There is widening disparity in nuclear-cytoplasmic asynchrony as a cobalamin- or folate-deficient cell divides, until the more mature generations of daughter cells die in the marrow or are arrested (as megaloblastic cells) at various stages of the cell cycle. All proliferating cells exhibit megaloblastosis, including the luminal epithelial mucosal cells of the entire gastrointestinal tract, cervix, vagina, and uterus. However, megaloblastic changes are most striking in the blood and bone marrow. Ineffective hematopoiesis extends into long bones, and the bone marrow aspirate—which is superior to the biopsy for observing megaloblastosis—exhibits trilineal hypercellularity, especially of the erythroid series. Indeed, the plethora of bone marrow morphologic changes can lead an untrained observer to the diagnosis of erythroleukemia. The appearance of exuberant cell proliferation with numerous mitotic figures is misleading because these cells are actually proliferating very slowly (see box on Morphology in Megaloblastosis From Cobalamin and Folate Deficiency).

Erythroid hyperplasia reduces the myeloid-to-erythroid ratio from 3:1 to 1:1. Proerythroblasts are not as obviously abnormal as later forms; they may simply be larger (promegaloblasts). Megaloblastic changes are most strikingly displayed in intermediate and orthochromatic stages, which are larger than their normoblastic counterparts. In contrast to the normally dense chromatin of comparable normoblasts, megaloblastic erythroid precursors have an open, finely stippled, reticular, and sieve-like pattern (Fig. 1). The orthochromatic megaloblast, with its hemoglobinized cytoplasm, continues to retain its large sieve-like immature nucleus, in sharp contrast to the clumped chromatin of orthochromatic normoblasts. The nucleus is often eccentrically placed in these large oval or oblong cells, and lobulation or indentation of nuclei with bizarre karyorrhexis is often seen. In cells destined for the circulation as macro-ovalocytes, the nucleus may occasionally not be completely extruded. Of the potential progeny of proerythroblasts that develop into later megaloblastic forms, 80% to 90% die in the bone marrow. Marrow macrophages effectively scavenge dead or partially disintegrated megaloblasts. This is the basis for ineffective erythropoiesis (intramedullary hemolysis).

Fig1. MEGALOBLASTIC ANEMIA. The peripheral smear (A) exhibits macro-ovalocytosis and a hypersegmented polymorphonuclear leukocyte (inset). The bone marrow aspirate (B) shows megaloblastic changes in both granulopoiesis and erythropoiesis. The biopsy (C) is hypercellular and shows sheets of immature erythroid precursors with the appearance of a high mitotic rate. These can mimic acute erythroleukemia or even metastatic tumor cells. Details from the cells in the aspirate (D) compared with normal hematopoiesis at same magnification (E). Note the giant metamyelocyte and band form. In megaloblastic anemia, megakaryocytes also have nuclear atypia, including abnormal nuclear segmentation (F). Thus, the bone marrow aspiration and biopsy should be assessed for morphology, special stains, flow cytometry, and cytogenetic analysis. If the marrow is not obviously megaloblastic but the iron stain reveals absent stores, review the morphologic evaluation again with special emphasis on granulocytic precursors and promegaloblasts, and look for more subtle megaloblastic changes.

Leukopoiesis is also abnormal. There is an absolute increase in these cells, which are large and have similar sieve-like chroma tin. Spectacular giant (20 to 30 μm) metamyelocytes and “band” forms that are often seen are pathognomonic for megaloblastosis (see Fig. 1). There may be bizarre nucleoli with small cytoplasmic vacuoles. It is probable that giant metamyelocytes cannot easily traverse marrow sinuses, and their maturation into circulating hypersegmented polymorphonuclear neutrophils (PMNs) is unlikely. Granulation of the cytoplasm remains unaffected.

Megakaryocytes may be normal or increased in numbers and may exhibit additional complexities in megaloblastic expression (see Fig. 1). Complex hypersegmentation (i.e., pseudohyperdiploidy) is associated with liberation of fragments of cytoplasm and giant platelets into the circulation. The net output of platelets is decreased in severe megaloblastosis, and abnormal but reversible platelet dysfunction has been documented.

In early cobalamin or folate deficiency, normoblasts may dominate the marrow with only a few megaloblasts seen. Complete trans formation to megaloblastic hematopoiesis is observed in florid cases and is reflected by various degrees of pancytopenia.

The earliest manifestation of megaloblastosis is an increase in mean corpuscular volume (MCV) with macro-ovalocytes (up to 14 μm) (see Fig. 1). Because these cells have adequate hemoglobin, the central pallor, which normally occupies about one-third of the cell, is decreased. By contrast, thin macrocytes have larger than normal central pallor (Table 1). In severe anemia, poikilocytosis and anisocytosis are evident. Cells containing remnants of DNA (i.e., Howell-Jolly bodies), arginine-rich histone, and nonhemoglobin iron (i.e., Cabot rings) may be observed. Extramedullary megaloblastic hematopoiesis may also result in a leukoerythroblastic picture.

Table1. Clinical Conditions Not to Be Confused With Megaloblastosis

Nuclear hypersegmentation of DNA in PMNs strongly suggests megaloblastosis when associated with macro-ovalocytosis (see Fig. 1). Normally fewer than 5% of PMNs have more than five lobes, and no cells have more than six lobes in the peripheral blood; megaloblastosis is suggested when greater than 5% PMNs have more than five lobes or 1% PMN have more than six lobes. (See box on Diagnostic Issues: Information From the Peripheral Smear and Bone Marrow Aspirate.)

Ineffective use of iron results in an increased percentage of saturation of transferrin and increased iron stores. If there is associated iron deficiency, the MCV may be normal, and only iron therapy can unmask the megaloblastic manifestations in the peripheral blood. In thalassemia, the entire erythrocyte morphology normally expected in megaloblastosis is masked; however, megaloblastic leukopoiesis is still observed. Significant intramedullary hemolysis (ineffective erythropoiesis) involving more than 90% of megaloblastic precursors is reflected by a lowered absolute reticulocyte count, increased bilirubin (up to 2 mg/dL), decreased haptoglobin, and increased lactate dehydrogenase (LDH) often above 1000 units/mL. There is also a modest decrease in the circulating RBC life span. (See box on Masked Megaloblastosis.)

Megaloblastosis in rapidly proliferating cells of the gastrointestinal tract leads to a variable degree of morphologic changes and atrophy of luminal epithelial cells. This leads to functional defects, which can include malabsorption of cobalamin and folate in some patients. A vicious cycle whereby megaloblastosis begets more megaloblastosis is established that can be interrupted only by specific therapy with cobalamin or folate.

اخر الاخبار

اخبار العتبة العباسية المقدسة

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الآخبار الصحية

سرّ بسيط لصحة القلب.. أطعمة تخفض الكوليسترول خلال أسابيع

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مواضيع ذات صلة

Presentations Associated with Sideroblastic Anemia or Porphyrinuria

Sideroblastic Anemia and Porphyrinuria Caused by Drugs

Addison’s Disease

Cushing’s Disease

Sideroblastic anemias

Osteoporosis

Pathophysiology of Beta-Thalassemia Syndromes

Etiology and Pathophysiology of Anemia of Chronic Inflammation

Goitre and Thyroid nodules

Pathogenesis of Cobalamin Deficiency

Clinical Manifestations of Iron Overload

Pathobiology of Acquired Iron Overload