Genetic test for hemochromatosis debated

Study results show that a phenotype test alone does not always detect this blood disorder's genetic mutation.

By Victoria Stagg Elliott, amednews staff. Sept. 25, 2000.

Phenotypic tests for hemochromatosis fail to diagnose half the people who have the genetic mutation for the disorder because they do not have the characteristic high blood iron levels, according to a preliminary study published in the September Annals of Internal Medicine. The researchers also point out that there is no proof yet that all patients with the genetic mutation will develop the condition.

"This seems to suggest [genetic testing] is going to be an overly sensitive way to pick up homozygotes for hemochromatosis," said Ernest Beutler, MD, chair of the department of molecular and experimental medicine at the Scripps Research Institute in California. He is also the primary author of the study.

Links

The study, which looked at 10,000 patients in a large HMO in California and has, since publication, been expanded to 25,000, is the latest twist in the debate over how to deal with this iron overload disease linked to everything from arthritis to heart failure. Hemochromoatosis is easy to treat with periodic blood-letting, but doctors have always struggled to diagnose it.

"Our study shows two things about the phenotype that is produced by the homozygous state," said Dr. Beutler. "First of all, many of the patients don't have elevated iron levels. Secondly, they didn't have symptoms that were any different from the control population. That is reason to question whether screening for hemochromatosis by genetic analysis or by the serum iron method really will save as many lives as people have suggested."

Many who work with hemochromatosis patients, however, are still advocating population-wide testing. The National Institutes of Health is also running a large-scale study looking at the feasibility of hemochromatosis screening in primary-care settings.

"It's a no-brainer for screening because we have effective treatment," said Bruce Bacon, MD, director of the division of gastroenterology at St. Louis University.

The next question, though, is how to screen. Should tests look for genetic mutation or abnormally high levels of iron in the blood?

About five people out of 1,000 are homozygous for the mutations in the HFE gene linked to hemochromatosis, and the genetic test is commercially available.

Dr. Beutler said the test does have value, particularly for those who already have abnormal phenotype tests.

"The question of population screening is different," he said. "Is it cost effective and is it to the patient's advantage to have everybody tested for hemochromatosis?" If it is, he added, then the next question is what to look for. Is it best to test the genotype or the chemical phenotype that indicates high transference saturation or high ferritin?

Hemochromatosis specialists, however, stressed that people who are homozygous for the genotype have a higher likelihood of developing the condition.

"If you identify by genotype a 22-year-old woman who's had three babies, she may have no phenotype. But after she stops having babies and maybe after she stops her menses, she will develop more of a phenotype and in fact have disease," Dr. Bacon said.

Experts did agree, however, that the ideal screening tests for large populations probably would be phenotypic and would look at the iron saturation of the blood. Genetic tests are expensive, said Dr. Bacon, who recommended the fasting transferrin saturation test as a screening tool. "Whenever those values are abnormal, get genetic testing."

The next part of the study will follow the 101 homozygote patients picked out from the thousands screened.

"There isn't any question that there are some homozygotes for hemochromatosis who develop cirrhosis and diabetes and cardiac failure. That's clearly not true with the majority so what is different? That's what we're trying to find out," Dr. Beutler said.

ADDITIONAL INFORMATION:

Weblink

Text of the report "The Effect of HFE Genotypes on Measurements of Iron Overload in Patients Attending a Health Appraisal Clinic," from the Sept. 5 Annals of Internal Medicine. (http://www.annals.org/issues/current/full/200009050-00008.html)

American HemochromatosisSociety (http://www.americanhs.org/)

The AMA's Genetics and Molecular Medicine page (http://www.ama-assn.org/ama/pub/physician-resources/medical-science/genetics-molecular-medicine/news.shtml)