Cobalamin deficiency megaloblastic anemia

Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria 677 Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12 677 Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration 678... 

Cobalamin deficiency can create a secondary deficiency of active THF by preventing its release from the storage pool through the AT-methyl THF-homocysteine methyltransferase reaction, and thus also result in megaloblastic anemia. Progressive peripheral neuropathy also results from cobalamin deficiency. TTeating a cobalamin deficiency with folate corrects the megaloblastic anemia but does not halt the neuropathy. 

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. 

Vitamin B12 (cobalamin) serves as a cofactor for several essential biochemical reactions in humans. Deficiency of vitamin B12 leads to megaloblastic anemia (Table 33-2), gastrointestinal symptoms, and neurologic abnormalities. Although... 

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. 

Vitamin B12 (cobalamin) has as its active forms, methylcobalamin and deoxyadenosyl cobalamin. It serves as a cofactor for the conversion of homocysteine to methionine, and methylmalonyl CoA to succinyl CoA. A deficiency of cobalamin results in pernicious (megaloblastic) anemia, dementia, and spinal degeneration. The anemia is treated with IM or high oral doses of vitamin B12. There is no known toxicity for this vitamin. 

Deficiency of MTRR can produce homo-cystinuria accompanied by megaloblastic anemia (a type of anemia characterized by the presence in the blood of large, immature red blood cells). This condition is also known as cobalamin-responsive homocystinuria and is classified as the cbl E complementation type of... 

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... 

One aspect of vitamin B12 deficiency is that it results in the accumulation of W5-methyl-THF. N5-Methyl-THF is synthesized in mammals by an irreversible reaction (as shown above) if it cannot be utilized because of a deficiency of vitamin B12, then it accumulates. This causes a depletion of the other forms of THF, resulting in a deficiency of THF. Megaloblastic anemia (pernicious anemia) is associated with a deficiency of cobalamin... 

Cobalmin Deficiency. Pernicious anemia is the disease associated with vitamin Bi2 deficiency. It is usually caused by the inability to produce intrinsic factor. Indeed, many times the vitamin must be administered by injection. The blood picture, a megaloblastic anemia, is indistinguishable from that caused by folic acid deficiency. Indeed folic acid supplements can mask the blood picture. This is illustrated in Fig. 8.53. Removal of ad-enosyl cobalamin eliminates the regeneration of tetrahydrofolate during the methylation of homocysteine to methionine. Folic acid supplements provide a fresh source of tetrahydrofolate coenzymes. DNA synthesis can continue and new erythrocytes form. Excess folic acid also may compete for the available vitamin, further exacerbating vitamin deficiency. 

Vitamin B12 is stable to temperatures up to 250°C (482°F) in acidic or neutral solutions. Dietary B12 deficiency is rare among meat eaters but not in strict vegetarians. The average total body content of vitamin B12 is about 2.5 mg, most of which is in the liver (1 /u,g of Bi2 per gram of hepatic tissue). There is extensive reutilization of cobalamin and an active enterohepatic circulation. The principal disease caused by vitamin B12 deficiency is megaloblastic anemia. Deficiency also causes neurological abnormalities that become irreversible if allowed to persist. 

B. Megaloblastic anemia is caused by a decrease in the synthesis of deoxythymidylate and the purine bases usually caused by a deficiency in either THF or cobalamin or both. This results in decreased DNA synthesis, which results in abnormally large hematopoietic cells created by perturbed cell division and DNA replication and repair. This patient exhibits signs of chronic alcoholism, which often leads to a folate deficiency. This can occur due to poor dietary intake, decreased absorption of folate due to damage of the intestinal brush border cells and resulting conjugase deficiency, and poor renal resorption of folate. 

Causes of megaloblastic anemia Folate and cobalamin deficiency. Patients with folate deficiency have similar hematologic and GI findings but do not have the neurologic symptoms as with cobalamin deficiency. 

Explain why cobalamin deficiency leads to megaloblastic anemia. 

Megaloblastic anemia has two most likely causes, deficiency of folate and deficiency of cobalamin. Often treatment of patients with cobalamin deficiency improves in terms of their hematologic features with treatment with folate but not in their neurologic symptoms. What is the most likely explanation for this explanation ... 

Jean Ann Tonich developed a folate deficiency and is on the verge of devel-j oping a cobalamin (vitamin B12) deficiency as a consequence of prolonged moderately severe malnutrition related to chronic alcoholism. Before folate therapy is started, the physician must ascertain that the megaloblastic anemia is not caused by a pure B12 deficiency or a combined deficiency of folate and B12. 

If folate is given without cobalamin to a B 12-deficient patient, the drug only partially corrects the megaloblastic anemia because it will bypass the methyl-folate trap and provide adequate FH4 coenzyme for the conversion of dUMP to dTMP and for a resurgence of purine synthesis. As a result, normal DNA synthesis, DNA repair, and cell division occur. However, the neurologic syndrome, resulting from hypomethylation in nervous tissue, may progress unless the physician realizes that B12 supplementation is required. In Jean Ann s case, in which the serum B12 concentration was borderline low and in which the dietary history supported the possibility of a B12 deficiency, a combination of folate and B12 supplements is required to avoid this potential therapeutic trap. 

Megaloblastic anemia (pernicious anaemia) results from a deficiency of cobalamin and THF. 

The deficiencies of cystathionine )5-synthase (CBS), sulfite oxidase, and methylenetetrahydrofolate reductase (MTHFR) may all result in central nervous system dysfunction, in particular mental retardation [1-3]. Defects of CBS and sulfite oxidase both cause dislocated lenses of the eyes, but the phenotypes are different otherwise. The manifestations of CBS deficiency, the most common of these disorders, and MTHFR deficiency range from severely affected to asymptomatic patients both may cause vascular occlusion. Deficiency of sulfite oxidase is clinically uniform, but genetically heterogeneous, and functional deficiency of the enzyme can result from several inherited defects of molybdenum cofactor biosynthesis [2, 4]. Hereditary folate malabsorption and defects of cobalamin transport (transcobala-min II deficiency) or cobalamin cofactor biosynthesis (cblC-G diseases) may cause megaloblastic anemia, in addition to CNS dysfunction [3, 5, 6]. 

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