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 — As noted above, hemochromatosis (iron overload) can be caused by changes 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 ("H" stands for hereditary or "high"; "Fe" is the chemical symbol for iron). The most common HFE mutation is called "C282Y." There are also less-common mutations in HFE as well as mutations 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 about 10 percent of people of European ancestry but having only one copy of the C282Y mutation (inherited from only one parent) rarely causes iron overload.

In fact, most people do not develop iron overload if they carry the HFE C282Y variant, especially if only inherited from one parent, and even if inherited from both parents. The reasons that some people develop iron overload and some do not are still being studied. In general, men who develop iron overload tend to do so at a younger age than women. (See 'Risk factors' below.)

Risk factors — Hereditary hemochromatosis is more likely to be seen in men than in women because women lose iron during their menstrual periods and during pregnancies.

In the United States, about 5 in every 1000 people of European ancestry (0.5 percent) have hereditary hemochromatosis, although some are unaware of its presence. Family members of people with an HFE mutation should undergo testing since they may have the mutation without knowing it. (See 'Implications for the family' below.)

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 men and even later in women.

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 family member is diagnosed (see 'Implications for the family' below). As a result, about 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). About 75 percent 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. 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 (such as hepatitis B or C) or who use excess alcohol, so it is important to identify and treat these conditions simultaneously. (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 in immune cells 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 accumulation can cause in people with hemochromatosis.

●Darkening of the skin – Accumulation of iron in the skin, along with accumulation of the pigment melanin, can darken the skin and give a person a tanned appearance.

●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 can interfere with the pituitary's control of sex hormones. In men, pituitary damage can lead to impotence and/or loss of libido (sex drive). In women, pituitary damage can cause menstrual periods to stop or become irregular. (See "Patient education: Sexual problems in men (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 the presence of complications.

Blood tests — Three blood tests are usually recommended to determine the amount of excess iron in the body.

●Iron levels – Most people with hemochromatosis have elevated levels of iron in the blood.

●Transferrin saturation – Transferrin is a protein that binds iron and transports it between the tissues. The transferrin saturation (also called TSAT) increases as the body's iron stores increase. This test is one of the most sensitive tests for detecting early hemochromatosis. A transferrin saturation greater 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 greater than 300 ng/mL in men and 200 ng/mL in women support a diagnosis of hemochromatosis. However, ferritin levels can also be increased by many common disorders other than hemochromatosis.

Genetic tests — Genetic testing can reveal the presence of the HFE C282Y mutation associated with hemochromatosis. H63D is another mutation seen in some people with hemochromatosis; however, people with H63D mutation are much less likely to have symptoms than those with a C282Y mutation.

TESTS TO DIAGNOSE TISSUE IRON OVERLOAD — Doctors use a few different methods to determine whether a person has iron overload.

MRI methods — Once a person has blood tests that show excess iron in their body, it may be helpful to determine how much iron has been deposited in tissues such as the liver or heart. 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.

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 especially useful if other causes of liver disease are being considered. In many straightforward cases, a liver biopsy is not necessary because other tests are able to confirm the diagnosis. (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 (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 generally can be used to provide blood transfusions for other people. Because red blood cells contain iron, over time, phlebotomy removes excess iron and returns iron stores back to normal levels. Phlebotomy is appropriate and beneficial for most people with evidence of iron overload, 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, and level of ferritin in the blood; when ferritin levels are significantly elevated for a person's age and sex, phlebotomy should be started. Some physicians do not recommend starting phlebotomy until tissue iron overload is documented by one of the methods listed above.

●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 in patients who feel excessive fatigue within 24 hours of the procedure.

Typically, 1 unit of blood (about 500 mL or 1 pint) is removed at a time. This is usually done once per week in the beginning, and later 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 about 30 or fewer phlebotomy sessions. In people who have symptoms at the time of diagnosis, 50 or more phlebotomies 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 drops the ferritin by about 30 ng/mL. If an MRI scan shows serious iron accumulation in the heart or liver, it is useful to repeat the procedure 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 entails removing about 1 unit of blood approximately every two to four months.

●Effectiveness of phlebotomy – Phlebotomy can effectively 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.

•Phlebotomy can prevent complications of iron overload in people who do not yet have complications. It can also help to ensure a normal life expectancy. For example, 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 about 20 percent of people with 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 men who are less than 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 organ meats (eg, liver).

However, people with hereditary hemochromatosis should avoid iron supplements (including multivitamins plus iron), and they may also be advised to avoid vitamin C supplements, which promote iron absorption. 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. Some 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 and anemia. However, chelation therapy is seldom used in people with hereditary hemochromatosis because phlebotomy is a simpler and possibly more effective treatment, and 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 THE FAMILY — Hereditary hemochromatosis is almost always caused by a gene mutation 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 brother or sister of a person with one copy of the HFE C282Y mutation from each parent will also have inherited two copies, provided that both of the parents only carry one copy of the mutation.

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 serum iron studies. If these are abnormal, then genetic testing can be performed. It is important to discuss the advantages and disadvantages of family screening with a healthcare provider.

Blood tests — Screening for hemochromatosis includes blood tests to determine a person's transferrin saturation and ferritin levels. (See 'Blood tests' above.)

Genetic tests — Genetic tests are also commonly performed if iron levels are elevated or if there is a family history of hemochromatosis. This testing may not be necessary for all first-degree relatives; the genetic profile of the affected family member may indicate which relatives should be tested. If both parents are known to be carrying the HFE C282Y mutation, the child is generally tested at some point. 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

●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 mutation in the HFE gene (one from the mother and one from the father). However, not everyone who inherits mutations in HFE will develop hemochromatosis.

●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 men).

●Tests are available to diagnose hemochromatosis. Family members (eg, parents, siblings, children) of people with hereditary hemochromatosis should also be tested. Early testing and treatment can help to prevent complications.

●The most common treatment of hereditary hemochromatosis is removal of blood (phlebotomy), which lowers the iron level. Blood removal is similar to the process of donating blood. It is usually done once per week until the iron levels are normal. This may require 9 to 12 months of weekly blood removal. After that, iron levels are measured with a blood test every month or two, blood removal is done every two to four months to manage the iron level. Treatment is usually needed for a lifetime.

●People with hemochromatosis do not need to follow a special diet. Iron supplements and vitamin C 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 healthcare provider 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 healthcare 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

(www.niddk.nih.gov/)

●The Centers for Disease Control and Prevention

(www.cdc.gov)

●American Liver Foundation

(www.liverfoundation.org)

●Hemochromatosis Foundation

(www.hemochromatosis.org)

●American Hemochromatosis Society

(www.americanhs.org)

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