Diagnosis of Pheo / Para...
Biochemical diagnosis of pheochromocytomas and paragangliomas: A guide for patients in 2012
Graeme Eisenhofer PhD, Professor & Chief, Division of Clinical Neurochemistry, Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, University Hospital Dresden, Dresden, Germany
What are pheochromocytomas and paragangliomas? Pheochromocytomas are tumors that arise from the adrenal glands, which sit atop each kidney. Paragangliomas are tumors that arise from similar cells, but at non-adrenal gland locations; they most commonly occur in the abdomen, but can also develop in the chest, head and neck. Both types of tumors are usually suspected because of effects produced by secretions of certain hormones, called catecholamines. Secretion of catecholamines by the tumors causes increases in blood pressure and a wide range of symptoms (e.g., headaches, sweatiness, palpitations, anxiety, panic attacks).
What are catecholamines? There are three catecholamines, the most well known of which is adrenaline (epinephrine) formed almost entirely in the adrenal glands. The other catecholamines include noradrenaline (norepinephrine) and dopamine. Noradrenaline is secreted mainly by nerves that go to the blood vessels, heart and other organs. Noradrenaline is also formed in the adrenal glands where it is converted to adrenaline. Dopamine is the building block catecholamine from which noradrenaline is formed.
Which catecholamines are formed by what tumors? The three catecholamines are formed within tumors in different amounts depending on tumor type. About a half of all pheochromocytomas produce both adrenaline and noradrenaline in various proportions, while the other half produce only noradrenaline. In contrast, most paragangliomas secrete only noradrenaline, but others produce both dopamine and noradrenaline in varying amounts, including some that produce only dopamine. Other paragangliomas, particularly those of the head and neck, produce no catecholamines.
Which catecholamines cause what effects? It is only the tumors that produce adrenaline, noradrenaline or both catecholamines that cause increases in blood pressure and symptoms such as headaches, sweatiness, and palpitations. Tumors that produce only dopamine, as well those that produce no catecholamines, do not cause high blood pressure or the usual symptoms. However, some tumors that produce adrenaline or noradrenaline do not secrete the hormones in large enough amounts to produce increases in blood pressure or symptoms of catecholamine excess. Such tumors and tumors that produce only dopamine are usually found for other reasons.
What biochemical tests are used for diagnosis of pheochromocytomas and paragangliomas? Biochemical tests used for diagnosis of pheochromocytomas and paragangliomas include measurements in blood or urine of the catecholamines and various breakdown products (metabolites) of the catecholamines. The metabolites most commonly measured include normetanephrine, the breakdown product of noradrenaline, and metanephrine, the breakdown product of adrenaline. These two metabolites, normetanephrine and metanephrine, are commonly referred to in the plural form as the “metanephrines”. It is incorrect to refer to these metabolites in their single form as “normetanephrines” and “metanephrines”. In addition to normetanephrine and metanephrine, some laboratories also measure methoxytyramine, which is the breakdown product of dopamine. Another biochemical test still offered by some laboratories involves measurements in urine of vanillymandelic acid (commonly referred to as VMA), which represents the final major breakdown product of both noradrenalne and adrenaline. Measurements of plasma chromogranin A (CgA) are another test sometimes used to diagnose pheochromocytomas and paragangliomas. Chromogranin A is not a catecholamine or a catecholamine metabolite, but is secreted by the same cells that secrete catecholamines.
What biochemical tests are recommended for diagnosis of pheochromocytomas and paragangliomas? It is recommended that initial testing for pheochromocytomas and paragangliomas always include measurements of either or both urine or blood levels of metanephrines.
Why are measurements of catecholamines by themselves not recommended for biochemical diagnosis? The catecholamines formed in nerves, adrenal glands or in pheochromocytomas and paragangliomas are packaged and concentrated within cells in very tiny bag-like structures known as storage vesicles. The catecholamine contents of these storage vesicles are normally secreted by nerves to control blood pressure and the beating of the heart or they are secreted by the adrenal glands in response to stress. Pheochromocytomas and paragangliomas also can secrete catecholamines, but these secretions are not controlled and some tumors do not always secrete catecholamines. In the latter situation catecholamines in urine and blood will be normal and their measurements will fail to show up a tumor. This is called a false-negative test result, which is not good for patients with the tumors since the tumors will remain undetected. These tumors nevertheless are still highly dangerous, since secretion of catecholamines by the tumors can be provoked under certain situations (e.g., childbirth, accidents, surgery, certain medications), resulting in dangerous increases in blood pressure or even death.
Why are measurements of metanephrines recommended for diagnosis? As outlined above the catecholamines formed in nerves, adrenal cells and pheochromocytoma or paraganglioma tumor cells are packaged in a highly concentrated form within tiny bag-like structures called storage vesicles. These storage vesicles are slightly porous and constantly leak catecholamines into the fluid inner contents (cytoplasm) of the cells. High concentrations of those catecholamines inside this cellular fluid is not good for the cells. The cells therefore have ways of dealing with this by breaking down the catecholamines into metabolites. It is because of this that most initial metabolic breakdown of catecholamines occurs in the same cells in which the catecholamines are formed. Metabolic breakdown also occurs after secretion from the cells, but the initial metabolic breakdown of catecholamines after release by cells is relatively minor compared to the metabolism within the cells. Importantly, the breakdown of catecholamines within pheochromocytoma and paranganglioma cells occurs by a process that produces the metanephrines. These metabolites of the catecholamines are therefore formed continuously within the tumors cells. Since this process is independent of catecholamine release, measurements of the metanephrines provide advantages for diagnosis compared to catecholamines. As outlined above the catecholamines may not always be secreted by tumors. In such situations measurements of catecholamines will not show that a pheochromocytoma or paraganglioma is present, whereas the metanephrines formed continuously with tumors cells will be elevated and thus show the presence of a tumor.
What about urine vanillymandelic acid - VMA? Catecholamines undergo many sequential steps during their metabolic breakdown. Formation of metanephrines is just one of three initial of the sequential steps that lead to formation of VMA, which is the final metabolic breakdown product of both noradrenaline and adrenaline. VMA is formed almost totally in the liver, in part from metanephrines extracted from blood by liver cells, but mainly from different breakdown products formed in the nerves that control blood pressure and heart function. Therefore, VMA does not provide a good test for diagnosis of pheochromocytomas and paragangliomas and is no longer recommended for this purpose.
What about chromogranin A - CgA? CgA is secreted like the catecholamines from the same storage bags (vesicles) that contain the catecholamines. Therefore, like the catecholamines blood levels of CgA can also be normal when tumors are not secreting the contents of the vesicles. Nevertheless measurements of CgA can be useful under certain circumstances, some of which are outlined later.
How do measurements of metanephrines in urine and blood differ? The metanephrines measured in urine are in fact largely different metabolites from the metanephrines measured in plasma. The metanephrines released into the bloodstream from catecholamine-producing tumors are further metabolized in other parts of the body by addition of a sulfate group. This makes the metabolites more easy to excrete into urine. Nevertheless, measurements of metanephrines in urine are nearly as good measurements in blood for diagnosis. Some clinicians prefer the urine test and others the blood test. The blood test has advantages in certain situations, but is not always available and at some places may not be as reliable as the urine test. In the United States measurements of metanephrines are now usually carried out by good modern methods involving mass spectrometry. It can be useful to find out what measurement methods are used. If measurements are by high pressure liquid chromatography or involve mass spectrometry then they are likely to be reliable.
For testing in common circumstances involving high blood pressure and symptoms suggestive of a catecholamine-producing tumor, testing can be carried out by any qualified clinician with an up-to-date knowledge of endocrine tumors and access to a good laboratory for biochemical measurements of blood or urine for metanephrines. For other patients, such as those requiring individualized attention as outlined above, testing is best done at specialist centers with staff experienced in hereditary causes of pheochromocytomas and paragangliomas, as well as how to best follow-up affected patients and others with a previous history of the tumors. Referral to specialist centers in cases of positive test results can also facilitate more efficient follow-up testing in order to better confirm and then locate tumors. Treatment of patients and particularly their pre- to post-surgical care is best undertaken by staff experienced with all recommended approaches, such as laparascopic surgical removal and adrenal sparing surgery where this may be indicated.
