Welcome and thank you for joining us today. I'm here today with Dr. Jaap Lenders and Dr. Christina Pomperocchi, who I will introduce them in a few minutes. My name is Rochelle Michette.
I'm moderating today's webinar and the data manager at the University of New Mexico's Cancer Research Center, but I am here today as a patient and a volunteer. My personal story with theocomocytoma, or Theo as I will reference it, started about two years ago. I went to the emergency room with really intense abdominal pain.
And they did a scan and they found a tumor on my adrenal gland. And they did another scan probably a week later to rule out metastatic tumor. And then it took eight months to see an endocrinologist because we have a provider shortage here in New Mexico where I live. And she ordered...
blood and urine test because I was symptomatic. So I was having kind of anxiety episodes and then heart palpitations. So my plasma results or blood results were quote borderline.
So we retested and my normetinephrine, which is a metabolite of Norepinephrine or adrenaline was a little less than two times the upper limit both times that we tested it even though the second time I had waited until I was having an episode and after that she called me and we talked and she said you know you probably just have high levels of norepinephrine maybe that's just how you're designed and when I got off the phone I was Really distraught and thought about it and then I sent her a long letter or message saying that I didn't agree and that my body didn't feel like it was mine probably a quarter of the time and so she listened to me and then she ordered a functional test imaging sorry called an MIBG and then when that we got the results. She thought that that was pretty clear. So we immediately scheduled time with a surgeon in the area who was known for doing adrenalectomies and he's done the most PEO surgeries that we know of in New Mexico.
So I was admitted into the hospital about five days before surgery to safely increase the pre-op medication because I did not have high blood pressure. I had lower levels of blood pressure, which is kind of, I presented differently, I think, than a lot of patients in that regard. And then while I was in the hospital, the surgeon had to consult with the hospital system endocrinology team because my endocrinologist was out of the UNM hospital system.
And they felt, that team felt that I did not have pheochromocytoma because of my blood tests were only less than two times the upper limit. And I actually considered not having the surgery. It's kind of a scary thing to do. But I went ahead with it and I'm glad that I did because it was confirmed.
A week or so after the surgery, the pathology report came back that it really was a pheochromocytoma tumor, and it was about a little bit less than three centimeters. So glad I decided to do that. I later discovered that the lab used the incorrect protocol.
And so that's... Part of the reason I'm here today is because I have a vested interest in getting the best, most up-to-date information out there for providers, patients, and labs to diagnose as many of these very serious diseases as possible. This program is brought to you by the Theopara Alliance. It is to empower patients with pheochromocytoma or paraganglioma, their families and medical professionals through advocacy, education, and a global community of support while helping to advance research that accelerates treatment and cures.
Special thanks to Lanthea's Progenics for making the webinar series possible through an educational grant. We have four upcoming announcements. Our next monthly peer support meeting will be on Tuesday, July 11th at 7 30 p.m. Eastern, 4 30 Pacific. Our next educational webinar entitled Five Years Since Azedra FDA Approval, What Have We Learned?
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Our agenda is... Dr. Lenders and Pamparaki will present for about 30 minutes, then followed by Q&A from the community. We'll first ask questions submitted before the WMADOC, then you can also type in your questions into the chat section here, and we'll do our best to have all the questions answered if time allows. Many people ask variations of the same questions, so listen carefully for questions that are similar, questions that are less... case-specific are appreciated.
So the more general, the better. Disclaimer, this content and the content of this and all episodes of the education webinar series is not influenced by our sponsors and is presented by independent healthcare professionals. The information presented on this webinar is for educational purposes only and should not substitute the advice of your doctor.
or medical team because they have in-depth knowledge of your medical history and current situations. Now I'd like to introduce our expert presenters. Jacques Lenders received his medical degree in 1975 at Radboud University in Nijmegen, the Netherlands. After training as an internist, he joined the staff at the Department of General Internal Medicine at Radboud University Medical Center. While working as a visiting associate at the National Institute of Health in 1992, he developed, along with Dr. Graham Eisenhofer, an assay for measurements of plasma-free metanephrines as a diagnostic test for pheochromocytoma.
Upon his return to Nijmegen as a staff member, he focused his research on diagnostic and clinical aspects of catecholamine-producing tumors and became one of the founders of Radboud Adrenal Center. In addition, from 2009 until January of 23, he worked as a part-time affiliate staff member of the Department of Internal Medicine, University Medical Center Gustav Chares, Dresden, Germany. His many additional contributions to the medical world include initiating the Working Group on Endocrine Hypertension of the European Society of Hypertension, And serving as a member of the executive board of Pheochromocytoma Research Support Organization, he has co-authored over 300 research articles, reviews, and book chapters, recently served as chairman of the first Pheochromocytoma Paraganglioma Clinical Practice Guideline Task Force of the Endocrine Society, and is immediate past chair of the PheoPara Alliance Medical Advisory Board.
Dr. Lenders is currently Professor Emeritus of Internal Medicine at Radboud University Medical Center. Christina Pomperocchi received her medical degree in 2010 from the University of Janina School of Medicine, where she went on to specialize in internal medicine, endocrinology, and diabetes. She is author of numerous research papers and several book chapters and holds, along with Dr. Graham Eisenhopper and others, two patents. Dr. Pamparaki has more than 10 years of clinical experience, most of which has focused on endocrinology. She currently holds the position of Senior Endocrinologist at University Hospital Karl Gustav Chares, Dresden, Germany, where she also serves as the Head of Clinical Research Adrenal Unit.
Dr. Lenders and Dr. Pamparaki, welcome. Hello, thank you very much for the very kind invitation. And we are very happy that we have the opportunity to discuss with you today the biochemical testing for pheochromocytoma and paranglioma. And I will share this session with Professor Lenders.
So I cannot see my slides. Yes, perfect. So we can go to the first slide. So this presentation of 30 minutes will be focused on the questions that you have sent to us.
And after the presentation, we will have the opportunity to discuss these and other questions that you may have. And some of these questions that you have already sent to us are shown in this slide. In particular, you have asked us how if we should measure catecholamines or metanephrines to detect pheochromocytoma.
If we should measure metanephrines in blood or urine, how should we collect blood and urinary samples? You were also interested in knowing if medication can affect the results, the concentrations of the metabolites. You were also interested in the upper cutoffs, in the reference values, if there are some specific reference values, if they have age adjusted.
In addition, you also were wondering about if the diagnostic test that we are currently using has a good diagnostic performance. In other words, if it is a reliable test to use. And finally, you wanted to ask us how we should follow up patients with slightly elevated test results or patients that follow up programs after an operation of an adrenal tumour. So you probably all know that pheochromocytomas and paragangliomas, we usually also call them PPGLs, are neuroendocrine tumors that secrete catecholamines.
As you can see in this slide, catecholamines are the dopamine, norepinephrine and epinephrine. Most of the paragangliomas and pheochromocytomas secrete their catecholamines in a periodical way, in an episodic, paroxysmal way. not always in the same, not continuously. However, catecholamines are metabolized in the ketoplasm of the chromaffin cells in a continuous way, independent of the catecholamines. So we have the metanephrines, and these metanephrines are 3-methoxytiramine, normetanephrine, and metanephrine.
We can measure metanephrines in blood either as free or conutated. metanephrines. The conjugated metanephrines are formed by the free metanephrines by the action of a specific enzyme that is located in the gastrointestinal tract. There are some differences between the free and the congenitative metanephrines, but we will discuss them later on.
I would also like to just say that in urine, we can measure free metanephrines or fractionated metanephrines. The fractionated metanephrines is the combination of the free and the commutative metanephrines together. So your first question was should we measure catecholamines or metanephrines? This question is easy to answer.
As I said before catecholamines are secreted episodically, paroxysmally, but metanephrines are produced by the metabolism of catecholamines in a continuous way. So it is a superior metabolite to a diagnosed PPGL. Currently, the Endocrine Society Guideline indicates clearly that we should measure metanephrines for the diagnosis of PPGL, and catecholamines are not routinely used.
So the next question is where we should measure this metanephrines. This metanephrines can be measured either in blood or urine. In blood, we measure the free metanephrines, and this is important.
because the con the conutated metanephrines that i have previously shown you have not such good diagnostic performance as the free metanephrines and this is because the free metanephrines are mainly from formed in the chromaffin cells where the conutative metanephrines also reflect origins from the gastrointestinal tract with other words are not so specific for chromaffin cells in addition the conutative metanephrines are cleared by the kidneys and are much more influenced by the kidney function than the free metanephrines. In urine, now we can measure either free or fractionated metanephrines. We usually measure 24-hour urine samples, but in some cases, such as in young children, where the urinary collections are very troublesome, we can also measure spot urine taken in the morning as the overnight samples.
So another question that you had was how to collect blood for metanephrines. There is too much information out there. So should we measure raw blood in a seated or in a supine position?
And if we are supine, how long should we stay in this position? So is there a specific way to collect our tubes? And should we have precautions for food? Should we be careful what to eat or not to eat?
So it is very important to know these details because pre-analytical precautions can indeed minimize false positive results. So according to the endocrine society guidelines we should draw blood samples after at least 20 minutes of supine rest using an intravenous cannula. It is also important that when the blood is drawn it should be kept on ice and directly go to the lab. We should avoid measuring these metabolites when we are sick, under emotional stress, under hypertensive crisis or in an emergency because there is the risk for false positive results. And finally, with regards to the diet, we should know that dietary catecholamine has an negligible effect on plasma or metanephrines.
So we should not worry too much, especially when we measure blood, if we have eaten something. But if we include in the panel the other third metabolite, 3-methoxytyramine, then indeed dopamine products, tyramine products can increase the levels of 3-methoxytyramine. And the easiest way to go is to instruct.
We instruct our patients to fast overnight and or if it is not possible to avoid these products that may influence this metabolite. Now in urine, we collect urinary samples without any need for acids or preservative agents, as was the case for catecholamine. So we don't need to do any preparation in the bottles. However, it is important that we know that we need the whole 24-hour urine collection, not to start in the noon and until morning or overnight.
So it is important to collect. correctly our samples. It is also important that we avoid vigorous exercise and again it is important to know what kind of metanephrines are going to be measured. In case we measure free metanephrines in urine then we shouldn't worry about diet but if we measure fractionated metanephrines then indeed we should be more careful and avoid amine rich products. If in some cases 24-hour urine collections are troublesome as I already indicated before as in young children then in this case we can also have spot urine in the morning when we wake up but we should be very careful as Professor Lenders will explain you later because in such cases we need specific reference intervals.
So many people argue why is the supine position for the plasma measurement so important? We have data that have shown that transition from the seated to the supine position can lead to a time-dependent decline of catecholamines, as you can see in the first two figures, but also a decline of metanephrines, as you can see in the second two figures. And there is a plateau or the steady niveau after 20 or 30 minutes of supine rest.
So it is important that we stay supine for at least 20 minutes. And it is important because we indeed can reduce significantly false positive results. So to sum up what we have already discussed.
What are the advantages of the blood sampling and what are the disadvantages of the blood sampling? The blood samples, as is important to know, that have a little bit higher diagnostic performance than the urinary samples, as already shown in a very big prospective clinical trial. So overall have a little bit higher diagnostic performance than urine. And this is specifically important for patients that are tested due to known genetic disease or due to previous history of PPGR, so pheochromocytoma and paraganglioma. Blood sampling has also other advantages.
For instance, in blood, we can also include methoxytyramine, this third metabolite that I have initially shown you. Whereas in urine, we cannot use methoxytyramine. In addition, the plasma samples are also preferred in patients with advanced chronic kidney disease. So there are lots of advantages in the blood sampling. And of course, it's much more convenient for the patient rather than 24-hour urine collections.
On the other hand, blood sampling has also disadvantages. For instance, it is not very easy to stay 20 minutes in supine rest and it's also not convenient. The clinical settings may not have this infrastructure and enough room for everybody so that they can take samples after 20 minutes of supine rest. In addition, it is not a good biomarker to measure when we are under emotional or physical stress if we have needle phobia, especially among children.
So in such cases, if we cannot follow the precautions, it's better to use the urinary samples. Now, let's go to the urinary metanephrines. What are the advantages? Exactly the fact that if we have needle phobia or stress or physical stress, it's better to measure 24-hour urine than blood. It's also more convenient in some clinical settings that do not have places to measure all patients.
after 25-20 minutes of supine rest. Among the disadvantages of the urinary collections are the fact that have a little lower diagnostic performance than the plasma, that we cannot add methoxy tyramine. Methoxy tyramine in urine is useless. Of course it's a little bit troublesome to gather the samples 24 hours, especially if we have children.
And finally, urinary samples, as I already mentioned, are not at all reliable in... patients with advanced chronic kidney disease. And perhaps I already mentioned, with urine samples, we usually deal with incomplete collections, which is also not appropriate. So the next question we had from you is medication. How do they affect our results?
First of all, there are medications that can influence our analytical methods. I will talk about it right away. And secondly, there are medications that they can have a pharmacodynamic actions on the catecholamine systems, and this will follow in the next slide. When we measure plasma-free metanephrines, the gold standard method to measure these metabolites is liquid chromatography with tandem mass spectrometry, this LC-MS that you see in the second part of the table.
This method, liquid chromatography with tandem mass spectrometry, is a method. that it's mostly free from analytical interferences. So we shouldn't worry too much.
There are also, there are only some minor reports that specific medication like midodrine or a specific derivate of amphetamine that can influence metanephrines in plasma. So theoretically for plasma-free metanephrines, when we use the appropriate assay, which is the liquid chromatography with tandem aspectometry, we shouldn't worry about medication too much. On the other hand, if we measure urinary metanephrines, then the method that is usually used is this liquid chromatography with electrochemical detection, this LCECD.
These methods are also very good methods, but it's more prone to influences by medication. And we should remember that some medications like acetaminophen or amoxicillin, rifambicin or sulfasalazine or... less often a labitalol, it's a vita blocker, they may influence urinary levels of metanephrine.
So we should be aware of that. And to be honest, also the lab is aware of such interferences. Now let's see how medication can affect pharmacodynamic actions. So indeed, there are medications that apart from influences in the assays, they can pharmacodynamic actions on the sympathetic system, on the catecholamine system.
Here in this slide you can see the most important medication. They are not all of them, but it's the most usually seen, let's say, in clinical setting. And we should be aware that this medication may cause false positive results. What we should do in clinical setting when a patient has such medication?
First of all, wait for the results. If the results are negative, we are fine. We should do nothing.
If the results are positive, then we should... consult with our clinician and then it may be that we should interrupt the medication or replace it with another similar medication that does not have such influences on our metabolites. Okay, thank you very much, Christina.
I will continue and frequently... asked question is and also this time is what cutoff levels or upper reference limits should we use to determine what level of methanephrines is normal or abnormal so how can we decide whether the test result is elevated or not and the question that's related to that is should we when we determine this reference value should we adjust for the age of the patient. And I will show you in this graph the relationship between the age on the x-axis and on the y-axis, plasma and metanephrine, just as an example.
Plasma and metanephrine in a large number of patients without a pheochromocytoma or peregrinoma. And as you can see, the higher the pH, the higher the level of Plasma and NOMAD and never. Without any correction by age, we would use this straight line, this dashed straight line here as the upper cutoff for all ages. But we need to realize, and you can see that here, these are all false positives that will result in false positives of 11% of the patient.
Now, without any correction by age, we would use that straight line. But if we adjust for age and we did that based on the large number of data in the model using this formula that came out of it, we get this curvilinear upper cutoff level until about 60, 65 when it levels off. And.
And if we do that, you can see that the upper cutoff ranges from when you have a kid of five years old, it's about 0.55 nanomoles per liter. But if you go up to 60 or 65, it is about 1.09 nanomoles per liter. So using this adjusted upper cutoff, this curvilinear curve. line here that will result in less false positives not 11 but four percent still false positive but considerably less so this is an important uh issue here and also the answer should we adjust for age yes to determine the the the cut off we should take into account the age of the patient Now to make things a little bit simpler but also a bit less precise, is to calculate cutoff levels for several age classes, as you see here, using this formula.
And this is done from plasma, normatin, nephrin here, and you see here from the age of 5 to 17, 0.55, so it's more discontinuous, it's 1.09. over the age of 65. But at the same time, we need to realize for metanephrine and 3-metoxyethylamine, we do not need to adjust for age. And we have just one cutoff level over all ages, 0.45, 0.11 nanomoles per liter. So only for plasma non-metanephrine, plasma-free non-metanephrine, we need to adjust for age, as you see here.
What about the upper reference limits for urinary metanephrines? Well, I show you now the upper reference limits as we have determined in Dresden for non-metanephrine. 24-hour urine, no metanephrine, metanephrine, and there's a difference between males and female patients in the three, but certainly in the fractionated metanephrines, also a difference.
Males have higher excretion than females. But we need to realize, and that's the disclaimer, these reference values have been established in the Drazen lab in a large population, but nevertheless, this cannot be used in any... any other lab somewhere else in the world.
It will be probably very close, but it's not exactly the same. Before I address the test performance, so how do these tests perform, how is the diagnostic accuracy of these different tests, I first want to discuss how to interpret false negative and false positive test results. A false negative test result is defined as a normal test result in a patient who has a pheochromocytoma.
So it's falsely wrong, false negative. On the other hand, in patients without a pheochromocytoma and you get a positive test result and the patient has no tumor, it is false positive. So an abnormal test result in the patient without the pheochromocytoma. So this is the definitions we need to keep in mind. Now if we do the following sample in the simple cartoon and we have for instance let's say 100 patients with a pheochromocytoma, a proven pheochromocytoma, and we measure plasma metanephrines, urinary pheofractionated metanephrines, a plasma urinary catacholemines, you can see that only very few false negative results in these 100 patients, only two.
It's already seven for the urinary free affectionate metanefranc, and it's even more, sorry, it is even more for plasma urinary catecholamines. So that emphasizes and support the previous conclusion from what Christina said, metanefranc are preferred over catecholamines for the diagnosis of via homosatoma and peregrine bioma. Now what about if we do the same for the false positive test results in 100 patients who have no pheochromocytoma?
Theoretically, ideally, all 100 patients should have normal test results, they should not be positive. But in real practice, in real life, you see there are similar false positive number of test results for plasma metanephylens, urinary free metanephylens, urinary cut claimants. But we have to take to keep in mind that these numbers are based on plasma or blood sampled after supine rest for at least 20 minutes. And if you sample, you don't do this, you take the blood sample in a patient who has a high sympathetic activity, you see you have a much more number of patients with false positive test results.
So this re-emphasizes to take into to keep these pre-analytical instruction at least 20 minutes of supine rest to keep that in practice now this slide summarizes the diagnostic performance how good are these tests plasma versus urinary test of normatin ephraim methanephrine and metoxythera and we consider these three separate metabolites as one test in this case and here you can see that the sensitivity, so this is the 100% minus this is the false negative, so the plasma-free nearly 88%. For urinary-free metanephrines, it's less, 93.4, and just as for urinary fractionated metanephrines. So the sensitivity is slightly better for plasma-free than for urinary methods.
On the other hand, the specificity or let's say the reverse false positive test results, you see there is not much of a difference, at least not between plasma-free metanephrines and urinary-free metanephrines, although it's slightly less in urinary fractionated metanephrines. So if you cannot, if a central is not able to take the plasma-free metanephrines and measure it after at least 20 minutes of supine rest, there's an alternative. measure either free urinary metanephrines or urinary fractionated metanephrines, we are a little bit less, but still can be used as an alternative.
What are the reasons for false negative test results of plasma and urinary metanephrines? Well, first of all, if you don't do the sampling in the correct way, and this applies to both blood and urine, a very small tumours, where you might have false negative test results. And very rarely some tumors do not produce catecholamines and consequently also there's no production of metanephrines.
But that's quite rare that they do not produce anything. What about false positive test results? What is the reason for that? The same if you do incorrect blood sampling. So if you don't take a plasma sample seated, no rest, the patient is hurrying in, come in the clinic, they could not find a parking place for his car, he is stressed and you take a blood sample, there's a high chance you will have a false positive test result.
So all stressful conditions anyway. patients with acute illness. In general, it doesn't make sense to take blood samples in the emergency department when the patient is acutely sick or in the intensive care unit where patients are very sick.
There's a high, very high risk of false positive test results. And finally, as Christine already pointed out, there may be interference of medication. Now there's an important...
important question as always, and that was also very instructive, the story from Rachel. So what to do if the test results are only slightly elevated? That means they are higher than the upper cutoff you see here on the x-axis.
Let me show first the slide. These are a large number of patients with no pheochromocytoma or paraganglioma, and these are patients who have the tumor. And they show you here the fourth increase of normatinephrine above the cutoff.
So this is the cutoff level that is used for these patients. And this is twice the upper cutoff. So that's what Rochelle also said.
Well, her result was less than twice the upper cutoff. So it was somewhere in the gray area here, you see. And as you can see, both patients who have no tumor or patients who have the tumor, There are some patients that have slightly elevated test results, also the patients who have a new tumor, but certainly also the patients who have the tumor.
So this is very important to realize. Now let me see. These are the slightly elevated test results. Now I show you the right panel here.
And that's it. I will take you through this slowly because it's not easy. You see that these patients have all different symbols. And the symbols are explained here.
These are patients, the purple bullets here, are patients who have an elevation in all three metabolites. All three metabolites are elevated. These are the patients two. nomethenephrine and methenephrine are elevated, but this is another patient who has an elevated nomethenephrine and metoxythiramine.
And as you can see here in the numbers, you can see that the patient who has no tumor, well, they are very low, these elevations of these combinations, but if you look at the right side, in the patients who have the tumor, about 70% has an elevation. in at least two or even three metabolites. Now the patient and you see now this single elevations and only normatin ephraim or only metanephrine or only metoxytheramine and again although normatin ephraim is higher than for metanephrine and metoxytheramine in the patients who have no tumor the false positives you can see also that in the patients who have the tumor this is the indicates that nometanephrine is the metabolite that's mostly affected in patients with the tumor.
Less so for metanephrine and metoxytheramine. And these are the patients who were completely negative. So all three were negative. Now, so this led us to conclude that elevations of two or more metabolites, either one of these three possibilities, or an elevation more than... twofold, more than twofold the upper cutoff, these patients have a high probability and that's more than 95, even 99 percent that these patients have a tumor and let's say more than 90 percent of the cases.
So these patients should go to imaging immediately. So finally the last issue. How do we deal with patients after unilateral adrenolectomy?
Now we have to realize that there are not many studies, there are a few studies, two studies that show, that have looked into what is about the plasma and urinary levels of metanephrines in patients who had a previous adrenolectomy. And in general, you could say, grosso modo, 20 to 25%, the levels are lower than in the control group. However, and that's very important, I want to stress that, we have no specific reference limits for patients after adrenolectomy.
So yes, we expect and we can see that the levels are lower, but we do not have specific reference limits for these patients. And there's one solution to this problem because you would say well if you have no reference limits who would you ever know if the patient had a VO in the past and had an adrenalectomy. What will happen in the future? The solution, the only solution is that you follow up these patients in time. So if you follow up these patients closely they will show any relevant increase over time that will go up if there's a recurrence of the tumor but of course this needs follow-up so you can't tell the patient you don't need to come back you have to follow up the patient finally there are two uh algorithms these algorithms and we it was very difficult not to get around to get around uh algorithms but and i i can't discuss them in detail but they are in our endocrine reviews paper which i will show you soon So if you suspect the patient is suspected to have a PPGL, a pheo or paraganglioma, you measure the metabolites, metanephrines and metoxytheramine.
And if all three are normal and the pre-test probability is very low, then you can consider the PPGL as excluded. However, if it's the pre-test probability, the chance, because the patient has a... Huge number of symptoms, typical symptoms, and the suspicion is high, then false negative results are possible, but very rare.
So you need to repeat the results at least. And that's certainly the case for patients who have, let's say, an incidentaloma, who had a previous pheochromocytoma, had a hereditary predisposition to genetic mutation. Now, if there is an elevation in a single metabolite or it's less than twice the upper reference limit, so an elevation in a single metabolite less than twice, again, we have to know what is the pre-test probability that the patient has PPGEL.
And if it's low, repeat it after three to six months. If it's high, the chance is higher that the positive test result you will have a VO and you need to consider a chronidine test if only normatin and ethan is elevated or you go to imaging. If you have an elevation of more than twice the upper reference limit or an elevation of two or more metabolites and irrespective what is the pre-test probability the chance that the patient has a VO is more than 80 percent and proceed to imaging.
So that is in a in a quick And the similar slide you can see here for fractionated urinary metanephrines. And I want to stress here, it's three times the approach left from the single metabolite. And here it's also more than three times or an elevation of both non-metaphyl and metanephrine. So otherwise, it's more or less similar. But you can read this in our recently published review paper in Endocrine Reviews.
where you can find all the details of these follow-ups. So thank you very much and we are happy to take some more questions. Okay, I have the questions that were submitted beforehand. Let's see how many we can get through.
This one is actually from the Facebook group. There's a large population on there. Can you discuss, and it was partly covered, but part of it I don't think was completely covered. Can you discuss when it is appropriate to do supine and upright catecholamines and the significance of a clonidine suppression test for borderline results?
A lot of people are diagnosed with POTS, postural orthostatic tachycardia syndrome, and sometimes it is actually Pheo and vice versa. Would love some discussion on this as a question that is asked a lot. Thank you.
So if I... Zaks, do you want to go over? Yes, yes, please.
So, yes, for some other, let's say, diseases like POTS, you can measure catecholamines. And they might be elevated. And then the question is, are we sure it's POTS or could it be a VEO?
Now, I would say if it is a VEO, or you think it might be a VEO, Then in that case, I would measure metanephrines. So you cannot go on with your catecholamines. You could say, well, okay, I have my elevated catecholamines.
I have my elevated norepinephrine because it is specific to norepinephrine. And I do a clonidine test. But we know from previous studies that if you do a clonidine test with either plasma norepinephrine or plasma nometanephrine, The diagnostic accuracy of using normetanephrine is higher than that of norepinephrine. So in general, yes, if you do plasma catecholamine testing, because of suspicion of POTS, you find a high plasma norepinephrine, you wonder whether there's a VEO, I would go to plasma-free metanephrines. And if then only the...
I'm still in the sharing mode, I think. Yeah, you can see the slides. So if it still elevates here, your norm metanephrine, you see, and you really think because there's a high suspicion, then you can do this clonidine test. But for that, you need to measure norm metanephrine, not norm epinephrine. I hope that answers.
All right. Let's see. Can you please talk about comogranin A and how it can measure paragangliomas activity? Yeah. Christina, you want to do this or?
Yeah, I can start and you can add on. So I will be simple in my, let's say, answer. Crobogranin A has significantly worse diagnostic performance than metanephrine. So there is no reason to use a test which is worse than the one that we are currently using. So we do not use chromogranin A.
Another issue with chromogranin A is that it is influenced from many things, from medication, from disease, from the thyroid disease to parathyroid, from cancers to medication like proton inhibitors. So it's influenced from many, many, many things. parameters that we cannot control. And the third important issue for chromogranin A is that we measure it with immunoassays and every lab has its some reference intervals that are not validated. We do not know exactly if the levels are high or not.
So it's quite problematic to use chromogranin A and to be honest, we do not use it in daily clinical practice because as I said initially, we have a much, much superior test on our hands than chromogra in A. All right. Why would the plasma norepinephrine and dopamine be elevated greater than two times the upper limit of normal repeatability, but 24-hour urine collection rate whole ones are normal repeatedly. Patient is very symptomatic with a history of hyperparathyroidism and ovarian cystadenoma.
I'm not completely sure I fully understand the question. So why is, why is in a patient... I think they're asking, I would read it as why, why is the on plasma two times every limit, repeatedly, but why is the urine normal repeatedly? They're asking why there's this difference.
For norepinephrine you mean? Or nomethanephrine? Yes, yes.
And dopamine, sorry. Or norepinephrine and dopamine. Yeah, well, the plasma norepinephrine is a... let's say an indicator of sympathetic activity.
So if you have a very high sympathetic activity for some reason, and that can, there are a bunch of, if let's say in the acute phase of a myocardial infarction, or if you have chest pain, or if you have cardiac failure, you get that gets, that's accompanied by a high sympathetic activity. And this kind of physical source of high sympathetic activity induces high plasma norepinephrine. Now you would expect then it would be also elevated in the urine.
Yes, in general that's probably the case, although the urine is something that is diluted over 24 hours, while the plasma level is at a certain time point. So you can at a certain time point you can have a very high if you have chest pain. angina pectoris or cardiac ischemia and you take a blood sample you get a high sympathetic tone high plasma norepinephrine but if you take the blood the urine over 24 hours this peak the short-lasting peak of high plasma norepinephrine is diluted in the 24-hour urine so in some cases there may be let's say um um disparate results between plasma versus urine you And then I can chime in with my own personal experience because my plasma norepinephrine was just about two times upper limit. And then my urine was just barely above, just slightly above the upper limit. So that's my personal experience.
Yeah. Okay. What testing is suggested for a patient with prior highly secretory pheochromocytoma who continues to have symptoms? You did mention that there are no reference ranges for post-pheo surgery, but...
Yeah, yeah. You want to... Yeah, so I believe, yeah, the thing...
irrelevant if the patient has symptoms or not. I think that the biochemical tests are the same that we choose. So we would go for the plasma-free metanephrines if available, if we can follow the precautions like supine rest and so on, or 24-hour urine-free or fractionated metanephrines. So we do the symptoms and signs, even if the patient has many symptoms and signs. If there is no previous history of PPGL or there is no genetic pathogenic variants that are positive, the patient still has a low probability of the disease.
So we can choose on what we have, either plasma-free metanephrines or urinary-free unfractionated metanephrines. So we can use all of three of them. Sorry to interrupt, Christina, but this is a patient who had previously...
biochemically active previously. That's what I understand. Then if I would personally go for the plasma-free metanephrines because the patient is not under low risk then. He has a moderate risk of having a recurrent disease.
But if plasma-free metanephrines were, for some reason, I could not perform them, then I could also use a urinary-free or fractionated metanephrine. So, yeah. all these patients are whatsoever in follow-up so uh if if there was some um suspicion that something is going wrong we could always follow up with a second blood sample or a second urinary sample so it's yeah all right um how can we teach and share this with our health care team who has different thoughts on testing That's a tough one.
Yeah, well, there is a clinical guideline, the first one that, and the only one that had been published in 2014 by the Endocrine Society, and there we already argued that plasmamethenephrines is the way to go, and we should take blood samples after supine rest. Everything is already there. But especially, it's not only in the US, but some other parts of the world, taking the patient supine in a room where the patient is lying quietly with an invalid IV line, that's apparently it's difficult to organize in some centers. In the Netherlands, I know all centers do.
but we are a small country, but it's also difficult and not practical for many centers, for instance, in the UK. But so what you could do and what some people do, they just take a blood sample in the seated position without rest. And they say, if it's normal, you are done because then you are pretty sure the patient has no pheochromocytoma. But if it's elevated, the patient has to come back and you You need to take the blood sample after supine rest. You have to do the whole procedure, but now as it should be.
So, well, I think from the scientific point of view, the best way to do is directly just put a line in, keep the patient supine, relaxed, in a comfortable environment, and take a blood sample. Then you are done. But I think most physicians know, at least in Europe, but I know there's also some resistance in many places because it's pretty laborious for the clinical staff and the nurses, etc.
And it's probably, maybe in the US, it's more costly. I don't know if that's any reason, I don't think so. Yeah, well, other possibilities are meetings. The primary care field usually, at least in the Netherlands and Europe, usually do not do plasma metanephrines or urinary metanephrines. It's only done in the secondary referral centers and hospitals.
But in the US it might be different. And in that case, we should teach also primary care physicians. But the most important point in the diagnosis of pheochromocytoma paraganglioma is that the diagnosis has to be considered.
I don't think it's the biochemical test. There is a problem with the biochemical test, sure. But the first barrier in more quickly and more...
Appropriate diagnosis is the consideration. Many physicians never see it and hardly think about it. It's very tough for primary care physicians to think about a VEO because maybe they see it once in their life. Right. My endocrinologist had been practicing for 30 years and I believe she'd only had four patients with VEO.
Yeah. within as an endocrinologist. So it is very rare. That can be an impediment itself. Yeah.
Yeah. So that, well, that's another point. You remind me of that, is that I think the clinical care for patients with pheochromocytoma and peregrine glomer should be concentrated in a limited number of centers because if you see one patient a year, that's not enough to get experience with it. And that's why the alliance organized this.
clinical centers of excellence to designate the centers that have the experience to deal with patients with pheo-paraganglioma. All right. Oh, sorry.
Yes, the centers of excellence. Right. Absolutely. That's a really good resource for patients and clinicians. All right.
Well, Thank you to Dr. Lenders and Dr. Pamparocchi for your time and dedication to the patient community. This webinar will be available in a few days on YouTube and on the website. And we will transcribe the Q&A portion and we'll have that available as well. Sign up for our e-news and follow us on social. If this information has been useful to you and you're interested in donating, you can do so at theopara.org forward slash donate.
Special thanks again to Lane Theosprogenics for making this webinar series possible through an educational grant. Thank you to everyone who attended today. Thank you very much, Rochelle. Welcome. also Mike organized it and they made thanks for the organization thank you very much