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Pathophysiology of the sideroblastic anemias

Author
Sylvia S Bottomley, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

Sideroblastic anemias feature congenital or acquired defects affecting the biosynthesis of heme, iron-sulfur (Fe-S) cluster generation, or mitochondrial protein synthesis within red cell precursors. The diverse circumstances under which these disorders are encountered, and the continuing discovery of molecular defects associated with the phenotype, underscore a broad spectrum of causes [1-4]. Yet, in a large proportion of patients the underlying mechanism remains undefined [1,4-6]. A conventional classification of the sideroblastic anemias provides an inclusive reference for their discussion and diagnosis (table 1).

In order to maintain a continual replacement of senescent red cells, approximately 85 percent of body heme is generated within the erythron. Heme synthesis is directly impaired in the two common forms of congenital sideroblastic anemia: the X-linked form because of deficient erythroid 5-aminolevulinate synthase (ALAS2), and the autosomal recessive disorder because of defects in the erythroid mitochondrial transporter SLC25A38. In the other congenital and most acquired forms, the production of heme is impaired secondarily (eg, when defects disrupt Fe-S cluster biogenesis), or the pathogenesis of the ring sideroblast abnormality is not defined. (See "Causes of congenital and acquired sideroblastic anemias".)

Deranged heme synthesis in the developing red cell leads to decreased hemoglobin production with the formation of hypochromic and microcytic red cells and other misshaped erythrocytes (picture 1). These red cells are the progeny of the ring sideroblasts that constitute the diagnostic hallmark of any sideroblastic anemia and are detected in the Prussian blue stained smear of the marrow aspirate, as shown in the upper panel (picture 2). The ultrastructure of the iron-positive cytoplasmic granules of ring sideroblasts is indicated by electron dense deposits within mitochondria, as shown in the lower panel (picture 2), reflecting accumulated iron, in a unique mitochondrial ferritin [7,8], that has been delivered to the developing erythroblast normally, but cannot be utilized. In those sideroblastic anemias in which cellular hemoglobin production does not appear to be affected, the red cell morphology is normocytic or macrocytic.

This topic review will address the physiologic consequences of defective heme production, namely the ineffective erythropoiesis and the associated iron overload. The molecular pathology of recognized genetic defects leading to impaired heme synthesis and other abnormalities in the sideroblastic anemias are discussed separately. (See "Causes of congenital and acquired sideroblastic anemias".) The clinical manifestations, diagnosis, and treatment of these disorders are also discussed separately. (See "Sideroblastic anemias: Diagnosis and management".)

INEFFECTIVE ERYTHROPOIESIS

The presence of ineffective erythropoiesis is suspected on morphologic grounds when anemia is associated with erythroid hyperplasia in the bone marrow in the absence of a reticulocyte response in the peripheral blood. In this situation, erythroid progenitor cells are intact, and erythropoietin production in response to anemic hypoxia is appropriately increased. However, cellular maturation involving either nuclear (DNA synthesis) or cytoplasmic (hemoglobin production) processes is disrupted, giving rise to faulty erythroblasts, many of which are destroyed within the bone marrow (ie, intramedullary hemolysis) via mechanisms that include apoptosis [9,10].

         

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Literature review current through: Nov 2016. | This topic last updated: Wed Jul 24 00:00:00 GMT+00:00 2013.
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