Megaloblastic marrow

Deficiency of folic acid leads to a megaloblastic anaemia because it is necessary for the production of purines and pyrimidines, which are essential precursors of deoxyribonucleic acid (DNA). The megaloblastic marrow of cobalamin deficiency is due to interference with folic acid utilisation and the morphological changes of cobalamin deficiency can be reversed by folic acid. It is vital to realise that folic acid does not provide adequate treatment for pernicious anaemia. Nor does vitamin 3 2 provide adequate treatment for the megaloblastic anaemia of folic acid deficiency, although a partial response may occur because vitamin plays a role in folate metabolism. 

The second hematological sign of folate deficiency involves the pathway of red blood cell synthesis. Early erythroblasts accumulate in folate deficiency, initially in the bone marrow, where they can be easily detected by the clinician, and then in the bloodstream. Because of the large size of early erythroblasts, the marrow containing the accumulated cells is called a megaloblastic marrow. Generally, marrow samples are taken from the hip (pelvis), though they can also be taken from the sternum. 

PA is characterized by megaloblastic anemia, megaloblastic marrow, and, occasionally, neurological symptoms. The hematological characteristics of the disease are indistinguishable from those of folate d idency. The biochemical signs of the disease include low serum B12 and elevated MMA. The neurological problems affect about 25% of those with the disease and include numbness of the feet and... 

The reported need for intrinsic factor to potentiate the effect of Bis in cultures of megaloblastic marrow (Callender and Lajtha, 1951b) is discussed on page 165. 

Reisner and Swan (1954) found that neither vitamin B12 nor intrinsic factor, nor both of them together, influenced the production of nucleated cells in suspension cultures of megaloblastic marrow. But in cultures on chicken plasma clots or on glass surfaces, when mitosis was more active than in suspension cultures, vitamin Bn had a marked stimulatory effect. Thus they were unable to confirm the theory that vitamin Bn must be activated by intrinsic factor before it becomes effective in marrow culture. 

These have been reviewed by Jukes (1952). Suggestions that vitamin Bis participates in the formation of citrovorum factor from pteroylglutamic acid are reviewed by Welch and Nichol (1952). In one patient who died shortly after treatment with vitamin Bis, only 60% of the foUc acid substances in the liver were present as citrovorum factor, whereas in two normal patients nearly all the hepatic activity was present as citrovorum factor (Girdwood, 1952a). It is clear, however, that the megaloblastic marrow of untreated pernicious anemia cannot be due solely to a failure to convert pteroylglutamic acid to citrovorum factor. 

Deficiency of fohc acid itself—or deficiency of vitamin Bi2, which leads to functional fohc acid deficiency—affects cells that are dividing rapidly because they have a large requirement for thymidine for DNA synthesis. ChnicaUy, this affects the bone marrow, leading to megaloblastic anemia. 

Hydroxyurea inhibits cell synthesis in the S phase of the DNA cycle. It is used selectively in the treatment of psoriasis, especially in those with liver disease who would be at risk of adverse effects with other agents. However, it is less effective than methotrexate. The typical dose is 1 g/day, with a gradual increase to 2 g/day as needed and as tolerated. Adverse effects include bone marrow toxicity with leukopenia or thrombocytopenia, cutaneous reactions, leg ulcers, and megaloblastic anemia. 

There are many causes of the clinical condition referred to as anaemia. One particular type, whose cause can be traced to a genuine metabolic defect is megaloblastic anaemia and is due to a deficiency of the vitamins B12 (cobalamin) and/or folate. These vitamins are required for normal cell division in all tissues, but the rapid production of red cells makes them more susceptible to deficiency. In megaloblastic anaemia the blood haemoglobin concentration falls the synthesis of haem is not impaired. Examination of the blood reveals the appearance of larger then normal cells called macrocytes and megaloblasts are found in the bone marrow. 

Megaloblastic anemia results from insufficient active THF to support cell division in the bone marrow. Methotrexate inhibits DHF reductase, making it a useful antineoplastic drug. Folate deficiencies may be seen during pregnancy and in alcoholism. 

IV use at high doses or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia, or megaloblastic anemia. POP in patients with Acquired Immunodeficiency Syndrome (AIDS) A DS patients may not tolerate or respond to TMP-SMZ. 

Patients with folic acid deficiency may have diarrhea and nausea, but the principal symptoms are weakness and easy fatigability due to megaloblastic anemia arising from impaired cell division in the bone marrow. 

The answer is D. Several vitamin deficiencies can cause anemia due to reduced DNA synthesis in the erythropoietic cells of the bone marrow, especially folic acid and vitamin Bj2 (cobalamin), which are particularly prevalent among elderly patients due to poor diet and reduced absorption. In addition, deficiencies of either folic acid or vitamin Bj2 could produce the megaloblastic anemia seen in this patient. However, the absence of neurologic symptoms, a hallmark of vitamin Bj2 deficiency, makes that diagnosis less likely than folic acid deficiency. 

Megaloblastic anemia is characterized by the appearance of large cells in the bone marrow and blood due to defective maturation of hematopoietic cells. Folic acid or vitamin B12 deficiency will result in this type of anemia. Malabsorption, impaired use, chronic infections, and drugs can lead to folic acid or vitamin B12 deficiency. 

Vitamin B12 is used to treat or prevent deficiency. The most characteristic clinical manifestation of vitamin B12 deficiency is megaloblastic, macrocytic anemia (Table 33-2), often with associated mild or moderate leukopenia or thrombocytopenia (or both), and a characteristic hypercellular bone marrow with an accumulation of megaloblastic erythroid and other precursor cells. The neurologic syndrome associated with vitamin Bi2 deficiency usually begins with paresthesias in... 

At higher dosage, methotrexate may cause bone marrow depression, megaloblastic anemia, alopecia, and mucositis. At the doses used in the treatment of inflammatory bowel disease, these events are uncommon but warrant dose reduction if they do occur. Folate supplementation reduces the risk of these events without impairing the antiinflammatory action. 

The effects of cobalamin deficiency are most pronounced in rapidy dividing cells, such as the erythropoietic tissue of bone marrow and the mucosal cells of the intestine. Such tissues need both Die N5-N10-methylene and N10-formyl forms of tetrahydrofolate for Ihe synthesis of nucleotides required for DNA replication (see pp. 291, 301). However, in vitamin B12 deficiency, the N5-methyl form of tetrahydrofolate is not efficiently used. Because the methylated fonn cannot be converted directly to other forms of tetrahydrofolate, tie Ns-methyl form accumulates, whereas the levels of the other forms decrease. Thus, cobalamin deficiency is hypothesized to lead to a deficiency of the tetrahydrofolate forms needed in purine and thymine synthesis, resulting in the symptoms of megaloblastic anemia. 

Adverse Effects. The primary side effects of azathioprine are related to suppression of bone marrow function, including leukopenia, megaloblastic anemia, and similar blood dyscrasias. Other side effects include skin rash and gastrointestinal distress (appetite loss, nausea, vomiting) hepatic dysfunction can also occur when higher doses are used. 

Examination of the bone marrow, although important, will only confirm that the hemopoiesis is megaloblastic. A deficiency of folic acid will also cause a megaloblastic anemia and it is not possible to identify the cause on the basis of morphology. A serum assay of both vitamins will usually indicate which is responsible. If the patient is vitamin B12 deficient, the next step is to carry out a vitamin B12 absorption test to confirm that the deficiency is due to a lack of intrinsic factor. Preferably this should not be done until the patient s vitamin B12 and hemoglobin levels have returned to normal, since the gastric and intestinal cells are also affected by a lack of vitamin B12 aborption may be less than optimal if it is attempted too early. Patients with pernicious anemia also have a histamine-fast achlorhydria and gastric atrophy. The disease appears to have an autoimmune basis and antibodies to intrinsic factor can be demonstrated in the serum of more than half of affected patients. 

A 6-month-old child was breast-fed exclusively by a mother who had been a strict vegetarian for at least 7 years. He was totally unresponsive to stimuli. His hemoglobin was 5.7 g/dL, and his bone marrow aspirates showed megaloblastic changes in blood cells. His serum folate and iron were normal. His urine contained increased amounts of homocystine, methylmalonic acid, and glycine. Propose a reason for this infant s illness, and discuss its biochemical etiology. Discuss other possible reasons for the same or similar symptoms in a patient. Explain the abnormal serum and urine chemistries. 

Figure 28-1. Characteristic features of vitamin B12 or folate deficiency in the peripheral blood include larger-than-normal mature red blood cells (oval macrocytes with an elevated mean corpuscular volume) and large hypersegmented neutrophils (1 neutrophil with six nuclear lobes or more than 5% neutrophils with five nuclear lobes).These characteristics are associated with megaloblastic changes in the bone marrow and are the result of fewer cell divisions due to impaired DNA synthesis.

Some authors use the term adult onset pernicious anemia to distinguish this condition from rare disorder subdivisions of pernicious anemia due to congenital defects in IF secretion or structure or to various types of entero-cyte cobalamin malabsorption. In all other situations, the term vitamin B12 deficiency is used, and an associated anemia, if consequent on it, is called megaloblastic anemia, bearing in mind that identical appearances of the peripheral blood and the bone marrow may be... 

Normocytic, normochromic anaemia (normal size, normal haemoglobin content) can be caused by damage to the bone marrow or by blood loss. Macrocytic (or megaloblastic), normochromic anaemia (large cells, normal amount of haemoglobin) is due to deficiency of folic acid or B12, or both. Microcytic, hypochromic anaemia (small cells, small amount of haemoglobin) is the most common type and is due to iron deficiency. 

Hematologic Leukopenia, megaloblastic anemia, thrombocytopenia, bone marrow suppression... 

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