Differential If a patient has the characteristic signs and symptoms of a<unk>  and the decision is made to pursue additional biochemical (blood work) evaluation, the differential diagnosis is important as it is more likely to be something other than a<unk>  given the relative frequency of 0.8 per 100,000 person-years. +Differential Diagnosis of<unk>  by System Endocrine Cardiovascular Neurologic Psychiatric Other Hyperthyroidism Heart Failure Migraine Anxiety Porphyria Carcinoid Syndrome Arrhythmias Stroke Panic Disorder Medications Hypoglycemia Ischemic Heart Disease Epilepsy Substance Use Menopausal Syndrome Baroreflex Failure Meningioma Factious Disorder Medullary Thyroid Carcinoma – POTS – Notes Biochemical evaluation Gold standard Elevated plasma free metanephrines is considered the gold standard diagnosis for<unk> . Over 10 studies have confirmed that the sensitivity and specificity of this test is 97% and 93% respectively; however, there is still concern for false positive results in the correct clinical scenario. When interpreting a biochemical analysis for<unk> , the provider must pay close attention to the (1) conditions of the collection, (2) all medications the patient is taking, and (3) their diet. # Conditions of Collection: Unlike many routine laboratory tests that can be drawn at a moments notice, there are several recommendations that should be followed to ensure the ideal conditions and an accurate sample. Current research indicates that blood work should only be drawn after a patient has been resting supine (flat on their back) for 30 minutes before collection. Specific supine reference values should be used in this scenario. Ensuring these conditions is difficult and may be cost-prohibitive at most institutions. In these cases, a rested, supine draw can be repeated following a positive result in a seated position to eliminate false-positive results. # Pharmaceutical Interference: Many prescription, over-the-counter, and illicit substances can interfere with the proper collection of plasma metanephrines and lead to false-positive results. Providers should review a patient's medication list in-detail and have a discussion if temporarily discontinuing any of the interfering medications is possible. The most reported medications to result in falsely elevated metanephrines include: β-adrenoceptor blockers, phenoxybenzamine, tricyclic antidepressants, monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors (SNRI), and methyldopa. As the majority of these medications are commonly prescribed for psychiatric conditions, a conversation with the prescriber may be necessary to facilitate alternative therapeutic options while the patient is undergoing evaluation for a<unk> . After any possible prescription medications have been held, it is important to review any over-the-counter medications/supplements as well as the commonly used acetaminophen and pseudoephedrine cause false elevations in metanephrine levels. Finally, it is important to have open, non-judgemental discussions about the patient's recreational substance use. Amphetamines, nicotine, and cocaine can result in marked plasma norepinephrine levels. # Lifestyle and Diet: As with most lab work, the patient should refrain from eating (fasting) after midnight the night prior to their collection. However, there are further recommendations specific to a metanephrines collection, including abstaining from nicotine, alcohol, and exercise for at least 12 hours prior to their lab draw. Patients should also avoid catecholamine-containing foods (fruits, fruit drinks, chocolate, caffeine, tomatoes, beans, nuts, and potatoes) for a minimum of 24 hours prior to collection. While the above (3) conditions are likely to contribute to false-positive results if not controlled for, any value greater than 3 to 4 times the upper reference limit of normal should be considered diagnostic for a<unk> . Alternative tests Twenty-four hour urinary metanephrines are an acceptable alternative if the plasma test is unavailable. Other additional biomarkers can be helpful to aid in the diagnosis of<unk>  as well, most notable is Chromogranin A. In comparison to the specificity of elevated catecholamines in the<unk>  patient, chromogranin A is a non-specific polypeptide that is high in a variety of neuroendocrine tumors. However, a 2006 report from Italy found that over 90% of studied<unk>  patients demonstrated elevated chromogranin A levels. If metanephrine values are equivocal, chromogranin A can be used as an adjunct marker to predict the presence of a tumor. Borderline elevated metanephrines present a diagnostic challenge to the physician - the first step is to repeat the labs, taking extra precautions to follow the gold standard diagnosis described above, including the conditions of collection, pharmaceutical interference, and any potential diet and lifestyle habits that could alter the results. If the offending medications cannot be discontinued or repeated labs remained the same, consider administering a clonidine suppression test. In the 1970s, the drug clonidine hydrocloride swept the market as a novel agent for hypertension; however, the reported side-effects (nausea, vomiting, drowsiness, dryness of the eyes and mouth, constipation, and generalized weakness) limit compliance and have vastly diminished prescriptions. While the adverse side-effects with clonidine are inconvenient, the most dangerous aspect of clonidine is withdrawal rebound hypertension - that is, when the medicine is abruptly discontinued, blood pressure may rapidly return or surpass the original value. However, a one-time, weight-based dose can be utilized in limited settings to help determine disease status. After fasting overnight, patient's will present to their testing site for a baseline metanephrines blood draw and clonidine administration. They will remain supine for (3) hours and a repeat blood draw will be taken. A positive result (indicating a<unk>  will occur if the plasma metanephrine levels remain elevated after clonidine is given. If the results are the same or fall, the test is negative and the patient does not have a<unk> . It is important to note that if a patient does not have a<unk> , they may become extremely hypotensive following clonidine. Patients should not depend on themselves for transport following this test. Plasma methoxytyramine is a breakdown product of the catecholamine, dopamine. Paragangliomas of the head and neck commonly secrete dopamine, but are referred to as "biochemically silent" because they do not cause the characteristic symptoms associated with a<unk> . However, methoxytyramine can be utilized to detect the tumors of the head and neck. Further research indicates that the biomarker is also a useful indicator of metastatic disease - which is the only current biochemical evidence of metastases to date. Biochemical phenotypes Structure of epinephrineWhile diagnostic, laboratory values can also provide physician's with important information about the type, location, size, and associated tumor genotype. There are (3) major, well-recognized biochemical phenotypes that can be used by health care providers to direct patient care. # Adrenergic (Epinephrine and metanephrine) #* More likely to indicate an adrenal tumor #* When plasma metanephrine levels were elevated to greater than 15% of the combined levels of normetanephrine and metanephrine, an adrenal tumor or a recurrence of an adrenal tumor that had already been excised can be predicted #* Patients are more likely to present with the classic, paroxysmal (episodic) symptoms described above # Structure of norepinephrineNoradrengeric (Norepinephrine and normetanephrine) #* More likely to indicate an extra-adrenal tumor #* Patients are more likely to present with continuous, persistent<unk> -related symptoms (hypertension and tachycardia) compared to those that are classically episode with an adrenergic phenotype #* Common in patients with von-Hippel Lindau and succinate dehydrogenase subunit X genetic variants # alt=Dopaminergic (Dopamine and 3-methoxytyramine) #* More likely to indicate an extra-adrenal tumor of the head and neck #* Patients are more likely to be asymptomatic; however, they may present with non-specific signs of nausea, vomiting, abdominal pain, diarrhea, and weight loss secondary to the stimulation of dopamine receptors throughout the gastrointestinal tract #* Particularly prevalent in patients with succinate dehydrogenase subunit B genetic variants Across both an adrenergic and a noradrenergic phenotype, the greater the sum of plasma or urinary concentrations of metanephrine and normetanephrine, the larger the expected tumor diameter. Tumor localization Anatomic imaging Anatomic imaging refers to computed tomography (CT) CAT scan or magnetic resonance imaging (MR) scans. These imaging modalities serve to initially locate the tumor and provide detailed information about size, morphology, and structural relation to adjacent internal structures. Traditionally, a patient presents to their physician for symptoms concerning for a<unk> , which prompts a biochemical evaluation. If the results are positive, the patient is referred for anatomic imaging with a CT or MR scan. However, as anatomic imaging becomes more readily available, patients are referred to an endocrinologist after an incidental (unanticipated finding) adrenal nodule is found on a scan ordered for another reason. For example, "Patient M" presents to his local emergency room for abdominal pain and a CT is ordered to rule-out appendicitis; however, the radiologist notes there is a 3.5 centimeter right adrenal mass. While there has not been a consensus on if CT or MR is the preferred imaging modality in<unk> , each method has its associated strengths and weaknesses. As CT expose the patient to ionizing radiation, MR is preferred in children and pregnant women. Furthermore, the intravenous contrast used in CT can cause kidney damage and should therefore be avoided in patients with pre-existing damage. However, patients who struggle with being in confined spaces for extended periods of time (claustrophobia) cannot often tolerate an MR as the machine is close-ended compared to the open-ended design of a CT. When patients become anxious and begin
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