Version May 2024
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HEMOCHROMATOSIS OVERVIEW — The term "hemochromatosis" refers to excess iron in the body. Hereditary hemochromatosis is a type of hemochromatosis caused by a change (sometimes referred to as a variant or mutation) in one of the genes that controls iron absorption from food in the digestive tract. Over time, the excess iron accumulates in tissues throughout the body, leading to iron overload.
Signs of iron overload may include liver damage (cirrhosis), joint pains, changes in skin coloration, heart failure, diabetes mellitus, sexual dysfunction, and rarely, thyroid disease or liver cancer.
Early identification and treatment of hemochromatosis can prevent complications. Treatment typically involves regular phlebotomy (removal of blood) since blood cells contain a large amount of the body's iron.
HEMOCHROMATOSIS CAUSES — Hemochromatosis (iron overload) can be caused by changes (also called "variants") in one of the genes that control how your body absorbs iron from food. When hemochromatosis has a genetic cause, it is referred to as "hereditary hemochromatosis" because the genetic changes are typically inherited.
In most cases, an altered gene is inherited from both parents. A gene called HFE is most often involved (the "H" stands for hereditary or high; "Fe" is the chemical symbol for iron). The most common HFE variant associated with hemochromatosis is called "C282Y." There are also variants in other genes that can (very rarely) cause hereditary hemochromatosis.
A change in the HFE gene that can lead to hereditary hemochromatosis is found in approximately up to 10 percent of people of European ancestry, but having only one copy of the C282Y variant (inherited from only one parent) does not cause iron overload unless another cause is present.
In fact, most people do not develop iron overload even if the HFE C282Y variant is inherited from both parents. The reasons that some people develop iron overload and some do not are still being studied. In general, males who develop iron overload tend to do so at a younger age than females. (See 'Risk factors' below.)
Risk factors — In the United States, approximately 5 in every 1000 people of European ancestry (0.5 percent) have hereditary hemochromatosis, although some are unaware of it. Relatives of people with the HFE C282Y variant should undergo testing since they may have the variant without knowing it. (See 'Implications for relatives' below.)
Iron overload is more likely to be seen in males than in females; this is because females lose iron during their menstrual periods and pregnancies.
HEMOCHROMATOSIS SYMPTOMS — Symptoms of hemochromatosis usually show up in adulthood after the body has accumulated a significant amount of excess iron. Symptoms generally occur after age 40 in males and even later in females.
In the past, before there was genetic testing for hereditary hemochromatosis, iron overload often was not diagnosed until it had been present for years to decades (when the person noticed symptoms and sought medical care).
Today, most people with hereditary hemochromatosis are identified in young adulthood because they undergo testing after a relative is diagnosed (see 'Implications for relatives' below), or when having blood testing for other reasons. As a result, approximately three-fourths of people with hereditary hemochromatosis are diagnosed before they have symptoms, and most people do not have complications at the time of diagnosis.
Liver disease — The liver is one of the main organs where iron is stored. Accumulation of iron in the liver can cause abnormal liver function, liver fibrosis (scarring), and cirrhosis (extensive scarring of the liver) (figure 1). Approximately three-fourths of people who have symptoms at the time of diagnosis have abnormal liver function.
Cirrhosis can cause a number of complications and can ultimately lead to liver failure or death; this generally only applies to people with severe iron accumulation over a period of decades. People with cirrhosis are also at increased risk for developing liver cancer. Liver disease is often worse in people with hereditary hemochromatosis who also have chronic hepatitis B or C or who use excess alcohol, so it is important to identify and treat these conditions as well. (See "Patient education: Hepatitis B (Beyond the Basics)" and "Patient education: Hepatitis C (Beyond the Basics)" and "Patient education: Cirrhosis (Beyond the Basics)".)
Weakness and lethargy — Most people who have symptoms at the time of diagnosis have weakness and lethargy (a feeling of mental and physical sluggishness).
Infections — Hemochromatosis can increase the risk of infections with specific types of bacteria. Accumulation of iron interferes with their ability to fight off certain bacteria, and certain bacteria grow well in an iron-rich environment.
Other conditions — In addition to the liver, iron can accumulate in other organs. The following is a list of some of the places iron can accumulate and the problems this can cause in people with hemochromatosis.
●Darkening of the skin – Iron in the skin, along with the pigment melanin, can darken the skin and give a person a tanned appearance or may sometimes cause skin to look grey.
●Joint pain – The cause of joint pain in people with hemochromatosis is not completely understood. One hypothesis is that the excess iron leads to the collection of calcium crystals in the joint spaces. These crystals can cause joint pain and, over time, joint deformity. The joints of the hands, especially the knuckles of the second and third fingers, are most commonly affected.
●Osteoporosis – Some individuals can develop osteoporosis or osteopenia (bone weakening), leading to fractures.
●Diabetes mellitus – Accumulation of iron in the pancreas can interfere with insulin production and cause diabetes mellitus. (See "Patient education: Type 2 diabetes: Overview (Beyond the Basics)".)
●Reproductive problems – Accumulation of iron in the pituitary gland in the brain can interfere with the pituitary's control of sex hormones. In males, pituitary damage can lead to impotence and/or loss of libido (sex drive). In females, pituitary damage can cause menstrual periods to stop or become irregular. (See "Patient education: Sexual problems in males (Beyond the Basics)" and "Patient education: Absent or irregular periods (Beyond the Basics)".)
●Heart disease – Accumulation of iron in the heart can cause enlargement of the heart and can interfere with its normal electrical conduction system, which affects the heart rhythm. In severe cases, heart failure can develop. Rarely, heart disease is the first sign of hemochromatosis.
●Thyroid disease – Accumulation of iron in the thyroid gland can cause hypothyroidism (reduced thyroid function). (See "Patient education: Hypothyroidism (underactive thyroid) (Beyond the Basics)".)
Some of these problems get better with treatment, especially if treatment is started early and sufficient iron is removed from the body. However, some of these complications may not be reversible.
HEMOCHROMATOSIS DIAGNOSIS — It is important to diagnose hereditary hemochromatosis early in the course of the disease because early treatment can help prevent complications. Diagnostic tests can help differentiate hereditary hemochromatosis from other conditions that cause similar symptoms, such as alcoholic liver disease. Tests can also determine the severity of hemochromatosis and its complications.
Blood tests — Two blood tests are usually recommended to determine the amount of excess iron in the body. These tests may be done as part of an "iron studies panel."
●Transferrin saturation – Transferrin is a protein that binds iron and transports it between the tissues. Some laboratories use a test called "total iron binding capacity" (TIBC), which essentially measures the same thing.
The transferrin saturation (also called TSAT) measures the amount of iron bound to transferrin, which increases as the body's iron stores increase. This test is the most sensitive for detecting early hemochromatosis. A TSAT higher than 45 percent should be investigated further.
●Ferritin levels – Ferritin is a protein that reflects the body's stores of iron. Blood ferritin levels increase when the body's iron stores increase; however, levels of ferritin usually do not rise until iron stores are high. Therefore, the results of this test may be normal early in the course of hemochromatosis.
Ferritin levels above 300 ng/mL in males or above 200 ng/mL in females support a diagnosis of hemochromatosis. However, ferritin levels can also be increased by disorders other than hemochromatosis. Only a small number of people with high ferritin actually have hemochromatosis.
Genetic tests — Genetic testing can reveal the HFE C282Y variant associated with hereditary hemochromatosis. H63D is another variant seen in some people with hereditary hemochromatosis; however, its relevance to hemochromatosis is very limited and controversial.
TESTS TO DIAGNOSE TISSUE IRON OVERLOAD — Once a person has blood tests that show excess iron in their body, other tests are used to determine how much iron has been deposited in tissues such as the liver or heart.
MRI methods — Magnetic resonance imaging (MRI) methods called R2, R2*, or T2* are imaging tests that have been developed to provide useful information about the level of accumulation of iron. This is most commonly used.
Liver biopsy — A liver biopsy is another test that can be used to determine if the liver is affected by iron overload. This test is most useful if other causes of liver disease are being considered. In many straightforward cases, a liver biopsy is not necessary. (See "Patient education: Liver biopsy (Beyond the Basics)".)
HEMOCHROMATOSIS TREATMENT — Treatment of hereditary hemochromatosis requires removal of excessive iron from the body, usually by periodically removing blood (referred to as "therapeutic phlebotomy").
Treatment can help prevent complications and even reverse some complications after they occur. Treatment is usually continued throughout a person's life, although it may be temporarily discontinued in some cases, such as during pregnancy.
Therapeutic phlebotomy (blood removal) — Therapeutic phlebotomy entails periodic removal of blood. The process is very similar to donating blood (and involves removing about the same amount). The blood removed by therapeutic phlebotomy can be used to provide blood transfusions for other people.
Phlebotomy removes iron by removing red blood cells, which contain a large portion of the body's iron. Over time, phlebotomy returns iron stores back to normal levels. Phlebotomy is appropriate and beneficial for most people with excess iron stores from hereditary hemochromatosis, including older adults and people who have no symptoms.
The decision to begin phlebotomy in a person with hereditary hemochromatosis is usually based on a person's age, sex, level of ferritin in the blood, and results of magnetic resonance imaging (MRI) or liver biopsy. When iron overload is present, phlebotomy should be started.
●Phlebotomy procedure – Phlebotomy is generally safe and can be performed in an infusion center, blood bank, hospital, or even a person's home. People undergoing phlebotomy should drink an adequate amount of fluids and avoid exercise if they feel excessive fatigue within 24 hours of the procedure.
Typically, 1 unit of blood (approximately 500 mL or 1 pint) is removed at a time. This is usually done once per week in the beginning. Later it can be extended to every other week.
Blood counts and ferritin levels are usually monitored every 4 to 12 weeks during treatment. These values help to determine when the excess iron stores have been depleted; they also help determine if phlebotomy has caused anemia by depleting iron too rapidly. If anemia occurs, phlebotomy may be temporarily stopped.
In people with hemochromatosis who do not have symptoms at the time of diagnosis, the excess iron stores are removed after approximately 15 to 30 or fewer phlebotomy treatments. In people who have symptoms at the time of diagnosis, 50 or more phlebotomy treatments may be needed to deplete excess iron stores.
Some young people with hemochromatosis who have not had time to accumulate much iron may only require four to six phlebotomies to remove the excess iron. Each unit of blood lowers the ferritin by approximately 30 ng/mL. If an MRI scan shows serious iron accumulation in the heart or liver, it is useful to repeat the MRI to make sure that iron is being removed effectively.
●Maintenance phlebotomy – After excess iron has been removed, maintenance phlebotomy is essential to prevent iron from accumulating again. This is because the body continues to absorb iron even if the iron levels are normal or elevated. Maintenance phlebotomy involves phlebotomy approximately every two to four months.
●Effectiveness of phlebotomy – Phlebotomy can effectively remove iron and resolve some, but not all, complications of hemochromatosis. If complications have not yet occurred, phlebotomy is very effective in preventing them, as long as sufficient iron is removed from the body. Most people will have a normal life expectancy.
•Phlebotomy can help prevent the potentially life-threatening complications of cirrhosis and liver cancer. It can also resolve or greatly improve poor liver function, liver enlargement, and liver pain. Phlebotomy is most likely to reverse liver disease when it is in an early stage, but phlebotomy can still improve liver function in people who have developed cirrhosis. Phlebotomy may not reverse cirrhosis or lessen the risk of liver cancer that is associated with cirrhosis.
•Phlebotomy can resolve or markedly improve weakness, fatigue, and lethargy; and darkening of the skin.
•Phlebotomy may resolve joint pain and heart disease. Studies suggest that phlebotomy improves joint symptoms in approximately 20 percent of people with hereditary hemochromatosis. Phlebotomy is most likely to reverse heart disease when it is in an early stage.
•Phlebotomy only rarely improves joint deformity, pituitary disease, susceptibility to certain infections, diabetes, and thyroid disease. Phlebotomy is most likely to restore normal levels of sex hormones in males who are under 40 years of age.
Can I be a blood donor? — A common question is whether a person with hereditary hemochromatosis can serve as a blood donor. The scientific and clinical answer is yes. Hereditary hemochromatosis is not a blood disease; the red blood cells and other blood components are not affected, and hereditary hemochromatosis cannot be transmitted by blood. Some blood centers will, and others will not, accept blood from donors with hereditary hemochromatosis.
Dietary considerations — People who are receiving treatment for hemochromatosis do not have to follow a special diet. There is no evidence that the condition is worsened by consuming moderate amounts of iron-rich foods such as red meat and liver.
However, people with hereditary hemochromatosis should avoid iron supplements (including multivitamins plus iron).
Alcoholic beverages may be consumed in moderation. However, drinking more than two alcoholic beverages per day increases the risk of cirrhosis. People with hemochromatosis and liver disease should avoid alcohol completely.
People with hemochromatosis should avoid eating uncooked seafood because it may contain bacteria that grow well in an iron-rich environment, at least until their iron overload has been treated.
Chelation therapy (deferoxamine or deferasirox treatment) — Chelation therapy refers to treatment with a drug that removes iron from the body. Examples are deferoxamine, deferasirox, or deferiprone. These drugs tightly bind iron and remove it from the body, lowering iron stores.
Chelation is sometimes used in people who have iron overload but cannot undergo phlebotomy because they also have anemia. However, chelation therapy is seldom used in people with hereditary hemochromatosis, because phlebotomy is a simpler and possibly more effective treatment that avoids potential side effects of chelation drugs.
Treatment of complications — Although phlebotomy can alleviate or even completely resolve some complications of hemochromatosis, other measures may be necessary to treat complications that persist.
For example, liver disease may progress to cirrhosis and may require liver transplantation; diabetes may require insulin therapy. (See "Patient education: Cirrhosis (Beyond the Basics)" and "Patient education: Type 2 diabetes: Insulin treatment (Beyond the Basics)".)
IMPLICATIONS FOR RELATIVES — Hereditary hemochromatosis is almost always caused by a genetic change that is passed from both parents to a child. Therefore, clinicians usually recommend that first-degree relatives (parents, siblings, and children) of people with hemochromatosis undergo testing.
There is a 25 percent chance that a full sibling of a person with one copy of the HFE C282Y variant from each parent will also have inherited two copies, provided that both of the parents only carry one copy of the variant.
The primary goal of screening is to detect hereditary hemochromatosis before there are symptoms or complications. Screening is generally not needed until adulthood, when the individual can give informed consent for testing. The optimal age is between 18 and 30 years; during this time, the condition can be detected, but serious tissue damage has not yet occurred.
The optimal strategy for screening is by blood tests for ferritin and transferrin saturation (TSAT), which may be done as part of an "iron studies panel." If these are abnormal, then genetic testing can be performed. It is important to discuss the advantages and disadvantages of family screening with a doctor, genetics expert, or other expert in hemochromatosis.
Blood tests — Screening for hemochromatosis includes blood tests to determine a person's TSAT and ferritin levels. (See 'Blood tests' above.)
Genetic tests — Genetic tests are also commonly performed if the ferritin or TSAT is increased or if there is a family history of hereditary hemochromatosis. This testing may not be necessary for all first-degree relatives; the genetic profile of the affected person may indicate which relatives should be tested.
If both parents are known to be carrying the HFE C282Y variant, the child is generally tested after they are able to consent (typically, 18 year or older). Your doctor can talk with you about the best age to perform the testing.
HOW WILL HEMOCHROMATOSIS AFFECT MY LIFE? — Most people with hemochromatosis have a normal life expectancy. Survival may be shortened in people who are not treated and develop cirrhosis or diabetes mellitus.
SUMMARY
●Definitions and causes – Hemochromatosis refers to excess iron in the body. The extra iron builds up in organs and can damage them. Without treatment, the iron overload causes these organs to stop working properly, which can lead to death.
Hereditary hemochromatosis is a genetic disorder that typically occurs in individuals who inherit two copies of the C282Y variant in the HFE gene (one from the mother and one from the father). However, not everyone who inherits HFE variants will develop hemochromatosis.
●Symptoms – Symptoms of hemochromatosis usually appear after age 40 and may include liver enlargement (figure 1), weakness, infections, darkened skin, and joint pain. People with hemochromatosis are more likely to develop heart disease, diabetes mellitus, thyroid problems, and hormonal changes (eg, bone thinning, irregular or missed menstrual periods, sexual problems in males).
●Testing – Tests are available to diagnose hemochromatosis. Blood tests include ferritin and transferrin saturation (TSAT); these are the most important initial tests. If there is concern for organ injury, magnetic resonance imaging (MRI) or liver biopsy can be performed. Genetic testing provides important confirmation but is not needed for treatment. First-degree relatives (parents, siblings, children) should also be tested for ferritin and TSAT, and sometimes with genetic testing. Early testing and treatment can help to prevent complications.
●Treatment – The most common treatment of hereditary hemochromatosis is removal of blood (phlebotomy), which lowers the amount of iron in the body. Phlebotomy is similar to the process of donating blood. It is usually done once per week until the body iron levels have decreased to normal. This may require up to 9 to 12 months of weekly phlebotomy treatments. After that, iron levels are measured with a blood test every month or two, phlebotomy is done every two to four months to manage the iron stores. Treatment is usually needed for a lifetime.
●Dietary considerations – People with hemochromatosis do not need to follow a special diet. Iron supplements should be avoided. Drinking alcohol occasionally (one or two drinks per week) is probably safe unless the person has liver disease (cirrhosis or hepatitis). Raw fish products should not be consumed.
WHERE TO GET MORE INFORMATION — Your doctor, nurse, or genetics expert is the best source of information for questions and concerns related to your medical problem.
This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for health care professionals, are also available. Some of the most relevant are listed below.
Patient level information — UpToDate offers two types of patient education materials.
The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Patient education: Hemochromatosis (The Basics)
Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.
Patient education: Cirrhosis (Beyond the Basics)
Patient education: Liver biopsy (Beyond the Basics)
Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.
Clinical manifestations and diagnosis of hereditary hemochromatosis
HFE and other hemochromatosis genes
Methods to determine hepatic iron content
Approach to the patient with suspected iron overload
Management and prognosis of hereditary hemochromatosis
The following organizations also provide reliable health information:
●National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
●National Institute of Diabetes and Digestive and Kidney Diseases
●The Centers for Disease Control and Prevention
●American Liver Foundation
●Hemochromatosis Foundation
●American Hemochromatosis Society
●Haemochromatosis International
(www.haemochromatosis-international.org)
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ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges the extensive contributions of William C Mentzer, MD, and Bruce R Bacon, MD, to earlier versions of this and many other topic reviews.
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