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The catecholamines (dopamine, epinephrine, and norepinephrine) are derived from tyrosine via a series of enzymatic conversions. All 3 catecholamines are important neurotransmitters in the central nervous system and also play a crucial role in the autonomic regulation of many homeostatic functions, namely, vascular tone, intestinal and bronchial smooth muscle tone, cardiac rate and contractility, and glucose metabolism. Their actions are mediated via alpha and beta adrenergic receptors and dopamine receptors, all existing in several subforms. The 3 catecholamines overlap, but also differ in their receptor activation profile and consequent biological actions. The systemically circulating fraction of the catecholamines is derived almost exclusively from the adrenal medulla, with small contributions from sympathetic ganglia.
The catecholamines are normally present in the plasma in minute amounts, but levels can increase dramatically and rapidly in response to change in posture, environmental temperature, physical and emotional stress, hypovolemia, blood loss, hypotension, hypoglycemia, and exercise.
In patients with pheochromocytoma (a potentially curable tumor of catecholamine-producing cells of the adrenal medulla), or less commonly of sympathetic ganglia (paraganglioma), plasma catecholamine levels may be continuously or episodically elevated. This results in episodic or sustained hypertension and in intermittent attacks of palpitations, cardiac arrhythmias, headache, sweating, pallor, anxiety, tremor, and nausea. Intermittent or continuous elevations of the plasma levels of 1 or several of the catecholamines may also be observed in patients with neuroblastoma and related tumors (ganglioneuroblastomas and ganglioneuromas) and, very occasionally, in other neuroectodermal tumors.
At the other end of the spectrum, inherited and acquired syndromes of autonomic dysfunction or failure and autonomic neuropathies are characterized by either inadequate production of 1 or several of the catecholamines or by insufficient release of catecholamines upon appropriate physiological stimuli (eg, change in posture from supine to standing, cold exposure, exercise, stress).
Diagnosis of pheochromocytoma and paraganglioma, as an auxiliary test to fractionated plasma and urine metanephrine measurements (plasma metanephrine is the preferred test for this diagnosis)
Diagnosis and follow-up of patients with neuroblastoma and related tumors, as an auxiliary test to urine vanillylmandelic acid and homovanillic acid measurements
Evaluation of patients with autonomic dysfunction or failure or autonomic neuropathy
Diagnosis of Pheochromocytoma:
This test should not be used as the first-line test for pheochromocytoma, as plasma catecholamine levels may not be continuously elevated, but only secreted during a "spell." By contrast, production of metanephrines (catecholamine metabolites) appears to be increased continuously. The recommended first-line laboratory tests for pheochromocytoma are:
-PMET / Metanephrines, Fractionated, Free, Plasma: the most sensitive assay
-METAF / Metanephrines, Fractionated, 24 Hour, Urine: highly specific and almost as sensitive as PMET
However, plasma catecholamine measurements can still be useful in patients whose plasma metanephrine or urine metanephrine measurements do not completely exclude the diagnosis. In such cases, plasma catecholamine specimens, if drawn during a "spell," have a 90% to 95% diagnostic sensitivity when cutoffs of >750 pg/mL for norepinephrine and >110 pg/mL for epinephrine are employed. A lower value during a "spell," particularly when plasma or urinary metanephrine measurements were also normal, essentially rules out pheochromocytoma. Unfortunately, the specificity of these high-sensitivity cutoff levels is not good for separating tumor patients from other patients with similar symptoms. When more specific (95%) decision levels of 2,000 pg/mL for norepinephrine or 200 pg/mL for epinephrine are used, the assay's sensitivity falls to about 85%.
Diagnosis of Neuroblastoma:
Vanillylmandelic acid, homovanillic acid, and sometimes urine catecholamine measurements on spot urine or 24-hour urine are the mainstay of biochemical diagnosis and follow-up of neuroblastoma. Plasma catecholamine levels can aid diagnosis in some cases, but diagnostic decision levels are not well established. The most useful finding is disproportional elevations in 1 of the 3 catecholamines, particularly dopamine, which may be observed in these tumors.
Diagnosis of Autonomic Dysfunction or Failure and Autonomic Neuropathy:
Depending on the underlying cause and pathology, autonomic dysfunction or failure and autonomic neuropathies are associated with subnormal resting norepinephrine levels, or an absent rise of catecholamine levels in response to physiological release stimuli (eg, change in posture from supine to standing, cold exposure, exercise, stress), or both. In addition, there may be significant abnormalities in the ratios of the plasma values of the catecholamines to each other (normal: norepinephrine>epinephrine>dopamine). This is observed most strikingly in the inherited dysautonomic disorder dopamine-beta-hydroxylase deficiency, which results in markedly elevated plasma dopamine levels and a virtually total absence of plasma epinephrine and norepinephrine.
Catecholamines in plasma are chemically labile and the specimens must be handled carefully, both because of rapid specific metabolism and rapid oxidation on exposure to air. For example, plasma-free norepinephrine has a half-life of approximately 2 minutes. To enhance accuracy, one must pay careful attention to the circumstances of specimen collection and to the preparation of the patient (see Specimen Required).
Many alterations in physiologic and pathologic states can profoundly affect catecholamine concentrations.
Any environmental factor that may increase endogenous catecholamine production should be avoided. These include noise, stress, discomfort, body position, and the consumption of food, caffeinated beverages, or nicotine. Caffeine and nicotine effects are short term, a few minutes to hours only.
Other substances and drugs that may also affect the results include:
1. Substances that result in increased release or diminished metabolism of endogenous catecholamines
-Monamine oxidase inhibitors (MOIs): a class of antidepressants with marked effects on catecholamine levels, particularly if the patient consumes tyrosine rich foods, such as nuts, bananas, or cheese
-Catecholamine reuptake inhibitors including cocaine and synthetic cocaine derivatives, such as many local anesthetics, some of which are also antiarrhythmic drugs (eg, lidocaine)
-Some anesthetic gases, particularly halothane
-Withdrawal from sedative drugs, medical or recreational, in particular alcohol, benzodiazepines (eg, Valium), opioids and some central-acting antihypertensive drugs, particularly clonidine, but, generally not cannabis or other hallucinogens such as lysergic acid diethylamide (LSD), mescal, or peyote
-Vasodilating drugs (eg, calcium antagonists, alpha-blockers)
-Tricyclic antidepressants usually exert a negligible effect
2. Substances that reduce or increase plasma volume acutely (eg, diuretics, radiographic contrast media, synthetic antidiuretic hormone [eg, desmopressin 1-deamino-8-d-arginine vasopressin: DDAVP])
3. Drugs that are metabolized to endogenous catecholamines. In the main, this concerns carbidopa and L-dopa. These drugs are converted to dopamine, and dopamine measurements in patients taking these drugs will be artifactually elevated. Since isolated dopamine elevations are extremely rare, they should always be viewed with suspicion. A review of the HPLC trace should be requested. On a careful review, our methodology usually, but not always, allows us to identify the unmetabolized parent drug, alongside dopamine.
Historically, a third category of potentially interfering substances was represented by molecules that are either similar in chemical structure, antibody epitopes, or chromatographic migration pattern to the catecholamines, or have metabolites that can be mistaken for the catecholamines. The current HPLC-based assay is not subject to any significant direct interference of this kind. In particular, the following drugs, which used to be considered potential interferences, do not cause problems that cannot be resolved, in most cases, with the current assay: acetaminophen, allopurinol, amphetamines and its derivatives (methamphetamine, methylphenidate [Ritalin], fenfluramine, methylenedioxymethamphetamine [MDMA: ecstasy]), atropine, beta-blockers (atenolol, labetolol, metoprolol, sotalol), buspirone, butalbital, carbamazepine, chlorazepate, chlordiazepoxide, chlorpromazine, chlorothiazide, chlorthalidone, clonidine, codeine, diazepam, digoxin, dimethindene, diphenhydramine, diphenoxylate, dobutamine, doxycycline, ephedrine and pseudoephedrine, fludrocortisone, flurazepam, guanethidine, hydralazine, hydrochlorothiazide, hydroflumethiazide, indomethacin, insulin, isoprenaline, isosorbide dinitrate, L-Dopa, methenamine mandelate (mandelic acid), methyldopa, methylprednisolone, nitrofurantoin, nitroglycerine, oxazepam, pentazocine, phenacetin, phenformin, phenobarbital, phenytoin, prednisone, probenecid, progesterone, propoxyphene, propranolol, quinidine, spironolactone, tetracycline, thyroxine, and tripelennamine.
On occasion, when interference cannot be resolved an interference comment will be reported.
The variability associated with age, gender, and renal failure is uncertain.
Supine: 70-750 pg/mL
Standing: 200-1,700 pg/mL
Supine: < or =111 pg/mL
Standing: < or =141 pg/mL
<30 pg/mL (no postural change)
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2. Hernandez FC, Sanchez M, Alvarez A, et al: A five-year report on experience in the detection of pheochromocytoma. Ann Intern Med 2000;33:649-655
3. Pacak K, Linehan WM, Eisenhofer G, et al: Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 2001;134:315-329
4. Alexander F: Neuroblastoma. Urol Clin North Am 2000;27:383-392
5. McDougall AJ, McLeod JG: Autonomic neuropathy, I. Clinical features, investigation, pathophysiology, and treatment. J Neurol Sci 1996;137:79-88
6. Lenders JW, Pacak K, Walther MM, et al: Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002;287:1427-1434