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

and red cell folate levels fall steadily during pregnancy, even in well- neurologic problems may develop in cobalamin-deficient patients
nourished women who are not taking a folic acid supplement. Con- treated with folate alone. High doses of cobalamin may produce a par-
214
versely, hypersegmented neutrophils, usually a reliable clue to early tial response in folate deficiency. 73
megaloblastic anemia, are inconspicuous in early megaloblastic anemia The diagnosis of nontropical sprue rests on (1) the demonstration
of pregnancy. 215 of malabsorption, (2) noninvasive serologic testing including detection
Increased Cell Turnover Because of increased marrow cell turn- of antibodies to gliadin, endomysium, tissue transglutaminase, and
223
over, the folate requirement rises sharply in chronic hemolytic anemia. deamidated gliadin, (3) a jejunal biopsy showing villus atrophy, and
216
During bouts of acute hemolysis that can occur in these anemias, the (4) the response to a gluten-free diet. In 80 percent of patients, a gluten-
marrow may become megaloblastic within days. free diet gradually reverses the functional disorder by correcting folate
Folic acid deficiency may arise in chronic exfoliative dermatitis, malabsorption. 224
217
in which folate losses of 5 to 20 mcg/day may occur. Patients with
psoriasis who are treated with methotrexate have an added reason for Nonhematologic Effects of Folate Deficiency
developing signs of folate deficiency. Pretreating such patients with The hematologic problems associated with folate deficiency have been
folate may prevent these signs without impairing the therapeutic effect recognized for decades. However, folate deficiency has been associated
217
of methotrexate. During hemodialysis, folate is lost in the dialysis with a number of serious disorders not involving the hematopoietic sys-
fluid. 218 tem. Moreover, these disorders occur at folate levels usually regarded
as low normal. They include developmental, neurologic, cardiovascular,
Clinical Features and neoplasic diseases. 225
The clinical picture of folate deficiency includes all the general manifes-
tations of megaloblastic anemia plus the following specific features: (1) Abnormalities of Neural Tube Closure
a history and laboratory studies indicating folate deficiency, (2) absence A close association exists between mild folate deficiency and congenital
of the neurologic signs of cobalamin deficiency (see “Cobalamin Defi- anomalies of the fetus, most notably defects in neural tube closure, but
ciency” below), and (3) a full response to physiologic doses of folate. also abnormalities involving the heart, urinary tract, limbs, and other
226
sites. A portion of the neural tube closure defects appear to be asso-
Laboratory Features ciated with antibodies against folate receptors that may be overcome by
227
The earliest specific indicator of folate deficiency is a low serum or higher folate intake. Mutations and polymorphisms affecting enzymes
plasma folate. Raised plasma levels of homocysteine may precede the of folate metabolism, especially the common 677C→T polymorphism
lowering of plasma folate. However, elevated homocysteine has poor of the MTHFR gene (also designated as MTHFR 677C→T), also pre-
228
specificity as there are several causes of a raised plasma homocysteine. dispose to congenital anomalies. As noted above, this polymorphism
219
Plasma folate follows folate intake closely, so an isolated low serum results in diminished conversion of its substrate methylene FH to
4
folate (less than approximately 3 ng/mL) may simply indicate a drop in methyltetrahydrofolate, supporting the view that it is the role of folate in
5
folate intake over the preceding few days. Similarly, a low plasma folate, methylation through methionine synthesis (see Table 41–1) that is crit-
except in malabsorption, rises quickly on refeeding. ical in embryonic development. Folic acid fortification programs, which
220
A better indicator of the tissue folate status is the red cell folate, were mandated in the United States and Canada in the mid-1990s, have
which remains relatively unchanged while a red cell is circulating and been highly successful as a public health measure in reducing the inci-
thus reflects folate status over the preceding 2 to 3 months. Red cell dence of neural tube defect births by between 20 and 50 percent. 229,230
folate usually is quite low in folate-deficient megaloblastic anemia. How- Cobalamin also plays a significant role as a risk factor for neural
ever, red cell folate also is low in more than 50 percent of patients with tube defects. Levels of TC in normal pregnant women correlate with
100
cobalamin-deficient megaloblastic anemia owing to the poor reten- their likelihood of bearing an infant with a defect in neural tube clo-
tion of methyltetrahydrofolate monoglutamate within the cells; conse- sure. Patients in the lowest quintile of TC concentration are five times
quently, red cell folate cannot be used to distinguish between folate and more likely to give birth to a defective infant as patients in the highest
cobalamin deficiencies. Conversely, red cell folate may be normal in the quintile. Evidence indicates that in populations exposed to folic acid
231
megaloblastic state that occurs, often with little accompanying anemia, fortification, there is an approximately threefold increase in the risk
in rapidly developing folate deficiency (see “Acute Megaloblastic Ane- of neural tube defects in offspring of mothers in the lowest quartile of
mia” below). 221 TC. 232
The dU suppression test has been used in research on pathoge- Several poorly defined neuropsychiatric abnormalities that respond
netic mechanisms in megaloblastic states. It adds little to the clinical to folate therapy have been reported in patients with folate deficiency.
evaluation of a megaloblastic anemia. The test is further discussed in The most convincing associations are with depressive illness. 225,233
“Deoxyuridine Suppression” below.
Vascular Disease
Differential Diagnosis Even a mildly elevated homocysteine level is a major independent risk
Macrocytosis without megaloblastic anemia occurs in alcoholism, liver factor for atherosclerosis and venous thrombosis, possibly because of
disease, hypothyroidism, aplastic anemia, certain forms of myelodyspla- an effect on the vascular endothelium. In folate deficiency, homo-
234
sia, pregnancy, and any condition associated with reticulocytosis (e.g., cysteine levels may rise considerably, resulting in varying degrees of
autoimmune hemolytic anemia). Macrocytosis has also been reported hyperhomocysteinemia. This is true also in cobalamin and pyridoxine
222
among smokers. However, MCV rarely exceeds 110 fL in these condi- deficiencies; consequently, the notion of seeking to ameliorate hyper-
tions, whereas in folate deficiency, uncomplicated by causes of microcy- homocysteinemia and thus diminish the risk of cardiovascular disease
tosis, the MCV is usually over 110 fL. has seemed appealing. However, the effect of lowering homocysteine
A full hematologic response to physiologic doses of folate (i.e., levels by the use of folate, cobalamin, and pyridoxine supplements, on
200 mcg daily) distinguishes folate deficiency from cobalamin defi- the risk of recurrent vascular disease is unclear. Although there is some
235
ciency, in which a response occurs only at pharmacologic doses of folate evidence that such supplements reduce risk, contradictory evidence
(e.g., 5 mg daily). This is not recommended as a diagnostic test because suggests that supplement use may actually increase the risk of in-stent

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