CO Nutrition and Health

g of this amount is storage iron. The total iron requirement during the entire
course of pregnancy averages | g and, therefore, exceeds the amount of
storage iron in most women. However, an increase in efficiency of dietary
iron absorption compensates in part for the limited iron stores. Most of the
additional iron is needed for growth of the fetus and placenta during the last
half of pregnancy (Bothwell et al. 1979).

Even with the normal adaptive increase in iron absorption that takes place
during pregnancy, iron stores may become depleted. For this reason,
clinicians commonly recommend an iron supplement that provides the
equivalent of about 30 mg of elemental iron or more per day during the last
half of pregnancy. After delivery, the iron requirement of the mother is
temporarily reduced below normal as the expanded mass of red cells
decreases to baseline levels.

Mild iron deficiency in the pregnant woman generally has no detectable
effect on hemoglobin concentration in the newborn. However, the severe

_iron deficiency anemia seen in pregnant women in some developing coun-
tries can cause decreased placental weight and birth weight as well as
anemia in the newborn (Singla et al. 1978).

Men and Postmenopausal Women. Normally, iron stores increase through-
out adult life in men and after menopause in women (Cook, Finch, and
Smith 1976), so overt nutritional iron deficiency rarely develops in these
groups. Among older persons, anemia is more commonly associated with
chronic diseases, inflammation, and infections than with iron deficiency.
However, factors that can predispose these groups to iron deficiency ane-
mia include frequent blood donations (three or more times a year) and
blood losses due to chronic aspirin ingestion, bleeding ulcers, and colorec-
tal cancers.

Frequent aspirin consumption impairs blood coagulation and leads to
blood loss from the intestine, usually in minute amounts that can be
detected only by sensitive tests. For example, one study found that 300 mg
of aspirin taken three times a day for a week increased intestinal blood loss
to 5 ml/day (which averages several times normal menstrual losses) from a
normal average of 0.5 ml/day (Pierson et al. 1961).

When there is no known basis for iron deficiency anemia, lesions such as a
peptic ulcer or carcinoma may cause chronic and inapparent blood loss
from the intestine. Parasitic infestation, particularly with hookworm,-com-
monly causes inapparent intestinal blood loss in some developing coun-
tries, but is relatively rare in the United States. /

476
Anemia @|

Consequences of Iron Deficiency

The manifestations of iron deficiency can be subtle and depend on the
relative severity of functional impairment caused by reduced levels of the
“essential” iron compounds (Dallman 1982). These manifestations are
related to the effects of iron deficiency on other tissues, to the resultant
anemia, or to a combination of the two (Dallman 1986). One difficulty in
interpreting studies in this area is that the effects of impaired iron status
may differ among iron-deficient individuals who are—or are not—anemic.

Work Performance. Studies in humans as well as in rats show that iron
deficiency causes a substantial reduction in work capacity, particularly
when the concentration of hemoglobin falls below 10 g/dl, which is 2 to 4 g/
di below the lower limit of normal for adults. Some studies in humans
indicate that even mild anemia can decrease performance in brief, hard
exercise (Viteri and Torun 1974). To determine the practical significance of
these findings for productivity, manual laborers in developing countries
who were suffering from iron deficiency anemia were studied. For exam-
ple, among men on a rubber plantation in Indonesia (Basta et al. 1979) and
women on a tea plantation in Sri Lanka (Edgerton et al. 1979), the produc-
tivity of iron-deficient individuals was significantly less than that of work-
ers with a normal hemoglobin concentration. After iron supplementation,
the performance of the iron-deficient subjects improved, with the greatest
improvement occurring in those who had the lowest initial hemoglobin
concentrations.

In these studies, it has not been possible to distinguish the extent to which
this impaired work performance is due to anemia per se or to the tissue
abnormalities accompanying iron deficiency. Experiments with rats have
shown that dietary iron deficiency also results in a marked impairment in
the oxidative production of cellular energy in skeletal muscle (Finch et al.
1976; McLane et al. 1981; Davies et al. 1984). The major consequence of
this muscle impairment is a lessened capacity for prolonged exercise or
physical endurance, whereas anemia primarily restricts the performance of
brief, strenuous exercise (McLane et al. 1981; Davies et al. 1984).

Body Temperature Regulation. An impaired capacity to maintain body
temperature in a cold environment is another characteristic of iron defi-
ciency anemia. This abnormality is related to decreased secretion of thy-
roid-stimulating hormone and thyroid hormone (Beard et al. 1984) and to
the anemia itself; studies of the iron-deficient rat show that a transfusion of
red blood cells corrects the abnormality. Furthermore, normally fed rats

477
C) Nutrition and Health

develop impaired heat production when they are made anemic by an
exchange transfusion that replaces red blood cells with plasma that lacks
hemoglobin.

Behavior and Intellectual Performance. Increasing evidence suggests that
changes in behavior and impaired development and intellectual perfor-
mance may result from iron deficiency (Lozoff and Brittenham 1986; Pollitt
1985). Most studies have evaluated infants between 6 months and 2 years of
age using the Bayley Scale of Infant Development, a test to evaluate
sensory development, fine and gross motor skills, and language develop-
ment in this group. By this standard, infants who are even mildly iron
deficient have a statistically significant decrease in responsiveness, activi-
ty, and attentiveness and have increased body tension, fearfulness, and
tendency to fatigue (Lozoff et al. 1982b). The long-term significance of
these observations has not been determined. Of particular interest is the
observation that these deficits are most profound in the oldest infants (19 to
24 months), in whom iron deficiency may have been present for the longest
period (Lozoff et al. 1982a). Another important finding is that even infants
with very mild iron deficiency anemia, or simply with early evidence of
impaired hemoglobin production, do not score as well as infants with no
laboratory evidence of iron deficiency or evidence merely of depleted iron
stores (Lozoff et al. 1982b; Oski et al. 1983; Walter, Kovalskys, and Stekel
1983). Although the results of these studies are not as conclusive, the
behavioral abnormalities are significant because the brain’s rapid rate of
growth and differentiation during infancy might make it particularly vulner-
able to nutrient deficiencies. Because the same adverse environmental
factors that lead to iron deficiency could also be responsible for behavioral
deficits, these studies are difficult to interpret. This complexity may help to
explain why some children display a rapid improvement in the Bayley score
after iron treatment (Oski et al. 1983), whereas others do not (Lozoff et al.
1982a, 1982b).

Resistance to Infections. Decreased resistance to infection is characteristic
of iron deficiency in both humans and experimental animals (Beisel 1982;
Vyas and Chandra 1984; Dallman 1986). Iron-deficient children have abnor-
malities in lymphocytes and neutrophils, two types of white blood cells that
help defend against infections (see chapter on infections and immunity).
Although infections are associated with decreases in measures of iron
status, these decreases may not be related to deficient iron intake.

Despite numerous studies that show an impaired resistance to infection
under laboratory conditions, no conclusive evidence demonstrates that
iron deficiency itself causes an increased rate of infections in free-living

478
Anemia O

individuals. Iron deficiency anemia and infections are both common among
poor populations, but a cause-and-effect relationship, although plausible,
has not been established (Strauss 1978). These issues are discussed further
in the chapter on infections and immunity.

Lead Poisoning. Iron deficiency substantially increases the risk of lead
poisoning, particularly in young children. Iron-deficient individuals absorb
increased amounts of lead (Watson et al. 1986), and elevated blood lead
concentrations have been observed among some children with laboratory
evidence of iron deficiency (Yip and Dallman 1984).

Prevention of Iron Deficiency

Iron deficiency can be prevented by increasing dietary iron intake, improv-
ing the bioavailability of iron in the diet, or decreasing body losses of iron.
Dietary iron intakes can be improved by increasing the consumption of
iron-rich foods, administering iron supplements to specific target popula-
tions, and fortifying certain food products with iron. Parental awareness of
appropriate diet is especially important for infants, whose diet is relatively
simple. Typically, an infant’s diet is discussed during routine health mainte-
nance visits.

Fortification of cereal and grain products is a relatively inexpensive and
effective means of increasing iron intake (International Nutritional Anemia
Consultative Group 1982; Clydesdale and Wiemer 1985). These foods
usually reach the population as a whole in adequate amounts to make a
difference without the need for individual counseling. Nevertheless, sev-
eral aspects of fortification are controversial. Because some iron com-
pounds are poorly absorbed (Cook and Reusser 1983; Yetley and Glins-
mann 1983; Hurrell 1984), it is difficult to document that eating fortified
foods helps prevent iron deficiency, especially because baseline data are
unavailable. Readily absorbed forms of iron react with foods and some-
times decrease shelf life. One compound that may strike a reasonable
compromise between shelf life and bioavailability is finely powdered metal-
ic iron, although some studies find that this form, too, is poorly absorbed
(Elwood et al. 1968; Hallberg, Brune, and Rossander 1986).

Continuation of breastfeeding for 6 months or more confers substantial
protection against development of iron deficiency in full-term infants (AAP
Committee on Nutrition 1985). Iron-fortified infant formula, which was
introduced about two decades ago in the United States, has gradually
supplanted most unfortified formulas and fresh cow milk as infant food
during the first year of life (Martinez and Nalezienski 1979). In a large

479
CO Nutrition and Health

survey conducted in 1984, 77 percent of 5- to 6-month-old infants in the
United States who were receiving cow milk formula were consuming the
iron-fortified form (Martinez 1985). Today, iron deficiency in otherwise
healthy infants is almost entirely restricted to those on a diet of fresh cow
milk (Sadowitz and Oski 1983) or unfortified cow milk formula (Saarinen
1978).

Vitamin C (Ascorbic Acid) Fortification. The absorption of iron from
fortified cereals can be increased twofold to threefold if the cereals are also
fortified with about 5 mg of vitamin C per mg of iron (International Nutri-
tional Anemia Consultative Group 1982; Cook and Bothwell 1984). Some of
the effectiveness of iron-fortified infant formulas in preventing iron defi-
ciency has been attributed to their fortification with this vitamin (Stekel
1984).

Iron Supplements. Supplementation has the disadvantage of requiring
extra effort and expense compared with fortified foods. People do not
always remember to take medications consistently and regularly. Supple-
ments are less available to the poor and other groups most likely to be iron
deficient. Supplementation is, however, a reasonable approach to preven-
tion of iron deficiency in breastfed premature infants, in pregnant women,
and in targeted high-risk population groups. In these situations, a large
amount of dietary iron is provided over a short period of time. Its useful-
ness for a given individual requires evaluation by a qualified health profes-
~ sional. Iron supplement use and recommendations to increase dietary iron
intake are usually not necessary for the general population. Among Ameri-
cans as a whole, poor iron status is relatively rare (LSRO 1984b) and iron
supplements are not associated with improved iron status (Looker et al.
1987). An additional concern is that increased iron intake can harm individ-
uals who are susceptible to iron overload (LSRO 1984b).

Federal Food Programs. Because iron deficiency is more common among
the poor than among persons above the poverty line (DHHS/USDA 1986),
iron status should improve as a result of Federal food programs that serve
socioeconomically disadvantaged groups. In one study, infants and chil-
dren who had not received aid from the WIC program in 1973-74 were far
more frequently anemic than a similar population in 1977 who were en-
rolled in the WIC program since birth (Miller, Swaney, and Deinard 1985).
' ‘Although differences unrelated to iron intake probably existed between the

two groups, which might account for differences.in iron status, the foods

provided by the WIC program included several sources of iron or enhan-

480
Anemia e)

cers of iron absorption: formula fortified with 12 mg of iron per liter for
infants up to 12 months of age, and iron-fortified infant cereal and ascorbic
acid-fortified fruit juice for infants between 6 and 12 months of age.

Potentially Adverse Consequences. Under ordinary circumstances, a mod-
est excess of dietary iron (over requirements) does not have adverse
consequences. On the other hand, increased iron intake might be harmful
for some individuals. A much discussed example is the hereditary condi-
tion hemochromatosis, in which abnormal amounts of tissue iron accumu-
late over the years as a result of a genetic defect in absorption, eventually
damaging the liver, heart, pancreas, and adrenal glands (Bothwell et al.
1979). A subset of homozygous individuals with hemochromatosis usually
develops symptoms by middle age. Heterozygous carriers of the hemo-
chromatosis gene may be at slightly increased risk for iron overload (Brown
1981), but the clinical significance of this risk is uncertain. Although there is
no direct evidence that current levels of iron fortification are harmful,
concerns have been raised that any increased level of iron in the food
supply may harm individuals susceptible to iron overload. Individuals who
require repeated blood transfusions for relatively rare conditions, such as
thalassemia, may also accumulate excess iron, which is then deposited in
soft tissues. Fortification iron adds an undesirable, but relatively small,
load compared with that administered by transfusion.

Excessive iron intake may affect the absorption of other trace elements.
Although a high dose of iron medication impairs the absorption of zinc or
copper administered at the same time (Solomons and Jacobs 1981), this
interaction probably does not occur at the much smaller fortification levels.
Of greater concern is the possibility of compromised zinc or copper absorp-
tion in groups who take larger amounts of iron as supplements, such as
infants and pregnant women (Breskin et al. 1983; Hambidge et al. 1987).

Excessive iron administration may increase the risk of infection (Pearson
and Robinson 1976; Beisel 1982). The basis for this concern is that a high
degree of unsaturation in the iron-binding protein transferrin suppresses
the growth of many bacteria. Conditions of iron overload are associated
with very low levels of unsaturation. Although this issue may be important
in clinically diagnosed iron overload, recent U.S. survey data have found a
low prevalence of abnormally high transferrin saturation values in the
general population (LSRO 1984b).

481

 
C) Nutrition and Health

Role of Folate and Vitamin B,. in Anemia

Although deficiencies of folate or vitamin B,, are relatively rare among the
general U.S. population, certain groups are particularly at risk for develop-
ing these nutrient deficiencies. Folate deficiency is of special concern. Its
extent in the general population is virtually unknown. Low socioeconomic
groups at vulnerable stages of the life cycle are at greatest risk—pregnant
women (especially adolescents), infants (especially those who are small or
premature), young children, and older persons (Shojania 1984). Surveys of
the folate status of these groups have been too limited in sample size and
methodology to permit adequate evaluation (LSRO 1986).

Folate requirements for pregnant women are greatest in the last trimester
of pregnancy; however, most women’s diets meet these requirements.
Oral folate supplementation during this period is often recommended for
high-risk groups. Premature infants, particularly those of very low birth
weight, may need more folate to support their growth than is provided by
infant formula or breast milk. Under a physician’s guidance, this folate can
be supplied as an oral supplement. Infants fed primarily unfortified goat
milk are also at risk for folate deficiency because of the unusually low folate
content of this food.

Other risk factors for folate deficiency include chronic disease and use of
alcohol and drugs. Chronic and severe diarrhea, as in tropical sprue or
celiac disease, for example, can cause folate deficiency. Folate deficiency
also occurs among alcoholics (see chapter on alcohol). As discussed in the
chapter on drug-nutrient interactions, individuals who use oral contracep-
tives and other medications may be at increased risk for folate deficiency,
but the extent and public health significance of these interactions is uncer-
tain (LSRO 1984a).

A dietary vitamin B,, deficiency can occur in strict vegetarians who avoid
all foods derived from animals, including eggs and dairy products. Nursing
infants of women consuming such diets or of women who are vitamin By>-
deficient are also at risk because the vitamin B,, content of the breast milk
decreases as the mother’s vitamin B,, stores decline (Shojania 1984). Any
strict vegetarian who becomes pregnant should be advised to supplement
her diet with vitamin B,,.

482
Anemia C

Implications for Public Health Policy
Dietary Guidance

General Public

Prevention of nutrition-related anemia depends on adequate dietary intake
of iron, vitamin B,,, and folate as well as the full complement of other
essential nutrients. Except for younger children and women of reproduc-
tive age, who are at greater risk for iron deficiency, it appears that current
iron consumption levels are sufficient for most of the population.

Special Populations

Routine health care for infants and pregnant women, the groups at highest
risk for anemia, should include laboratory evaluation for anemia and
nutritional advice on methods to ensure adequate iron intake. Nonpreg-
nant women in their childbearing years and adolescents are also at greater
risk for iron deficiency anemia; these individuals should be monitored and
should receive special counsel on preventing iron deficiency. Frequent
blood donors, another high-risk group, should be advised by blood bank
personnel about dietary methods to enhance iron intake and absorption.
Groups who may need iron supplements, such as premature infants, preg-
nant women, women with excessive menstrual bleeding, frequent blood
donors, strict vegetarians, and regular aspirin users, should also receive
advice from health professionals on enhancing iron bioavailability from the
diet. Specific education efforts directed toward these special groups, even
though difficult, are needed.

Folate deficiency anemia usually occurs among women late in the course of
pregnancy, among small and premature infants, and among alcoholics.
These groups, especially from low-income families, should receive advice
about dietary and supplemental sources of this vitamin.

Strict vegetarians who consume no foods of animal origin, especially
women who are pregnant or nursing, should be advised to consume supple-
mental sources of vitamin B,5.

Nutrition Programs and Services

Food Programs

Because groups that benefit from food programs are those at highest risk
for anemia, such programs should continue to be made available to high-

483
C Nutrition and Health

risk groups and should encourage consumption of foods rich in iron and
folate. Evidence suggests that current levels of iron fortification are safe
and adequate, and no changes should be recommended at this time.

Food Labels

Evidence related to the role of iron and folate in anemia suggests that food
labels should indicate the content of these nutrients.

Special Populations

Patients with anemia should receive counseling and assistance to develop
diets that have adequate amounts of bioavailable iron, folate, or vitamin B 2
from dietary or supplemental sources.

Research and Surveillance

Research and surveillance issues of special priority related to the role of
diet in anemia should include investigations into:

© Screening for earlier stages of iron deficiency using tests that identify
iron depletion (e.g., erythrocyte protoporphyrin).

® Elucidation of the health consequences of conditions of iron depletion
_prior to development of anemia.

@ Validation of methodologies for identification of the extent of deficien-
cies of iron, folate, and vitamin B,, in the general population and in
high-risk groups.

@ Interactions between iron, folate, vitamin B,,, and other nutrients
consumed in the diet.

© Improved methods for analysis of the folate content of food.

@ Determination of iron requirements at various stages of the life cycle
and under various physiologic conditions.

@ Identification of appropriate levels and types of iron in the food supply
for individuals with hereditary conditions of excess iron absorption.

@ Identification of the level of iron intake that confers maximum protec-
tion against major infections.

@ Determination of trends in iron fortification in the U.S. food supply.

® Development of effective methods to educate the general public and
high-risk groups about consuming.diets adequate in iron and folate.

484
Anemia ie

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Oski, F.A.; Honig, A.S.; Helu, B.; and Howanitz, P. 1983. Effect of iron therapy on behavior
performance in nonanemic, iron-deficient infants. Pediatrics 71:877-80.

Pearson, H.A., and Robinson, J.E. 1976. The role of iron in host resistance. Advances in
Pediatrics 23:1-33. .

Pierson, R.N., Jr.; Holt, P.R.; Watson, R.M.,; and Keating, R.P. 1961. Aspirin and gastroin-
testinal bleeding. Chromate 51 blood loss studies. American Journal of Medicine 31:259-65,

Pollitt, E. 1985. Effects of iron deficiency with and without anemia on mental development
among infants and preschool children. In Nutritional anthropology, ed. FE. Johnson. New
York: Liss.

Rios, E.; Hunter, R.E.; Cook, J.D.; Smith, N.J.; and Finch, C.A. 1975. The absorption of iron
as supplements in infant cereal and infant formulas. Pediatrics 55:686-93.

Rossander, L.; Hallberg, L.; and Bjorn-Rasmussen, E. 1979. Absorption of iron from break-
fast meals. American Journal of Clinical Nutrition 32:2484-89,

Saarinen, U.M. 1978. Need for iron supplementation in infants on prolonged breast feeding.
Journal of Pediatrics 93:177-80.

Saarinen, U.M., and Siimes, M.A. 1977. Iron absorption from infant formula and the optimal
level of iron supplementation. Acta Pediatrica Scandinavica 66:719-22. :

Saarinen, U.M.; Siimes, M.A.; and Dallman, PR. 1977. Iron absoprtion in infants: high
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and by the concentration of serum ferritin. Journal of Pediatrics 91:36-39.

Sadowitz, P.D., and Oski, FA. 1983. Iron status and infant feeding practices in an urban
ambulatory center. Pediatrics 72:33-36.

Shojania, A.M. 1984. Folic acid and vitamin B,> deficiency in pregnancy and in the neonatal
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Singla, P.N.; Chand, S.; Kharma, S.; and Agarwal, K.N. 1978.-Effect of maternal anemia on
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Solomons, N.W., and Jacobs, R.A. 1981. Studies of the bioavailability of zinc in man. IV.
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Stekel, A. 1984. Prevention of iron deficiency. In fron nutrition in infancy and childhood, ed.
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Stekel, A.; Olivares, M.: Pizarro, F.; Chadud, P.: Lopez, I.;and Amar, M. 1986. Absorption of
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Stockman, J.A. 1987. Iron deficiency anemia: have we come far enough? Journal of the
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Strauss, R.G. 1978. Iron deficiency, infections, and immune function: a reassessment. Ameri-
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Svanberg, B.; Arvidsson, B.; Norrby, A.; Rybo, G.; and Solvell, L. 1975. Absorption of
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Center for Health Statistics.

Vazquez-Seone, P.; Windom, R.; and Pearson, H.A. 1985. Disappearance of iron deficiency
anemia in a high-risk infant population given supplemental iron. New England Journal of
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Viteri, EE., and Torun, B. 1974. Anemia and physical work capacity. Clinical Hematology
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Vyas, D., and Chandra, R.K. 1984. Functional complications of iron deificiency. In fron
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Walter, T.; Kovalskys, J.; and Stekel, A. 1983. Effect of mild iron deficiency on infant mental
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Watson, W.S.; Morrison, J.; Bethel, M.I.F.; Baldwin, N.M.; Lyon, D.T.B.; Dobson, H.;
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Journal of Clinical Nutrition 44:248-56.

Yetley, E.A., and Glinsmann, W.H. 1983. Regulatory issues regarding iron bioavailability.
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Yip, R., and Dallman, P.R. 1984. Developmental changes in erythrocyte protoporphyrin: roles
of iron deficiency and lead toxicity. Journal of Pediatrics 104:710-13.

Yip, R.; Schwartz S.; and Deinard, A.S. 1984. Hematocrit values in white, black, and
American Indian children with comparable iron status: evidence to support uniform diag-
nostic criteria for anemia among all races. American Journal of Diseases of Children
138:824-27.

Yip, R.; Binkin, N.J.; Fleshood, L.; and Trowbridge, F.L. 1987. Declining prevalence of
anemia among low-income children in the United States. Journal of the American Medical
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Yip, R.; Walsh, K.M.; Goldforb, M.G.; and Binkin, N.J. 1987. Declining prevalence of anemia
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Chapter 13

Neurologic Disorders

The man is, above all else, the mind of the
man, and not only the mind as an organ of
conscious thought but the mind as an organ
of bodily nutrition. . . .

James J. Putnam
Boston Medical and Surgical Journal (1899)

Introduction
Historical Perspective

Since biblical times, brain function and certain nutritional factors have
been thought to be related, but knowledge of the interaction between
nutrition and neurology is still sparse. Scientific interest in the link between
nutrition and brain function began in the early 19th century when Magendie
proposed that the central nervous system controlled appetite (Anand 1961,
Widdowson 1982). Due to the predominance of theories that hunger was
purely a peripheral sensation (Cannon and Washburn 1912), it was not until
the 1930’s that control of feeding began to be attributed to specific regions
of the brain.

Classically, nutritional deficiencies have also been related to brain func-
tion. Starvation was shown to produce a variety of overt behavioral
changes as well as mental deterioration (Blanton 1919), and severe mal-
nutrition in animals is now associated with impaired brain development and
learning (Winick 1976). The absence of specific vitamins or minerals from
the diet has been known for many years to produce behavioral or neu-
rologic symptoms in animals (Funk 191 1). In the early 20th century, disor-
ders of the human nervous system were observed as consequences of
deficiencies of certain vitamins, copper, and magnesium in the diet (Wid-
dowson 1972). In most industrialized societies, however, only a few nutri-
tional deficiency diseases, such as those associated with alcoholism (see
chapter on alcohol), occur with sufficient frequency to be of substantial
concern to policymakers and the public.

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Because the brain appears to be protected by the blood-brain barrier from
fluctuations in plasma nutrient levels caused by eating, it has been difficult
to demonstrate effects of specific foods or dietary components on brain
function. Furthermore, the nutrient transport and cellular uptake mecha-
nisms as well as the factors affecting the nutrient content of the brain are
not fully understood (Pardridge 1986). In laboratory animals, brain levels of
certain essential constituents have been reported to vary markedly as a
function of the nature and timing of food consumption (Pardridge 1977:
Wurtman, Hefti, and Melamed 1981; Blusztajn and Wurtman 1983), but
whether human neurotransmitter systems are affected by the intake of
dietary precursors (Wurtman, Wurtman, and Growdon 1981b; Blusztajn
and Wurtman 1983) is as yet uncertain.

This chapter reviews these and other nutritional aspects of neurologic
phenomena, and because cerebrovascular diseases account for sucha large
proportion of neurologic cases and hospital admissions, it also reviews the
relationship between diet and stroke.

Significance for Public Health

Stroke is the most common life-threatening neurologic disease in the
United States: It ranks third after heart disease and cancer as a cause of
death and is also a major cause of long-term disability (NCHS 1986).
Although stroke mortality rates have declined dramatically in recent years
(see chapter on high blood pressure), in part as a result of improved high
blood pressure management, about 500,000 new cases still occur annually.
About 2 million Americans are estimated to suffer from stroke-related
disabilities at an annual cost of more than $11 billion (NINCDS 1986). The
mortality rate among black Americans is almost twice that of whites.
Because a significant portion of the important risk factors for stroke are
under behavioral control, efforts to reduce these risks seem to be especial-
ly worthwhile.

Other neurologic conditions are also prevalent in the U.S. population.
Approximately 2 million Americans suffer from epilepsy, at an estimated
health care cost of $3 billion. Chronic headaches afflict 40 million people in
the United States and are responsible for 8 million annual visits to a
physician and 64 million days of work lost due to pain. Alzheimer’s disease
affects 2 to 3 million Americans, at an estimated annual health care cost of
up to $50 billion (NINCDS 1986). Whether any appreciable fraction of these
conditions can be prevented or ameliorated by dietary means is unknown
but seems unlikely given current evidence.

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Neurologic Disorders @|

Scientific Background

Nutritional Needs of the Nervous System

The brain and nervous system probably require the full complement of
essential nutrients and energy to develop and to maintain their neurons and
supporting cells. Although it seems reasonable to expect that a deficiency
of any one of the essential nutrients or of energy would impair the develop-
ment and subsequent maintenance of these structurally and functionally
complex tissues, evidence to support this hypothesis has been difficult to
obtain (Shoemaker and Bloom 1977; Nowak and Munro 1977).

The human brain normally metabolizes 100 to 150 g of glucose per day as
fuel, but the mature nervous system is relatively insensitive to restrictions
of energy and protein. During starvation, it adapts and uses ketones,
derived from breakdown of body fat stores, for energy and thus spares
blood glucose and conserves body protein. The documented behavioral
changes that occur in starving individuals—depression, apathy, irritability,
and loss of libido—do not necessarily reflect damage to the nervous system
(Kerndt et al. 1982).

Most direct research on the neurologic effects of nutritional deprivation has
been performed on experimental animals. In part because of species vari-
ability in the time course of neurologic development, the results of this
research may not be applicable to humans.

Additional information on the effects of dietary deficiencies on human
brain development and nervous system function derives from “natural
experiments” of human starvation or inadequate dietary intake. With a few
notable exceptions, it has been difficult to separate the effects of nutritional
deficits in these situations from those of other environmental, social, and
medical problems that often accompany poor nutritional status (Pollitt and
Thomson 1977).

Nonetheless, severe deficiencies of vitamins, especially the B-complex
group, impair nervous system function (Dreyfus 1988; Lipton, Mailman,
and Nemeroff 1979). Thiamin deficiency causes beriberi neuropathy as well
as a peripheral neuropathy and polyneuritis that leads to Wernicke-Kor-
sakoff’s syndrome (paralysis of the eye muscles, loss of muscular coordina-
tion, and memory loss) in long-term alcoholics (Dreyfus 1988; see chapter
on alcohol). Inadequate niacin intake causes pellagra, with symptoms that
include intellectual impairment and dementia, in individuals of all ages.

Deficiency caused by vitamin B,> malabsorption in untreated pernicious

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anemia or as a result of a long-term vitamin B ,, deficient vegetarian diet can
result in subacute degeneration of the spinal cord, optic nerves, cerebral
white matter, and peripheral nerves (Dreyfus 1988). Severely deficient
intakes of other vitamins of the B-complex group also affect neurologic
function. In the early stages, these symptoms are readily overcome by
increased dietary intake of the appropriate vitamin, but nerve damage in
later stages appears to be irreversible (Lipton, Mailman, and Nemeroff
1979). Whether subclinical deficiencies of these vitamins affect nervous
system function is as yet uncertain (Goodwin, Goodwin, and Gary 1983).

Deficiencies of other nutrients may relate to defects in nervous system
function. For example, iodine deficiency during brain development causes
mental retardation and neuromotor abnormalities. Chronic iron deficiency
is associated with deficits in cognitive abilities (Lozoff et al. 1987). A few
cases of vitamin E deficiency-induced spinal cord, cerebellar, and periph-
eral nerve degeneration with muscle wasting have been reported among
patients with severe cholestatic liver disease or malabsorption syndromes
(Muller, Lloyd, and Wolff 1983; Laplante et al. 1984; Weder et al. 1984).
Levels of vitamin E are greatly reduced in the peripheral nerves of such
patients (Traber et al. 1987). In most cases, neurologic damage resolves
with administration of vitamin E (Sokol et al. 1985), suggesting that vitamin
E deficiency may be responsible.

The effects of nutritional deficiencies on the developing nervous system are
difficult to interpret. Studies in rats have almost always restricted total
dietary intake rather than that of specific nutrients. These studies have
indicated that nutritional deprivation at various stages of fetal and postnatal
development produces its own constellation of defects. Early maternal
malnutrition reduces fetal brain weight and brain protein and DNA con-
tent. Postnatal malnutrition also induces deficits in brain weight and, in
addition, reduces myelination and dendrite formation and retards develop-
ment of mature enzyme patterns (Shoemaker and Bloom 1977). These
changes persist even after adequate nutrition is restored (Nowak and
Munro 1977; Winick 1976). In experimental studies of pregnant animals,
diets deficient in zinc and folate result in high rates of malformations such
as neural tube defects and spina bifida in the offspring ( Hurley and Shrader
1972; see chapter on maternal and child nutrition). Supplementation of
these animals resulted in a significant reduction in the incidence of these
congenital nervous system defects.

Studies in animals have shown that the neuropathology resulting from
intrauterine starvation or postnatal malnutrition does not produce recog-
nizable focal lesions but instead produces diffuse anatomical effects that

494
Neurologic Disorders e

appear to be spread throughout the brain. Different effects occur in differ-
ent brain regions depending on the rate of cell division within each region.
Because changes of this type provide little information about functional
connections, the significance of these changes for cognitive and behavioral
function is uncertain (Nowak and Munro 1977).

The relevance of animal studies for human brain development and cog-
nitive functioning is also uncertain. Reduced cellularity and myelination
have been shown to occur in the brains of severely nutritionally deprived
human infants. Malnutrition during and after pregnancy produces human
infants with lower birth weights, smaller stature, and, therefore, smailer
head circumferences and lower brain weights. None of these changes,
however, has been demonstrated to affect higher mental processes (Dob-
bing 1984).

Dietary Precursors of Brain Neurotransmitters

Nervous system function is mediated through the work of various neu-
rotransmitters such as serotonin, the catecholamines (dopamine and nor-
epinephrine), and acetylcholine. These neurotransmitters are manufac-
tured by the action of enzymes in the brain on the precursor amino acids
tryptophan, tyrosine, and choline, respectively. Because the brain cannot
make adequate quantities of the various precursors, it must rely on uptake
from the bloodstream. Studies in animals have suggested that meal com-
position can affect plasma levels of the precursors and, therefore, synthesis
of these neurotransmitters (Wurtman, Hefti, and Melamed 1981; Pardridge
1977).

Whether the various high dose dietary contributions to precursors of brain
neurotransmitters affect neurologic function in animals other than the rat is
uncertain (Trulson 1985). The effects of dietary precursors of neu-
rotransmitters on animal function and behavior are also uncertain (see
chapter on behavior). Also unknown is whether dietary precursors of
neurotransmitters can alter normal human behavior (Spring 1986; Young
1986) or correct abnormal behavior (Growdon 1979a; Van Praag and Lemus
1986).

Clinical investigators have tested the utility of neurotransmitter precursors
as treatments for diseases associated with neurotransmitter deficiencies
such as Alzheimer’s and Parkinson’s diseases, depression, and sleep disor-
ders (Growdon 1981; Growdon and Wurtman 1982; Growdon and Gibson
1982; Young 1986; Van Praag and Lemus 1986). There is no evidence that
such conditions result from nutritional deficiencies. Thus, tryptophan,
tyrosine, and choline (as such or as phosphatidylcholine) were given in

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these studies in purified form independent of other food constituents. In the
case of choline, doses were greater than would ordinarily be consumed in
the normal diet.

Pharmacologic amounts of L-tryptophan, for example, have been adminis-
tered to human subjects to induce sleep (Hartmann 1982), treat insomnia in
older persons (Jenicke 1985), relieve anxiety and suppress food consump-
tion in obese persons (Wurtman, Hefti, and Melamed 1981), suppress
posthypoxic myoclonus (Growdon 1979b), and treat certain pain syn-
dromes (Hosobuchi, Lamb, and Bascom 1980; Lieberman et al. 1982; King
1980). However, the effectiveness of tryptophan for these purposes has not
been established, and its use remains controversial (DeFeudis 1987). Simi-
larly, tyrosine, the dietary precursor of the neurotransmitters dopamine
and norephinephrine, has been used to accelerate dopamine turnover in
patients with Parkinson’s disease (Growdon and Melamed 1982) and to
treat patients with mild Parkinson’s disease (Growdon 1981) or endogenous
depression (Van Praag and Lemus 1986); however, these applications are
also preliminary and require further confirmation.

Large doses of choline and purified phosphatidylcholine, precursors for
the neurotransmitter acetylcholine, have been reported to improve the
symptoms of patients with tardive dyskinesia (Growdon and Wurtman
1982) and mania (Cohen et al. 1980). These observations remain to be
confirmed. Similar treatment of patients with Huntington’s disease, Gilles
de la Tourette’s syndrome, familial ataxias, and epilepsy has produced
negative or inconclusive results (Wood and Allison 1982).

Despite a single report that suggests that the administration of phos-
phatidylcholine for at least 6 months might retard the progression of
Alzheimer’s disease in a subset of older patients with this disorder (Little et
al. 1985), more than a dozen additional studies have found choline to be
ineffective in the treatment of this condition (Bartus et al. 1982). Evidence
is also lacking for the hypothesis that Alzheimer’s disease is a consequence
of the breakdown of phosphatidylcholine in neuronal membranes to pro-
duce choline for acetylcholine biosynthesis (Blusztajn and Wurtman 1983).

Key Scientific Issues

® Role of Diet in Cerebrovascular Disease (Stroke)
® Role of Diet in Other Neurologic Disorders
®@ Role of Noncaloric Dietary Components in Neurologic Disorders

496
Neurologic Disorders O

Role of Diet in Cerebrovascular Disease (Stroke)

Stroke is the sudden loss of brain function caused by one of four vascular
events: thrombosis, or blood clot, in a cerebral artery; embolism, or
blockage, of a cerebral artery by a circulating clot; stenosis, or narrowing,
of a cerebral artery by atherosclerosis; or hemorrhage from rupture of a ~
cerebral artery. These events deprive the brain of blood and oxygen and
cause tissue death and irreversible damage to nervous tissue. The effects of
the damage depend on the location and size of the tissue loss. Symptoms
range from those too trivial for the victim to notice to major sensory
deficits, blindness, paralysis, speech loss, coma, and death. Although
some return of function is possible in tissues damaged but not destroyed,
losses persisting beyond weeks are likely to be permanent.

Persons at greatest risk for stroke are those with hypertension and diabetes
_ and those who smoke cigarettes and display impaired cardiac function due
to coronary heart disease, congestive heart failure, or hypertensive heart
disease. These major risk factors for stroke are in part related to nutri-
tional, dietary, and lifestyle factors. Current evidence suggests that certain
dietary substances that promote high blood pressure. or diabetes may
increase the likelihood of stroke. Thus, excessive dietary consumption of |
calories (if it results in obesity), sodium, and alcohol may increase the risk
for stroke. The evidence that links dietary factors to high blood pressure
and diabetes is reviewed in detail in the chapters devoted to those topics.
Although there is a wealth of evidence supporting the relationship between
diet, blood cholesterol levels, and atherosclerotic coronary disease (see
chapter on coronary heart disease), the link to cerebrovascular disease is
less clear.

Persons with hypertension are at greatly increased risk for stroke. This risk
increases with elevations in blood pressure regardless of age and sex; it
decreases when blood pressure is reduced. How hypertension predisposes
to stroke is not fully understood, but it appears to injure cerebral artery
walls. Diabetes and high blood cholesterol may also act, alone or in
concert, to injure the inner wall of a cerebral artery. Through consequent
platelet interaction, the injury becomes the site of plaque formation and
subsequent atherosclerosis. Thus, hypertension seems to be the precursor
of the hemorrhagic, the stenotic, and the embolic types of stroke.

Moderate sodium restriction (Koolen and Van Brummelen 1984; Kawasaki

etal. 1978), high potassium intake (Treasure and Ploth 1983; Langford 1983,
Kaplan et al. 1985), vegetarian diets (Ophir et al. 1983), calcium (Blaustein

497
e Nutrition and Health

and Hamlyn 1983; McCarron et al. 1984), weight reduction, and alcohol
restriction all have been suggested as factors associated with blood pres-
sure lowering. Of these, weight reduction and restriction of sodium have the
most evidence to substantiate this association, but excessive consumption
of alcohol is associated with increased rates of hypertension (Klatsky et al.
1977; MacMahon and Norton 1986; Potter and Beevers 1984). Epi-
demiologic evidence associates excessive drinking with increased frequen-
cy of subarachnoid hemorrhage and cerebral infarction (Hillbom and Kaste
1978, 1982), and heavy alcohol intake has been identified as an independent
risk factor for stroke in humans (Gill et al. 1986).

The effect of dietary potassium on stroke has also been investigated re-
cently. In a prospective study, individuals consuming somewhat higher
levels of potassium from food sources had a reduced risk for stroke-
associated mortality (Khaw and Barrett-Connor 1987). The effects of spe-
cific dietary factors on causation of stroke warrant further investigation.

Role of Diet in Other Neurologic Disorders

Headache

Headache, one of the most common complaints evaluated by neurologists,
is estimated to affect 40 million Americans. Clinical investigations of the
role of foods in precipitating vascular or migraine headaches remain con-
troversial (Dreyfus 1988). The foods most frequently implicated often
contain tyramines (e.g., cheese, red wines) or more rarely phenylethyl-
amine (e.g., chocolates) (Dreyfus 1988; Egger et al. 1983). The “Chinese
Restaurant Syndrome” is associated with numbness around the mouth,
tingling, flushing of the face, dizziness, and headache (Kenny 1980). Use of
the artificial sweetener aspartame has been found not to be associated with
increased susceptibility to headache (Schiffman et al. 1987).

Current evidence suggests that dietary factors are unlikely to be responsi-
ble for most cases of headache, although toxicity of vitamin A, caused by
excess intake of supplements, has been reported to cause headaches. Until
conclusive evidence has established the link between certain foods and the
occurrence of headaches, especially migraine, it may be prudent for such
individuals to abstain whenever possible from those foods thought to
provoke an attack (Dreyfus 1988).

Epilepsy

Low levels of magnesium can cause seizures, and the magnesium-deficient
rat is used as a model of experimental epilepsy (Buck, Mahoney, and

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Neurologic Disorders C

Hendricks 1978). Magnesium deficiency in humans most often results from
kidney disease and is not a significant cause of epilepsy in people. A wide
variety of neurobehavioral symptoms common in the general population,
including epilepsy, have been reported to occur in people consuming the
artificial sweetener aspartame (Wurtman 1985). No well-controlled clinical
studies have indicated that a causal relationship exists. Ketogenic diets
(low in carbohydrate) have been used for decades to treat certain forms of
intractable epilepsy. The mechanism of action of this diet is not understood
(Withrow 1980), and it is tolerated poorly by some patients (Trauner 1985).
Furthermore, it is nutritionally inadequate, unpalatable, and inappropriate
for use in young children. Other specific nutrients such as vitamin D,; have
been suggested to have beneficial effects on seizure thresholds in rats
(Siegel et al. 1984), but more information is needed before conclusions can
be drawn about the role of diet in epilepsy.

Role of Noncaloric Dietary Components in Neurologic Disorders

Excessive Vitamin Intake

Vitamin A intoxication can result from the chronic use of relatively low
levels (14,000 IU/day in infants and 25,000 to 50,000 [U/day in adults) of the
vitamin (Farris and Erdman 1982), and toxic symptoms may appear sud-
denly with the onset of liver dysfunction due to other causes (Hatoff et al.
1982). Excessive intake of vitamin A causes reversible intracranial hyper-
tension, which when not so identified has led to needless surgery; it can
also occasionally result in headache, blurred vision, seizures, and encepha-
lopathy. High doses of pyridoxine (vitamin B,) have been used to treat
conditions such as carpal tunnel syndrome; however, excessive pyridoxine
in gram quantities has recently been associated with peripheral nerve
deterioration, and more recent studies indicate that lesser amounts may
produce toxic symptoms (Ditmars and Houin 1986; Dreyfus 1988, Schaum-
berg et al. 1983).

Endogenous and Exogenous Toxins

Naturally occurring food-borne toxins either consumed in the diet or
produced by the body as a result of rare metabolic diseases also affect the
mature nervous system; brain damage resulting from lung, liver, or kidney
failure is a common example. Moreover, rare metabolic diseases or inborn
errors of metabolism can cause naturally occurring food constituents to
become toxic (e.g., copper in Wilson’s disease, phenylalanine in phen-
ylketonuria) (Dreyfus 1988). The seeds of certain cycad plants contain
neurotoxic substances that, when ingested by experimental animals, cause
symptoms similar to those of amyotrophic lateral sclerosis (ALS), parkin-

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sonism, or Alzheimer’s disease (Spencer et al. 1987). However, in man, the
role of cycad plants and other dietary factors in ALS is still controversial
(Garruto and Yase 1986). Other neurotoxins have caused acute poisonings
on those rare occasions when they have contaminated foods in large
quantities. These include ingestion of lead-contaminated paint, soil, or
food and water (Mahaffey 1981); industrial contamination of shellfish with
methyl mercury; and paralytic poisons produced by certain shellfish (Hat-
ten et al. 1983).

Specific dietary constituents, such as heavy and trace metals, may have
especially adverse effects on the nervous systems of older adults. For
example, increased amounts of aluminum and calcium have been reported
in brains of patients with Alzheimer’s disease, and concentrations are
especially high in the damaged neurons of the cortex (Linton et al. 1987),
particularly in association with the senile plaques and tangles. Whether
aluminum causes the cellular damage or accumulates simply because the
cells are dying has not been established (see chapter on aging).

Food Additives

Numerous compounds added to foods can affect the nervous system.
Some investigators have reported that very high levels of the dipeptide
sweetener aspartame raise brain levels of tyrosine in rats and, as a conse-
quence, impair synthesis of catecholamine neurotransmitters (Yokogoshi
et al. 1984; Pardridge 1977), but others have not been able to identify such
effects (Potts, Bloss, and Nutting 1980; Torii et al. 1986). The rat, unlike
humans, rapidly converts phenylalanine (a component of aspartame) to
tyrosine. Until aspartame has been tested in well-controlled human clinical
studies, its effects on the nervous system remain speculative.

Drug-Nutrient Interactions

Some of the drugs used to treat neurologic diseases can lead to vitamin
deficiencies by changing the metabolism of the vitamins, causing a second-
ary impairment of brain function (see chapter on drug-nutrient interac-
tions). Dilantin, used to treat epilepsy, can increase folate requirements and
cause vitamin K deficiency in the infants of mothers treated with this drug.
In addition to the hypertensive medication effects on mineral metabolism
described in the chapter on drug-nutrient interactions, hydralazine is a
vitamin B, antagonist that can cause peripheral neuropathy. Tranquilizers
such as chlorpromazine and other phenothiazines may cause hyperphagia
and weight gain. Monoamine oxidase inhibitors can cause acute hyperten-
sive crises, including excruciating headaches or fatal intracranial hemor-

500