Infections and Immunity 0

Enteric pathogens are thought to alter the permeability of the intestinal
mucosa, permitting entry of normally excluded, immunogenic mac-
romolecules, although conclusive evidence is lacking. Uptake of intact egg
protein (ovalbumin) in humans and animals with gastroenteritis has been
demonstrated (Keljo et al. 1987; Walker 1981; Gruskay and Cooke 1955). If
operative, the effect of such uptake may result in induction of allergy,
autoimmunity (particularly immune complex-mediated disease), and other
disorders (Walker 1981).

Nonimmunologic Mechanisms

The causes of nonimmunologic adverse reactions to foods include food
toxicities, food poisonings, and pharmacologic or metabolic reactions.
Such intolerances occur more frequently than true food allergies and are
related to dose as well as to the concurrent presence of medications, other
diseases, or genetic errors of metabolism.

One example is sulfite-induced asthmas. Sulfur dioxide and sulfiting agents
are widely used to retard deterioration of perishable produce, to condition
dough, to prevent microbial growth, and to provide antioxidant action. The
average intakes of sulfite and sulfite derivatives are estimated to be 6 mg
per capita per day but are higher for wine and beer drinkers and for
individuals consuming larger amounts of sulfite-treated foods. These
amounts may exceed current estimates of safe levels of intake (IFT 1986).
Approximately 1 to 8 percent of people with asthma are sensitive to
ingestion of sulfite, and those using steroid control agents are affected
more frequently. Adverse reactions vary with the individual's sensitivity
threshold, the type of sulfiting agent, and the type of food in which it is
consumed (Bush, Taylor, and Busse 1986). The FDA has proposed that
sulfite be declared on labels when levels exceed 10 ppm as total sulfite
dioxide and that its "Generally Recognized As Safe" (GRAS) status be
rescinded, but no final rules have been issued.

Other examples include asthma induced by tartrazine, a yellow dye used to
color medicines, soft drinks, and foods; a syndrome caused by mono-
sodium glutamate (see chapter on neurologic disorders); and symptoms
caused by preservatives such as benzoic acid and sulfiting agents (Butkus
and Mahan 1986). Nonimmunologic reactions also include lactose intol-
erance (an intestinal deficiency of the digestive enzyme lactase) and celiac
sprue, the inability to metabolize gluten (see chapter on gastrointestinal
diseases). In addition, toxic contaminants such as bacteria, insect parts,

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and molds; vasoactive amines (e.g., histamine) found in tomatoes, avo-
cados, cheeses, pineapples, and wines; and caffeine may cause symptoms
in sensitive individuals. Other gastrointestinal diseases, such as reflux
peptic esophagitis, peptic ulcers, gallbladder disease, and mesenteric vas-
cular insufftciency are associated with acute symptoms after eating. Per-
sons suffering adverse reactions may mistakenly attribute the cause to a
food allergy rather than to their underlying illness (AAAI 1984). Finally,
psychologic mechanisms can provoke physical and mental symptoms of
food sensitivity that do not appear to be mediated by the immune system.
In individuals with psychologically induced allergic symptoms, no phys-
iologic or biochemical nonimmunologic mechanisms can be identified
(May 1984) and true immunologic mechanisms are rarely found (Johansson
1984).

Prevention and Treatment

Individuals with food intolerances should exclude the offending foods from
their diet either completely or partially. Those with potentially life-threat-
ening sensitivities should carry an epinephrine-containing syringe (Atkins
1983) and wear a bracelet identifying the problem. Desensitization shots,
oral desensitization, and use of bee pollen are not effective treatments for
food allergies (Butkus and Mahan 1986).

The likelihood of an infant developing an IgE-mediated reaction is esti-
mated at 58 percent when both parents are affected, 38 percent when one
parent is affected, and 12.5 percent when neither parent is affected (Butkus
and Mahan 1986). Special precautions should be taken in feeding infants at
high risk, especially during the first year (GIaser 1966). Some research
suggests that the incidence of food allergies is decreased if breastfeeding is
continued for 3 to 6 months (Hamburger et al. 1983; Saarinen and Kajosaari
1980; Chandra 1979). Other research, however, disputes this suggestion
(Kovar et al. 1984). Because some food antigens are transferred through the
breast milk to the infant, mothers should avoid foods to which the infant is
sensitive. Likewise, formula-fed infants sensitive to cow milk or to soy-
bean-based formulas should be given formulas prepared from casein hy-
drolysate (Butkus and Mahan 1986). Delaying the introduction of solid
foods, especially those most likely to induce allergies, may prevent or
minimize the development of food allergies (Chandra 1979; Hamburger et
al. 1983). As a general rule, new foods should be introduced into the infant
diet one at a time to permit observations of allergic reactions (see chapter
on maternal and child nutrition).

452


Infections and Immunity 0   .-

Food-borne Microbial Diseases

Ingestion of water or foods that are contaminated with chemicals, patho-
genic micro-organisms, or the toxins they elaborate can lead to illness.
Food-borne pathogens commonly cause diarrhea, vomiting, abdominal
cramps, or other gastrointestinal symptoms. Less commonly, they affect
the liver or nervous system. Symptoms range from minor discomfort to
severe disease and even death. Their causes are listed in Table 1 I-1, In
1982, the factors most common to food-borne disease outbreaks. in order
of frequency, were (1) improper food handling, (2) food from an unsafe
source, (3) inadequate cooking, (4) poor personal hygiene. and (5) contami-
nated equipment (CDC 1985). Appropriate public health procedures relat-
ed to food handling and storage can usually prevent these problems.

The preferred treatment for most forms of food-borne illnesses is fluid and
electrolyte replacement for dehydration caused by diarrhea (Rohde et al.
1983). Antimicrobial drugs may be useful in some instances: in rare cases,
such as botulism poisoning, an antitoxin should be administered. How-
ever, because most food-borne illnesses are self-limiting and antibiotics
may disturb normal bacierial flora and prolong the illness, antibiotic thera-
py is not routinely used (Altman 1985). Food-borne infections that trigger
an acute-phase response will be accompanied by nutritional losses com-
parable to those seen in other infections.

The major microbial causes of food-borne illness are bacteria, viruses, and
parasites. Chemical contamination of foods occasionally causes illness.
Bacterial food poisoning, the most common type, is caused by ingestion of
water or food that contains living organisms or toxins they produce or
enterotoxins produced in the intestine after their ingestion. These diseases
are most common in the developing world where the water supply is
inadequately treated and food easily becomes contaminated.

As mentioned earlier, food-borne illnesses affect large numbers of people
in the United States. For example, more than 40,000 cases of salmonellosis
(excluding typhoid fever) were reported to CDC in 1982 (CDC 19831,
although only about 2,000 of them were confirmed. Among these cases,
eight deaths were reported (CDC 1985). More than 18,000 cases of
shigellosis were reported in the United States in 1982; although the true
incidence is thought to be considerably higher (CDC 1983), only 116 of the
reported cases were confirmed (CDC 1985). At least one outbreak of
gastrointestinal disease has been traced to Campylobacter fetus contami-

453


0 Nutrition and Health

nation of raw milk (Klein et al. 1986), but some investigators believe that
the incidence of campylobacter-induced illness is greater than the total
combined cases of salmonellosis and shigellosis (Blaser 1983; Skirrow
1977; Archer and Kvenberg 1985). Clostridium perfiingens was confirmed
as the etiologic agent in nearly 2,000 cases of food-borne illness in 1982
(CDC 1985). Clostridium botulinurn causes an average of 15 outbreaks of
food-borne botulism annually in the United States, with 21 outbreaks
involving 30 people and 8 deaths reported for 1982 (CDC 1985). An esti-
mated 20,000 cases of Yersiniu infection occur annually in the United
States, causing acute abdominal symptoms (Kvenberg and Archer 1987).
Although more than 23,000 cases of hepatitis A were reported to the CDC
in 1982 (CDC 1983), only 325 cases were confirmed (CDC 1985). Hepatitis
A is transmitted almost exclusively by the fecal-oral route through food
and water contaminated by food handlers. In 1982, approximately 5,008
cases of food-borne Norwalk gastroenteritis were reported to the CDC
(CDC 1985). These derived from two large outbreaks, one related to eating
bakery items with contaminated icing and the other associated with eating
contaminated coleslaw. Other outbreaks have involved shellfish and drink-
ing water.

Implications for Public Health Policy

Dietary Guidance

General Public

Adequate nutrient and energy intake is critical to the maintenance of
optimal immune function. However, evidence related to the role of specific
dietary factors such as fatty acids, vitamin C, or zinc is insufficient to
recommend changes in dietary guidance policy for the general public.
Evidence related to the role of microbial and chemical contamination of
food and water in human health suggests that the general public should
receive information on appropriate food handling and storage methods to
prevent outbreaks of food-borne disease.

Although the overall public health significance of breastfeeding in the
United States is uncertain, studies in developing countries have shown the
importance of breastfeeding in preventing diarrhea1 diseases and in reduc-
ing their severity. The immune protection conferred by breastfeeding also
helps reduce the severity of certain infectious diseases among infants.
Breastfeeding should continue to be recommended to pregnant women and
to new mothers as the optimal method of infant feeding.

454


Infections and Immunity O

Although the relationship between malnutrition and changes in immune
function observed with aging is not well understood, it is clear that ade-
quate intake of nutrients is basic to the adequate immune protection in
older Americans.

Special Populations

Infections produce well-documented adverse effects on nutritional status,
and nutritional rehabilitation restores immune function and reduces the
severity of infectious disease complications. Thus, the nutritional status of
persons with infectious illnesses should be assessed regularly, and appro-
priate nutritional support measures should be instituted whenever neces-
sary. Qualified health professionals should advise persons with food al-
lergies and intolerances on the diagnosis of these conditions and on diets
that exclude foods and food substances that induce symptoms.

Nutrition Programs and Services

Food Labels

Evidence related to diet-immune function interactions reinforces the need
for food manufacturers to include explicit and complete ingredient state-
ments to protect individuals who may have severe adverse reactions to
foods.

Food Services

Current evidence about the role of dietary factors in the maintenance of
optimal immune function has no special implications for change in policy
related to food service programs. Evidence related to the spread of infec-
tions suggests that food service personnel should receive adequate training
in sanitary food handling and storage procedures.

Food Products

Evidence related to diet-immune function interactions suggests that food
product manufacturers should take special precautions to use good man-
ufacturing practices to avoid contamination with ingredients that may
produce severe reactions and to reduce microbial and chemical contatnina-
tion during production and storage. Manufacturers should continue to
develop new products that are free of substances likely to induce allergic
symptoms in susceptible individuals.

455


-

u Nutrition and Health

Special Populations

Patients with infectious diseases should be treated as rapidly and effective-
ly as possible to minimize the depletion of body nutrients. Convalescing
patients should be counseled and assisted in the development of diets that
provide adequate intake of nutrients to regain an appropriate nutritional
status. Patients with food intolerances should be counseled and assisted in
the development of diets that omit foods and food factors that induce
symptoms.

Research and Surveillance

Research and surveillance issues of special priority related to interactions
between diet, infection, and immunity should include investigations into:

o The mechanisms by which generalized malnutrition depresses the
function of specific components of the immune system.
0 The effects of deficient or excess intake of single nutrients such as
vitamin A, zinc, iron, or dietary fat on specific elements of the immune
system and on immune function.
0 The mechanisms by which deficient or excess intake of single nutrients
might depress or improve immune system function.
o The factors in breast milk that protect infants from infectious disease.
o The role of breast milk in transmitting allergens, infectious agents, or
toxicants such as drugs.

o The role of nutrition in maintaining adequate immune function in older
persons.

o The mechanisms by which infectious diseases alter nutrient metabo-
lism and impair nutritional status.
o The most effective means of restoring nutritional status to mal-
nourished individuals recovering from infectious illnesses.
o The identification of natural food products and chemical additives that
induce adverse physiologic responses and the mechanisms by which
they do so.

o The basic biochemistry of food antigens and biologically active com-
ponents.

o The effects of processing and digestion of food substances with conver-
sion to or inactivation of allergenic fractions.
o The value of therapeutic procedures designed to induce tolerance to
food antigens.

456


Infections and Immunity 0

o The prevalence of food-borne infections and intolerances and immuno-
logic reactions to food in the population.
o The identification of behavioral determinants of unsanitary food han-
dling and storage procedures and the development of effective educa-
tional methods to prevent transmission of food-borne illnesses.
o The effect of nutritional status on susceptibility to infectious diseases,
including HIV infection, and on the complications of AIDS.

457


O Nutrition and Health

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Tracey, K.J.; Lowry. S.F.; and Cerami, A. 1988. Cachectin: a hormone that triggers acute
shock and chronic cachexia. Journal of Infectious Diseases 157(3):413-20.

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Infections and Immunity 0

Victora. C.G.; Smith, P.G.: Vaughan, J.P.; Nobre. L.C.: Lombardi. C.: Teixeira. A.M.;
Fuchs. S.M.; Moreira. L.B.; Gigante, L.P.: and Barros. EC. 1987. Evidence for protection by
breast-feeding against infant deaths from infectious diseases in Brazil. Lancet ii:319-?I.
Walker. W.A. 1981. Antigen uptake in the gut: immunological implications. Immrrnolo~~
Toduy (Feb):3&34.

Watson, R.R. 1984. Nutrition, disease resistance. und immrtne.fitnction. New York: Dekker.

Weissman, 1. 1988. Approaches to an understanding of pathogenic mechanisms in AIDS.
RevieM's ofinfertious Diseases 10(2):385-98.
Welsh, J.K., and May. J.T. 1979. Anti-infective properties of breast milk. Jortrmrl ofPediatrics
94: l-8.

Winick. M.. ed. 1979. Hunger disease. New York: Wiley.

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Chapter 12

Anemia

She was very anaemic. Her thin lips were
pale, and her skin was delicate, of a faint
green colour, without a touch of red even in
         the cheeks.
    W. Somerset Maugham
   OfHuman Bondage, 1915

Introduction

Anemia occurs when the concentration of the pigment hemoglobin in red
blood cells falls below normal. Hemoglobin is essential for delivering
oxygen from the lungs to the body's tissues, and anemia impairs the
capacity of the blood to supply the tissues with oxygen for the production
of cellular energy in the form of adenosine triphosphate. Severe deficits in
the delivery and use of oxygen increase fatigability, decrease work capaci-
ty, impair brain function, and lessen ability to maintain body temperature
(Bothwell et al. 1979; Dallman, Siimes, and Stekel 1980; Finch 1982;
Dallman 1986).

Historical Perspective

Chlorosis, the green sickness or "virgin's disease," was a condition associ-
ated with anemia that afflicted young women in Europe and North America
from about 1500 to 1900 (see quotation). Chlorotic women appeared pale
and suffered weakness, lassitude, breathlessness, and menstrual disor-
ders. This condition was attributed to lovesickness, ovarian insufficiency,
or the pressure from a tight corset on the spleen. Treatment consisted of
bloodletting and the administration of iron tonics and pills, especially in the
19th century after it was established that the disease involved iron deficien-
cy (Loudon 1980). Today, with improved nutrition and better health care,
chlorosis is no longer observed. However, iron deficiency is still prevalent
(Crosby 1987).

The credit for introducing iron into therapeutic use is usually given to the
18th~century English physician Sydenham, who observed improvements

465


O Nutrition and Health

in his anemic patients when he prescribed a "steel tonic" prepared by
steeping iron filings in Rhine wine (McCollum 1957).

Iron was one of the first substances identified as essential in the human
diet. The physiologic function of iron in hemoglobin and its role in anemia
was determined over a 200-year period, from the 1680's, when Boyle first
analyzed the chemical composition of blood, to the 1860's, when iron was
first recognized as an essential nutrient for animals.

Although chlorosis disappeared during the first part of the 20th century, a
relatively rare but more deadly nutritional anemia continued to puzzle
clinicians and scientists until the 1920's. In 1849, Addison first described
pernicious anemia, so called because no cure could be discovered. Not
until 1926 was it learned that extracts of liver-now known to contain
vitamin B,,-could cure the disease (Herbert 1984). A few years later, Wills
discovered that an impure extract of liver could reverse a macrocytic
anemia found in Hindu women in Bombay, particularly in those who were
pregnant. Scientists now know that this extract contained folic acid and that
requirements for this vitamin increase during pregnancy.

The first public health efforts in the United States to prevent iron deficien-
cy occurred during World War II when the Food and Drug Administration
developed regulations for the fortification of cereal and grain products,
including flour (Food and Nutrition Board 1974; Yetley and Glinsmann
1983). Infant cereals were first fortified with iron after about 1950, and
infant formulas began to be fortified with iron in the late 1950's (Marsh,
Long, and Stierwolt 1959). As a result of this and other public health
measures reviewed in this chapter, rates of iron deficiency have declined
rapidly.

Significance for Public Health

Anemia has genetic, environmental, and nutritional causes. For example,
the most frequent causes of anemia among older persons are infection and
chronic disease. Iron deficiency, however, is the most common cause of
anemia among young women and children and is the major focus of this
discussion. When used precisely, the terms anemia, iron deficiency, and
iron deficiency anemia all have distinct meanings. Anemia signifies a blood
hemoglobin concentration that is two standard deviations below the mean
for normal individuals of the same age and sex. Although iron deficiency is
generally the most common cause of anemia, there are many other nutri-
tional, genetic, and environmental causes as well. In this chapter, iron
deficiency refers to a lack of iron that not only results in loss of iron stores,

466


Anemia 0

but that also would be expected to impair iron-dependent physiologic
functions. The term "impaired iron status" has a similar connotation
(LSRO 1984b) and is applied to individuals in whom two or more laboratory
tests of iron metabolism are abnormal. Iron deficiency anemia refers to
anemia that results from iron deficiency or impaired iron status. Iron-
dependent physiologic functions can become impaired before anemia de-
velops. These issues are discussed in greater detail below.

Iron deficiency has received much attention over the years in the United
States, although its overall prevalence is low. The best recent estimates of
impaired iron status are derived from the second National Health and
Nutrition Examination Survey (NHANES II), conducted by the National
Center for Health Statistics between 1976 and 1980 (LSRO 1984b;
Dallman, Yip, and Johnson 1984).

Iron-dependent physiologic functions can be impaired before anemia be-
comes apparent (see below). To estimate the prevalence of impaired iron
status, with or without concurrent anemia, survey results were analyzed
by averaging the results of three methods that detect iron deficiency at
varying stages of development of anemia. The prevalence of impaired iron
status revealed by these methods is given by age and gender in Table 12-1.
These methods found the highest prevalences of iron deficiency among
children ages 1 to 2 (9.3 percent), women ages 15 to 19 (7.2 percent), and
women ages 20 to 44 (6.3 percent). The lowest prevalence, less than 1
percent, was in men between the ages of 15 and 64.

Because iron deficiency anemia represents a late stage of impaired iron
status, rates of clinical anemia would be expected to be even lower than
these figures. Both anemia and iron deficiency were less common in
NHANES II than was anticipated from the limited data of earlier surveys
(Dallman, Yip, and Johnson 1984). Furthermore, the anemia surveillance
data collected primarily on low-income children by the Centers for Disease
Control show a gradual decline in overall prevalence of anemia (as as-
sessed by stringent laboratory criteria), from 7.8 percent in 1975 to 2.9
percent in 1985 (Anonymous 1986; Stockman 1987; Yip, Binkin, et al.
1987). Prevalences among middle-income children were even lower (Yip,
Walsh, et al. 1987). The paucity of moderate or severe anemia in recent
analyses may indicate that iron deficiency is becoming less common in the
United States.

Among infants and younger children in the United States, increased breast-
feeding, greater use of iron-fortified infant formula and cereals, and de-
creased consumption of cow milk during infancy have also improved iron

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u Nutrition and Health

               Table 12-l
Estimates for Percent Prevalence of Impaired Iron Status:
Average of Estimates Using Three Methodsa: NHANES II, 1976-90

As-
(years)

Males and
Females          Males           Females
     Average percent prevalence (range)

l-2        9.3 (9.2-9.4)
3-t        4.3 (3.6-5.5)
S-10       3.9 (3.2-4.5)
11-14                    4.1 (3.5-12.1)      2.8 (2.7-6.1)
15-19                  0.6 (0.1-0.9)      7.2 (2.5-14.2)
2OA4                   0.7 (0.648)      6.3 (4.0-9.6)
45-64                    2.0 (1.9-2.0)       4.4 (3.8-4.8)
65-74                  2.8 (1.8-3.6)      3.2 (2.7-3.7)
*Three methods:
1. Prevalence of two or three abnormal laboratory values using serum ferritin, transferrin
  saturation, and erythrocyte protoporphyrin.

2. Prevalence of two or three abnormal laboratory values using mean red cell volume,
transfenin saturation, and erythrocyte protoporphyrin.
3. Relative prevalence of anemia derived from the rise in median hemoglobin after
exclusion of persons with abnormal laboratory values.

Source: Life Sciences Research office. 1984. Assessment of the iron nutdtional status of
   the U.S. population based on the data collected in the second National Health
   and Nutrition Examination Survey, 1976-1980, ed. S.M. Pilch and F.R. Senti,
   p. 65, Bethesda, MD: Federation of American Societies for Experimental Biology.

status. Some of these changes may have resulted from public health
programs aimed at prevention of iron deficiency.

Although iron deficiency anemia can occur in all socioeconomic groups, it
has historically been most common among the poor (LSRO 1984b; DHHSI
USDA 1986) and is still the case today (Yip, Binkin, et al. 1987; Yip, Walsh,
et al. 1987). This observation provides a basis for the particular attention to
iron nutrition in Federal programs such as the School Lunch Program and
the Special Supplemental Food Program for Women, Infants, and Children
(WIG). The WIC program provides iron-fortified formulas and cereals and
periodic health screenings and has been associated with improved iron
status in its participants independent of socioeconomic status (Yip, Binkin,
et al. 1987).

Studies in Sweden have shown a decline in anemia rates among women,
from 30 percent in 1%5 to 7 percent only 10 years later (Hallberg et al.
1979). This declim! was attributed to a relatively high level of fortification


Anemia 0

offood with iron, and the increased use of iron tablets, increased consump-
tion of ascorbic acid, and the effects of oral contraceptive use. Extrapola-
tion of these results to women in the United States, however, must be made
with caution because both the severity of anemia and levels of fortification
differ in the two countries.

Variations in diagnostic criteria according to age and sex present an addi-
tional difficulty in interpreting data on prevalence rates of anemia. Screen-
ing programs often use hemoglobin status as an initial criterion for diag-
nosis. Hemoglobin levels, however, differ with age and gender and must be
compared with appropriate standards. They may also differ with race. Data
from NHANES indicate that hemoglobin levels are somewhat lower
among black than among white Americans (LSRO 1984b). and some stud-
ies have suggested that such differences remain even after diet, gender, and
socioeconomic factors are taken into account. However. other studies
found that the small differences of mean hemoglobin values between
blacks and whites may be attributable to a subset of blacks who have mild
hereditary anemia such as thalassemia traits (Yip. Schwartz, and Deinard
1984; Castro et al. 1985). Whether these observations mean that the hemo-
globin levels of blacks and whites should be compared with different
standards is as yet uncertain.

Scientiic Background

Causes of Anemia

There are three main causes of anemia: (1) reduced production of red blood
cells and hemoglobin; (2) hemolysis, or increased destruction of red blood
cells; and (3) loss of blood from the circulation, as in internal or external
bleeding. Because the synthesis of blood cells requires many cellular and
metabolic steps, a deficiency of any nutrient essential to hemoglobin
production produces adverse effects on these processes. Good nutrition is
fundamental to adequate red cell production. Nutritional anemia may be
due to a dietary deficiency of iron, folate, vitamin B,*, protein, vitamin E,
vitamin A, vitamin B,, riboflavin, vitamin C, zinc, or copper. Because the
most common nutritional cause of anemia in the United States and in other
developed countries is iron deficiency (LSRO 1984b; Dallman, Yip, and
Johnson 1984), it is the principal focus of this discussion. Deficiencies of
folate (LSRO 1984a), vitamin Blz, and other nutrients are far less signifi-
cant causes. Other causes of anemia include the inherited or acquired
inability to use nutrients required for hemoglobin production, chronic
inflammatory or infectious diseases, and lead poisoning. Normal levels of
hemoglobin also vary according to genetic factors such as race. Thus,


O Nutrition and Health

diagnosis of anemia must distinguish nutritional from other potential
causes and must relate hemoglobin levels to appropriate standards.

Nutritional anemia should be distinguished from deficiencies per se of iron,
folate, or vitamin B,,, because an individual may have manifest any one of
these deficiencies without being anemic. Iron deficiency, for example, in
its early stages is typically present without anemia. The term "iron defi-
ciency anemia" signifies that the iron deficiency has become severe enough
to depress the hemoglobin concentration below the normal range. Al-
though this chapter focuses on nutritional anemia, there are many addition-
al health consequences of nutritional deficiencies that occur concomitantly
with anemia but are not caused by the anemia itself. For example, iron is
not only required for hemoglobin biosynthesis but is also an essential
component of many enzymes required for the production of energy in cells
throughout the body. In iron deficiency, the impairment of these and other
iron-dependent processes may account for disorders in immune function
and behavior that are not directly attributable to the anemia. Similarly, the
impaired nerve function of vitamin B,, deficiency occurs independently of
anemia. Thus, anemia is just one possible consequence of these nutritional
deficiencies.

Role of iron in the Body

The total amount of iron in the body is slightly less than the weight of a 5-
cent coin, about 4 g for adult males (Bothwell et al. 1979). Most of this iron
is used to transport and use oxygen in the production of cellular energy.
The distribution of iron in the bodies of men, women, and infants is given in
Table 12-2. An average of about 58 percent of the body's iron for men and
73 percent for women is contained in hemoglobin, and 11 percent for men
and 14 percent for women is present in myoglobin (which stores oxygen
and makes it available to the muscle when it is needed during contraction).
A smaller but critically important amount of iron, about 3 percent, is
present in iron-containing enzymes such as the cytochromes, which are
required for the production of cell energy.

In addition to these essential iron compounds that fulfill physiologic func-
tions, two proteins, ferritin and hemosiderin, serve as a storage reserve.
These storage compounds account for an average of 25 percent of body
iron in men and 10 percent in women and are located primarily in the liver,
spleen, and bone marrow. There, they serve as alternate sources of iron to
produce essential compounds when dietary supplies are insufflcient. The
vulnerability of an individual to iron deficiency depends on the abundance
of these iron reserves. In some individuals, however, these reserves can
accumulate to toxic levels, most often as a result of a genetically deter-

470


Anemia O

Table 12-2

Total Body Iron and Storage Iron

             Men

Total iron, g        4.0
Hemoglobin iron, %  58
Myoglobin iron, %   11
Enzyme iron, %     3
Storage iron, %     25

Source: Bothwell et al. 1979.

Women

2.7
73
14
3
10

Infants
(age 1 year)

  0.45
78
  6
  5
  11

mined failure to reduce iron absorption when stores are adequate. This and
other causes of iron overload suggest a need for prevention of excessive
iron intake in certain individuals.

Almost all compounds containing iron in the body are continuously broken
down and resynthesized (Bothwell et al. 1979). The iron released by the
degradation of hemoglobin and other iron-containing proteins is efficiently
conserved and reused to replace these compounds. An important conse-
quence of this metabolism is that very little iron is lost from the body on a
daily basis, except when bleeding occurs. In adult men, normal iron losses
in the feces, sweat, and sloughed cells amount to about 0.9 mg/day,
equivalent to less than one-tenth of 1 percent of iron stores. This amount is
readily absorbed from the diet. Women in their childbearing years require
an average of 1.3 mg/day to make up for the additional iron that is lost in
menstrual blood (Bothwell et al. 1979). In children, a proportionately more
generous amount of iron is required for growth (Dallman, Siimes, and
Stekell980). Consequently, premenopausal women and children are more
likely to develop iron deficiency than are men.

Iron Absorption

The bioavailability of iron-that is, the amount absorbed from food-is
determined both by the nature of the diet and by regulatory mechanisms in
the intestinal mucosa that reflect the body's physiologic need for iron. Two
types of iron are present in food: heme iron, which is found principally in
animal products, and nonheme iron, found mainly in plant products.

Nonheme Iron. Most of the iron in the diet, usually more than 80 percent, is
present as nonheme iron and consists primarily of iron salts. The composi-
tion of a meal determines nonheme iron solubility in the upper part of the
small intestine, which, in turn, determines the absorItion of the iron

471


0 Nutrition and Health

(Hallberg 1981; Charlton and Bothwell 1983). Consequently, the amount of
iron finally absorbed is influenced by other constituents of the diet that
either enhance absorption by increasing iron solubility or inhibit absorp-
tion by decreasing solubility in the intestine. For example, nonheme iron
absorption from a representative meal containing enhancers such as meat,
fish, or chicken is about four times greater than when foods containing
inhibitors (e.g., milk, cheese, or eggs) are substituted (Cook and Monsen
1976).

Iron absorption tends to be poor from meals in which whole grain cereals
and legumes predominate, but the addition of even relatively small amounts
of meat or foods containing vitamin C (ascorbic acid) substantially in-
creases the absorption of iron from the entire meal. Compared with water,
orange juice or foods containing vitamin C increase absorption of nonheme
iron from a meal. Tea and coffee, on the other hand, decrease absorption of
nonheme iron when compared with water (Hallberg 1981; Rossander,
Hallberg, and Bjom-Rasmussen 1979).

Breast milk is relatively low in iron, but its iron is relatively well absorbed
(Saarinen, Siimes, and Dallman l'977) in comparison with iron in cow milk
or unfortified cow milk formula. This increased iron absorption may ex-
plain why breastfed infants are less vulnerable to iron deficiency than
infants fed unfortified cow milk formula.

The absorption of iron from infant foods varies with the form of iron, its
concentration, the total iron content and composition of the meal, and,
presumably, the iron status of the child. For example, one study found that
only about 4 percent of the iron was absorbed from a cow milk formula that
was fortified with about 12 mg of iron per liter in the form of ferrous sulfate
and with ascorbic acid (Rios et al. 1975; Saarinen and Siimes 1977). Even at
this low percentage of absorption, the amount of iron in fortified formula
meets the Recommended Dietary Allowances for this age group. Other
investigators have reported higher rates of absorption, especially from
formulas supplemented with both iron and ascorbic acid (Stekel et al.
1986).

Heme Iron. Heme iron comes from the hemoglobin and myoglobin in meat,
poultry, and fish. Although heme iron accounts for a smaller proportion of
iron in the diet than nonheme iron, its role is important; the body absorbs a
much greater percentage of heme iron, and its absorption is less affected by
other dietary constituents than absorption of nonheme iron (Hallberg
1981).

472


Anemia 0

When both forms of iron in the diet are considered, men absorb an average
of about 6 percent of total dietary iron and women absorb 13 percent in their
childbearing years (Charlton and Bothwell 1983). The higher absorption in
women is related to their lower iron stores and helps to compensate for iron
losses of menstruation.

Intestinal Regulation. The regulation of iron entry into the body takes place
in the mucosal cell of the small intestine (Charlton and Bothwell 1983), and
transferrin may act as an iron carrier (Huebers and Finch 1987). If iron
stores are low, as is true for most women and children, transfertin in the
intestinal mucosa readily takes up iron and increases the proportion ab-
sorbed from the diet. The saturation of transferrin is decreased in iron
deficiency. Conversely, the high iron stores typical of men and older
women reduce the percentage of iron absorbed, thereby offering some
protection against iron overload (which is discussed later in this chapter).

Key Scientific Issues

o Role of Iron in Anemia
o Role of Folate and Vitamin B,, in Anemia

Role of Iron in Anemia

Because iron is one of the earth's most abundant elements, it may seem
surprising that iron deficiency should ever become a nutritional problem.
One explanation is that the most common forms of iron in food are rela-
tively insoluble and cannot be absorbed from the intestine. Other factors
predisposing to iron deficiency are related to evolving changes in the diet,
not only during past millennia, but also within the last century (Eaton and
Konner 1985). As noted above, iron is best absorbed from diets that are rich
in meat, poultry, fish, and ascorbic acid and is poorly absorbed from diets
consisting primarily of whole grain cereals and legumes (Hallberg 1981;
Charlton and Bothwell 1983). Even though whole grain foods contain
substantial amounts of iron, the form of iron cannot be as readily dissolved
and absorbed. Thus, in some cases, the iron content of whole grain cereals
and legumes may not wholly compensate for their decreased absorption.
This problem may be one reason that iron deficiency anemia remains much
more common in developing countries than in the United States where
cereal grain products are commonly fortified with iron (Florentino and
Guirriec 1984.

473


0 Nutrition and Health

Stages of Iron Depletion

Iron depletion occurs in three stages (Cook and Finch 1979). The first
involves a decrease in iron stores (as measured by a decrease in serum
ferritin) without loss of essential function. This stage is not associated with
adverse physiologic consequences, but it does represent a condition of
vulnerability. In the United States, women of childbearing age, for exam-
ple, may characteristically have very low iron stores, but in only a very
small number is there a progression to anemia (LSRO 1984b). The risk of
developing anemia is minimized by the body's ability to increase iron
absorption as iron stores diminish.

The second stage is characterized by biochemical changes that reflect the
lack of sufficient iron for normal production of hemoglobin and other
essential iron compounds, as indicated by a fall in transferrin saturation
levels and an increase in erythrocyte protoporphyrin. Because the hemo-
globin concentration has not yet fallen below levels considered anemic, this
stage is regarded as iron deficiency without anemia.

The third stage is frank iron deficiency anemia, which occurs when hemo-
globin production has been sufficiently depressed to result in a hemoglobin
concentration (and mean corpuscular volume) below the normal reference
range for individuals of the same age and sex. In this chapter, the term iron
deficiency refers to the second and third stages.

Causes of Iron Deficiency

The major causes of iron deficiency are insufficient assimilation of iron
from the diet, dilution of body iron by rapid growth, and blood loss
(Bothwell et al. 1979; Dallman, Siimes, and Stekel 1980). Because the
manifestations of iron deficiency are rarely obvious, most cases are de-
tected by laboratory tests done at a routine examination. The groups at
highest risk for iron deficiency are infants, children, adolescents, and
women, especially pregnant women, between the ages of menarche and
menopause (LSRO 1984b).

Age-Related Factors in Susceptibility

Infants. The prevalence of iron deficiency among infants is highest between
about 4 months, when neonatal iron stores accumulated during fetal life are
first likely to become depleted, and 3 years of age (Dallman, Siimes, and
Stekel 1980). During this period, total iron in the body should more than
double to accommodate a rapid rate of growth and an increase in red cell
mass. Excessive consumption of cow milk, which is a poor source of iron
and commonly associated with occult intestinal blood loss in early infancy,

474


Anemia O

is a frequent cause of iron deficiency in young infants (Fomon et al. 198 1).
In premature infants and in twins, iron deficiency anemia may develop as
early as 3 months after birth because their neonatal iron stores are smaller
and weight gain is proportionately greater than in full-term or single infants.
In older children, iron deficiency results from inadequate dietary intake
and is associated with poverty (DHHSIUSDA 1986).

Adolescents. Iron deficiency is common during adolescence (LSRO 1984b;
Dallman, Yip, and Johnson 1984). Boys gain an average of 10 kg, or 22 lb,
during the peak year of their growth spurt, usually between 12 and 15 years
of age. At about the same age as the growth spurt. and in relation to sexual
maturation, the concentration of hemoglobin increases between 0.5 and 1 .O
g/dl/year towards values that are characteristic of adult men. The double
burden of increased red cell mass and increased hemoglobin concentration
requires an increase of about 25 percent in total body iron during the year of
peak growth. Adolescent girls also need more iron. Their average weight
gain during the peak years of the growth spurt-9 kg, or 20 lb, usually
between 10 and 12 years of age-is almost as great as in boys. Although the
concentration of hemoglobin changes very little during this period, the
onset of menstruation imposes additional iron needs.

Women of Childbearing Ages. The major factors that predispose to iron
deficiency anemia in this group are menorrhagia (excessive loss of blood
during menstruation) and pregnancy (Bothwell et al. 1979). Heavy blood
loss occurs in about 20 percent of women (Hallberg et al. 1966). The use of
intrauterine devices increases the prevalence of menorrhagia to about 30 to
50 percent of women, depending on the type used (Israel, Shaw, and Martin
1974). Oral contraceptives, on the other hand, decrease menstrual blood
loss by about half and are rarely associated with menorrhagia (Hefnawi,
Askalani, and Zaki 1974).

Many women with menorrhagia are usually unaware that they have greater-
than-normal menstrual blood loss (Hallberg et al. 1966). For this reason,
blood tests at routine health examinations can sometimes detect anemia in
women, even when the history of menstrual blood loss is unimpressive.

Iron deficiency anemia may develop during pregnancy (Svanberg et al.
1975) because of the increased requirements for iron to supply the expand-
ing blood volume of the mother as well as the rapidly growing fetus and
placenta. True anemia, however, must be distinguished from low hemo-
globin values that normally occur as a result of blood volume expansion and
must be diagnosed with the use of appropriate standards. Healthy women
who are not pregnant have about 2.6 g of total body iron, but only about 0.3

475