Is hemochromatosis the root of the problem?

Iron overload disease is about to get big press

Iron is the root of many evils. That’s the conclusion of some researchers at the Centers for Disease Control and Prevention (CDC) in Atlanta who believe that hemochromatosis, or iron overload disease, is more prevalent than first thought. Many cases of cirrhosis, arthritis, heart disease, and even cancer may be tied to an excess of the essential metal, the researchers report.

"In CDC we have been very compelled by the information on iron overload and hemochromatosis in particular," says Sharon McDonnell, MD, MPH, medical epidemiologist. Some of that information came from a demonstration screening project at the San Diego Kaiser Permanente health maintenance organization (HMO), conducted by the CDC last year. The goal of the screening project was simple: to find out whether iron overload disease was as prevalent as some medical journals have suggested.

The most common genetic disease

Until 10 years ago, hemochromatosis was considered an obscure genetic disorder affecting perhaps two patients in every 10,000 to 20,000. Today, it’s considered the most common genetic disease, affecting one in 200 Americans (about 1 million to 1.5 million cases). Another 27 million may carry the gene, and it’s unknown whether they might suffer symptoms as a result.

"Hemochromatosis is only one of many genes that’s going to hit us fast and furious" in the future, predicts Muin Khoury, MD, PhD, section chief of the CDC’s Task Force on Genetics. The gene associated with hemochromatosis was discovered last year. Khoury says two mutations of the gene seem to account for most cases of the disease among Caucasians.

There are actually two types of iron overload disease, primary and secondary. By far, the former is more common than the latter. About 85% to 95% of iron overload disease is considered "primary" — that is, there’s an excessive absorption of iron from the gastrointestinal tract that begins early in life and continues until death.

Disease often diagnosed too late

The body normally regulates how much iron it absorbs from foods and supplements based on what it has in storage, McDonnell says. Normally no more than a gram of iron is held in storage at any one time. "But in iron overload, the person continues to absorb iron from the diet until the storage component gets bigger and bigger," she says. The end result is spillover of iron into the tissues where it can exert its toxic effects — including oxidative damage.

Clinically, hemochromatosis is linked to a number of serious, chronic diseases — most notably cirrhosis. According to Quanhe Yang, PhD, of the CDC, liver disease tops the list of "comorbidity" factors associated with hemochromatosis, followed by heart disease, cancer, diabetes mellitus, and cancer of the liver.

The trouble is, Yang says, that doctors are more likely to diagnose hemochromatosis when it’s too late — on autopsy — than while the patient is still alive. That’s partially due to the subtle, progressive nature of the disease. Although iron accumulation begins early in life, concrete symptoms might not show up until late adulthood. A baby with hemochromatosis may have no symptoms whatsoever; a teenager may have fatigue and joint and stomach pain, as well as two symptoms not likely to be detected on your average school physical: elevated liver enzymes and impotence.

Even if a young person is tested for iron overload disease, it may be inaccurate. The current method of testing has problems, McDonnell says. Transferrin saturation — TS for short — is a ratio measurement of serum iron and total iron binding capacity (TIBC). But the test doesn’t give static results — in fact, they can vary by as much as 30%. Biological activity has something to do with that variability, but there may be lab issues as well, she says.

To ensure that the test was more accurate for its demonstration project at the San Diego Kaiser Permanente HMO, the CDC repeated the test when the first one turned out high, then confirmed that result with a phlebotomy. The screening project eventually tested 15,000 patients. Three percent were found to have an elevated TS the first time around. On repeat, two-thirds of those patients were found to be normal.

In the end, the CDC found the prevalence of iron overload was about 5/1,000 patients and diagnosed an additional 25 family members. White men made up almost 3¼4 of the cases. For the first time, the disease was found in Asians and Hispanics. In fact, McDonnell says the overall incidence in Hispanics may be very high. About 17% of the positive cases at San Diego Kaiser were Hispanic — a number equal to the proportion of Hispanic patients using the HMO. Interestingly, about half the positive cases had not come to the HMO for anything other than a checkup.

McDonnell says the CDC is now grappling with a touchy issue: whether to advise routine screening for iron overload disease. An expert panel recommended last year that young adults should be screened during routine physical exams — a recommendation that especially holds true for those in high-risk groups, such as patients with elevated liver enzymes or liver disease, diabetes, impotence, heart failure, or any family history of iron overload.

Is routine testing economical? That’s hard to say. Mark Messonnier, PhD, an economist with the CDC’s Epidemiology Program Office, analyzed the cost of diagnosing and treating hemochromatosis vs. treating the possible complications that might result from not treating it.

The proposed routine screening would include an initial and repeat TS if necessary, plus a liver biopsy — the gold standard in hemochromatosis diagnosis — if liver enzymes were elevated or a diagnostic phlebotomy if liver tests were normal. Treatment would involve maintenance phlebotomies.

Purely from a direct medical dollars standpoint, hemochromatosis screening is a loser. Messonnier found that it cost more to screen and treat hemochromatosis than to treat the complications that might result from the disease. The biggest problem appears to be the cost of the phlebotomies. Messonnier says if these can be halved (from about $5,000 to $2,800), a screening/treatment program can be cost-effective. Messonier’s analysis only includes direct medical dollars and not things like loss of productivity. "Even though screening may not be cost-saving, it doesn’t mean it’s not cost-effective," he says.

"We have an awful lot of evidence to compel us into action," McDonnell says, including statistics that show men and about 40% of women with hemochromatosis will develop some sort of fatal complication or organ damage if the disease is left untreated. McDonnell suggests one quick strategy for detection is to add TS to routine blood panels. "Serum iron is really not a useful test for this. It would be much better to add the TIBC," she says.

The treatment for hemochromatosis sounds like something out of the Dark Ages: regular visits to a phlebotomist for bloodletting. If iron levels are especially high, treatments are numerous at first but gradually diminish to maintenance bleeds of about four times a year. And what becomes of that drawn blood? Well that’s another contentious issue. Until now, the U.S. Food and Drug Administration has treated blood drawn from hemochromatotics as "different."

"The requirement by the FDA is that blood taken by therapeutic bloodletting has to be labeled, that’s all," McDonnell says. "It doesn’t mean you can’t use it." And in some cases, it has been used — during the Persian Gulf War, for example. But, according to Margit Krikker, MD, founder and medical director of the Hemochromatosis Foundation, these labels discourage physicians from using the blood. Krikker says "the blood is normal and safe."

And there’s lots of it. A typical de-ironing takes about 40 units of blood per person a year. Maintenance bloodlettings can take up to 10 units a year. "Multiply that by one million people, and that’s a lot of blood," McDonnell says.

For pharmacists, the days of casually recommending iron supplementation may be over, McDonnell says. Ironically, at the same time McDonnell was advising caution on iron supplementation, another branch of the CDC announced the results of an analysis of data from the National Health and Nutrition Examination Survey. It revealed that millions of women and children in America are iron deficient.