The Endocrine Society Guideline on pheo

The Endocrine Society, the world's largest scholarly society on endocrine diseases, just released its clinical practice guideline on pheo and para (http://www.endocrine.org/education-and-practice-management/clinical-practice-guidelines). The writing committee includes leading international experts on pheo and para.

Before the publication of this guideline, the North American Neuroendocrine Tumor Society (NANETS) published a guideline in 2010, and the First International Symposium on pheo published another guideline in 2007. The authors of the 3 guidelines overlap significantly. I am very familiar with the two previous guidelines.

I have read the new guideline in detail and am pleased to find that some of my own work is cited. Overall, the Guideline is thoughtful, up-to-date, succinct, and clear. I congratulate the writing committee on its completing such a wonderful piece. It has 6 parts: biochemical testing, imaging, genetic testing, perioperative management, surgery, and personalized approach. The Guideline is a great resource for physicians and patients. If the Guideline is followed, the majority of clinical scenarios will be covered very well and the clinical decisions will be correct most of the times. For non-specialists, the Guideline is a great resource for decision making regarding pheo.

I like the Guideline so much that I cannot think of almost anything that I have to change if I had been involved in the writing. As a pheo specialist, I do find a few places in the Guideline where some discussions are worthwhile. You can call me nitpicker but you will see why the following issues can actually matter in clinical practice.

Table 1. I would add heart problems without clear causes as another indication for testing. Over 10% of patients with pheo present with cardiovascular complications. Most patients with heart disease, indeed, do not have pheo, but those without clear common causes should be tested for pheo. For example, most patients with heart failure do not have pheo and pheo testing is not needed if a clear cause such as severe coronary heart disease is present. A young patient with heart failure of unknown (“idiopathic”) causes, however, should be tested for pheo. Pheo-induced cardiomyopathy is reversible upon pheo removal so that it is worthwhile to test for pheo in patients with heart problems without clear causes.

1.4. “All positive results require follow-up.” This recommendation is not incorrect but deserves some comments. In real world, most positive results are false alarms. In my experience, more than 50% of patients with positive results can be safely reassured that they don’t have pheo and further testing is not needed. A common example is an elderly patient with hard-to-control hypertension who has a slight elevation of pheo test results. I would be very comfortable in telling the patient that further testing for pheo is not needed. The Guideline goes on to say that the ways of follow-up should be determined by the pre-test probability and by clinical judgment, and that clinical follow-up (i.e. without further testing or imaging) is appropriate in select cases.

4.2. “We recommend preoperative medical treatment for 7 to 14 days to allow adequate time to normalize blood pressure and heart rate.” This recommendation is the only one that I have serious issues with. 1) This recommendation assumes that all pheos are the same and gives a general recommendation without considering the individual perioperative risks of each pheo. An incidentally found 1-cm pheo and a 7-cm pheo causing cardiac arrest are certainly different and should be prepared differently. 2) It perpetuates a long-held but likely incorrect notion that the goal of preoperative preparation is to normalize blood pressure and heart rate. Not uncommonly, patients with very active pheos have normal blood pressure and heart rate. An un-experienced doctor may feel that preoperative preparation is not needed because those patients already “achieve” the goals of preoperative preparation. Normal blood pressure and heart rate are important before operation but they should not be the goals of preoperative preparation. The real goal should be to revert or prevent pheo-induced cardiomyopathy.

A major challenge in writing clinical guidelines is to make balanced recommendations covering both common and uncommon clinical situations. A guideline will become too long and cumbersome if it tries to cover all situations. The Endocrine Society Guideline on pheo did a great job in balancing the common and uncommon situations. When we read guidelines, we should bear in mind that they are intended as “guidelines” and it is up to us to apply the guidelines to each unique patient. In other words, the physicians and patients should make the final clinical decisions, using the guidelines as a reference but not the only reference. Clinical experience and literature review are perhaps more important than following guidelines. As the Endocrine Society Guideline on pheo emphasizes, a multi-disciplinary team on pheo is the key to optimal pheo diagnosis and management.

Dr. Pheo

Five years!

On March 19, 2009, when I started the blog, I was really not sure how it would do in the long term. With the enthusiastic support from readers all over the world, the blog has been running for exactly 5 years. I will keep the blog running as long as someone has a question on pheo but cannot find the answer elsewhere.

Thank you very much for your support!

Dr. Pheo

Tis the season to be false positive

If the interpretation of pheo marker results is already complicated, our current season adds one more variable for us to consider.

A seasonable paper on seasonal variations of pheo marker levels was just published. The researchers charted pheo blood marker levels in each month of the entire year in people without pheo. They found that the normetanephrine levels were about 20% higher in wintertime than in summertime. The normetanephrine levels did not vary between seasons in patients with pheo. As you probably have guessed, the study was done in the Netherlands and Germany (one city in each country) where there are big temperature differences between winter and summer. Actually, during the same wintertime, the normetanephrine levels are a little higher in the colder city. To prove that the cold temperature causes elevation of normetanephrine levels, the researchers warmed the forearms where blood was drawn and found the levels dropped.

The 20% higher blood normetanephrine levels in wintertime do not sound too much but can make a result from high normal to borderline abnormal. We already know that anxiety, stress, sleep apnea, hypertension, older age, and some medications are associated with higher normetanephrine levels. All these factors, including wintertime, need to be weighed before a decision is made about the lab results. As I have reiterated many times before, the pheo diagnosis should not be based on a single lab test but should be based on the totality of the patient’s condition. Clinical presentation, lab results, and imaging characteristics are all important.

It would be interesting to do the same study in a tropical area like Hawaii. We would predict that the blood normetanephrine levels in people without pheo remain similar throughout the year.

The new wintertime confounding factor in pheo test result interpretation reminds us once again that a test result is influenced by many factors. Simply calling a test result positive or negative will result in misdiangosis. 

Dr. Pheo

Low-risk and high-risk pheo

Happy Thanksgiving! This will be the last piece for 2013. I wish everyone a great holiday season and a wonderful year of 2014!

When we, health care professionals and lay people alike, talk about pheo, we seem to assume all pheos are the same. In medical textbooks, pheo is mostly discussed in a way that gives the reader the impression that if one has a pheo, one will have all the classical signs and symptoms of pheo. In the lay communications, the heterogeneity of pheo is even less appreciated. One pheo, however, can be very different from another. I have written about clinically “silent” pheo, pheo associated with normal blood pressure, pheo that causes frank cardiovascular problems, small pheo, pheo caused by genetic mutations, etc. Understanding the heterogeneity of pheo is critical to tailor pheo management to an individual patient with a particular pheo.

Preoperative management of pheo has been controversial since the very beginning. I myself have advocated careful preoperative preparation for every patient with pheo. On the other hand, there are many different ways of preoperative preparation used by experts, all with similar excellent outcome. Recently, one review article proposes risk stratification for pheo, which may help reconcile the paradox.

The article divides pheos into 3 categories: low-, intermediate-, and high-risk, according to the risk of heart complications a particular pheo can impose on a patient. Low-risk pheos are those smaller than 3 cm in diameter. This article proposes that specific preoperative preparation is not needed for low-risk pheos. High-risk pheos are those that already cause obvious cardiovascular complications such as arrhythmia, heart attack, heart failure, or stroke. Careful preparation is needed for high-risk pheos and the doctors need to coordinate their care so that the preparation regimen is safe and effective. Intermediate-risk pheos are those that are none of the above. The preparation regimen should be individualized. The higher the relative risk of cardiovascular complications a pheo has, the more careful and longer the preparation it requires. 

It needs to be emphasized that this risk stratification is based on clinical observation and just a proposal. It has not been prospectively tested. What am I doing? I currently still carefully prepare everyone. If a patient does have a low-risk pheo, I am more relaxed with the regimen.

Dr. Pheo

Sorry but I missed many of you!

I just realized 2 days ago that my email software had placed all the alert messages from the Dr. Pheo blog in a strange new folder. You can see that obviously I am not very savvy on software stuff. I have been wondering lately why readers do not ask questions any more. At one time, I entertained thoughts that perhaps I had answered most questions so that readers wouldn't ask any more. Then 2 days ago, I tried to see the content of a strange folder in my email software and saw 30 questions from this blog.

I have since dutifully answered all of them but the answers are quite untimely. I apologize. The lesson learned is that if I do not see questions from this blog, I should check all the email folders.

Dr. pheo

Another "dopamine-producing" pheo

Some days ago, I got a call from a physician asking me for suggestions on how to proceed with a “dopamine-producing” pheo. The patient was an elderly man with labile blood pressure and varying heart rate. Pheo was suspected. Urine dopamine levels were >5000 mcg/24 hours (normal reference range: 60-450). But was it a pheo?

I usually get 1 or 2 calls on potential "dopamine-producing" pheo every year. True dopamine-producing pheos are extremely rare and do not cause clear symptoms. These tumors are usually localized outside the adrenal glands and may present as metastatic tumors. They are usually clinically silent until they grow very big and causing abdominal discomfort. Specifically they do not cause hypertension per se. Only about half of the patients have high dopamine only and the other half have high dopamine and high epinephrine or norepinephrine as well.

In any given situation, the most common cause of very high urine or plasma dopamine is the medication Carbidopa-Levodopa (Sinemet) for Parkinson disease. These patients usually have every high dopamine but normal or slightly elevated epinephrine or norepinephrine. Levodopa is presumably converted into dopamine which is then detected by the catecholamine measurement. Parkinson disease and related conditions such as multiple system atrophy often cause sympathetic instability in the forms of fluctuating blood pressure and heart rate, orthostatic hypotension, and syncope, all of which resemble pheo symptoms.

I therefore asked the physician if the patient had Parkinson disease. He was reasonably surprised and told me the patient did have Parkinson. I then asked if the patient took Sinemet. He checked the medication list but Sinemet was not on the list. I was not swayed. Many patients think Parkinson is a disease of old age and Sinemet some kind of food supplement so they do not tell their doctor they are taking it. Luckily the patient was still in the clinic. The physician told me he would ask the patient about Sinemet and call me back. He didn't call me back. I assumed the patient was taking Sinemet, as all of the patients I had been asked about are.

Dr. Pheo

P.S. I have not written about pheo for 7 months for various reasons. My job is more demanding, to be sure. Also, there has not been a major advancement in the pheo field in the last 7 months, in my opinion. 

Pheo and heart II

I first wrote about pheo and heart 4 years ago (April 2009). At that time, my instinct was that heart damage is a key issue for pheo. Over the years, after seeing more patients with heart complications caused by pheo and discussing with colleagues about the issue, I increasingly appreciate the intricacies of pheo-induced cardiomyopathy.

Pheo-induced cardiomyopathy is not a new finding. The first two cases of pheo known to medicine were both about pheo-induced cardiovascular collapse in modern terms. The correlation of pheo and cardiomyopathy was clearly and convincingly reported in the 1960s. Hundreds of case reports of pheo-induced cardiomyopathy have been published in the last 50 years. The problem is that pheo is very rare and pheo-induced cardiomyopathy is even rarer. Many cardiologists and endocrinologists simply are not aware of the concept of pheo-induced cardiomyopathy. Part of the reason why pheo-induced cardiomyopathy is not well known is that there are few, if any, systemic studies on pheo-induced cardiomyopathy.

In the last year, two very similar systemic studies were published on pheo-induced cardiomyopathy. Both studies were retrospective review of experience of a large single medical center (in Prague and Los Angeles, respectively). In both studies, the authors focused on patients without known history of pheochromocytoma but presenting with cardiovascular complications such as arrhythmia, heart attack, heart failure, or stroke. Their results were strikingly similar as well. The Prague study included 145 patients, 28 of them (19%) presented with cardiovascular complications. The Los Angeles study was about half the size with 76 patients, but still 9 of them (12%) presented with heart complications. Because both medical centers are large tertiary referral centers and tend to see sicker patients, the incidence of cardiovascular complications may be overestimated but the 12-19% incidence is at least true in large hospitals. Both studies showed that there are no good predictors on which patients will get cardiovascular complications. Specifically, most patients with cardiovascular complications do not have hypertension. There may be a higher risk for cardiovascular complications if the pheo is biochemically very active and large. I have mentioned in a previous post that pheos smaller than 3 cm do not cause cardiovascular complications. Both studies showed that once correctly diagnosed and managed, the pheo-induced cardiomyopathy is reversible. The moral of the studies is that if a patient presents with cardiovascular complications, pheo is a possibility, even if the patient has no history of hypertension. It is also reassuring that the cardiomyopathy is reversible after pheo removal.

Dr. Pheo