Folate deficiency is usually the result of inadequate dietary intake, sometimes complicated by increased metabolic demands. Although folate is present in nearly all foods, it is destroyed by 10 to 15 minutes of cooking, and as a result folate stores are marginal in a surprising number of healthy persons. The risk of overt folate deficiency is highest in those with a poor diet (the economically deprived, the indigent, and the elderly) or those with increased metabolic needs (pregnant women and patients with chronic hemolytic anemias, such as sickle cell disease).
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Deficiency may also stem from problems with absorption or metabolism. Food folates are predominantly in polyglutamate form and must be split into monoglutamates for absorption, a conversion that is inhibited by acidic foods and substances found in beans and other legumes. Some drugs, such as phenytoin (dilantin), also interfere with folate absorption, whereas others, such as methotrexate, inhibit folate metabolism. Malabsorptive disorders, such as celiac disease and tropical sprue, that affect the upper third of the small intestine where folate is absorbed, may also impair folate uptake.
The metabolism and functions of folate are complex. Here it is sufficient to note that its conversion within cells from dihydrofolate to tetrahydrofolate by dihydrofolate reductase is particularly important. Tetrahydrofolate acts as an acceptor and donor of one-carbon units in several reactions that are required for the synthesis of deoxythymidine monophosphate (dTMP). If intracellular stores of folate fall, insufficient dTMP is synthesized and DNA replication is blocked, leading to megaloblastic anemia.
Clinical Features. The onset of the anemia of folate deficiency is insidious, being associated with nonspecific symptoms such as weakness and easy fatigability. The clinical picture may be complicated by the coexistent deficiency of other vitamins, especially in alcoholics. Because the cells lining the gastrointestinal tract, like the hematopoietic system, turn over rapidly, symptoms referable to the alimentary tract, such as sore tongue, are common. Unlike in vitamin B12 deficiency (described later), neurologic abnormalities do not occur.
The diagnosis of a megaloblastic anemia is readily made from the examination of smears of peripheral blood and bone marrow. The anemia of folate deficiency is best distinguished from that of vitamin B12 deficiency by measuring serum and red cell folate and vitamin B12 levels.
Vitamin B12 is widely present in foods, is resistant to cooking and boiling, and is even synthesized by gut flora. Thus, unlike folate, vitamin B12 deficiency is virtually never caused by inadequate intake except in vegetarians who scrupulously avoid milk and eggs. Instead, deficiencies typically arise from some abnormality that interferes with vitamin B12 absorption, a complex process involving the following steps: 1.
Peptic digestion releases dietary vitamin B12, allowing it to bind a salivary protein called haptocorrin.
2.
On entering the duodenum, haptocorrin–B12 complexes are processed by pancreatic proteases; this releases B12, which attaches to intrinsic factor secreted from the parietal cells of the gastric fundic mucosa.
3.
The intrinsic factor–B12 complexes pass to the distal ileum and attach to cubilin, a receptor for intrinsic factor, and are taken up into enterocytes.
4.
The absorbed vitamin B12 is transferred across the basolateral membranes of enterocytes to plasma transcobalamin, which delivers vitamin B12 to the liver and other cells of the body.