NORD gratefully acknowledges Paul Adams, MD, Professor of Medicine, University of Western Ontario, for assistance in the preparation of this report.
Hereditary hemochromatosis (HH) is a general term for several rare genetic disorders that are characterized by the accumulation of iron in various organs of the body such as the liver, heart and pancreas. The abnormally stored iron can damage affected organs, potentially causing a variety of different symptoms. The most common form of hemochromatosis is known by several different names including hemochromatosis type I, HFE-related hemochromatosis, hereditary hemochromatosis and classic hereditary hemochromatosis. Iron accumulation in classic hereditary hemochromatosis occurs slowly over many years. Eventually, iron accumulation causes tissue damage and impaired functioning of affected organs. In many affected individuals, symptoms may not become apparent until some point between 40-60 years of age. Onset is usually earlier for men compared to women. Common symptoms include abdominal pain, weakness, lethargy, and unintended weight loss. Without treatment, classic hereditary hemochromatosis can progress to cause serious, life-threatening complications including failure of affected organs.
There are several different disorders associated with excess iron accumulation in the body. Collectively, these different disorders are grouped under the name iron overload disorders. These disorders are caused by mutations to different genes and have different clinical presentations. Classic hereditary hemochromatosis is caused by mutations of the HFE gene. This report primarily deals with classic hereditary hemochromatosis caused by mutation of the HFE gene.
The symptoms of classic hereditary hemochromatosis develop gradually over many years because of the excess accumulation of iron in the body. Symptoms usually become apparent at some point between 40-60 years of age, but may develop early or later. Symptoms rarely develop before 20 years of age. The specific symptoms that occur may vary depending upon the specific organs affected. The severity of the disorder may also vary. Some individuals may have mild, undetected cases, while others have serious complications including organ failure.
It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Common early symptoms of classic hereditary hemochromatosis include joint inflammation and pain (arthritis) especially in the small joints of the fingers, fatigue, weakness, abdominal pain, unintended weight loss, and an abnormally enlarged liver (hepatomegaly). An abnormally enlarged spleen (splenomegaly) may also occur.
Additional symptoms occur depending on the specific organs involved. In classic hereditary hemochromatosis the liver, pancreas, heart, and skin are most commonly affected and (if left untreated) can potentially lead to serious complications.
Liver abnormalities associated with classic hereditary hemochromatosis include hepatomegaly, and scarring of the liver (cirrhosis), high blood pressure of the branches of the portal vein (portal hypertension), which is the main vein that carries blood from the intestines to the liver. Liver disease can eventually progress to cause liver failure. Early on, some affected individuals may have abnormal liver function tests (e.g., elevated liver enzymes) in the absence of any observable clinical signs. Individuals with classic hereditary hemochromatosis are at a greater risk of developing liver cancer than the general population. A specific form of liver cancer potentially associated with classic hereditary hemochromatosis is hepatocellular carcinoma.
Some HH patients have type 2 diabetes with insulin resistance and high serum insulin. It has been rare to document low serum insulin dependent diabetes in hemochromatosis. In population based studies, there has been no evidence that diabetes is increased in affected individuals who have two copies of the C282Y mutation in the HFE gene.
Individuals with classic hereditary hemochromatosis may experience a variety of heart abnormalities including irregular heart rhythms, enlargement of the heart and disease of the heart muscle (cardiomyopathy). Eventually, affected individuals may experience a limited ability to circulate blood to the lungs and the rest of the body resulting in fluid build-up in the heart, lungs and various body tissues (congestive heart failure).
Progressive darkening of patches of skin (increased skin pigmentation), sometimes referred to as bronzing, is another common finding of classic hereditary hemochromatosis. This condition occurs due to the accumulation of melanin in the skin.
Some men with classic hereditary hemochromatosis may also have underactive testes and some women may have underactive ovaries (hypogonadism). In such cases, the testes and ovaries fail to produce sufficient sex hormones. The pituitary gland may also be affected in individuals with classic hereditary hemochromatosis. In some individuals, the pituitary may fail to produce sufficient amounts of some or all of the hormones it normal produces (hypopituitarism). Hypopituitarism can cause a wide variety of symptoms including fatigue, headaches and abdominal pain. As a result of hormonal deficiencies affected males may experience impotence and affected women may experience loss of menstrual periods (amenorrhea) or early menopause. Some affected individuals may also have loss of interest in sex (decreased libido).
Additional symptoms have been associated with classic hereditary hemochromatosis. These symptoms are common to all individuals as they age. It is not known whether classic hereditary hemochromatosis makes people more susceptible to such symptoms. Such symptoms include loss of the cartilage that normally cushions joints (osteoarthritis), general loss of bone mass (osteoporosis) that can predispose individuals to fractures, an underactive of the thyroid gland (hypothyroidism), shortness of breath, and loss of body hair (outside of normal male pattern baldness).
Classic hereditary hemochromatosis is caused by mutations of the HFE gene. This mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Investigators have determined that the HFE gene is located on the short arm (p) of chromosome 6 (6p21.3). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 6p21.3” refers to band 21.3 on the short arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Hepcidin is a specialized protein that is the primary regulator of iron absorption in the body, including regulating the uptake of iron by the gastrointestinal tract. Mutations of the HFE gene result in the deficient levels of functional hepcidin in the body, which in turn leads to excess absorption of iron in the gastrointestinal tract. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low iron levels) or damage affected organs (due to high iron levels). Excess levels of iron eventually accumulates in the tissues and organs of the body, potentially damaging the function of affected organs and ultimately leading to the characteristic symptoms of classic hereditary hemochromatosis.
Several different mutations of the HFE gene have been identified as causing classic hereditary hemochromatosis. Most individuals with classic hereditary hemochromatosis inherit two copies of a specific HFE gene mutation known as “C282Y”. Although most people who inherit two C282Y mutations develop classic hereditary hemochromatosis, studies suggest that up to 30 percent of those with the mutations do not develop associated findings (variable penetrance and expressivity).
Some other individuals with classic hereditary hemochromatosis inherit one copy of the C282Y mutation and one copy of a different HFE gene mutation known as “H63D” (compound heterozygotes for C282Y/H63D). Reports suggest that the presence of the second (i.e., H63D) mutation appears to predispose individuals to expression of the disease in some cases. However, the disorder does not appear to develop in those who inherit two copies of the H63D mutation (i.e., and no copies of the C282Y mutation). Therefore, the role of H63D mutations in causing or contributing to classic hereditary hemochromatosis is not fully understood.
Because of the highly variable nature of classic hereditary hemochromatosis, it is likely that additional factors, including genetic, physiological and environmental ones, all play a role in the development and progression of the disorder in each individual. More research is necessary to determine the exact underlying mechanisms that are involved in the development and progression of classic hereditary hemochromatosis.
The exact prevalence of classic hereditary hemochromatosis is unknown. The disorder is thought to be the most common autosomal recessive disorder in Caucasian populations. In individuals of Northern European descent the prevalence is estimated to be as high as 1 in 227 individuals in the general population. Approximately 10 percent of the Caucasian population is estimated to be a “carrier” for classic hereditary hemochromatosis (i.e., has one mutation of the HFE gene). Some individuals who have genetic mutations that cause classic hereditary hemochromatosis do not develop symptoms of the disorder, making it difficult to determine the true frequency of classic hereditary hemochromatosis in the general population.
Hemochromatosis is seen more often (and tends to be more severe) in men than women. Some researchers believe that this may be due, in part, to a woman’s monthly blood loss through menstruation. Consequently, iron accumulation is slower in women than men, and the average age of diagnosis for women is approximately 10 years later than in men (usually after menopause).
A diagnosis of classic hereditary hemochromatosis is made based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.
According to the medical literature, early diagnosis based on clinical features can be difficult since some individuals may have iron overload of relatively moderate degree or short duration with only certain or no obvious characteristic symptoms. Therefore, it is important that the disorder is considered for any individuals with unexplained enlargement of the liver (hepatomegaly), scarring of the liver (cirrhosis), increased pigmentation of the skin, loss of sexual drive (libido), disease of the heart muscle (cardiomyopathy), diabetes mellitus, or joint inflammation (arthritis).
When the disorder is suspected, blood tests are performed to detect abnormally increased levels of iron in the blood; elevated blood levels of an iron compound that is used as an indicator of the body’s iron stores (serum ferritin levels), and increased transferrin saturation. Transferrin is a protein involved in the transport of iron from the intestine into the bloodstream.
A liver biopsy (needle biopsy through the skin and microscopic study of liver tissue) was once used to help obtain a diagnosis of classic hereditary hemochromatosis. However, liver biopsy has shifted from a diagnostic test to a prognostic test in typical C282Y homozygotes. In addition, a liver biopsy may be useful in establishing the presence and extent of cirrhosis.
In addition, specialized imaging tests such as magnetic resonance imaging (MRI) may reveal increased density of the liver due to excess iron accumulation. MRI uses a magnetic field and radio waves to provide detailed cross-sectional images of certain organs and tissues such as the liver.
A diagnosis of classic hereditary hemochromatosis can be confirmed by molecular genetic testing, which can detect characteristic mutations of the HFE gene that can cause the disorder.
Family members of those with a confirmed diagnosis of classic hereditary hemochromatosis should also undergo diagnostic evaluation to help detect or rule out the disorder.
Classic hereditary hemochromatosis is treated by removing excess iron from the body. Since much of the iron in the body is present in red blood cells, therapy involves the regular removal of blood via a vein (phlebotomy) to reduce excess body iron. A phlebotomy is a simple and safe procedure. Initially, phlebotomy may be required about once or twice a week. Weekly phlebotomies may continue to be necessary for up to approximately two years. Once ferritin and transferrin saturation levels stabilize, phlebotomy may then be conducted periodically as required (e.g., approximately once every three months for men and once or twice a year for women), based upon ongoing assessment of iron storage levels. Generally, men require the removal of more blood than women.
There is no agreement in the medical literature as to whether individuals who have abnormal laboratory tests (e.g., elevated serum ferritin concentration), but do not have associated clinical symptoms require treatment with phlebotomy. Because the disease is believed to run a benign course in many individuals who only have abnormal lab tests, some researchers prefer to hold off on phlebotomies and instead simply conduct regular follow up testing and observation.
However, treatment to remove excess iron in individuals who already have clinical symptoms of classic hereditary hemochromatosis is crucial to help to prevent chronic disease, organ damage, and potentially life-threatening complications.
In rare cases where phlebotomy therapy is not possible (e.g., in individuals with anemia, cardiac disease or advanced cirrhosis), the drug deferoxamine may be used to help reduce excess levels of iron in the body. Deferoxamine is an iron chelator, a drug that binds to iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. Another oral iron chelator, exjade, has been studied in classic hereditary hemochromatosis.
Additional treatment for this disorder is symptomatic and supportive. Supportive therapy may be necessary for individuals who experience organ damage due to excess iron levels. For example, individuals with end stage liver disease may require a liver transplant.
Genetic counseling may be of benefit for affected individuals and their families.
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