Anemia of Chronic Disease PDF

Introduction

The anemia associated with chronic disease (ACD) is characterized by abnormal iron distribution, decreased red cell life span, and impaired erythropoietin response. The ACD continues to intrigue clinicians and basic scientists alike, ever since the definitionof thisentity (1)summarizedinseveralmajor reviews (2–4). The characteristic combination of decreased serum iron, decreased serum transferring, and normal or increased serum ferritin distinguishes it from iron deficiency anemia (IDA). The main features of abnormal iron handling involving impaired reutilization of iron derived from senescent nonviable erythrocytes decreased erythrocyte survival and a relative failure of the marrow to compensate for increased red cell loss have all been defined as early as 1957 in the remarkable pioneering studies of Freireich et al. (5). Apart from IDA, ACD is the second most common anemia of mankind and, its prevalence among hospitalized patients exceeds even that of IDA. Although initially designated anemia of infection (1), it is clear that the same entity may be encountered in chronic diseases in which inflammation is caused by noninfections conditions such as rheumatoid arthritis and other connective tissue disorders, malignant disease, or trauma. The common denominator of these conditions is inflammation, mediated by cytokines. It is also clear that acute injury such as trauma or severe infection or even typhoid vaccination may result within hours or days in hypoferremia indistinguishable from that of ACD, and hence the term chronic is not necessarily an essential feature of ACD. Thus, anemia of inflammation would be a much more appropriate definition. However, the term ACD is now widely accepted, it is mostly encountered in chronic disorders, and any further preoccupation with semantics may be futile.

Understanding the abnormalities of iron homeostasis in ACD is inseparable from understanding the normal mechanisms of iron handling. Iron is an essential component of proteins that play a key role in respiration, energy production, detoxification of harmful oxygen species and cell replication. Despite the abundance of iron in nature, the solubility of its stable ferric form is extremely low. Hence, living organisms were compelled to develop efficient mechanisms for iron transport and storage.

In recent years, a number of key mechanisms have been described which are responsible for adaptation to changing environmental conditions (6). Production of the iron storage protein ferritin and the transferrin receptor (TfR) protein is reciprocally regulated by a translational mechanism in which the iron regulatory protein (IRP) is reversibly bound to the iron response elements (IRE) of their respective mRNAs. A similar iron-dependent translational mechanism may affect the expression of divalent metal transporter I (DMTI) responsible for the uptake of ferrous iron from the brush border of duodenal enterocytes, and ferroportin (IregI) responsible for the export of ferrous iron through the basolateral membrane of the same cells. The brush border ferric reductase converts ferric to ferrous iron for use by DMTI, and Hephaestin, a transmembrane-bound ferroxidase, converts ferrous to ferric iron, creating a concentration gradient of errous iron across the cell membrane facilitating iron egress. At low iron conditions, the translation of TfR, DMT1, and ferroportin is enhanced, with the opposite occurring at high iron conditions. In addition, a new protein, Hepcidin, has been described recently and is probably the most important regulator of iron homeostasis (7). Hepcidin functions as an inhibitor of iron absorption and presumably of iron release from macrophages. Its production is increased by iron overload and inflammation and is suppressed by iron deficiency. Thus, in iron deficiency powerful compensatory mechanisms involving increased activity of iron transport proteins and inhibition of Hepcidin are activated in order to restore normal iron balance. However, these mechanisms are only partly effective, and iron deficiency anaemia (IDA) is one of the most common nutritional deficiencies in the global population.

The timeliness of the present volume on ACD is underscored by a number of recent developments. The discovery of Hepcidin and its inter-relation with the genes for HFE, hemojuvelin (8), and possibly transferrin receptor-2 revolutionized our understanding of the abnormal iron homeostasis of ACD. These recent discoveries offer new insights into the enigma of increased ferritin synthesis in ACD preceding the development of hypoferremia (9), and the inter-relation of IRE, IRP NO, and cytokines (10) in the pathogenesis of ACD. The chapters covering the regulation of iron metabolism, the systemic inflammatory response, and the newly described regulatory molecules of iron metabolism will provide a comprehensive insight into the molecular mechanisms involved in ACD. The implications of the unique combination of hypoferremia and cellular siderosis in inflammation will be discussed in the chapters covering iron and immunity, iron withholding as a defense strategy, and the two chapters on the positive and negative effects on infectious and malignant disease of ACD and of its correction. Failure of the erythropoietin response is central to the development of anemia in ACD and the introduction of recombinant erythropietin to the management of ACD has been the most important recent development in the treatment of its anemia. The reader will find a wealth of information on these aspects in the chapters on erythropoietin and erythropoiesis, the inhibition of erythroid progenitor cell proliferation, human recombinant erythropoietin, and the inter-relation of iron and erythropoietin administration in ACD. However, the effects of anemia correction on the clinical course of the underlying disease by the different therapeutic measures are not known so far, and major attempts should be undertaken to clarify this most important issue depending on the nature of the underlying disease.

Further understanding of the mechanism of anemia will be offered in the chapters on iron-limited erythropoiesis, erythrophagocytosis, and decreased red cell survival. Finally, on the practical side, special chapters will cover the issues of diagnostic tests in ACD, the use of iron, blood transfusions, and new therapeutic options in the treatment of ACD. For the specialists, particular chapters have been devoted to ACD in systemic infection, cancer, rheumatic and autoimmune disorders, anemia in intensive care patients, chronic renal disease, inflammatory bowel disease, and the anemia associated with transplantation.

It is believed that this volume will satisfy the need for an up-to-date compilation of knowledge in the field of ACD. It is intended to be used by students, clinicians, and investigators alike. It should be remembered, however, that much is still to be learned about this common and enigmatic clinical entity. Although Hepcidin is clearly a central player in the drama of ACD, it does not appear to interact with iron directly and the manner in which it is able to influence the function of other well-defined proteins of iron transport and storage is at this stage unknown. Finally, one should always keep in mind that ACD is a secondary phenomenon and that successful treatment of the underlying disease responsible for the inflammatory condition is the ultimate goal of treatment.