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Iron OverloadYelena Z. Ginzburg, MD and Beth H. Shaz, MD

Iron overload results from diseases of excess gastrointestinal iron absorption or from iatrogenic causes like chronic transfusion or excessive parenteral iron admin-istration. Patients with transfusion-requiring anemias may accumulate close to 10 g of iron each year. Hepcidin is the central regulator of systemic iron homeosta-sis and is insufficiently elevated in states of primary and secondary iron overload, thought to either cause or compound the degree of iron overload, respectively. The clinical manifestations, diagnosis, and management of iron overload are discussed below.

An average 70 kg male has 3–3.5 g of total body iron. Most of the iron in the body is used for making hemoglobin (Hb). The supply of iron to erythroid precursors in the bone marrow and to other tissues is largely maintained by daily recycling of iron from senescent erythrocytes. Two to three million red blood cells (RBCs) are pro-duced every second and require 30–40 mg of iron to make 30 pg of Hb per RBC, a total of 6 g of Hb daily. Only 1–2 mg of iron on average is absorbed daily from the diet to replace ordinary iron losses. Iron absorption is tightly regulated to maintain iron balance because no physiological mechanism exists for iron elimination in humans and other animals.

Pathophysiology: Due to this limitation in iron excretion, patients with transfusion-requiring anemias are subject to a significant iron load, often leading to parenchymal iron deposition and overload. Each RBC product contains 200–250 mg of iron. Thus, a patient who is transfused with four RBC units per month will accu-mulate 9.6 g of iron per year. Furthermore, diseases associated with iron overload in the absence of transfusion (e.g. hereditary hemochromatosis and ß-thalassemia intermedia) result from persistence of iron absorption despite ample or even exces-sive iron stores.

Hepcidin is the central regulator of systemic iron homeostasis, exerting its effect by controlling the surface expression of the only known iron export protein, ferro-portin (FPN-1), found on macrophages and duodenal enterocytes. Hepcidin binds FPN-1, causes its internalization and degradation, and results in cessation of iron release from cells. Regulation of hepcidin has been extensively studied in recent years. It is known that hepcidin is regulated by iron, hypoxia, inflammation, and erythropoiesis. Primary iron overload diseases are associated with insufficient hep-cidin, which leads to inappropriately high iron absorption. Transfusion-dependent diseases (e.g. ß-thalassemia major and myelodysplastic syndrome) result in iron overload both as a consequence of insufficiently increased hepcidin associated with persistently increased iron absorption, as well as the excess iron acquired with RBC transfusion.

Yelena Z. Ginzburg, MD and Beth H. Shaz, MD450

Clinical Manifestations: Clinical features of iron overload include hepatic dysfunction, cardiac dysfunction (cardiomyopathy and arrythmias), diabetes, impotence, arthropathy and fatigue. How tissue iron accumulates and results in toxicity has not been clearly delineated. Indirect evidence supports the claim that non-transferrin bound iron (NTBI) leads to organ iron deposition. Normally, iron circulates bound to transferrin (which is highly iron saturated in iron-overloaded patients) or ferritin (whose plasma levels generally reflect iron stores but also increase in chronic inflammatory states). The pathologically relevant fraction of NTBI is that which is translocated across cell membranes in an unregulated man-ner and leads to excessive iron accumulation in the liver, heart, pancreas and other endocrine organs. That fraction is called labile plasma iron and is redox active. Thus, excess iron leads to the generation of reactive oxygen species which have the potential to oxidize lipids, proteins, and nucleic acid, resulting in tissue damage in multiple organs.

Much of this information on the consequences of chronic transfusion is extrapo-lated from long-term studies of transfusion-requiring patients with ß-thalassemia major. Until the 1970s, transfusion-requiring patients with ß-thalassemia major died of cardiac iron overload before the age of 20 years. Since then, with the institution of iron chelation therapy, patients have a prolonged survival and a delayed onset of cardiac iron overload.

Although subclinical iron overload found by magnetic resonance imaging (MRI) or liver biopsy may be evident after 20 RBC units transfused (4–5 g of iron), collagen for-mation and portal fibrosis in the liver takes two years and symptomatic cardiac disease 10 years to show after chronic transfusions.

Diagnosis: The diagnosis of iron overload requires clinical correlation of the signs and symptoms noted above with an estimation of total body iron accumulation/stores. Estimating total body iron stores is imprecise and can be accomplished via direct and indirect methods. Indirect methods include serum ferritin concentration, heart and liver MRI, and supraconducting quantum interface device (SQUID); the later modality provides the greatest accuracy at high cost and is not widely avail-able. Direct measurements can be accomplished by liver biopsy with increased accu-racy albeit as a consequence of an invasive procedure not without risk. Furthermore, MRI evidence suggests that liver iron accumulation is not predictive of cardiac iron overload.

Management: Primary iron overload (e.g. hereditary hemochromatosis) can be treated with therapeutic phlebotomy (see Chapter 80). Secondary iron overload (i.e. chronically transfused) patients succumb to the complications of iron overload if untreated; iron chelation therapy should be instituted when serum ferritin concentra-tion reaches 1000 μg/l, typically once 120 ml of RBCs/kg of body weight have been transfused. Iron chelating agents directly bind iron, and the iron:chelator complex is excreted in the urine or feces. Although the chelation and excretion process is not efficient, its effectiveness with chronic use has been demonstrated in patients with ß- thalassemia major. In most cases, compliance with iron chelation therapy significantly

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reduces the complications of iron overload and leads to an improved quality of life. The therapeutic goal is to maintain liver iron concentration at below 5 mg/g liver dry weight and serum ferritin below 1000–1500 μg/l.

Both parenteral (deferoxamine) and oral (deferiprone or deferasirox) iron chelat-ing agents are available for use in the US. Deferoxamine is typically administered via daily overnight subcutaneous infusion. Deferiprone was approved by the FDA in 2011 as second-line therapy and is administered orally three times per day. Deferasirox has a longer half-life and is administered orally once per day. These different chelating agents exhibit differences in organ specific efficacy and their varying side effect profiles require different patient follow-up recommendations. Combination therapy or switch-ing between chelators may be required in cases of inadequate response to individual chelators.

Chronic RBC transfusion therapy is used to treat complications of sickle cell dis-ease, which may result in secondary iron overload. Exchange transfusion may be used instead of simple transfusion which reduces the overall transfused iron burden (see Chapters 50 and 74).

Recommended ReadingBassett ML, Hickman PE, Dahlstrom JE. (2011). The changing role of liver biopsy in

diagnosis and management of haemochromatosis. Pathology 43, 433–439.Cao A, Galanello R. (2010). Beta-thalassemia. Genet Med 12, 61–76.Ganz T, Nemeth E. (2011). Hepcidin and disorders of iron metabolism. Annu Rev Med

62, 347–360.Li H, Ginzburg YZ. (2010). Crosstalk between iron metabolism and erythropoiesis. Adv

Hematol 2010, 605435.Mahesh S, Ginzburg Y, Verma A. (2008). Iron overload in myelodysplastic syndromes.

Leuk Lymphoma 49, 427–438.Porter JB, Shah FT. (2010). Iron overload in thalassemia and related conditions: thera-

peutic goals and assessment of response to chelation therapies. Hematol Oncol Clin North Am 24, 1109–1130.