Hemochromatosis

Hemochromatosis is an inherited disease in which too much iron builds up in the body. The extra iron is toxic and can damage the organs. If hemochromatosis is not treated, it can lead to illness or death. Type 1 hemochromatosis, also called primary or hereditary hemochromatosis, is inherited and is the most common type. Secondary hemochromatosis is caused by anemia, alcoholism, and other disorders.

Other Names

Other names for the inherited form of hemochromatosis include:^[1]

• Primary hemochromatosis
• Familial hemochromatosis
• Genetic hemochromatosis
• Haemochromatosis (British spelling)
• Iron storage disorder
• HH
• HC
• HLAH
• Bronzed cirrhosis
• Bronze diabetes
• Pigmentary cirrhosis
• Troisier-Hanot-Chauffard syndrome
• Von Recklinghausen-Applebaum disease

Types

Strictly speaking, hemochromatosis is a general term that refers to the effect of very high iron levels on the body’s organ systems. This can happen because of a genetic or inherited disorder (primary) or due to some other disease (secondary). Types of primary hemochromatosis include:

1. Type 1 hemochromatosis, also known as hereditary hemochromatosis: Symptoms tend not to show up until middle age in men, and after menopause in women.
2. Type 2 hemochromatosis, also known as juvenile hemochromatosis: this type leads to severe iron overload and liver and heart disease in adolescents and young adults between the ages of 15 and 30.
3. Type 3 hemochromatosis: Symptoms show up between youth and middle age, usually by age 3.
4. Type 4 hemochromatosis, also known as ferroportin disease: Symptoms show up in middle age, like Type 1. It is seen mostly in Africans and people of African descent.^[2][3]

Rarely, iron overload shows up in neonates. Rapid iron buildup in the baby’s liver in neonatal hemochromatosis can lead to death or at least the need for a liver transplant shortly after birth.^[4]

Usually when hemochromatosis is talked about by doctors or is in the news, it refers to the common hereditary disease, Type 1 hemochromatosis.

Hereditary hemochromatosis

Hemochromatosis is most often inherited. Types 1-3 are autosomal recessive genetic conditions, which means that two copies of the gene causing the disease must be inherited, one copy from each parent. (Type 4 is Autosomal Dominant|autosomal dominant, meaning that a single copy of the gene can produce disease.)^[5] The genes most commonly involved in type 1 hemochromatosis are called HFE genes. Abnormal HFE genes cause the body to absorb too much iron. Humans inherit two copies of most of the genes in the body, one from each parent. Type 1 hemochromatosis occurs in patients who inherit two copies of the abnormal HFE gene, one from each parent. When an individual has inherited two faulty HFE gene copies, his DNA is said to carry the HH mutation. A number of abnormal genes can lead to hemochromatosis.^[6]

Patients who inherit one abnormal HFE gene and one normal HFE gene are "carriers" of the disease. Carriers do not usually develop the disease, but they can pass the abnormal gene on to their children. About 9% of people in the United States and as many as 22% in Europe are believed to be hemochromatosis carriers.^[6]

If both parents are carriers of an abnormal HFE gene, then each of their children has a 1 in 4 chance of inheriting a pair of abnormal HFE genes.

Hereditary hemochromatosis is not 100% penetrant. This means that even people who have two abnormal genes do not always get the disease. In fact, about 38% to 50% of such people develop iron overload, and 10% to 33% develop symptoms.^[7]

Secondary hemochromatosis

In secondary hemochromatosis, another disorder increases body iron stores enough to cause disease. Such disorders include:

• Certain anemias, such as thalassemia and aplastic anemia
• Atransferrinemia,^[8] aceruloplasminemia,^[9] and DMT1 (divalent metal transporter gene) mutations,^[10] all rare inherited diseases
• Chronic liver disease, such as hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis (NASH)^[11]

Secondary hemochromatosis can sometimes be caused by too much iron from:

• Iron intake (from oral iron pills or injected iron)
• Long-term kidney dialysis
• Blood transfusions: Patients requiring multiple transfusions of red blood cells can develop hemochromatosis, also called transfusional hemosiderosis in this case. The transfused blood contains large amounts of iron, which cannot be eliminated from the body. Many patients with hereditary transfusion-dependent anemias, such as thalassemia, develop hemochromatosis that can be blamed on their transfusions as well as their underlying disease, and may require lifelong chelation therapy to prevent catastrophic organ damage.^[12]

Causes

Type 1 hemochromatosis is mainly caused by a defect in a gene called HFE, which helps regulate the amount of iron absorbed from food. The two known mutations of HFE are C282Y and H63D. C282Y is the most important. In people who inherit C282Y from both parents, the body absorbs too much iron and hemochromatosis can result. Those who inherit the defective gene from only one parent are carriers for the disease but usually do not develop it; however, they still may have higher-than-average iron absorption.

Neither juvenile hemochromatosis nor neonatal hemochromatosis are caused by an HFE defect. Juvenile and neonatal hemochromatosis are caused by a mutation in a gene called hemojuvelin. Type 4 hemochromatosis is caused by ferroportin mutations.

Risk Factors

Having a pair of abnormal HFE genes (one from each parent) is the major risk factor for hemochromatosis. However, only about 10% to 33% of people with two copies of the abnormal gene actually develop signs or symptoms of the disease.^[7]

Although both men and women can inherit the gene defect, men are more likely than women to be diagnosed with hereditary hemochromatosis at a younger age. On average, men develop symptoms and are diagnosed between 30 to 50 years of age. For women, the average age of diagnosis is about 50.

Effects of too much iron

Excessive iron generates destructive molecules called free radicals, which cause damage to the organs. The body has no way of getting rid of excess iron, with the exception that menstrual blood and pregnancies do carry some iron away. This is why women become symptomatic later in life than men. The tiny bit of iron that is lost naturally from the body does so through skin flaking and feces, but in people who absorb too much iron in their diets, these losses aren't enough to compensate.

Other risk factors

Alcoholism is a risk factor for symptomatic hemochromatosis. A family history of certain diseases is also associated with a higher risk of hemochromatosis. Some of these diseases are heart attack, liver disease, diabetes, arthritis, and erectile dysfunction (impotence).

Risk factors for developing secondary hemochromatosis are discussed above, under "Causes."

Signs and Symptoms

Early symptoms include weakness, weight loss, change in skin color, Abdominal Pain|abdominal pain, loss of libido, and symptoms of diabetes mellitus. Some people never have any symptoms or complications, even with high iron levels. Others have serious side effects or die from the disease. Certain factors can affect how serious the disease is. For example, other genes besides the hemochromatosis genes may change or lessen the severity of the disease. Vitamin C in the diet can increase the amount of iron the body absorbs from food and make hemochromatosis worse. Alcohol use can increase liver damage and cirrhosis. Certain conditions, such as hepatitis, can damage or weaken the liver.

Hemochromatosis can affect many parts of the body and can cause many different signs and symptoms. Many of these are similar to those of other, more common diseases. Some people with the hemochromatosis genes may never have any signs or symptoms at all. It is important to remember that hemochromatosis develops over the patient's lifetime and may progress very slowly. This means that patients do not usually complain of all of the symptoms of hemochromatosis at once, but may have complained about them over a long time.

Signs and symptoms of hemochromatosis usually are not seen until middle age. Men are more likely to develop complications such as diabetes or liver cirrhosis, and women are more likely to have general symptoms such as fatigue. Signs and symptoms also vary based on how far the disease has advanced.

Common signs and symptoms of early-stage hemochromatosis include:

• Fatigue
• Joint pain
• General weakness
• Weight loss
• Abdominal pain
• Palpitations (a fluttering sensation in the chest)
• Skin darkening or “hyperpigmentation” (present in three-quarters of all patients)
• Loss of libido (sex drive)

Common signs and symptoms of mid-stage hemochromatosis (as more iron builds up in the body) include the following:

• Joint damage and pain (arthritis)
• Enlargement of the liver or detection of altered liver enzymes in routine blood tests
• Reproductive organ failure (for example, impotence, shrinkage of the testicles, loss of sex drive, infertility, absence of the menstrual cycle, and early menopause)
• Heart problems (for example, chest pain, shortness of breath, and abnormal heart rhythms)

Common signs, symptoms, and conditions of advanced-stage hemochromatosis include the following:

• Poor liver function: Iron overload can lead to cirrhosis, failure, or cancer of the liver)
• A high blood sugar level: Glucose intolerance or diabetes)
• Chronic (frequent or repeated) abdominal pain
• Severe fatigue
• Poor hormone production of the pituitary and thyroid glands
• Damage to the adrenal gland
• Heart failure: Iron overload can damage the heartmuscle, leading to heart failure
• Changes in skin color: For example, yellowish skin, tan skin not caused by the sun, and reddish palms not caused by use of the hands
• Cancer
• Damage to the immune system with lowered ability to fight certain infections, specifically from Listeria, Yersinia Enterocolitica|Yersinia enterocolitidis and Vibrio vulnificus species. These organisms are "iron-loving," or siderophilic.

Related Problems

In hemochromatosis, the extra iron can build up in almost all of the internal organs, especially in the skin, liver, heart, pancreas and joints. Organ failure can result if too much iron accumulates. An old term for hemochromatosis is “bronze diabetes” because the pancreas is involved and the skin becomes pigmented. Indeed, the condition can make the skin appear suntanned and give the impression that the person is healthy. In fact, skin pigmentation is a sign of worsening disease.

• Liver: Hemochromatosis can enlarge or scar the liver so it does not work properly (cirrhosis), liver failure, or cancer of the liver.
• Heart: Hemochromatosis can cause irregular heart rate or rhythm (arrhythmia) and lead to heart failure.
• Pancreas: Hemochromatosis can lead to diabetes mellitus, since the pancreas makes innsulin.
• Joints: Hemochromatosis can build up in the joints, causing an aching pain or arthralgia.

Diagnosis

Hemochromatosis is diagnosed based on medical and family history, a physical exam, and diagnostic tests and procedures. The disease is sometimes found during the diagnosis of other diseases or conditions such as arthritis, liver disease, diabetes, heart disease, and impotence.

Medical and family history

Since hemochromatosis is a chronic disease, the patient's full medical history is relevant. The doctor will want to know:

• Current symptoms, including when they started
• Possible causes of secondary hemochromatosis, such as taking too much iron (blood transfusions, pills or injections) or vitamin C
• A family history of hemochromatosis
• A parent or sibling whose medical history suggests undiagnosed hemochromatosis

Physical exam

Physical exam findings in hemochromatosis can include abnormal heart rhythms, joint deformity or swelling, abnormally dark skin color, and an enlarged liver.

Blood tests

Blood tests are used to find out how much iron is in the body, and the location in which this iron is stored. Types of blood tests that may be used include the following:

• Transferrin saturation (TS): Transferrin transports iron. It is the earliest biochemical marker to become abnormal in hemochromatosis. A high TS level (greater than 80%) suggests hemochromatosis is present,^[13] since it indicates the degree to which available iron storage sites are filled. To be accurate, this blood test is performed after an overnight fast.
• Serum ferritin level: Ferritin is an iron storage protein. Levels are increased when iron overload is present to try to stop the iron from depositing in the tissues and reaching dangerously high concentrations in the blood. The serum ferritin level may be tested if the TS level is high. Mild iron excess corresponds to values less than 500 µg/L, medium to 500–1000, and severe > 1000.^[13]
• Liver function tests: These blood tests may be done to check the level of damage to the liver. Liver damage may indicate the presence of hemochromatosis. In people who have been diagnosed with hemochromatosis, these blood tests may show how far the disease has advanced. Liver function tests often may be normal, however, even when liver damage is advanced, so the tests are not perfect.

Depending on how abnormal blood test results are, doctors may recommend the next diagnostic step, genetic testing.

Genetic testing

In people with abnormal iron, or people with an immediate relative with hemochromatosis, genetic testing can be done to show whether there are zero, one, or two copies of the abnormal HFE gene. The test is accurate in more than eight out of ten cases. It can identify people who have two copies of the abnormal gene, but it cannot predict which of these people will go on to develop iron overload disease. The most common HFE mutation is called C282Y, and a less frequent one is H63D. The test may overlook people who have hemochromatosis caused by other types of genes, although this is far less common. Genetic testing can be carried out in two ways. A cheek test uses a cotton swab to collect cells from the inside of the mouth. A whole blood test uses a sample of blood from a vein in the arm.

A patient with two copies of the C282Y mutation is diagnosed with hemochromatosis and, depending on transferrin levels, treatment may be initiated at this stage. In patients with one mutation each of H63D and C282Y, a liver biopsy may be necessary for diagnosis.

Genetic testing may be done with genetic counseling for couples planning to have a family when one or both parents have hemochromatosis or have a family history of the disease. Counseling can determine if one or both parent(s) carry the abnormal HFE gene, and the likelihood of passing the HFE genes to their children.

Quantitative phlebotomy

Quantitative phlebotomy (blood removal) may be done to check a diagnosis of hemochromatosis. A phlebotomy is a similar experience to giving blood, with about one pint of blood removed at each session. This has become a less common procedure since the gene responsible for hemochromatosis was discovered.

Liver biopsy

Liver biopsy is important for the diagnosis of hemochromatosis, as well as to assess how advanced the disease is when it is diagnosed. A liver biopsy can show how much iron is in the liver and can diagnose liver scarring (fibrosis, cirrhosis) and cancer which accompany hemochromatosis. During a liver biopsy, liver cells are removed by a long needle inserted through the skin. The cells are then examined under a microscope. Genetic testing has largely replaced liver biopsies. However, in patients diagnosed after the age of 40, they are still used for staging.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is a test that can show the amount of iron in the liver. MRI uses magnetic fields to show images of organs and structures inside the body. It provides more detail than an x-ray for some kinds of problems.

Superconducting quantum interference device

Superconducting quantum interference device (SQuID), like MRI, measures the amount of iron in the liver using an exquisitely sensitive magnetometer. It is available at only a few medical centers.

Treatment

Treatments for hemochromatosis include therapeutic phlebotomy, iron chelation therapy, changes in diet, and other treatments for complications. The disease affects many organ systems, so many specialists may be involved in treatment.

Goals of treatment

The goals of treating hemochromatosis are to reduce the amount of iron stored in the body to normal levels, prevent or delay organ damage from iron overload, treat complications of the disease, and maintain normal iron levels over the long term (for life). This is because the damage caused by hemochromatosis is a direct result of iron poisoning the organs.

Therapeutic phlebotomy (periodic blood removal)

This type of treatment is used to remove iron from the body in a process much like donating blood. Blood contains high levels of iron as hemoglobin in the red blood cells, a molecule that carries oxygen in the blood. Therapeutic phlebotomy generally begins soon after diagnosis. Blood removal can be done at blood donation centers, hospital donation centers, or a doctor's office.

Therapeutic phlebotomy is usually advised for people with very high serum ferritin levels and people who have signs and symptoms of hemochromatosis. In the first stage of treatment, about 1 pint of blood is removed once or twice a week. After iron levels return to normal, typically phlebotomy is still required, but only about every 3 months. Treatment is usually lifelong once it has been started.

Iron chelation therapy

Iron chelation therapy uses medicine to remove excess iron from the body. It is a good option for people who cannot undergo repeated blood removal. This includes people who have secondary hemochromatosis because of hereditary anemias; their blood count is too low to allow blood to be safely removed. Many of these people actually require blood transfusions instead of blood removal.

Injected iron chelation therapy can be done in the doctor's office. Oral iron chelation therapy can be taken at home. The medicines used for chelation therapy include:

• Deferoxamine mesylate (Desferal): This medicine is injected either in a muscle, under the skin, or through a vein.
• Deferasirox (Exjade): This is an oral medicine that binds with the extra iron and then leaves the body in the feces.
• Deferiprone (Ferriprox) is an experimental oral medicine that binds with the extra iron and then leaves the body in the urine or feces.

Changes in diet

Because the lifelong iron accumulation is due to the body's absorbing too much iron from the diet, an important step in managing hemochromatosis is minimizing dietary iron. Patients should:

• Avoid taking iron supplements, including iron pills, injections of iron, or multivitamins that contain iron
• Limit vitamin C intake, since vitamin C increases the amount of iron the body absorbs

Patients should also:

• Avoid uncooked fish and shellfish, because some fish and shellfish contain bacteria (Vibrio vulnificus and Yersinia enterocolitidis) that could cause infection in people with hemochromatosis; and limit alcohol intake.
• Avoid drinking. Alcohol increases the risk for liver disease and can make liver disease worse. Drinking alcohol when the liver is already fibrosed or cirrhotic rapidly results in liver failure, which is usually fatal.

Prevention

Primary hemochromatosis is a hereditary condition, passed from parents to children through the genes. Specialist genetic testing and counseling can help parents with the hemochromatosis genes determine their chances of passing the genes on to their children. The organ damage from iron overload that results from inheriting two mutated copies of the HFA gene can be prevented if the diagnosis is made by genetic testing. In such people, early treatment with phlebotomy may prevent the late problems. In people with iron overload disease which has already caused medical problems, further complications can be prevented with phlebotomy therapy. Secondary hemochromatosis from recurrent transfusion may sometimes be delayed by starting iron chelation therapy early, but usually hemochromatosis does develop in these patients eventually.

Screening

Screening means testing for a disease when a person has no symptoms. Currently, there is debate over whether to routinely perform genetic screening on the general public for the condition. A recent review by the U.S. Preventive Services Task Force concluded that there is not enough evidence to recommend doing so.^[7] The trouble with routinely screening people who have no symptoms is that not all mutations lead to actual disease (it is not completely penetrant, so many people who test positive for mutations will worry and undergo treatment unnecessarily. Also, it isn't clear how beneficial very early treatment would be (compared to treatment after a routine, midlife diagnosis). Finally, there are real concerns that people with the genes would be stigmatized or discriminated against by employers or insurance providers even if they never develop any illness.^[14]

Expected Outcomes

Hemochromatosis can be treated effectively with phlebotomy (repeated blood removal). How well the treatment works depends on how much organ damage has already occurred before treatment begins. If hemochromatosis is found and treated early, complications can be prevented, delayed, or even reversed. With early diagnosis and treatment, a normal lifespan is possible. When organ damage has already occurred, treatment may prevent further damage and improve life expectancy, but it may not be able to reverse existing damage. If not treated, hemochromatosis can lead to severe organ damage or even death.

Living with Hemochromatosis

Response to treatment

People have varied responses to treatment. Some people undergoing frequent blood removal may feel fatigued. People who are in advanced stages of the disease or who are receiving aggressive (very strong) treatment that weakens them may need help with daily tasks and activities. At first, frequent phlebotomies may be needed for anywhere from 6 months to 3 years. How long this treatment is needed depends on how much extra iron is in the body. Even after this, ongoing treatment may be needed 2 to 6 times a year to keep the iron from building back up again. In secondary hemochromatosis, a syringe pump may need to be used to infuse chelation therapies at all times. Often patients find this treatment to be inconvenient, but it is very effective in delaying the development of symptoms.

Ongoing health care needs

Ongoing medical needs may include the following:

• Continuing phlebotomy
• Taking medicines as prescribed
• Regular checkups

People having phlebotomies may need to change their usual work times to schedule treatments. They may also need to change work schedules to allow for periods of fatigue, especially when they are having aggressive treatment that weakens them.

Epidemiology

Type 1 hemochromatosis 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 are also affected. According to the CDC, approximately 1 million Americans have the pair of gene mutations that can cause hemochromatosis.^[15]Put in other terms, about 5 people out of 1,000, (0.5%)of the U.S. Caucasian population carry two copies of the hemochromatosis gene and are susceptible to developing the disease. About 9% of Americans carries one abnormal gene.^[6] Hemochromatosis is less common in African Americans, Asian Americans, Hispanics/Latinos, and American Indians.

A Canadian study found that three to four of every 1000 people of European descent is affected.^[16]

Not everyone with the pair of genes gets sick. Estimates of how many people actually develop signs and symptoms vary, but it is thought that about 10% to 33% do so.^[7]

Research

For a list of clinical trials investigating hemochromatosis, click here.

Expected Outcome

The outlook for people with hemochromatosis depends on how much organ damage has already occurred at the time of diagnosis. Early diagnosis and treatment are important. Treatment may be able to prevent, delay, or sometimes reverse complications of the disease. Treatment may lead to higher energy levels and better quality of life. For people who are diagnosed and treated early, normal lifespans are possible. If left untreated, hemochromatosis can lead to severe organ damage and even death.

Interesting Facts

• It has been suggested that the composer Beethoven died from complications of hemochromatosis, since he had a dark complexion, suffered from chronic abdominal pain, and died of unexplained liver failure.^[17]
• Hemochromatosis has been dubbed the "Celtic Curse" by the president of the American Hemochromatosis Society, because it is so common in people of Irish, Welsh, and Scots ancestry.^[18]

References

1. ↑ NIH Genetics Home Reference—Hemochromatosis
2. ↑ Gordeuk VR, Caleffi A, Corradini E et al. Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells Mol Dis. 2003 Nov-Dec;31(3):299-304. Abstract
3. ↑ Schimanski LM, Drakesmith H, Merryweather-Clarke AT et al. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. Blood. 2005 May 15;105(10):4096-102. Epub 2005 Feb 3. Abstract | Full Text
4. ↑ Murray KF, Kowdley KV. Neonatal hemochromatosis. Pediatrics. 2001 Oct;108(4):960-4. Abstract | Full Text
5. ↑ Online Mendelian Inheritance in Man: Hemochromatosis
6. ↑ ^{6.0 6.1 6.2} Hanson EH, Imperatore G, Burke W. HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology. Am J Epidemiol. 2001 Aug 1;154(3):193-206. Abstract | Full Text
7. ↑ ^{7.0 7.1 7.2 7.3} Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2006 Aug 1;145(3):209-23. Abstract | Full Text
8. ↑ Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF. Molecular characterization of a case of atransferrinemia. Blood. 2000 Dec 15;96(13):4071-4. Abstract | Full Text
9. ↑ Kono S, Miyajima H. Molecular and pathological basis of aceruloplasminemia. Biol Res. 2006;39(1):15-23. Abstract | Full Text
10. ↑ Mims MP, Guan Y, Pospisilova D et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005 Feb 1;105(3):1337-42. Epub 2004 Sep 30. Abstract | Full Text
11. ↑ Sebastiani G, Walker AP. HFE gene in primary and secondary hepatic iron overload. World J Gastroenterol. 2007 Sep 21;13(35):4673-89. Abstract | Full Text
12. ↑ Fargion S, Taddei MT, Gabutti V et al. Early iron overload in beta-thalassaemia major: when to start chelation therapy? Arch Dis Child. 1982 Dec;57(12):929-33. Abstract | Full Text
13. ↑ ^{13.0 13.1} Brissot P, de Bels F. Current approaches to the management of hemochromatosis. Hematology Am Soc Hematol Educ Program. 2006:36-41. Abstract | Full Text
14. ↑ Alper JS, Geller LN, Barash CI, Billings PR, Laden V, Natowicz MR. Genetic discrimination and screening for hemochromatosis. J Public Health Policy. 1994 Autumn;15(3):345-58. Abstract
15. ↑ CDC: Hemochromatosis FAQ
16. ↑ Harrison H, Adams PC. Hemochromatosis. Common genes, uncommon illness? Can Fam Physician. 2002 Aug;48:1326-33. Abstract | Full Text
17. ↑ Davies PJ. Was Beethoven's cirrhosis due to hemochromatosis? Ren Fail. 1995 Jan;17(1):77-86. Abstract
18. ↑ American Hemochromatosis Society: Discovering Your Celtic Connection

External Links

Online Mendelian Inheritance in Man: Hemochromatosis

American Hemochromatosis Society

Canadian Hemochromatosis Society

The Haemochromatosis Society (Great Britain)

Haemochromatosis Society Australia Inc.

Iron Disorders Institute: Hemochromatosis