In the last two months, I have explained why the glucagon stimulation test and adrenal venous sampling should not be used any more for the purpose of pheo diagnosis. In this piece, I will go over a good test that has some value in pheo diagnosis; this is the clonidine suppression test.
First of all, why do we need this test? As I have described in previous postings, the results of pheo markers are not black and white. Most people with normal results do not have pheo. The risk of pheo is substantial if the results are 2-3-fold higher than normal. Those are the easier ones to interpret. The results are harder to digest if they are slightly elevated (higher than normal, but less than 2-3-fold elevated). Clonidine suppression test is intended to clarify the meaning of slightly elevated pheo markers.
Clonidine is a medication used for treating hypertension. It works on the brain to decrease the “sympathetic tone”, that is, the intensity of nerve signals to the adrenal medulla. Clonidine suppresses the release of catecholamines and metanephrines from normal adrenal medulla. Pheo is a tumor of the adrenal medulla and it essentially does things on its own. Catecholamines and metanephrines released from a pheo are less suppressed by clonidine than the normal adrenal medulla. Clonidine is thus used to differentiate pheo from normal.
The test is not really standardized and every center has its own protocol and interpretation criteria. The patient has to be off diuretics, tricyclics, and beta blockers for 1-5 days and off all medications for 12 hours. After an overnight fast, the patient goes to the clinic in the morning, and catecholamines and metanephrines are measured at baseline and 3 hours after taking clonidine. The passing results (no pheo) are 50% decrease and/or back to normal.
The major adverse effect of the test is hypotension, which can be severe.
There are a few caveats about the clonidine suppression test. 1) It should never be considered as a “gold standard” for pheo diagnosis. It is just one of the tests that help diagnosing pheo. 2) The results of the clonidine suppression test can be confusing too. Catecholamines and metanephrines may be trending toward different directions. Some markers may be even higher after clonidine. 3) The test is not needed for most patients. Even in the patient who should benefit most from it, I always find that it confirms my clinical suspicion rather than adds new information. 4) It is contra-indicated if the patients can not be off the medications.
My own experience is that the best use of the clonidine suppression test is for comforting patients who are very anxious about their borderline pheo markers and want all possible reassurance that they do not have pheo.
Dr. Pheo
Tuesday, April 6, 2010
Wednesday, March 17, 2010
Adrenal venous sampling, another outdated test
I started this blog a year ago. I am very happy to see that it has been well received by the readers and I hope it will continue to be helpful to people with suspected or diagnosed pheo and to colleagues.
The clinical research on pheo is growing at an amazing speed. Almost every month, interesting reports appear in reputable journals. In this month's Journal of Clinical Endocrinology and Metabolism, a paper written by Dr. Young at Mayo Clinic (he is on Dr. Pheo's pheo doctor list) and associates provide pretty definitive evidence that another old test for pheo diagnosis, adrenal venous sampling (AVS), should not be used any more. It remains a great test for some other adrenal disorders.
AVS had been invented way before the modern tests and imaging methods were used; it probably has seen its best times. Most younger endocrinologists are not even aware of this test, for a good reason, as it is seldom used for diagnosing pheo in the last 20 years. AVS is invasive and requires significant experience to do it right. A radiologist would insert a cannula into each of the main veins in the patient's groin and advance it into the adrenal veins. Catecholamines are then measured in the adrenal veins and in a peripheral vein. If one side shows much higher levels of catecholamines than the other side, it is then concluded that this side may have a pheo, at least so believed by the proponents of this test.
I missed the heydays of AVS. I never ordered it myself because I never felt it was needed in my own practice. I have taken care of patients who had this test done to them. It is invariably ordered by an endocrinologist who completed training many years ago, and the indications are not clear. The situation is usually like this: a patient would have some pheo symptoms and pheo markers are elevated but CT/MRI and MIBG scan do not clearly show any adrenal tumors. Someone would then suggest AVS. In my limited experience, AVS does not help in any tangible ways. On the other hand, it often reinforces a misconception that the patient has a pheo. In spite of my strong belief, it is not easy to convince my colleagues not to use it because there have not been studies to show the fallacy of AVS, until this paper appears.
This paper is not a typical study of diagnostic test. It does not address sensitivity or specificity. Rather, it shows the results of AVS in patients without pheo. The major observations are: 1) catecholamine levels are much higher in the adrenal veins than in peripheral veins (no surprise as they are supposed to be); 2) the catecholamine levels vary tremendously between individuals (300-fold difference); 3) catecholamines in the right adrenal veins tend to be higher than in the left one (can be as high as 83-fold). All the above are considered by some as evidence of pheo but remember all those patients do NOT have pheo. The data from this paper thus cast a large doubt on the value of AVS.
Regardless of what criteria are used for interpreting AVS results, the most important fact on AVS is that it has no clear indications in modern medicine and should not be ordered in the first place for diagnosing pheo. I cannot think of a clinical situation where AVS will aid in the diagnosis or localization of pheo.
I’d like to hear your experience on AVS.
Dr. Pheo
The clinical research on pheo is growing at an amazing speed. Almost every month, interesting reports appear in reputable journals. In this month's Journal of Clinical Endocrinology and Metabolism, a paper written by Dr. Young at Mayo Clinic (he is on Dr. Pheo's pheo doctor list) and associates provide pretty definitive evidence that another old test for pheo diagnosis, adrenal venous sampling (AVS), should not be used any more. It remains a great test for some other adrenal disorders.
AVS had been invented way before the modern tests and imaging methods were used; it probably has seen its best times. Most younger endocrinologists are not even aware of this test, for a good reason, as it is seldom used for diagnosing pheo in the last 20 years. AVS is invasive and requires significant experience to do it right. A radiologist would insert a cannula into each of the main veins in the patient's groin and advance it into the adrenal veins. Catecholamines are then measured in the adrenal veins and in a peripheral vein. If one side shows much higher levels of catecholamines than the other side, it is then concluded that this side may have a pheo, at least so believed by the proponents of this test.
I missed the heydays of AVS. I never ordered it myself because I never felt it was needed in my own practice. I have taken care of patients who had this test done to them. It is invariably ordered by an endocrinologist who completed training many years ago, and the indications are not clear. The situation is usually like this: a patient would have some pheo symptoms and pheo markers are elevated but CT/MRI and MIBG scan do not clearly show any adrenal tumors. Someone would then suggest AVS. In my limited experience, AVS does not help in any tangible ways. On the other hand, it often reinforces a misconception that the patient has a pheo. In spite of my strong belief, it is not easy to convince my colleagues not to use it because there have not been studies to show the fallacy of AVS, until this paper appears.
This paper is not a typical study of diagnostic test. It does not address sensitivity or specificity. Rather, it shows the results of AVS in patients without pheo. The major observations are: 1) catecholamine levels are much higher in the adrenal veins than in peripheral veins (no surprise as they are supposed to be); 2) the catecholamine levels vary tremendously between individuals (300-fold difference); 3) catecholamines in the right adrenal veins tend to be higher than in the left one (can be as high as 83-fold). All the above are considered by some as evidence of pheo but remember all those patients do NOT have pheo. The data from this paper thus cast a large doubt on the value of AVS.
Regardless of what criteria are used for interpreting AVS results, the most important fact on AVS is that it has no clear indications in modern medicine and should not be ordered in the first place for diagnosing pheo. I cannot think of a clinical situation where AVS will aid in the diagnosis or localization of pheo.
I’d like to hear your experience on AVS.
Dr. Pheo
Monday, February 1, 2010
Adieu, Glucagon Stimulation Test
In the olden days, there were a few dynamic tests to diagnose pheo. In those days, none of the biochemical tests and imaging methods that we take for granted today was available. If you and I feel frustrated now over diagnosing a pheo, imagine how people felt then!
The glucagon stimulation test was one of the dynamic tests invented in those days. Glucagon is a hormone produced by the alpha cells in the pancreatic islets (insulin is by the beta cells in the same islets). Glucagon has many functions. The main one is to increase blood glucose levels (that’s why it is used to treat hypoglycemia). It also stimulates the heart and increases blood pressure. At the beginning, increase of blood pressure after glucagon was used to diagnose pheo; later, the test changed to increase of norepinephrine after glucagon.
The glucagon stimulation test began to fade away after better tests for pheo were discovered. It is seldom used in the last 20 years. Whether it has any unique value in modern-day medicine, however, is never satisfactorily answered. I have been asked by my own patients about the glucagon stimulation test and some patients wonder if the test can uncover a hidden pheo. A recent study systemically examined the body’s response to glucagon and largely settled the question.
This study shows that norepinephrine increases dramatically after glucagon in only about ¼ to ½ of pheo patients. In the other ½ to ¾ of pheo patients, the increase in norepinephrine levels is too small to have any diagnostic value. In other words, it is not sensitive enough. In the subgroup of patients who have borderline metanephrine results and need further testing, the performance of glucagon stimulation test is similar.
The glucagon stimulation test is not without risks. A few patients had hypertensive crisis. One patient developed visual problems that eventually recovered in a few months.
This study, along with a few others, clearly demonstrates that the glucagon stimulation test has no place in diagnosing pheo in modern medicine. We should not use it any more for the purpose of diagnosing pheo.
Dr. Pheo
The glucagon stimulation test was one of the dynamic tests invented in those days. Glucagon is a hormone produced by the alpha cells in the pancreatic islets (insulin is by the beta cells in the same islets). Glucagon has many functions. The main one is to increase blood glucose levels (that’s why it is used to treat hypoglycemia). It also stimulates the heart and increases blood pressure. At the beginning, increase of blood pressure after glucagon was used to diagnose pheo; later, the test changed to increase of norepinephrine after glucagon.
The glucagon stimulation test began to fade away after better tests for pheo were discovered. It is seldom used in the last 20 years. Whether it has any unique value in modern-day medicine, however, is never satisfactorily answered. I have been asked by my own patients about the glucagon stimulation test and some patients wonder if the test can uncover a hidden pheo. A recent study systemically examined the body’s response to glucagon and largely settled the question.
This study shows that norepinephrine increases dramatically after glucagon in only about ¼ to ½ of pheo patients. In the other ½ to ¾ of pheo patients, the increase in norepinephrine levels is too small to have any diagnostic value. In other words, it is not sensitive enough. In the subgroup of patients who have borderline metanephrine results and need further testing, the performance of glucagon stimulation test is similar.
The glucagon stimulation test is not without risks. A few patients had hypertensive crisis. One patient developed visual problems that eventually recovered in a few months.
This study, along with a few others, clearly demonstrates that the glucagon stimulation test has no place in diagnosing pheo in modern medicine. We should not use it any more for the purpose of diagnosing pheo.
Dr. Pheo
Friday, January 1, 2010
“Adrenal medulla hyperplasia”
Recently I saw an elderly patient with episodic hypertension. The pheo markers were mildly elevated at times but normal at others. Before I saw the patient, abdominal and pelvic CT had already been done and some thickening of left adrenal gland was noted. No tumors were identified. MIBG scan had also been done, and there was a slight uptake in the left adrenal area. A few of those involved in the patient’s care believed that she/he had pheo. The patient also firmly accepted the pheo diagnosis after reading about pheo. Once again, I was the pain-in-the-neck doctor and told the patient that it was very unlikely that she/he had pheo. Then someone brought up the issue of “adrenal medulla hyperplasia” and wondered if it was not pheo, it might be “adrenal medulla hyperplasia”. I have followed the literature on this alleged condition for a while and would like to share my thoughts here with you.
Adrenal medulla, the inner part of adrenal gland where pheo is derived from, is part of the sympathetic nervous system (the “fight-and-flight” system). The exact role of adrenal medulla in blood pressure control is still not so clear. For example, most patients with bilateral adrenalectomy do not have low blood pressure. In the earlier part of last century, adrenalectomy was used to treat hypertension with mixed results. The adrenal medulla has a very small mass of less than 1 gram. The adrenal medulla of some patients indeed becomes bigger with more cells (“hyperplasia”). In patients with multiple endocrine neoplasia type 2 (MEN2), adrenal medulla hyperplasia occurs before pheo develops. In patients with long-standing hypertension, the adrenal gland tends to be bigger and both cortex and medulla are bigger.
In the literature, there are a handful of reports claiming adrenal medulla hyperplasia can cause symptoms very similar to that of pheo. In these reports, usually the patients have labile hypertension and pheo is suspected. The pheo markers are either normal or mildly elevated. The adrenal glands are either normal or mildly enlarged but clearly without a tumor on CT or MRI. MIBG scan typically is borderline positive. These reports then claim the patients immediately get better after unilateral or bilateral adrenalectomy. The pathology exam of course shows adrenal medulla hyperplasia.
Based on my own experience, my discussion with other experts on pheo, and review of literature, I simply think there are no adequate evidence and no need to consider the so-called adrenal medulla hyperplasia as a disease in clinical practice. My reasoning is as follows:
1. Adrenal medulla hyperplasia is either a pre-tumor lesion or a secondary change caused by hypertension rather than causing hypertension.
2. Nowadays most patients with labile hypertension can be satisfactorily controlled by medications.
3. There are no universal criteria accepted by pathologists to diagnose adrenal medulla hyperplasia.
4. Most patients with “adrenal medulla hyperplasia” do not have labile hypertension.
5. The diagnosis of “adrenal medulla hyperplasia” is often a hindsight after pheo is not found in the adrenal.
6. Most patients continue to experience the same symptoms after adrenalectomy.
As medicine is ever-developing, I can imagine that adrenal medulla hyperplasia may indeed cause symptoms in a small number of patients. The problem is that many patients will undergo unnecessary and ineffective adrenalectomy if we allow “adrenal medulla hyperplasia” to be in the differential diagnosis of hypertension. The proponents of “adrenal medulla hyperplasia” need to establish a clear set of diagnostic criteria to identify the few patients who might benefit from adrenalectomy.
Dr. Pheo
Adrenal medulla, the inner part of adrenal gland where pheo is derived from, is part of the sympathetic nervous system (the “fight-and-flight” system). The exact role of adrenal medulla in blood pressure control is still not so clear. For example, most patients with bilateral adrenalectomy do not have low blood pressure. In the earlier part of last century, adrenalectomy was used to treat hypertension with mixed results. The adrenal medulla has a very small mass of less than 1 gram. The adrenal medulla of some patients indeed becomes bigger with more cells (“hyperplasia”). In patients with multiple endocrine neoplasia type 2 (MEN2), adrenal medulla hyperplasia occurs before pheo develops. In patients with long-standing hypertension, the adrenal gland tends to be bigger and both cortex and medulla are bigger.
In the literature, there are a handful of reports claiming adrenal medulla hyperplasia can cause symptoms very similar to that of pheo. In these reports, usually the patients have labile hypertension and pheo is suspected. The pheo markers are either normal or mildly elevated. The adrenal glands are either normal or mildly enlarged but clearly without a tumor on CT or MRI. MIBG scan typically is borderline positive. These reports then claim the patients immediately get better after unilateral or bilateral adrenalectomy. The pathology exam of course shows adrenal medulla hyperplasia.
Based on my own experience, my discussion with other experts on pheo, and review of literature, I simply think there are no adequate evidence and no need to consider the so-called adrenal medulla hyperplasia as a disease in clinical practice. My reasoning is as follows:
1. Adrenal medulla hyperplasia is either a pre-tumor lesion or a secondary change caused by hypertension rather than causing hypertension.
2. Nowadays most patients with labile hypertension can be satisfactorily controlled by medications.
3. There are no universal criteria accepted by pathologists to diagnose adrenal medulla hyperplasia.
4. Most patients with “adrenal medulla hyperplasia” do not have labile hypertension.
5. The diagnosis of “adrenal medulla hyperplasia” is often a hindsight after pheo is not found in the adrenal.
6. Most patients continue to experience the same symptoms after adrenalectomy.
As medicine is ever-developing, I can imagine that adrenal medulla hyperplasia may indeed cause symptoms in a small number of patients. The problem is that many patients will undergo unnecessary and ineffective adrenalectomy if we allow “adrenal medulla hyperplasia” to be in the differential diagnosis of hypertension. The proponents of “adrenal medulla hyperplasia” need to establish a clear set of diagnostic criteria to identify the few patients who might benefit from adrenalectomy.
Dr. Pheo
Monday, December 7, 2009
Interferences with pheo tests
The 5 pheo tests are subjected to interferences by quite a few factors. I list those factors here according to their significance. The most important message, however, is that these factors are usually not a big deal and can be rather easily figured out by an expert. Reaching a pheo diagnosis requires all things considered, rather than any evidence in isolation.
Major interferences:
1. In many diseases, catecholamines and metanephrines levels are indeed genuinely elevated, and can be rather high. About 30 such diseases are known. Obstructive sleep apnea, severe anxiety, and essential hypertension are the most common ones.
2. Any major stress, such as stroke, severe infection, and bad pain, elevate catecholamines and metanephrines levels.
3. Some drugs such as cocaine, phenoxybenzamine, tricyclic antidepressants, and monoamine oxidase inhibitors can also elevate catecholamines and metanephrines levels. Sinemet elevates dopamine levels tremendously.
Minor interferences:
Eating, standing, the stress of venipuncture, and old age. These conditions usually elevate catecholamines and metanephrines levels only slightly.
Variable interferences:
These are caused by drugs (usually beta blockers) and they are assay-dependent. The clinicians and the lab should communicate about them.
Errors:
Clerical and lab errors are also realistic possibilities. They are rare but can happen.
When I order pheo tests, I actually tell the patients initially not to worry about any interferences. If the results are normal (which is the case in most patients), the patient does not have pheo. If the results are elevated (usually in 20% of cases), I will then decide on a case-by-case basis.
This will be the last post this year. Happy holidays! I will continue posting next year.
Dr. Pheo
Major interferences:
1. In many diseases, catecholamines and metanephrines levels are indeed genuinely elevated, and can be rather high. About 30 such diseases are known. Obstructive sleep apnea, severe anxiety, and essential hypertension are the most common ones.
2. Any major stress, such as stroke, severe infection, and bad pain, elevate catecholamines and metanephrines levels.
3. Some drugs such as cocaine, phenoxybenzamine, tricyclic antidepressants, and monoamine oxidase inhibitors can also elevate catecholamines and metanephrines levels. Sinemet elevates dopamine levels tremendously.
Minor interferences:
Eating, standing, the stress of venipuncture, and old age. These conditions usually elevate catecholamines and metanephrines levels only slightly.
Variable interferences:
These are caused by drugs (usually beta blockers) and they are assay-dependent. The clinicians and the lab should communicate about them.
Errors:
Clerical and lab errors are also realistic possibilities. They are rare but can happen.
When I order pheo tests, I actually tell the patients initially not to worry about any interferences. If the results are normal (which is the case in most patients), the patient does not have pheo. If the results are elevated (usually in 20% of cases), I will then decide on a case-by-case basis.
This will be the last post this year. Happy holidays! I will continue posting next year.
Dr. Pheo
Sunday, November 22, 2009
Happy Holidays
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
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
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
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