Cobalamin deficiency anemia

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 most likely reason for cobalamin deficiency is pernicious anemia (failure to absorb vitamin B 2 in the absence of intrinsic factor from parietal cells). Vitamin Bjj absorption also decreases with aging and in individuals with chronic pancreatitis. Less common reasons for Bjj deficiency include a long-term completely vegetarian diet (plants don t contain vitamin Bjj) and infection with Diphyllobothrium latum, a parasite found in raw fish. Excess vitamin B,2 is stored in the body, so deficiencies develop slowly. 

Contraindications Folic acid deficiency anemia, hereditary optic nerve atrophy, history of allergy to cobalamins... 

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. 

Stopeck A Links between Helicobacter pylori infection, cobalamin deficiency, and pernicious anemia. Arch Int Med 160 1229-1230,2000. 

A large number of disorders are associated with cobalamin deficiency in infancy or childhood. Of these, the most commonly encountered is the Imerslund-Graesbeck syndrome, a condition that is characterized by inability to absorb vitamin B,2, with or without IF, and proteinuria. It appears to be due to an inability of intestinal mucosa to absorb the vitamin B,2 IF complex. The second most common of these is congenital deficiency of gastric secretion of IF. Very rarely, congenital deficiency of vitamin B12 in a breast-fed infant is due to deficiency of vitamin B12 in maternal breast milk as a result of unrecognized pernicious anemia in the mother. This is rare because most women with undiagnosed and untreated pernicious anemia are infertile. Additionally, there are some rare methylmalonic acidemias (acidurias) caused by inborn errors in homocysteine and methionine metabolism that are responsible for disorders in vitamin B status. ... 

J. Lindenbaum, E. B. Healton, D. G. Savage, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. New England Journal of Medicine 318,1720 (1988). 

Other potentially useful tests include antibody testing and serum gastrin levels. Positive anti-intrinsic factor antibodies may be present in approximately half of patients with pernicious anemia, but is highly specific for the disease. Additionally, an estimated 85% of patients have anti-parietal cell antibodies, but they are nonspecific, as 3% to 10% of healthy patients have these antibodies. Fasting serum gastrin levels are elevated in more than 70% of patients with cobalamin deficiency and may be useful in assessing patients with borderline... 

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 ... 

Cobalamln Cobalamin or vitamin Bj2 is another vitamin required for the metabolism of amino acids, fatty acids, nucleic acids, and carbohydrates. Cobalamin deficiency can cause severe and irreversible damage in the brain, nervous, cardiovascular, and hematopoietic (pernicious anemia) systems [4]. Animals, plants, and fungi do not synthesize vitamin Bj2, which can only be produced by some microorganisms. To date, the best cobalamin producer is Propionibacterium freudenreichii, which is currently applied for industrial production. 

The most frequent cause of cobalamin deficiency is insufficient absorption due to a lack of Intrinsic Factor. This condition is more generally known as pernicious anemia and is caused by the occurrence of autoantibodies against parietal cells and Intrinsic Factor, blocking its capacity to bind cobalamin and preventing its absorption. Less frequent causes are abnormal intestinal flora, partial or total gastrectomy, tropical sprue, fish tapeworm infestation, and the congenital Intrinsic Factor abnormality and Intrinsic Factor receptor dysfunction (Imerslund-Grasbeck disease). 

This partially explains the dramatic pro-folate effect of methionine seen in patients with pernicious anemia and perfused livers of cobalamin deficient animals (Herbert and Sullivan, 1963 ... 

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... 

Cobalamine can only be resorbed in the small intestine when the gastric mucosa secretes what is known as intrinsic factor—a glycoprotein that binds cobalamine (the extrinsic factor) and thereby protects it from degradation. In the blood, the vitamin is bound to a special protein known as trans-cobalamin. The liver is able to store vitamin Bi2 in amounts suf cient to last for several months. Vitamin B12 deficiency is usually due to an absence of intrinsic factor and the resulting resorption disturbance. This leads to a disturbance in blood formation known as pernicious anemia. 

Strict vegetarian diet or after diseases affecting cobalamin absorption. The main effects of vitamin deficiency are pernicious anemia, macrocytosis, and neurological problems. A particularity of this vitamin is that it can be stored especially in the liver and kidneys. 

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. 

Cyanocobalamin and the derivative hydroxo-cobalamin, given IM or deep subcutaneously, are indicated for treating vitamin B12 deficiency. Only in strict vegetarians oral preparations may be effective. Oral preparations with added intrinsic factor mostly are not reliably in patients with pernicious anemia. More than half the dose of cyanocobalamin injected is excreted in the urine within 48 hours and the therapeutic advantages of doses higher than 100 pg are questionable because of this rapid eiimination. As... 

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... 

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. 

Methylmalonyl-CoA mutase is a cobalamin-linked enzyme of mitochondria that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. A reduction of this enzyme due to vitamin B12 deficiency will result in a metabolic block with the urinary excretion of methylmalonic acid, and the measurement of this metabolite has been used to confirm a deficiency of vitamin B12. The test has also been useful in investigating rare abnormalities of this enzyme that result in the excretion of methylmalonic acid in the presence of adequate vitamin B12. Given an oral loading dose of valine or isoleucine will increase the urinary excretion of methylmalonic acid in patients with a vitamin B12 deficiency (G4). However, Chanarin and his colleagues (CIO) found that one-quarter of their patients with pernicious anemia excreted a normal concentration of methylmalonic acid even after a loading dose of valine. Normal subjects excrete up to 15 mg of methylmalonic acid in their urine over a 24-hour period (Cll). 

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... 

Regulation of homocysteine metabolism appears to be especially important in the central nervous system, presumably because of the critical role of methyl transfer reactions in the production of neurotransmitters and other methylated products. It has been known for decades that mental retardation is a feature of the genetic diseases, such as CBS deficiency, that cause severe hyperhomocysteinemia and ho-mocystinuria. Impaired cognitive function is also seen in pernicious anemia, which causes hyperhomocysteinemia due to deficiency of cobalamin (see Chapter 28). Hyperhomocysteinemia also may be linked to depression, schizophrenia, multiple sclerosis, and Alzheimer s disease. The molecular mechanisms underlying these clinical associations have not yet been delineated. 

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. 

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