Hereditary Hemochromatosis (HH)

---

Overview

• What is Hereditary Hemochromatosis (HH)?

  Hereditary hemochromatosis (HH) is the most common form of iron overload syndromes, i.e. diseases in which too much iron builds up in one’s body. This extra iron is toxic to the body and can damage organs, lead to illness or even death.

  There are three types of iron overload syndromes:

  1. Primary iron overload syndromes: In these inherited disorders, the genes that control the absorption of iron from the intestine are abnormal. This causes the intestine to absorb more iron than the body needs. Hereditary hemochromatosis is the most common form of primary iron overload syndrome.
  
  
  2. Secondary iron overload syndromes: In this condition, there is no genetic defect, but the intestine is stimulated to absorb more iron by other disorders. Examples of these disorders are anemias (low blood counts) due to ineffective production and removal of red blood cells (thalassemia, aplastic anemia, and sickle cell anemia), chronic liver disease, and too much alcohol.
  
  
  3. Parenteral iron overload: This occurs in patients who have received excessive amounts of iron either as blood transfusions or intravenous iron.
• What is the cause of HH?

  HH includes several genetic abnormalities, which cause the body to absorb excess iron from food. Since there is no way for the body to get rid of absorbed iron (other than bleeding or shedding of skin and intestinal cells), people with HH have to store the excess iron in cells of the liver, heart, pancreas, joints and other organs, such as the pituitary gland, resulting in damage to these organs.

• Who gets HH?

  The most common genetic abnormality in HH is an abnormality of the HFE gene, which can be seen in about 90% of patients with HH. Inheritance is in an autosomal recessive pattern (explain in patient level). Mutations in several other genes besides HFE are responsible for the remaining 10% of patients with HH. HFE related HH is one of the most common inherited disorders among Caucasians, with two copies of the HFE gene mutation seen in about 1 in 200-400 persons in the general population. The highest occurrence is in people of Irish and Scandinavian origin, whereas the lowest is among those of African descent.

  A person who inherits the defective gene from both parents (someone who is homozygous) may develop HH. Studies indicate that about 60% of those who are homozygous for the HFE defect develop increased iron levels, but only some develop complications because of this iron overload. People who inherit the defective gene from only one parent (someone who is heterozygous) are carriers for the disease but usually do not develop it, although they may have slightly increased iron levels.

• What are the symptoms of HH?

  Symptoms usually occur earlier in men than in women, most commonly in the fourth to fifth decades of life (30-40 years of age). Women usually are protected from developing symptoms until after menopause, as regular menstrual blood loss or iron loss during pregnancy and breast-feeding loses just enough iron to keep the disease under control. Many of the early symptoms of HH are nonspecific, including weakness fatigue, and joint pains. These non-specific, and can be caused by a number of other medical problems unrelated to HH. With over 30 different symptoms associated with HH, the disease can be extremely difficult to diagnose. Your doctor needs to have a high degree of clinical suspicion to diagnose this.

  If untreated, or not diagnosed early enough, iron will continue to build up in the organs and can lead to:

  • Diabetes
  • Impotence or decreased sex drive in men, early menopause in women
  • Joint pain
  • Abnormal heart rhythms
  • Heart failure
  • Elevated liver enzymes, cirrhosis of the liver (end stage liver disease), or liver cancer

  Many patients with advanced HH also have color changes in their skin giving it a bronzed appearance. This was one of the first clinical features recognized with this disorder, and is the origin of the name “hemochromatosis.” This condition has also been called “bronze diabetes” for the same reason.

• How is HH diagnosed?

  Blood tests can determine whether the amount of iron stored in the body is too high. The tests commonly performed are iron level, transferrin saturation, ferritin and unsaturated iron-binding capacity.

  The transferrin saturation test determines how much iron is held by the protein that carries iron in the blood. A fasting transferrin saturation of 45 percent or higher, on at least two occasions, is considered a sign of iron overload and further tests need to be performed to confirm the condition.

  The serum ferritin test acts as an indirect measure of iron storage in the body. Normal serum ferritin levels for males and postmenopausal females range from 20-300 μg/L. For premenopausal females, the normal range is between 20 and 200 μg/L. People with advanced HH may have serum ferritin levels as high as 15,000 μg/L. However, conditions other than HH can cause high serum ferritin levels, including other chronic liver diseases, infection, cancer, heart disease, AIDS, metabolic disorders, and inflammatory conditions such as arthritis.

  If either of these tests shows higher than normal levels of iron in the body, doctors can order a test called “HFE mutation analysis” to detect the HFE gene mutations, which will confirm the diagnosis. The test “HFE mutation analysis” determines mutations identified in the HFE gene. These are called C282Y/H63D. S65C is another gene mutation which is less common than either C282Y or H63D. Commercial laboratories now frequently report on all 3 mutations on clinical HFE mutation analysis.

  When patients have two copies of C282Y (one from each parent), they have HH. If they only have one copy of the C282Y, they are a carrier. Most patients with either one or two copies of the H63D or S65C mutation have no evidence of iron overload. If the mutation is not present, HH is not the reason for the iron buildup and the doctor will look for other causes.

  Because HH is easily detected through tests for blood iron levels and by looking for mutations in the hemochromatosis gene (HFE), more doctors are diagnosing individuals with the disease before they have symptoms.

• When do HH patients need treatment?

  In a patient with two copies of C282Y gene abnormalities, treatment should be initiated if serum ferritin is high (>300 ng/mL in men and >200 ng/mL in women), along with a total iron saturation of ≥ 45%.

  Patient with one copy of C282Y and one copy of H63D, have a low risk of developing iron overload complications, but liver injury can develop in such patients if they have additional liver diseases such as fatty liver, diabetes, or consume alcohol in excess. If patient has such risk factors, they need to be evaluated, and treated for other issues, before being treated for iron overload.

• How is HH treated?

  Treatment is simple, inexpensive, and safe. The first step is to rid the body of excess iron. This process is called phlebotomy, which means removing blood the same way it is drawn from donors at blood banks. Based on the severity of the iron overload, a pint of blood (500ml) is taken once or twice a week for several months to a year, and occasionally longer. A phlebotomy of one unit of blood usually drops the ferritin level by about 30 μg/L. Blood ferritin levels are tested periodically to monitor iron levels. The goal is to bring blood ferritin levels to the low end of normal and to keep them there. That means bringing the ferritin down to 50-100 ng/L.

  Once iron levels return to normal, maintenance therapy begins, which involves removing a pint of blood every 2 to 4 months for life. Some people may need phlebotomies more often. Many patients who are having maintenance phlebotomy do so as blood donors. An annual blood ferritin test will help determine how often blood should be removed. Regular follow-up with a specialist who has an interest in hemochromatosis or iron overload disorder is also necessary. This may be a hematologist (blood doctor) or a gastroenterologist/hepatologist (digestive or liver doctor).

  If treatment begins before organs are damaged, associated conditions—such as liver disease, heart disease, arthritis, and diabetes—can be prevented. The outlook for people who already have these conditions at diagnosis depends on the degree of organ damage. For example, treating HH can stop the progression of liver disease in its early stages, which leads to a normal life expectancy. However, if cirrhosis, or scarring of the liver, has developed, the person’s risk of developing liver cancer increases, even if iron stores are reduced to normal levels. People with diabetes resulting from damage to the pancreas usually see an improvement if not a reversal of their diabetes, depending on how much damage has occurred. Treatment cannot cure the conditions associated with established HH, but it will help most of them improve. Abnormal liver tests, heart dysfunction, and fatigue may improve with treatment, but joint pain, diabetes and decreased sex drive may not. Skin pigmentation slowly improves after treatment.

  You do not need to restrict dietary iron when undergoing phlebotomy. People with HH should not take iron or vitamin C supplements. Patients who have liver damage should not drink alcoholic beverages because they may further damage the liver or eat raw seafood because of a risk for a serious infection.

• Who should receive screening and counseling for HH?

  Screening for HH—testing people who have no symptoms—is not a routine part of medical care or checkups. However, siblings of patients who have HH should have their blood tested to see if they have the disease or if they are carriers. First degree relatives of patients who have the disease should be offered testing. Testing should include transferrin saturation, ferritin, and HFE Mutation analysis (gene test). When considering testing of children of a patient, it may be easier to test the other parent first. If he/she is negative for any HFE Mutations, then the children can only be carriers. However, if the other parent has a gene mutation, then the children should be offered gene testing. Whenever genetic testing is done, a certified genetic counselor should be available and informed consent should be obtained.

  Doctors should counsel patients to have their close relatives be tested and consider testing people who have joint disease, severe and continuing fatigue, heart disease, elevated liver enzymes, impotence, and diabetes because these conditions may result from HH.

• What is the likely survival of the HH patient?

  Patients with HH without liver cirrhosis do not have different survival rates from that of general population, whereas survival of patients with HH and liver cirrhosis is significantly low.

• Can HH patient donate blood?

  During initial as well as maintenance phase of treatment, blood removed from HH patient has been used for transfusions. There are no universal policies whether blood from patients with HH should be used for donation or not. Many blood banks have a policy of not accepting blood from patients with HH, although others have done so without any complications.