Pernicious Bone marrow

The story of vitamin B12 began with pernicious anemia, a disease that usually affects only persons of age 60 or more but which occasionally strikes children.3 Before 1926 the disease was incurable and usually fatal. Abnormally large, immature, and fragile red blood cells are produced but the total number of erythrocytes is much reduced from 4-6 x 106 mm-3 to 1- 3 x 106 mm-3. Within the bone marrow mitosis appears to be blocked and DNA synthesis is suppressed. The disease also affects other rapidly growing tissues such as the gastric mucous membranes (which stop secreting HC1) and nervous tissues. Demyelination of the central nervous system with loss of muscular coordination (ataxia) and psychotic symptoms is often observed. 

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. 

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... 

Classification according to cause includes, for example, aplastic anaemia, which is due to bone marrow damage haemorrhagic anaemia due to blood loss haemolytic anaemia due to damage to red cell membranes iron deficiency anaemia due to lack of iron pernicious anaemia due to deficiency in B12 and so on. 

Anaemias are classified according to the size and haemoglobin content of erythrocytes or to the cause of the condition. In the latter classification bone marrow damage causes aplastic anaemia haemorrhagic and haemolytic anaemia are due to blood loss or damaged red cell membranes respectively, iron deficiency and pernicious anaemia are due to deficiency of iron and vitamin B12 respectively. 

Parietal cells also secrete intrinsic factor, which is necessary for the absorption of vitamin B12. Vitamin B12 is a cofactor of enzymes which synthesise tetrahydrofolic acid, which in turn is needed for the synthesis of DNA components. An impairment of DNA synthesis will affect rapidly dividing cell populations, among them the haematopoietic cells of the bone marrow, which may result in pernicious anaemia. This condition may result from a destruction of the gastric mucosa by, for example, autoimmune gastritis or the resection of large parts of the lower ileum, which is the main site of vitamin B12 absorption, or of the stomach. 

Pernicious anemia microscopic abnormalities of blood and bone marrow correlating with B12-deficiency... 

Osgood demonstrated that pernicious anemia serum delays maturation of megaloblastic bone marrow (see LI). The work of Callender and Lajtha (see G20) points out that addition of normal gastric juice potentiates the effect of vitamin B12 in counteracting this maturation-delaying effect of pernicious anemia serum. A B12 binder separated from normal gastric juice by electrophoresis or ammonium sulfate precipitation was also shown to enhance the B12 effect on maturation of the erythro-blasts, when added to bone marrow (P2, P3). The relation of this maturation-promoting factor to Castle s intrinsic factor is not clearly defined (see G20). 

Vitamin B-12 is necessary for red biood ceiis to mature prop-eriy in the bone marrow. Peopie with pernicious anemia iose their abiiity to make intrinsic factor, a substance secreted by the stomach s membrane iining that enabies vitamin B-12 to be absorbed from the intestine. Without an adequate amount of vitamin B-12, the body is unabie to synthesize DNA properiy, which affects red blood cell production. 

Cyanocobalamin (vitamin B12), injected into a muscle, travels to the bone-marrow and is accumulated there after a dilution of 10 -fold in the body fluids. Even a microgram, injected in this way, is enough to cause new reticulocytes to form in the marrow of a patient suffering from pernicious anaemia. The process of distribution has been followed with Co. 

Fig. 4-22. Bone marrow smear from a patient with pernicious anemia with numerous megaloblastic erythroid precursors (Wright s stain)...

Studies of the effect of vitamin B12 on the overall rate of DNA and RNA synthesis have yielded contradictory results. Although there have been reports suggesting, for example, that vitamin B12 deficiency reduces the rate of DNA and RNA synthesis in regenerating liver, in better controlled experiments in which P-incorporation was measured in the nucleic acid of a variety of tissues, an effect of vitamin B12 seems to be excluded. In the bone marrow of pernicious anemia patients, the DNA per cell is not altered, but the capacity of the bone marrow stem cells to mature into normoblasts is affected. When vitamin B12 is added to the culture medium, cells mature normally. 

Lack of vitamin Bjj leads to the blood disease pernicious anemia, with deterioration of the cells in bone marrow responsible for replacing blood. In the end serious anemia can arise. A lack of vitamin Bj may also lead to disturbances in the nervous system. 

In pernicious anemia, the bone marrow is hyperplastic and contains many large young cells which are designated megaloblasts. The peripheral blood shows severe macrocytic anemia, leucopenia with a high percentage of old polymorphonuclear leucocytes, and thrombocytopenia. Erythrocyte destruction is excessive, as manifested by an increase in the level of bilirubin in serum and a rise in urobilin excretion in the urine. An abnormality of tyrosine metabolism is demonstrated by the excretion of certain phenolic compounds in the urine. Hydrochloric acid is absent from the gastric juice. 

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. 

That vitamin B12 can be utilized locally by bone marrow cells and corrects a qualitative abnormality in cellular ribonucleic acid in patients with pernicious anemia. 

Red blood cell formation and control of pernicious anemia. Vitamin B-12 is essential for the blood-forming organs of the bone marrow to function properly. Without sufficient B-12 coenzymes, the red blood cells do not mature normally, with the result that large, immature cells (megalo-blasts) form and are released into the blood, causing megaloblastic anemia. 

The working hypothesis used to explain the common effects of folate and Bjl2 deficiency in the production of megaloblastic anemia is the interference with folate-mediated one carbon turnover. Therefore, it is impossible to discuss the role of vitamin B12 in leukocyte function without consideration of its role in regeneration of reduced folate coenzymes. A role for vitamin B12 in the transport of folate into white blood cells has been postulated. Tissen and Herbert (1973) found impaired transport of Me THF (but not PGA) into bone marrow cells from patients with vitamin B12 deficiency. The THF uptake was also reduced in PHA stimulated peripheral lymphocytes from patients with pernicious anemia (Lavoie et al. 1974). In both cases cellular uptake of Me-THF was increased by the vitro addition of the vitamin to the culture media. Lavoie et al. also found a reduced transfer of the methyl group to non folate compounds in peripheral lymphocytes from vitamin B12 deficient subjects. It is possible that vitamin B12 is not directly involved with the entry of folates into the cell but the impaired transport could reflect a pile up of Me-THF inside the cell due to reduced use. 

However, Sakamoto et al. (1975) found a nine-fold increase in the activity of this enzyme in bone marrow cultures from patients with pernicious anemia. This discrepancy could be explained by the difference in the cell type used or to the type of cofactor employed in the assay system. The authors speculate that increased activity in vitro reflects the stimulated synthesis of the apoenzyme to compensate for the reduced levels of the folate coenzyme. 

Smith and Baker, 1960), ribonucleotide reductase (Fujioka and Silver, 1971) and thymidine kinase (Nakao and Fujioka, 1968) have been reported to be elevated in cultures of bone marrow or peripheral lymphocytes from patients with pernicious anemia. 

Cyanocobalamin (Bjj), which is not present in grains and vegetables, also acts as a coenzyme, especially in bone marrow, neurons, and gastrointestinal epithelial cells. It is involved in hemoglobin formation, and plays a major role in the prevention of pernicious or macrocytic anemia (fewer and larger red blood cells than normal) and the maintenance of nerve tissues. The acute deficiency can also cause mental disorders. It is important to point out that cyanocobalamin is the only vitamin that requires a specific factor for its absorption. This factor is called intrinsic castle and is a muco- or glycoprotein secreted by the stomach. 

Pernicious anemia is one of many types of anemia, a disease marked by a reduction in red blood cells, or in the oxygen-carrying substance hemoglobin found in these cells. Red blood cells need vitamin B 2 to mature properly in the bone marrow. In pernicious anemia, vitamin 6,2 is unavailable due to lack of the so-called intrinsic factor, a glycoprotein responsible for the intestinal absorption of the vitamin. For this reason, oral application of vitamin Bj2 is ineffective. Vitamin Bj2 must be injected directly into the circulatory... 

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