Hereditary Hemochromatosis
To Your Health -- CHRC Newsletter
Last Reviewed: August 2005
By Brennan Scott, M.D., PAMF Gastroenterology
What is hemochromatosis?
The term hemochromatosis was first used in 1889 to describe the condition of bronze-colored skin, diabetes, and cirrhosis of the liver. Initially thought to be a disease of the blood (hence hemo), it was found in the early twentieth century to be a hereditary disorder of iron metabolism. Hereditary hemochromatosis is a disease of excess iron storage caused by increased intestinal absorption of ingested iron. This extra iron is deposited in various organs which eventually can lead to tissue damage. Excess iron storage can also be caused by other diseases; when this is the case the term secondary hemochromatosis is often used. This article will focus specifically on hereditary hemochromatosis.
Hereditary hemochromatosis, occasionally referred to as "bronze diabetes," is the most common genetic disorder among Caucasians of European descent. The major genetic mutation was described in 1996 and is known as the C282Y mutation on chromosome number 6. More than ninety percent of people with clinical evidence of the disease have 2 copies of this gene. Other gene mutations are less common and unlikely to cause symptomatic disease.
Iron and your body
Iron is an essential mineral in the human body playing an important role in many different types of cells and proteins. The adult body contains 3-4 grams of iron. The majority of this, approximately 2.5 grams, is circulating in the blood as part of the oxygen-carrying protein hemoglobin which is present in red blood cells. One gram of iron is found in tissues as part of the iron storage protein ferritin; most of this extra iron is stored in the liver. Other iron-containing proteins and enzymes that use iron as part of chemical reactions in tissues account for approximately 400 mg of additional iron. A smaller amount of iron is circulating in blood plasma bound to an iron carrying protein known as transferrin. This protein combines with iron that has been absorbed from intestinal cells and carries it to the cells that need it. Cells signal their need for iron by placing receptors for transferrin receptors on their surface. Another protein called HFE is involved in regulating the amount of iron that is absorbed from the intestine and then distributed throughout the body. In hereditary hemochromatosis excess iron is absorbed for unclear reasons, and the most common genetic mutations leading to hereditary hemochromatosis are in this HFE gene.
Iron enters and leaves the body in several ways. The average western daily diet contains 15-25 milligrams of iron of which ten to twenty percent is absorbed. Additional iron may be obtained from vitamin supplements or blood transfusions. The primary location for the absorption of iron is the first part of the small intestine (duodenum). Iron is lost from the body slowly by several different mechanisms. Sweat carries a small amount of iron with it, and loss of aged cells from the skin, digestive tract and urinary tract account for about 1 mg of iron loss per day. Menstrual bleeding results in a small amount of continued blood loss in pre-menopausal women. Small amounts of iron may also be lost in blood from the digestive tract, for example from stomach irritation or colon polyps.
Who is at risk for hemochromatosis?
Hemochromatosis is a worldwide disease but is particularly common in people of Northern European origins. It is an autosomal recessive disorder, meaning that in order to have the disease one must have inherited two copies of the abnormal gene (one from each parent). Approximately ten percent of Caucasians in the United States carry one copy of the mutated gene and are therefore carriers of the disease. Approximately five out of every one thousand American Caucasians carry two abnormal genes and are said to have hereditary hemochromatosis, a large proportion of whom will show signs and symptoms of the disease.
How does hemochromatosis affect the body?
Hemochromatosis develops slowly and rarely manifests before adulthood. Excess iron will begin to accumulate from birth. Asymptomatic iron overload with 10-20 grams of iron stored in internal organs develops between a patient's twenties and forties. Symptomatic disease usually begins after age 40 when there is 20 grams or more of iron in the body. The disease can affect many different organs and cause an array of symptoms. Generalized symptoms such as malaise and fatigue are commonly associated with hemochromatosis but are also encountered with many other diseases as well as in the general population. Historically, patients were only diagnosed after the disease had become advanced, when serious and sometimes irreversible organ damage had occurred. With increased awareness of the disease and better and more available testing it can be diagnosed at a younger age before there are symptoms or significant organ damage.
What organs are affected?
Liver - A large portion of the excess iron is stored in the liver. This can cause liver enlargement and liver inflammation, often manifested as abnormal liver blood tests. Over time this can lead to liver scarring and in some patients even to cirrhosis. Cirrhosis from hemochromatosis leads to a 20-fold increase in the risk of liver cancer over the general population. Cirrhosis and liver cancer, although serious complications, evolve over a long period of time and only in a small percentage of patients.
Skin - Often called "bronze diabetes" in the past, hemochromatosis can cause a darkening of the skin. This is caused by an increase in melanin which is the skin's natural pigment, not by actual deposition of iron in the skin as was previously thought. This occurs only with more advanced disease and is seen less commonly as awareness of the disease has increased and treatment is begun earlier.
Joints - Hemochromatosis can cause an arthritis which is clinically similar to osteoarthritis. The small joints of the fingers are the most common site of pain but other joints can be involved as well.
Endocrine (hormonal system) organs - Progressive iron deposition in the pancreas, in association with advanced liver disease, can eventually lead to diabetes in a large proportion of patients with hemochromatosis. Impotence is common in men with hemochromatosis due to low testosterone levels. Osteoporosis is often seen due to low levels of certain hormones. Other hormonal abnormalities such as hypothyroidism (under-active thyroid gland) may occur but are less common.
Heart - Excess iron deposition in heart muscle can lead to decreased ability of the heart to contract and pump blood efficiently. The heart's innate electrical system can be affected leading to life-threatening abnormal heart rhythms.
How is hemochromatosis diagnosed?
The chief diagnostic tool in evaluating for hereditary hemochromatosis is blood testing. Most of the iron in the blood is bound to proteins and simple blood tests can be done to evaluate the levels of these proteins. An elevated level of the storage protein ferritin or an elevated transferrin saturation (how much iron is bound to its transfer protein transferrin) is often the first clue to the diagnosis. A more advanced genetic test which can identify the two most common gene mutations can be done by blood testing as well; this can help confirm the diagnosis. Needle biopsy of the liver in certain cases can help make the diagnosis and evaluate for liver scarring or cirrhosis (advanced liver damage).
The American Association for the Study of Liver Diseases has published guidelines on who should be tested for hemo-chromatosis. Patients who have symptoms which can be manifestations of hemochromatosis and in whom other causes for those symptoms have been excluded should be tested for the disease. First degree relatives (immediate family) of patients with confirmed hemochromatosis should undergo genetic testing to determine if they are carriers of one or more abnormal genes. The diagnosis should also be considered in patients who have been found to have abnormal iron levels on routine testing.
How is hereditary hemochromatosis treated?
The mainstay of treatment for hemochromatosis is iron removal via phlebotomy. Although this may conjure images of medieval medicine, it is very similar to blood donation. It involves the placement of a catheter into a vein in the arm for the removal of approximately one pint (unit) of blood. Each unit (approximately 500cc) of blood contains about 250 mg of iron. This procedure is repeated once or twice weekly until the ferritin level drops into the normal range (to a goal of less than 50 ng/ml), and then periodically thereafter. In some forms of iron overload chelation therapy may be used. For this treatment, drugs are given that bind to the excess iron in the body. The drug is then excreted from the kidneys taking the extra iron with it. This is more expensive and has many potential side effects so it is not commonly used for hereditary hemochromatosis. Vitamin C can increase circulating iron levels so patients are told to avoid supplementation. Excess alcohol ingestion should be avoided as well as it can accelerate liver damage.
What is the prognosis?
Most patients with hemochromatosis will have a normal life expectancy. However, death rates from liver cancer, liver failure, diabetes, and heart failure are higher than in patients without the disease. Early detection and treatment can prevent or minimize these complications. Treatment can reverse some of the changes caused by excess iron accumulation but not all. Malaise and fatigue will often improve markedly with treatment, as can early liver disease, heart function, and skin pigmentation. Diabetes and other hormonal abnormalities, cirrhosis, and particularly arthritis are much less likely to improve.
Summary
Hereditary hemochromatosis is a common inherited condition which can affect multiple organs and cause a wide range of symptoms. Many of the clinical findings are nonspecific which may lead to a delay in diagnosis. Early recognition is important in order to prevent or limit long-term organ damage. Patients who have a family history of hereditary hemochromatosis or who have signs or symptoms compatible with the disease should be tested. Screening for the disease involves simple blood tests, with more advanced testing considered if indicated. Research is ongoing to determine the exact mechanisms of abnormal iron metabolism. There is also active research into several newly discovered gene mutations that can cause classic hemochromatosis as well as an earlier onset juvenile form.