Genetic Disorder Profile: Hemochromatosis

Genetic Disorder Profile: Hemochromatosis For more about the gene that causes hereditary hemochromatosis, see the HFE Gene Profile. The following disease information was adapted from NIH Publication No. 00-4621.

Disorder Description Hereditary hemochromatosis (HH), the most common form of iron overload disease, is an inherited disorder that causes the body to absorb and store too much iron. Excess iron is stored throughout the body in organs and tissues including the pancreas, liver, and skin. Without treatment, the iron deposits can damage these organs and tissues.

Inheritance HH is an autosomal recessive disorder caused by mutations in the HFE gene, which regulates the amount of iron absorbed from food. A person who inherits a defective gene from each parent will develop hemochromatosis. A person who inherits a defective gene from one parent is a carrier but usually does not develop the disease. Carriers, however, might have a slight increase in iron absorption.

Incidence HH is one of the most common genetic disorders in the United States. It most often affects Caucasians of Northern European descent, although other ethnic groups also are affected. About 5 people in 1000 (0.5%) of the U.S. Caucasian population carry two copies of the hemochromatosis gene and are susceptible to developing the disease. One person in 8 to 12 is a carrier. Hemochromatosis is less common in African Americans, Asian Americans, Hispanic Americans, and American Indians.

Symptoms Joint pain is the most common complaint of people with hemochromatosis. Other common symptoms include fatigue, lack of energy, abdominal pain, loss of sex drive, and heart problems. Symptoms tend to occur in men between the ages of 30 and 50 and in women over age 50. However, many people have no symptoms when they are diagnosed.

Hereditary Hemochromatosis Timeline 1865 - Hemochromatosis is first described by Tousseau, who cared for a diabetic patient with cirrhosis of the liver and bronzed skin pigmentation, classic symptoms of HH. 1889 - Von Recklinghausen names the disease "hemochromatosis" and identifies an iron-containing pigment in the liver cells of cirrhosis patients. 1935 - Sheldon describes the hereditary nature of the disease in his text Haemochromatosis. 1977 - Stevens reported that a gene for HH may be located on chromosome 6 near the HLA-A locus. Simon concluded that HH demonstrates recessive inheritance. 1996 - Feder identifies the hemochromatosis gene and the missense mutations (Cys282Tyr and His63Asp) that cause HH. The hemochromatosis gene was originally HLA-H, but was later changed to HFE. 1997 - CDC and the National Human Genome Research Institute sponsor a meeting to examine issues related to the discovery of HFE. A panel of experts conclude that large-scale population screening is not recommended. 1998 - Research by Roldan links acute liver failure to iron supplementation in a 29-yea- old woman whose HH went undiagnosed. To increase physician awareness of HH, a special December issue of the Annals of Internal Medicine features 11 articles on the disease. Timeline References

Complications

Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM No. 235200 (September 10, 2001)

If the disease is not detected early and treated, iron will accumulate in body tissues and may eventually lead to serious problems such as the following.

Jennifer Farmer . "Hereditary Hemochromatosis." MARHGNews. Mid-Atlantic Regional Human Genetics Network. Summer 1999.

Arthritis Liver disease, including enlarged liver, hepatitis, cirrhosis, cancer, and liver failure Heart abnormalities, such as irregular heart rhythms or congestive heart failure Impotence Early menopause Abnormal pigmentation of the skin, making it look gray or bronze Damage to the pancreas, possibly causing diabetes Thyroid deficiency Damage to the adrenal gland

Diagnosis and Genetic Testing A thorough medical history, physical examination, and routine blood tests help rule out other conditions that could be causing symptoms. This information often provides helpful clues, such as a family history of arthritis or unexplained liver disease. Blood tests can determine whether the amount of iron stored in the body is too high. Transferrin Saturation Test: Determines how much iron is bound to the protein that carries iron in the blood. The blood test for transferrin saturation is widely available and relatively inexpensive, but it may have to be done twice with careful handling to confirm a diagnosis. Serum Ferritin Test: Shows the level of iron in the liver. Liver Biopsy: Procedure in which a needle is inserted through the rib cage and abdominal cavity to obtain a sample of liver tissue for testing Molecular Genetic Testing: Direct DNA testing for two HFE gene mutations (C282Y and H63D) associated with hemochromatosis is available at a number of laboratories. These genetic tests offer a detection rate of about 87% for HH; therefore, a person who has the mutant gene could test negative. Genetic testing is the only way to determine whether or not someone is a carrier of the disease [1].

Treatment Treatment is simple, inexpensive, and safe. The first step is to rid the body of excess iron. The process is called phlebotomy, which means removing blood. Depending on how severe the iron overload is, a pint of blood is taken once or twice a week for several months to a year, occasionally longer. Blood ferritin levels are tested after every four phlebotomies to monitor iron levels. The goal is to bring blood ferritin levels to the low end of normal and keep them there (that means less than 9 to 50 micrograms of blood ferritin per liter). Depending on the amount of overload at diagnosis, reaching normal levels can take up to 100 phlebotomies. Once iron levels return to normal, maintenance therapy, which involves removing a pint of blood every 1 to 4 months for life, begins. Some people may need it more often. An annual blood ferritin test will help determine how often blood should be removed. The earlier hemochromatosis is diagnosed and treated, the better. If treatment begins before any organs are damaged, associated conditions such as liver disease, heart disease, arthritis, and diabetes can be prevented. Individuals who have already developed complications from hemochromatosis may not be cured but usually can be helped. The main exception is arthritis, which does not improve even after excess iron is removed. People with hemochromatosis should not take iron supplements. Those who have liver damage should not drink alcoholic beverages because they further damage the liver.

Q. Since effective treatment is available for a genetic disorder as common as HH, why isn't population screening recommended? A. A lot of uncertainties still surround the initiation of population screening for this and other genetic disorders. One uncertainty is that different genetic mutations can result in varying degrees of disease severity. For example, people who have two copies of the H63D mutation generally develop a very mild form of the disease or may never develop any symptoms at all. Diagnosing a genetic disease in an asymptomatic individual could have negative psychological effects. Another uncertainty is that current genetic-testing methods are unable to detect about 10% of mutations, so many people at risk for developing iron overload later in life may be undiagnosed [4]. As with any attempt at population screening for disease, the possibility of discrimination is always present. In the United Kingdom, where hemochromatosis is the most common genetic disease, the private health insurance company for a man diagnosed with the disorder refused to cover treatment because the insurer considered hemochromatosis to be a preexisting condition [5]. Other instances of discrimination have been reported by individuals applying for life insurance. Although some states have policies addressing genetic discrimination, the coverage, protections afforded, and enforcement schemes vary from state to state. Currently, no federal legislation has been passed relating to genetic discrimination in individual insurance coverage or to genetic discrimination in the workplace. Until a better understanding of the complex genotype-phenotype relationship associated with hereditary hemochromatosis is achieved and more of the many uncertainties associated with disease screening are resolved, the need for large-scale population screening will continue to be debated.

Organizations and Support Groups American Hemochromatosis Society

Iron Disorders Institute The Canadian Hemochromatosis Society

Government Resources Clinical Trials for Hemochromatosis at ClinicalTrials.gov Iron Overload and Hemochromatosis - A collection of hereditary hemochromatosis resources maintained by the Centers for Disease Control and Prevention (CDC) MEDLINEplus: Hemochromatosis - Links to resources from the National Institutes of Health and other hemochromatosis organizations

Diagnostic Testing Iron Tests - Overview of some laboratory tests involved in diagnosing hereditary hemochromatosis, provided by Lab Tests Online, a peer-reviewed, noncommercial resource on clinical lab testing. "DNA Testing for Hereditary Hemochromatosis" - Article featured in the Spring 1997 issue of the Genetic Drift Newsletter by the Mountain States Genetic Network (MoSt GeNe).

Other Hemochromatosis Resources Your Genes, Your Health: Hemochromatosis - A multimedia guide, funded by the Josiah Macy, Jr. Foundation, that visually depicts what causes hemochromatosis, how it is inherited, how it is diagnosed, how it is treated, and what it is like to have the disease. Hemochromatosis Education and Research - Information about hemochromatosis targeted to both health care providers and patients. This resource is provided by the University of Washington Division of Gastroenterology.

References 1. Kris V. Kowdley et al. "Hereditary Hemochromatosis." In GeneReviews at GeneTest-GeneClinics. and < http://www.genetests.org> (Updated March 31, 2000, accessed December 21, 2001) 2. Michele Reyes and Muin J. Khoury. "Screening for Hereditary Hemochromatosis: Still Premature." GeneLetter 2 (17), August 2001. 3. Wylie Burke et al. "Hereditary Hemochromatosis. Gene Discovery and its Implications for Population-Based Screening." JAMA 280 (2): 172-8. 4. Jennifer Farmer. "Hereditary Hemochromatosis." MARHGNews. Mid-Atlantic Regional Human Genetics Network. Summer 1999. 5. "MPs Call for Tough Controls on Human Genetics." GenEthics News. July/August 1995. Last Updated: December 3, 2002