Chromogranin A

Chromogranin A (CGA) is one of the most important tests in the diagnosis of neuroendocrine tumors. Unfortunately, it is also one of the trickiest tests to interpret. I am asked very frequently by patients and colleagues on interpretation of CGA.

CGA is a protein. It is produced in neuroendocrine cells and released into the circulation. CGA is metabolized to fragments and cleared by the kidney. CGA is actually a hardy protein. It is very stable in serum at long incubation at 37°C, or even after repeated freezing and thawing. It reflects the cumulative secretory activity of all those cells. So CGA can be elevated by any of the many types of neuroendocrine cells. CGA indirectly reflects tissue or tumor mass. CGA is elevated in most patients with pheochromocytoma or paraganglioma.

Several issues need to be considered when interpreting the CGA results. One problem is that the reference range differs among labs. In Quest, the upper limit of normal is 36 ng/mL, while in Labcorp, it is 5 nmol/L (equivalent to 245 ng/mL). The Quest test is more useful. (Note added on July 26, 2010: One reader contests this point. Please see comment 25 and others.)

CGA can be elevated in benign and reversible conditions. In a type of gastritis (atrophic gastritis), acid production is decreased, which in turn stimulates CGA production from the stomach.

The most common cause of elevated CGA in clinical practice is anti-acid treatment, especially proton pump inhibitors for acid reflux. CGA will increase even after days of PPI in healthy volunteers. The prevalence of elevated CGA is common in patients on PPI, and more than 60% patients on PPI have elevated CGA after 4 years.

Because CGA is cleared by the kidney, CGA is elevated in kidney failure.

CGA can be elevated in several other diseases: hepatocellular carcinoma, prostate cancer, adrenal incidentaloma, pituitary tumors, and rheumatoid arthritis.

In summary, CGA is an important marker for neuroendocrine tumors. In routine clinical practice, the most common cause of high CGA is anti-acid treatment. Kidney failure and atrophic gastritis are also causes of high CGA. In a patient is not taking anti-acids or has chronic kidney failure, high CGA levels raise suspicion of neuroendocrine tumor or other tumors, including pheochromocytoma.

Obviously, CGA is not specific for pheochromocytoma and is less important than metanephrines in the diagnosis of pheochromocytoma. CGA can be used in combination with metanephrines to increase diagnostic accuracy for pheochromocytoma.

Dr. Pheo

A sexual side effect of phenoxybenzamine

As the cliché goes, the best teacher of a doctor is the patient. There is nothing more true about it, especially on side effects of a drug.

Years ago, I had the opportunity of seeing a very pleasant 30-something male patient. He had been diagnosed with pheo by another doctor and saw me for a second opinion. He had been on phenoxybenzamine for the alleged specific anti-pheo effects for more than a year. His blood pressure was well controlled by phenoxybenzamine. After reviewing the numerous tests and imaging studies, I determined that he did not have pheo. I recommended using a diuretic medication for blood pressure control, instead of using the expensive phenoxybenzamine. He was so relieved once he learned that he would not absolutely need phenoxybenzamine—but not due to financial reasons. He told me that he could not have children while on the drug but his wife and he so much wanted to start a family. An inquisitive soul, I asked him to elaborate. The patient shyly told me that he had not had ejaculates after he was on phenoxybenzamine.

That was the first time I learned this very common side effect of phenoxybenzamine in men. We all know the standard common side effects such as nasal stuffiness, orthostatic hypotension, and fatigue. Ejaculatory failure happens in almost every man taking phenoxybenzamine. Most men do not complain of this side effect, probably because the treatment is usually short-term and patients have anxiety before operation so that they do not attempt sexual activity. Men may also be embarrassed to talk about this what is perceived by some as a sensitive but trivial symptom.

The mechanism of ejaculatory failure is not retrograde ejaculation, rather, patients simply do not transfer seminal fluid (the bulk of ejaculates) to be ejaculated. The good news is that this sexual side effect is completely reversible in 1-2 days after discontinuing phenoxybenzamine. And phenoxybenzamine does NOT affect libido, potency, or orgasm.

Prazosin and doxazosin usually do not cause ejaculatory problems but sometimes they do.

After I learned this side effect from that patient, I always inform my male patients of this unique side effect of phenoxybenzamine. Most of them appreciate my warning. Some would say “Doc, sex is the last thing I am thinking of now.” Hey, you never know. Sexual activity is generally not contraindicated in patients with pheo, provided that it is not particularly violent.

Dr. Pheo

Pheo growth speed

One important feature of pheos is that they always grow. The growth speed of pheo, however, is only known for patients with von Hippel Lindau disease. For people with true sporadic pheo (~70% of all pheos), we have little knowledge on the growth speed of their pheos. The reason is that familial pheos can be monitored but sporadic pheos are usually resected once they are diagnosed. Only under two conditions, patient's choice of delaying surgery and omission of pheo testing of incidentally-identified adrenal mass, the growth speed of sporadic pheos can be assessed.

I recently took care of a patient with likely sporadic pheo. This patient's adrenal pheo increased from 0.6 x 1.2 cm to 3.0 x 3.6 cm in 6 years. This patient is among the few I know with recorded growth speed of a sporadic pheo.

The information on pheo growth speed is much needed to tell patients what they will expect of their tumor. I would like to do a survey of the growth speed of pheo, whether with genetic mutations or not. If you have a pheo that was imaged multiple times, please let me know the size of the tumor, the time interval in-between imaging, and whether you have a pheo syndrome (with mutations) or not. I thank you in advance.

Dr. Pheo

A familial pheo risk calculator

Two papers on risks of familial pheo appear in the May, 2009 issue of the Journal of Clinical Endocrinology and Metabolism. One Paper describes experience in about 500 Italian patients, the other over 200 Spanish patients. The paper on Italian patients is particularly informative. With the three large studies now available (the original landmark study in 2002 published in the New England Journal of Medicine and these two new papers), I feel it is time to quantify the probability of having familial pheo. I have prepared a calculator of risks for familial pheo. The calculator is based on the 3 above large studies. The calculator has only five input variables:

1) Primary location of your pheo/paraganglioma
2) Age at diagnosis
3) Family history of pheo or paraganglioma (Yes/No)
4) Single or multiple pheo/paraganglioma (Single/Multiple)
5) Do you have any of the following diseases in addition to pheo/paraganglioma (Yes/No): medullary thyroid cancer, hyperparathyrodism, hirschsprung's disease, mucosa neuroma, hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumor, and skin neurofibroma?

As this is a blog format, I can not post the calculator on line. If you tell me the answer to the 5 variables, I will tell you your risk of having a familial pheo. The calculator has its intrinsic limitations and perhaps even errors; and the results are only as good as the accuracy of the 5 variables. Also I can not tell you the chances of any particular mutated genes.

Of course, the calculator only gives you an estimate of risk and only your doctor and you shall decide whether to do genetic testing. You should use the results of the calculator responsibly and at your own risk; I can not be held liable for any adverse consequences.

Dr. Pheo

Silent? No way!

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.

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, University of California Los Angeles

Iowa
Thomas O'Dorisio, University of Iowa

Massachusetts
Robert Dluhy, Brighams & Womans Hospital

Michigan
Richard Auchus, University of Michigan

Minnesota
William Young, Mayo Clinic

Missouri
Ruth Decker, St. Lukes Hospital

Ohio
Charis Eng, Cleveland Clinic

Pennsylvania
Raymond Townsend, University of Pennsylvania

Texas
Camilo Jimenez, MD Anderson Cancer Center

DC
Karel Pacak, National Institute of Health
Constantine Stratakis, 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
Roderick Clifton-Bligh, Royal North Shore Hospital

Name a good pheo doctor

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