Page 624 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 39 Megaloblastic Anemias 533

(including fatigue, cognitive changes, lower quality-of-life measures, economic status and ethnic diet where cooking and choice of foods
and subtle symptoms of neuropathy) that cannot be directly attrib- vary from region to region. For example, in Benin, central Africa, the
uted to cobalamin deficiency, despite the fact that these very symptoms prevalence of folate deficiency anemia was 20%, and in Zimbabwe,
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are often seen in symptomatic cobalamin deficiency; often this trig- 30% had low folate levels, whereas in Sudan it was nearly 60%. In
gers testing with a serum cobalamin test, and a borderline result that Sri Lanka, one-half of schoolchildren had low-folate status, but less
spontaneously reverts to normal, or minimally fluctuates above or than 1% had folate deficiency in Thailand, which likely relates to the
below the cutoff value, or remains stable without change over many abundant consumption of greens and meats by Thais. Even in the
years generates a new set of problems, including the need to label this United States, before folate fortification of food, about 20% of
entity and thereby make clinical decisions. the population had low-folate status, and in Venezuela, 30% had
Although some experts do not feel obliged to treat, preferring to low-folate status before such fortification. Decreased availability of
wait for overt symptoms, others feel ethically bound to treat even folate-rich foods (in winter, after natural disasters, or during the wet
without overt clinical manifestations; indeed, such clinical manifesta- season in central Africa), poverty, various cultural or ethnic diets
tions can be very subtle and are detected only by sophisticated neu- (consisting of maize, rice, or well-cooked beans and vegetables), and
rophysiologic or imaging studies that are expensive and impractical cooking techniques that destroy food folate, coupled with the anorexia
for routine clinical practice. In support of earlier therapy in this that accompanies chronic illnesses, are just a few of the reasons for
clinical setting, there is compelling clinical evidence that combined rapid development of folate deficiency. 15,22
B-vitamin supplementation to reduce homocysteine can reduce brain In Western countries, food faddism, alcoholism, or unbalanced
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atrophy and both cognitive and clinical decline (see section on slimming diets usually lead to decreased folate intake in young
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Homocysteine and Mild Cognitive Impairment). to middle-aged individuals. Edentulous or infirm persons or
After replenishing potentially depleted cobalamin stores with neglected older adults who are too ill to prepare their meals, as well
parenteral cobalamin therapy, oral supplementation for 4 to 6 months as psychiatric patients, are particularly at risk for nutritional folate
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on and 4 to 6 months off may afford an adequate cobalamin status deficiency (see box on Etiopathophysiologic Classification of Folate
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in most patients as an alternative to continuous therapy. A key Deficiency).
factor is the cost of cobalamin (and the lack of side effects associated Folate fortification of foods in the West has led to widespread
with cobalamin therapy); for example, parenteral cobalamin, which elimination of folate deficiency and related anemia, 182,183 leading to
can be purchased on the Internet for $15 for each 10 mg/10 mL vial, questions of whether testing for folate deficiency is even justified. 184,185
would last a year after replenishing stores. The additional purchase Vigilance must nevertheless be exercised among the elderly who are
of 30-gauge 1 2 -inch insulin U100 syringes for monthly subcutane- still at risk for both folate and cobalamin deficiency. 186–188
ous injection could be less costly than even generic tablets of 1 mg
taken daily.
Pregnancy and Infancy
PATHOGENESIS OF FOLATE DEFICIENCY Pregnancy and lactation are associated with significantly higher
folate requirements (over 400 µg/day) for growth of the fetus,
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Folate deficiency is usually recognized in the course of certain clinical placenta, breast, and other maternal tissues. Folate requirement
presentations that predispose to negative folate balance and subse- increases throughout pregnancy and is maximal near term. There is
quent deficiency. It is instructive therefore to conceptualize cellular also increased urinary loss of folate in pregnancy (about 14 µg/day
folate deficiency as arising from etiologic categories of decreased versus approximately 4.2 µg/day in nonpregnant women) because
supply (i.e., reduced intake, absorption, transport, or use) or increased of a lower renal threshold. Poor preparation for pregnancy, with a
requirement (i.e., metabolic consumption, destruction, or excretion). poorly balanced diet and preexisting multifactorial nutritional anemia
However, in the same patient more than one mechanism may result that remains unaddressed, is a major factor accounting for serious
in net folate deficiency. The precise contribution of one mechanism pregnancy complications and adverse birth outcomes. Therefore
over the other is often not obvious, and specific tests to define each additional folate during pregnancy is required to prevent both preg-
mechanism are not routinely available for clinical use. Thus the clini- nancy complications (preeclampsia, placental abruption or infarc-
cal context is especially important. Megaloblastic manifestations of tions, recurrent miscarriage) and poor pregnancy outcomes (preterm
folate deficiency are discussed within the context of the history and delivery, neural-tube defects [NTDs], congenital heart defects, and
physical examination (discussed later). Cases of neuropathy in adults intrauterine growth retardation). Low-folate status associated with
attributed to folate deficiency are rarely encountered; when they are, short interpregnancy intervals or twin pregnancies also predisposes to
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the possibility of alcoholism with thiamine deficiency must be con- preterm births. All this demand for folate must somehow be met
sidered. In any case, every patient with neuropathy, myelopathy, or by increased folate intake.
psychiatric manifestations associated with megaloblastosis must be However, the vast majority (over 90%) of pregnant women in
investigated in detail to rule out cobalamin deficiency. Gastrointestinal resource-poor countries consume less than the estimated average
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megaloblastosis begets further folate malabsorption, which propagates requirement of folate ; in addition, a substantial number also
a vicious cycle of folate deficiency in the short term and cobalamin consume less than optimum amounts of several other minerals, such
deficiency in the long term. With the exception of drug-induced as iron, and micronutrients, including cobalamin, as noted earlier.
defects or inborn errors of folate metabolism that result in decreased For example, studies on women from groups with low socioeconomic
use of intracellular folates, all causes, irrespective of mechanism, result status from North India 29,30 have estimated that the daily intake of
in reduced net delivery of folates to normal proliferating cells. folic acid ranged between 75 µg and 167 µg, which is far lower than
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the 400 µg/day required to prevent birth defects. This is simple to
remedy. When given daily or even twice weekly, the combination of
Nutritional Causes of Folate Deficiency iron (100 mg elemental iron) and folic acid (0.5 mg) has been shown
to significantly improve several cognitive abilities of schoolgirls in
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The body stores of folate are adequate for only about 4 months India, which renders them better prepared for pregnancy in the
although those with higher folate stores could take longer to become future. This is all the more important because of results from experi-
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frankly deficient. Individuals who are chronically in negative folate mental studies designed to define the influence of gestational folate
balance may only require a brief “nudge”—from superimposition of deficiency on the fetus (discussed later). Thus pregnancy with poor
an associated illness that leads to hemolysis, anorexia, or folate folate intake is the most common cause of megaloblastic anemia in
malabsorption—to “tip” them into frank folate deficiency. The the world.
incidence of folate deficiency varies from country to country and even As noted earlier, the placenta has a large number of folate recep-
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within regions in the same country. This is highly influenced by the tors, which facilitate binding and transport of folates to the