Whenever a new test is reported, its performance is always great (why report it if not?). There are multiple reasons why the test performs well in the original reports. The diagnosis criteria are strict and clear, the tests are run by experts with strict quality control measures, the clerical errors are minimized, etc. When the test is used by more people, it usually becomes not as great. One example is the pheo test "plasma metanephrines."
In the first few studies of this test, the sensitivity (if you have pheo, the test will be positive) and specificity (if you don't have pheo, the test will be negative) both approach 100%. In a very well-designed, definitive study (published in 2002), the sensitivity and specificity are indeed close to 100% but only in people with family history of pheo. In patients without family history of pheo, the sensitivity is also nearly 100%, but the specificity is about 85%. That means, if you do not have a family history of pheo and if your doctors suspect you have pheo but you do not actually have pheo, the chance that the test will still be positive is 15% (false positive). In most cases, it is the normetanephrine that is false positive rather than metanephrine. I am sure you know what I am talking about if you have ever read a plasma metanephrines test report. The metanephrines test gives two values, metanephrine and normetanephrine.
How does the plasma metanephrines test perform in the real world? Earlier this year, a report was published comparing the performances of all 5 tests for pheo in a large US hospital. The 5 tests are plasma metanephrines, plasma catecholamines, urine metanephrines, urine catecholamines, and urine VMA. The study has quite a few limits; the major one being that not a lot of patients eventually prove to have pheo (which is also a strength because it reflects the fact that pheo is rare). With these limits, this study shows that the sensitivity and specificity of all 5 tests are about the same. The nicest thing about the study is that it gives positive predictive value (PPV) and negative predictive value (NPV) of the 5 tests in the real world.
The PPV and NPV are different from sensitivity and specificity because they depend on how the ordering physician selects patients to be tested. Let's not get entangled in technicality but the PPV of a test means that if you have a positive test for pheo, what the chance is that you actually have pheo. The NPV means that if your test result is negative, what the chance is that you actually do not have pheo. In this community-based study, the PPVs of all these tests range from 15-30%. That means if you have a pheo test at this hospital and it is positive, the chance that you indeed have pheo is about 15-30%. If the test is only moderately elevated, the PPVs are even much lower and range from 2-15%. The NPVs of all these tests are excellent: close to 100%. That means if you have a normal test result (from just any of the 5 tests) at this hospital, you are pretty sure that you do not have pheo.
Make no mistake. I do think that the plasma metanephrines is the best test for pheo. It is scientifically sound, highly reproducible, and not as interfered by medications as some other tests. I can also do clonidine suppression test based on the plasma metanephrines. I use it as the main test to diagnose pheo. It is just that the test results need to be interpreted by an expert.
Dr. Pheo
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Hi Dr.,
ReplyDeleteI've written several times before. I had the skin graft to cover the defect in my throat with the hardware showing through. Recovering well. I started a round of Sutent, and my blood cats came back norepinephrine at 7900, dopamine at 90, and the "interp catech plasma" with an explanation: "specimen received by the lab contained inadequate volume. Testing was performed using sub-optmal volume which may affect assay sensitivity and precision, etc." I get this same explanation every time. What can I do differently to get the the value of the plasma catecholamines? More blood? Different lab? It's going to ARUP Lab, Salt Lake City, Utah. Hope this made sense.
p.s. I have about 7 tumors now in neck, lungs and spine. PET/CT scan scheduled in 2 weeks
Dear Pam,
ReplyDeleteIt is a common problem. You do need more blood. The technicians who draw the blood often do not know how much blood they need. On the other hand, the values from a smaller volume often are rather accurate.
Dr. Pheo
It really doesn't matter what test you take when the facility that does the test doesn't follow protocol... or makes up their own. Have had to on several occasions ask the technician to pull and read the protocol. They want to do a spot draw. With the PFM the indwelling catheter is a problem in the USA since you need a nurse and a not a tech to do this type of blood draw. Last test the nurse ended up "milking" the vein to get blood to flow into the collection tube. At least they had ice available to put the sample on this time. If I ever get a high reading under these circumstances it will be highly suspect.
ReplyDeleteYou are exactly right. That is really the difference between a clinical trial and real world.
ReplyDeleteDr. Pheo
Did you go to the conference in New Jersey last week? Any 'new " news?
ReplyDeleteDo you have any opinion on the Y-90 treatment being done in Switzerland for pheo/para patients?
ReplyDeleteI did not go to the pheo/para meeting.
ReplyDeleteDr. Pheo
The Y-90 treatment for pheo/para has some effects but not dramatic. Side effects are small. The pheo/para has to be positive for octreotide for this treatment.
ReplyDeleteDr. Pheo
Hi Dr. Pheo,
ReplyDeleteReally appreciate all of your information! I've been diagnosed with Pheochromocytoma very recently, and I've sought a 2nd opinion. I'm in the situation where two separate doctors prescribe different medications. One prescribes Prazosin 1mg, while the other prescribes Phenoxybenzamine 10mg. I'm female in fine health otherwise. MRI shows tumor is 5cm diameter; bloodwork is normal; 24 hr urine test shows extremely high levels indicating pheo. Neither doctor above seems confident about the medication, and I'd venture not much experience in this area. Awaiting to discuss this case with Dr. Siperstein at Cleveland Clinic as well (can you vouch for Dr. Siperstein, if you know him?). Any advice much appreciated! BR, GG
Forgot to ask... what are the pros and cons of taking Prozasin versus Phenoxybenzamine? Is one preferred over the other, or how to decide?
ReplyDeleteDear GG,
ReplyDeleteI don't know Dr. Siperstein. Dr. Bravo at Cleveland Clinic is an expert.
Either prozasin or phenoxybenzamine is OK. Most doctors perfer phenoxybenzamine because of its theorectical advantage and the large experience with it.
The most important issues are clear diagnosis and sufficient preoperative preparation.
Dr. Pheo
I had a PET/CT scan yesterday which showed widespread metastesis(?) in lymph nodes and bones. I had 3 cycles of Sutent earlier this year when there were 7 lesions with great results, but had to stop for several months. I've had 2 more cycles, and now there are too many lesions to count. An MIBG scan two years ago showed no uptake. My oncologist says it's time for CAV chemo. Is there any reason to try another MIBG scan? Do I have any other options besides traditional chemotherapy?
ReplyDeleteDear Pam,
ReplyDeleteIt is unlikely that the new metastatic pheos take up MIBG so another MIBG scan probably is not needed. Whether traditional chemo is a good idea depends on your general condition. If you are in a good physical shape, the chemo can help. It is always important to control blood pressure and to prevent fracture.
Dr. Pheo
Is there any reason why Chromogranin A would without any treatment decline from 135.3 ng/ml on 6/17 to 100.6 on 7/17 to 58.1 on 8/5? I don't have the results of the latest assay for which blood was drawn on 10/2, because Quest told my doctor that, "they discovered some sort of interference with your recent assay for CgA, with non-linear results with serial dilutions."
ReplyDeleteI had an MIBG and a CT in mid-July, but nothing was found.
I read that plums, tomatoes and eggplant can increase CgA. I ate a lot of all of those foods during the summer, especially in July.
Actually I am not aware of any food items that interfere with CGA assay. The food you describe do interfere with 5-HIAA assay (a marker for carcinoid). I think most likely the second assay CGA is spurious. You can repeat it in the same lab.
ReplyDeleteDr. Pheo
Do you have an opinion on medicinal marijuana to off-set the side effects of both multiple paraganglioma and the side effects of chemo for us?
ReplyDeleteI don't have direct experience on medical marijuana on pheo or chemo side effects. I do know that there are claims that it cures metastatic pheo although no details are given. If the mainstream measures fail, I do not object trying alternative therapies by my own patients. If you try medical marijuana, you should tell your doctor.
ReplyDeleteDr. Pheo
Dear Dr. Pheo,
ReplyDeleteIs it possible for me to post an ad about a research study interview for patients with pheochromocytma or paraganglioma on your blog (involving evaluating a condition specific HRQOL questionnaire)? I'm sorry I haven't been able to figure out a way to contact you more directly.
Regards,
Victoria
Dear Victoria,
ReplyDeleteYou are welcome to do so for pure research purpose. Please let me know how I can facilitate.
Dr. Pheo
Many thanks Dr. Pheo. I greatly appreciate it. These questionnaires are being evaluated for future clinical trial use.
ReplyDeleteIs it ok if I leave the following ad as a comment? Or would you be able to post it yourself?
Regards,
Victoria
Oxford Outcomes is conducting a qualitative research study involving interviews with pheo/para patients in order to evaluate the clarity, relevance, and comprehensiveness of two questionnaires (one cancer specific and one pheo/para specific), and to evaluate how effective these questionnaires are at assessing the quality of life and symptoms of patients with pheochromocytoma or paraganglioma. Interviews will be used to evaluate their appropriateness for use during clinical trials when they will be used to determine treatment benefit from the perspective of the patient.
We are seeking U.S. patients, 18 years of age or older, with a documented (medical record) diagnosis of either pheochromocytoma or paraganglioma with active symptoms or who are within 60 days of curative therapy.
Participating would involve a brief interview, lasting approximately 1 hour. Our office is located in the Washington DC metro area. If in-person interviews are not feasible, interviews can take place over the phone. Participants will be compensated for their time. Please contact Victoria at 240-482-0034 if you are interested in participating or would like to learn more. Oxford Outcomes is conducting this study on behalf of Molecular Insight Pharmaceuticals. Our study has been registered under clinicaltrials.gov and can be found here: http://clinicaltrials.gov/ct2/show/NCT00911729.
I had a right adrenalectomy in 1979 for a pheochromocytoma. I had a cardiac arrest during the surgery & developed severe pulmonary edema. Obviously I did survive, although I was diagnosed with catecholamine myocarditis after the surgery. I have been reasonably healthy since then, although I do have Type II diabetes & hypertension which has been well-controlled. I developed reactive asthma several years ago after a bout of pneumonia. Periodically over the years I have had episodes of tachycardia. Recently I had another Holter monitor that indicated sinus tachycardia, occ. PACs & episodes of PAT. I was sent to a cardiologist who believes I have hypertensive heart disease as a result of the pheo 30 years ago & the aging process. He ordered an echo which I have not yet discussed with him, but the report indicated diastolic dysfunction, 58% ejection fraction, mild mitral & tricuspid regurgitation. He did start me on Lopressor 50mg BID. Most of the time my pulse is still in the 90s, but I have not been aware of any episodes of tachycardia in the 150-200 range that I had been having on occasion. What has been your experience with long-term survivors such as I am? Is heart disease going to be a major problem for me due to the damage of years ago? I am 61 years old.
ReplyDeleteDear spurgin,
ReplyDeleteSeveral issues need to be considered here.
1. Pheo recurrence. As you had a pheo at a young age of 31, the possibility for you to have a mutation is rather substantial. You should do yearly testing of plasma metanephrines. Now that you have cardiac symptoms, you especially need to test whether you have recurrence.
2. Pheo myocarditis is reversible after pheo removal. Compared with the population at large, most patients do not have any additional heart problems after their pheo is completely resected.
3. Of course, hypertension, diabetes, and age can all cause heart problems by themselves.
In summary, you should test whether you have pheo recurrence first. If you do, remove the pheo. If you don't, it is unlikely your current heart problems are consequences of the pheo myocarditis 30 years ago. You should still test yearly for pheo recurrence.
Dr. Pheo
Dr. Pheo
ReplyDeleteSleep disturbance is described as a symptom of pheos. Albeit one that could be easily overlooked as insomnia - a condition that affects the general population in great numbers. Is there any thing that would distinguish sleep disturbances due to pheos from that of ordinary insomnia? Is a pheo sleep disturbance more due to increased metabolic activity, blood pressure, heart rate, body temperature? Or is it the more subtle activity going on with the hormones that disrupts the circadian rhythm and/or interferes with the HPA Axis or other feedback loops of the endocrine system?
Is there any prescription sleep medicine that is contradicted for patients with pheos?
Dear DJPheo,
ReplyDeleteI actually don't know much about this issue. The insomnia is probably due to the excess catecholamines but the other potential causes are possible. I would treat with alpha blockers to normalize blood pressue and beta blockers to normalize heart rate. After those, I will treat insomnia symptomatically. I am not aware of any hypnotics that are contraindicated (after treatment with alpha and/or beta blockers).
Dr. Pheo
Hi Dr. Pheo,
ReplyDeleteThank you for explaining about PPV and NPV. Could you give me a little more info about this recent study that you are referring to? I would like very much to read more about it. The name of the university, the title of the article, or the names of some of the authors should help me to "find" it.
The part about: "if you have a normal test result (from just any of the 5 tests) at this hospital, you are pretty sure that you do not have pheo." especially interests me.
When I had my pheo many years ago....the only test that were positive was the metanephrine
part of the fractionated 24 hr urine test for metanephrines. The normetanephrines, catecholamines and VMA were all normal or below normal. (And even the metanephrine result was only elevated aprox 2 and 1/2 times.)
I definitely agree with you that the test results need to be interpreted by an expert. None of the local doctors/specialists felt that I had a pheo. However Dr. Wm. Young
was able to tell me on the telephone that he was more than 99% sure that I DID have a pheo after I told him what my fractionated urine metanephrine level was. He was correct of course and I went to the Mayo for my surgery.
I was also wondering how many patients were involved in this study.
Dear tues1day,
ReplyDeleteHere is info on this paper:
Journal: Endocrine Practice. 2009 Jul-Aug;15(4):313-21.
Title: Ordering pattern and performance of biochemical tests for diagnosing pheochromocytoma between 2000 and 2008.
Author: Yu R.
Affiliation: Cedars-Sinai Medical Center, Los Angeles.
When it comes to individual patient, many factors need to be considered to make a diagnosis. Lab test is a very important factor but not the only factor. Sometimes, pheo can be diagnosed even if all lab tests are apparently normal.
Dr. Pheo
My husband has been diagnosed with a probable pheo based upon biochemical tests. Key value was the latest plasma free normetanephrine of 2.31, blood processed at Mayo's lab.
ReplyDeleteA I-123 MIBG was negative. No anatomical imaging of any kind has been done. We were told that CT and a clonidine suppression test were "of no use to us".
We are concerned, however, that it is possible that this is a false positive.
When all biochemical testing was done (24-hour urine, catecholamines, and metanephrines) he had untreated adrenal insufficiency and was in pain. Also, during the last draw for metanephrines he was having some sort of reaction to Lugol's.
Addiionally, the hospital drawing the blood did not fast him, did not draw supine, no rest, no catheter, and I don't think the tube was chilled, although I'm not absolutely sure about the tube. I have no idea what they did with the blood after they drew it.
Under those conditions, am I correct to think that the catecholamines (at least plasma) results are probably pretty much invalid?
Re. the metanephrines, I seem to find some conflicting information I cannot resolve. On the one hand, I read that plasma free metanephrines from a pheo are different than those produced by the sympathetic nervous system. But... I also read there can be false positives and wonder about the adrenal insufficiency, etc.
Mayo's lab requires supine testing, catheter, etc. for catecholamines, not metanephrines (from reading the sampling procedures and discussion on their lab website). However, the NIH specifies supine rest and a catether for both. I did read from a recent NIH article, that in normals metanephrines increase 30 percent from supine to seated. So - could this normetanephrine value be a false positive, or do the sampling conditions sound sufficient?
Finally, the NIH specifies that medications that may interfere such as muscle relaxors, benzos, etc. must be discontinued for 2 weeks prior to testing. However, Mayo's lab specifically says that those medications no longer interfere with testing, and that interferences can be resolved. My husband was on some such medications, but I do not believe that his medication list was sent with the blood to Mayo. Is it necessary to send a list of medications along with the bloods?
We believe this testing perhaps needs to be redone, as "cleanly" as possible, and would very much appreciate your help in asessing if these results so far are potentially a false positive, and how important those other factors are if we do a re-test.
Thinking about it, I figured I might as well "go for broke" and put up all the test results so far - note the conditions they were performed under, in my post above. He does have clinical signs and symptoms (volatile b.p., tachycardia, etc.) He is under 30 years old. No known family history of pheo, but some family history of hypertension and aortic aneurism, and a grandparent with sudden cardiac death at a young age.
ReplyDeleteMIBG I-123 was negative - although we have never gotten any explanation for what lit up, beneath his bladder and on the to the right of midline.
#1 Quest 7/09 - on lopressor 75mg bid
Metanephrine.........<25 (<=50)
Normetanephrine 184 HIGH (<=148)
Total metanephrine 195 (<=205)
Quest 24-hour urine
Norepinephrine 123 HIGH (15-100)
Epinephrine <3 (2-24)
Dopamine 582 HIGH (52-480)
Total catecholamines <126 HIGH (26-121)
Normetanephrine 823 HIGH (44-540)
Metanephrine 761 HIGH (26-230)
Total metanephrines 1584 HIGH (90-690)
#2 Mayo lab 8/09 - on lopressor 75mg bid
Norepinephrine 1152 HIGH (70-750 supine)
(200-1700 stand)
Epinephrine <10 (0-110 supine)
(0-140 standing)
Dopamine 53 HIGH (<30)
Normetanephrine 2.16 HIGH (<.90)
Metanephrine <.20 (<.50)
#3 Mayo lab 9/09 off lopressor
Normetanephrine 2.31 HIGH (<.90)
Metanephrine <.20 (<.50)
Any insight you have would be welcomed. We're trying to decide whether or not to try to repeat the testing, and/or push for a CT, or just get referred to the NIH or Mayo or something. We'd like to have some reasonable certainty that it IS a pheo, before we run around the country.
Thank you.
Dear T,
ReplyDeleteThe catecholamines and metanephrines, either from blood or urine, are elevated in stress.
The clonidine suppression test is underutilized in many places.
The nervous system also produces normetanephrine and to a smaller extent metanephrine. These are the same molecules produced by the adrenal medulla and pheo.
In my own experience, although measures need to take to draw the blood, if the phlebotomist does a reasonably good job, metanephrines can be drawn any time without an indweling catheter, so long as the patient is not significantly stressed.
The Mayo test of metanephrines is not chemically interfered with most drugs, but certain drugs cause physiological elevation of metanephrines (they are really higher but may not be due to pheo).
In summary, I suggest the following:
1. Repeat the plasma metanephrines when he is not stressed.
2. If the repeat results are normal, pheo is ruled out.
3. If they are still mildly elevated (<2.5 fold upper limit of normal), do the clonidine suppression test.
4. If they are markedly elevated (>2.5 fold), do abdominal CT with and without contrast.
By the way, you need to find an expert on pheo to make a reliable diagnosis.
Dr. Pheo
Thank you so much for your very promt and helpful reply. You have confirmed what we suspected, and have been pushing for. I do have one question re. what you said:
ReplyDelete"certain drugs cause physiological elevation of metanephrines (they are really higher but may not be due to pheo)."
Is there somewhere I can find a definitive list of those medications? My husband is on a number of meds.
The current physician believes himself to be an expert on pheos. However, he doesn't seem to go along with what you, the NIH, or the research we find suggests. His plan was to begin alpha blockers, wait a year, and redo the MIBG. We will be seeking other options.
Sorry, last question - do I gather you do not believe that we need to repeat the cateholamines also? We were suggesting it, as to be considered for the NIH study it is required, as well as a CT.
Do you think we should let the current docs repeat the bloods and do a CT? Or simply try to go elsewhere immediately?
Sorry, forgot to ask one last thing. In addition to drugs which can raise catecholamine/metanephrine leves in the blood - are there some that can lower them?
ReplyDeleteFor example, do benzos, muscle relaxers, opiates, or any others do so?
Is there a list anywhere that I could see?
Thank you yet again.
I will write a new post on effects of medications on pheo testing. Please read that post.
ReplyDeleteDr. Pheo