Vitamin BI2 deficiency

C. The only effective treatment of pernicious anemia is supplementation of vitamin B12.It is important to determine whether megaloblastic anemia is from a deficiency of folic acid or vitamin B12. Treatment of vitamin Bi2-deficient anemia with folic acid may result in neurological damage if vitamin Bi2 is not adequately supplemented. 

Contraindications Pernicious anemia, other megaloblastic anemias secondary to vitamin Bi2 deficiency... 

Bi2 are only about 2 meg, it would take about 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if Bi2 absorption were stopped. Vitamin B12 in physiologic amounts is absorbed only after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa. Intrinsic factor combines with the vitamin Bi2 that is liberated from dietary sources in the stomach and duodenum, and the intrinsic factor-vitamin Bi2 complex is subsequently absorbed in the distal ileum by a highly selective receptor-mediated transport system. Vitamin Bi2 deficiency in humans most often results from malabsorption of vitamin B12 due either to lack of intrinsic factor or to loss or malfunction of the specific absorptive mechanism in the distal ileum. Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products. 

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... 

Enzymatic reactions that use folates. Section 1 shows the vitamin B 12-dependent reaction that allows most dietary folates to enter the tetrahydrofolate cofactor pool and becomes the "folate trap" in vitamin Bi2 deficiency. Section 2 shows the dTMP cycle. Section 3 shows the pathway by which folate enters the tetrahydrofolate cofactor pool. Double arrows indicate pathways with more than one intermediate step. 

B16. Bjokenheim, B., Optic neuropathy caused by vitamin BI2 deficiency in carriers of the fish tapeworm Diphyllobothrium latum. Lancet 1, 688-690 (1966). 

Small Intestinal (SI) Bacterial Overgrowth Pancreatic Insueeiciency Lactase Deeiciency Vitamin BI2 Deficiency/Pernicious Anemia... 

Macrocytic anemias are characterized by increased mean corpuscular volume (110 to 140 fL). One of the earliest and most specific indications of macrocytic anemia is hypersegmented polymorphonuclear leukocytes on the peripheral blood smear. Vitamin Bj2 and folate concentrations can be measured to differentiate between the two deficiency anemias. A vitamin Bj2 value of less than 150 pg/mL, together with appropriate peripheral smear and clinical symptoms, is diagnostic of vitamin Bi2-deficiency anemia. A decreased RBC folate concentration (less than 150 ng/mL) appears to be a better indicator of folate-deficiency anemia than a decreased serum folate concentration (less than 3 ng/mL). 

As a result of the reduced activity of the mutase in vitamin B12 deficiency, there is an accumulation of methyhnalonyl CoA, some of which is hydrolyzed to yield methylmalonic acid, which is excreted in the urine. As discussed in Section 10.10.3, this can be exploited as a means of assessing vitamin B12 nutritional status. There may also be some general metabolic acidosis, which has been attributed to depletion of CoA because of the accumulation of methyl-malonyl CoA. However, vitamin B12 deficiency seems to result in increased synthesis of CoA to maintain normal pools of metabolically useable coenzyme. Unlike coenzyme A and acetyl CoA, neither methylmalonyl CoA nor propionyl CoA (which also accumulates in vitamin B12 deficiency) inhibits pantothenate kinase (Section 12.2.1). Thus, as CoA is sequestered in these metabolic intermediates, there is relief of feedback inhibition of its de novo synthesis. At the same time, CoA may be spared by the formation of short-chain fatty acyl carnitine derivatives (Section 14.1.1), which are excreted in increased amounts in vitamin B12 deficiency. In vitamin Bi2-deficient rats, the urinary excretion of acyl carnitine increases from 10 to 11 nmol per day to 120nmolper day (Brass etal., 1990). 

Although the FIGLU test depends on folate nutritional status, the metabolism of histidine wUl also be impaired and a positive result obtained, in vitamin B12 deficiency, because of the secondary deficiency of folate (Section 10.3.4.1). About 60% of vitamin Bi2-deficient subjects show increased FIGLU excretion after a histidine load. 

Pernicious anemia is the megaloblastic anemia due specifically to vitamin Bi2 deficiency, in which there is also spineil cord degeneration and peripheral neuropathy. It is a disease of later life. Only about 10% of patients are under age 40 by the age of 60, about 1% of the population is affected, rising to 2% to 5% of people over age 65, as a result of atrophic gastritis and thus impaired absorption of vitamin B12 (Section 10.7.1). 

The data in Table 9.2 concern a study in rats. The animals were raised on nutritionally complete diets or vitamin Bi2-deficient diets for 3 months. Then urine was collected over the course of a day and used for analysis of metabolites related to folate and vitamin B12 (FIGLU and methylmalonic acid). The data show that B12 deficiency induces a dramatic increase in urinary FIGLU. Rats do not require a... 

Higginbottom, M. C., Sweetman, L., and Nyhan, W. L. (1978). A syndrome of methylmalonic aciduria, homocysteinuria, megaloblastic anemia, and neurological abnormalities in a vitamin Bi2-deficient breast-fed infant of a strid vegetarian. N. Engl. J. Med. 299, 317-323. 

Akesson, B., Fehling, C., and Jagerstad, M. (1979). Lipid composition and metabolism in liver and brain of vitamin Bi2-deficient rat sucklings. Br.. Nutr. 41, 263-274. 

Isolated nutritional deficiencies. Iron, folate, or vitamin Bi2 deficiency may manifest as anemia, which may be mild vitamin K deficiency as a bleeding tendency and vitamin D deficiency as bone disease. They are reflected by a variety of signs and symptoms (glossitis, pallor, dermatitis, petechiae, bruising, hematuria, muscle or bone pain, or neurological abnormalities). 

Because all vitamins are essential, it is difficult to state that one vitamin is more important than another. Nevertheless, folic acid, with its coenzyme role in purine biosynthesis, can be considered crucial for some of the cells most fundamental biochemistry, cell division. This vitamin is intimately tied to vitamin (cobalamin), which has made estimating its DRIs difficult. Also, conditions that can cause a folic acid deficiency also can result in a vitamin Bi2 deficiency. 

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. 

Patients have been described who have a vitamin Bi2 deficiency that is not correctable by IF. In the Schilling test with or without added IF, these patients have a low urinary output of radioactivity. This finding could be due to a deficiency or defect in the ileal receptor protein. More commonly, it occurs when there is an acquired ileal defect such as a bacterial overgrowth (blind loop syndrome) or tropical sprue. 

Pernicious anemia. Purine biosynthesis is impaired by vitamin Bi2 deficiency. Why How might fatty acid and amino add metabolism also be affected by a vitamin deficiency ... 

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