Hemochromatosis is an iron metabolism disorder that may be inherited or acquired. People with hemochromatosis accumulate more iron than their body needs. As the body does not have a way to excrete excess iron, there is a progressive buildup of iron in tissues and organs.
Eventually, the iron overload can lead to dysfunction and failure of several organs, notably the heart, liver, and endocrine portion of the pancreas. Complications include arthritis, diabetes, liver cirrhosis, heart arrhythmias and heart failure, and an increase in skin pigmentation called “bronzing.”
There are two types of hemochromatosis: primary hemochromatosis, an inherited form that is passed from one generation to the next, and secondary hemochromatosis, which is caused by some other disease or underlying condition.
Primary or Hereditary Hemochromatosis (HH)
Hereditary hemochromatosis (HH), also called primary hemochromatosis, is one of the most common genetic disorders in the U.S., affecting about one million people, most of them Caucasians. The disease is usually caused by a mutation in the HFE gene. Everyone has two copies of the HFE gene – one inherited from their mother and one inherited from their father.
The mutations lead to changes in the building blocks of proteins, termed amino acids, and they are commonly referred to by the changes they induce in these amino acids. For example, the most common mutation involves changing from an amino acid called cysteine (C) to one called tyrosine (Y) in the 282nd amino acid of the protein made by the HFE gene; this mutation is called C282Y.
There are several mutations in the HFE gene that can cause hemochromatosis. The probability of developing iron overload depends on the combination of genes inherited.
Secondary or Acquired Hemochromatosis
Secondary hemochromatosis is an acquired iron overload that can be due to a variety of other diseases and conditions. Examples include:
Chronic liver disease, such as chronic hepatitis C infection, alcoholic liver disease, or nonalcoholic steatohepatitis (NASH)
Some forms of anemia
Recurrent blood transfusions
Rarely, oral iron supplementation
The following lists possible gene combinations for the HFE gene:
Two copies of C282Y or a copy of C282Y together with a copy of H63D or S55C mutant genes places a person at the highest risk for HH.
Two copies of H63D, S55C, or one copy each of H63D and S55C puts a person in the low risk category and is only rarely associated with HH.
A single copy of C282Y, H63D or S65C means that the person is a carrier. Carriers do not develop the disease, but they can pass it on to their offspring if they have children with someone who is also a carrier.
Of course, other genes besides the HFE gene can affect a person’s ability to metabolize iron, so no combination of genes guarantees that someone will or will not develop the disease. For example, it is estimated that only about 25% of men and about 1% of women who have two copies of the C282Y mutation will ever develop organ damage related to excess iron.
HH affects more men than women, and symptoms of the disorder emerge at an earlier age for men, typically at about 30 to 50 years old. Two other rare forms of inherited hemochromatosis, neonatal and juvenile hemochromatosis, can cause severe iron overload in children and young adults. These disorders are caused by mutations in a different gene, one called hemojuvelin. In fact, a small percentage of cases of HH are due to mutations in genes coding for other proteins, including hemojuvelin as well as transferrin-receptor 2, ferroportin and hepcidin. Tests for these mutations are not widely available, however.
The tests below are used to detect and diagnose hemochromatosis and evaluate body organs for the severity of iron overload. They may also be used to monitor the effectiveness of treatment. Genetic testing may be used to confirm a diagnosis, but since many people who have genetic mutations associated with the disease never develop symptoms, blood tests are considered the most reliable form of diagnosis.
Laboratory testing typically includes:
Serum iron — used to check iron levels in the blood
Total iron-binding capacity (TIBC) — measures the total amount of iron that can be bound by proteins in the blood; transferrin is the primary iron-binding protein and the TIBC test is a good indirect measurement of transferrin availability.
Transferrin saturation — a calculation using the iron and TIBC test results, representing the percentage of the transferrin that is saturated with iron; it is elevated with hereditary hemochromatosis (HH) but is not specific for it.
Serum ferritin — used to evaluate the body’s iron stores; it may be elevated with HH but is not specific for it. In those who have HH genes, normal levels mean low risk for developing organ damage.
Liver panel — a group of tests used to evaluate liver function
Genetic testing — can be used to help confirm a diagnosis of HH. Most cases of HH, about 80-90%, are caused by two copies of a C282Y mutation in the HFE gene. The presence of the C282Y mutation does not necessarily mean that a person will develop the disorder but does indicate an increased risk, and men are more likely to be affected than women. The largest population study found about a 25% risk among men and 1% risk among women.
Sometimes an H63D or S65C mutation of the HFE gene or paired combinations of the three may cause HH. Rarely, the condition may be due to another genetic abnormality.
Liver biopsy — in rare cases, the diagnosis is confirmed by examination of a liver biopsy specimen for iron accumulation and liver damage.
The goals of hemochromatosis treatment are to reduce the amount of iron in the body and maintain it at near normal concentrations, to minimize permanent organ damage, and to address complications. If a person has secondary hemochromatosis, then treatment should also address the underlying disorder or condition. Because not all individuals who have the genetic changes need treatment, only those who have organ damage from excess iron are generally treated.
Hemochromatosis is usually treated with phlebotomy therapy, which typically involves the removal of a unit of blood. The frequency and length of treatment depend on the cause and degree of iron overload; for example, in those with severe iron overload, phlebotomy may initially be done once or twice a week, but after the excess iron is removed, phlebotomy may only be done a few times a year.
There is no cure for hereditary hemochromatosis, but it can be successfully managed over a person’s lifetime.
Someone who has secondary hemochromatosis may not require long-term blood removal treatment if the underlying condition can be resolved, and if their iron overload is due to many transfusions, it may not be possible to do phlebotomy if the need for transfusions is still present. There are also drugs that bind iron and allow it to be excreted in the urine, and these may be used for people who cannot safely have phlebotomy performed.