Dr. Pheo's blog

A presidential tumor

2012-01-03T20:35:00.001-08:00

I hope everyone has had a great holiday season. As the presidential campaign is gaining more steam, it is interesting to point out that pheo is a very presidential tumor.

President Dwight Eisenhower had severe, labile hypertension and multiple heart attacks and strokes. He died of congestive heart failure in 1969. Autopsy unexpectedly identified a 1.5-cm left adrenal pheo. Some notable physicians believe that the president’s pheo might have even contributed to his heart attack in 1955. The president had one of the best cardiologists (Dr. Paul Dudley White) as his personal physician and pheo was already well known as a cause of hypertension in the 1950’s. One may wonder why pheo was not thought of by the president’s medical team. Having seen quite a few patients with small pheos, I actually do not think the president’s pheo was clinically significant. Had the pheo been found and resected before his death, the president’s clinical course would not have been much different.

Steven Kubby sought to become the Libertarian Party’s nominee for president in 2008. Mr. Kubby is well known for his support of medical marijuana use. He has malignant pheo. He also had one of the best cardiologists (Dr. Vincent DeQuattro) as his doctor. Mr. Kubby received conventional treatment for malignant pheo, then he found marijuana. He claimed that marijuana solely controls his pheo symptoms and tumor growth. There is no medical literature on marijuana and pheo. Although marijuana can be used to increase quality of life in patients with severe malignant pheo, I am not aware of any mainstream doctors who prescribe it as the only treatment of malignant pheo.

All the information about the above two patients with pheo was gathered from public sources available to all.

Happy New Year!

Dr. Pheo

Report from ISP 2011 Part II

2011-09-17T21:11:00.000-07:00

After chatting with the organizers, I realized that the primary reason to have the meeting in Disney Paris was financial—similar hotels in downtown Paris would cost twice as much. In addition, there is a grand chateau nearby that is undeniably French.

On 9/16, the lectures were mostly on progress in basic and clinical research. Regarding basic research, it seems rather clear that there are two “clusters” in pheo pathogenesis. The clusters concept is not entirely new (I wrote on the clusters before) but now the molecular details are worked out to a large extent. The scheme of pheo pathogenesis is a labyrinth of interconnected molecules. As I also do basic research myself, I am sometimes sarcastic about this kind of scheme. If everything affects everything else, how do we break the pathways? We need to figure out what the “driver” molecule is. But is there such a driver?

Some researchers reported the results of experimental targeted therapy in cell models, animal models, and in patients. The animal models are particularly intriguing and are real breakthroughs.

This meeting is very heavy on characterizing patients with SDH mutations and their individual mutations. The European countries are leading this effort. I have always wondered if SDH mutations are more common in Europe. In this meeting, I saw again some small countries reporting hundreds of patients with SDH mutations. I myself have not seen many patients in the US with clear familial paraganglioma syndromes. An alternative explanation is the difference in health care system. I cannot tell you how many patients I no longer follow due to their change of insurance plan. The national insurance system in Europe is a blessing to patients with rare and complicated diseases like pheo.

During the meeting, especially around 3 am when I was suddenly awake and trying unsuccessfully to go back to sleep, I reflected on the big picture of pheo patient care and where we should direct our research resource. I will elaborate my thoughts in later posts.

Dr. Pheo

Report from ISP 2011 Part I

2011-09-16T00:33:00.000-07:00

The 3rd International Symposium on Pheochromocytoma (called “ISP 2011” by the organizers) is being held in a Disneyland Hotel outside Paris. I am here attending this meeting. It is a 4-day meeting but most academic activities are concentrated on Sept 15 and 16.

The specific Disneyland hotel is kind of an odd choice of venue for an American attendee like me. I would pick a downtown Paris hotel on the left bank. Apparently my European colleagues are tired of Paris and prefer a place on a theme park. The hotel is full of little cute girls and boys dressed in Disney costumes, or pestering their parents to buy them a set or 2 of. The hotel is so serious about the Disney theme that you see Monsieur Mickey everywhere, including on shower curtain. At one moment today, I felt I was at home until someone said Bonjour to me. And a bottle of coke costs 3.5 Euros.

The meeting itself is simply fantastic so far. Today’s lectures and posters are actually very educational to me even though I believe I knew a few things about pheo before the meeting (I indeed presented a poster on pheo clinical care). Really great is the discussion with colleagues. All the big shots on pheo are here, including most doctors I recommended as pheo experts in a post 2 years ago. I am pleased to say that we share similar experience and opinions on many controversial issues. Patient support groups also have a prominent presentation.

The following is an incomplete list of new things I learned today:
1. Practical half-life of plasma metanephrines is longer than most people thought. Plasma metanephrines can linger for one month after complete pheo resection.
2. Most attendees agree on the importance of preoperative preparation even when the patient does not have hypertension at the time of diagnosis.
3. First-hand accounts of the discovery processes of the novel pheo genes TMEM127, SDHAF2, and MAX, by the discoverers themselves.
4. The 3 novel genes, however fascinating for studying pheo pathogenesis, probably have limited value in clinical care for most patients.
5. Apart from family history and clinical predictors, pheo markers and pheo tissue staining can also predict specific mutations.
6. No real progress in pathological diagnosis of malignant pheo. Basically even an expert pathologist cannot accurately tell if a primary pheo is benign or malignant.
7. Surgical indications of head and neck paragangliomas.
8. Still there are no commercial labs that can do plasma methoxytyramine in the US.
9. More and more people realize that pheo causes heart damage. I have observed that for many years and it is nice to see people now agree.
10. Some new vagaries of pheo. For example, cardiomyopathy can have a waxing-and-waning course even after phenoxybenzamine.

To be continued…

Dr. Pheo

"Pheo interest group"

2011-07-19T18:09:00.000-07:00

As pheo is a rare disease, it is no surprise that many doctors have little experience on pheo. Ideally patients with suspected pheo should be seen at large centers with extensive experience such as Mayo Clinic or National Institute of Health. On the other hand, most patients with suspected pheo do not actually have pheo and the management of pheo is not that complicated in most cases. Having traveled long distances, many patients with suspected pheo would feel that they probably could have saved the trip if their primary doctors had simply communicated with the experts in large centers about their conditions. A recent paper addresses the above situation somewhat, albeit indirectly.

In this paper, doctors at one center examined whether a "pheo interest group" could improve the diagnosis and treatment of pheo. The pheo interest group is nothing more than a group of doctors with a common interest in this rare disease. A few of the doctors have a large personal experience with pheo. The doctors compared the diagnostic accuracy and management of pheo before and after the formation of the pheo interest group and found that the quality of care improved after the group formation.

It might be expected that quality of care of course would be higher if the patients were seen by pheo specialists. This paper, however, shows that the pheo specialists do not have to see the patients directly. A phone call or email exchange between the primary doctor and a pheo specialist often does the job. The pheo specialist would review the clinical history, lab test, and imaging results (if available) provided by the primary doctor and arrive at a conclusion. The specialist only communicates with the primary doctor, without seeing the patient. The medical responsibility still rests in the primary doctor's hands. The primary doctor chooses to adopt the opinions of the specialist or not. As alluded in this paper, most primary doctors would adopt those opinions after they have had positive experience with the pheo specialists.

The moral: an inexperienced doctor should seek help from pheo specialists for diagnosis and management of pheo. Will the specialists be happy to answer the questions from non-specialists? They should. Take me as an example. I have been approached by doctors in my practice area and from remote places for pheo-related questions. I am happy to answer them. First of all, these questions are not very frequent so do not cost a lot of time. Second, I often learn new things on pheo from my colleagues who have questions in pheo. Last, it is rewarding for me to help my colleagues and patients (indirectly). I always make sure to emphasize that my opinions are "friendly" and non-binding. It is the primary doctor's responsibility to decide what to do.

Dr. Pheo

All those exons and MAX

2011-06-21T23:20:00.000-07:00

It is now a good time to do translational research on pheo. A clinician/researcher myself, I am following pheo research closely and I can tell that translational research on pheo is getting great results.

Translational research directly addresses mechanisms of human diseases. Translational research is the interface between basic and clinical research. The recent boom in translational research, in my opinion, is driven by two forces: patient advocacy groups and new technologies. Patient advocacy groups are more like corporate now. They usually hire MBAs to manage their operations and use more sophisticated strategies to advance their causes. New technologies are being developed almost every day. The new technologies need to find applications to show they are worthwhile in answering medical questions. With the synergy of those two forces, new technologies are more and more applied to less common diseases. Compared with common diseases, less common diseases, such as pheo, are more easily studied with the new technologies because they are more homogeneous. For example, there are so many types of prostate cancer, making a common etiology less likely. While pheo, by virtue of its rarity and uniform pathology, share more common features between each other.

One such new technology, exonomics, sequences almost every exon of the genome. Exons are the DNA stretches that actually encode proteins. (Introns, on the other hand, are DNA stretches that do not.) Because proteins are the doers and movers of biology, sequencing the exons likely yields insight of genetic causes of diseases.

Today, I noted a paper just published online which identifies a new tumor suppressor gene for pheo called MAX. The Spanish doctors include 3 families of familial pheo who do not have any mutations in known genes important for pheo. The exons of a lot of genes are sequenced in this study and MAX mutations appear to cause pheo in the 3 families. Now the list of pheo genes is getting even longer: RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, NF1, TMEM127, and MAX. Does this mean we have to sequence every gene in all patients? Of course not. Each patient’s unique family history and pheo presentation are still the basis for clinical care. Rather, this study demonstrates the power of careful translational research. For such research to be successful, the clinicians must identify a group of patients that share key common clinical features. Scientists, on the other hand, must know all the details of the technology and sieve through the data to find the real molecular deficit. The importance of patient participation of such research cannot be overemphasized.

Dr. Pheo

Adrenal biopsy and pheo

2011-03-24T18:46:00.000-07:00

Adrenal tumors are fairly common. Diagnosis and follow-up of adrenal tumors can be costly and inconvenient. So a reasonable question is "why don't we biopsy an adrenal mass to get a definitive diagnosis?" Here I will try to convince the readers that adrenal biopsy is seldom necessary or useful except in one situation. Most important to me is the one particular safety issue of adrenal biopsy: biopsy of a pheo can be catastrophic.

The one situation where we need adrenal biopsy is to determine the staging of a cancer. For example, one unfortunate patient has lung cancer and an adrenal mass. If the adrenal mass is benign, then the patient's lung cancer is of a lower stage. If the adrenal mass is lung caner metastasis, then the same lung cancer is of an advanced stage. Only biopsy of the adrenal mass will give definitive staging information of the patient's cancer.

Adrenal biopsy is not needed for the vast majority of adrenal masses because the diagnosis of adrenal mass can be confidently made in most patients without biopsy. Let me explain why. How do we know someone has an adrenal mass? Either the patient has clinical symptoms (e.g. paroxysmal hypertension) with suggestive biochemical test results (e.g. elevated plasma metanephrines) so that a functioning adrenal mass (e.g. pheo) is suspected, or CT or MRI is done on the abdomen for some other purposes (such as abdominal pain or cancer staging). In both cases, the imaging characteristics of the adrenal mass tell a lot about it. The size, density, enhancement, and appearance on various MRI protocols all matter. With additional biochemical testing, a good doctor is able to make the correct diagnosis of the adrenal mass.

One may wonder, OK, adrenal biopsy probably is not needed, but will it give important additional information? This issue is a little complicated for non-specialists. For the most common clinical question whether an adrenal mass is adenoma or carcinoma, adrenal biopsy can not answer. Regarding pheo, we just simply do not biopsy a pheo to confirm the diagnosis because doing so is too risky without any benefits.

Although generally very safe, adrenal biopsy can be potentially lethal if done to an unappreciated (or worse, suspected) pheo because of the risk of hypertensive crisis. Here are the basic facts: 5% of all incidentally identified adrenal masses are pheo and the percentage is higher if the mass is pheo-like on imaging. In addition, 6-24% of adrenal masses suspected to be malignancy or metastasis are actually pheo. It is not that every attempted biopsy of a pheo will result in hypertensive crisis. It happens in about 15% of times. Although this number does not sound very high, the extreme danger and the total avoidability of hypertensive crisis makes adrenal biopsy unacceptable in any patients without negative pheo test results.

To prevent hypertensive crisis from happening, ask these following questions before adrenal biopsy:
1. Is this adrenal biopsy really needed? (Answer: only needed for cancer staging.)
2. If adrenal biopsy is needed, have pheo markers been tested? (Answer: please test pheo markers and only do biopsy if the markers are considered negative.)

Dr. Pheo

Pheo in pregnancy

2011-01-23T20:22:00.000-08:00

Pheo in pregnancy is very rare. Most people with pheo are diagnosed after they are 40. If they know they have pheo, younger women would have the tumor removed before becoming pregnant. When pheo does occur in pregnancy, it usually is a big surprise and can have serious consequences to the mother and the fetus. Pheo in pregnancy is one of those “cannot afford to miss” diseases. Once suspected, diagnosis and treatment are usually straightforward and the mother and fetus can expect great outcomes.

Pheo in pregnant women is usually subclinical before pregnancy. The metabolic changes during pregnancy and the growing uterus tend to make the tumor more active. In my experience, pheo-induced hypertension usually occurs later in pregnancy but it can occur much earlier. Clinically it is difficult to differentiate between preeclampsia and pheo. My suggestion to obstetricians is to have a low threshold to test pheo. If the blood pressure is hard to control or there are paroxysmal symptoms such as palpitation, sweating, and headache, I would test pheo just not to miss it. In the vast majority of pregnant women, the test results are negative and pheo is ruled out. In those with clearly elevated pheo markers (the markers are usually markedly elevated in pregnancy), abdominal MRI is then done and the pheo is usually in one of the adrenal glands. CT and MIBG scan are contraindicated in pregnancy due to the associated radiation to the fetus. If pheo is diagnosed in the 1st or 2nd trimester (< 24 weeks), the woman is treated with phenoxybenzamine and beta blocker for preoperative preparation and the tumor is resected laparoscopically. If pheo is diagnosed in the 3rd trimester, the woman is still treated with phenoxybenzamine and beta blocker. When fetus is mature enough, Cesarean section is done, followed by tumor resection.

As pheo in pregnancy is a dramatic disease, there are always a few case reports every year, each with a little different flavor in it. The conclusion of most cases is to consider pheo in a pregnant woman with unusual hypertension. The case brought up by reader DJPheo was about a 27-year-old woman. Biochemical diagnosis was very clear but initial abdominal MRI did not identify a tumor. She received a PET/CT scan which localized the tumor. As DJPheo points out, the case raised a few issues. First, it is surprising that the abdominal MRI did not identify the mass (which is sizable at 5.7 x 2.8 x 3.1 cm) adjacent to the spine. Second, what should be done next if the mass is not seen even by experienced radiologist on abdominal MRI? Most would recommend MRI of the pelvis, chest, and neck. Third, if no tumor is seen after MRI of neck and trunk, what should be done next? I would make sure the blood pressure is well controlled and wait until after delivery (probably safer by C-section) for MIBG scan or PET. At any rate, this case should not be construed as evidence supporting PET/CT scan for localizing pheo in pregnancy. Rather the moral is that you need to find a good radiologist to read the MRI images.

Dr. Pheo

Corticosteroid and pheo

2010-11-23T08:26:00.000-08:00

This interesting topic is suggested by a reader. The relationship between corticosteroid and pheo is multifold and involves several fundamental physiological issues.

Firs of all, the close proximity of the adrenal cortex and adrenal medulla is an intriguing phenomenon. The adrenal glands are small organs. An adrenal gland actually is further divided into two organs, the cortex (secreting corticosteroid) and medulla (where pheo is derived from), each with related but different functions. Why is the adrenal medulla wrapped around by the cortex? Why isn't the medulla located inside other organs, say, the spleen or liver, or a free-standing organ like a ganglion? I can only think of two other organs, pituitary and pancreas, which are also further divided into two organs. In the case of pituitary, anterior and posterior; pancreas, exocrine and endocrine. The question is still unsettled. Existing evidence suggests that the corticosteroid secreted by the adrenal cortex is important in maintaining the medulla what it is. If one takes the cells from the medulla and puts them in culture, those cells automatically differentiate into neuronal cells. If one adds high concentrations of corticosteroid into the culture, the medulla cells will remain neuroendocrine cells and do not differentiate into neuronal cells. As the medulla cells are derived from the neurocrest during embryonic development, it is hypothesized that the migrating neurocrest cells encounter adrenal cortex cells (which provide high concentrations of corticosteroid) and really like them and stay with them. Thus the story of adrenal cortex and adrenal medulla.

Second, corticosteroid stimulates catecholamine production and release from cultured adrenal medulla cells. Corticosteroid increases catecholamine production by upregulating the key enzymes for catecholamine production. The mechanisms for which corticosteroid stimulates catecholamine release are not clear and may not be straightforward.

Third, corticosteroid prepares the target tissues of catecholamines to be responsive to catecholamines. That is why patients with adrenal insufficiency often have low blood pressure even when they have high catecholamine levels.

Lastly, there have been a number of case reports on pheo crisis induced by corticosteroid use. The pheo crisis usually starts a few hours after corticosteroid use. There may be hemorrhage within the pheo. In patients with known pheo or an adrenal tumor of unclear nature, corticosteroid should be avoided if possible. When corticosteroid is used, patients should be closely monitored. In my own experience, pheo crisis by corticosteroid is rare and not a predictable event.

On a separate note, I have been very busy recently. To readers who are used to my quick responses, I may appear to become sloppy. I apologize. I am still following this blog closely but not as frequently as before. Please rest assured that I will respond to your questions, just not as timely.

Have a great Thanksgiving!

Dr. Pheo

Report from NANETS meeting

2010-10-31T13:19:00.000-07:00

I just returned from the NANETS meeting. Before the meeting, I had hoped that I would get to meet colleagues interested in pheo and see new studies on pheo at the NANETS meeting held in Santa Fe, October 29 and 30. NANETS stands for North American Neuroendocrine Tumor Society. It is a very nice society of doctors who treat neuroendocrine tumors. Pheo is a neuroendocrine tumor. Although the meeting was very informative on carcinoid and pancreatic endocrine tumors, there were literally only one study on pheo and one talk that mentioned pheo in passing.

The one study by a researcher in Dallas essentially showed that the mTOR pathway probably is not particularly important in the transformation from benign to malignant pheo and mTOR inhibitors (such as RAD001) probably won’t work for malignant pheo. The talk on modern gene testing by Dr. Marx at NIH briefly mentions the controversial issue of prenatal diagnosis of MEN2 (I had an earlier post on this topic in this blog) but did not delve further into pheo gene testing.

Dr. Pheo

Coping with a frustrating disease

2010-09-11T15:34:00.000-07:00

In an earlier post, I described my experience on alternative diagnosis for patients who have pheo symptoms but without pheo. Most patients cope with their conditions very well and go on with their lives. A small number of patients would see multiple physicians, get numerous tests and imaging studies, and try all kinds of medications, herbs, or behavioral therapies, just to get a definitive diagnosis and to get back to their "perfect" health. As a pheo specialist, I am often the doctor who tells them not only they don't have pheo but a clear diagnosis cannot be established. I explain that further diagnostic work-up is unlikely to yield a definitive diagnosis. I then discuss the skills of coping with a frustrating disease.

First of all, these patients do have a disease. And the disease is not their fault. They just simply have it and they have not done anything to make the disease afflict on them.

Second, medicine has its limits. In spite of the ever-growing progress in medicine, there are many things we don't know in medicine. Sometimes, a definitive diagnosis cannot be reached no matter how hard one may try. We have to wait for the disease to fully reveal itself over time.

Third, look at the brighter side. Although we don't know the diagnosis, we do know that it is not a bad one. It is not cancer, not heart disease, not a disease that will cost a limb or organ, and not deadly if the symptoms have been going on for many years.

Lastly, the most important issue is coping with the disease. What is the purpose of perfect health? What are the important things in life? Can one pursue the goals in life with the disease? What limits one from doing the desired things? The best approach is to focus on functionality rather than on perfect health. If one can do the things one wants to do, that's not too bad even with the disturbing symptoms mimicking pheo. I like to use a car metaphor. Most of us want to have fancy expensive cars but most of us cannot get those cars. If we keep lamenting on the lack of those cars, we lose the purpose of life. Those of us without fancy cars will get a car we can afford with the functions that we think are the most important. Then we drive the car to do the things we want to do. Simply owning a fancy car won't necessarily drive us somewhere.

Dr. Pheo

Should you see Dr. Pheo?

2010-08-06T22:36:00.000-07:00

A few readers have expressed interest in seeing me for a formal consultation. I appreciate their encouragement. I do often see patients from other parts of the state or country. Seeing an outside expert has some pros and cons.

Pro 1. Definitive answer to specific questions. By the time you feel the need of seeing an outside expert, usually you already have done a lot of tests and imaging and received various opinions. The outside expert has the vantage position of reviewing all of the information and your natural clinical course. Of course the expert is also most experienced on some specific diseases. Whether the answer is yes, no, or further studies needed, you will have an answer.

Pro 2. Getting the best diagnostics and treatments. The outside expert usually works in an academic medical center and works closely with other experts. They can see things that were omitted before and usually do things “right”. Further diagnostic procedures and surgical operations are usually carried out by expert physicians as well.

Con 1. An expert is an expert on certain diseases but not on all diseases. Sometimes my patients are impressed by my knowledge on pheo and other neuroendocrine tumors and they assume that I know everything. I always explain that I do know a lot about pheo and other rare tumors and I am a good general endocrinologist as well, but my knowledge on other medical conditions is limited. Thus an expert can give you definitive answer to your specific question but she/he cannot solve all of your health problems.

Con 2. Follow-up is challenging. Patients and their diseases are ever-changing. For chronic and non-emergent questions, you can easily communicate with the expert by phone or email. For acute issues, it is important to ask a local physician who knows your condition well. Remember that the outside experts usually have responsibilities in research, teaching, and administration, besides clinical care. The expert may go to a scientific conference or vacation. All these make accessibility an issue.

Con 3. Extra cost and insurance coverage issues. These are self-explanatory.

Based on my experience, I believe there are some general rules-of-thumb on whether a patient should see an out-of-town specialist and how the patient can benefit the most from an outside expert. Here are my recommendations:

1. Find a local doctor who you trust and like and who has some basic knowledge on your condition. For pheo-related diseases, an endocrinologist or an internist is a good choice. This doctor has to be open-minded and comfortable at learning new knowledge.

2. Either ask the local doctor to identify an expert or find one yourself. Ask your doctor to contact the expert, explaining why the patient needs to see the expert and what specific questions need to be answered.

3. Before you go, send all doctor’s notes, lab results, CT/MRI and other imaging studies on CDs (not just the reports) to the expert.

4. When you are there, remember the specific questions your doctor and you want to ask the expert. Be realistic about what the expert can do (give definitive answers to specific questions) and cannot do (cure all ills). The expert may already have arranged additional diagnostics and possibly sessions with a surgeon or other experts so that you will have more efficient use of time there.

5. After you return, work closely with your local doctor and make sure that the local doctor and the expert communicate. Carry out the plan laid out by the expert and consult the expert on non-emergent questions. For emergency questions, you have to be lucky to be able to locate the expert all the time. Your local doctor is your best help.

What about seeing Dr. Pheo? All the rules apply. In addition, I will ask you to respect my wish to be anonymous as Dr. Pheo. Of course you will know my real name before you actually see me but please do not divulge Dr. Pheo’s identity publicly. I will post one of my email addresses later.

By the way, I will be on vacation from late August to Early September and may not have internet access during that time.

Dr. Pheo

If not pheo, what do I have?

2010-07-28T20:00:00.001-07:00

Pheo is a rare disease. In my practice, I see many patients who are suspected by their doctors of having pheo. After evaluating the patients, I generally find that only about 10% of them really have pheo, but the other 90% do not. The patients' response is usually predictable. Those who are diagnosed by me to have pheo are happy (and apprehensive, of course) after I discuss the nature of the disease and treatment plan. Those who do not have pheo are disappointed and frustrated. From the patients' point of view, they don’t care too much whether they have pheo or not per se, but they do want to feel better. If it is not pheo, what else is wrong?

About half of the patients for whom pheo is ruled out, especially young patients with hypertension, just have “essential hypertension”. Essential hypertension is a vague diagnosis simply meaning that the doctors don’t know why the patients have hypertension. Most patients with essential hypertension have a family history of hypertension. Their hypertension has multiple causes but none of the causes stands out obviously.

About a quarter of patients have obstructive sleep apnea (OSA). Patients with OSA are in a chronic stress mode so that they have catecholamine surges. OSA is pretty common and affects 5-10% of all people. Many people do not know they have OSA. The doctor has to probe whether the patient snores or has daytime somnolence. If the patient has suggestive symptoms, a consultation from a sleep specialist or pulmonologist is very valuable. The effects of CPAP treatment can be dramatic.

Another quarter of patients have anxiety disorder. People tend to have negative emotional reactions toward anxiety disorder. Some would wonder why they have the disease if they are not really anxious about anything. Anxiety disorder is a disease that we don’t know the cause of, just as depression is a disease that we don’t know the cause of. Patients should be evaluated by a psychiatrist to make the anxiety disorder diagnosis and to provide treatment.

There are nearly 30 other diseases that can also mimic pheo. These are generally much rarer and I do not see them often. Finally, I want to emphasize that the above is based on my personal experience; other doctors may have a different view.

Dr. Pheo

Is MIBG scan still needed?

2010-06-17T18:18:00.001-07:00

MIBG is a chemical that has similar structure to that of catecholamines. Radioiodine-labeled MIBG is taken up by both normal adrenal medulla and pheo. Because pheo is usually much larger than the adrenal medulla, if one exists, it tends to light up with MIBG much more than normal adrenal medulla.

When MIBG scan began to be used clinically in the 1980s, CT and MRI were not yet available in clinical care. Initial clinical studies indeed showed that the MIBG scan was a great test, boasting a sensitivity of 90% (meaning that if there is a pheo, the chance that it will be shown is 90%) and a specificity of 95-100% (meaning that if you don’t have a pheo, the chance that no signal will be shown is 95-100%). The very high specificity was especially appealing to those clinicians who had little experience on pheo. Pheo is a disease nobody wants to miss. So, the reasoning goes, if MIBG scan result is negative, pheo can be ruled out.

Since the 1980s, better biochemical tests have become available and CT and MRI household names. Of course the new tests and CT and MRI have their own problems but every patient suspected to have pheo get those. Should the patient also get an MIBG scan? Will the MIB scan provide new information on whether the patient has pheo in the first place, or if she/he has pheo, how many and where they are?

In this month, two papers with opposite views appear respectively in Journal of Clinical Endocrinology and Metabolism and Endocrine Practice, the former being the world’s leading endocrinology journal, the latter a smaller journal with a readership of mostly American practicing endocrinologists. The first paper is an analysis of 15 clinical studies on MIBG using iodine 123. The conclusion is that MIBG scan has a sensitivity of 94% and specificity of 92%. The authors of this paper believe that their paper “supports the continued utility of I-123 MIBG imaging in the diagnosis and management of patients with pheochromocytoma.”

The second paper is a retrospective clinical study of MIBG scan (both I-131 and I-123) in a large US hospital in the last 14 years. There are quite a few interesting findings in this paper. First, MIBG scan is not really indicated in 76% of patients (in other words, three quarters of modern-day MIBG scans are wasted). Second, the sensitivity and specificity are both only about 70%. Lastly, the most important finding is that the MIBG scan does not provide any new information after biochemical testing and CT or MRI. Even worse, about 35% of the MIBG scans provide misleading information (i.e. showing adrenal uptake but patient does have pheo or no uptake but patient has pheo). The authors of this paper conclude that MIBG scan “is not necessary for most patients in modern practice.”

Why do these two papers have opposite conclusions on the MIBG scan? Like everything else, the devil is in the details. The 15 studies analyzed in the first paper are all well-controlled clinical studies performed by expert clinicians. They use very stringent and clearly defined criteria to call the MIBG scan result positive or negative. As matter of fact, borderline adrenal uptake is considered a negative result. In the second paper, the MIBG scan is ordered by clinicians with various experience on pheo. Borderline adrenal uptake is considered positive result. The authors’ rationale is that most clinicians and patients treat any adrenal uptake as alarming, which I do agree with. If borderline uptake is considered negative, the sensitivity and specificity increase to about 90%. Even that, the MIBG scan still does not provide useful new information. The first paper unfortunately does not address the utility of MIBG scan after biochemical testing and CT or MRI. Besides the second paper, a couple of other papers in the last few years also fail to show that MIBG scan has any clinical utility.

What do I do? My own experience is that MIBG scan seldom helps. I do order it in the following patients who I already diagnose as having pheo: young patients (<50-year-old), patients with family history or mutations, patients with previous pheo, and patients with multiple pheo, patients who have adrenal masses on both sides, and patients in whom CT/MRI does not find the pheo. Those patients are rare, though.

Dr. Pheo

Prenatal diagnosis of pheo-causing mutations

2010-05-23T21:09:00.000-07:00

For people carrying mutations that cause pheo, the risk of having children with the same mutation is 50%. The decision on whether to have children is ultimately a personal decision, and is largely influenced by people's own experience with the mutations. Most people with pheo-causing mutations do decide to have children and are happy with their decisions. Some of my patients choose not to have children because they feel the burden on the children and themselves would be too big.

Some patients wonder if these mutations can be diagnosed before implantation or in early pregnancy. This is a complicated ethical issue. The technology is certainly available. Since the mutations are already known in most cases, finding the mutation is present or not is straightforward. If the mutation is found, to discard a fertilized egg or terminate an early pregnancy means very differently to different people, and extreme views exist. All the genetic syndromes that have pheo as a component are usually not very bad, and people with these syndromes can have very productive life, making the prenatal diagnosis controversial.

Currently these prenatal diagnostics are not offered to most people. If you have a very negative experience with a genetic pheo syndrome and desire to have children without it, you may want to talk with your doctor to see if it is possible to do a prenatal diagnosis.

Dr. Pheo

Clonidine suppression test

2010-04-06T21:49:00.001-07:00

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

Adrenal venous sampling, another outdated test

2010-03-17T22:24:00.000-07:00

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

Adieu, Glucagon Stimulation Test

2010-02-01T09:23:00.000-08:00

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

“Adrenal medulla hyperplasia”

2010-01-01T14:50:00.000-08:00

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

Interferences with pheo tests

2009-12-07T12:34:00.000-08:00

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

Happy Holidays

2009-11-22T19:23:00.000-08:00

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

Pheo tests in the real world

2009-10-01T21:39:00.000-07:00

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

Dr. Pheo's musings on health care cost

2009-09-01T07:55:00.000-07:00

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

Chromogranin A

2009-08-01T21:27:00.000-07:00

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

A sexual side effect of phenoxybenzamine

2009-07-01T22:41:00.000-07:00

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

Pheo growth speed

2009-06-16T18:39:00.000-07:00

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

A familial pheo risk calculator

2009-05-26T22:12:00.000-07:00

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

Silent? No way!

2009-05-11T20:58:00.001-07:00

You may have heard the term “silent pheo”. The sole purpose of this post is to convince you that “silent pheo” is a dangerous term and should be avoided at all cost. So next time you hear someone mentioning “silent pheo”, you tell the person there is no such a thing. Every time I hear the term, I get goose bumps and try to correct the person.

The term “silent pheo” or “subclinical pheo” apparently refers to a pheo in a patient who does not have hypertension or paroxysmal attacks. There are quite a few situations where a patient indeed has a pheo or paraganglimoa but does not have classical symptoms of pheo. Most paragangliomas in the neck and chest do not produce significant amounts of catecholamines. I would rather call these tumors "nonfunctional" rather than "silent". Very small pheos produce only small amounts of catecholamines so that they do not cause clinical symptoms. In the above two situations, blood tests for pheo show normal results. Most pheos in adrenal glands, retroperitoneal space, and bladder do produce catecholamines and are therefore "functional". The majority of patients with pheo have at least subtle symptoms that can be elicited by experienced physicians or realized in retrospect after removal of the tumor.

Some patients indeed have no apparent hypertension in spite of very functional pheos. These patients tend to be mismanaged and are at the highest risk of complications around surgery. Here are the reasons. These patients tend to be young and healthy before they have pheo. Their bodies try very hard to accommodate the bombardment of catecholamines by shrinking their blood volume. My experience is that their blood pressure may be normal while sitting or standing but rises when they lie down. An inexperienced doctor may think they have so-called "desensitization" of catecholamine receptors and can go ahead with surgery without preparation. Disaster happens if they do. They will have very high blood pressure while the tumor is manipulated and profound hypotension after the tumor is resected. Then they will get a lot of intravenous fluid their hearts can not handle. It will be a mess!

The bottomline is that if a patient has normal blood test results, whatever tumor the patient has may not be sufficiently functional. If the patient has elevated blood markers for pheo, the patient should be treated as having a functional pheo and undergo careful preoperative preparation, regardless of having hypertension or not. A young, otherwise healthy patient with a large pheo and high levels of markers but without hypertension is the most vulnerable one. That patient particularly deserves careful preoperative preparation.

Dr. Pheo

Dr. Pheo's Pheo Dr.

2009-04-28T21:37:00.000-07:00

I have two criteria for entering doctors into this list: 1) great clinicians, and 2) clinical researchers with >=3 papers on pheo. Both criteria have to be met to be on this list. You will see that the list is pretty short. Pheo is a rare disease, and a doctor usually has to practice at a metropolitan area to see enough patients to become an expert. I need the readers to send me more names and I will check them and select those who meet my criteria. These doctors are mostly endocrinologists and I know personally quite a few of them. They are real experts on pheo.

The list is by no means comprehensive and will be updated frequently based on reader feedback. For example, at least one or two doctors in the list are semi-retired and I don’t know how long they will practice. In addition, if I have missed a great clinician who also does clinical research on pheo, please let me know.

California
Paul Fitzgerald, University of California San Francisco
Run Yu, Cedars-Sinai Medical Center

Florida
Larry Kvols, H. Lee Moffitt Cancer Center

Iowa
Thomas O'Dorisio, University of Iowa

Massachusetts
Robert Dluhy, Brighams & Womans Hospital

Michigan
Brahm Shapiro, University of Michigan

Minnesota
William Young, Mayo Clinic

Missouri
Ruth Decker, St. Lukes Hospital

New York
William M. Manger, New York University

Ohio
Emmanual Bravo, Cleveland Clinic

Pennsylvania
Raymond Townsend, University of Pennsylvania

Texas
Camilo Jimenez, MD Anderson Cancer Center

DC
Karel Pacak, National Institute of Health

Canada
Shereen Ezzat, University of Toronto

UK
Ashley B. Grossman, St. Bartholomew’s Hospital

France
Pierre-Francois Plouin, Hopital Europeen Georges Pompidou

Germany
Hartmut Neumann, University of Freiburg
Graeme Eisenhofer, University of Dresden

Netherlands
Jacques Lenders, St Radboud University

Sweden
Barbro Eriksson, Uppsala University

China
Zhengpei Zeng, Peking Union Medical College

Japan
Yukio Hirata, Tokyo Medical and Dental University
Mitsuhide Naruse, Kyoto Medical Center

Australia
Bruce Robinson, Sir Charles Gairdner Hospital

Name a good pheo doctor

2009-04-19T20:49:00.000-07:00

I am compiling a list of doctors and medical centers that are experienced in pheo. I hope readers will share their PERSONAL experience with their own doctors and medical centers that they feel do a great job with pheo. Please indicate only the doctor's name and state, and the medical center's name. No other information please. I don't want any physician ad here at all.

I would ask you to only list a doctor who actually diagnosed or treated you. Name the doctor or center as comments to this post. Please only list if you are a pheo patient yourself. I hope we can come up with an accurate list of good pheo doctors voted by patients.

I may or may not list the doctors or centers in my own list, depending on the investigative work I will do to check. I have my own angle: from a fellow physician.

Dr. Pheo

Pheo imaging: now you see it, now you don't

2009-04-17T19:32:00.000-07:00

Today I will go over some intricacies of pheo imaging. The post is suggested by readers and I will answer some particular questions they have.

For most patients with real pheo, finding the tumor is rather straightforward. Most pheos are about 4-6 cm in diameter and have unique features. CT or MRI describes pheo well. An MIBG scan is then done to see whether there are other pheos lurking in the dark somewhere in the body. Unfortunately for some patients with real pheo and for a lot of patients who do not really have a pheo, imaging can be confusing.

First, for Peep, let's discuss how radiologists make a diagnosis. I work closely with quite a few great radiologists and begin to know their mindset. Radiologists are great at seeing things most other doctors don't see. But they will never be completely sure what the things are because many things can appear the same way. They need clinical information to make a judgment. So Peep, when your urine test results were very high, they will search your body from neck to pelvis trying to find something that might be pheo. A lymph node, or an uncommon normal variation of the shape of a normal organ, can be interpreted as potential pheo. Now the urine results are normal, radiologists will think you probably don't have pheo and take the same findings as what they normally are: lymph node or normal variations. So the same radiological finding in two patients can be read by radiologists as two different diseases. Think this way, the same red liquid in a fancy glass in an expensive restaurant probably is some great wine, while it must be melt lollipop if you see it on the pavement with a stick in the middle. Therefore, Peep, you may have some structures that are not exactly common but can be normal. What they are depends on the risk of your really having a pheo.

Second, for Dennis, let's discuss about MIBG scan. This is the single most misinterpreted imaging for pheo. MIBG scan itself is a great test. It is just some doctors do not know what to make of it. Technically, as Dennis points out, there is an I-131 MIBG, and there is an I-123 MIBG. In a nutshell, don't use the I-131 MIBG for diagnosis (it is used for treatment of pheo). Only use the I-123 MIBG which has a much better signal/background ratio. I-123 just gives much sharper pictures. Second, MIBG scan does not diagnose anyone with pheo, it just shows where the pheo is. As I discussed in a comment before, normal folks often have one adrenal taking more MIBG than the other but they don't have pheo. Nuclear medicine doctors, like radiologists (and any other doctors), will try to find a pheo if they are told there is really a pheo in a patient. If you use photoshop, Dennis, you will know that you can find something you like by adjusting the threshold, the contrast, or the color. If they know the patient has low risk, they will think a little spot might be just a fluke.

The key thing is communication between the endocrinologist and the radiologist. I used to routinely discuss with radiologists on every single case. Now that I know a little about pheo imaging, I still read every patient's images and I will call the radiologists when I feel something is not right. A pheo specialist should be a mini-radiologist on the adrenal gland, at least. My radiologist friends will call me as well if they feel something is not right.

Back to Dennis' point, the most likely place where endocrinologists and radiologists communicate to each other is an academic center with experience on pheo.

Dr. Pheo

Pheo and heart

2009-04-11T21:25:00.000-07:00

Endocrine diseases seem to always affect the heart in some ways. Thyroid diseases certainly cause abnormal heart functions and diabetes causes atherosclerosis. The other day, I joked with a cardiologist that they should "steal one more disease from endocrinologists." This disease is pheochromocytoma.

The heart of a pheo patient is bombarded with catecholamines. Although most patients with pheo do not have obvious heart symptoms except for palpitation, ECG reveals subtle abnormalities in about half of the patients with pheo. In patients with large pheos, all kinds of severe heart problems can show up. I have seen myocardial infarction, congestive heart failure, and life-threatening arrhythmia in patients with pheo.

As patients with heart problems usually go to see cardiologists, and because pheo is so rare and not on the radar screen of cardiologists in the initial work-ups, delay in diagnosis is rather common. I am not here to say that all patients with common heart diseases should test for pheo. That would be impractical and common things are common. But if a relatively young patient without clear risk factors develops heart disease, pheo should be considered.

Surprisingly, little is known on why catecholamines cause heart damage. Another disease called Takotsubo cardiomyopathy has a lot in common with pheo. Takotsubo cardiomyopathy is a heart muscle diseases in patients with sudden and severe emotional or physical stress. If any colleagues have insights in heart diseases in pheo, please comment here.

The morals are: 1) if you have pheo but don't have heart symptoms, you should at least do an ECG to make sure you don't have a significant heart problem; 2) if you have heart problems and nobody knows why, consider pheo, at least as a long shot.

Dr. Pheo

Follow-up after pheochromocytoma resection

2009-04-06T19:34:00.000-07:00

OK. Now you are diagnosed with pheochromocytoma, carefully prepared before resection, and operated by a great surgeon. Are you out of the loop yet? What shall you do next?

For patients with truly sporadic pheochromocytoma, 90% is the chance that they are cured. The remaining 10% may have recurrence or metastasis in the future. The problem is that the doctors can NOT predict who will be the lucky 90% and who will be the unlucky 10%. Therefore no patients should think that they are absolutely cured and all patients should have follow-up.

My own approach to patients with apparently sporadic pheochromocytoma is to measure plasma metanephrines 1 month after surgical resection to make sure there is no hidden tumor somewhere. Too early measurements can be false positive because I suspect based on my experience that there is some kind of depot of metanephrines in the body that is only depleted in a month. If the metanephrines are normal, I then measure them yearly or whenever they have symptoms suggestive of pheochromocytoma or when an adrenal or other mass is identified incidentally.

If a patient has familial form of pheochromocytoma or a gene mutation is identified, then the patient will have a much higher chance of recurrence or metastasis. Yearly plasma metanephrines are definitely needed. Imaging studies may be indicated depending on which form of familial pheochromocytoma or which gene mutations. Other components of the syndromes need to be screened; patients' family members need to be tested and carriers need to be regularly screened.

Now I have finished the basic topics on pheochromocytoma. I will write more on my personal experience and more interesting topics. If the contents of my blog are mostly based on my own experience and there is not much existing study on the topic, I will clearly state that at the beginning of the post. I welcome colleagues and patients to critique and to suggest. I will also just use "pheo", instead of the full name.

What to do if pheochromocytoma is diagnosed

2009-04-05T17:47:00.000-07:00

This topic is suggested by Dennis.

First of all, making the diagnosis of pheochromocytoma is not a trivial decision. It means more imaging studies and the eventual surgical operation. The patient has to ask two questions: 1) whether the diagnosis is correct, and 2) if the diagnosis is correct, how to proceed with further workups and management.

The experience of the doctor who makes the diagnosis is probably the most critical indicator of whether the diagnosis is correct. The average physicians see few patients with pheochromocytoma in their entire professional life, and they make the diagnosis themselves for even fewer patients. A reasonable question the patient needs to ask the physician is "how many patients with pheochromocytoma have you taken care of?" Most doctors won't be offended by this question. If the doctor has seen fewer than 3 patients, the doctor's experience on pheochromocytoma is too little to make an accurate diagnosis.

The other factor is the doctor's practice environment. Doctors affiliated with an academic center with a large experience on pheochromocytoma have more resources on pheochromocytoma. They know physicians with more experience, they know which radiologists to refer the patients to, and they know which surgeons have the best reputation on pheochromocytoma resecton.

The best doctors on pheochromocytoma are those working in an academic center and doing clinical research on pheochromocytoma. These doctors deal with this disease as part of their career and they have accumulated a large experience on this tumor. They also usually have a program on systemically follow patients after surgical resection.

If the diagnosis is made by an experienced physician, the diagnosis is probably correct. If the diagnosis is made by an inexperienced physician, it may not be necessarily correct, and to have a second opinion from an experienced physician is very prudent. If the patient has the means, it is always a good idea to have a second opinion from another experienced physician even if the diagnosis was already made by an experienced physician, especially when the first physician was not very sure.

To select a surgeon follows the same logic. The best surgeons are those working in an academic center with a large experience on pheochromocytoma and they have operated on more than a few patients with pheochromocytoma. They have seen the tricky perioperative course and work closely with endocrinologists.

As Dennis puts it, a patient should not settle for mere convenience after diagnosed with pheochromocytoma for the first time. Seeking opinions from experienced physicians is very important.

Screening for mutations: in whom, and how?

2009-04-03T19:07:00.000-07:00

Thank you again, Foxy, for asking an intriguing question on screening for gene mutations that cause pheochromocytoma. As this is a question of general interest, I put it as a new topic.

The chemicals a tumor produces do not tell much about whether the tumor is likely caused by a known mutation. Pheochromocytomas in MENII usually produce epinephrine, while those in VHL usually make norepinephrine. And in general, most pheochromocytomas tend to make norepinephrine, with or without mutations. Extra-adrenal pheochromocytomas (called paragangliomas) in familial paraganglioma (SDH mutations) and in Carney's triad (unknown gene mutations) may not produce catecholamines. Although these patterns of catecholamine secretion exist, they do not help in determining whether a patient should be screened.

Neither does tumor size or patient sex.

Some other clinical parameters do help. 1) Positive family history certainly suggests familial pheochromocytoma. 2) Age. The younger (<50), the more likely a patient has mutations causing pheochromocytoma. 3) Multifocal pheochromocytomas suggest mutations. 4) Signs of genetic syndromes. For example, a patient may already have meduallary thyroid carcinoma. If a patient has any of these, then genetic testing has higher yield.

Should any patient with pheochromocytoma be screened? At last year's International Symposium on Pheochromocytoma (ISP 2008, Cambridge, UK) which I attended, this topic was lively debated and the arguments were divided at the Atlantic Ocean. The European doctors seem to root for testing everyone as the tests are covered by either insurance or research centers. American doctors are more hesitant. No insurance companies in America I know cover genetic testing of pheochromocytoma in a patient without family history. A few American centers do offer testing in a research setting but the patients have to enter a trial of some sort. It can cost a patient thousands of dollars to do all the commercially available tests.

The other issue is which gene(s) to test first. Six (6) genes are known to cause pheochromocytoma: RET, VHL, NF1, SDHB, SDHD, and SDHC. Clinical history provides some help. Bilateral pheos: RET and VHL first. Extra-adrenal pheos: SDHB, SDHD, and VHL first. The hit rate is not very high even with these clinical history-based strategy. Above all, only 30% of patients without family history really have a mutation known to cause pheochromocytoma.

In my own practice, I highly encourage patients with family history to test for mutations. In those without family history, I explain the above and let them decide. Most patients without family history elect not to do genetic testing. They are followed clinically and by tests and imaging. It is unfortunate that genetic testing even in patients with family history are still not covered by insurance in many instances.

Suggestions on posting questions

2009-04-02T22:36:00.000-07:00

As readers begin to post comments or questions, I note that it may be hard for me to find questions posted under earlier topics. I would like to ask readers to post specific questions on pheochromocytoma under the most recent topic, whatever it is. For example, if you want to ask about interpretation of a specific chromogranin A test, please post the question under this topic simply because it is the most recent one and the question is easier for me to find.

Please still post comments or editorial questions under the specific topic you like to comment on.

I am not really savvy on the technical aspects of blogging. If there are better ways, please let me know.

Thanks.

Dr. Pheo

Doctor-patient interaction: in response to Foxy's question

2009-04-02T21:33:00.000-07:00

Thank you, Foxy, for your comments and question. You have just touched upon an important but overlooked issue in physician-patient relationship. You astutely observe that some doctors can be nervous and defensive when they are seeing patients with rare diseases (including PHEOCHROMOCYTOMA) that they know little about. There is no simple solution to the problem but I can provide some background here so that we can think of creative ways to solve the problem.

Physicians are used to be viewed as knowledgeable experts. They are supposed to help patients, to guide, and to cure. Many physicians also have a large ego as well and enjoy the role of a healer and its associated prestige. When they see a patient who suffers from a disease they know almost nothing, all the pretext of their psyche suddenly does not exist any more. A good number of physicians take this as an opportunity to learn with the patient and acknowledge their ignorance and willingness to learn, while some others will act out and use defensiveness to hide their embarrassment.

Although I don't think patients are to blamed for the problem, patients are indeed also part of the issue. Patients sometimes unknowingly encourage bad physician behaviors. For example, some patients may take arrogance as confidence of a physician. Some patients like black-and-white decisions and take discussion of nuances as indecisiveness of a physician.

At the end of the day, I guess the physician-patient relationship is like any other relationships--you relate with the one you like, and you separate from the one you dislike, and face the consequences.

Finding a good physician should aim at different goals at different disease stages. For definitive diagnosis, you need an expert on pheochromocytoma even though the expert may not be a perfect lady/gentleman. For surgical resection, you need an expert surgeon who has many cases before yours. For follow up, the character of the doctor is more important than knowledge and above all, you may not have a local expert in the first place.

As many of my own patients are from out-of-town, they often ask me how to pick a local doctor to coordinate the care for pheochromocytoma. The advice I give to my own patients is the follows: 1) you trust and like the doctor, 2) the doctor has an open mind on diseases she/he is not familiar with. The specialty of the doctor is not so important.

Let's not even start mentioning the hurdles on choosing physicians placed by HMO, the insurances, and other societal beings.

Dr. Pheo

My credential

2009-04-02T18:20:00.000-07:00

One reader suggests that I add my credential. Here is a bit about my credential:

I have an MD degree and a PhD degree (in one of the biological sciences). I am board-certified in Internal Medicine and Endocrinology. I practice as a specialist in pheochromocytoma and other neuroendocrine tumors in a large US hospital. I do clinical research in pheochromocytoma.

I never copy and paste any sentences to my blog. In other words, I type every letter in my blog.

The initial blogs are common situations in pheochromocytoma and I say the same words many times to my patients. Therefore I write them down here so that any one interested can read them. I anticipate I will answer more questions than write on general topics in the near future.

The real testament of my credential will be and should be whether my answers to specific questions make sense, help patients and colleagues, and are later confirmed to be correct.

Surgical resection of pheochromocytoma

2009-04-01T18:51:00.000-07:00

There are 3 surgical approaches to remove a pheochromocytoma: 1) open adrenalectomy, 2) laparoscopic adrenalectomy, and 3) cortex-preserving partial adrenalectomy.

The open adrenalectomy used to be the only approach but is now usually reserved for large (>10 cm) tumors. The whole adrenal gland along with the tumor is removed.

Laparoscopic adrenalectomy is the main procedure nowadays and is performed for most patients with pheochromocytoma. Again, the whole adrenal gland along with the tumor is removed.

Cortex-preserving partial adrenalectomy only removes the tumor but preserves the adrenal cortex (at least in theory). It is possible only in some patients. It is appealing to young patients with familial pheochromocytoma. These patients will have multiple pheochromocytomas on both adrenal glands and have to take medications for many many years if they have both adrenal glands removed at a young age.

The most important factors for a successful operation are experienced surgeon and anesthesiologist, and of course, careful preoperative preparation. The specific approach a surgeon adopts is less a factor. The surgeon has to be proficient in the specific approach she/he uses.

Preoperative preparation for pheochromocytoma

2009-03-31T18:19:00.000-07:00

Once a patient is diagnosed with pheochromocytoma, the patient needs to start medical treatment until she/he is ready for surgical resection. The preoperative medical preparation is often not optimal in clinical practice. Preoperative preparation, however, is critical for an uneventful operation and postoperative recovery.

First of all, pheochromocytoma is not an indication for urgent operation. There is time to prepare the patient for surgical resection of the tumor. For the uninitiated doctors and patients, the diagnosis of pheochromocytoma could elicit a sense of excitement and urgency. They would intuitively imagine that it makes sense to remove the tumor as soon as possible. While pheochromocytoma should be removed as soon as possible, the patient has to be prepared meticulously for the surgery.

The technical part of surgical resection of a pheochromocytoma is not complicated by itself. The tricky part is the patient's "hemodynamic status" during and after operation. "Hemodynamic status" means the patient's hear rate, blood pressure, and quality of the microcirculation inside organs. Pheochromocytoma differs from most other tumors because it produces catecholamines which increase blood pressure and heart rate to dangerous levels. Anesthesia and manipulation of the tumor often release large bouts of catecholamines that dramatically change the patient's "hemodynamic status". Preoperative preparation help prevent these complications and that's why it should be given to all patients.

The preoperative preparation needs to achieve 3 goals: 1) normalization of blood pressure, 2) replenishment of the patient's body fluid, and 3) recovery of heart function. All 3 goals are critically important and all should be met before the operation. Clinically inapparent abnormal heart functions are rather common in patients with pheochromocytoma and these should be reversed as much as possible before the operation.

There are 3 components in the preoperative preparation: 1) blood pressure medications, 2) salty food or intravenous infusion of fluids, and 3) a sufficient duration of the preparation for at least 2 weeks.

Depending on the patient's individual conditions, the doctors may make some adjustment on the regimen of preoperative preparation.

In my own experience, pheochromocytoma resection nowadays is remarkably safe if the patient is carefully prepared before the operation. The same operation can become disastrous if the patient is not carefully prepared. And most importantly, there is no reason why a patient is not carefully prepared. No excuse. Period.

Dr. Pheo

The final diagnosis of pheochromocytoma

2009-03-30T18:53:00.000-07:00

The final diagnosis of pheochromocytoma is based on three critical pieces of evidence: 1) elevated biochemical markers for pheochromocytoma, 2) an adrenal tumor, and 3) agreement between the extent of marker elevation and the imaging characteristics of the tumor. I have discussed 1) and 2) in previous posts, I will focus on 3) in this one.

What I mean for "agreement" is that the tumor size and the levels of markers should be roughly matching because larger tumors tend to have higher marker levels. For example, if a patient has plasma normetanephrine levels 20 fold elevated and has a 2-cm left adrenal tumor, the small adrenal tumor is not the pheochromocytoma that produces such high levels of plasma normetanephrine. There should be another tumor somewhere in the body. Another example. If a patient has plasma normetanephrine levels 1.5 fold elevated but has a left adrenal tumor measuring 5.5 cm, this left adrenal tumor is probably not a pheochromocytoma. I cannot give a very quantitative rule about marker levels and tumor size because there are no such rules. A doctor's experience is key here. The good news is that most tumors do have agreement between marker levels and tumor size on the first imaging study.

Dr. Pheo

The first follower of this blog

2009-03-30T18:35:00.000-07:00

Today I noticed that this blog has its first follower. I thank you, my friend, to follow this blog. I promise all of you that you will find this blog providing much-needed information on pheochromocytoma diagnosis and treatment. I want to take this opportunity to remind you of asking me questions about pheochromocytoma or commenting on the contents of my blog.

I believe that my blog has a unique niche among all websites on pheochromocytoma. The most important feature of this blog is that it is interactive. It will be just like a doctor friend who has in-depth knowledge in pheochromocytoma. Either you are not sure whether you have pheochromocytoma, or you do have it but are not sure what the best treatment is, or you want to know how you should be followed after tumor resection, you can ask Dr. Pheo. In the future, after many questions are asked and answered, you probably will find your questions already answered by reading past articles. As pheochromocytoma and neuroendocrine tumors are so intriguing, I am sure that I will always have something to write about, and you will always have something to ask about.

Dr. Pheo

Imaging studies for diagnosing pheochromocytoma

2009-03-29T20:50:00.000-07:00

If a doctor feels that the biochemical tests show a reasonable chance for pheochromocytoma, the doctor will order abdominal CT or MRI to see if there is an adrenal tumor. Abdominal ultrasound is not good enough for characterizing an adrenal tumor. On CT, most pheochromocytomas appear as a high-density mass, and on MRI, several protocols will determine if an adrenal mass is more likely to be a benign adenoma or "atypical" or "consistent with" pheochromocytoma.

A contrast material will be given intravenously. The contrast material is given because it will tell if a given organ or tumor has a lot fo blood supply or not. Pheochromocytoma has many blood vessels in it, thus it shows "enhancement" (just means it appears much brighter after contrast material is given.)

Sometimes, the biochemical tests suggest pheochromocytoma but CT or MRI does not find any adrenal masses. Now two things are possible: either the patient has pheochromocytoma but the tumor is somewhere else, or the patient does not actually have pheochromocytoma. The doctor should pause and weigh the evidence and decide which way to go.

If the biochemical tests strongly suggest that a patient has pheochromocytoma, regardless of imaging results, a functional scan called "MIBG" is done afterwards. Pheochromocytoma is very savvy in taking up MIBG. The value of MIBG scan is questionable for most patients but is considered an extra layer of caution. The MIBG scan can be falsely positive for some patients.

How is pheochromocytoma diagnosed?

2009-03-26T17:26:00.000-07:00

Once pheochromocytoma is suspected in a given patient, biochemical tests need to be done first. A common mistake is doing an abdominal imaging test before biochemical tests are done. Imaging tests should only be done after biochemical tests highly suggest pheochromocytoma.

There are actually a few issues with biochemical tests that can make the test selection and test result interpretation rather complicated. There are 5 biochemical tests for pheochromocytoma: 2 measure chemicals in the blood, 3 measure chemicals in the urine. The 2 blood tests are called "plasma catecholamines" and "plasma fractionated metanephrines". The 3 urine tests are called "24-hour urine catecholamines", "24-hour urine metanephrines", and "24-hour Vanillylmandelic acid (VMA)". Another blood test called "chromogranin A (CGA)" may be occasionally used but this test is secondary to the other 5 tests.

So which test or tests to use? There are no clear or definitive answers to this question. A doctor has to take several issues into consideration. Usually only specialists like Dr. Pheo myself knows most of the nuts and bolts of all those tests but even specialists sometimes do not know what the best test is. In an ideal situation, "plasma fractionated metenephrines" are the test Dr. Pheo prefers for a variety of reasons. For a certain patient in certain situation, any one of the 5 tests can be the best test.

Now the results are back. What do they mean? Test results should not be simply labeled as "normal" or "abnormal". The extent of elevation of the results compared with normal reference range is very important. Test results are also open to interference by medications, diseases, and human errors. So if you have a test result that is only 20% above the normal range, don't panic. Chances are you don't have pheochromocytoma. On the other hand, a 20% increase may indicate pheochromocytoma in other people. Really tricky, isn't it? Although Dr. Pheo myself is very comfortable in interpreting test results for most patients, Dr. Pheo at times has to ponder on some results for days before making a call.

How pheochromocytoma is suspected?

2009-03-24T18:11:00.000-07:00

In the present times and for the majority of patients, pheochromocytoma becomes a concern in 3 situations: symptoms, adrenal tumor, and familial syndromes.

The symptoms of pheochromocytoma are very diverse thus pheochromocytoma has earned the name as a "master mimicker" of other diseases. The symptoms can be as simple as mild hypertension but can also be as dramatic as strokes. The unique symptoms of pheochromocytoma "spells" are not as common nowadays as described in the classic literature. The spells may be elicited by emotional stress, exertion, pressure to the abdomen, or other stimuli the patients themselves often can figure out and avoid. The spells start with a sudden sense of doom or extreme fear, accompanied with headache, heart pounding, sweating, eye sensitivity to light, and other symptoms. A spell can last a few minutes to much longer. Blood pressure is invariably increased initially during a spell but blood pressure may drop to hypotension range due to reflexes of the body. Unusual hypertension and one or more components of the spell may make the doctor suspect pheochromocytoma. Only 0.2%-2% people with these symptoms actually have pheochromocytoma while symptoms are caused by other diseases in the majority of patients.

A mass in the adrenal glands is another reason for the doctor to suspect pheochromocytoma. Up to 5% of adrenal masses are pheochromocytoma. Therefore, tests for pheochromocytoma should be performed whenever a patient is found to have an adrenal mass. Pheochromocytoma found this way can be "silent" and the patient may be even free of symptoms.

The third situation is monitoring people who are carriers for mutations that cause familial tumor syndromes. Multiple endocrine neoplasia type II (MENII), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and familial paraganglioma syndrome are the most common syndromes. Carriers of the mutations related to these syndromes need to be screened periodically by blood tests and imaging.

Of course a combination of any of the 3 situations can occur.

What is pheochromocytoma?

2009-03-20T21:31:00.000-07:00

Pheochromocytoma is a tumor from the inner part of the adrenal gland. Each person has two adrenal glands, one on each side of the body. The adrenal gland is located on top of the kidney (thus the name ad-renal). The adrenal gland has an outer layer and an inner core. The outer layer is called cortex while the inner core called medulla. Pheochromocytoma is a tumor from the adrenal medulla. There are other cells in the body that are very similar to the cells in adrenal medulla and they can also produce pheochromocytoma as well. In that case, the pheochromocytoma is called paraganglioma.

Pheochromocytoma makes substances called catecholamines. These substances constrict blood vessels, increase blood pressure, deplete the body of fluids, and hurt the heart. Catecholamines are also normally produced by the adrenal medulla. Only in excess amounts, catecholamines cause harm to the body.

Pheochromocytoma is indeed very rare. Because a common symptom of pheochromocytoma is hypertension, pheochromocytoma is often considered in patients with unusual hypertension. Another reason that pheochromocytoma is often an issue is adrenal mass identified through the wide use of abdominal imaging.

Pheochromocytoma is a tricky disease. It can be deadly if not diagnosed or treated properly. On the other hand, if diagnosed and treated properly, patients with pheochromocytoma can be completely cured. Although the most common presentation of pheochromocytoma is hypertension, pheochromocytoma can mimics many other diseases such as anxiety, palpitation, or heart attack. In a recent study, it is shown that more than 20% of patients who undergo surgical removal of a presumable pheochromocytoma end up not having pheochromocytoma. Similarly more than 20% of patients who indeed have pheochromocytoma are diagnosed as a dangerous surprise.

I welcome patients and colleagues to post comments or questions to this blog and we can go over all aspects of pheochromocytoma on a case-by-case basis. Please keep any personal information confidential. For example, even if you yourselves may have hypertension and a concern for pheochromocytoma, just say "a friend of mine (or my cousin Johnny), 45-year-old man, has hypertension for a year and his doctor tells him that he may have pheochromocytoma."

Introduction by Dr. Pheo

2009-03-19T17:31:00.000-07:00

Hi,

I am a medical specialist in pheochromocytoma and other neuroendocrine tumors. These tumors are rare and a general doctor may not have enough experience in them. Diagnosis and treatment of these tumors are therefore often sub-optimal. I would like to share my experience with patients and colleagues through this blog and hope all of us will benefit.

I will initially keep my identity anonymous. Please keep in mind that I do NOT establish a physician-patient relationship between me and another person through communicating with this blog. I can NOT offer specific medical opinions on this blog. I am happy to provide general information regarding your question. You are solely responsible for the consequences of using the information I provide here. If you have a question, please keep your personal information confidential and use general precautions as you would in any communications over the internet.

I can not promise that I will check the blog frequently. For questions you consider urgent, please direct them to your own physicians.

Best regards,

Dr. Pheo