Study May Lead to Improved Methods to Diagnose and Treat Potentially Deadly Condition

A disorder that causes iron overload is more prevalent among different ethnic groups than previously believed, according to the results of the largest and most diverse screening study ever conducted of hemochromatosis, or iron overload disease.

Results of the ongoing Hemochromatosis and Iron Overload Screening (HEIRS) Study identified Asians and Pacific Islanders as having the greatest prevalence of elevated blood iron test levels of all ethnic groups studied. In addition, Caucasians were found to have a relatively high genetic tendency to develop the disease. High blood iron levels were also found, though less commonly, in African Americans, Latinos and Native Americans. The full results of the screening phase of the study appear in the April 28 issue of the New England Journal of Medicine.

UC Irvine researchers participated in this study, in which more than 100,000 patients were screened by five medical centers in the United States and Canada. The 20,400 screened at UCI was its largest number ever for a study.

"Hemochromatosis was always assumed to occur most often in Caucasians, but few studies have been conducted to see how many genetically susceptible people actually get the disease," said Christine McLaren, professor of epidemiology, who helped lead the UCI portion of the study. "This study allowed us to explore how often the disease occurs and help determine who can benefit most from early screening. The results of the study also may help scientists in the future develop more effective ways to screen people for the disease."

Hemochromatosis is a potentially fatal disorder caused by abnormally high levels of iron in the body, which can lead to accumulations of iron in vital body organs, causing an increased risk of disorders such as diabetes, arthritis, sexual dysfunction, liver disease and liver cancer, and heart disease. There is no cure, but early detection usually leads to effective treatment that prevents complications of the disease.

The disorder was considered rare until researchers uncovered its hidden genetic cause -- a mutation in the hemochromatosis gene (HFE) -- and realized that it may affect more than 1 million Caucasian Americans, making it one of the most common inherited diseases in the world. Little had been known, however, about iron overload in other racial and ethnic groups.

The major results of the study include the finding that in Caucasians, who are most likely to have the HFE gene mutation associated with iron overload, 4.4 per 1,000 people had two copies of the faulty gene. This was much less common in other ethnic groups, occurring in an estimated 1.1 per 1,000 Native Americans, 2.7 per 10,000 Latinos, 1.4 per 10,000 African Americans, 1.2 per 10,000 Pacific Islanders, and 3.9 per 10 million Asians. Most participants with two copies of the mutant HFE gene had elevated iron test levels. Men with two copies of the mutant gene were more likely to report a history of liver disease than participants without the mutation.

"Our findings about hemochromatosis and iron overload in Caucasians confirm findings from previous, more limited, studies," said Dr. Gordon McLaren, professor of hematology and oncology at UCI and a physician at the U.S. Department of Veterans Affairs Long Beach Healthcare System, and co-leader of the UCI portion of the study. "And our findings in other ethnic groups have improved our understanding of the prevalence of these conditions among minorities. What surprised us most was that Asians and Pacific Islanders had the highest average blood iron test levels, even though they had the lowest prevalence of the gene mutation."

The researchers found that Asians and Pacific Islanders have the highest blood protein levels that suggest iron overload disease. Of the Asians screened, 4.8 percent were found to have these factors; of Pacific Islanders, 3.1 percent. (In comparison, 1.7 percent of Caucasian tested had these factors.)

It is unclear whether this means that Asians and Pacific Islanders who have these high blood levels actually have hemochromatosis or iron overload or, if so, that they have a different, undiscovered genetic mutation which can also cause iron overload. The researchers are hopeful that the later phases of this study, which involve a more detailed visit and follow-up by the participants' primary care physicians, will help answer these important questions.

The study also indicated that some African Americans may have an iron-overload disorder not attributable to the common HFE mutation found in Caucasians, possibly an unknown genetic mutation that leads to iron-overload disorder.

About the study:

The UCI researchers enrolled study participants at the UCI Family Health Centers in Anaheim, Orange, Santa Ana and Westminster, and at the Gottschalk Medical Plaza on the UCI campus. Participants also were enrolled from the Asian Health Center of the Vietnamese Community of Orange County Inc., Healthcare Systems 2000 of Garden Grove, Huntington Beach Community Clinic, and Kaiser Permanente Medical Care Program in Tustin-Santa Ana, as well as from the Laguna Beach Community Clinic and the Nhân Hòa Comprehensive Healthcare Center in Garden Grove. The UCI field center is one of five nationwide (and the only one in California) that conducted the studies.

At each site, approximately 20,000 study participants were enrolled. Altogether, the HEIRS study recruited more than 100,000 participants in primary care settings and blood-drawing laboratories at five field centers in the United States and Canada. In addition to UCI, the field centers include Howard University (Washington, D.C.); Kaiser Permanente Center for Health Research, Northwest and Hawaii (Portland, Ore. and Honolulu); London Health Sciences Centre (London, Ontario); and the University of Alabama at Birmingham. Initial screening examinations included a brief questionnaire and a blood sample to test for mutations of the HFE gene and blood tests for iron levels. A central laboratory that tests blood samples from study participants is located at the University of Minnesota (Minneapolis). A coordinating center that collects, stores and helps to analyze the data for the study is located at Wake Forest University (Winston-Salem, N.C.).

Working with the McLarens at UCI on the study are researchers with the departments of epidemiology, hematology and oncology, pediatrics, gastroenterology, and family and internal medicine. Funding for the UCI portion of the study totaled $4.7 million and was provided by the National Heart, Lung and Blood Institute and the National Human Genome Research Institute.

The next phase of the HEIRS study will look at results of clinical exams of patients with high test levels of blood iron and those with two copies of the faulty HFE gene.

About hemochromatosis:

Hemochromatosis is a genetic disorder in which too much dietary iron is absorbed by the small intestine. However, most people who carry the gene don’t know they have it. The five-year HEIRS study focused on the incidence of iron overload among Caucasians and also examined whether iron overload is common among certain other ethnic groups in the United States and Canada.

At the start of the study, it was known that most cases of iron overload in Caucasians resulted from a mutation in the hemochromatosis gene, called HFE, which was first discovered in 1996. It was also known that the gene controls how the body absorbs iron from the diet. The gene mutation, called C282Y, causes the disease by increasing the absorption of iron and raising its levels in the bloodstream. Once in the blood, iron is attached to a protein called transferrin, which normally delivers only the amount of iron needed to the body’s organs. In hemochromatosis, transferrin becomes saturated with iron and continues to deliver iron to already overloaded organs, causing damage to the body.

The researchers compared not only the iron saturation of transferrin, but also a protein called ferritin, which reflects the amount of iron stored in body tissues. Combining the two tests may make screening for the disease more effective.

Most people can carry one copy of the mutated gene without having any symptoms, if they also carry a normal version of the gene. If parents pass on two faulty versions of the gene to their offspring, however, the children may suffer from hemochromatosis.

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