Which patients should be screened for hemochromatosis?

When David Little, MD, associate professor of family medicine at Wright State University in Dayton, Ohio, sees a patient with symptoms suggesting hemochromatosis, he orders several phenotypic diagnostic tests. After a confirmed diagnosis, he discusses genetic testing in a very specific way.

"Genetic testing I reserve for people with the disease and their family members, to see who else might be at risk," he said.

It's all part of a revolution. A decade ago, hemochromatosis was a rare genetic disorder that most primary care physicians had only read about in textbooks. Now, it's inching its way up the index of suspicion, and researchers and policy-makers are struggling with the question of what role genetic testing should play in screening for it.

"Screening is a complicated topic," said Paul Adams, MD, professor of medicine at London Health Sciences Center in Ontario, who has been researching the issue for years. "It's better to diagnose early rather than late, but the gene test is very specific. Not everybody is marching towards bad complications of hemochromatosis, and there may be some negative aspects of screening."

Most organizations, including the U.S. Centers for Disease Control and Prevention, advise against using this genetic test for the general population and recommend that it be used like Dr. Little does, at least at the moment.

Increasingly, though, the question is being asked whether it is possible that there might be a role for this test somewhere between screening only family members and screening everybody in the population. Could there be specific groups for whom this test would be beneficial?

The American College of Physicians is debating what its policy on this issue will be. Also, the first paper -- out of dozens expected over the next few months -- from the large-scale Hemochromatosis and Iron Overload Screening Study was published in the April 28 New England Journal of Medicine.

New insights

This study recruited nearly 100,000 patients. Researchers tested participants' blood for iron levels and genetic mutations. This first paper found that the C282Y mutation, long implicated in the disease, was linked to elevated iron levels in whites but did not explain high iron in non-whites. Asians and Pacific Islanders, on average, had the highest iron levels but were least likely to have this particular gene mutation. Authors of the paper said the finding indicates that this kind of genetic testing would have little utility outside of the Caucasian population.

" 'Screen the whole world' is not going to be the recommendation," said Dr. Adams, the lead author.

The forthcoming papers are expected to narrow the field even further. They should answer questions about the benefits of screening and about the disease's natural history.

But numerous sticking points remain about this kind of genetic testing that might not be settled by the overall screening study.

For example, there is significant debate over how penetrance of the gene should be clinically defined. This most recent study described it as having elevated lab values for iron and, by that standard, penetrance was as high as 88% in Caucasian men. But some experts feel that penetrance should be defined as causing actual illness.

"It can be a very severe disease and needs to be treated, but physicians have to be careful not to be treating lab findings. We need to treat patients," said Ernest Beutler, MD, professor and chair of the Dept. of Molecular and Experimental Medicine at the Scripps Research Institute in California, who has also researched the issue.

In addition, it is beginning to become evident that iron metabolism might not be as simple as just this single gene. One abnormal gene could be balanced or amplified by another. Environmental factors also might contribute.

"We're learning how incredibly complicated iron homeostasis is, and there are some things we don't know," said Bruce R. Bacon, MD, one of the authors of the accompanying commentary and director of the division of gastroenterology and hepatology at St. Louis University School of Medicine in Missouri.

There is also the question of what to do with a positive genetic test. Once iron overload develops, treatment is simple blood-letting. But what should be done with people who just have the gene but no abnormal lab values or symptoms?

"A lot of this genetic testing is not ready for prime time because it's not that easy to predict who is going to develop disease," said Nancy Stevens, MD, MPH, an associate professor of family medicine at the University of Washington. "It isn't clear what the intervention would be."

But while policy-makers and researchers wrestle with these questions, some patients are taking matters in their own hands. The American Hemochromatosis Society last month launched a "Do-It-Yourself" campaign urging people concerned about the disease to order the test directly.

Such efforts are opposed by most physicians. The American Medical Association adopted policy last year that direct-to-consumer genetic testing should be discouraged and that states should restrict such testing to individuals under the care of a qualified health care professional.