Dear readers,
The Dr. Pheo's blog has been running for 8 months. Since the very beginning, readers have been giving me very positive feedbacks. Up to now, the blog has covered almost all aspects of pheo and I hope that patients and families benefit from reading these posts.
As the holiday season is approaching, I want to take this opportunity to wish all patients, their families and friends, and all those interested in this disease a very happy holiday season.
Dr. Pheo
Sunday, November 22, 2009
Thursday, October 1, 2009
Pheo tests in the real world
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
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
Tuesday, September 1, 2009
Dr. Pheo's musings on health care cost
I usually do not pay much attention to political arguments. In these days, however, I cannot go a single day without hearing discussions on health care or health insurance reform. A lot of discussions, I feel, are not on the really important issues. Today, I'd like to share my thoughts on one of the key issues in health insurance reform: health care cost.
The one thing everyone seems to agree upon is that the health care cost is too high for our society to afford and "we" spend way too much money on health care in America but only to achieve the same levels of health that other developed countries achieve with much less cost. But who are "we"? Am I one of the "we"? Are the readers of this blog some of the "we"? Who are responsible for the high cost in health care? How do we cut down the cost?
I, as a physician, may contribute to the high cost. For example, although I know that the MIBG scan probably does not add much to the localization of pheo if CT or MRI already finds a clear adrenal tumor in a middle-aged patient with high markers, I order the MIBG scan anyway for this patient because I worry about the small possibility that there may be a second pheo somewhere that I may miss otherwise. Although the literature and my own research show that ordering multiple tests for pheo is not necessary, I sometimes do order 2 markers because there is a small chance that there may be a lab error.
As a patient, you may also contribute to the high cost. Yearly follow-up of pheo markers is sufficient after pheo resection; some patients, though, insist on testing every 3 months because they worry about the small chance that they may have a fast-growing pheo. Some patients demand to have an MRI even after CT shows clear results because MRI does have a small advantage over CT in describing the pheo.
All medically justified costs are not waste. But who determines if a test or a treatment is justified? In reality and in theory, the physicians are the ones who eventually determine if a cost is justified. The insurance clerk who declined the coverage of your MRI just acted on the recommendations made by physicians hired by the insurance company. Although physicians have the intellectual capacity to perform this function, the society as a whole has to decide on a few key issues to make physicians exercise their best judgment on cost justification.
1. Do we trust physicians to do this job at the first place? If we don't, who else do we trust?
2. If we trust physicians, how do we make sure that physicians always exercise their best judgment without playing favoritism?
3. What is the maximal acceptable risk? If there is a 1/million chance a pheo may be missed, most reasonable people don't worry about it. What if the chance is 1/1,000, or 1/100, or 1/10?
4. How much do we want to pay for "peace of mind" and how much physical discomfort is intolerable?
5. Who is responsible for the risk? If I do not order an MIBG on a patient who I feel rather sure only has a solitary pheo but it turns out that the patient does have metastasis, whose fault is it? Am I free of blame because I exercised my best judgment?
6. What is the appropriate mechanism to reward physicians so that physicians are motivated both to avoid unnecessary tests and treatments and to use all necessary tests and treatments?
7. Do the answers to the above questions depend on whether a patient pays everything by her/himself, has private insurance, has public insurance, or has no insurance at all?
Our society has to be reasonable and responsible to achieve an efficient, equitable, and satisfying health care system.
Dr. Pheo
The one thing everyone seems to agree upon is that the health care cost is too high for our society to afford and "we" spend way too much money on health care in America but only to achieve the same levels of health that other developed countries achieve with much less cost. But who are "we"? Am I one of the "we"? Are the readers of this blog some of the "we"? Who are responsible for the high cost in health care? How do we cut down the cost?
I, as a physician, may contribute to the high cost. For example, although I know that the MIBG scan probably does not add much to the localization of pheo if CT or MRI already finds a clear adrenal tumor in a middle-aged patient with high markers, I order the MIBG scan anyway for this patient because I worry about the small possibility that there may be a second pheo somewhere that I may miss otherwise. Although the literature and my own research show that ordering multiple tests for pheo is not necessary, I sometimes do order 2 markers because there is a small chance that there may be a lab error.
As a patient, you may also contribute to the high cost. Yearly follow-up of pheo markers is sufficient after pheo resection; some patients, though, insist on testing every 3 months because they worry about the small chance that they may have a fast-growing pheo. Some patients demand to have an MRI even after CT shows clear results because MRI does have a small advantage over CT in describing the pheo.
All medically justified costs are not waste. But who determines if a test or a treatment is justified? In reality and in theory, the physicians are the ones who eventually determine if a cost is justified. The insurance clerk who declined the coverage of your MRI just acted on the recommendations made by physicians hired by the insurance company. Although physicians have the intellectual capacity to perform this function, the society as a whole has to decide on a few key issues to make physicians exercise their best judgment on cost justification.
1. Do we trust physicians to do this job at the first place? If we don't, who else do we trust?
2. If we trust physicians, how do we make sure that physicians always exercise their best judgment without playing favoritism?
3. What is the maximal acceptable risk? If there is a 1/million chance a pheo may be missed, most reasonable people don't worry about it. What if the chance is 1/1,000, or 1/100, or 1/10?
4. How much do we want to pay for "peace of mind" and how much physical discomfort is intolerable?
5. Who is responsible for the risk? If I do not order an MIBG on a patient who I feel rather sure only has a solitary pheo but it turns out that the patient does have metastasis, whose fault is it? Am I free of blame because I exercised my best judgment?
6. What is the appropriate mechanism to reward physicians so that physicians are motivated both to avoid unnecessary tests and treatments and to use all necessary tests and treatments?
7. Do the answers to the above questions depend on whether a patient pays everything by her/himself, has private insurance, has public insurance, or has no insurance at all?
Our society has to be reasonable and responsible to achieve an efficient, equitable, and satisfying health care system.
Dr. Pheo
Saturday, August 1, 2009
Chromogranin A
Chromogranin A (CGA) is one of the most important tests in the diagnosis of neuroendocrine tumors. Unfortunately, it is also one of the trickiest tests to interpret. I am asked very frequently by patients and colleagues on interpretation of CGA.
CGA is a protein. It is produced in neuroendocrine cells and released into the circulation. CGA is metabolized to fragments and cleared by the kidney. CGA is actually a hardy protein. It is very stable in serum at long incubation at 37°C, or even after repeated freezing and thawing. It reflects the cumulative secretory activity of all those cells. So CGA can be elevated by any of the many types of neuroendocrine cells. CGA indirectly reflects tissue or tumor mass. CGA is elevated in most patients with pheochromocytoma or paraganglioma.
Several issues need to be considered when interpreting the CGA results. One problem is that the reference range differs among labs. In Quest, the upper limit of normal is 36 ng/mL, while in Labcorp, it is 5 nmol/L (equivalent to 245 ng/mL). The Quest test is more useful. (Note added on July 26, 2010: One reader contests this point. Please see comment 25 and others.)
CGA can be elevated in benign and reversible conditions. In a type of gastritis (atrophic gastritis), acid production is decreased, which in turn stimulates CGA production from the stomach.
The most common cause of elevated CGA in clinical practice is anti-acid treatment, especially proton pump inhibitors for acid reflux. CGA will increase even after days of PPI in healthy volunteers. The prevalence of elevated CGA is common in patients on PPI, and more than 60% patients on PPI have elevated CGA after 4 years.
Because CGA is cleared by the kidney, CGA is elevated in kidney failure.
CGA can be elevated in several other diseases: hepatocellular carcinoma, prostate cancer, adrenal incidentaloma, pituitary tumors, and rheumatoid arthritis.
In summary, CGA is an important marker for neuroendocrine tumors. In routine clinical practice, the most common cause of high CGA is anti-acid treatment. Kidney failure and atrophic gastritis are also causes of high CGA. In a patient is not taking anti-acids or has chronic kidney failure, high CGA levels raise suspicion of neuroendocrine tumor or other tumors, including pheochromocytoma.
Obviously, CGA is not specific for pheochromocytoma and is less important than metanephrines in the diagnosis of pheochromocytoma. CGA can be used in combination with metanephrines to increase diagnostic accuracy for pheochromocytoma.
Dr. Pheo
CGA is a protein. It is produced in neuroendocrine cells and released into the circulation. CGA is metabolized to fragments and cleared by the kidney. CGA is actually a hardy protein. It is very stable in serum at long incubation at 37°C, or even after repeated freezing and thawing. It reflects the cumulative secretory activity of all those cells. So CGA can be elevated by any of the many types of neuroendocrine cells. CGA indirectly reflects tissue or tumor mass. CGA is elevated in most patients with pheochromocytoma or paraganglioma.
Several issues need to be considered when interpreting the CGA results. One problem is that the reference range differs among labs. In Quest, the upper limit of normal is 36 ng/mL, while in Labcorp, it is 5 nmol/L (equivalent to 245 ng/mL). The Quest test is more useful. (Note added on July 26, 2010: One reader contests this point. Please see comment 25 and others.)
CGA can be elevated in benign and reversible conditions. In a type of gastritis (atrophic gastritis), acid production is decreased, which in turn stimulates CGA production from the stomach.
The most common cause of elevated CGA in clinical practice is anti-acid treatment, especially proton pump inhibitors for acid reflux. CGA will increase even after days of PPI in healthy volunteers. The prevalence of elevated CGA is common in patients on PPI, and more than 60% patients on PPI have elevated CGA after 4 years.
Because CGA is cleared by the kidney, CGA is elevated in kidney failure.
CGA can be elevated in several other diseases: hepatocellular carcinoma, prostate cancer, adrenal incidentaloma, pituitary tumors, and rheumatoid arthritis.
In summary, CGA is an important marker for neuroendocrine tumors. In routine clinical practice, the most common cause of high CGA is anti-acid treatment. Kidney failure and atrophic gastritis are also causes of high CGA. In a patient is not taking anti-acids or has chronic kidney failure, high CGA levels raise suspicion of neuroendocrine tumor or other tumors, including pheochromocytoma.
Obviously, CGA is not specific for pheochromocytoma and is less important than metanephrines in the diagnosis of pheochromocytoma. CGA can be used in combination with metanephrines to increase diagnostic accuracy for pheochromocytoma.
Dr. Pheo
Wednesday, July 1, 2009
A sexual side effect of phenoxybenzamine
As the cliché goes, the best teacher of a doctor is the patient. There is nothing more true about it, especially on side effects of a drug.
Years ago, I had the opportunity of seeing a very pleasant 30-something male patient. He had been diagnosed with pheo by another doctor and saw me for a second opinion. He had been on phenoxybenzamine for the alleged specific anti-pheo effects for more than a year. His blood pressure was well controlled by phenoxybenzamine. After reviewing the numerous tests and imaging studies, I determined that he did not have pheo. I recommended using a diuretic medication for blood pressure control, instead of using the expensive phenoxybenzamine. He was so relieved once he learned that he would not absolutely need phenoxybenzamine—but not due to financial reasons. He told me that he could not have children while on the drug but his wife and he so much wanted to start a family. An inquisitive soul, I asked him to elaborate. The patient shyly told me that he had not had ejaculates after he was on phenoxybenzamine.
That was the first time I learned this very common side effect of phenoxybenzamine in men. We all know the standard common side effects such as nasal stuffiness, orthostatic hypotension, and fatigue. Ejaculatory failure happens in almost every man taking phenoxybenzamine. Most men do not complain of this side effect, probably because the treatment is usually short-term and patients have anxiety before operation so that they do not attempt sexual activity. Men may also be embarrassed to talk about this what is perceived by some as a sensitive but trivial symptom.
The mechanism of ejaculatory failure is not retrograde ejaculation, rather, patients simply do not transfer seminal fluid (the bulk of ejaculates) to be ejaculated. The good news is that this sexual side effect is completely reversible in 1-2 days after discontinuing phenoxybenzamine. And phenoxybenzamine does NOT affect libido, potency, or orgasm.
Prazosin and doxazosin usually do not cause ejaculatory problems but sometimes they do.
After I learned this side effect from that patient, I always inform my male patients of this unique side effect of phenoxybenzamine. Most of them appreciate my warning. Some would say “Doc, sex is the last thing I am thinking of now.” Hey, you never know. Sexual activity is generally not contraindicated in patients with pheo, provided that it is not particularly violent.
Dr. Pheo
Years ago, I had the opportunity of seeing a very pleasant 30-something male patient. He had been diagnosed with pheo by another doctor and saw me for a second opinion. He had been on phenoxybenzamine for the alleged specific anti-pheo effects for more than a year. His blood pressure was well controlled by phenoxybenzamine. After reviewing the numerous tests and imaging studies, I determined that he did not have pheo. I recommended using a diuretic medication for blood pressure control, instead of using the expensive phenoxybenzamine. He was so relieved once he learned that he would not absolutely need phenoxybenzamine—but not due to financial reasons. He told me that he could not have children while on the drug but his wife and he so much wanted to start a family. An inquisitive soul, I asked him to elaborate. The patient shyly told me that he had not had ejaculates after he was on phenoxybenzamine.
That was the first time I learned this very common side effect of phenoxybenzamine in men. We all know the standard common side effects such as nasal stuffiness, orthostatic hypotension, and fatigue. Ejaculatory failure happens in almost every man taking phenoxybenzamine. Most men do not complain of this side effect, probably because the treatment is usually short-term and patients have anxiety before operation so that they do not attempt sexual activity. Men may also be embarrassed to talk about this what is perceived by some as a sensitive but trivial symptom.
The mechanism of ejaculatory failure is not retrograde ejaculation, rather, patients simply do not transfer seminal fluid (the bulk of ejaculates) to be ejaculated. The good news is that this sexual side effect is completely reversible in 1-2 days after discontinuing phenoxybenzamine. And phenoxybenzamine does NOT affect libido, potency, or orgasm.
Prazosin and doxazosin usually do not cause ejaculatory problems but sometimes they do.
After I learned this side effect from that patient, I always inform my male patients of this unique side effect of phenoxybenzamine. Most of them appreciate my warning. Some would say “Doc, sex is the last thing I am thinking of now.” Hey, you never know. Sexual activity is generally not contraindicated in patients with pheo, provided that it is not particularly violent.
Dr. Pheo
Tuesday, June 16, 2009
Pheo growth speed
One important feature of pheos is that they always grow. The growth speed of pheo, however, is only known for patients with von Hippel Lindau disease. For people with true sporadic pheo (~70% of all pheos), we have little knowledge on the growth speed of their pheos. The reason is that familial pheos can be monitored but sporadic pheos are usually resected once they are diagnosed. Only under two conditions, patient's choice of delaying surgery and omission of pheo testing of incidentally-identified adrenal mass, the growth speed of sporadic pheos can be assessed.
I recently took care of a patient with likely sporadic pheo. This patient's adrenal pheo increased from 0.6 x 1.2 cm to 3.0 x 3.6 cm in 6 years. This patient is among the few I know with recorded growth speed of a sporadic pheo.
The information on pheo growth speed is much needed to tell patients what they will expect of their tumor. I would like to do a survey of the growth speed of pheo, whether with genetic mutations or not. If you have a pheo that was imaged multiple times, please let me know the size of the tumor, the time interval in-between imaging, and whether you have a pheo syndrome (with mutations) or not. I thank you in advance.
Dr. Pheo
I recently took care of a patient with likely sporadic pheo. This patient's adrenal pheo increased from 0.6 x 1.2 cm to 3.0 x 3.6 cm in 6 years. This patient is among the few I know with recorded growth speed of a sporadic pheo.
The information on pheo growth speed is much needed to tell patients what they will expect of their tumor. I would like to do a survey of the growth speed of pheo, whether with genetic mutations or not. If you have a pheo that was imaged multiple times, please let me know the size of the tumor, the time interval in-between imaging, and whether you have a pheo syndrome (with mutations) or not. I thank you in advance.
Dr. Pheo
Tuesday, May 26, 2009
A familial pheo risk calculator
Two papers on risks of familial pheo appear in the May, 2009 issue of the Journal of Clinical Endocrinology and Metabolism. One Paper describes experience in about 500 Italian patients, the other over 200 Spanish patients. The paper on Italian patients is particularly informative. With the three large studies now available (the original landmark study in 2002 published in the New England Journal of Medicine and these two new papers), I feel it is time to quantify the probability of having familial pheo. I have prepared a calculator of risks for familial pheo. The calculator is based on the 3 above large studies. The calculator has only five input variables:
1) Primary location of your pheo/paraganglioma
2) Age at diagnosis
3) Family history of pheo or paraganglioma (Yes/No)
4) Single or multiple pheo/paraganglioma (Single/Multiple)
5) Do you have any of the following diseases in addition to pheo/paraganglioma (Yes/No): medullary thyroid cancer, hyperparathyrodism, hirschsprung's disease, mucosa neuroma, hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumor, and skin neurofibroma?
As this is a blog format, I can not post the calculator on line. If you tell me the answer to the 5 variables, I will tell you your risk of having a familial pheo. The calculator has its intrinsic limitations and perhaps even errors; and the results are only as good as the accuracy of the 5 variables. Also I can not tell you the chances of any particular mutated genes.
Of course, the calculator only gives you an estimate of risk and only your doctor and you shall decide whether to do genetic testing. You should use the results of the calculator responsibly and at your own risk; I can not be held liable for any adverse consequences.
Dr. Pheo
1) Primary location of your pheo/paraganglioma
2) Age at diagnosis
3) Family history of pheo or paraganglioma (Yes/No)
4) Single or multiple pheo/paraganglioma (Single/Multiple)
5) Do you have any of the following diseases in addition to pheo/paraganglioma (Yes/No): medullary thyroid cancer, hyperparathyrodism, hirschsprung's disease, mucosa neuroma, hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumor, and skin neurofibroma?
As this is a blog format, I can not post the calculator on line. If you tell me the answer to the 5 variables, I will tell you your risk of having a familial pheo. The calculator has its intrinsic limitations and perhaps even errors; and the results are only as good as the accuracy of the 5 variables. Also I can not tell you the chances of any particular mutated genes.
Of course, the calculator only gives you an estimate of risk and only your doctor and you shall decide whether to do genetic testing. You should use the results of the calculator responsibly and at your own risk; I can not be held liable for any adverse consequences.
Dr. Pheo
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