revised Feb 5, 2000

Iron and the Heart

Iron Overload: A Manifestation of Modern Civilisation

Iron deficiency has been the primary hemeatological problem faced by humans throughout history. In many parts of the world, it continues to be a major scourge. Iron overload has become a problem only with advances in technology that have prolonged life and made feasible repeated blood transfusions. Hereditary hemochromatosis, the best characterised genetic cause of iron overload, generally manifests after about the third decade of life. As late as 1890, the median life expectancy in Europe was only 40 years, meaning that most people with hereditary hemochromatosis died of other causes before developing complications of the disorder.

Medical researchers discovered blood antigens only at the beginning of the 20th century. Routine blood transfusion was not feasible until the 1940's. Prior to the 1960's when repeated transfusion therapy became widespread in the industrialized world, patients with chronic severe anemias, such as thalassemia major, succumbed to complications of the anemia.

The manifestations of iron overload are relatively uniform, irrespective of cause. Cardiac dysfunction is a primary cause of death in people with iron overload. The heart does not accumulate iron disproportionately to other organs. The key to the heart╣s central role in the pathology of iron overload lies in the need for the complex array of cells and structures in the heart to function coordinately. Half of the liver can be lost to fibrosis or cirrhosis, and a person can still survive. This is not true of the heart. As importantly, the consequences of disrupted signal transduction between the AV node and the ventricles can be catastrophic and even fatal.

Etiology of Iron Overload

Hereditary hemochromatosis

Hereditary hemochromatosis reflects a fractional increase in dietary iron absorption. Tissue iron reaches dangerous levels after thirty or forty years. The gene responsible for hereditary hemochromatosis, HFE, resides on chromosome 6. Discovered in 1996, the gene encodes a protein that is homologous to the Class I HLA antigens. The alteration in HFE protein that produces hereditary hemochromatosis involves the mutation of a cysteine to a tyrosine at position 282 (C282Y). People who have one copy of the mutant HFE gene are carriers who only rarely develop iron overload (usually in association with a second defect.) People with two copies of the mutant protein can develop iron overload and potentially a myriad of problems. Nearly 90% of people who have hereditary hemochromatosis have the C282Y mutation in HFE.

Only recently have investigators gained insight into the mechanism by which the mutation in HFE alters cellular iron metabolism. Iron in the circulation is bound to the protein, transferrin, which maintains it in a non-toxic state. Cells contain receptors for transferrin on their plasma membranes which mediate cellular iron uptake. Transferrin receptors bind iron-transferrin complexes which are taken into endosomes. Iron is separated from transferrin in the endosome, and is shuttled into the interior of the cell. The iron-free transferrin (apotransferrin) is recycled into the circulation and is free to bind and transport additional iron atoms. The HFE protein associates with transferrin receptors in the plasma membrane, thereby reducing transferrin binding to the receptor and slowing their internalisation (Feder et al., 1998).

The C282Y mutation in HFE disrupts the folding of the protein. The mutant protein does not associate with the transferrin receptor and does not act as a break on iron uptake by cells. These insights do not fully explain the increase in gastrointestinal iron absorption, which is the root of hereditary hemochromatosis. They are, however, the first observations that mechanistically connect HFE and iron metabolism. Improved understanding of the complex process of intestinal iron absorption should surmount this shortcoming.

Hereditary hemochromatosis is remarkably common. About 10% to 12% of people of European background are heterozygous for the condition (Cardoso, et al, 1998). The number of people who are homozygous for the condition approaches one in three hundred (Ryan, et al, 1998). This makes hereditary hemochromatosis one of the most prevalent genetic conditions in the world (Powell et al., 1998). Interestingly, the clinical expression of the disorder is less than predicted by frequency calculations. Variable penetrance, perhaps related to secondary genetic or environmental conditions must influence clinical manifestations. The C282Y mutation appears to be uncommon cause of iron overload people of African origin (Monaghan, et al, 1998).

Transfusional iron overload

A unit of blood (250 millilitres) contains about 225 milligrams of iron. The iron is an integral component of the heme in hemeoglobin and cannot be removed from the blood. Senescent red cells are destroyed by reticuloendothelial cells, primary in the liver and spleen. The iron from the hemeoglobin is not excreted. The element is either used to make new red cells or is placed in storage (primarily in the liver).

People with chronic severe anemias often require regular transfusions to survive. Patients with thalassemia major, a condition in which the genes encoding hemeoglobin produce defective protein and consequently defective red cells, require up to two units of blood every three weeks to avoid the deadly consequences of their severe anemia (Giardina and Hilgartner, 1992). Nearly all of the iron from the transfused red cells goes into storage, and eventually produces severe iron overload. These patients confront as their primary problem not anemia, but organ damage from iron (Piomelli and Loew, 1991). Inherited disorders (such as thalassemia major) or acquired conditions, such as dysmyelopoietic anemia, can lead to transfusional iron overload. The redistribution of the excess iron to storage sites means that these patients suffer the same consequences as those with hereditary hemochromatosis.

Cardiac Manifestations of Iron Overload

Iron deposition in the cardiac myocytes is the initial event in iron-mediated cardiac injury. Transferrin receptors on the cell surface mediate this process through the well-characterized transferrin cycle. Iron-saturated transferrin attaches to these receptors and releases iron to the interior of the cell. The excess iron is stored in hemosiderin.

Iron that is stored in hemosiderin is innocuous (Bonkovsky, 1991). This iron is in equilibrium, however, with a very small pool of so-called │free iron▓ in the cell. This pool of iron is so small that its size has never been satisfactorily determined. Better termed, loosely-bound iron, this material catalyzes the formation of reactive oxygen species through Fenton chemistry. These reactive oxygen species are the agents of cell injury.

Iron overload promotes the production of a number of reactive oxygen species. Of these, the most damaging is the hydroxyl radical (ÇOH) (McCord, 1993),(Farber, 1994). The molecule is both extremely short-lived and extremely active in its interaction with biological molecules (Abdalla, et al., 1992). Lipid peroxides, protein disulfide bridges, and DNA cross linking are some of the problems that occur with iron-mediated generation of reactive oxygen species (Enright, et al., 1992).

Cardiac cells are particularly sensitive to oxidant-mediated injury since they must perform a number of complex functions which include contraction and transmission of electrical impulses. With iron loading, cardiac cells in culture begin to fail. Cardiac myocytes loose their characteristic pattern of beating under these culture conditions. Desferrioxamine, a powerful iron chelator that binds iron in culture and prevents generation of reactive oxygen species by the Fenton reaction, can restore normal cellular activity (Link, et al., 1999).

Congestive cardiomyopathy is the most common cardiac defect that occurs with iron overload, but other problems have been described including pericarditis, restrictive cardiomyopathy, and angina without coronary artery disease. A strong correlation exists between the cumulative number of blood transfusions and functional cardiac derangements in patients with thalassemia (Scopinaro, et al., 1993). Echocardiographic assessement of patients with ▀-thalassemia major who receive concurrent chelation therapy with desferrioxamine shows no difference relative to controls in the the fractional shortening (Lattanzi, 1993). The integrated backscatter of the interventricular septum and posterior wall are higher than normal, perhaps due to iron deposition.

The physical examination is surprisingly benign even in patients with heavy cardiac iron deposition. Once evidence of cardiac failure appears, however, heart function rapidly deteriorates, often without response to medical intervention. Biventricular failure produces pulmonary congestion, peripheral edema, and hepatic engorgement. This potentially lethal cardiac complication has been reversed on occasion by vigorous iron extrication.

Iron deposition in the Bundle of His and the Purkinje system impairs signal conduction from the atrial pacemaker to the ventricles. Patients sometimes die suddenly, presumably due to arrhythmias. At one time, patients treated with the chelator desferrioxamine for transfusional iron overload received supplements of ascorbic acid in the range of 15 to 30 mg/kg per day to promote iron mobilisation. Reports of sudden death prompted cessation of this practice. At lower doses (2 to 4 mg/kg), ascorbic acid is a safe adjunct to chelation therapy in patients with transfusional iron overload.

Echocardiography in children and radionuclide ventriculography in adults are the most useful non-invasive diagnostic techniques. The echocardiographic abnormalities correlate roughly with the number of transfusions. Exercise radionuclide ventriculograms are particularly sensitive in the detection of cardiac dysfunction in patients with iron overload.

The degree to which aggressive chelation therapy can reverse cardiac dysfunction has been a subject of vigorous debate. A number of short-term reports existed which suggest that chelation can restore function in patients with significant cardiac compromise (Aldouri, et al., 1990). More recently, investigators examined a cohort of patients with ▀-thalassemia major who were transfused while receiving chelation therapy (Olivieri, et al., 1994). Analysis of the data showed that only repeated plasma ferritin values of greater than 2,500 ng/ml was associated with cardiac-related death.

Another group of investigators recently reviewed the outcome of aggressive treatment of patients who had transfusional iron overload with associated cardiac dysfunction (Porter, in press). This group of 19 patients suffered from severe congestive heart failure, in some cases, cardiac arrythmias in others, and in a few instances from both problems. The patients received intravenously administered desferrioxamine on a 24-hour per day regimen. For routine chelation, most physicians administer the drug over 12- to 16-hour intervals. In addition to the aggressive chelation therapy, the investigators worked with cardiologists to administer the most current conventional cardiac regimen for their heart problems.

The results were dramatic. The mean ejection fraction of the patients with congestive heart failure improved from 30% to 50%. Arrythmias were controlled, and no patient suffered sudden death. Sudden death is a common occurrence in iron-overloaded patients, and presumably reflects malignant arrythmias. The anti-arrythmic medications were stopped without incidence in many of the patients after they were well-established on their iron chelation regimen. The plasma ferritin values were over 10,000 ng/ml in many of the patients at the onset of treatment. These values declined, but never approached normal values.

Bone marrow transplantation is now an option for some patients with ▀-thalassemia major (Lucarelli, et al., 1993) (Giardini, et al., 1994). This intervention often cures patients of the disorder. The correction of the the underlying hemolytic anemia creates a clinical situation analagous to hereditary hemochromatosis: patients are iron-overloaded with hemoglobin values. Some investigators have taken advantage of this situation to use phlebotomy as a means of removing the iron that accumulates over years of transfusion therapy, even in patients who maintain an iron chelation regimen (Angelucci, et al., 1998). Phelebotomy removes iron and improves cardiac function in most of these patients (Marrioti, et al., 1998).

The lessons from these reports are two-fold. First, early chelation therapy prevents cardiac dysfunction in patients with transfusional iron overload. Second, congestive cardiomyopathy and arrythmias in these patients are not fixed lesions. Unlike the situation with ischemic cardiomyopathy, the cardiac myocytes have not be destroyed by the pathologic events which produced the dysfunction. Iron overload injures myocytes by production of free radicals that interfere with their function. Until fixed lesions occur (these cells will eventually die), the injury can be halted and reversed by chelators that block production of free radicals. Aggressive intervention with cardiac support and chelation therapy is indicated in patients with iron-mediated cardiac dysfunction.

Iron and Ischemic Heart Disease

An important question concerning iron and the heart is whether body iron stores in the normal range increase susceptibility to myocardial infarction. A number of small anecdotal reports lie on either side of the issue, and are uninformative. A study published in 1992 examined the relationship between plasma ferritin levels and coronary artery disease in a cohort of about 2,000 men in Finland (Salonen, et al., 1992). The data indicated that elevated plasma ferritin levels increased the risk of acute myocardial infaction by over two-fold.

Plasma ferritin levels are a good serogate of body iron stores. However, a variety of common problems can skew this assay, including chronic inflammation and smoking. These investigators attempted to compensate for this factor by using a newer test, the plasma transferrin receptor assay, in a small sample of about 200 men (Tuomainen, et al., 1998). Results in this smaller study were consistent with those which the group reported in 1992.

Investigators from first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study also addressed the question, using a multivariate Cox proportional-hazards model (Sempos, et al., 1994). Using transferrin saturation as an index of body iron stores, the researchers analyzed data on over 4,500 people between the years of 1971 and 1987. They found no statistically significant relationship between transferrin saturation and coronary heart disease. An epidemiologic study involving about 2,000 men in Iceland was consistent with the NHANES report (Magnusson, et al., 1994). The issue of the role of body iron stores in the "normal" range in coronary artery disease remains open. The variable results in epidemiologic studies from different countries suggests that iron plays a small role, if any, in this arena.