Chapter 100. Megaloblastic Anemias (Part 4)

Biochemical Basis of Megaloblastic Anemia The common feature of all megaloblastic anemias is a defect in DNA synthesis that affects rapidly dividing cells in the bone marrow. All conditions that give rise to megaloblastic changes share in common a disparity in the rate of synthesis or availability of the four immediate precursors of DNA: the deoxyribonucleoside triphosphates (dNTPs): dA(adenine)TP and dG(guanine)TP (purines), dT(thymine)TP and dC(cytosine)TP (pyrimidines). In deficiencies of either folate or cobalamin, there is failure to convert deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), the precursor of dTTP (Fig.100-1). ...
Nội dung trích xuất từ tài liệu:
Chapter 100. Megaloblastic Anemias (Part 4) Chapter 100. Megaloblastic Anemias (Part 4) Biochemical Basis of Megaloblastic Anemia The common feature of all megaloblastic anemias is a defect in DNAsynthesis that affects rapidly dividing cells in the bone marrow. All conditions thatgive rise to megaloblastic changes share in common a disparity in the rate ofsynthesis or availability of the four immediate precursors of DNA: thedeoxyribonucleoside triphosphates (dNTPs): dA(adenine)TP and dG(guanine)TP(purines), dT(thymine)TP and dC(cytosine)TP (pyrimidines). In deficiencies ofeither folate or cobalamin, there is failure to convert deoxyuridine monophosphate(dUMP) to deoxythymidine monophosphate (dTMP), the precursor of dTTP (Fig.100-1). This is because folate is needed as the coenzyme 5,10-methylene-THFpolyglutamate for conversion of dUMP to dTMP; the availability of 5,10-methylene-THF is reduced in either cobalamin or folate deficiency. An alternativetheory for megaloblastic anemia in cobalamin or folate deficiency ismisincorporation of uracil into DNA because of a build-up of deoxyuridinetriphosphate (dUTP) at the DNA replication fork as a consequence of the block inconversion of dUMP to dTMP. Cobalamin-Folate Relations Folate is required for many reactions in mammalian tissues. Only tworeactions in the body are known to require cobalamin. Methylmalonyl CoAisomerization, which requires adocobalamin, and the methylation of homocysteineto methionine requires both methylcobalamin and both 5-MTHF (Fig. 100-1). Thisreaction is the first step in the pathway by which 5-MTHF, which enters bonemarrow and other cells from plasma, is converted into all the intracellular folatecoenzymes. The coenzymes are all polyglutamated (the larger size aiding retentionin the cell), but the enzyme folate polyglutamate synthase can use only THF, notMTHF, as substrate. In cobalamin deficiency, MTHF accumulates in plasma,while intracellular folate concentrations fall due to failure of formation of THF,the substrate on which folate polyglutamates are built. This has been termed THFstarvation, or the methylfolate trap. This theory explains the abnormalities of folate metabolism that occur incobalamin deficiency [high serum folate, low cell folate, positive purine precursoraminomidazole carboxamide ribonucleotide (AICAR) excretion; Table 100-2] andalso why the anemia of cobalamin deficiency will respond to folic acid in largedoses. Clinical Features Many symptomless patients are detected through the finding of a raisedmean corpuscular volume (MCV) on a routine blood count. The main clinicalfeatures in more severe cases are those of anemia. Anorexia is usually marked andthere may be weight loss, diarrhea, or constipation. Glossitis, angular cheilosis, amild fever in the more severely anemic patients, jaundice (unconjugated), andreversible melanin skin hyperpigmentation may also occur with deficiency ofeither folate or cobalamin. Thrombocytopenia sometimes leads to bruising, andthis may be aggravated by vitamin C deficiency or alcohol in malnourishedpatients. The anemia and low leukocyte count may predispose to infections,particularly of the respiratory or urinary tracts. Cobalamin deficiency has alsobeen associated with impaired bactericidal function of phagocytes. General Tissue Effects of Cobalamin and Folate Deficiencies Epithelial Surfaces After the marrow, the next most affected tissues are the epithelial cellsurfaces of the mouth, stomach, and small intestine and the respiratory, urinary,and female genital tracts. The cells show macrocytosis, with increased numbers ofmultinucleate and dying cells. The deficiencies may cause cervical smearabnormalities. Complications of Pregnancy The gonads are also affected, and infertility is common in both men andwomen with either deficiency. Maternal folate deficiency has been implicated as acause of prematurity, and both folate and cobalamin deficiency have beenimplicated in recurrent fetal loss and neural tube defects, discussed below. Neural Tube Defects Folic acid supplements at the time of conception and in the first 12 weeksof pregnancy reduce by ~70% the incidence of neural tube defects (NTDs)(anencephaly, meningomyelocele, encephalocele, and spina bifida) in the fetus.Most of this protective effect can be achieved by taking folic acid, 0.4 mg daily atthe time of conception. The incidence of cleft palate and harelip can also be reduced byprophylactic folic acid. There is no clear simple relationship between maternalfolate status and these fetal abnormalities, although overall the lower the maternalfolate, the greater the risk to the fetu ...