HHC is common

• There are relatively easy tests to determine carrier status (the C282Y and H63D genes) and iron overload (transferrin saturation and ferritin).

• Treatment is cheap, technically easy, and acceptable to most patients.

• Early treatment can prevent considerable disability, suffering, and costly treatment of the complications of HHC.

Despite these arguments, most public health bodies and governments are not recommending screening. Their arguments revolve around the fact that not everyone who has two copies of c282Y develops the disease (although the vast majority do) and the ethical problems relating to prediction of disease. However, everyone agrees that once a patient has been diagnosed, his or her first-degree relatives should be offered screening. This is done by checking for the presence of the C282Y and H63D mutations on a blood test. If present, the transferrin and ferritin should be measured to assess the iron load. in younger stage i patients these should be repeated periodically. if the gene tests are negative, it means that individual has not inherited the same susceptibility to develop HHC as his or her family member. As explained above, there is still a theoretical chance that the individual could develop the disease through some other as yet unknown mutation, but this risk is extremely small.

Treatment and Outcome

The treatment is to remove iron from the body until body stores are normal and then maintain this level. Blood contains about 0.5 mg of iron per mL. Removing a unit of blood (the normal amount given during a blood donation) therefore removes 200 to 250 mg of iron. As long as the patient is healthy, it is possible to remove a unit of blood every week or fortnight without any adverse effects. in the presence of heart failure or other chronic disease this may have to be slowed down. Frequent removal of blood (termed venesection or phlebotomy) is continued until the ferritin level is below 100 m g/L. This may take up to two years. Venesection is then continued just often enough to keep the ferritin at this level. This is usually two to four times a year.

Although patients do not have to limit their dietary intake of iron strictly, which they may find unpleasant, they should take some precautions. Vitamin C and iron supplementation should be avoided. Vitamin C promotes iron absorption. Both of these may be found in multivitamins or other health supplements or health drinks. Red meat is a potent source of iron and should be limited. Alcohol should be avoided in those with clinical liver involvement and limited in stage ii. Raw shellfish are best avoided since there have been deaths in HHC patients from Vibrio vulnificus infections.

Complications of HHC such as diabetes, heart failure, or endocrine deficiencies are treated as they would be in any other patient. See the osteoarthritis and cppd sections for treatment of these forms of arthritis. in the past transfusion services generally did not accept blood for transfusion into other patients if the donor suffered from a chronic illness. Many HHC patients are very healthy, however, and there is nothing wrong with their blood. increasingly, therefore, transfusion services are accepting HHC blood, and many patients welcome the opportunity to help provide this service.

obviously, venesection is not an option for patients who require regular transfusions to maintain an adequate red cell level (thalassemia, sickle-cell anemia, etc.). Currently the only alternative for these patients is desferrioxamine. Desferriox-amine is a chelating agent, which means that it binds very tightly to iron and therefore removes fairly large amounts of iron from the body as it is excreted. it is given as an infusion under the skin and can remove 10 to 20 mg of iron per day. if done on a daily basis, this is just less than half the amount removed by weekly venesection.

Roughly a third of untreated HHC patients die of heart failure, a third of liver failure or its complications, and a third from liver cancer. Treatment has been shown to improve the five year survival of these patients from only 33 percent to 89 percent. Since Feder and colleagues' discovery of the two important gene mutations and the development of relatively simple blood tests to aid the diagnosis, many more patients have been diagnosed at a much earlier stage. it is hoped that this will bring their life expectancy very close to that of the normal population. However, further long-term studies of patients being currently diagnosed will be needed to see if this in fact happens.

With successful treatment the liver and spleen get smaller, liver function improves (although any cirrhosis present remains), heart failure resolves, and diabetes improves in about half the patients. Reduced sex hormone production and the arthritis are not affected by treatment. if the disease is treated before cirrhosis develops, there is no increased risk of liver cancer.

hemophilia An inherited disorder of the blood-clotting mechanism that increases the risk of bleeding. Hemophilia A, caused by a deficiency of clotting factor Viii, affects about 80 percent of hemophiliacs and is more common and more severe than hemophilia B which is also known as Christmas disease and is caused by deficiency of clotting factor IX.

Cause

Hemophilia results from mutations in the genes for factor VIII and IX. These genes lie on the X chromosome, and males, because they carry only one X chromosome, are affected by hemophilia if they have the abnormal chromosome. Women, on the other hand, because they have two X chromosomes, one inherited from each parent, are unlikely to have two abnormal chromosomes and are protected from disease. However, if they have one abnormal X chromosome they are carriers, and their children will have a 50 percent chance of having hemophilia if they are male and a 50 percent chance of being a carrier if they are female. Approximately one-third of patients with hemophilia do not have a history of affected family members, and the disease is then thought to have arisen from a new mutation. Although hemophilia is thought of as being a disorder of blood, one of the problems it causes, bleeding into muscles and joints, can result in acute and chronic musculoskeletal problems.

Symptoms

Patients with a very low level, less than 1 percent of normal, of factor VIII or IX activity are severely affected and often develop symptoms caused by spontaneous bleeding before they are two years old. Patients with less severe hemophilia often have factor levels that are 5 percent or more of normal and may develop symptoms only after surgery or trauma.

The symptoms caused by bleeding depend on the site affected. Bleeding into soft tissue and muscle causes pain and swelling in the area. A large collection of blood (hematoma) can cause damage to nerves and other tissues directly through pressure and indirectly by cutting off the nerves' blood supply. Hematomas slowly resorb but cause damage and scarring to the surrounding tissues and can result in contractures that prevent a limb from straightening. Bleeding into a joint is called hemarthrosis and causes severe pain, swelling, and difficulty moving. Most patients with severe hemophilia suffer spontaneous hemarthrosis in early childhood, usually when they start to walk.

In later life, acute hemarthrosis can occur spontaneously or after minor trauma. Acute hemarthrosis usually resolves over two weeks, but recurrent episodes of bleeding into a joint damages it and can cause chronic inflammation resulting in swelling, deformity, pain, and loss of function. How blood damages the joint is not known exactly. Activation of platelets and white blood cells and the release of iron are all thought to play a role in damaging cartilage and stimulating abnormal growth of the syn-ovium or joint lining.

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