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598 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 599

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coronary restenosis or other adverse cardiovascular outcome. On potentially initiate cancer. On the other hand, the growth of established
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the other hand, an accelerated rate of decrease in stroke mortality has neoplastic clones might be accelerated by additional folate, allowing
been observed in the United States and Canada that coincided with the more rapid tumor progression. The situation is rendered even more
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introduction of folic acid fortification in these countries. The dispa- complex if the potential role of folate in epigenetic regulation of gene
rate designs of these studies makes it difficult to draw firm conclusions expression is considered. Folate is necessary for synthesis of the univer-
regarding the question of whether lowering of plasma homocysteine in sal methyl donor, SAMe, which is required for both cytosine and histone
subjects at risk for cardiovascular disease has any ameliorative or dele- methylation. In this pathway, too, the role of folate theoretically may be
terious effect on outcome. In a meta-analysis of eight randomized trials cancer promoting or cancer protective, depending on whether onco-
involving over 37,000 individuals, the authors concluded that supple- genes or tumor-suppressor genes are silenced by methylation of CpG
mentation with folic acid in various combinations with vitamin B and islands in DNA or by conformational changes in chromatin resulting
12
vitamin B for periods of up to 7.3 years, despite an overall reduction of from histone methylation. The question of a possible effect of increased
6
plasma homocysteine of 22 percent and 25 percent in folic acid fortified folate intake through the use of folic acid supplements on overall and
and non-fortified populations, respectively, there were no significant site-specific cancer incidence was recently examined in a meta-analysis
effects on cardiovascular events, overall cancer, or mortality. Critical of 50,000 individuals. The authors concluded that there was no substan-
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factors might relate to several considerations including the preexisting tial increase or decrease in incidence over a 5-year period of folic acid
degree of vascular damage in relation to the time of the intervention and supplement use. 251
the form and dosage of administered vitamins.
Another potential link between folate deficiency and morbidity risk Therapy, Course, and Prognosis
that relates to hyperhomocysteinemia is the association between ele- Folate, usually in the form of folic acid, 1 to 5 mg/day, is given orally,
vated homocysteine levels and incident dementia or cognitive impair- although 1 mg usually is sufficient. At this dose, anemia usually is cor-
ment without dementia, independent of the vascular complications rected even in patients with malabsorption. A parenteral preparation
of hyperhomocysteinemia. 240,241 The MTHFR polymorphism MTHFR containing 5 mg/mL of folate also is available.
677C→T leads to increased homocysteine levels in subjects with low Treatment for tropical sprue consists of the usual doses of folate,
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folate or cobalamin levels, although controversy exists as to whether plus cobalamin if indicated. To prevent relapse, treatment should be
MTHFR 677C→T contributes to an increased incidence of vascular dis- maintained for at least 2 years. Broad-spectrum antibiotics are helpful
ease. Like folate, cobalamin seems to be important in decreasing the risk adjuncts, although antibiotics alone fail to correct the condition.
of vascular disease. A 1561C→T polymorphism in the gene for glu- Pregnant women must be given at least 400 mcg of folate per day.
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252
tamate carboxypeptidase-II increases serum folate and decreases serum As to the possibility of overlooking cobalamin deficiency resulting from
homocysteine in the homozygote, possibly protecting against vascular folate administration, although pernicious anemia (PA) in women of
disease. 244 childbearing age is rare in whites, this is not the case among persons of
African and Hispanic descent. 253,254 In pregnant women at risk for cobal-
HELLP Syndrome amin deficiency (e.g., vegans or patients with malabsorption), the risk of
Severe folate deficiency reportedly mimics the hemolysis, elevated an associated cobalamin deficiency is easily prevented with vitamin B ,
liver enzymes, low platelets (HELLP) syndrome (preeclampsia with 1 mg given parenterally every 3 months during the pregnancy. 12
liver swelling and abnormal liver function studies in pregnant women; Therapeutic doses of folate partially and temporarily correct the
Chap. 8). In these patients, the diagnosis of severe folate deficiency hematologic abnormalities in cobalamin deficiency, but the neurologic
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can be made based on the presence of anemia and a megaloblastic blood manifestations can progress, with disastrous results. Therefore, both
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film and marrow. Serum and red cell folate, serum cobalamin, homo- folate status and cobalamin status must be evaluated early in the workup
cysteine, and methylmalonic acid levels all should be assayed before of a megaloblastic anemia. If treatment is urgent and the nature of the
treatment is started. The patient should immediately be given high deficiency is unclear, both folate and cobalamin can be given after suit-
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doses of folate plus cobalamin, the latter in case the megaloblastic ane- able specimens have been obtained for assay.
mia actually results from cobalamin deficiency, a possibility rendered Patients who receive low-dose methotrexate therapy as an immu-
more likely in folic acid-fortified populations. A major goal of treatment nosuppressant may develop side effects, the worst of which is hepato-
is preventing preterm delivery of the fetus. toxicity. The incidence of side effects, including hepatotoxicity, has been
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correlated with reduced folate levels. Administration of folic or folinic
Colon Cancer acid can prevent or greatly diminish the major side effects without
A large study of nurses in the United States indicated that supplementa- reducing the therapeutic effect of low-dose methotrexate. Coadminis-
tion with more than 400 mcg of folic acid per day reduces the incidence tration of folic acid together with vitamin B also reduces side-effects
12
of colon cancer by 31 percent. Furthermore, individuals who are without adversely affecting the therapeutic efficacy of the newer multi-
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homozygous for the 677C→T MTHFR mutation also have a decreased targeted antifolate drug, pemetrexed. 257
incidence for colon cancer compared with 677C→T heterozygotes and
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normal controls. Other evidence points to possible deleterious effect
of folic acid on colon cancer incidence. Although only circumstantial, a COBALAMIN DEFICIENCY
recent epidemiologic study reported that after several successive years Etiology and Pathogenesis
of a declining incidence of colorectal cancer in the United States and There are several causes and varying degrees of severity of cobalamin
Canada, there was a significant increase in the rate in both countries depletion and deficiency. From the hematologic standpoint, it is con-
that coincided with and followed the introduction of folic acid fortifi- venient to divide the causes of B deficiency into those that frequently
12
cation. These apparently contradictory observations may be reconcil- lead to megaloblastic anemia and those that usually do not. 64,258
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able because of the several roles of folate on cellular proliferation and Table 41–4 lists disorders that lead to cobalamin deficiency.
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repair as well as on the stage of tumorigenesis. Because folate is criti- Decreased Uptake Caused by Impaired Absorption Cobal-
cal for de novo thymidine synthesis, it plays an important part in DNA amin deficiency most often results from defective absorption, most
repair, thus correcting mutations and DNA strand breaks that could commonly PA, a condition characterized by failure of gastric intrinsic

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