I. Incidence
II. Genetics and Iron Overload
III. Clinical Complications
IV. Management
V. Research Implications

GLOSSARY
arrhythmia general term for an irregularly or rapidity of the
heartbeat, an abnormal heart rhythm. cardiomyopathy heart muscle disease. ejection fraction the fraction of blood ejected from the heart
into the arteries, normally this ranges from 60–75%; a low
ejection fraction is less than 40%; often used as a marker of
left ventricular contractility. heart failure failure of the heart to pump sufficient blood from
the chambers into the aorta; inadequate supply of blood
reaches the organs and tissues. myocardium the heart muscle.

• I. INCIDENCE
  Hereditary hemochromatosis is not an uncommon condi¬tion. Approximately 10% of individuals of European and particularly Celtic background are heterozygous carriers who only develop iron overload if there is a second defect added to environmental and nutritional factors.
• II. GENETICS AND IRON OVERLOAD
  The gene responsible for hemochromatosis, HFE, was discovered in 1996 and resides in chromosome 6 which involves the mutation of a cysteine to tyrosine at position 282 (C282Y). Iron is kept in a soluble state in the blood because it binds to the protein transferrin. Cellular iron uptake takes place at transferrin receptors. Figure 1 shows the transferrin shuttle pathway. Normally iron is separated from transferrin in the endosome and is shuttled into the interior of the cell.
• III. CLINICAL COMPLICATIONS A. Myocardial Damage Mechanisms
  Iron-saturated transferrin attaches to cell transferrin recep¬tors and excess iron gains entry into the cell (see Fig. 1). Although much of the iron is stored as hemosiderin, for example, within the Kuffer cells of the liver, and causes no damage to tissues, some free iron is released into paren-chymal cells. Free iron catalyzes the formation of reactive oxygen species and the hydroxyl radical causes damage to cells. With damage and destruction of cells there is by collagen and fibrous tissue that weakens the muscular wall of the heart. Severe damage and weak¬ness primarily to heart muscle is called cardiomyopathy. Less blood is ejected from the left ventricle and heart failure symptoms and signs occur. The weakened heart muscle is stretched and the heart becomes dilated, resulting in a dilated cardiomyopathy, but some restriction to filling of the heart occurs and there are also features of a restric¬tive cardiomyopathy (see the chapter Cardiomyopathy). Excessive iron is distributed throughout the myocardium and in the electrical conducting tissues and arrhythmias may occur.
• IV. MANAGEMENT
  Venesection with removal of 500 ml of blood every 2 weeks for several months followed by monthly venesection for a year usually results in a reduction of serum ferritin level to less than 50 mg/L. Venesections are continued every 3 months or more frequently to maintain a ferritin level 50 mg/L range. Alcohol increases absorption of iron and should be curtailed, especially because cirrhosis is an outcome of the iron overload. If the serum iron is kept within the normal range before serious cardiac involvement has occurred, the prognosis is good. If cardio-myopathy resulting in heart failure has occurred, the prognosis is poor.