What is hereditary hemochromatosis?
Hereditary hemochromatosis is a genetic disorder in which too much iron builds up in the body. The body extracts iron from foods. If you absorb more of this mineral than you get rid of, iron builds up in the tissues and organs. Over time, this buildup can become toxic and cause changes, including:
- Liver enlargement, liver cancer, cirrhosis and/or liver failure
- Diabetes, from excess iron in the pancreas
- Darker skin pigmentation, from iron deposits in the skin
- Cardiomyopathy (changes in the heart muscle that prevent part or all of the heart from contracting normally and can lead to heart failure)
- Stiff and painful joints
- Abdominal pain
- (In men) infertility, loss of libido and impotence
- Weakness, lethargy and confusion
How common is hereditary hemochromatosis?
In the United States, about one in 10 people of northern European ancestry (for example, Scottish, Irish or English) is a carrier (one copy of the gene has a change). Given the high number of carriers, as many as 1 in 150 Caucasians may have two changes in the gene, making them more likely to develop hemochromatosis. Only about half the people with two changes in the gene will develop symptoms. On the other hand, some people with only one detectable change develop symptoms. They probably have another genetic change somewhere, but it doesn’t show up on genetic testing. Some cases probably are never diagnosed (that is, they go unreported) because the symptoms and complications of the disease develop so gradually.
Who is at risk of hereditary hemochromatosis?
Hereditary hemochromatosis is more common among Caucasians. African-Americans and Asian Americans could carry the gene, but it is less common.
Because the buildup of high levels of iron in the body is gradual, symptoms normally do not appear until middle age. That’s why hereditary hemochromatosis is most commonly diagnosed in men between 40 and 60 and in women after menopause.
Is there a cure?
No, but treatment for hereditary hemochromatosis is 100% effective. High iron levels can be lowered by periodically removing a small amount of blood. Removing blood from the body (a process called phlebotomy) prevents excess iron from being stored in organs and tissues. Treatment is most effective when hereditary hemochromatosis is detected early. Unfortunately, many people do not know they have an increased risk of hereditary hemochromatosis until they develop symptoms. If treatment is started early enough, some symptoms may be reversible or never appear at all. In later stages, symptoms may not be reversible.
The Gene For Hereditary Hemochromatosis
What is the hereditary hemochromatosis gene?
The hereditary hemochromatosis gene helps to regulate the amount of iron absorbed by the body. The gene tells the body how to make a certain protein that is involved in moving and storing iron.
An altered hereditary hemochromatosis gene can change the way the body transports or stores iron, leading to iron overload.
What changes in the gene lead to hereditary hemochromatosis?
The most common changes in the gene are named C282Y and H63D. These names describe the locations of the changes within the gene.
The C282Y change is the most common and most significant. Most people — but not all — who inherit two copies of the C282Y change will develop hereditary hemochromatosis. Up to one-third of people with two C282Y changes do not develop any symptoms.
A person with two H63D changes has less than a 1% chance of developing hereditary hemochromatosis.
A person with one C282Y change and one H63D change has about a 5% chance of developing hereditary hemochromatosis.
How do you get hereditary hemochromatosis?
Every child inherits two hereditary hemochromatosis genes — one from each parent. A child who inherits two altered (mutated) copies of the gene will have an increased risk of hereditary hemochromatosis. A person who inherits an altered gene from only one parent will not develop the disease, but can pass the altered gene on to his or her children.
How does hereditary hemochromatosis develop?
The symptoms you might develop, and when you might develop them, depend on your iron level. The buildup of iron occurs over many years.
In addition to your genetic makeup, other factors affect your body’s iron level, and therefore how the altered gene affects your body:
- Gender: Men have a higher risk of developing hereditary hemochromatosis (women do not build up iron as quickly as men do because women lose iron-rich blood through menstruation and pregnancy).
- Diet: People take in different amounts of iron in their diets.
- Alcohol intake: Drinking too much alcohol can accelerate the buildup of iron.
Should You Be Tested?
Should you have a test for hereditary hemochromatosis?
Many doctors believe all adults should be screened for hemochromatosis by a transferrin saturation test. That way, people at risk could get early treatment. DNA testing makes the most sense if you have a family history of the disease, or if you are experiencing symptoms.
Should I be tested if I have no signs of hereditary hemochromatosis?
If you have a family history of hereditary hemochromatosis, you might want to find out if you could be a carrier or are susceptible to getting hemochromatosis. If a family member has already tested positive for one or two changes in the gene, your risk of carrying an altered gene is increased. If you don’t have any signs of hereditary hemochromatosis and a test — such as the transferrin saturation — determines that you have an increased risk of the disease, you could take action now to help prevent some of the consequences of the disease (or stop it from developing altogether). Talk with your doctor about getting your iron levels checked through a transferrin saturation test. If it is high, then you might need treatment.
If I don’t have a family history of the disease, should I be tested?
If you do not have a family history of hereditary hemochromatosis, your chances of being a carrier depend on your family’s ethnic background. The C282Y and H63D changes are most common in people with ancestors from northern, western and central Europe. Because the medical community has not established clear guidelines for testing based on ethnic background alone, talk to your doctor about your options. Most doctors would not recommend a gene test unless you or one of your relatives have a high iron level.
What does family history tell me?
If you have a family member with hereditary hemochromatosis, you might be a carrier (have one altered gene) or you might have the disease (have two altered genes). Most people with two copies of the C282Y change eventually develop hereditary hemochromatosis. However, up to one-third of people with two C282Y changes will not develop the disease.
Should I be tested if I have symptoms of hereditary hemochromatosis?
Testing can confirm whether someone with symptoms of hereditary hemochromatosis has the disease. If you have symptoms, see your doctor. Symptoms are most obvious late in the disease. By then, treatment is less effective. Tell your doctor if you have a family history of hereditary hemochromatosis or if your ethnic background is European. Based on this information, your doctor can decide which test is right for you.
Understanding Test Results and Options
How Do You Make Sense Of The Results?
If I test positive, what does that mean for my family and me?
There are three tests for hereditary hemochromatosis: transferrin saturation, ferritin and DNA.
If your transferrin saturation or ferritin levels are high, you may have hereditary hemochromatosis. Because hemochromatosis refers to any type of iron overload, your doctor will need to investigate the cause of your condition. Other conditions, such as inflammation and cancer, can cause a high ferritin level.
To determine if you have hereditary hemochromatosis you will need DNA testing. A positive DNA test means you have changes in the hereditary hemochromatosis gene. Symptoms of hereditary hemochromatosis occur in:
- About 3% or fewer of people with only one change (C282Y or H63D)
- About 5% of people with one C282Y gene and one H63D gene
- About 1% of people with two H63D changes
- Up to 2/3 of people with two C282Y changes
It’s hard to predict who will develop symptoms of hereditary hemochromatosis, even with DNA testing. That does not mean testing has no purpose. DNA testing helps identify people who should have their iron levels checked regularly. DNA testing also helps to decide who needs a liver biopsy. People with two C282Y changes and a high iron level should consider a liver biopsy to look for cirrhosis. Most importantly, testing helps people seek treatment before any damage begins.
If a DNA test reveals that you have two changes, it means your parents are both carriers of the altered gene. Carriers do not typically have the disease, because they have one normal copy of the gene as well as one altered copy. If both your parents are carriers, your brothers and sisters each have a 25% chance of inheriting two altered genes.
If you are a carrier, it means one or both of your parents must have been a carrier, too. This means your brothers and sisters have at least a 50% chance of having inherited one altered gene from one of your parents.
Once a change is identified in a person, other family members might want to get DNA testing.
Could I get a positive test result, but not have hereditary hemochromatosis (a “false positive”)?
The transferrin saturation test can be falsely elevated if you did not fast before the test.
If you were fasting, getting a false-positive result depends on the “cut-off” value used for the test. Cut-off levels range from 45% to 62%. Recommendations to make 45% the cut-off are designed to detect as many true positives as possible. If your value is higher than 45%, the possibility of hereditary hemochromatosis increases. If the cut-off were 50%, there would be fewer false positives, but testing would also miss some people with hereditary hemochromatosis.
Choosing cut-off values is difficult because the percent saturation that reliably indicates hereditary hemochromatosis will vary with diet, age and gender.
The ferritin test could be elevated from another illness that causes inflammation, or from some types of cancer (a “false” positive for hemochromatosis).
The false-positive rate is essentially zero for the DNA test. In other words, if the DNA test is positive, a change has been detected in your hereditary hemochromatosis gene. However, whether or not that change will likely lead to hereditary hemochromatosis depends on which specific change you have and on other factors such as gender and dietary habits.
Could I get a negative test result, but actually have the disease (a “false negative”)?
A false negative for the transferrin saturation test depends on the cut-off value. If the cut-off were 50% saturation, then people with hereditary hemochromatosis who had values from 45% to 50% would get negative test results even though they have the disease. Based on previous studies of people with two hereditary hemochromatosis gene changes, a cut-off value of 45% detected 100% of men with hereditary hemochromatosis but only 91% of women with the condition.
Because iron builds up gradually in people with hereditary hemochromatosis, a person with the genetic change could have a normal ferritin level. For example, younger people with one or two changes in the gene have not had enough time to build up high levels of iron. Ferritin testing is not recommended for hemochromatosis screening because up to half of people with two C282Y changes will have a normal ferritin – a high false negative rate!
The false-negative rate is very low for the DNA test. If you have one of the known changes, the test will find it more than 99% of the time.
Note: Detecting changes in the hereditary hemochromatosis gene explains most cases of hereditary hemochromatosis, but some cases appear to be caused by a different gene.
What if the DNA test shows I am a hereditary hemochromatosis carrier?
If you inherit a defective gene from only one parent, you are considered a carrier of the disease. Your chances of actually developing hereditary hemochromatosis are 5% or less. That’s because hereditary hemochromatosis is usually inherited as a recessive disease: You need two altered genes, rather than one, to have symptoms.
If you have two C282Y changes, get your ferritin level checked yearly. If the level is high, your doctor will routinely remove some iron by taking out a portion of your blood. This process will continue until you get down to a normal ferritin level.
Some combinations of genes cause the disease in only a small percentage of people with those combinations. For example, what should you do if you have the combination C282Y and H63D? Or what if you have only one change, but there have been some people with that change who developed hereditary hemochromatosis? In both cases, you should get your transferrin saturation checked periodically. (Your doctor can help you to decide how often.) The goal is to detect iron storage problems before any damage is done.
If I have a change in the hereditary hemochromatosis gene, can I have children who don’t have the change?
Yes, but you need to “do the math” to understand the risks of passing on the change in the gene. If you have one copy of the gene and your partner has two normal genes, you have a 50% chance of passing the altered gene to each child. If you and your partner both have an altered hereditary hemochromatosis gene, your child has a:
- 25% chance of inheriting two altered copies of the gene
- 50% chance of inheriting one altered copy and 1 normal copy
- 25% chance of inheriting two normal copies of the gene
Even with these risks, being a carrier would not stand in the way of having children. In fact, knowing that you and your partner are carriers of the gene could make your children healthier. Because the carrier rate is so high in the Caucasian population, there are plenty of children born with hereditary hemochromatosis who don’t know it until they become adults and get some symptoms. Knowing your carrier status would allow your children to receive earlier screening and treatment as a result of that knowledge.
During pregnancy, can I determine the risk my baby has of developing hereditary hemochromatosis?
In theory, prenatal testing is available for any type of DNA test, but it would be very unusual to have prenatal testing for a disease like hereditary hemochromatosis. The disease has no effects for years and doesn’t need treatment until adulthood. But if you decide to have the test, a doctor can use either chorionic villus sampling or amniocentesis to get a sample of tissue from the fetus. A lab then tests the tissue to determine if the fetus has inherited a change.
If I DON’T have a change in the hereditary hemochromatosis gene, can I have children who DO have a change in the gene?
If you do not carry an altered gene, your children cannot inherit the gene from you. They could still get the gene from your partner if he or she is a carrier.
If my partner or I have a change in the hereditary hemochromatosis gene, should my children be tested?
Hereditary hemochromatosis is an adult disease. There is no need to test a child. Even with two altered genes, nothing would be done until your child becomes an adult. Although there are no specific guidelines, it would be reasonable for your child to be tested with either the transferrin saturation test or the DNA test after turning 18.
How do the tests work?
There are three types of tests for hereditary hemochromatosis. All require a blood sample:
Transferrin Saturation Test
Transferrin saturation (TS) testing determines whether your iron level is too high.
Iron moves around your body by attaching itself to different molecules. Transferrin grabs iron and moves it from one place to another. The higher your TS, the higher your iron level.
With the TS test, a lab measures the iron level in your blood and the percentage of transferrin molecules that are NOT bound to iron. The lab uses those two values to estimate the percentage of transferrin that is bound to iron. When a binding site is occupied by iron, it is saturated. Typically, this test is done before a DNA test.
Ferritin testing is another way to determine whether your iron level is too high. Ferritin is a protein in your blood that contains iron. Saying that your ferritin level is high is another way of saying that your body is storing too much iron. This test works well for monitoring people who already know they have a change in the gene. For example, the level can be checked before and after treatment. It’s not such a good test for screening people who don’t know if they have a change in the gene.
The DNA test looks for changes in the hereditary hemochromatosis gene. The test specifically looks for the most common changes: C282Y, H63D and S65C (another common change in the gene, but one that has not been shown to cause any hemochromatosis symptoms).
The DNA test is important because two people with hereditary hemochromatosis might not have the same change in the gene. Depending on your DNA test results, your doctor might choose to follow your iron levels more or less frequently.
What do the tests cost?
The transferrin saturation test and ferritin test each cost about $75. The DNA test costs about $200. Costs vary depending on the lab doing the testing. Note: Screening family members with the DNA test has been shown to be more cost effective than screening with the transferrin saturation test because the genetic test only needs to be done once.
Does insurance pay for these tests?
Most health-insurance companies pay for “diagnostic testing,” which means the test is being done to confirm a diagnosis in a person who already has symptoms. However, there are many different plans, and you should check whether diagnostic genetic testing is a covered service before having the test performed.
Many insurance companies will not pay for a predictive test (a test for a person who does not have symptoms), especially if there is nothing that can be done to prevent the condition (no change in patient management). In the case of hereditary hemochromatosis, there is a change in management for a person known to have the genetic changes. If you are considering this test, call your insurance company and ask about its coverage.
How long does it take to get results?
You should receive the results of the transferrin saturation test within a day or two. The DNA test takes about two or three weeks. The laboratory sends the results to the medical center that ordered the test. You should have a return appointment to discuss your results.
Can a health-insurance company raise my rates or drop me from coverage if I test positive?
In 2008, the U.S. government passed a law called GINA (Genetic Information Nondiscrimination Act). This law prohibits discrimination by health insurers and employers on the basis of genetic information. Learn more here.
Also, this may depend on whether you have group insurance or are self-employed. Both federal and state laws usually cover people with group insurance, while state laws only cover people who are self-employed. Also, the Federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health insurance discrimination based on any “health status-related factor” (including genetic information) by group health plans. Unfortunately, this act does not apply to the self-employed.
Some states have enacted legislation to cover the gaps. Many states prohibit health-insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim. Texas bans the use of genetic information by any group health plans, and Alabama prohibits discrimination based upon predisposition to cancer.
These laws generally do not cover life insurance, long-term care and disability insurance. People with life and disability coverage provided by their employers are unlikely to have this insurance affected by a genetic test result.