Page 634 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 39 Megaloblastic Anemias 543

existing program have proven to be contextually acceptable and Caveats Related to the Use of Laboratory Tests in Developing Countries
efficacious in improving folate and cobalamin (in addition to vitamin (see Table 39.4)
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A and iron) status in Himalayan villages of India. Such programs
are critically important to the health of both women and their chil- Masking of Nutritional Folate Deficiency by Associated Cobalamin
dren (discussed later). Table 39.8 summarizes conditions that warrant Deficiency and/or Malaria
routine folate or cobalamin supplementation. In developing countries, the majority of the population is either veg-
Following food fortification, the total folate intake of most U.S. etarian or near-vegetarian; these diets are monotonous, low in fresh
children 1 to 13 years of age does meet the estimated average require- vegetables, fruits, and in animal-source foods. Such a diet predisposes
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ment, but children given supplements are at risk for exceeding the to a combination of nutritional cobalamin and folate (and iron) defi-
tolerable upper intake level; this remains a concern because the long- ciencies, particularly among women and children. With cobalamin
term effects are unknown. Whereas folic acid supplements consumed deficiency, the failure in utilization of intracellular folate for one-carbon
in excess of 1 mg/day can mask hematologic symptoms of cobalamin metabolism, results in folate leaking out of cells, thereby raising the
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deficiency, it has been found that 94% of U.S. adults who do not serum folate. What this means is that the presence of cobalamin
consume supplements, or who consume less than 400 µg of folic acid deficiency will consistently mask the coexistence of folate deficiency
whenever there is (undue) over-reliance by the clinician in using the
per day from supplements, do not exceed the upper limit in intake biomarker of the serum folate level as a gold standard to diagnose
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for folic acid. There is also no evidence that taking high-folate folate deficiency. This is a surprisingly common error in the contem-
supplements or consuming large amounts of folate-fortified foods porary literature—a fact that inadvertently downplays (with disastrous
places individuals at risk for exacerbating any underlying cobalamin consequences) the seriousness of folate deficiency among millions of
deficiency. 280 these particularly vulnerable women and children. Added to this is the
Is there a role for cobalamin fortification of foods? A strong case fact that in many such regions, there is also the scourge of endemic
can be made to consider the fortification of flour (or other contextu- malaria with its propensity for hemolysis (and release of the 30-fold
ally relevant food vehicle in developing countries) with small amounts higher red cell folate into plasma). Once again, in such settings, the
of cobalamin to serve the majority of the population whose dietary serum folate concentration will yield normal-to-high values, predictably
underestimate the tissue folate status, and serve to mask the diagnosis
intake of animal-source foods is poor. However, this type of fortified of mild-to-moderate folate deficiency in these patients who desperately
food will not benefit those (in developed countries) with food- require folate to support compensatory hematopoiesis and for growth
cobalamin malabsorption; these individuals usually need the equiva- and development (See Table 39.4 and Summary of the Clinical Useful-
lent of 1 mg of oral cobalamin daily, an amount that could not ness of Tests for Cobalamin and Folate Deficiencies).
possibly be achieved by the small amount of cobalamin added to The only solution to correctly identifying whether these patients
fortify foods. Other issues related to cobalamin analogue formation are at risk for nutritional folate deficiency is to obtain a good dietary
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upon exposure to light or mixing with other food ingredients and history and identify those at risk for nutritional insufficiency. (Other
other stability issues during storage have not been resolved; hence this formal assessment includes use of 24-h food recall, estimated/weighed
topic remains a work in progress. record, or locally validated food-frequency questionnaires to evaluate
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Indeed, knowledge
the quality and quantity of nutrients consumed.)
Immigrants from developing countries often continue to consume of dietary folate and cobalamin intake should always trump the results
their native diet (which is usually low in animal-source foods) after of conventional blood tests for folate deficiency, which are flawed in
resettling in the United States; this was earlier documented among this clinical setting. From the practical standpoint, all individuals at
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Indian physician trainees in New York. Recently, when two-thirds risk for nutritional anemia caused by deficiency of iron, folate, and
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of Bhutanese refugees were diagnosed to have cobalamin deficiency, cobalamin (including both adults 150 and children ) should be given
this prompted the Centers for Disease Control & Prevention to rec- prophylactic oral cobalamin, folate (and iron) replacement; and in
ommend supplemental cobalamin together with nutrition advice. 282 malarious zones, these should be combined with antimalarial drugs
Although Plasmodium falciparum possesses two folate transporter and insecticide-treated bed nets.
proteins that can facilitate membrane transport of folic acid, folinic Overreliance on Laboratory Data at the Expense of Clinical
acid, the folate precursor p-amino benzoic acid (pABA), and the Information—A Case Study
human folate catabolite pABAG n , rescue experiments on parasites in The majority of women and children in developing countries suffer from
vitro show that pABA was the only effective salvage substrate at combined nutritional iron, cobalamin, and folate deficiency—the three
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physiologic levels. Recently, the safety of using low-dose folic acid key causes of nutritional anemia. There are often additional congenital
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(1 mg/day) in 467 pregnant women with malaria was affirmed ; or acquired causes for hemolytic anemia in a single individual, such
however, high-dose folic acid (5 mg/day) will allow for resistance, as malaria, bacteremia, hemoglobinopathy, or glucose-6-phosphate
with potential adverse outcomes in children. 285–287 dehydrogenase deficiency. There is therefore potential for a clinician to
make several critical interrelated errors: First, despite dire poverty and
near-famine conditions, mere inattention and failure to obtain a good
HYPERHOMOCYSTEINEMIA dietary assessment of (deficient) iron, cobalamin, and folate intake in
these vulnerable patients will lead to an underestimation of the extent of
deficiency of these nutrients. Second, this can be coupled with a lack
Normally homocysteine is metabolized by the methylation reaction of appreciation of the potential for one deficient micronutrient to have
(discussed earlier) and by a second trans-sulfuration pathway, which on the blood test result of another. For example, cobalamin deficiency
essentially eliminates homocysteine as a potential source of methio- or hemolysis will invariably raise the serum folate level and lead to
nine. In the trans-sulfuration pathway, cystathionine β-synthase cata- an underestimation (and misdiagnosis) of the fact of tissue folate
lyzes the condensation of homocysteine with serine in the presence deficiency. Third, a failure to replace all three deficient nutrients in a
of pyridoxyl phosphate (vitamin B 6 ) to form cystathionine, which is given individual will invariably lead to a failure in restoring hemoglobin
values to optimum; but then again, replacing one or even two out of
further cleaved by a vitamin B 6 –dependent γ-cystathionase to form three key missing nutrients cannot possibly be expected to secure a
cysteine and α-ketobutyrate. The cysteine that is formed can be used complete resolution of anemia.
for synthesis of the antioxidant glutathione, a key component that
defends against oxidative stress within cells. In some tissues like liver,
homocysteine can also be remethylated to methionine by the transfer
of a one-carbon moiety from betaine by the enzyme, homocysteine Chronic hyperhomocysteinemia is established as a major risk
methyltransferase, which is restricted to the liver and kidney. Thus factor in occlusive vascular diseases. These include myocardial infarc-
the level of plasma homocysteine depends on genetically regulated tions from coronary atherosclerosis, extracranial carotid artery steno-
levels of essential enzymes in one-carbon metabolism, the intake of sis, vascular disease in end-stage renal failure, thromboangiitis
folic acid or food folates, vitamin B 6, cobalamin, and other acquired obliterans, aortic atherosclerosis, venous thromboembolism, placental
conditions (dehydration, renal dysfunction, antifolates, and nitrous abruption or infarction, and recurrent stillbirths. Hyperhomocyste-
oxide). inemia is also associated with reduced bone mineral density and