Clinical Features. As in anemia of iron deficiency, the serum iron levels usually are low in the anemia of chronic disease, and the red cells may be slightly hypochromic and microcytic. Unlike iron deficiency anemia, however, storage iron in the bone marrow and serum ferritin are increased and the total iron-binding capacity is reduced. Administration of erythropoietin and iron can improve the anemia, but only effective treatment of the underlying condition is curative.
The two principal causes of megaloblastic anemia are folate deficiency and vitamin B12 deficiency. Both vitamins are required for DNA synthesis and the effects of their deficiency on hematopoiesis are essentially identical. However, the causes and consequences of folate and vitamin B12 deficiency differ in important ways. We will first review some of the common features and then touch on those that are specific to folate and vitamin B12 deficiency.
Megaloblastic anemia stems from metabolic defects that lead to inadequate biosynthesis of thymidine, one of the building blocks of DNA. As we will discuss, folate and vitamin B12 are both essential factors for the synthesis of thymidylate, which is required for DNA replication. Thymidine deficiency causes abnormalities in rapidly dividing cells throughout the body, but the hematopoietic marrow is most severely affected. Because the synthesis of RNA and cytoplasmic elements proceeds at a normal rate and thus outpaces that of the nucleus, the hematopoietic precursors show nuclear-cytoplasmic asynchrony (described later). This maturational derangement contributes to the anemia in several ways. Many red cell progenitors are so defective in DNA synthesis that they undergo apoptosis in the marrow (ineffective hematopoiesis). Others mature into red cells but do so after fewer cell divisions, further diminishing the output of red cells. Granulocyte and platelet precursors also are affected (although not as severely) and most patients present with pancytopenia (anemia, thrombocytopenia, and granulocytopenia).
Fig. 12.11 Megaloblasticanemia.Aperipheralbloodsmearshowsahyper-segmentedneutrophilwithasix-lobednucleus.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.)
MORPHOLOGYCertainmorphologicfeaturesarecommontoallformsofmegaloblasticanemia.Thebonemarrowismarkedlyhypercellularandcontainsnumerousmegaloblasticerythroidprogenitors.Megaloblasts arelargerthannormalerythroidprogenitors(normoblasts)andhavedelicate,finelyreticulatednuclearchromatin(indicativeofnuclearimmaturity).Asmegaloblastsdifferentiateandacquirehemoglobin,thenucleusretainsitsfinelydistributedchromatinandfailstoundergothechromatinclumpingtypicalofnormoblasts,aclassicexampleofnuclear-cytoplasmicasynchrony.Thegranulocyticprecursorsalsodemonstratenuclear-cytoplasmicasynchrony,yieldinggiant metamyelocytes. Megakaryocytesmayalsobeabnormallylargeandhavebizarremultilobednuclei.
Fig.12.11 ),whichappearbeforetheonsetofanemia.Normalneutrophilshavethreeorfournuclearlobes,butinmegaloblasticanemiastheyoftenhavefiveormore.Theredcellstypicallyincludelarge,egg-shaped macroovalocytes; theMCVoftenisgreaterthan110fL(normal,82–96fL).Althoughmacrocytesappearhyper-chromic,inrealitytheirhemoglobincontentisnormal.Large,misshapenplateletsalsomaybeseen.Morphologicchangesinothersystems,especiallythegastrointestinaltract,alsooccur,givingrisetosomeoftheclinicalmanifestations.