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