Page 635 - Hematology_ Basic Principles and Practice ( PDFDrive )

544 Part V Red Blood Cells

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increased incidence of fractures, increased small-vessel cerebrovas- improvement in cognition by such therapy among those with mild
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cular disease–related strokes, 290,291 dementia, and Alzheimer disease. 292 cognitive impairment. This is consistent with another randomized
Raised maternal plasma levels of homocysteine primarily from controlled trial (in a region without folate fortification of food) that
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cobalamin and folate deficiency are associated with various pregnancy demonstrated beneficial effects of folates on cognition over 3 years.
complications. These include preeclampsia and spontaneous preg- A randomized controlled trial of oral folic acid and cobalamin supple-
nancy loss, 253,293–296 placental abruption, 293,295,297 recurrent pregnancy mentation to prevent cognitive decline in community-dwelling older
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loss, 293,295,298 fetal growth restriction, 294,295 preterm birth, and still- adults with depressive symptoms concluded that long-term supple-
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birth. The adverse outcomes for the baby include NTDs and mentation of daily oral 400 µg folic acid plus 100 µg cobalamin
congenital malformations. 294,295 Normalization of maternal homocys- promotes improvement in cognitive functioning after 24 months,
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teine level with cobalamin and folate and improvement of these particularly in immediate and delayed memory performance.
pregnancy outcomes for some complications 295,298 indicate that some While awaiting larger confirmatory trials, these studies suggest that
of these risks can be reduced with good nutrition. homocysteine-lowering therapy can slow down the accelerated rate
of brain atrophy that is found with mild cognitive impairment.
Homocysteine-Lowering Trials and Primary Versus
Secondary Prevention Homocysteine Lowering and the Progression of
Diabetic Nephropathy
Most homocysteine-lowering intervention trials have been under-
powered; they have looked at populations in which the serum Even though patients with diabetic nephropathy have elevated levels
homocysteine level has been borderline elevated rather than being of homocysteine, attempts to use a combination of high doses of oral
elevated to the higher level (over 20 µM); and they have only had a B vitamins (folic acid, pyridoxine, cobalamin) to reduce homocyste-
follow-up of less than 5 years. Moreover, many of the intervention ine concentrations have now been shown to worsen their kidney
trials have been compromised by the advent of food fortification with disease and place them at greater risk for dying from serious vascular
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folate or by enrolled patients who were consuming multivitamins events. Hence there is no justification for using high-dose B vita-
containing folic acid. A recent review of this “homocysteine contro- mins in this setting or outside the framework of properly conducted
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versy” has noted that the duration of follow-up in most studies has clinical research.
been too short (and likely dictated by the dramatic results from the
use of antihypertensives and statins, which required only short
follow-up to demonstrate positive effects). The point made is that FOLATE FORTIFICATION OF FOOD AND THE
such expectations are unrealistic for atherosclerosis because the ath- RISK FOR CANCER
erosclerotic plaque commonly takes 30 to 40 years to develop into a
full-blown clinical event. Moreover, there is a distinct difference Three large prospective studies 304–306 suggest that long-term folate
between primary prevention of the earliest stages of a disease process intake actually decreases the risk for initiation or early development of
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and attempts to intervene after demonstrated vascular damage (sec- colorectal cancer ; in addition, there appears to be a diminished to
ondary prevention). (Indeed, it was only longer follow-up for 10 to nonexistent influence on (precancerous) adenomas. A recent meta-
15 years that established the primacy of blood glucose control in analysis of 13 randomized trials that compared the incidence of
management of patients with diabetes.) cancer of all types in ~50,000 individuals led to the conclusion that
Despite the failure of homocysteine-lowering therapy in several folic acid supplementation does not significantly increase or decrease
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trials related to secondary prevention of atherosclerotic disease, this the risk of cancer over a 5-year treatment period. Collectively, these
has not eliminated the possibility of a beneficial role of lowering papers provide reassurance that the fortification of food to prevent
homocysteine in primary prevention of diseases. Indeed, clinical trials NTDs in women of childbearing age has not led to harm among the
that used folates have suggested that folate also has a role in reduction remaining “nontargeted” population of adults. There also could be
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in strokes, reduction in the rate of cognitive decline among healthy long-term benefits in primary prevention (see Table 39.5).
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older adults, and a reduction in age-related (sensorineural) hearing
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loss. There is also Grade A evidence from randomized controlled
trials for a role of folate in combination with cobalamin for reduction FUTURE DIRECTIONS
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of hip fractures, subclinical atherosclerosis, and stroke preven-
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tion. In addition, the value of a triple combination of folate, pyri- In this age of spiraling costs for health care delivery, and the ongoing
doxine, and cobalamin to reduce age-related macular degeneration in debate on ways to reduce these costs, few instances in internal medi-
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women was shown by a relatively small study (see Table 39.5). cine and hematology yield more satisfying dividends than diagnosing
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Despite support by an observational epidemiology study, larger and treating cobalamin and folate deficiency using generic vitamins
studies are required. 302 that are “dirt-cheap”—costing only a few cents a day. These condi-
By inference, in addition to clinical presentation with nutritional tions are devastating when undiagnosed or misdiagnosed or when
anemia, patients can also present with any of these additional clinical cobalamin deficiency is treated with folate alone. Recognition of
conditions, as well as a variety of pregnancy complications with or various populations at risk and the clinical scenarios in which folate
without poor pregnancy outcomes (affecting the newborn), when they and cobalamin deficiency are likely to be present, and the availability
have long-standing untreated hyperhomocysteinemia. of sensitive and specific tests, should reduce uncertainty in diagnosis.
The studies on folate supplementation during pregnancy that identi-
fied new folate-responsive NTDs and neurocristopathies are a para-
Homocysteine and Mild Cognitive Impairment digm for identification of hitherto unrecognized roles for other
nutrients in human development. The significant impact of supple-
All inherited diseases involving a severe elevation of homocysteine are mental folates in relieving human suffering consonant with reducing
associated with cognitive deficit and poorer neurocognitive perfor- costs for intensive and long-term care of infants with prematurity or
mance. Accelerated brain atrophy is often a characteristic among NTDs is a major achievement and an outstanding example of cost-
those with mild cognitive impairment who then go on to develop effective preventive medicine. Other recent advances from random-
Alzheimer disease. Now a randomized controlled trial from the ized controlled studies indicate beneficial effects of supplemental
United Kingdom, where folate fortification of food is not mandatory, folate and cobalamin in the prevention of diverse diseases. The
among elderly patients with mild cognitive impairment has identified structural characterization of folate receptors offers unprecedented
that lowering of homocysteine level by B vitamins over 2 years did potential to develop a new generation of antifolates that can occupy
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slow the rate of brain atrophy by almost 30%. There was also the receptor-binding pocket and thereby starve cancer cells that