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584 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 585

pteroyldiglutamate, pteroylhexaglutamate). Therapeutic folic acid (pte-
as peripheral neuropathy, spastic paralysis with ataxia (so-called combined roylglutamic acid, abbreviated PteGlu, or F) has one glutamic acid and
system disease of the spinal cord), dementia, psychosis, or some combina- the pteridine ring is not reduced.
tion of these features. “Subtle” cobalamin deficiency, which may manifest as To form a functional compound, folate must be reduced to tetrahy-
neurologic symptoms without anemia, appears to be relatively widespread drofolate (FH ; see Fig. 41–1B). In this reduction, dihydrofolate (FH ) is
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among the elderly. The incidence of gastric cancer is increased by a factor of an intermediate. A single enzyme, FH reductase, catalyzes both F→FH
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two to three in patients with PA. Other causes of cobalamin deficiency are gas- and FH →FH .
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tric resection; stasis of the small intestinal contents as a result of blind loops, The folate family consists largely of FH derivatives bearing a one-
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strictures, or hypomotility; and disease or resection of the terminal ileum, the carbon substituent (symbolized as FH -C). The varieties of FH -C differ
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with regard to the identity of the one-carbon unit and the site of its
site of vitamin B –intrinsic factor complex absorption. Individuals on a vegan attachment to FH . Figure 41–2 shows one-carbon substituents of bio-
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diet can become cobalamin deficient. Cobalamin deficiency is diagnosed by chemical significance and their major interconversions.
measuring the level of either total or TC-bound vitamin in the blood or by These substituents are attached to FH through N ,N , or both
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measuring serum methylmalonic acid, which accumulates in the bloodstream (see Fig. 41–2). Specific enzymes interconvert these various FH deriv-
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in patients with cobalamin deficiency. The cause of cobalamin deficiency was atives through oxidations that require nicotinamide adenine dinucleo-
determined by the Schilling test, a measure of cobalamin absorption, but the tide phosphate (NADP) and reductions that utilize the reduced form of
test is obsolete and no replacement is currently available. In patients with NADP, NADPH. 2
nutritional megaloblastic anemia, folate or cobalamin deficiency as the cause Reduced derivatives of folic acid usually are sensitive to air oxida-
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of the anemia must be determined. If a patient with cobalamin deficiency is tion. An important exception is N -formyl FH , also called citrovorum
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treated with folic acid, the anemia may be corrected but the neurologic abnor- factor, leucovorin, or folinic acid, which, because of its stability, is the
malities persist, progress or may be aggravated. Patients with cobalamin defi- form preferred for clinical use.
ciency usually are treated with parenteral cobalamin but large doses of oral
cobalamin may be used. NUTRITION
Megaloblastic anemia can develop as an acute disorder with rapid devel- Sources
opment of leukopenia and/or thrombocytopenia. Nitrous oxide anesthesia or Folic acid comes from many sources. The richest vegetable sources are
abuse is responsible for some cases of acute megaloblastic anemia. The ane- asparagus, broccoli, endive, spinach, lettuce, and lima beans. Each veg-
mia is rarely also seen in patients with a marginal folate status in intensive etable contains more than 1 mg of folate per 100 g dry weight. The best
care units or severe hemolytic anemia through increased folate demand for fruit sources are oranges, lemons, bananas, strawberries, and melons.
augmented erythropoiesis. The condition resembles an immune cytopenia Folates also are abundant in liver, kidney, yeast, mushrooms, and pea-
nuts. Since the advent of folic acid fortification of the food supply, the
but can be ruled out by examining the marrow, which exhibits a floridly meg- median daily intake of folate from an average American diet is estimated
aloblastic picture. to be 350 mcg. Foods are readily depleted of folate by excessive cook-
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Other causes of megaloblastic anemia include drugs (e.g., hydroxyurea, ing, especially with large amounts of water, discarded before ingestion.
nucleoside analogues) and certain inborn errors of metabolism. Of the
inherited conditions, TC deficiency is singled out because it causes a severe Daily Requirements
megaloblastic anemia in infants who respond completely to high-dose cobal- In the normal adult, the minimum daily requirement for folic acid
amin. Irreversible neurologic complications supervene if the deficiency is not is approximately 50 mcg. The average diet contains many times this
detected in time. Megaloblastic-like morphologic features of varying degree amount, but some of the folate may be unavailable. Accordingly, the
are seen in the myelodysplastic syndromes, and in acute leukemia of the ery- officially recommended dietary allowance of food folate for an adult is
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throleukemia type. Megaloblastic anemia seen in association with refractory 0.4 mg. This figure is derived through considerations of the nutrient
requirements to satisfy the needs of 97 to 98 percent of healthy indi-
anemia with excess sideroblasts occasionally responds to very high doses of viduals and the relative differences in absorption and bioavailability
pyridoxine. between dietary folate and the more bioavailable synthetic folic acid.
One microgram of food folate is the dietary equivalent of 0.6 mcg folic
acid added to food. The body is thought to contain approximately 5 mg
FOLATE of folate. When folate intake is reduced to 5 mcg/day, megaloblastic
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anemia develops in approximately 4 months. 5
Folate and cobalamin (vitamin B ) play key roles in the metabolism of Folic acid requirements increase in hemolytic anemia, leukemia,
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all cells, particularly proliferating cells. and other malignant diseases, in alcoholism and during growth; in
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pregnancy and during lactation requirements increase threefold to six-
CHEMISTRY fold. Adequate folate supplies are particularly important in pregnant
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The group of compounds referred to as folates consists of folic acid and and lactating women, in whom the recommended daily allowance is
increased to 600 and 500 mcg/day, respectively, to meet requirements.
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its various derivatives. Folic acid (pteroylglutamic acid) is composed of
a pteridine moeity, a p-aminobenzoate residue, and an L-glutamic acid
residue (Fig. 41–1A). The first two together are called pteroic acid. In METABOLISM
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nature, folates occur largely as conjugates in which multiple glutamic Folate-Dependent Enzymes
acids are linked by peptide bonds involving their γ-carboxyl groups FH is an intermediate in reactions involving the transfer of one-carbon
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(Fig. 41–1B). Additionally, the naturally occurring polyglutamated units from a donor to an acceptor. Table 41–1 summarizes the metabolic
folates are reduced in the 5, 6, 7, and 8 positions of the pteridine systems of animal tissues known to require folic acid coenzymes.
ring (as described below, Fig. 41–1B). Conjugates are named accord- One-carbon units enter the folate pool principally via the serine
ing to the length of the glutamate chain (e.g., pteroylmonoglutamate, hydroxymethyltransferase (SHMT) reaction which requires pyridoxal

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