In addition to being elevated in over two-thirds of patients with SDHB and SDHD mutations, 3-methoxytyramine is also a marker of multifocality and extra-adrenal in location. Together with a diagnosis of SDHB mutation, a 5-fold higher levels of 3-MTY signifies malignant nature of the tumor with metastasis. (26,77,108) Furthermore, although rare, cases of PHEOs in patients with NF1, VHL, MEN2A and MEN2B secreting high levels of dopamine and/or 3-methoxytyramine, have also been reported. (109-112)


Advanced Imaging Modalities

After catecholamine excess has been established biochemically, imaging studies for localization of primary tumor and determination of metastates should be done. The diagnosis pf pheochromocytoma is usually challenging due to the variety of clinical presentation and anatomic and functional imaging results. It is important to use the most appropriate available imaging modality, with good sensitivity without compromising specificity.

Anatomic imaging with the use of computerized tomography (CT) has been the preferred initial procedure for localization of PHEOs owing to its high sensitivity of 90%. (11,113) However, its limitation has been observed in extra-adrenal, recurrent and metastatic lesions. (114-115) MRI, on the other hand is more advantageous in detecting extra-adrenal lesions, and is indicated in those with allergy to contrast, pregnant or pediatric patients, and those whose contrast medium is a contraindication. (10) Ultrasound sensitivity is poor but very useful in the detection of liver metastasis and lesions in the urinary bladder. (116)

Table 7 reviews the sensitivity and specificity of imaging modalities in metastatic PHEO. Sensitivity of CT and MRI is variable. In a multicenter the study involving patients with adrenal malignancy, the sensitivity of contrast-enhanced CT (CECT) was found to be at 59% only. (117) In a study involving patients with biochemical catecholamine excess, the patient based sensitivity of CT/MRI was 67% with lesion-based sensitivity of 44%.118 In contrast, a study involving 216 patients suspected of pheochromocytoma and paraganglioma, it has been found that CT/MRI is highly sensitive, as high as 95.7% for nonmetastatic tumors and 74.4% in metastatic tumors. (119-120)

In contrast to anatomic imaging, functional imaging offers the advantage of higher specificity in detecting multifocal and metastatic tumors and can characterize tumoral metabolic activity.  (119-122) 123I- or 131I-metaiodobenzylguanidine (MIBG) scintigraphy has the structure similar to NE so it can enter cells thru NE transporters. 123I-MIBG is more sensitive and has better detection rate.68,116,123-124 On the other hand, single-photon emission computed chromatography (SPECT) has been used with CT/MRI for colocalization. A recent report has shown the highest sensitivity with 123I-MIBG SPECT/MRI in the detection of adrenal PHEOs, especially in cases where PHEO is ruled out. (125) With the advancement of imaging techniques, the limitation with MIBG becomes more apparent notably in missed metastasis yielding false-negative results in patients with succinate dehydrogenase subunit B (SDHB) mutations. (68,126) 124IMIBG is reserved for volume determination prior to 131IMIBG therapy for metastatic PHEO. (127)

Positron emission tomography (PET) is becoming widely used and offers favorable attributes, such as less imaging time, low radiation exposure, and superior spatial resolution. 18F-fluorodeoxyglucose (FDG) PET is the preferred procedure for malignant tumors, especially SDHB-related PHEO since cancer cells readily uptake glucose. (120) However, its performance is not specific since it can detect other kinds of tumors. (68)

18F-fluorodopamine (FDOPA) is a more specific tracer since structure is similar to dopamine, a catecholamine precursor, and therefore enters the cell through NE transporter. (116,124,128) This imaging modality has high sensitivity for metastatic tumors. (129-131) Newer PET scanning tracers have been developed and showed promising results in detection of metastasis and characterization of metabolic activity of the tumor cells namely the DOTA peptides- DOTATATE, DOTATOC, and DOTANOC. 68Ga-DOTATOC PET/CT was found superior to FDOPA PET/CT in the diagnosis of metastatic tumors.(132) Ongoing research is being undertaken to observe further these findings in a bigger cohort. For chromaffin tumors that express somatostatin receptors, 111In-DTPA octreotide or 111In DTPA-pentetreotide have proven useful. (68,133)


Conclusion and Insight

In this review, the diagnosis of pheochromocytoma is revisited to address the evolving clinical presentation that increases morbidity and mortality due to delay in diagnosis and treatment.  The discussion centered on the progress in the approaches of early diagnosis of PHEO through complete history and physical examination, and improved analytical approaches and inclusion of an important metabolite, methoxytyramine, in the biochemical assessment. We have also emphasized the introduction of cardiovascular imaging 2D echocardiogram and cardiac MRI in the early assessment of patients with equivocal biochemical and imaging results. In this aspect, as have been shown in previous reports, the resultant cardiomyopathy from chronic catecholaminemia is reversible and catecholamine unloading in the circulation leads to significant clinical improvement. We have also pointed out the advances in the imaging procedures, which led to better diagnostic accuracy in the early detection of metastasis and recurrence. Finally, we have elucidated how the clinical presentation, biochemical profile and imaging characteristics of PHEO correlated well with specific gene mutations. With the aforementioned progress we have come up with recommendations summarized in an algorithm shown in (Figure 4).


Declaration of Interests

The authors declare that there is no conflict of interest that could be perceived prejudicing the impartiality of this review.



The review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.



We would like to thank the technical support of Ms. Jacquelin Ombac.


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Table 1. Sample preparation, collection, and storage for hormonal tests in pheochromocytoma

Hormonal test/s

Preparation & Collection



& Epinephrine




















Supine at least 20 mins

With an indwelling cannula


Tubes with heparin or EDTA

Placed on ice

Stored until -20 ⁰C, perform assay within 30 days


Containers with HCI

Light-proof containers

Storage at 4 ⁰C, long-term storage at -20 ⁰C or lower


Overnight fast

Avoid amine-rich foods* for

24 hrs

Supine at least 30 mins

With an indwelling cannula


Tubes with heparin or EDTA

Placed on ice

Stored until -20 ⁰C, perform assay within

30 days


Avoid amine-rich foods for

24 hrs




Containers with HCI

Light-proof containers

Storage at 4 ⁰C, long-term storage at

-20 ⁰C or lower


& Metanephrine
















Supine at least 30 mins

With an indwelling cannula


Tubes with heparin or EDTA

Placed on ice

Stored until -20 ⁰C, perform assay within

30 days


Acidification of sample not needed

Light-proof containers

Storage at 4 ⁰C, long-term storage at

-20 ⁰C or lower



Overnight fast

Avoid amine rich foods

Supine at least 30 mins

With an indwelling cannula

Avoid amine rich foods


Tubes with heparin or EDTA

Placed on ice

Stored until – 20 ⁰C, perform assay within

30 days

Acidification of sample not needed

Light-proof containers

Storage at 4 ⁰C, long-term storage at

-20 ⁰C or lower

*Amine-rich foods: beer, wine, cheese, bananas, pineapple, nuts, cereals


Table 2. Precautionary measures in the sample preparation and biochemical interpretation of results in pheochromocytoma

Clinical setting

Effect on Plasma and Urine NMN, MN or MTY

Precautionary Measures


2x increase from childhood to 60 years old

Age-specific reference values

Position on blood extraction -seated vs. supine

Up to 30% increase in seated position in plasma NMN and MN

30 min rest before blood extraction

High amine-rich diet

Increase in urine NMN

2x increase in MTY

Avoid beer, wine, cheese, bananas, pineapple, nuts and cereals for 24 hours

Renal Impairment

<4x increase in plasma NMN

<2x increase in MN

MN less affected

Correlate with other parameters

Essential hypertension

Up to 50% increase in plasma NMN and MN

Establish reference values

Decompensated congestive heart failure

2x to 4x increase in plasma NMN

Stabilize patient and repeat test

Plasma MN not affected

Stroke/Intracerebaral hemorrhage

>2x increase in plasma NMN

Biochemical test one week after event


30% increase in urine NMN

Stabilize illness and repeat test

Plasma MN not affected

NMN; normetanephrine, MN; metanephrine, MTY; methoxytyramine, OSA; obstructive sleep apnea. Adapted from Dobri et al. 201475


Table 3. Medians and reference intervals (2.5 and 97.5 percentiles) for plasma normetanephrine and metanephrine according to gender and six age groups



Age (years)

Normetanephrine (nmol/L)

Metanephrine (nmol/L)





































































































Presence of different symbols (*†§) indicates differences (P < 0.005) in normetanephrine or metanephrine between men and women or among different age groups

Adapted from Eisenhofer et al. 2013134


Table 4. Diagnostic test performance of plasma metanephrines with different upper cut-offs and models adjusting for age


Upper cut-offs (nmol/L)

Test performance




Sensitivity (%)

Specificity (%)

Fixed – 97.5 percentiles





Age-dependent linear model





Age-dependent curvilinear model





Age-dependent curvilinear model





Age-adjusted score model





NMN, normetanephrine; MN, metanephrine; NA, not applicable (based on a score)

Adapted from Eisenhofer et al. 2013134.


Table 5. Main actions of catecholamines on the various receptors and their common manifestations in pheochromocytoma

Target organ system

Receptor types

Sympathetic action

Common manifestations in pheochromocytoma

Skin and mucosa

α1, α2

Vasoconstriction, localized secretion of sweat glands

Pallor, diaphoresis

Peripheral vascular

α1, α2, β2

Vasoconstriction α1, α2 Vasodilation β2


Orthostatic hypotension


α1, D1




β1, β2, D1

Increase in heart rate, contractility, automaticity, conduction velocity

Palpitations, tachycardia, angina


α1, β2

Pulmonary arteriole vasoconstriction, tracheal and bronchial muscle relaxation



α1, α2, β2

Decrease gastrointestinal motility and secretion, constricts sphincters increases liver glycogenolysis and gluconeogenesis, increases pancreatic release of insulin and glucagon

Nausea, abdominal pain, constipation, hyperglycemia



Increase renin secretion



β1, β3

Increase lipolysis

Weight loss


Table 6. Dramatic clinical presentations, laboratory and imaging findings and clinical outcome of patients with unsuspecting pheochromocytoma


Clinical Features

Age (years)

20's to 40's

Signs and symptoms

Headache, agitations, diaphoresis, nausea, vomiting

Acute coronary syndrome

Severe congestive heart failure



Elevated creatine kinase

Normal to elevated troponin


Normal angiogram

Dyskinesia, hypokinesia, akinesia by 2D Echo

Diffuse myocardial edema by cardiac MRI

Postoperative persistence of myocardial fibrosis

Clinical outcome

Resolution of signs and symptoms after adrenalectomy

Normalized LV function and ejection fraction

Persistent systolic and diastolic impairment



Table 7. Anatomic and Functional Imaging of Pheochromocytoma





Anatomic Imaging





Cistaro A. et al. (2015)



Timmers HJ et. Al. (2009)

97% for nonmetastatic

38% for nonmetastatic


100% for metastatic



Timmers HJ et. al. (2009)

92% for nonmetastatic




58% nonmetastatic

100% for metastatic



Timmers HJ et. al. (2012)

95.7% for nonmetastatic


74,4% for metastaatic


Fiebrich HB et. al (2009)



Functional Imaging





Bandopadhyaya GP et. al. (2015)



Timmers HJ et. al. (2012)

75% for nonmetastatic


50 % for metastatic


Fottner C.et.al (2010)



Fiebrich HB et. al (2009)



Timmers HJ et. al. (2009)

78% for 123I-MIBG in nonmetastatic


76% for 131I-MIBG or 123I in nonmetastatic


92% for nonmetastatic

123I-MIBG, 131I-MIBG or 123I


85% metastatic 123I-MIBG

65%131I-MIBG or 123I


Ilias I. et. al. (2008)

87.5% for nonmetastatic,


88.9% for metastatic


(18)F-DOPA PET/CT Scan


Bandopadhyaya GP et. Al. (2015)



Cistaro A. et al. (2015)



Timmers HJ et. Al. (2012)

76.8% for nonmetastatic


82.5 % for metastatic


Fottner C. et.al (2010)



Luster M et. Al. (2010)



Flebrich HB et. Al (2009)



Imani F. et. Al (2009)



Timmers HJ et. Al. (2009)

78% nonmetastatic


77% nonmetastatic


97% metastatic


Ilias I. et. Al. (2008)

87.5% for nonmetastatic




91.4% for metastatic



Sharma P. et. Al (2014)




Yamamoto S. et. Al (2012)




Trampal C. et. al. (2004)



123I-metaiodobenzylguanidine (MIBG), positron emission tomography (PET)), F-3,4-dihydroxyphenylalanine (F-DOPA), Hydroxyephedrine (HED)


Figure 1

Figure 1. Sympathoadrenal cell lineage development to become adrenal and extra-adrenal chromaffin cells through different signaling pathways. BMP-4 has shown to be the major induction factor for maturation of SA progenitor cells. In the presence of transcription factors MASH-1, Phox2a, Phox2b, Hand2, Gata2/3 and Insm1 during the migration of chromaffin cells, they acquire catecholaminergic features and phenotype. Several crosstalk pathways between GC/GR signaling, GR/MAPK pathways, IGF-1, FGF-2, and NGF receptor trkA have been described which is vital for chromaffin survival. GC-signaling is likewise crucial in the induction of adrenaline synthesizing enzyme phenyl ethanolamine-N-methytransferase (PNMT).


Figure 2. (A) Synthesis of catecholamines, namely, dopamine, epinephrine (E) and norepinephrine (NE) begins with the uptake of the the amino acid L-tyrosine by adrenomedullary and sympathoneuronal cells Tyrosine is derived form the diet or synthesized from phenylalanine and is converted to 3,4-dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase (TH), the rate limiting step. L-DOPA is decarboxylysed to dopamine, which is actively transported to vesicles where intravesicular enzyme, dopamine-β- hydrolase (DPH) converts it to NE. NE leaks into the cytoplasm where phenyl ethanolamine N-methyltransferase (PNMT), an enzyme exclusive to adrenomedullary cells, converts it to E that is transported back into the vesicles. (B) The enzyme catechol-O-methytransferase (COMT), which is present both extra- and intramedullary is responsible for conversion of DA to methoxytyramine (MT), NE to normetanephrine (NMN), and E to metanephrine (MN). Sympathetic nerves contain the enzyme monoamine oxidase (MAO) which deaminates NE to 3-4-dihydroxyphenylglycol (DHPG). DHPG is methylated by COMT to 3-methoxy-4-hydroxyphenylglycol (MHPG), which is converted by aldehyde dehydrogenase (AD) in the liver to the metabolite vanillylmandelic acid (VMA). These catechol O-methyl metabolites are produced in excess by tumorous chromaffin cells of pheochromocytoma in the adrenal, sympathetic neurons and extraneuronal metastatic lesions. Metanephrines exist in plasma and urine in both free and sulfate-conjugated form. The sulfate-conjugated forms are catalyzed by a specific sulfotransferase is enzyme, sulfotransferase family, cytosolic, 1A phenol-preferring member 3 (SULT1A3), which is found in gastrointestinal tissues. Measurements of urine metanephrines utilize an acid hydrolysis step to convert the sulfate-conjugated metabolites to free forms. Thus, such measurements reflect the total metanephrines.


Figure 3

Figure 3. Computed tomography (CT) scan (A) of a 20-year old female, non-obese, nonsmoker with 1-year history of hypertension and highest BP of 180/120. The adrenal mass measures 7.0 x 5.0 cm. Pathology confirmed PHEO with vascular invasion. Pre-operative 2D-echocardiographic study (B) showed dyskinesia of the septum


Figure 4. Algorithm for diagnosis of sporadic (A) and syndromic (B) pheochromocytoma.

Algorithm C depicts the imaging modalities for both. Adapted from Martucci & Pacak (2014)* Docardiac MRI if patient is with moderate to severe CV symptoms: dyspnea, orthopnea, chest pain with or without evidence of myocardial injury, such as abnormal ECG, elevated troponin or creatine kinase.

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