Megaloblastic erythropoiesis

Shuster et al. (Sll) measured B12 levels in the sera of 20 patients with psoriasis and found normal levels in all but one. Folic acid levels were decreased below normal in 21 out of 28 patients, urinary FIGLU excretion was elevated in 19 of 30, and in 5 of 9 patients sternal marrow puncture revealed megaloblastic erythropoiesis, thereby implying a true folate deficiency. Neither serum iron deficiency nor lack of absorption of folate could be implicated as a cause of the folate deficiency, and presumably it is related to the skin lesions. 

Some of the clinical consequences in SS disease include megaloblastic erythropoiesis, aplastic crisis, stroke, bone pain crisis, proneness to infection particularly by Pneumococcus, Salmonella, and Haemophilus due to hypos-plenism and acute chest syndrome. Prophylactic use of penicillin and antipneumococcal and Haemophilus vaccines has aided in the management of life-threatening infectious complications of SS disease. Neonatal screening has been used in the identification of infants with sickle cell disease so that risk of infection can be modulated by appropriate immunizations and penicillin prophylaxis. The acute chest syndrome characterized by chest pain is due to clogged pulmonary capillaries in a small number of studies, patients have been treated with inhaled nitric oxide, which dilates blood vessels with clinical improvement. 

Cobalamin is also a crucial cofactor in the conversion of homocysteine to methionine. When this reaction is impaired, folate metabolism is disturbed, resulting in folate-deficient tissues, and consequently, megaloblastic erythropoiesis. 

FOLATE DEFICIENCY Folate deficiency is a common complication of diseases of the small intestine, which interfere with the absorption of dietary folate and the recirculation of folate through the enterohepatic cycle. In acute or chronic alcohohsm, daily intake of dietary folate may be severely restricted, and the enterohepatic cycle of the vitamin may be impaired by toxic effects of alcohol on hepatic parenchymal cells this is the most common cause of folate-deficient megaloblastic erythropoiesis. However, it also is the most amenable to therapy, inasmuch as the reinstitution of a normal diet is sufficient to overcome the effect of alcohol. Disease states characterized by a high rate of cell turnover, such as hemolytic anemias, also may be complicated by folate deficiency. Additionally, drugs that inhibit dihydrofolate reductase (e.g., methotrexate and trimethoprim) or that interfere with the absorption and storage of folate in tissues (e.g., certain anticonvulsants and oral contraceptives) can lower the concentration of folate in plasma and may cause a megaloblastic anemia. 

Pernicious anemia arises when vitamin B,2 deficiency blocks the metabohsm of folic acid, leading to functional folate deficiency. This impairs erythropoiesis, causing immature precursors of erythrocytes to be released into the circulation (megaloblastic anemia). The commonest cause of pernicious anemia is failure of the absorption of vitamin B,2 rather than dietary deficiency. This can be due to failure of intrinsic factor secretion caused by autoimmune disease of parietal cells or to generation of anti-intrinsic factor antibodies. 

Pharmacology Exogenous folate is required for nucleoprotein synthesis and maintenance of normal erythropoiesis. Folic acid stimulates production of red and white blood cells and platelets in certain megaloblastic anemias. 

Alcohol has a dose-related toxic effect on erythropoiesis. In this context, vacuolization of the nuclei and plasma of the proerythroblasts (so-called McCurdy cells) can mostly be observed. The mean corpuscular volume of erythrocytes (MCV) increases with rising alcohol consumption in 50—60% of patients, particularly when consuming high-proof alcoholic drinks. Megaloblastic anaemia... 

Hemolytic Disease and Ine/fectiVe Erythropoiesis. As discussed previously, Hp levels are a sensitive indicator of in vivo hemolysis, as long as other causes of decreased levels are excluded. Splenomegaly and ineffective hematopoiesis are also associated with decreased levels. The latter, with increased hemolysis of red cells and their precursors in the bone marrow space, is seen in megaloblastic anemias... 

Hemolysis, if sufficiently severe, produces an LD isoenzyme pattern similar to that in myocardial infarction. Megaloblastic anemias, usually resulting from the deficiency of folate or vitamin cause the erythrocyte precursor cell to break down in the bone marrow (ineffective erythropoiesis), resulting in the release of large quantities of LD-1 and LD-2 isoenzymes. Marked elevations of the total LD activity in serum— up to 50 times the upper reference limit—have been observed in the megaloblastic anemias. These elevations rapidly return to normal after appropriate treatment. 

The demand for folate is increased in people with thalassemia because of a more rapid cell turnover due to ineffective erythropoiesis. Where this demand cannot be met, a megaloblastic anemia may be superimposed on the thalassemia (R14, G8). This may be difficult to recognize because the abnormal synthesis of the globin moiety of hemoglobin may prevent the development of characteristic megaloblasts. A similar situation may occur in iron-deficiency anemia where characteristic megaloblasts will not develop until... 

Exogenous folate is required for nucleoprotein synthesis and maintenance of normal erythropoiesis. Folic acid stimulates production of red and white blood cells and platelets in certain megaloblastic anemias. Folic acid is the precursor of tetrahy-drofolic acid, which is involved as a cofactor for transform-ylation reactions in the biosynthesis of purines and thymidylates of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective DNA synthesis that leads to mega-loblast formation and megaloblastic and macrocytic anemias. 

These hematopoietic precursor cells when exposed to too little folate and/or vitamin B12 show slowed cell division, but cytoplasmic development occurs at a normal rate. Hence, the megaloblastic cells tend to be large, with an increased ratio of RNA to DNA. Megaloblastic erythroid progenitors are usually destroyed in the bone marrow (although some reach the circulation). Thus, marrow cellularity is often increased but production of red blood cells is decreased, a condition called "ineffective erythropoiesis."... 

Jean Ann Tonich s megaloblastic anemia was treated, in part, with folate supplements (see Clinical Comments). Within 48 hours of the initiation of folate therapy, megaloblastic or "ineffective" erythropoiesis usually subsides, and effective erythropoiesis begins. 

Samuel Fenwick (1877, 1880) found gastric atrophy in pernicious anemia and appreciated the nutritional significance of this observation. Erlich and Lazarus (1898) considered that the megaloblastic state of bone marrow might be due to an arrest of maturation, with reversion to a fetal type of erythropoiesis. 

Diluting normal serum reduces its maturing effect. Lajtha (1950) demonstrated that when a marrow with a normoblastic erythropoiesis is cultured for 72 hours in pernicious anemia serum, megaloblasts may appear. This led him to conclude that the megaloblast is a pathological variant of a normoblast and that both states are reversible. 

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