Deferasirox Versus Venesection in Patients With Hemochromatosis and for Treatment of Transfusional Siderosis in Myelodysplastic Syndrome: Diagnostics and New Biomarkers.

The two most important causes of iron overload disease in humans are the iron-loading disorder hereditary hemochromatosis (HC), and transfusional siderosis in patients with chronic hematological diseases like myelodysplastic syndrome (MDS), thalassemia, and leukemia.

Hemochromatosis. In HC the molecular regulation of iron uptake across the intestinal mucosa is disturbed, leading to hyperabsorption and accumulation of iron in parenchymal tissues such as the liver, pancreas, endocrine organs and heart. Hepcidin, a small peptide hormone synthesized in the liver, apparently functions as the master regulator of systemic iron homeostasis by its ability to control the efflux of iron from the enterocytes and macrophages into blood plasma. This happens by diminishing the iron transfer capacity through the basolateral, transmembrane protein, ferroportin. Expression of hepcidin is carefully adjusted by the iron status of the hepatocytes through a multimolecular signal transducing pathway which acts as a positive feedback mechanism with increased hepcidin synthesis in iron overload (and inflammation). Mutation of one of the signal molecules, leads to inadequate hepcidin synthesis. The most common are the classic C282Y and H63D point mutations of the hemochromatosis protein HFE, which disturbs its interaction with the transferrin receptor 1, the first step in the hepcidin signal cascade. Homozygosity for C282Y is the strongest risk factor for serious iron overload and disease which develops after a long-lasting, asymptomatic period. In Norway the prevalence of C283Y homozygosity is approximately 0.75 in both genders. The preclinical, biochemical phenotype of HC is disclosed by blood tests with elevated transferrin saturation as a marker of hyperabsorption of iron, and increasing ferritin concentration as a surrogate marker of a growing iron overload. As an alternative to liver biopsy, magnetic resonance imaging (MRI) seems to be a powerful non-invasive method to directly assess the iron content of the liver and heart.

Myelodysplastic syndrome and transfusional siderosis. Transfusional iron overload is the result of multiple blood transfusions supplied over a long time period, each of which adds approximately 220 to 250 mg of extra iron to the body. Because iron loading occurs via a parenteral route with the macrophages as the primary target cells, the normal homeostatic mechanisms are not responding adequately and the plasma hepcidin level can be normal or even increased. Even if excess iron is better tolerated in macrophages than in parenchymal cells, a life-threatening iron overload develops much faster with transfusional siderosis than HFE-associated HC. Myelodysplastic syndrome (MDS) is a heterogeneous group of stem cell disorders with inefficient hematopoiesis and increased risk of developing acute myeloid leukemia. The MDS International Prognostic Scoring System (IPSS) which is based on numbers of cytopenias, cytogenetic features and number of blasts in the bone marrow, enables separation of four risk groups with the following median survival years: low-risk patients, 5.7 years; intermediate-1, 3.5 years; intermediate-2, 1.2 years; and high-risk 0.4 years. Many patients become transfusion-dependent and get serious transfusional iron overload. Iron chelation is recommended to low-risk and intermediate-1 patients with probable need of lifelong transfusion therapy.

Consequences of iron overload. If not interrupted, continuous iron loading will at some point start to gradually damage vital organs such as liver, heart and endocrine organs, and lead to serious disease and a shortened lifetime. At the molecular level persistently increased amounts of reactive, small molecular weight iron complexes or the sporadic presence of free iron in blood and tissues, are probably the fundamental pathogenetic mechanism in iron overload. These substances are highly toxic due to their strong ability to catalyze the formation of free radicals such as Reactive Oxygen Species (ROS). The activity of free radicals with damage of native molecules (e.g. DNA) and cellular structures is considered to be the first step in organ and tissue injury. In blood, reactive iron exists as Non-Transferrin Bound Iron (NTBI), mainly in the form of small molecular weight iron-citrate complexes. NTBI is rapidly taken up by the liver and other organs where it adds to the intracellular, reactive labile iron pool (LIP). The presence of NTBI and LIP has been found to correlate with hepatic and cardiac damage in transfusional siderosis and HC. In addition, the homeostasis of other trace metals may be abnormal in iron overload. Little is known about this issue, which warrants a deeper study.

Treatment. In HC, the preferred iron removal therapy is venesection, whilst transfusional iron overload is treated with iron chelators.