PART
Nutrition
Chapter 44  tion Board of the Institute of Medicine provides guidance as to nutrient
Nutritional Requirements
Elizabeth P. Parks, Asim Maqbool,
Ala Shaikhkhalil, Veronique Groleau,
Kelly A. Dougherty, and
Virginia A. Stallings
Nutritional intakes for infants, children, and adolescents should
provide for maintenance of current weight and support normal growth
and development. The infancy growth period is rapid, critical for neu-
rocognitive development, and has the highest energy and nutrient
requirements relative to body size compared with other periods of
growth. It is followed by the childhood period of growth, during which
60% of total growth occurs, and is finally followed by the puberty
phase. Nutrition and growth during the first 3 years of life predict adult
stature and some health outcomes. The major risk period for growth
stunting (impaired linear growth) is between 4 and 24 months of age.
It is critical to identify nutrient deficiencies promptly and to address
them aggressively early in life, because they can impart lasting adverse
effects on growth and development. Dietary intake not only meets
energy requirements but also provides macronutrients and micronu-
trients essential for sustaining the functioning of multiple vital pro-
cesses. Nutrient deficiencies can limit growth, impair immune function,
and increase morbidity and mortality. The significant global burden of
malnutrition and undernutrition is the leading worldwide cause of
acquired immunodeficiency and the major underlying factor for mor-
bidity and mortality globally for children <5 yr of age.
The nutrition transition in many developing countries as popula-
tions change from traditional diets to the Western diet has resulted in
increased life expectancy and adult stature in these populations. Unfor-
tunately, this nutrition transition is also frequently accompanied by
decreased physical activity, and in parallel to decreases in the incidence
and prevalence of communicable (infectious) diseases, there are
increases in the incidence and prevalence of noncommunicable dis-
eases such as noninsulin-dependent diabetes, cardiovascular disease,
obesity, inflammatory bowel disease, and certain cancers.
Consequently, it is important to view the impact of nutrition on
health from various perspectives: to prevent deficiency, to promote
adequacy, and to prevent or reduce the risk for acquiring diseases
associated with excess intakes, such as obesity, diabetes, and cardiovas-
cular disease. Advances in our understanding of the roles of vitamin
D, polyunsaturated fatty acids (PUFAs), and total fiber have changed
our focus from recommendations for deficiency to nutritional intakes
associated with optimal health. In addition, the 2006 World Health
Organization (WHO) growth charts, which are recommended for all
children until 2 years of age, are not only descriptive, but are also pro-
scriptive on how children with adequate nutrition and health care
should grow. Identification and provision of appropriate and adequate
nutrition in infancy and childhood are critical to not only support
normal growth and development, but also to provide the foundation
for lifelong health and well-being.
268
VI
DIETARY REFERENCE INTAKES
The dietary reference intake (DRI) established by the Food and Nutri-
needs for individuals and groups across different life stages and by
gender (Tables 44-1 to 44-4).
Key DRI concepts include the estimated average requirement (EAR),
the recommended dietary allowance (RDA), and the tolerable upper
limit of intake (UL) (Fig. 44-1). The EAR is the average daily nutrient
intake level estimated to meet the requirements for 50% of the popula-
tion, assuming normal distribution; the RDA is an estimate of the daily
average nutrient intake to meet the nutritional needs of >97% of the
individuals in a population, and it can be used as a guideline for indi-
viduals to avoid deficiency in the population. When an EAR cannot be
derived, an RDA cannot be calculated; therefore, an adequate intake
(AI) is developed as a guideline for individuals based on the best avail-
able data and scientific consensus. The UL denotes the highest average
daily intake at which no adverse health effects are associated for almost
all individuals in a particular group. The relationships among EAR,
RDA, and UL are characterized in Figure 44-2.
ENERGY
Energy includes both intake and expenditure. Deficits and excesses of
energy intake yield undesirable health consequences. Inadequate
energy intake can lead to growth faltering, catabolism of body tissues
and inability to provide energy substrate, whereas excess energy intakes
can increase the risk for obesity. Adequacy of energy intake in adults
is associated with maintenance of a healthy weight. The 3 components
of energy expenditure in adults are the basal metabolic rate, thermal
effect of food (energy required for digestion and absorption), and
energy for physical activity. Additional energy intake is required to
support growth and development for children.
The estimated energy requirement (EER) is the average dietary
energy intake predicted to maintain energy balance in a healthy indi-
vidual and accounts for age, gender, weight, stature, and physical activ-
ity level (see Table 44-1). The Dietary Guidelines for Americans 2010
recommend 60 min of moderately intense daily activity for children
>2 yr of age to maintain a healthy weight and to prevent or delay pro-
gression of chronic noncommunicable diseases such as obesity and
cardiovascular disease. The EER was determined based on empirical
research in healthy persons at different physical activity levels, includ-
ing levels different from the recommended levels. They do not neces-
sarily apply to children with acute or chronic diseases. EER is estimated
by equations that account for total energy expenditure, as well as
energy deposition for healthy growth. The EER for infants, relative to
body weight, are approximately twice those for adults because of the
increased metabolic rate and requirements for weight maintenance and
tissue accretion affecting growth.
The nutrients that provide energy intake in the child’s diet are fats
(∼9 kcal/g), carbohydrates (∼4 kcal/g), and proteins (∼4 kcal/g). They
are referred to as macronutrients. Alcohol intake also contributes to
energy intake (∼7 kcal/g). The EER does not specify the relative energy
contributions of macronutrients. Once the minimal intakes of each of
the respective macronutrients are attained to meet physiologic require-
ments and to achieve adequacy (sufficient protein intake to meet
specific amino acid requirements, fat for essential fatty acids, and
neurologic development), the remainder of the intake is used to meet
energy requirements with some degrees of freedom and interchange-
ability among fats, carbohydrates, and proteins. This forms the basis
for the acceptable macronutrient distribution ranges (AMDRs) (see
Table 44-2), expressed as a function of total energy intake.
 Chapter 44  ◆  Nutritional Requirements  269

FAT
Table 44-1 Equations to Estimate Energy Requirement Fat is the most calorically dense macronutrient, providing approxi-
INFANTS AND YOUNG CHILDREN: EER (KCAL/DAY) = TEE + ED mately 9 kcal/g. For infants, human milk/formula are the main dietary
0-3 mo EER = (89 × weight [kg] − 100) + 175 sources of fat, whereas older children get fat from animal products,
4-6 mo EER = (89 × weight [kg] − 100) + 56 vegetable oils, and margarine. The AMDR for fats is 30-40% of total
7-12 mo EER = (89 × weight [kg] − 100) + 22 energy intake for children 1-3 yr and 25-35% for children 4-18 yr of
13-36 mo EER = (89 × weight [kg] − 100) + 20 age. In addition to being energy-dense, fats provide essential fatty acids
and play structural and functional roles; cholesterol moieties are pre-
CHILDREN AND ADOLESCENTS 3-18 YR: EER (KCAL/DAY) =
cursors for cell membranes, hormones, and bile acids. Fat intake
TEE + ED
facilitates absorption of fat-soluble vitamins A, D, E, and K. Both roles
Boys
3-8 yr EER = 88.5 − (61.9 × age [yr] + PA × [(26.7 × weight [kg] +
are particularly relevant in the context of neurological and ocular
(903 × height [m])] + 20 development.
9-18 yr EER = 88.5 − (61.9 × age [yr] + PA × [(26.7 × weight [kg] +
(903 × height [m])] + 25
Girls
3-8 yr EER = 135.3 − (30.8 × age [yr] + PA [(10 × weight [kg] +
Table 44-2 Acceptable Macronutrient Distribution
(934 × height [m])] + 20 Ranges
9-18 yr EER = 135.3 − (30.8 × age [yr] + PA [(10 × weight [kg] +
AMDR (% OF ENERGY)
(934 × height [m])] + 25
Children 1-3 yr Children 4-18 yr
ED, energy deposition; EER, estimated energy requirement; TEE, total energy
expenditure. Fat 30-40 25-35
PA indicates the physical activity coefficient:
For boys: ω6 PUFAs (linoleic acid) 5-10 5-10
PA = 1.00 (sedentary, estimated physical activity level 1.0-1.4)
PA = 1.13 (low active, estimated physical activity level 1.4-1.6) ω3 PUFAs (α-linolenic acid) 0.6-1.2 0.6-1.2
PA = 1.26 (active, estimated physical activity level 1.6-1.9) Carbohydrate 45-65 45-65
PA = 1.42 (very active, estimated physical activity level 1.9-2.5)
For girls: Protein 5-20 10-30
PA = 1.00 (sedentary, estimated physical activity level 1.0-1.4)
PA = 1.16 (low active, estimated physical activity level 1.4-1.6) AMDR, acceptable macronutrient distribution range; PUFA, polyunsaturated
PA = 1.31 (active, estimated physical activity level 1.6-1.9) fatty acid.
PA = 1.56 (very active, estimated physical activity level 1.9-2.5) Adapted from Otten JJ, Hellwig JP, Meyers LD, editors; Institute of Medicine:
Adapted from Kleinman RE, editor: Pediatric nutrition handbook, ed 6, Dietary reference intakes: the essential guide to nutrient requirements,
Elk Grove Village, IL, 2009, American Academy of Pediatrics. Washington, DC, 2006, National Academies Press.

Table 44-3 Dietary Reference Intakes: Macronutrients

LIFE
STAGE ADVERSE EFFECTS OF EXCESSIVE
FUNCTION GROUP RDA OR AI* (g/day) SELECTED FOOD SOURCES CONSUMPTION
TOTAL DIGESTIBLE CARBOHYDRATE
RDA based on its role as Infants Major types: starches and sugars No defined intake level for potential
the primary energy 0-6 mo 60* Grains and vegetables (corn, adverse effects of total digestible
source for the brain 7-12 mo 95* pasta, rice, potatoes, breads) carbohydrate is identified, but the upper
AMDR based on its role Children are sources of starch end of the AMDR was based on
as a source of kcal to >1 yr 130 Natural sugars are found in fruits decreasing risk of chronic disease and
maintain body weight Pregnancy and juices providing adequate intake of other
≤18 yr 175 Sources of added sugars: soft nutrients
19-30 yr 175 drinks, candy, fruit drinks, It is suggested that the maximal intake of
desserts added sugars be limited to providing no
more than 25% of energy
TOTAL FIBER
Improves laxation, Infants Includes dietary fiber naturally Dietary fiber can have variable
reduces risk of 0-6 mo ND present in grains (e.g., oats, compositions; therefore, it is difficult to
coronary heart disease, 7-12 mo ND wheat, unmilled rice) and link a specific source of fiber with a
assists in maintaining Children functional fiber synthesized or particular adverse effect, especially when
normal blood glucose 1-3 yr 190* isolated from plants or animals phytate is also present in the natural fiber
levels 4-8 yr 25* and shown to be of benefit to source
Males health As part of an overall healthy diet, a high
9-13 yr 31* intake of dietary fiber will not produce
14-18 yr 38* deleterious effects in healthy persons
19-21 38* Occasional adverse GI symptoms are
Females observed when consuming some isolated
9-13 yr 26* or synthetic fibers, but serious chronic
14-18 yr 26* adverse effects have not been observed
19-21 yr 25* Owing to the bulky nature of fibers, excess
Pregnancy consumption is likely to be self-limiting;
≤18 yr 28* therefore, an UL was not set for individual
19-21 yr 28* functional fibers
Continued
270  Part VI  ◆  Nutrition

Table 44-3 Dietary Reference Intakes: Macronutrients—cont’d

LIFE
STAGE ADVERSE EFFECTS OF EXCESSIVE
FUNCTION GROUP RDA OR AI* (g/day) SELECTED FOOD SOURCES CONSUMPTION
TOTAL FAT
Energy source Infants Infants: UL not set because there is no defined
When found in foods, is 0-6 mo 31* Human milk or infant formula intake of fat at which adverse effects
a source of ω3 and ω6 7-12 mo 30* Older children: butter, occur.
PUFAs 1-18 yr Insufficient evidence to margarine, vegetable oils, High fat intake will lead to obesity. The
Facilitates absorption of determine AI or EAR; whole milk, visible fat on meat upper end of AMDR is also based on
fat-soluble vitamins see AMDR Table and poultry products, invisible decreasing risk of chronic disease and
41-4 fat in fish, shellfish, some plant providing adequate intake of other
products such as seeds and nutrients
nuts, bakery products Low fat intake (with high carbohydrate) has
been shown to increase plasma
triacylglycerol concentrations and
decrease HDL cholesterol
ω6 POLYUNSATURATED FATTY ACIDS
Essential component of Infants Nuts, seeds; vegetable oils such No defined intake of ω6 level at which
structural membrane 0-6 mo 4.4* as soybean, safflower, corn oil adverse effects occur
lipids, involved with cell 7-12 mo 4.6* Upper end of the AMDR is based on the
signaling, precursor of Children lack of evidence that demonstrates
eicosanoids 1-3 yr 7* long-term safety and human in vitro
Required for normal skin 4-8 yr 10* studies that show increased free-radical
function Males formation and lipid peroxidation with
9-13 yr 12* higher amounts of ω6 fatty acids
14-18 yr 16* Lipid peroxidation is thought to be a
19-21 yr 17* component of atherosclerotic plaques
Females
9-13 yr 10*
14-18 yr 11*
19-21 yr 12*
Pregnancy
≤18 yr 13*
19-21 yr 13*
Lactation
≤18 yr 13*
19-21 yr 13*
ω3 POLYUNSATURATED FATTY ACIDS
Involved with neurologic Infants Vegetable oils, e.g., soybean, No defined intake level for potential
development and 0-6 mo 0.5* canola, flax seed oil; fish oils, adverse effects of ω3 PUFAs is identified
growth 7-12 mo 0.5* fatty fish; smaller amounts in Upper end of AMDR is based on
Precursor of eicosanoids Children meats and eggs maintaining the appropriate balance with
1-3 yr 0.7* ω6 fatty acids and on the lack of evidence
4-8 yr 0.9* that demonstrates long-term safety, along
Males with human in vitro studies that show
9-13 yr 1.2* increased free-radical formation and lipid
14-18 yr 1.6* peroxidation with higher amounts of
19-21 yr 1.6* PUFAs
Females Because the longer-chain n-3 fatty acids,
9-13 yr 1.0* eicosapentaenoic acid (EPA) and
14-18 yr 1.1* docosahexaenoic acid (DHA), are
19-21 yr 1.1* biologically more potent than their
Pregnancy precursor, linolenic acid, much of the work
≤18 yr 1.1* on the adverse effects of this group of
19-21 yr 1.4* fatty acids has been on DHA and EPA
Lactation Lipid peroxidation is thought to be a
≤18 yr 1.3* component in the development of
19-21 yr 1.3* atherosclerotic plaques
SATURATED AND TRANS FATTY ACIDS
The body can synthesize No dietary requirement Saturated fatty acids are present There is an incremental increase in plasma
its needs for saturated in animal fats (meat fats and total and LDL cholesterol concentrations
fatty acids from other butter fat), and coconut and with increased intake of saturated or trans
sources palm kernel oils fatty acids; therefore, the intakes of each
Trans fat: stick margarines, foods should be minimized while consuming a
containing hydrogenated or nutritionally adequate diet
partially hydrogenated
vegetable shortenings
 Chapter 44  ◆  Nutritional Requirements  271

Table 44-3 Dietary Reference Intakes: Macronutrients—cont’d

LIFE
STAGE ADVERSE EFFECTS OF EXCESSIVE
FUNCTION GROUP RDA OR AI* (g/day) SELECTED FOOD SOURCES CONSUMPTION
CHOLESTEROL
No dietary requirement Sources: liver, eggs, foods that
contain eggs, e.g., cheesecake,
custard pie
PROTEIN AND AMINO ACIDS†
Major structural Infants Proteins from animal sources, No defined intake level for potential
component of all cells 0-6 mo 9.1* e.g., meat, poultry, fish, eggs, adverse effects of protein is identified
in the body 7-12 mo 11.0 milk, cheese, yogurt, provide Upper end of AMDR was based on
Functions as enzymes, in Children all 9 indispensable amino acids complementing the AMDR for
membranes, as 1-3 yr 13 in adequate amounts and are carbohydrate and fat for the various age
transport carriers, and 4-8 yr 19 considered “complete groups
as some hormones Males proteins” Lower end of AMDR is set at approximately
During digestion and 9-13 yr 34 Proteins from plants, legumes, the RDA
absorption, dietary 14-18 yr 52 grains, nuts, seeds, and
proteins are broken ≥19 yr 56 vegetables tend to be
down to amino acids, Females deficient in ≥1 of the
which become the 9-13 yr 34 indispensable amino acids and
building blocks of ≥14 yr 46 are called “incomplete
these structural and ≤18 yr proteins”
functional compounds 19-21 yr 71 Vegan diets adequate in total
Nine indispensable protein content can be
amino acids must be “complete” by combining
provided in the diet; sources of incomplete
the body can make the proteins, which lack different
other amino acids indispensable amino acids
needed to synthesize
specific structures from
other amino acids
Note: Starred numbers are AI; bold numbers are RDA. RDAs and AIs may both be used as goals for individual intake. RDAs are set to meet the needs of 97-98% of
members in a group. For healthy breast-fed infants, the AI is the mean intake. The AI for other life-stage and gender groups is believed to cover the needs of all
members of the group, but lack of data prevents specifying with confidence the percentage covered by this intake. AMDR is the range of intake for a particular
energy source that is associated with reduced risk of chronic disease while providing intakes of essential nutrients. With consumption in excess of the AMDR, there is
a potential for increasing the risk of chronic diseases and/or insufficient intakes of essential nutrients. ND amounts are not determinable because of a lack of data
regarding adverse effects in this age group and concern with regard to a lack of ability to handle excess amounts. Source of intake should be from food only to
prevent high levels of intake.
*Adequate intake.
†Based on 1.5 g/kg/day for infants, 1.1 g/kg/day for 1-3 yr, 0.95 g/kg/day for 4-13 yr, 0.85 g/kg/day for 14-18 yr, 0.8 g/kg/day for adults, and 1.1 g/kg/day for
pregnant (using prepregnancy weight) and lactating women.
AI, adequate intake; AMDR, acceptable macronutrient distribution range; GI, gastrointestinal; LDL, low-density lipoprotein (cholesterol); ND, not determinable;
PUFA, polyunsaturated fatty acid; RDA, recommended dietary allowance; UL, upper limit.
Adapted from Food and Nutrition Board, Institute of Medicine: Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and
amino acids http://www.iom.edu/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx.

Table 44-4 Indispensable, Dispensable, and Conditionally Indispensable Amino Acids in the Human Diet
CONDITIONALLY PRECURSORS OF CONDITIONALLY
INDISPENSABLE DISPENSABLE INDISPENSABLE* INDISPENSABLE
Histidine† Alanine Arginine Glutamine/glutamate, aspartate
Isoleucine Aspartic acid Cysteine Methionine, serine
Leucine Asparagine Glutamine Glutamic acid/ammonia
Lysine Glutamic acid Glycine Serine, choline
Methionine Serine Proline Glutamate
Phenylalanine Tyrosine Phenylalanine
Threonine
Tryptophan
Valine
*Conditionally indispensable is defined as requiring a dietary source when endogenous synthesis cannot meet metabolic need.
†Although histidine is considered indispensable, unlike the other 8 indispensable amino acids, it does not fulfill the criteria of reducing protein deposition and
inducing negative nitrogen balance promptly upon removal from the diet.
Adapted from Otten JJ, Hellwig JP, Meyers LD, editors; Institute of Medicine: Dietary reference intakes: the essential guide to nutrient requirements, Washington,
DC, 2006, National Academies Press.
272  Part VI  ◆  Nutrition
EAR
50% 50%
34% 34%
RDA
2.5%
13.5% 13.5%
3 SD 2 SD 1 SD 0 1 SD 2 SD 3 SD
Mean
Median
Percentile
rank
2.5 16 50 84 97.5
Figure 44-1 Dietary reference intakes. Normal requirement distribu-
tion of hypothetical nutrient showing percentile rank and placement of
the estimated average requirement (EAR) and the recommended
dietary allowance (RDA) on the distribution. SD, standard deviation.
EAR
Risk of inadequacy
RDA UL
0.5
0.0
Observed level of intake
Figure 44-2 Dietary reference intakes: the relationship among the
estimated average requirement (EAR), the recommended dietary
allowance (RDA), and the tolerable upper limit of intake (UL). This
figure shows that the EAR is the intake at which the risk of inadequacy
is estimated to be 0.5 (50%). The RDA is the intake at which the risk of
inadequacy would be very small—only 0.02 to 0.03 (2-3%). At intakes
between the RDA and the UL, the risk of inadequacy and of excess are
estimated to be close to 0.0. At intakes above the UL, the potential
risk of adverse effects can increase.
Triglycerides are the most common form of dietary fat and are
composed of 1 glycerol molecule and 3 fatty acids. Triglycerides are
found in animal and vegetable fats. Simple sugars (refined grains and
high sugar drinks) are converted to triglycerides in the liver. Elevated
serum triglycerides are a risk factor for cardiovascular disease and part
of the metabolic syndrome. Decreasing simple sugars and increasing
complex carbohydrate intake reduce serum triglyceride levels.
Dietary saturated fatty acids (found primarily in animal fat and dairy
products), trans fats (found in hydrogenated margarines and oils), and
cholesterol increase the low-density lipoprotein (LDL) fraction of
serum cholesterol, a risk factor for the development of atherosclerosis.
Autopsy studies demonstrate that atherosclerosis begins early in child-
hood, even in infancy. Therefore, dietary advice to optimize cardiovas-
cular health should be dispensed for children starting at age 2 yr when
sufficient fat intake to sustain growth and brain development is less of
a concern.
Because saturated and monounsaturated fats can be synthesized
endogenously to support adequate structural and physiologic require-
ments, there is no AI or RDA set for these dietary components. Trans
fats have no known beneficial effects in humans; therefore, no corre-
sponding AI or RDA has been set. Similarly, an UL has not been set
for cholesterol, saturated, or trans fats because there is a positive linear
association between intake of these fats and increased risk for cardio-
vascular disease, without a threshold level at which risk is increased.
Diets low in saturated fats and cholesterol and without trans fats are
therefore preferred. For optimal cardiovascular health in the general
population, rather than limiting the total amount of fat intake, in most
cases, advice should focus on changing the type of fat that is consumed.
With respect to preventing obesity, all types of fatty acids have about
the same energy content and can contribute to increasing the risk for
obesity. The current dietary guidelines for children and adolescents
recommend that total fat should account for <30% of total daily energy
and saturated fat less than 10%, dietary cholesterol <300 mg/day, with
no trans fat.
Humans are incapable of synthesizing the precursor omega (ω) 3
(α-linolenic acid; ALA) and ω6 (linoleic acid; LA) PUFAs, and are
dependent on diet for these essential fatty acids. Essential fatty acid
2.5%
(EFA) deficiency is associated with desquamating skin rashes, alope-
cia, thrombocytopenia, impaired immunity, and growth deficits, but is
rare in the general population. Essential fatty acids are enzymatically
elongated and desaturated into longer-chain fatty acids; ALA can be
converted to eicosapentaenoic (EPA) and docosahexaenoic (DHA) ω3
PUFAs. LA is converted to arachidonic acid (ARA). Long-chain PUFAs
such as DHA and ARA play a variety of structural and functional roles;
they influence membrane fluidity and function as well as gene expres-
sion, and modulate the inflammatory response. ARA and DHA are
present in breast milk, often supplemented in infant formulas, and are
required for normal growth and development. DHA is present in the
retina and is involved in the visual evoked response in infants.
The conversion of ALA to EPA and DHA and of LA to ARA is
Risk of adverse effects
influenced by many factors, including type and amounts of dietary fats
1.0
and by enzymatic substrate affinity among competing ω3, ω6, ω9, satu-
rated, and trans fatty acids. The efficiency in conversion of ALA to a
longer-chain PUFA is minimal and variable. Approximately 0.5% of
0.5
dietary ALA is converted to DHA and 5% of ALA intake converted to
EPA; therefore, dietary intake of longer-chain PUFAs is an important
determinant of serum and tissue long-chain PUFA status. The biologic
0.0 activity and health benefits of ALA are thought to be derived via the
longer-chain PUFA products EPA and DHA. Consistent with these
findings of limited conversion of ALA to EPA and DHA, and that EPA
and DHA appear to confer the biologic role and health benefits, the
DRI stipulates that up to 10% of the AI for ω3 PUFA (ALA being the
major dietary constituent) can be replaced by DHA and EPA to support
normal neural development and growth.
The ratio of dietary intake of each type of PUFA influences their
relative amounts in different tissue compartments. A dietary ω6:ω3
PUFA ratio of 4-5 : 1 may be beneficial in reducing risk of disease and
may be associated with improved health outcomes, as compared to the
current 15-30 : 1 ratio observed in the United States.
PROTEINS
Proteins and amino acids have structural and functional roles in every
cell in the body. Proteins also provide approximately 4 kcal/g; however,
dietary protein intake is required to replenish the turnover of proteins
and to meet amino acid needs for growth. Dietary protein intake also
provides energy substrate when in excess or during periods of catabo-
lism. Inadequate energy intake and/or inadequate protein intake
increases catabolism of body protein reservoirs (i.e., lean body mass)
so as to provide substrate for energy and free amino acids required to
support normal physiologic function. Nitrogen losses, derived from
proteins, occur through urine, stool, and other bodily excretions.
Increased protein intake may be required for rare hypermetabolic
states, such as extensive burns. Protein energy malnutrition, although
relatively rare in the noninstitutionalized U.S. population, is more
common in the developing world. Protein energy malnutrition impairs
brain, immune system and intestinal mucosal functions.
DRI for protein is provided in Table 44-3. An UL for protein has not
been set. Intake of proteins or specific amino acids needs to be limited
in some health conditions, such as renal disease and metabolic dis-
eases, such as phenylketonuria and maple syrup urine disease, in which
specific amino acids can be toxic.
The amino acid content of dietary protein is also important. Certain
amino acids are indispensable and humans depend on dietary sources
to meet adequacy and prevent deficiency. Certain amino acids are

termed conditional essential/indispensable, meaning they become
essential in patients affected by some diseases or during a certain life
stage, such as with cysteine, tyrosine and arginine in newborns because
of enzymes immaturity (see Table 44-4). Human milk contains both
the indispensable and conditionally indispensable amino acids and
therefore meets the protein requirements for infants. Breast milk is
considered the optimal source of proteins for infants and is the refer-
ence amino acid composition by which biologic quality is determined
for infants. If a single amino acid in a food protein source is low or
absent but is required to support normal metabolism, that specific
amino acid becomes the limiting nutrient. For soy-based infant
formula, supplementation with the limiting amino acid (methionine)
is necessary.
To ensure appropriate growth and to promote satiety, children
should consume the recommended amount of protein. Specific recom-
mendations for appropriate dietary protein sources to meet indispens-
able amino acid requirements are available for groups adopting specific
diets, such as vegetarians and vegans. Inclusion of legumes and corn,
as well as the use of a variety of food sources to provide all of the
required amino acids is a strategy advocated for vegetarians and
vegans.
CARBOHYDRATES
Carbohydrates are abundant in many foods, including cereals, grains,
fruits, and vegetables, and provide approximately 4 kcal/g. Dietary
carbohydrates include monosaccharides, which contain 1 sugar mol-
ecule (glucose, fructose), disaccharides that contain 2 sugar molecules
(sucrose, lactose), oligosaccharides, polysaccharides (which contain
multiple sugar molecules in a chain or complex configuration) (starch),
and sugar alcohols. Carbohydrates (glucose) serve as an essential
energy source for erythrocytes and the central nervous system and a
major energy source for all cells. The requirements for carbohydrates
are based on the average minimum amount of glucose utilized by the
brain. Chronic low carbohydrate intake results in ketosis. Although an
UL for carbohydrates has not been set, a maximal intake of <25% or
<10% of total energy intake from added sugars has been proposed in
various dietary guidelines. Higher intakes of added sugar can displace
other macro- and micronutrients and increase risk for nutrient defi-
ciency and excessive energy intake. There is no distinct advantage or
benefit obtained from discretionary calorie intake such as that pro-
vided by the consumption of added sugars.
The recommended AMDR for carbohydrates (see Table 44-2) were
based upon data suggesting a risk for coronary heart disease with diets
high in carbohydrates and low in fat. These diets, compared to higher
fat intakes, result in high triglycerides, low high-density lipoprotein
(HDL) cholesterol, and small LDL cholesterol particles and are associ-
ated with a high risk of coronary heart disease, especially in sedentary
overweight individuals. Diets within the AMDR for carbohydrates and
fats minimize the risks of diabetes, obesity and coronary heart disease.
Diets with less than the minimum AMDR for carbohydrate most likely
do not meet the AI for fiber (see Table 44-3).
The majority of carbohydrates are present as starches or sugars in
food. Simple sugars (mono- and disaccharides) are often added to
foods and beverages during food preparation, processing, and packag-
ing to enhance palatability and as preservatives. Nondiet soft drinks,
juice drinks, iced tea, and sport drinks are among the major contribu-
tors to added sugars in the diet of U.S. children and adolescents. Added
sugars increase the risk for obesity, diabetes, and dental caries. Fructose
is one such added sugar in the form of high-fructose corn syrup, which
is nearly ubiquitous in the U.S. diet. Fructose increases HDL and tri-
glyceride production in the liver and serum uric acid levels which
increase systolic blood pressure and is associated with fatty liver disease
and metabolic syndrome. Excessive fructose intake, such as in the form
of fruit juices, is associated with diarrhea, abdominal pain, and failure
to thrive in children.
The glycemic index is a measure of the height of blood sugar levels
2 hours following ingestion against the reference standard (a slice of
white bread). The glycemic index has predictable effects on blood
glucose, hemoglobin A1C, insulin, triglycerides, and HDL cholesterol
Chapter 44  ◆  Nutritional Requirements  273
levels. Lower glycemic index foods are recommended and may reduce
the risk of insulin resistance and cardiovascular disease.
FIBER
Fiber consists of nondigestible carbohydrates mostly derived from
plant sources, such as whole grain, fruits, and vegetables, that escape
digestion and reach the colon nearly 100% intact. These compounds
were previously classified as being water soluble versus insoluble,
which may be a relatively less meaningful distinction, although still
commonly used. The DRI classification lists dietary fiber (nondigest-
ible carbohydrates and lignin that are intrinsic and intact in plants),
functional fiber (with known physiologic benefits in humans), and
total fiber (dietary plus functional).
Although fiber intake does not contribute significantly to energy
intake, it does play several important roles. The metabolic fate of fiber
is influenced primarily by the colonic bacteria, which depending on
the structure of the fiber, can render it susceptible to fermentation (e.g.,
pectin and oat bran). Common by-products of colonic fermentation
include carbon dioxide, methane (in addition to other gases), oligo-
fructases (also known as prebiotics-substrates that nourish beneficial
commensurate gastrointestinal microbiota), and short-chain fatty
acids (SCFAs). The common SCFAs produced by fermentation include
acetate, butyrate, and propionate. There is dynamic interplay between
the colonic bacterial milieu and the diet. SCFAs influence colonic
physiology by stimulating colonic blood flow and fluid and electrolyte
uptake. Butyrate is the preferred fuel for the colonocyte, and it might
have a role in maintaining the normal phenotype in these cells.
Dietary fiber might play an important role by diluting toxins, car-
cinogens, and tumor promoters; by decreasing transit time, thereby
decreasing colonic mucosal exposure; and by promoting their expul-
sion in the fecal stream. Dietary fiber resistant to colonic degradation
might also play a role in maintaining and promoting stool bulk and in
the regulation of intraluminal pressure and colonic wall resistance,
disordered colonic motility, or both. Lack of dietary fiber is associated
with constipation and diverticulosis.
All fiber slows gastric emptying and promotes satiety, and thus may
help to regulate appetite. Dietary fiber may decrease the rate of release
and absorption of simple sugars, and help in the regulation of blood
sugar, with lower postprandial blood sugars observed. Dietary fiber
has a low glycemic index, and may have a beneficial effect on insulin
sensitivity. Fiber also binds luminal cholesterol and reduces absorp-
tion and/or enterohepatic circulation of the cholesterol in bile salts
(with the intake of more viscous forms of dietary fiber, such as
pectin). Soluble fiber types (such as guar gum, oat products, pectin)
lower serum cholesterol, while insoluble fiber may reduce serum tri-
glycerides. However, fiber such as psyllium, resistant dextrins, and
resistant starch may also have a role in lowering both serum LDL and
triglycerides. Decreased fiber intake in Western society has been asso-
ciated with the increasing incidence and prevalence of diabetes,
obesity, cardiovascular disease, colon cancer, and inflammatory bowel
disease.
Data are insufficient to establish an EAR for dietary fiber. An AI for
dietary fiber has been established based on the intake levels associated
with reducing risk for cardiovascular disease and in lowering or nor-
malizing serum cholesterol (see Table 44-3). An UL has not been
established for fibers, which are not thought to be harmful to human
health. A general rule of thumb used for fiber intake in children is: age
(in years) + 5 = grams of fiber intake per day.
MICRONUTRIENTS
Vitamins and trace minerals or micronutrients play an essential role
in growth and development and contribute to a host of physiologic
functions. Many U.S. children have suboptimal intake of iron, zinc,
potassium, calcium, vitamin D, and vitamin K, and excess intakes of
sodium. Dietary recommendations for micronutrients were originally
established to prevent deficiency but also include the impact of micro-
nutrients on long-term health outcomes (Table 44-5). Food fortifica-
tion is an effective strategy to prevent some nutrient deficiencies, and
Text continued on p. 281
 274  Part VI  ◆  Nutrition

Table 44-5 Dietary Reference Intakes for Vitamins

LIFE-STAGE RDA SELECTED FOOD ADVERSE EFFECTS OF
NUTRIENT FUNCTION GROUP OR AI UL SOURCES EXCESSIVE CONSUMPTION SPECIAL CONSIDERATIONS
Biotin Coenzyme in Infants (µg/day) Liver No adverse effects of biotin in None
synthesis of fat, 0-6 mo 5* ND Smaller amounts in humans or animals have been
glycogen, and 7-12 mo 6* ND fruits and meats found; this does not mean there
amino acids Children (µg/day) is no potential for adverse
1-3 yr 8* ND effects resulting from high
4-8 yr 12* ND intakes
Males (µg/day) Because data on the adverse
9-13 yr 20* ND effects of biotin are limited,
14-18 yr 25* ND caution may be warranted
19-21 yr 30* ND
Females (µg/day)
9-13 yr 20* ND
14-18 yr 25* ND
19-21 yr 30* ND
Pregnancy (µg/day)
≤18 yr 30* ND
19-21 yr 30* ND
Lactation (µg/day)
≤18 yr 35* ND
19-21 yr 35* ND
Choline Precursor for Infants (mg/day) Milk, liver, eggs, Fishy body odor, sweating, Patients with trimethylaminuria, renal
acetylcholine, 0-6 mo 125* ND peanuts salivation, hypotension, disease, liver disease, depression,
phospholipids, and 7-12 mo 150* ND hepatotoxicity and Parkinson disease may be at risk
betaine Children (mg/day) for adverse effects with choline
1-3 yr 200* 1,000 intakes at the UL
4-8 yr 250* 1,000 AIs have been set for choline, but
Males (mg/day) there is little data to assess whether
9-13 yr 375* 2,000 a dietary supply of choline is needed
14-18 yr 550* 3,000 at all stages of the life cycle, and the
19-21 yr 550* 3,500 choline requirement might be met by
Females (mg/day) endogenous synthesis at some of
9-13 yr 375* 2,000 these stages
14-18 yr 400* 3,000
19-21 yr 425* 3,500
Pregnancy (mg/day)
≤18 yr 450* 3,000
19-21 yr 450* 3,500
Lactation (mg/day)
≤18 yr 550* 3,000
19-21 yr 550* 3,500
Folate aka folic acid, folacin, Coenzyme in the Infants (µg/day) Enriched cereal, Masks neurologic complications In view of evidence linking poor folate
pteroyl-polyglutamates given metabolism of 0-6 mo 65* ND grains, dark leafy in people with vit B12 deficiency intake with neural tube defects, all
as dietary folate equivalents nucleic and amino 7-12 mo 80* ND vegetables, No adverse effects associated women who can become pregnant
(DFE) acids Children (µg/day) enriched and with folate from food or should consume 400 µg/day from
1 DFE = 1 µg food folate = Prevents 1-3 yr 150 300 whole-grain breads supplements have been supplements or fortified foods in
0.6 µg folate from fortified megaloblastic 4-8 yr 200 400 and bread reported; this does not mean addition to intake of food folate from
food or as a supplement anemia Males (µg/day) products, fortified that there is no potential for a varied diet
consumed with food = 9-13 yr 300 600 ready-to-eat cereals adverse effects resulting from
0.5 µg of a supplement 14-18 yr 400 800 high intakes
taken on an empty stomach 19-21 yr 400 1,000 Because data on adverse effects
Females (µg/day) of folate are limited, caution
9-13 yr 300 600 may be warranted
14-18 yr 400 800 UL for folate applies to synthetic
19-21 yr 400 1,000 forms obtained from
Pregnancy (µg/day) supplements and/or fortified
≤18 yr 600 800 foods
19-21 yr 600 1,000
Lactation (µg/day)
≤18 yr 500 800
19-21 yr 500 1,000
Niacin Coenzyme or Infants (mg/day) Meat, fish, poultry, No evidence of adverse effects Extra niacin may be required by
Includes nicotinic acid amide, cosubstrate in many 0-6 mo 2* ND enriched and from consuming naturally persons treated with hemodialysis or
nicotinic acid (pyridine-3 biologic reduction 7-12 mo 4* ND whole-grain breads occurring niacin in food peritoneal dialysis or those with
carboxylic acid), and and oxidation Children (mg/day) and bread Adverse effects from niacin- malabsorption syndrome
derivatives that exhibit the reactions, thus 1-3 yr 6 10 products, fortified containing supplements can
biologic activity of required for energy 4-8 yr 8 15 ready-to-eat cereals include flushing and GI distress
nicotinamide metabolism Males (mg/day) UL for niacin applies to synthetic
Given as niacin equivalents 9-13 yr 12 20 forms obtained from
(NE) 14-18 yr 16 30 supplements, fortified food, or a
1 mg niacin = 60 mg 19-21 yr 16 35 combination of these
tryptophan Females (mg/day)
0-6 mo = preformed niacin 9-13 yr 12 20
(not NE) 14-18 yr 14 30
19-21 yr 14 35
Pregnancy (mg/day)
≤18 yr 18 30
19-21 yr 18 35
Lactation (mg/day)
≤18 yr 17 30
19-21 yr 17 35
Continued
Chapter 44  ◆  Nutritional Requirements  275
 276  Part VI  ◆  Nutrition

Table 44-5 Dietary Reference Intakes for Vitamins—cont’d

LIFE-STAGE RDA SELECTED FOOD ADVERSE EFFECTS OF
NUTRIENT FUNCTION GROUP OR AI UL SOURCES EXCESSIVE CONSUMPTION SPECIAL CONSIDERATIONS
Pantothenic acid Coenzyme in fatty Infants (mg/day) Chicken, beef, No adverse effects associated None
acid metabolism 0-6 mo 1.7* ND potatoes, oats, with pantothenic acid from food
7-12 mo 1.8* ND cereals, tomato or supplements have been
Children (mg/day) products, liver, reported; this does not mean
1-3 yr 2* ND kidney, yeast, egg there is no potential for adverse
4-8 yr 3* ND yolk, broccoli, effects resulting from high
Males (mg/day) whole grains intakes
9-13 yr 4* ND Because data on adverse effects
14-18 yr 5* ND of pantothenic acid are limited,
19-21 yr 5* ND caution may be warranted
Females (mg/day)
9-13 yr 4* ND
14-18 yr 5* ND
19-21 yr 5* ND
Pregnancy (mg/day)
≤18 yr 6* ND
19-21 yr 6* ND
Lactation (mg/day)
≤18 yr 7* ND
19-21 yr 7* ND
Riboflavin aka vitamin B2 Coenzyme in Infants (mg/day) Organ meats, milk, No adverse effects associated None
numerous redox 0-6 mo 0.3* ND bread products, with vitamin B2 consumption
reactions 7-12 mo 0.4* ND fortified cereals from food or supplements have
Children (mg/day) been reported; this does not
1-3 yr 0.5 ND mean there is no potential for
4-8 yr 0.6 ND adverse effects resulting from
Males (mg/day) high intake
9-13 yr 0.9 ND Because data on adverse effects
14-18 yr 1.3 ND of vitamin B2 are limited, caution
19-21 yr 1.3 ND may be warranted
Females (mg/day)
9-13 yr 0.9 ND
14-18 yr 1.0 ND
19-21 yr 1.1 ND
Pregnancy (mg/day)
≤18 yr 1.4 ND
19-21 yr 1.4 ND
Lactation (mg/day)
≤18 yr 1.6 ND
19-21 yr 1.6 ND
Thiamin aka vitamin B1, Coenzyme in the Infants (mg/day) Enriched, fortified, No adverse effects associated Persons who might have increased
aneurin metabolism of 0-6 mo 0.2* ND or whole-grain with vitamin B1 consumption need for vitamin B1 include those
carbohydrates and 7-12 mo 0.3* ND products, bread from food or supplements have being treated with hemodialysis or
branched-chain Children (mg/day) and bread been reported; this does not persons with a malabsorption
amino acids 1-3 yr 0.5 ND products, mixed mean there is no potential for syndrome
4-8 yr 0.6 ND foods whose main adverse effects resulting from
Males (mg/day) ingredient is grain, high intake
9-13 yr 0.9 ND ready-to-eat cereals Because data on adverse effects
14-18 yr 1.2 ND of vitamin B1 are limited, caution
19-21 yr 1.2 ND may be warranted
Females (mg/day)
9-13 yr 0.9 ND
14-18 yr 1.0 ND
19-21 yr 1.1 ND
Pregnancy (mg/day)
≤18 yr 1.4 ND
19-21 yr 1.4 ND
Lactation (mg/day)
≤18 yr 1.4 ND
19-21 yr 1.4 ND
Vitamin A Required for normal Infants (µg/day) Liver, dairy products, Teratologic effects, liver toxicity Persons with high alcohol intake,
Includes provitamin A vision, gene 0-6 mo 400* 600 fish, dark-colored (from preformed vitamin A only) pre-existing liver disease,
carotenoids that are dietary expression, 7-12 mo 500* 600 fruit, leafy hyperlipidemia, or severe protein
precursors of retinol reproduction, Children (µg/day) vegetables malnutrition may be distinctly
Given as retinol activity embryonic 1-3 yr 300 600 susceptible to the adverse effects of
equivalents (RAEs) development, and 4-8 yr 400 900 excess preformed vitamin A intake
1 RAE = 1 µg retinol, 12 µg immune function Males (µg/day) β-Carotene supplements are advised
β-carotene, 24 µg 9-13 yr 600 1,700 only to serve as a provitamin A
α-carotene, or 24 µg 14-18 yr 900 2,800 source for persons at risk for vitamin
β-cryptoxanthin 19-21 yr 900 3,000 A deficiency
To calculate RAEs from REs of Females (µg/day)
provitamin A carotenoids in 9-13 yr 600 1,700
food, divide the REs by 2 14-18 yr 700 2,800
For preformed vitamin A in 19-21 yr 700 3,000
food or supplements and for Pregnancy (µg/day)
provitamin A carotenoids in ≤18 yr 750 2,800
supplements, 1 RE = 1 RAE 19-21 yr 770 3,000
Lactation (µg/day)
≤18 yr 1,200 2,800
19-21 yr 1,300 3,000
Continued
Chapter 44  ◆  Nutritional Requirements  277
 278  Part VI  ◆  Nutrition

Table 44-5 Dietary Reference Intakes for Vitamins—cont’d

LIFE-STAGE RDA SELECTED FOOD ADVERSE EFFECTS OF
NUTRIENT FUNCTION GROUP OR AI UL SOURCES EXCESSIVE CONSUMPTION SPECIAL CONSIDERATIONS
Vitamin B6 Coenzyme in the Infants (mg/day) Fortified cereals, No adverse effects associated None
Comprises a group of 6 metabolism of 0-6 mo 0.1* ND organ meats, with vitamin B6 from food have
related compounds: amino acids, 7-12 mo 0.3* ND fortified soy-based been reported; this does not
pyridoxal, pyridoxine, glycogen, and Children (mg/day) meat substitutes mean there is no potential for
pyridoxamine, and sphingoid bases 1-3 yr 0.5 30 adverse effects resulting from
5′-phosphates (PLP, PNP, 4-8 yr 0.6 40 high intake
PMP) Males (mg/day) Because data on adverse effects
9-13 yr 1.0 60 of vitamin B6 are limited, caution
14-18 yr 1.3 80 may be warranted
19-21 yr 1.3 100 Sensory neuropathy has occurred
Females (mg/day) from high intakes of
9-13 yr 1.0 60 supplemental forms
14-18 yr 1.2 80
19-21 yr 1.3 100
Pregnancy (mg/day)
≤18 yr 1.9 80
19-21 yr 1.9 100
Lactation (mg/day)
≤18 yr 2.0 80
19-21 yr 2.0 100
Vitamin B12 aka cobalamin Coenzyme in nucleic Infants (µg/day) Fortified cereals, No adverse effects have been Because 10-30% of older people
acid metabolism 0-6 mo 0.4* ND meat, fish, poultry associated with consumption of malabsorb food-bound vitamin B12,
Prevents 7-12 mo 0.5* ND the amounts of vitamin B12 those >50 yr are advised to meet
megaloblastic Children (µg/day) normally found in food or their RDA mainly by consuming
anemia 1-3 yr 0.9 ND supplements; this does not foods fortified with vitamin B12 or a
4-8 yr 1.2 ND mean there is no potential for supplement containing vitamin B12
Males (µg/day) adverse effects resulting from
9-13 yr 1.8 ND high intake
14-18 yr 2.4 ND Because data on adverse effects
19-21 yr 2.4 ND of vitamin B12 are limited,
Females (µg/day) caution may be warranted
9-13 yr 1.8 ND
14-18 yr 2.4 ND
19-21 yr 2.4 ND
Pregnancy (µg/day)
≤18 yr 2.6 ND
19-21 yr 2.6 ND
Lactation (µg/day)
≤18 yr 2.8 ND
19-21 yr 2.8 ND
Vitamin C aka ascorbic acid, Cofactor for reactions Infants (mg/day) Citrus fruit, tomatoes, GI disturbances, kidney stones, Smokers require additional 35 mg/day
dehydroascorbic acid (DHA) requiring reduced 0-6 mo 40* ND tomato juice, excess iron absorption of vitamin C over that needed by
copper or iron 7-12 mo 50* ND potatoes, Brussels nonsmokers
metalloenzyme and Children (mg/day) sprouts, cauliflower, Nonsmokers regularly exposed to
as a protective 1-3 yr 15 400 broccoli, tobacco smoke should ensure they
antioxidant 4-8 yr 25 650 strawberries, meet the RDA for vitamin C
Males (mg/day) cabbage, spinach
9-13 yr 45 1,200
14-18 yr 75 1,800
19-21 yr 90 2,000
Females (mg/day)
9-13 yr 45 1,200
14-18 yr 65 1,800
19-21 yr 75 2,000
Pregnancy (mg/day)
≤18 yr 80 1,800
19-21 yr 85 2,000
Lactation (mg/day)
≤18 yr 115 1,800
19-21 yr 120 2,000
Vitamin E aka α-tocopherol A metabolic function Infants (mg/day) Vegetable oil, No evidence of adverse effects Patients on anticoagulant therapy
α-Tocopherol includes has not yet been 0-6 mo 4* ND unprocessed cereal from consuming vitamin E should be monitored when taking
RRR-α-tocopherol, the only identified 7-12 mo 5* ND grains, nuts, fruit, naturally occurring in food vitamin E supplements
form of α-tocopherol that Vitamin E’s major Children (mg/day) vegetables, meat Adverse effects from vitamin
occurs naturally in foods, and function appears to 1-3 yr 6 200 E–containing supplements may
the 2R-stereoisomeric forms be as a nonspecific 4-8 yr 7 300 include hemorrhagic toxicity
of α-tocopherol (RRR-, RSR-, chain-breaking Males (mg/day) UL for vitamin E applies to any
RRS-, and RSS-α-tocopherol) antioxidant 9-13 yr 11 600 form of α-tocopherol obtained
that occur in fortified foods 14-18 yr 15 800 from supplements, fortified
and supplements 19-21 yr 15 1,000 foods, or a combination of
It does not include the Females (mg/day) these
2S-stereoisomeric forms of 9-13 yr 11 600
α-tocopherol (SRR-, SSR-, 14-18 yr 15 800
SRS-, and SSS-α-tocopherol), 19-21 yr 15 1,000
also found in fortified foods Pregnancy (mg/day)
and supplements ≤18 yr 15 800
19-21 yr 15 1,000
Lactation (mg/day)
≤18 yr 19 800
19-21 yr 19 1,000
Continued
Chapter 44  ◆  Nutritional Requirements  279
 Table 44-5 Dietary Reference Intakes for Vitamins—cont’d
280  Part VI  ◆  Nutrition

LIFE-STAGE RDA SELECTED FOOD ADVERSE EFFECTS OF

NUTRIENT FUNCTION GROUP OR AI UL SOURCES EXCESSIVE CONSUMPTION SPECIAL CONSIDERATIONS
Vitamin K Coenzyme during the Infants (µg/day) Green vegetables No adverse effects associated Patients on anticoagulant therapy
synthesis of many 0-6 mo 2.0* ND (collards, spinach, with vitamin K consumption should monitor vitamin K intake
proteins involved in 7-12 mo 2.5* ND salad greens, from food or supplements have
blood clotting and Children (µg/day) broccoli), Brussels been reported in humans or
bone metabolism 1-3 yr 30* ND sprouts, cabbage, animals; this does not mean
4-8 yr 55* ND plant oil, margarine there is no potential for adverse
Males (µg/day) effects resulting from high
9-13 yr 60* ND intake
14-18 yr 75* ND Because data on adverse effects
19-21 yr 120* ND of vitamin K are limited, caution
Females (µg/day) may be warranted
9-13 yr 60* ND
14-18 yr 75* ND
19-21 yr 90* ND
Pregnancy (µg/day)
≤18 yr 75* ND
19-21 yr 90* ND
Lactation (µg/day)
≤18 yr 75* ND
19-21 yr 90* ND
Note: Starred numbers are AI, and bold numbers are RDA. RDAs and AIs may both be used as goals for individual intake. RDAs are set to meet the needs of 97-98% of members in a group. For healthy breast-fed
infants, the AI is the mean intake. The AI for other life stage and gender groups is believed to cover the needs of all members of the group, but lack of data prevents specifying with confidence the percentage covered
by this intake.
UL is the maximum level of daily nutrient intake that is likely to pose no risk of adverse effects. Unless otherwise specified, the UL represents total intake from food, water, and supplements. Because of a lack of
suitable data, ULs could not be established for potassium, water, and inorganic sulfate. In the absence of ULs, extra caution may be warranted in consuming levels above recommended intakes.
ND amounts are not determinable because of a lack of data of adverse effects in this age group and concern with regard to lack of ability to handle excess amounts. Source of intake should be from food only to
prevent high levels of intake.
*Adequate intake. *RDA for vitamin D in IU/day: 400 if <1 yr age, 600 if >1 yr, lactating, or pregnant.
AI, adequate intake; GI, gastrointestinal; ND, not determinable; PLP, pyridoxal phosphate; PMP, pyridoxamine phosphate; PNP, pyridoxine phosphate; RDA, recommended dietary allowance; UL, upper limit.
Adapted from Food and Nutrition Board, Institute of Medicine: Dietary reference intakes for calcium, phosphorous, magnesium, vitamin D, and fluoride (website), www.nap.edu/openbook.php?record_id=5776; Dietary
reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline (website), www.nap.edu/openbook.php?record_id=6015; Dietary reference intakes for vitamin C,
vitamin E, selenium, and carotenoids (website), www.nap.edu/openbook.php?record_id=9810; and Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese,
molybdenum, nickel, silicon, vanadium, and zinc (website), www.nap.edu/openbook.php?record_id=10026.

has been successfully implemented to prevent iodine and folate
deficiency.
Breast milk provides optimal intake of most nutrients including iron
and zinc. Although they present in lower amounts than in infant
formula, they are more bioavailable and sufficient to meet infant needs
until ~4-6 mo of age. After 4-6 mo of age, iron and zinc are required
from complementary foods, such as iron-fortified cereal and pureed
meats.
Iron requirements are higher during infancy and childhood as com-
pared to later life stages, and are higher for menstruating females as
compared to males of similar age groups (see Chapter 54). Iron present
in animal protein is more bioavailable than that found in vegetables
and other foods because it is already incorporated into heme moieties
in blood and muscle. Iron deficiency is the most common micronutri-
ent deficiency and is associated with iron-deficiency anemia and neu-
rocognitive deficits. Zinc deficiency affects millions of children and is
associated with increased risk for impaired linear growth (stunting),
impaired immune function, and increased risk for respiratory and
diarrheal diseases.
Breast milk is a poor source of vitamin D (see Chapter 51). Vitamin
D insufficiency is more common than previously thought in infants
and children. Vitamin D is central to calcium and bone metabolism,
but is also an important determinant of various nonosseous health
outcomes. Vitamin D is absorbed in the skin from sunlight and is also
present naturally in some foods and fortified in all cow milk products,
regardless of fat content, soy milk, almond milk, and orange juice.
Sunlight exposure varies by season. Therefore, for populations residing
in northern latitudes and/or who have darker skin, sunlight exposure
is unlikely to meet the vitamin D needs over the year; in these groups,
additional sunlight exposure and/or vitamin D supplementation may
be required to achieve optimal status.
Children with darker skin and those who do not consume fortified
products should be screened for vitamin D deficiency. The DRI for
vitamin D is based on its effects on calcium status and bone health.
The goal is to achieve serum levels of 25(OH) D levels above 50 nmol/L
(30 ng/dL), which is often achieved using vitamin D supplementation.
In 2010, the American Academy of Pediatrics increased total vitamin
D intake recommendations to 600 IU/day for infants and children. A
supplement was recommended for all breast-fed infants to ensure suf-
ficient intake.
Calcium adequacy is determined in part as a function of bone health
as measured by bone mineral content and density. The main storage
organs for calcium are the bones and teeth. Bone mineral accretion
occurs primarily in the pediatric age range, with peak bone mass being
achieved by the 2nd to 3rd decade of life. Calcium recommendations
vary by age and were also increased from AI to RDA, and the UL was
increased in 9-18 yr olds (Table 44-6).
Vitamin K is an important determinant of bone health, but is also
an important cofactor for coagulation factors (factors II, VII, IX, and
X; protein C; and protein S) (see Chapter 53). Status can be assessed
by prothrombin time, protein in the absence of vitamin K (PIVKA-II)
and the vitamin K–dependent coagulation factor levels. Neonates are
at risk for suboptimal vitamin K status, leading to an increased risk for
hemorrhagic disease of the newborn. Vitamin K prophylaxis at birth
is recommended for all newborn infants.
Potassium and sodium are the main intra- and extracellular cations,
respectively, and are involved in transport of fluids and nutrients across
the cellular membrane. There is an AI set for potassium related to its
effects in maintaining a healthy blood pressure, reducing risk for neph-
rolithiasis, and supporting bone health. Moderate potassium defi-
ciency can occur even in the absence of hypokalemia and can result in
increased blood pressure, stroke, and other cardiovascular disease.
Most American children have potassium intake below the current rec-
ommendations. African-Americans in particular are at increased risk
for potassium deficiency. For people at increased risk for hypertension
and who are salt sensitive, reducing sodium intake and increasing
potassium intake is advised. Leafy green vegetables, vine fruit (such as
tomatoes) and root vegetables are good food sources of potassium (see
Table 44-6). People with impaired renal function may need to reduce
Chapter 44  ◆  Nutritional Requirements  281
potassium intake as hyperkalemia can increase risk for fatal cardiac
arrhythmias among these patients.
Sodium has an AI, but given the risk of hypertension, an UL has
also been set. The UL threshold may be even lower in African-
Americans, who, on average, are more salt sensitive, and for those with
hypertension or preexisting renal disease. Dietary sodium intake also
displaces potassium intake. Elevated sodium: potassium ratios can
increase the risk for nephrolithiasis. Intakes of <2,300 mg (approxi-
mately 1 tsp) per day are recommended. The average daily salt intake
for most people in the United States and Canada exceeds both the AI
and UL. Most dietary salt in the United States is found in processed
foods, breads, condiments, and as a food preservative, and to enhance
palatability. For populations with or at risk for hypertension and renal
disease, sodium intake should be decreased to <1,500 mg/day and potas-
sium intake increased to >4,700 mg/day. For persons with hypertension,
additional dietary guidelines are available from the Dietary Approaches
to Stop Hypertension (DASH) eating plan.
WATER
The water requirement and content as a proportion of body weight are
highest in infants and decrease with age. Water intake is achieved with
liquid and food intake, and losses include excretion in the urine and
stool as well as insensible and evaporative losses through the skin and
respiratory tract. An AI has been established for water (see Table 44-6).
Special considerations are required by life stages and by basal meta-
bolic rate, physical activity, body proportions (surface area to volume),
environment, and underlying medical conditions. Breast milk and
infant formula provide adequate water, and additional water intake is
not required until complementary foods are introduced. Although
water contains no calories, the concern is that water intake might actu-
ally decrease breast milk intake and displace the intake of essential
nutrients during this metabolically very active life stage. The increased
fluid needs of infants and young children can be explained in part by
the high ratio of body surface area to volume in infancy and high
respiratory rate.
The consequences of inadequate fluid intake include dehydration,
impaired thermoregulation and heat dissipation, reduced activity tol-
erance and performance, and reduced intravascular fluid. These defi-
cits can result in an increased compensatory heart rate, hypotension
and syncope, and, if uncorrected, renal injury or nephrolithiasis.
Excess free water intake is usually better tolerated by healthy adults
than by younger children, who may be at increased risk for water
intoxication. Hyponatremia can result from excess free water intake
coupled with inadequate sodium intake. Fluid intake requirements and
restrictions are also influenced by underlying renal and hormonal dis-
orders, including diabetes, the syndrome of inappropriate antidiuretic
hormone secretion, and diabetes insipidus.
MEASURING NUTRITIONAL ADEQUACY
Growth according to expected patterns can be tracked using the 2000
Centers for Disease Control and Prevention (CDC) and 2006 WHO
growth charts (see Chapters 6 and 15). The WHO growth charts are
derived from longitudinal and cross-sectional data obtained from a
sample of healthy breast-fed infants and children (0-5 yr) who were
receiving adequate nutritional intake and medical care from Brazil,
Ghana, India, Norway, Oman, and the United States. Consequently, the
WHO growth charts are not only descriptive of population average and
distribution, but are also prescriptive regarding how adequately nour-
ished healthy children under best-care practices should grow. The
CDC and American Academy of Pediatrics recommend the use of the
WHO charts to monitor growth of all infants and children (breast and
bottle or infant formula fed) from birth to 2 yr of age, and the use of
the CDC 2000 growth charts for children 2 to 20 yr of age.
Although the WHO and CDC growth charts are recommended for
growth and nutritional assessment, a number of disease-specific charts
are available. It is noteworthy that many other disease- or syndrome-
specific growth charts are based on small samples of children, and
include children with suboptimal nutritional status. For these patient
Text continued on p. 286
Table 44-6 Dietary Reference Intakes for Select Micronutrients and Water
ADVERSE EFFECTS
LIFE-STAGE SELECTED FOOD OF EXCESSIVE
NUTRIENT FUNCTION GROUP AI (mg/day) UL (mg/day) SOURCES CONSUMPTION SPECIAL CONSIDERATIONS
Sodium Maintains fluid Infants Processed foods with Hypertension AI is set based on ability to obtain a
282  Part VI  ◆  Nutrition

volume outside of 0-6 mo 120 ND added sodium chloride Increased risk of nutritionally adequate diet for other
cells and thus 7-12 mo 370 ND (salt), benzoate, cardiovascular nutrients and to meet the needs for
normal cell Children phosphate; salted disease and stroke sweat losses for persons engaged in
function 1-3 yr 1,000 1,500 meats, bread, nuts, cold recommended levels of physical activity
4-8 yr 1,200 1,900 cuts; margarine; butter; Persons engaged in activity at higher
Males salt added to foods in levels or in humid climates resulting in
9-13 yr 1,500 2,200 cooking or at the table excessive sweat might need more than
14-21 yr 1,500 2,300 Salt is ∼ 40% sodium by the AI
Females weight UL applies to apparently healthy persons
9-13 yr 1,500 2,200 without hypertension; it thus may be
13-21 yr 1,500 2,300 too high for persons who already have
Pregnancy and Lactation hypertension or who are under the care
≥14 yr 1,500 2,300 of a health professional

Chloride With sodium, Infants Processed foods with In concert with Chloride is lost, usually with sodium, in
maintains fluid 0-6 mo 180 ND added sodium chloride sodium, results in sweat, as well as in vomiting and
volume outside of 7-12 mo 570 ND (salt), benzoate, hypertension diarrhea
cells and thus Children phosphate; salted AI and UL are equimolar in amount to
normal cell 1-3 yr 1,500 2,300 meats, nuts, cold cuts; sodium because most of sodium in diet
function 4-8 yr 1,900 2,900 margarine; butter; salt comes as sodium chloride (salt)
Males added to foods in
9-13 yr 2,300 3,400 cooking or at the table
14-21 yr 2,300 3,600 Salt is ∼60% chloride by
Females weight
9-13 yr 2,300 3,400
13-21 yr 2,300 3,600
Pregnancy and Lactation
≥14 yr 2,300 3,600
Potassium Maintains fluid Infants Fruits and vegetables, None documented Persons taking drugs for cardiovascular
volume inside/ 0-6 mo 400 None set dried peas, dairy from food alone, disease such as ACE inhibitors, ARBs,
outside of cells 7-12 mo 700 products, meats, nuts but potassium or potassium-sparing diuretics should
and thus normal Children from supplements be careful not to consume
cell function; acts 1-3 yr 3,000 No UL or salt substitutes supplements containing potassium and
to blunt the rise 4-8 yr 3,800 can result in might need to consume less than the
of blood pressure Males hyperkalemia and AI
in response to 9-13 yr 4,500 possibly sudden
excess sodium 14-21 yr 4,700 death if excess is
intake, and Females consumed by
decrease markers 9-13 yr 4,500 persons with
of bone turnover 13-21 yr 4,700 chronic renal
and recurrence of Pregnancy insufficiency
kidney stones ≥14 yr 4,700 (kidney disease) or
Lactation diabetes
≥14 yr 5,100
Vitamin D aka Maintains serum Infants (µg/day)* Fish liver oils, flesh of Elevated plasma Patients on glucocorticoid therapy might
calciferol calcium and 0-6 mo 10 25 fatty fish, liver and fat 25(OH)D require additional vitamin D
1 µg calciferol = phosphorus 7-12 mo 10 38 from seals and polar concentration
40 IU vitamin D concentrations Children (µg/day)* bears, eggs from hens causing
DRI values are 1-3 yr 15 63 that have been fed hypercalcemia
based on 4-8 yr 15 75 vitamin D, fortified milk
absence of Males (µg/day)* products, fortified
adequate 9-21yr 15 100 cereals
exposure to Females (µg/day)*
sunlight 9-21 yr 15 100
Pregnancy (µg/day)*
≤18 yr 15 100
Lactation (µg/day)
≤18 yr 15 100
19-21 yr 15 100
Calcium Essential role Infants Milk, cheese, yogurt, corn Kidney stones, Amenorrheic women (exercise- or
in blood 0-6 mo 200 1,000 tortillas, calcium-set hypercalcemia, anorexia nervosa–induced) have
clotting, muscle 7-12 mo 260 1,500 tofu, Chinese cabbage, milk alkali reduced net calcium absorption
contraction, nerve Children kale, broccoli syndrome, and
transmission, and 1-3 yr 700 2,500 renal insufficiency
bone and tooth 4-8 yr 1,000 2,500
formation Males
9-18 yr 1,300 3,000
19-21 yr 1,000 2,500
Females
9-18 yr 1,300 3,000
19-21 yr
Pregnancy
≤18 yr 1,300 3,000
19-21 yr 1,000 2,500
Lactation
≤18 yr 1,300 3,000
19-21 yr 1,000 2,500
Continued
Chapter 44  ◆  Nutritional Requirements  283
Table 44-6 Dietary Reference Intakes for Select Micronutrients and Water—cont’d
284  Part VI  ◆  Nutrition

ADVERSE EFFECTS
LIFE-STAGE SELECTED FOOD OF EXCESSIVE
NUTRIENT FUNCTION GROUP AI (mg/day) UL (mg/day) SOURCES CONSUMPTION SPECIAL CONSIDERATIONS
Iron Critical component Infants Heme sources: meat, GI distress Persons with decreased gastric acidity
of enzymes, 0-6 mo 0.27 40 poultry, fish may be at increased risk for deficiency
cytochromes, 7-12 mo 11 40 Nonheme sources: dairy, Cow’s milk is a poor source of
myoglobin, and Children eggs, plant-based bioavailable iron and is not
hemoglobin 1-3 yr 7 40 foods, breads, cereals, recommended for children <1 yr old
4-8 yr 10 40 breakfast foods Neurocognitive deficits have been
Males reported in infants with iron deficiency
9-13 yr 8 40 RDA for females increases with
14-18 yr 11 45 menarche related to increased losses
19-21 yr 8 45 during menstruation
Females Vegans and vegetarians might require
9-13 yr 8 40 iron supplementation or intake of
14-18 yr 15 45 iron-fortified foods
19-21 yr 18 45 GI parasites can increase iron losses via
Pregnancy GI bleeds
≤18 yr 27 45 Iron supplements can interfere with zinc
19-21 yr 27 45 absorption and vice versa; if
Lactation supplements are being used, the doses
≤18 yr 10 45 should be staggered
19-21 yr 9 45
Zinc Essential for proper Infants Meats, shellfish, legumes, Acutely zinc Zinc supplements interfere with iron
growth and 0-6 mo 2 4 fortified cereals, whole supplements cause absorption and vice versa; therefore, if
development, and 7-12 mo 3 5 grains GI irritation and supplements are being used, the doses
an important Children headache; chronic should be staggered
catalyst for 100 1-3 yr 3 7 effects of zinc Zinc deficiency can be associated with
specific enzymes 4-8 yr 5 12 supplementation stunting or impaired linear growth
Males include impaired
9-13 yr 8 23 immune function,
14-18 yr 11 34 changes in
19-21 yr 11 40 lipoprotein and
Females cholesterol levels,
9-13 yr 8 23 and reduced
14-18 yr 9 34 copper status
19-21 yr 8 40
Pregnancy
≤18 yr 12 34
19-21 yr 11 40
Lactation
≤18 yr 13 34
19-21 yr 12 40
 Water Maintains Infants (L/day) All beverages, including No UL because Recommended intakes for water are
homeostasis in 0-6 mo 0.7 None set water normally based on median intakes of generally
the body 7-12 mo 0.8 Moisture in foods functioning healthy persons who are adequately
Allows transport of Children High-moisture foods kidneys can handle hydrated
nutrients to cells 1-3 yr 1.3 include watermelon, >0.7 L (24 oz) of Persons can be adequately hydrated at
and removal and 4-8 yr meats, soups fluid per hour levels above or below the AIs provided;
1.7
excretion of waste Symptoms of water AIs provided are for total water in
Males (L/day)
products of intoxication temperate climates
9-13 yr 2.4
metabolism include All sources can contribute to total water
14-18 yr 3.3 hyponatremia, needs: beverages (tea, coffee, juice,
≥19 yr 3.7 which can result in soda, and drinking water) and moisture
Females (L/day) heart failure, and found in foods
9-13 yr 2.1 rhabdomyolysis Moisture in food accounts for ∼ 20% of
14-18 yr 2.3 (skeletal muscle total water intake
≥19 yr 2.7 tissue injury), which Thirst and consumption of beverages at
Pregnancy (L/day) can lead to kidney meals are adequate to maintain
≥14 yr 3.0 failure hydration
Lactation (L/day)
≥14 yr 3.8
Note: Bold numbers are RDA. RDAs and AIs may both be used as goals for individual intake. RDAs are set to meet the needs of 97-98% of members in a group. For healthy breast-fed infants, the AI is the mean intake.
The AI for other life-stage and gender groups is believed to cover the needs of all members of a group, but lack of data prevents specifying with confidence the percentage covered by this intake. UL is the maximum
level of daily nutrient intake that is likely to pose no risk of adverse effects. Unless otherwise specified, the UL represents total intake from food, water, and supplements. Because of a lack of suitable data, ULs could not
be established for potassium, water, and inorganic sulfate. In the absence of ULs, extra caution may be warranted in consuming levels above recommended intakes. ND amounts are not determinable because of a lack
of data on adverse effects in this age group and concern with regard to lack of ability to handle excess amounts. Source of intake should be from food only to prevent high levels of intake.
*Vitamin D RDA in IU/day: 40 if <1 yr, 600 if >1 yr of age or pregnant or lactating.
ACE, angiotensin-converting enzyme; AI, adequate intake; ARB, angiotensin receptor blocker; GI, gastrointestinal; ND, not determinable; RDA, recommended dietary allowance; UL, upper limit.
Adapted from Food and Nutrition Board, Institute of Medicine: Dietary reference intakes for water, potassium, sodium, chloride, and sulfate (website). http://www.nap.edu/openbook.php?record_id=10925.
Chapter 44  ◆  Nutritional Requirements  285
groups, disease-specific charts may be helpful to use in conjunction
with the WHO or CDC growth charts for comparison to children of
similar age and sex from the general population. The goal should be
to use this information to approximate growth as closely to that of the
general population as possible in these subsets of children, where and
when possible. In addition to anthropometry, other nutrient biomark-
ers can be used to assess status. For infants and children with specific
dietary or health concerns, consultation with lactation consultants,
registered dieticians, and/or physician nutrition specialists may also be
indicated.

Bibliography is available at Expert Consult.


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Bhutta ZA, Salam RA: Global nutrition epidemiology and trends, Ann Nutr Metab
61(Suppl 1):19S–27S, 2012.
Gidding SS, Dennison BA, Birch LL, et al: American Heart Association: dietary
recommendations for children and adolescents: a guide for practitioners,
Pediatrics 117:544–559, 2006.
Grummer-Strawn LM, Reinold C, Krebs NF: Use of World Health Organization
and CDC growth charts for children aged 0-59 months in the United States,
MMWR Recomm Rep 59:1–15, 2010.
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Washington, DC, 2011, The National Academies Press.
Institute of Medicine (IOM): Dietary Reference Intakes. The Essential Guide to
Nutrient Requirements, Washington, DC, 2006, National Academies Press.
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Keast DR, Fulgoni VL 3rd, Nicklas TA, et al: Food sources of energy and nutrients
among children in the United States: National Health and Nutrition
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Kleinman RE, editor: Pediatric nutrition handbook, ed 6, Elk Grove Village, IL,
2009, American Academy of Pediatrics.
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286  Part VI  ◆  Nutrition

Table 45-1 Selected Beneficial Properties of Human

Milk Compared to Infant Formula
Secretory IgA Specific antigen-targeted antiinfective
action
Lactoferrin Immunomodulation, iron chelation,
antimicrobial action, antiadhesive,
trophic for intestinal growth
κ-Casein Antiadhesive, bacterial flora
Oligosaccharides Prevention of bacterial attachment
Cytokines Antiinflammatory, epithelial barrier
function
Growth factors
Epidermal growth factor Luminal surveillance, repair of intestine
Chapter 45  Transforming growth Promotes epithelial cell growth (TGF-β)

Feeding Healthy Infants,

factor (TGF) Suppresses lymphocyte function (TGF-β)
Nerve growth factor Promotes neural growth

Children, and Adolescents Enzymes

Platelet-activating Blocks action of platelet-activating
Elizabeth P. Parks, Ala Shaikhkhalil, factor-acetylhydrolase factor

Veronique Groleau, Danielle Wendel, Glutathione peroxidase Prevents lipid oxidation

and Virginia A. Stallings Nucleotides Enhance antibody responses, bacterial
flora
Adapted from Hamosh M: Bioactive factors in human milk, Pediatr Clin North
Early nutrition plays an important role in the origin of adult diseases Am 48:69–86, 2001.
such as type 2 diabetes, hypertension, obesity, and the metabolic syn-
drome; therefore, appropriate feeding practices should be established
in the neonatal period and continued throughout childhood and ado- Table 45-2 Conditions for Which Human Milk Has
lescence to adulthood. Healthy feeding in children requires partner- Been Suggested to Possibly Have a
ships between family members, the healthcare system, schools, the Protective Effect
community, and the government.
Acute disorders Crohn disease
FEEDING DURING THE FIRST YEAR OF LIFE Diarrhea Childhood cancer
Otitis media Lymphoma
Breastfeeding Urinary tract infection Leukemia
The American Academy of Pediatrics (AAP) and World Health Orga- Necrotizing enterocolitis Recurrent otitis media
nization (WHO) have declared breastfeeding and the administration Septicemia Allergy
of human milk to be the normative practice for infant feeding and Infant botulism Obesity and overweight
nutrition. Breastfeeding has documented short- and long-term medical Insulin-dependent diabetes mellitus Hospitalizations
and neurodevelopmental advantages (Tables 45-1 and 45-2) and rare Celiac disease Infant mortality
contraindications (Table 45-3). Thus the decision to breastfeed should
be considered a public health issue and not only a lifestyle choice. The
AAP and the WHO recommend that infants should be exclusively knowledge of breastfeeding. As part of the discharge teaching process,
breastfed or given breast milk for 6 months. Breastfeeding should be issues surrounding infant feeding, elimination patterns, breast engorge-
continued with the introduction of complementary foods for 1 year or ment, basic breast care, and maternal nutrition should be discussed. A
longer, as mutually desired by mother and infant. The success of breast- follow-up appointment is recommended within 24-48 hr after hospital
feeding initiation and continuation depends on multiple factors, such discharge.
as education about breastfeeding, hospital breastfeeding practices and
policies, routine and timely follow-up care, and family and societal Nipple Pain
support (Table 45-4). Nipple pain is one of the most common complaints of breastfeeding
Feedings should be initiated soon after birth unless medical condi- mothers in the immediate postpartum period. Poor infant positioning
tions preclude them. Mothers should be encouraged to nurse at each and improper latch are the most common reasons for nipple pain
breast at each feeding starting with the breast offered second at the last beyond the mild discomfort felt early in breastfeeding. If the problem
feeding. It is not unusual for an infant to fall asleep after the first breast persists and the infant refuses to feed, consideration needs to be given
and refuse the second. It is preferable to empty the first breast before to nipple candidiasis. If present the mother should be treated with an
offering the second in order to allow complete emptying of both breasts antifungal cream that is wiped away before feeding, and the infant
and therefore better milk production. Table 45-5 summarizes patterns treated with oral medication.
of milk supply in the 1st week.
New mothers should be instructed about infant hunger cues, correct Engorgement
nipple latch, positioning of the infant on the breast, and feeding fre- In the second stage of lactogenesis, physiologic fullness of the breast
quency. It is also suggested that someone trained in lactation observe occurs. Breasts may become engorged: firm, overfilled, and painful as
a feeding to evaluate positioning, latch, milk transfer and maternal the pattern and volume of milk production is adjusting to the infant’s
responses, and infant satiety. Attention to these issues during the birth feeding schedule. Incomplete removal of milk as a result of poor breast-
hospitalization allows dialogue with the mother and family and can feeding technique or infant illness can cause engorgement. Breastfeed-
prevent problems that could occur with improper technique or ing immediately at signs of infant hunger will eventually prevent this
 Chapter 45  ◆  Feeding Healthy Infants, Children, and Adolescents  287

Table 45-3 Absolute and Relative Contraindications Table 45-4 Recommendations on Breastfeeding
to Breastfeeding Because of Maternal Management for Healthy Term Infants
Health Conditions
1. Exclusive breastfeeding for about 6 months
MATERNAL HEALTH • Breastfeeding preferred; alternatively expressed mother’s milk,
CONDITION DEGREE OF RISK or donor breast milk
• To continue for at least the first year and beyond as long as
HIV and HTLV infection In the United States, breastfeeding is mutually desired by mother and child
contraindicated • Complementary foods rich in iron and other micronutrients
In other settings, health risks of not should be introduced at about 6 mo of age
breastfeeding must be weighed against 2. Peripartum policies and practices that optimize breastfeeding
the risk of transmitting virus to the initiation and maintenance should be compatible with the AAP
infant and Academy of Breastfeeding Medicine Model Hospital Policy
Tuberculosis infection Breastfeeding is contraindicated until and include the following:
completion of approximately 2 wk of • Direct skin-to-skin contact with mothers immediately after
appropriate maternal therapy delivery until the first feeding is accomplished and encouraged
throughout the postpartum period
Varicella-zoster Infant should not have direct contact to • Delay in routine procedures (weighing, measuring, bathing,
infection active lesions blood tests, vaccines, and eye prophylaxis) until after the first
Infant should receive immune globulin feeding is completed
Herpes simplex Breastfeeding is contraindicated with • Delay in administration of intramuscular vitamin K until after
infection active herpetic lesions of the breast the first feeding is completed but within 6 hr of birth
• Ensure 8-12 feedings at the breast every 24 hr
CMV infection May be found in milk of mothers who are • Ensure formal evaluation and documentation of breastfeeding
CMV seropositive by trained caregivers (including position, latch, milk transfer,
Transmission through human milk causing examination) at least once for each nursing shift
symptomatic illness in term infants is • Give no supplements (water, glucose water, commercial infant
uncommon formula, or other fluids) to breastfeeding newborn infants
unless medically indicated using standard evidence-based
Hepatitis B infection Infants routinely receive hepatitis B
guidelines for the management of hyperbilirubinemia and
immune globulin and hepatitis B
hypoglycemia
vaccine if mother is HbsAg positive
• Avoid routine pacifier use in the postpartum period
No delay in initiation of breastfeeding is
• Begin daily oral vitamin D drops (400 IU) at hospital discharge
required
3. All breastfeeding infants should be seen by a pediatrician within
Hepatitis C infection Breast-feeding is not contraindicated 48 to 72 hr after discharge from the hospital
• Evaluate hydration (elimination patterns)
Alcohol intake Limit maternal alcohol intake to • Evaluate body weight gain (body weight loss no more than 7%
<0.5 g/kg/day (for a woman of average from birth and no further weight loss by day 5: assess feeding
weight, this is the equivalent of 2 cans and consider more frequent follow-up)
of beer, 2 glasses of wine, or 2 oz of • Discuss maternal/infant issues
liquor) • Observe feeding
Cigarette smoking Discourage cigarette smoking, but 4. Mother and infant should sleep in proximity to each other to
smoking is not a contraindication to facilitate breastfeeding
breastfeeding 5. Pacifier should be offered, while placing infant in back-to-sleep-
position, no earlier than 3 to 4 weeks of age and after
Chemotherapy, Breastfeeding is generally contraindicated breastfeeding has been established
radiopharmaceuticals
From American Academy of Pediatrics: Breast-feeding and the use of human
CMV, cytomegalovirus; HbsAg, hepatitis B surface antigen; HIV, human milk, Pediatrics 129:e827–e841, 2012.
immunodeficiency virus; HTLV, human T-lymphotropic virus.
Data from Schanler RJ, Krebs NF, Mass SB (eds): Breastfeeding handbook for
physicians, ed 2, Elk Grove Village, IL, 2014, American Academy of Pediatrics, Inadequate Milk Intake
pp 223–226.
Insufficient milk intake, dehydration, and jaundice in the infant can
become evident within the first week of life. Signs of insufficient milk
from occurring. To reduce engorgement, breasts should be softened intake include: lethargy, delayed stooling, decreased urine output,
prior to infant feeding with a combination of hot compresses and weight loss >7% of birth weight, hypernatremic dehydration, incon-
expression of milk. Between feedings a supportive bra should be worn, solable crying and increased hunger. Insufficient milk intake may be
cold compresses applied, and oral nonsteroidal antiinflammatory med- caused by insufficient milk production, failure of established breast-
ications administered. feeding, and health conditions in the infant that prevent proper breast
stimulation. Parents should be counseled that breastfed neonates feed
Mastitis 8-12 times a day with a minimum of 8 times per day. Careful attention
Mastitis occurs in 2-3% of lactating women and is usually unilateral, to prenatal history can identify maternal factors that may be associ-
manifesting with localized warmth, tenderness, edema, and erythema ated with this problem (failure of breasts to enlarge during pregnancy
after the second postdelivery week. Sudden onset of breast pain, or within the first few days after delivery). Direct observation of
myalgia, and fever with fatigue, nausea, vomiting, and headache can breastfeeding can help identify improper technique. If a large volume
also occur. Organisms implicated in mastitis include Staphylococcus of milk is expressed manually after breastfeeding, then the infant
aureus, Escherichia coli, group A streptococcus, Haemophilus influen- might not be extracting enough milk, eventually leading to decreased
zae, Klebsiella pneumoniae, and Bacteroides spp. Diagnosis is con- milk output. Late preterm infants (34-36 wk) are at risk for insuffi-
firmed by physical examination. Oral antibiotics and analgesics, while cient milk syndrome because of poor suck and swallow patterns or
promoting breastfeeding or emptying of the affected breast, usually medical issues.
resolve the infection. A breast abscess is a less common complication
of mastitis, but it is a more serious infection that requires intravenous Jaundice
antibiotics, incision, and drainage, along with temporary cessation of Breastfeeding jaundice is a common reason for hospital readmission
feeding from that breast. of healthy breastfed infants and is largely related to insufficient fluid
288  Part VI  ◆  Nutrition
Table 45-5 Patterns of Milk Supply
DAY OF LIFE MILK SUPPLY
Day 1 Some milk (~5 mL) may be expressed
Days 2-4 Lactogenesis, milk production increases
Day 5 Milk present, fullness, leaking felt
Day 6 onward Breasts should feel “empty” after feeding
Adapted from Neifert MR: Clinical aspects of lactation: promoting
breastfeeding success, Clin Perinatol 26:281–306, 1999.
intake during the first week of life (see Chapter 102.3). It may also be
associated with dehydration and hypernatremia. Breast milk jaundice
is a different disorder that causes persistently high serum indirect bili-
rubin in a thriving healthy baby that becomes evident later than breast-
feeding jaundice, but which generally declines in the 2nd to 3rd wk of
life. Infants with severe or persistent jaundice should be evaluated for
other medical causes (see Chapter 102.3) before ascribing the jaundice
to breast milk that might contain inhibitors of glucuronyl transferase
or enhanced absorption of bilirubin from the gut. Persistently high
bilirubin levels may require changing from breast milk to infant
formula for 24-48 hr and/or treatment with phototherapy without ces-
sation of breastfeeding. Breastfeeding should resume after the decline
in serum bilirubin. Parents should be reassured and encouraged to
continue collecting breast milk during the period when the infant is
taking formula.
Collecting Breast Milk
The pumping of breast milk is a common practice when the mother
and baby are separated for work, illness, or hospitalization of mother
or infant. Good hand washing and hygiene should be emphasized.
Electric breast pumps are more efficient and better tolerated by
mothers than mechanical pumps or manual expression. Collection
kits should be cleaned with hot soapy water, rinsed, and air dried after
each use. Glass or plastic containers should be used to collect the
milk, and milk should be refrigerated and then used within 48 hr.
Expressed breast milk can be frozen and used for up to 6 mo. Milk
should be thawed rapidly by holding under running tepid water and
used completely within 24 hr after thawing. Milk should never be
microwaved.
Growth of the Breastfed Infant
The rate of weight gain of the breastfed infant differs from that of the
formula-fed infant, and the infant’s risk for excess weight gain during
late infancy may be associated with bottle feeding. The WHO growth
charts are based on the growth of healthy breastfed infants through the
1st yr of life. These standards (http://www.who.int/childgrowth) are the
result of a study in which >8,000 children were selected from 6 coun-
tries. The infants were selected based on healthy feeding practices
(breastfeeding), good health care, high socioeconomic status, and non-
smoking mothers, so that they reflect the growth of breastfed infants
in the optimal conditions and can be used as prescriptive rather than
normative curves. Charts are available for growth monitoring from
birth to age 6 yr. The Centers for Disease Control and Prevention
(CDC) recommends use of the WHO growth charts for infants 0-23
months of age, and CDC growth charts for ages 24 mo to 20 yr.
Formula Feeding (Fig. 45-1)
Despite efforts to promote exclusive breastfeeding through 6 months,
less than 50% of women continue to breastfeed at 6 months. Most
women make their infant feeding choices early in pregnancy. Parental
preference is the most common reason for using infant formula.
However, infant formula is also indicated in infants whose intake of
breast milk is contraindicated for infant factors (e.g. inborn errors of
metabolism), and maternal factors (see Table 45-3). In addition infant
formula is used as a supplement to support inadequate weight gain in
breastfed infants.
Infant formulas marketed in the United States are safe and nutrition-
ally adequate as the sole source of nutrition for healthy infants for the
first 6 months of life. Infant formulas are available in ready-to-feed,
concentrated liquid or powder forms. Ready-to-feed products gener-
ally provide 20 kcal/30 mL (1 oz) and approximately 67 kcal/dL. Con-
centrated liquid products, when diluted according to instructions,
provide a preparation with the same concentration. Powder formulas
come in single or multiple servings and when mixed according to
instructions will result in similar caloric density.
Although infant formulas are manufactured in adherence to good
manufacturing practices and are regulated by the U.S. Food and Drug
Administration (FDA), there are still potential safety issues. Powder
preparations are not sterile, and although the number of bacterial
colony-forming units per gram of formula is generally lower than
allowable limits, outbreaks of infections with Enterobacter sakazakii
have been documented, especially in premature infants. The powder
preparations can contain other coliform bacteria but have not been
linked to disease in healthy term infants. Care must be taken in
following the mixing instructions to avoid over- or underdilution,
to use boiled or sterilized water, and to use the specific scoops pro-
vided by the manufacturer as scoop sizes vary. Water that has been
boiled should be allowed to cool fully to prevent degradation of heat
labile nutrients, specifically vitamin C. Well water should be tested
regularly for bacteria and toxin contamination. Municipal water can
contain variable concentrations of fluoride, and if the concentrations
are high, bottled water that is defluoridated should be used to avoid
toxicity.
Parents should be instructed to use proper handwashing techniques
when preparing formula and feedings for the infant. Guidance to
follow written instructions for storage should also be given. Once
opened, ready-to-feed and concentrated liquid containers can be
covered with aluminum foil or plastic wrap and stored in the refrigera-
tor for no longer than 48 hr. Powder formula should be stored in a
cool, dry place; once opened, cans should be covered with the original
plastic cap or aluminum foil, and the powdered product can be used
within 4 weeks. Once prepared, all bottles regardless of type of formula
should be used within 24 hours. Formula should be used within 2
hours of removal from the refrigerator and once a feeding has started,
that formula should be used within an hour or be discarded. Prepared
formula stored in the refrigerator should be warmed by placing the
container in warm water for ~5 min. Formula should not be heated in
a microwave, because it can heat unevenly and result in burns despite
appearing to be at the right temperature when tested.
Formula feedings should be ad libitum, with the goal of achieving
growth and development to the child’s genetic potential. The usual
intake to allow a weight gain of 25-30 g/day will be 140-200 mL/kg/
day in the first 3 months of life. The rate of weight gain declines from
3-12 months of age.
COW MILK PROTEIN–BASED FORMULAS
Intact cow milk–based formulas in the United States contain a protein
concentration varying from 1.8 to 3 g/100 kcal or (1.45-1.6 g/dL), con-
siderably higher than in mature breast milk (1.5 g/100 kcal). This
increased concentration is designed to meet the needs of the youngest
infants but leads to excess protein intake for older infants. In contrast,
breastfed infants receive protein intakes that match their needs at
various ages. The whey : casein ratio varies from 18 : 82 to 60 : 40; one
manufacturer markets a formula that is 100% whey. The predominant
whey protein is β-globulin in cow milk and α-lactalbumin in human
milk. This and other differences between human milk and cow milk–
based formulas result in different plasma amino acid profiles in infants
on different feeding patterns, but a clinical significance of these differ-
ences has not been demonstrated.
Plant or a mixture of plant and animal oils are the source of fat in
infant formulas; fat provides 40-50% of the energy in cow milk–based
formulas. Fat blends are better absorbed than dairy fat and provide
saturated, monounsaturated, and polyunsaturated fatty acids (PUFAs).
All infant formulas are supplemented with long-chain PUFAs, docosa-
hexaenoic acid (DHA), and arachidonic acid (ARA) at varying
 Chapter 45  ◆  Feeding Healthy Infants, Children, and Adolescents  289

Breast feeding 4-6 months Contraindicated – Yes

Cultural, religious choice Inadequate breast milk Metabolic Infectious

Vegetarianism Medical contraindication diseases diseases
Galactosemia to breast feeding

Metabolic formulas
Soy protein based Cow milk protein-based
formula formula

Transient Cow milk protein

lactose allergy (IgE mediated)*
intolerance

Same family
Lactose-free

Continue human milk or - Family history of allergy / atopy

4-6 months
formula intake - Cow milk protein allergy (non-IgE mediated)
- Cannot breast-feed
From 4-12 months
Cereals Hydrolysate formulas
Culturally based foods
Meats * On a clinical basis, differentiation of IgE mediated or non IgE
Fruits and vegetables mediated cow milk protein allergy is difficult and there is cross
reactivity with soy protein allergy. Therefore, a protein
Juices
hydrosylate formula is suggested.
Introduction of pureed
foods

Figure 45-1 Feeding algorithm for term infants. (From Gamble Y, Bunyapen C, Bhatia J: Feeding the term infant. In Berdanier CD, Dwyer J,
Feldman EB, editors: Handbook of nutrition and food, Boca Raton, FL, 2008, CRC Press, pp 271–284, Fig. 15-3.)

concentrations. ARA and DHA are found at varying concentrations in
human milk and vary by geographic region and maternal diet. No
studies in term infants have found a negative effect of DHA and ARA
supplementation, and some studies have demonstrated positive effects
on visual acuity and neurocognitive development. A critical review
concluded that there are no consistent effects of long-chain PUFAs on
visual acuity in term infants. A Cochrane review concluded that
routine supplementation of milk formula with long chain PUFAs to
improve the physical, neurodevelopmental, or visual outcomes of term
infants cannot be recommended based on the current evidence. DHA
and ARA are derived from single-cell microfungi and microalgae and
are classified as generally recognized as safe for use in infant formulas
at approved concentrations and ratios.
Lactose is the major carbohydrate in breast milk and in standard
cow milk–based formulas for term infants. Formulas for term infants
may also contain modified starch or other complex carbohydrates.
Carbohydrates comprise 69-75g/L of cow milk–based formula.
SOY FORMULAS
Soy protein–based formulas on the market are all free of cow milk–
based protein and lactose and use sucrose, corn syrup solids, and/or
maltodextrin to provide 67 kcal/dL. They meet the vitamin, mineral,
and electrolyte guidelines from the AAP and the FDA for feeding term
infants. The protein is a soy isolate supplemented with l-methionine,
l-carnitine, and taurine to provide a protein content of 2.45-2.8 g per
100 kcal or 1.7-1.8 g/dL.
The quantity of specific fats varies by manufacturer and is usually
similar to the manufacturer’s corresponding cow milk–based formula.
The fat content is 5.0-5.5 g per 100 kcal or 3.4-3.6 g/dL. The oils used
in both cow milk and soy formula include soy, palm, sunflower, olein,
safflower, and coconut. DHA and ARA are also added.
In term infants, although soy protein–based formulas have been
used to provide nutrition resulting in normal growth patterns, there
are few indications for use in place of cow milk–based formula. Indica-
tions for soy formula include galactosemia and hereditary lactase defi-
ciency, because soy–based formulas are lactose-free; and situations in
which a vegetarian diet is preferred. Most healthy infants with acute
gastroenteritis can be managed after rehydration with continued use
of breast milk or cow–based formulas and do not require a lactose-free
formula, such as soy-based formula. However, soy protein–based
formulas may be indicated when documented secondary lactose intol-
erance occurs. Soy protein–based formulas have no advantage over
cow protein–based formulas as a supplement for the breastfed infant,
unless the infant has one of the indications noted previously and are
not recommended for preterm infants. The routine use of soy protein–
based formula has no proven value in the prevention or management
of infantile colic, fussiness, or atopic disease. Infants with documented
cow protein–induced enteropathy or enterocolitis often are also sensi-
tive to soy protein and should not be given isolated soy protein–based
formula. They should be provided formula derived from extensively
hydrolyzed protein or synthetic amino acids. Soy formulas contain
phytoestrogens, which have been shown to have physiologic activity in
rodent models but a meta-analysis of the topic done by the Center for
the Evaluation of Risks to Human Reproduction concluded that there
is minimal concern for adverse developmental effects in infants fed soy
formula.
PROTEIN HYDROLYSATE FORMULA
Protein hydrolysate formulas may be partially hydrolyzed, containing
oligopeptides with a molecular weight of <5000 Da, or extensively
hydrolyzed, containing peptides with a molecular weight <3000 Da.
Partially hydrolyzed proteins have fat blends similar to cow milk–based
formulas, and carbohydrates are supplied by corn maltodextrin or corn
syrup solids. Because the protein is not extensively hydrolyzed, these
formulas should not be fed to infants who are allergic to cow protein.
In studies of formula fed infants who are at high risk of developing
290  Part VI  ◆  Nutrition
atopic disease there is modest evidence that childhood atopic derma-
titis may be delayed or prevented by the use of extensively or partially
hydrolyzed formulas, compared with cow milk–based formula. Com-
parative studies of the various hydrolyzed formulas have also indicated
that not all formulas have the same protective benefit. Extensively
hydrolyzed formulas may be more effective than partially hydrolyzed
in preventing atopic disease. Extensively hydrolyzed formulas are rec-
ommended for infants intolerant to cow milk or soy proteins. These
formulas are lactose free and can include medium-chain triglycerides,
making them useful in infants with gastrointestinal malabsorption as
a consequence of cystic fibrosis, short gut syndrome, prolonged diar-
rhea, and hepatobiliary disease.
AMINO ACID FORMULAS
Amino acid formulas are peptide-free formulas that contain mixtures
of essential and nonessential amino acids. They are designed for infants
with dairy protein allergy who failed to thrive on extensively hydro-
lyzed protein formulas. The effectiveness of amino acid formulas to
prevent atopic disease has not been studied.
Milk and Other Fluids
Neither breastfed nor formula-fed infants require additional water
unless dictated by high environmental temperature. Vomiting and spit-
ting up are common in infants. When weight gain and general well-
being are noted, no change in formula is necessary.
Whole cow milk should not be introduced until 12 mo of age. In
children between 12 and 24 mo of age for whom being overweight or
obesity is a concern or who have a family history of obesity, dyslipid-
emia, or cardiovascular disease, the use of reduced-fat milk is appro-
priate. Otherwise whole milk is recommended until age 24 months
changing to 2% at 24 months, and 1% at 3 yr of age for healthy chil-
dren. Regardless of the type, all milk consumed should be pasteurized.
Infants and young children are particularly susceptible to infections
such as E. coli, Campylobacter, and Salmonella found in raw or unpas-
teurized milk. For cultural and other reasons, such as parental prefer-
ence, goat milk is sometimes given in place of formula although this
is not recommended. Goat milk has been shown to cause significant
electrolyte disturbances and anemia because it has low folic acid
concentrations.
COMPLEMENTARY FEEDING
The timely introduction of complementary foods (solid and liquid
foods other than breast milk or formula, also called weaning foods or
beikost) during infancy is necessary to enable transition from milk
feedings to other table foods and is important for nutritional and
developmental reasons (Table 45-6). The ability of exclusive breastfeed-
ing to meet macronutrient and micronutrient requirements becomes
limiting with increasing age of the infant. The recommendation for
Table 45-6 Important Principles for Weaning
Begin at 6 mo of age
At the proper age, encourage a cup rather than a bottle
Introduce 1 food at a time
Energy density should exceed that of breast milk
Iron-containing foods (meat, iron-supplemented cereals) are
required
Zinc intake should be encouraged with foods such as meat, dairy
products, wheat, and rice
Phytate intake should be low to enhance mineral absorption
Breast milk should continue to 12 mo, formula or cow milk is then
substituted
Give no more than 24 oz/day of cow milk
Fluids other than breast milk, formula, and water should be
discouraged
Give no more than 4-6 oz/day of fruit juices; no sugar sweetened
beverages
Adapted from American Academy of Pediatrics: Pediatric nutrition handbook,
ed 6, Elk Grove Village, IL, 2008, American Academy of Pediatrics.
timing of complementary feed initiation is based on the benefits on
neurodevelopment and prevention of future comorbidities (see Table
45-2) from exclusive breastfeeding for 6 months. The AAP, WHO, and
European Society for Pediatric Gastroenterology, Hepatology, and
Nutrition Committee on Nutrition all recommend exclusive breast-
feeding for the first 6 months. Similar data on the benefits of the
exclusive use of formula for 6 months have not been published.
Some complementary foods are more nutritionally appropriate than
others to complement breast milk or infant formula. The food con-
sumption patterns of U.S. infants and toddlers demonstrate that nearly
all infants ≤12 mo consumed some form of milk every day; infants
>4 mo consumed more formula than human milk, and by 9-11 mo of
age 20% consumed whole cow milk and 25% consumed nonfat or
reduced-fat milk.
The most commonly fed complementary foods between 4 and
11 mo of age are infant cereals. Nearly 45% of infants between 9 and
11 mo of age consumed noninfant cereals. Infant eating patterns also
vary, with up to 61% of infants 4-11 mo of age consuming no vegeta-
bles. Among those who consumed vegetables, French fries were the
most common vegetables in toddlers. Positive changes in the last
decade include increased duration of breastfeeding, delayed introduc-
tion of complementary foods, and decreased juice consumption. Con-
tinuing concerns included lack of fruits and vegetables, diets low in
iron, essential fatty acids, fiber and whole grains, and high in saturated
fat and sodium. Table 45-6 summarizes the AAP recommendations for
initiating complementary foods.
The complementary foods should be varied to ensure adequate
macro- and micronutrient intake. In addition to complementary foods
introduced at 6 mo of age, continued breastfeeding or the use of infant
formula for the entire 1st year of life should be encouraged. Overcon-
sumption of energy-dense complementary foods can lead to excessive
weight gain in infancy, resulting in an increased risk of obesity in
childhood.
FEEDING TODDLERS AND
PRESCHOOL-AGE CHILDREN
Toddlerhood is a period when eating behavior and healthful habits can
be established and is often a confusing and anxiety-generating period.
Growth after the 1st yr slows, motor activity increases, and appetite
decreases. Birth weight triples during the 1st year of life and quadru-
ples by 2 yr of age, reflecting this slowing in growth velocity. Eating
behavior is erratic, and the child appears distracted as the child explores
the environment. Children consume a limited variety of foods and
often only “like” a particular food for a period of time and then reject
the favored food. The use of growth charts to demonstrate adequate
growth and to provide guidance about typical behavior and eating
habits will help allay concerns of parents. Important goals of early
childhood nutrition are to foster healthful eating habits and to offer
foods that are developmentally appropriate.
Feeding Practices
The period starting after 6 mo until 15 mo is characterized by the
acquisition of self-feeding skills because the infant can grasp finger
foods, learn to use a spoon, and eat soft foods (Table 45-7). Around
12 mo of age, the child learns to drink from a cup and may still
breastfeed or desire formula bottle feeding. Bottle weaning should
begin around 12-15 mo and bedtime bottles should be discouraged
because of the association with dental carries. Unless being used at
mealtime, the sippy cup should only contain water to prevent caries.
Sugar-sweetened beverages and 100% fruit juice should also be dis-
couraged from being used in bottles in all infants at all times. Cups
without a lid can be used for no more than 4-6 oz/day of 100% fruit
juice for toddlers. In the 2nd year of life, self-feeding becomes a norm
and provides the opportunity for the family to eat together with less
stress. Self-feeding allows the child to limit the child’s intake. Child
feeding is an interactive process. Children receive cues regarding
appropriate feeding behaviors from parents. Parents should ignore
negative eating behaviors unless the behavior jeopardizes the health
and safety of the child. In addition, parents should eat with their
 Chapter 45  ◆  Feeding Healthy Infants, Children, and Adolescents  291

Table 45-7 Feeding Skills Birth to 36 Months

AGE (mo) FEEDING/ORAL SENSORIMOTOR
Birth to 4-6 Nipple feeding, breast, or bottle
Hand on bottle during feeding (2-4 mo)
Maintains semiflexed posture during feeding
Promotion of infant–parent interaction
6-9 (transition Feeding more in upright position
feeding) Spoon feeding thin, pureed foods
Both hands to hold bottle
Finger feeding introduced
Vertical munching of easily dissolvable solids
Preference for parents to feed
9-12 Cup drinking
Eats lumpy, mashed food
Finger feeding for easily dissolvable solids
Chewing includes rotary jaw action
12-18 Self-feeding; grasps spoon with whole hand
Holds cup with 2 hands
Drinking with 4-5 consecutive swallows
Holding and tipping bottle
>18-24 Swallowing with lip closure Figure 45-2 MyPlate food guide. (From U.S. Department of Agricul-
Self-feeding predominates ture: mypyramid.gov. http://www.choosemyplate.gov/.)
Chewing broad range food
Up–down tongue movements precise
24-36 Circulatory jaw rotations
Chewing with lips closed of the food offered and the level of supervision during meals. Parents
One-handed cup holding and open cup drinking are encouraged to assess the quality of the food served at daycare by
with no spilling asking questions, visiting the center, and taking part in parent com-
Using fingers to fill spoon mittees. Free or reduced-price snacks and meals are provided in
Eating wide range of solid food daycare centers for low- and medium-income communities through
Total self-feeding, using fork
the U.S. Department of Agriculture (USDA) Child and Adult Care
Adapted from Arvedson JC. Swallowing and feeding in infants and young Food Program. Participating programs are required to provide meals
children. GI Motility online (2006) doi:10.1038/gimo17. and snacks that meet the meal regulations set by the USDA, guarantee-
ing a certain level of food quality. However, often for monetary reasons,
many daycare centers still struggle to provide high-quality meals and
toddlers and not simply feed them in order to model positive eating snacks.
behaviors.
The 2 yr old child should progress from small pieces of soft food to FEEDING SCHOOL-AGE CHILDREN
prepared table foods with precautions. At this stage, the child is not AND ADOLESCENTS
capable of completely chewing and swallowing foods, and particular MyPlate
attention should be paid to foods with a choking risk. Hard candies, The USDA MyPlate (www.choosemyplate.gov) is a basis for building
nuts, and raw carrots should be avoided. Hot dogs, sausages, and an optimal diet for children and adults (Fig. 45-2). MyPlate is based
grapes should be sliced length wise. Caregivers should always be vigi- on the Dietary Guidelines for Americans, 2010 and replaces MyPyra-
lant and present during feeding, and the child should be placed in a mid. MyPlate is aimed at the general public to provide a visual repre-
high chair or booster seat. The AAP discourages eating in the presence sentation of the different food groups and their portion sizes. In
of distractions such as television, tablets, mobile devices, and other addition to food group information, the website provides discretionary
screens, or eating in a car where an adult cannot adequately observe calorie information. It provides weight management strategies, and
the child. abilities to track calories and physical activity goals. A personalized
Young children have a natural preference for sweetened foods and eating plan based on these guidelines provide, on average over a few
beverages that begins in infancy. Reluctance to accept new foods is a days, all the essential nutrients necessary for health and growth, while
common developmental phase. A new food should be offered multiple limiting nutrients associated with chronic disease development.
times (8-15) before being considered rejected by the child. MyPlate can also be used as an Internet interactive tool that allows
Toddlers need to eat 3 healthy meals and 2 snacks daily. Milk con- customization of recommendations, based on age, sex, physical activ-
tinues to be an important source of nutrition. Guidelines for vitamin ity, and, for some populations, weight and height. Print material is also
D supplementation recommend a daily vitamin D intake of 600 IU/ available for families without Internet access.
day for all infants beginning in the first few days of life, and for children Recommendations based on MyPlate emphasize making half the
and adolescents who are ingesting <1000 mL/day of vitamin D-fortified plate vegetables and fruit, one half of the plate protein and grains,
milk or formula. Toddlers and preschool children often fail to meet the with protein having the smallest section. Protein replaces the meat
recommended servings of fruits, vegetables, and fiber, whereas intakes category as many protein sources are not from animals. A separate
of food with fat and added sugar are high. Giving vegetables at the dairy section is included. Physical activity recommendations to
beginning of the meal and increasing the portion size of vegetables achieve a healthful energy balance are not visually displayed, but are
served during meals can be an effective strategy for increasing vegeta- provided on the website. MyPlate has removed foods that have low
ble consumption in preschool children. nutritional value, such as sweetened sugar beverages, and sweetened
bakery products.
Eating in the Daycare Setting In the United States and in an increasing number of other coun-
Many U.S. toddlers and preschool children attend daycare and receive tries, the vast majority of children and adolescents do not consume a
meals and snacks in this setting. There is a wide variation in the quality diet that follows the recommendations of MyPlate. The intake of
292  Part VI  ◆  Nutrition
discretionary calories is much higher than recommended, with fre-
quent consumption of sweetened sugar beverages (soda, juice drinks,
iced tea, sport drinks), snack foods, high-fat meat (bacon, sausage),
and high-fat dairy products (cheese, ice cream). Intake of dark green
and orange vegetables (as opposed to fried white potatoes), whole
fruits, reduced-fat dairy products, and whole grain is typically lower
than recommended. Furthermore, unhealthful eating habits such as
larger-than-recommended portion sizes; food preparation that adds
fat, sugar, or salt; skipping breakfast and/or lunch; grazing; or follow-
ing fad diets is prevalent and associated with a poorer diet quality.
MyPlate offers a helpful and customer-friendly tool to assist pediatri-
cians counseling families on optimal eating plans for short- and long-
term health.
Eating at Home
At home, much of what children and adolescents eat is under the
control of their parents. Typically, parents shop for groceries and they
control, to some extent, what food is available in the house. It has been
demonstrated that modeling of healthful eating behavior by parents is
a critical determinant of the food choices of children and adolescents.
Counseling to improve diet should include guiding parents in using
their influence to make healthier food choices available and attractive
at home.
Regular family meals sitting at a table, as opposed to eating alone,
in the living room, or watching television/screens, are associated with
improved diet quality, perhaps because of increased opportunities for
positive parenting during meals. Such an ideal situation is recom-
mended but a challenge for many families who, with busy schedules
and other stressors, are unable to provide such a setting. Another
parenting challenge is to control the excess appetite of some children
and adolescents. Encourage children to eat at a slower pace and to
chew their food properly. Encourage conversation at the dinner table
to prolong eating to 15 minutes. Offering vegetables while children
are hungry at the beginning of the meal has been shown to increase
vegetable consumption. Useful strategies, when the child is still
hungry after a meal, include a 15- to 20-min pause (allow child to
engage in another activity) before a second serving or offering foods
that are insufficiently consumed, such as vegetables, whole grains, or
fruits.
Eating at School
The National School Lunch Program and the School Breakfast
Program provide low-cost meals to more than 5 billion children
nationwide. Guidelines for meals are taken from the Dietary Guidelines
for Americans and the Dietary Reference, 2005. Recommendations
regarding the use of age-grade portion sizes, and amounts of vegetable
and fruits, grains, and fats were included (Table 45-8). The training and
equipment for school food service staff, school community engage-
ment, parent education, and food industry involvement are among the
necessary components. The year 2020 is the target year for achieving
recommendations for sodium. In the meantime, while schools are
working on implementing changes, parents should be encouraged to
examine the weekly menu with their child and assist with their choices
ahead of time. If children bring their lunch from home recommenda-
tions for what constitutes a healthy lunch should be provided by the
Pediatrician. Parents can be directed to www.choosemyplate.org for
healthy lunch ideas. In addition parties within classrooms should be
limited to once a month.
Eating Out
The number of meals eaten outside the home or brought home from
takeout restaurants has increased in all age groups of the U.S. popula-
tion. The increased convenience of this meal pattern is undermined by
the generally lower nutritional value of the meals, compared to home-
cooked meals. Typically, meals consumed or purchased in fast-food or
casual restaurants are of large portion size, are dense in calories, and
contain large amounts of saturated fat, salt, and sugar, and low amounts
of whole grains, fruits, and vegetables. Although still a problem cur-
rently, trans fat is slowing being phased out of most commercial
Table 45-8 Revised National School Lunch Program
and School Breakfast Program
Recommendations
• Portion sizes of food are to be based on age-grade groups
• School lunches and breakfasts will have a minimum and
maximum calorie level, maximum saturated fat content, and a
maximum sodium content
• Foods must contain zero grams of trans fat per serving
• The inclusion of unsaturated vegetable oils is encouraged within
calorie limits
• Vegetables and fruits are not interchangeable
• Vegetable offerings at lunch must include 12 cup equivalent of
the following: dark green vegetables, bright orange vegetables,
and legumes
• No more than half of fruit servings may be in the form of juice
• At least 12 of bread/grain offered must be whole grain
• Milk must be fat-free if flavored and either fat free or 1% if plain
• Students must select a fruit option at breakfast with their meal,
and either a fruit or a vegetable at lunch for the meal to be
reimbursable.
Adapted from IOM (Institute of Medicine): School meals: building blocks for
healthy children. Washington, DC, 2010, National Academies Press.
restaurants. Although an increasing number of restaurants offer
healthier alternatives, the vast majority of what is consumed at restau-
rants does not fit MyPlate.
With increasing age, an increasing number of meals and snacks are
also consumed during peer social gatherings at friends’ houses and
parties. When a large part of a child’s or adolescent’s diet is consumed
on these occasions, the diet quality can suffer, because food offerings
are typically of low nutritional value. Parents and pediatricians need to
guide teens in navigating these occasions while maintaining a healthful
diet and enjoying meaningful social interactions. These occasions often
are also opportunities for teens to consume alcohol; consequently,
adult supervision is important.
NUTRITION ISSUES OF IMPORTANCE ACROSS
PEDIATRIC AGES
Food Environment
Most families have some knowledge of nutrition and intend to provide
their children with a healthful diet. The discrepancy between this fact
and the actual quality of the diet consumed by U.S. children is often
explained by challenges in the environment for families to make
healthful food choices. Because the final food choice is made by indi-
vidual children or their parents, interventions to improve diet have
focused on individual knowledge and behavior changes, but have had
limited success. A main determinant of food choice is taste, but other
factors also influence these choices. One of the most useful conceptual
frameworks for understanding the child’s food environment in the
context of obesity illustrates the variety of individual food and physical
activity choices. Many of these determinants are not under the direct
control of individual children or parents (Fig. 45-3). Understanding
the context of food and lifestyle choices helps in understanding lack of
changes or “poor compliance” and can decrease the frustration often
experienced by the pediatricians who might “blame the victim” for
behavior that is not entirely under their control.
Marketing and advertising of food to children is a particularly illus-
trative aspect of the food environment. Marketing includes strategies
as diverse as shelf placements, association of cartoon characters with
food products, coupons, and special offers or pricing, all of which
influence food purchase choices. Television advertising is an important
part of how children and adolescents hear about food, with an esti-
mated 40,000 TV commercials per yr, seen by the average U.S. child,
many of which are for food, as compared to the few hours of nutrition
education they receive in school. Additional food advertisement
increasingly occurs as brand placement in movies and TV shows, on
websites, and even video games.
 Chapter 45  ◆  Feeding Healthy Infants, Children, and Adolescents  293

Community, demographic,
and societal characteristics

Ethnicity Socioeconomic
Parenting styles and status
family characteristics
Peer and sibling
School lunch Child feeding
interactions
programs practices
Child characteristics Family TV
Types of foods and child risk factors* viewing Crime rates and
available in Age neighborhood
Gender Parent
the home SEDENTARY safety
Child monitoring of
Work hours BEHAVIOR child TV viewing
Nutritional DIETARY weight
knowledge INTAKE status Parent
PHYSICAL
preference
ACTIVITY School physical
for activity
Parent Familial susceptibility education
dietary intake to weight gain Parent activity programs
Leisure time patterns
Parent food
Parent encouragement
preferences
Parent weight of child activity
Accessibility of status Family leisure time
recreational facilities activity

Accessibility of convenience
foods and restaurants

Figure 45-3 A conceptual framework of the context of food and lifestyle choices. Child risk factors (shown in uppercase lettering) refer to child
behaviors associated with the development of overweight. Characteristics of the child (shown in italic lettering) interact with child risk factors and
contextual factors to influence the development of overweight (i.e., moderator variables). (From Davison KK, Birch LL: Childhood overweight: a
contextual model and recommendations for future research, Obes Rev 2:159–171, 2001. © 2001 The International Association for the Study of
Obesity.)

Using Food as Reward
It is a prevalent habit to use food as a reward or sometimes withdraw
food as punishment. Most parents use this practice occasionally, and
some use it almost systematically, starting at a young age. The practice
is also commonly used in other settings where children spend time,
such as daycare, school, or even athletic settings. Although it might be
a good idea to limit some unhealthy but desirable food categories to
special occasions, using food as a reward is problematic. Limiting
access to some foods and making its access contingent on a particular
accomplishment increases the desirability of that type of food. Con-
versely, encouraging the consumption of some foods renders them
less desirable. Therefore, phrases such as “finish your vegetables, and
you will get ice cream for dessert” can result in establishing unhealthy
eating habits once the child has more autonomy in food choices.
Parents should be counseled on such issues and encouraged to choose
items other than food as reward, such as inexpensive toys or sporting
equipment, family time, special family events, or collectable items.
Similar types of behavior are also seen in schools and extra-curricular
events. As opposed to rewarding or punishments of food (pizza/
candy) daycare providers, teachers, and counselors should be encour-
aged to use alternative rewards such as minutes of free time, sitting in
the teacher’s chair, being the teacher helper, and homework-free
nights.
Cultural Considerations in Nutrition
and Feeding
Food choices, food preparation, eating patterns, and infant feeding
practices all have very deep cultural roots. In fact, beliefs, attitudes, and
practices surrounding food and eating are some of the most important
components of cultural identity. Therefore, it is not surprising that in
multicultural societies, great variability exists in the cultural character-
istics of the diet. Even in a world where global marketing forces tend
to reduce geographic differences in the types of food, or even brands,
that are available, most families, especially during family meals at
home, are still much influenced by their cultural background. There-
fore, pediatricians should become familiar with the dietary character-
istics of various cultures in their community, so that they can identify
and address, in a nonjudgmental way and avoiding stereotypes, the
potential nutritional issues related to the diet of their patients.
Vegetarianism
Vegetarianism is the practice of following a diet that excludes animal
flesh foods, including beef, pork, poultry, fish, and shellfish. There are
several variants of the diet, some of which also exclude eggs and/or
some products produced from animal labor, such as dairy products
and honey. There are many different variations in vegetarianism:
◆ Veganism: excludes all animal products. It may be part of a larger
practice of abstaining from the use of animals products for any
purpose.
◆ Ovovegetarianism: includes eggs but not dairy products.
◆ Lactovegetarianism: includes dairy products but excludes eggs.
◆ Lactoovovegetarianism: includes eggs and dairy products.
◆ Flexitarian: recent term referring to a vegetarian who will
occasionally eat meat.
Another expression used for vegetarianism and veganism is “plant-
based diets.”
Other dietary practices commonly associated with vegetarianism
include fruitarian diet (fruits, nuts, seeds, and other plant matter gath-
ered without harm to the plant); Su vegetarian diet (a diet that excludes
all animal products as well as onion, garlic, scallions, leeks, or shallots);
a macrobiotic diet (whole grains and beans and, in some cases, fish);
and raw vegan diet (fresh and uncooked fruits, nuts, seeds, and vege-
tables). The safety of these restrictive diets has not been studied in
children. These diets can be very limited in macro- and micronutrients
and are not recommended for children. Implementing vegetarian diets
in teenage girls may be a sign of an eating disorder.
Vegetarianism is considered a healthful and viable diet; both the
Academy of Nutrition and Dietetics (formerly the American Dietetic
Association) and the Dietitians of Canada have found that a properly
planned and well-balanced vegetarian diet can satisfy the nutritional
294  Part VI  ◆  Nutrition
goals for all stages of life. Compared with nonvegetarian diets, vegetar-
ian diets have low levels of saturated fat, cholesterol, and animal
protein, and relatively higher levels of complex carbohydrates, fiber,
magnesium, potassium, folate, vitamins C and E, and phytochemicals.
Vegetarians have a lower body mass index, cholesterol, and blood pres-
sure, and are at decreased risk for cancer and ischemic heart disease.
Specific nutrients of concern in vegetarian diets include:
◆ Iron: Vegetarian diets have similar levels of iron compared to
nonvegetarian diets, but the iron has lower bioavailability than
iron from meat sources, and iron absorption may be inhibited by
other dietary constituents, such as phytate (see Chapter 54). Iron
stores are lower in vegetarians and vegans than in nonvegetarians;
and iron deficiency is more common in vegetarian and vegan
women and children. Foods rich in iron include iron-fortified
cereals, black beans, cashews, kidney beans, lentils, oatmeal,
raisins, black-eyed peas, soybeans, sunflower seeds, chickpeas,
molasses, chocolate, and tempeh.
◆ Vitamin B12: Plants are not a good source of B12 (see Chapter
49.7). Additional vitamin B12 can be obtained through dairy
products and eggs; vegans need fortified foods or supplements.
Breastfeeding by vegan mothers can place an infant at risk for
vitamin B12 deficiency.
◆ Fatty acids: Vegetarians and vegans may be at risk for low levels of
eicosapentaenoic acid (EPA) and DHA. The inclusion of sources of
linolenic acid (precursor of EPA and DHA), such as walnuts, soy
products, flaxseed, and canola oils, are recommended.
◆ Calcium and vitamin D: Without supplementation, vegan diets
are low in calcium and vitamin D putting vegans at risk for
impaired bone mineralization (see Chapter 51). Vitamin D-OH
levels should be monitored in vegans and supplemented for levels
<30 dL. Calcium sources include leafy greens (with low oxalate:
broccoli, kale, or Chinese cabbage). Calcium and vitamin D are
found in almond and soy milk, and fortified orange juice.
◆ Zinc: The bioavailability of zinc in plant sources tends to be low
because of the presence of phytates and fiber that inhibit zinc
absorption (see Chapter 54). Zinc is found in soy products,
legumes, grains, cheese, and nuts.
Organic Foods
Parents may prefer organic foods to feed children secondary to con-
cerns regarding chemical and hormonal treatment of animals and
produce. The nutritional differences between organic and conventional
foods m a y n o t b e clinically relevant. Children consuming organic
foods have lower or no detectable levels of pesticides in their urine
compared to those consuming nonorganic foods. It remains unclear
whether such a reduction in exposure to chemicals is clinically signifi-
cant. Organic foods tend to have higher antioxidant levels and lower
levels of cadmium. Similarly, despite concerns of parents, the amount
of bovine growth hormone in conventional milk is thought to be
neither significant nor biologically active in humans. Additionally,
milk consumption from estrogen-treated cows does not result in endo-
crine disruptions in infants. However other chemicals in the environ-
ment, such as bisphenol-A (found in plastics), nitrates, endocrine
disruptors, and phthalates, should be avoided. Organic certification of
a food also suggests the food source is not from a genetically modified
nutrient. Because the cost of these foods is generally higher than the
cost of other foods, a prudent approach is to explain to families that
the scientific basis for choosing organic foods is limited, but if it is their
preference and they can afford the added cost, there is no reason not
to eat organic foods.
Nutrition as Part of Complementary and
Alternative Medicine, Functional Foods,
Dietary Supplements, Vitamin Supplements,
and Botanical and Herbal Products
The use of nutrition or nutritional supplements as complementary or
alternative medicine is increasing, despite limited data on safety and
efficacy, especially in children. Many parents assume that if a food or
supplement is natural or organic, then there is no potential for risk
and some that supplements are beneficial. However, adverse effects of
some dietary supplements have been documented. It is difficult for
pediatricians to compete against the aggressive marketing through
multi-media sources of food supplements to families of healthy and
chronically ill children. Additionally, pediatricians must compete
against the word-of-mouth and advice from people without a scientific
background and those with significant conflicts of interest. One reason
to recommend caution to parents when it comes to dietary supple-
ments, including botanical and herbal products, is that in the United
States, unlike medications, these products are not evaluated for safety
and efficacy before marketing and do not undergo the same level of
quality control as medications. The potential for adverse effects or
simply for inefficacy is therefore high (see Chapter 64).
Pediatricians are often asked by parents if their children need to
receive a daily multivitamin. Unless the child follows a particular diet
that may be poor in one or more nutrients for health, cultural, or
religious reasons, or if the child has a chronic health condition that
puts the child at risk for deficiency in 1 or more nutrients, multivita-
mins are not indicated. A diet that follows the guidelines of MyPlate
contains sufficient nutrients to support healthy growth. Many children
do not follow all the guidelines of MyPlate, and parents and pediatri-
cians may be tempted to use multivitamin supplements just to make
sure that nutrient deficiencies are avoided. Use of a daily multivitamin
supplement can result in a false impression that the child’s diet is com-
plete and in decreased efforts to meet dietary recommendations with
food rather than the intake of supplements (see Chapter 44) The
average U.S. diet provides more than a sufficient amount of most nutri-
ents, including most vitamins. Therefore, multivitamins should not be
routinely recommended.
The Institute of Medicine recommends 600 IU of vitamin D per day
in all children who drink less than 1,000 mL/day of vitamin D–fortified
milk, representing the majority of U.S. children and adolescents. In
some specific populations of children at risk for deficiency, supplements
of vitamin B12, iron, fat-soluble vitamins, or zinc may be considered.
Food Safety
Constantly keeping food safety issues in mind is an important aspect
of feeding infants, children, and adolescents. In addition to choking
hazards and food allergies, pediatricians and parents should be aware
of food safety issues related to infectious agents and environmental
contaminants. Food poisoning with bacteria, viruses, or their toxins
are most common with raw or undercooked food, such as oysters, beef,
and eggs, or cooked foods that have not been handled or stored prop-
erly. The specific bacteria and viruses involved in food poisoning are
described in Chapter 340. Many chemical contaminants, such as heavy
metals, pesticides, and organic compounds, are present in various
foods, usually in small amounts. Because of concerns regarding their
child’s neurologic development and cancer risk, many questions arise
from parents, especially after media coverage of isolated incidents. A
recurring debate is the balance between the benefits of seafood for the
growing brain and cardiovascular health and the risk of mercury con-
tamination from consuming large predatory fish species. Pediatricians
need to become familiar with reliable sources of information, such as
the websites of the U.S. Environmental Protection Agency, the FDA,
or the CDC. The Food Safety Modernization Act provides the FDA
with authority to have stricter control over food production and dis-
tribution. The FDA can require that manufacturers develop food safety
plans. A good source of information for patients and parents can be
found at www.foodsafety.gov.
Nutritional Programming
Emerging epidemiologic evidence suggests that early nutrition starting
during fetal development can have long-term impact on growth, and
adult health. It is well established that undernutrition in early life can
exert a long-term impact in terms of reduced adult height and aca-
demic achievements; other data, however, suggest that intrauterine
growth restriction is associated with obesity and other adult cardiovas-
cular risk factors. Rapid weight gain in infancy, either following intra-
uterine growth restriction or a period of malnutrition, is associated
with an increased risk for later obesity. The process that explains these also eligible for the Supplemental Nutrition Assistance Program, for-
changes has been termed “programming.” merly known as the Food Stamp Program. This program provides
funds directly to families to purchase various food items in regular
Preventive Nutrition Counseling in Pediatric food stores.
Primary Care
An important part of the primary care well-child visit focuses on nutri- Bibliography is available at Expert Consult.
tion and growth because most families turn to pediatricians for guid-
ance on child nutrition. Preventive nutrition is one of the cornerstones
of preventive pediatrics and a critical aspect of anticipatory guidance.
The first steps of nutrition counseling are nutritional status assess-
ments, primarily done through growth monitoring and dietary intake
assessment. Although dietary assessment is somewhat simple in infants
who have a relatively monotonous diet, it is more challenging at older
ages. The goals of dietary assessment in the primary care setting need
to remain modest and include an idea of the eating patterns (time,
location, and environment) and usual diet by asking the parent to
describe the child’s dietary intake on a typical day or in the last 24 hr.
Pediatricians should encourage regularly scheduled meals and 1 or 2
snacks. Alternatively, a basic assessment of the child’s consumption of
vegetables, fruits, whole grains, low or nonfat dairy products, 100%
fruit juice and sugar-sweetened beverages should be assessed. For more
ambitious goals of dietary assessment, referral to a registered dietician
with pediatric experience is recommended.
Once some understanding of the child’s usual diet has been acquired,
existing or anticipated nutritional problems should be addressed, such
as diet quality, dietary habits, or portion size. For a few nutritional
problems, a lack of knowledge can be addressed with nutrition educa-
tion, but most pediatric preventive nutritional issues, such as overeat-
ing or poor food choices, are not the result of lack of parents’ knowledge.
Therefore, nutrition education alone is insufficient in these situations,
and pediatricians need to acquire training in behavior-modification
techniques or refer to specialists to assist their patients in engaging in
healthy feeding and eating behaviors. The physical, cultural, and family
environments in which the child lives should be kept in mind at all
times, so that nutrition counseling is relevant and changes are
feasible.
One important aspect of nutrition counseling is providing families
with sources of additional information and behavioral change tools.
Although some handouts are available from government agencies, the
AAP, and other professional organizations for families without Internet
access, an increasing number of families rely on the Internet to find
nutrition information. Therefore, pediatricians need to become famil-
iar with commonly used websites so that they can point families to
reliable and unbiased sources of information. Perhaps the most useful
websites for reliable and unbiased nutrition information for children
are the USDA MyPlate website, the sites of the CDC, FDA, National
Institutes of Health, and Institute of Medicine Food and Nutrition
Board for government sources and the AAP, American Heart Associa-
tion, and the Academy of Nutrition and Dietetics (formerly the Ameri-
can Dietetic Association) for professional organization resources.
Pediatricians should also be aware of sites that provide biased or even
dangerous information, so that they can warn families accordingly.
Examples include dieting sites, sites that openly promote dietary sup-
plements or other food products, and the sites of “nonprofit” organiza-
tions that are mainly sponsored by food companies or that have other
social or political agendas.

Food Assistance Programs in the USA

Several programs exist in the United States to ensure sufficient and
high-quality nutrition for children of families who cannot always
afford optimal nutrition. One of the most popular federal programs is
the Special Supplemental Nutrition Program for Women, Infants, and
Children (WIC). This program provides nutrition supplements to a
large proportion of pregnant women, postpartum women, and chil-
dren up to their 5th birthday. One of its strengths is that in order to
qualify, families need to regularly visit a WIC nutritionist, who can be
a useful resource for nutritional counseling. Other popular programs
include school lunches, breakfasts, and after-school meals, as well as
daycare and summer nutrition programs. Lower-income families are
 Chapter 45  ◆  Feeding Healthy Infants, Children, and Adolescents  295.e1
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Pediatrics 129:e827–e841, 2012.
Baranski M, Srednicka-Tober D, Volakakis N, et al: Higher antioxidant and
lower cadmium concentrations and lower incidence of pesticide residues in
organically grown crops: a systematic literature review and meta-analysis, J Nutr
112:794–811, 2014.
Burdge GC, Lillcrop KA: Nutrition, epigenetics, and developmental plasticity:
implications for understanding human disease, Annu Rev Nutr 30:315–339,
2010.
Committee on Nutrition American Academy of Pediatrics: Pediatric Nutrition
Handbook, ed 6, Elk Grove Village, IL, 2009, American Academy of
Pediatrics.
Crinnion WJ: Organic foods contain higher levels of certain nutrients, lower levels
of pesticides, and may provide health benefits for the consumer, Altern Med Rev
15(1):4–12, 2010.
Di Noia J: Defining powerhouse fruits and vegetables: a nutrient density approach,
Prev Chronic Dis 11:130390, 2014.
Flaherman VJ, Aby J, Burgos AE, et al: Effect of early limited formula on duration
and exclusively of breastfeeding in at-risk infants: an RCT, Pediatrics
131(6):1059–1065, 2013.
Forman J, Silverstein J: Organic foods: health and environmental advantages and
disadvantages, Pediatrics 130(5):e1406–e1415, 2012.
Gidding SS, Dennison BA, Birch LL, et al: Dietary recommendations for children
and adolescents: a guide for practitioners: consensus statement from the
American Heart Association, Circulation 112:2061–2075, 2005.
Grummer-Strawn LM, Reinold C, Krebs NF: Use of World Health Organization
and CDC growth charts for children aged 0-59 months in the United States,
MMWR Recomm Rep 59(RR–9):1–15, 2010.
Institute of Medicine (IOM): Dietary Reference Intakes. The Essential Guide to
Nutrient Requirements, Washington, DC, 2006, National Academies Press.
Jaafar SH, Jahanfar S, Angolkar M, et al: Pacifier use versus no pacifier use in
breastfeeding term infants for increasing duration of breastfeeding (review),
Cochrane Database Syst Rev 3:CD007202, 2011.
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Arch Pediatr Adolesc Med 166(3):208–215, 2012.
May AL, Dietz WH, The Feeding Infants and Toddlers Study 2008: opportunities
to assess parental, cultural, and environmental influences on dietary behaviors
and obesity prevention among young children, J Am Diet Assoc 110(12
Suppl):S11–S15, 2010.
Spill MK, Birch LL, Roe LS, et al: Eating vegetables first: the use of portion size to
increase vegetable intake in preschool children, Am J Clin Nutr 91:1237–1243,
2010.
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Services: Dietary Guidelines for Americans, 2010, ed 7, Washington, DC, 2010,
U.S. Government Printing Office.
Chapter 46  ◆  Nutrition, Food Security, and Health  295

Chapter 46 
Nutrition, Food Security,
and Health
Ann Ashworth

MALNUTRITION AS THE INTERSECTION OF

FOOD INSECURITY AND HEALTH INSECURITY
Undernutrition is usually an outcome of 3 factors, often in combina-
tion: household food supply, child-caring practices, and access to
health and water/sanitation services. In famine and emergency set-
tings, food shortage is the foremost factor, but in many countries with
widespread undernutrition, food production or access to food might
not be the most limiting factor. More important causes might be
repeated childhood infections, especially diarrheal diseases linked with
an unsafe environment and lack of exclusive breastfeeding, or inade-
quate complementary feeding practices, or the lack of time families
have available for appropriate infant or maternal care. Figure 46-1
shows some of the many causal factors on the pathway to undernutri-
tion and how they extend from household and community levels to
national/international levels. Inequitable distribution of resources
because of political, economic, and agricultural policies often denies
families their right to adequate land, water, food, healthcare, education,
and a safe environment, all of which can influence nutritional status.
Families with few economic resources who know how to care for
their children and are enabled to do so can often use available food
and health services to produce well-nourished children. If food
resources and health services are not available in a community, or not
utilized, or not accessible to some families, children might become
undernourished. Undernutrition is not confined to low-income coun-
tries. It has been noted in chronically ill patients in neonatal and
pediatric intensive care units in high-income countries and among
patients with burns, HIV, tuberculosis, cystic fibrosis, chronic diarrhea
syndromes, malignancies, bone marrow transplantation, and inborn
errors of metabolism. Severe malnutrition has been reported in affluent
communities in infants whose families believe in fad diets, and in
infants with food allergies fed nutritionally inadequate foods such as
rice “milk,” which has a very low protein and micronutrient content
(Fig. 46-2).

FOOD SECURITY
Food security exists “when all people, at all times, have access to suf-
ficient, safe, nutritious food to maintain a healthy and active life.” Four
main dimensions of food security can be identified: availability, access,
utilization, and stability. Availability refers to the supply of food
(reflecting the level of food production, food stocks, and net trade).
Access is at the household level, reflecting purchasing power, household
food production, and food/cash transfers received through social safety
net programs. The utilization dimension recognizes that even when a
household has access to food it is not necessarily shared equitably
within a household. Stability refers to being food secure at all times:
Examples of situations that affect stability are the “lean seasons” before
a harvest, natural disasters, political unrest, and rising food prices. To
be food secure, all 4 dimensions must be met simultaneously.
296  Part VI  ◆  Nutrition

Potential National Resources

Political, Economic Natural Disasters Conflict

Weak social systems, Drought, flood, Population
corruption, low GDP, hurricane, earthquake displacement,
high foreign debt, migration, disruption
poor infrastructure to agriculture/food
supply

Resources and Control

Food Inadequate Health

Insecurity Education Insecurity
Food unavailable, Poverty, women’s Inadequate health
unaffordable disempowerment, services, unhealthy
closely-spaced births environment

Inadequate Care
for Mothers and
Children
Psychosocial
deprivation

Inadequate Disease
Dietary Intake Anorexia, nutrient
Poor feeding losses, increased
practices, maternal requirements
competence, cultural
beliefs

Poor Growth
Impaired immunity,
frequent, more severe
infections

Undernutrition Figure 46-1 Basic, underlying, and immediate causes

of undernutrition.

Measuring Food Insecurity
The most commonly used measurement of food insecurity is “under-
nourishment” (chronic hunger), and is the proportion of the popula-
tion who are unable to meet daily energy requirements for light
activities. It is an estimate calculated by the Food and Agriculture
Organization (FAO) based on country-level Food Balance Sheets. It
does not take nutrient adequacy into account, but has the advantage
of being available for almost all countries annually (although with a
time-lag) and assists in monitoring global trends. In addition, FAO
measures food access by asking individuals about their experiences
over the last 12 mo, such as whether they ran out of food, or skipped
meals. The responses are graded from mild to severe food insecurity.
In 2011-2013, FAO estimated that about 842 million people, or 12%
of the world’s population, were undernourished, 98% of whom were in
developing countries. The majority are rural poor subsisting on small
plots of land or hired as laborers, and urban poor who lack the means
to grow or buy food. Alongside the 0.84 billion people who are under-
fed, there are 1.5 billion who are overfed reflecting global inequalities,
and the “double burden of malnutrition” in low- and middle-income
countries.
Nutrition, Food Security, and Poverty
Household food security tracks income closely. With rising incomes,
very poor households first increase their dietary energy intake to avert
hunger. If incomes rise further there is a shift to more expensive staple
foods and then to a more varied diet with a greater proportion of
energy from animal sources, fruits and vegetables, fats and sugars, and
less from cereals, roots and tubers. National economic growth tends to
be accompanied by reductions in stunting, but economic growth can
pass by the poor if they work in unaffected sectors, or are unable to
take advantage of new opportunities because of lack of education,
access to credit, or transportation, or if governments do not channel
resources accruing from economic growth to healthcare, education,
social protection, and other public services and infrastructure. There
is good evidence that economic growth reduces poverty, but does not
necessarily reduce undernutrition.
Food Security and Nutrition Targets
World leaders collectively agreed to 8 Millennium Development Goals
(MDGs) in 2000. MDG 1 aimed to eradicate extreme poverty and
hunger. The target to halve the proportion of people whose income is
less than $1 per day was reached at the global level 5 yr ahead of the
2015 target. This was greatly helped by the progress made by China
and India. Sub-Saharan Africa is unlikely to reach the target. The
reductions in hunger are broadly consistent with those of poverty
reduction, and rates of undernourishment in developing regions fell
from 23.2% in 1990 to 14.3% in 2011-2013. Sub-Saharan Africa is the
region least likely to achieve the target of halving undernourishment
by 2015. The prevalence of underweight children (another MDG
indicator of “hunger”) fell from 29% in 1990 to 17% in 2012 for the
 Chapter 46  ◆  Nutrition, Food Security, and Health  297

Table 46-1 Global Food Security and Nutrition Targets

ZERO HUNGER CHALLENGE
OBJECTIVES
• Access to an adequate and
stable food supply for all
• Elimination of stunting in
children <2 yr and no
malnutrition in pregnancy and
early childhood
• Sustainable food systems
• Doubling of smallholder
productivity and income,
particularly for women
• No loss or waste of food, and
responsible consumption
WORLD HEALTH ASSEMBLY
GLOBAL NUTRITION
TARGETS FOR 2025
• A 40% reduction in the
number of stunted children
<5 yr
• A 50% reduction in anemia in
women of reproductive age
• A 30% reduction in low
birthweight
• No increase in childhood
overweightness
• Increase exclusive
breastfeeding rates to at least
50% in the first 6 months
• Reduce and maintain
childhood wasting to less
than 5%

greenhouse gas emissions is essential to minimize climate

Figure 46-2 A 14 mo old girl with a “flaky paint” dermatitis. (From
Katz KA, Mahlberg MH, Honig PJ, et al: Rice nightmare: kwashiorkor
in 2 Philadelphia-area infants fed Rice Dream beverage, J Am Acad
Dermatol 52(5 Suppl 1):S69–S72, 2005.)
developing regions combined, but the rate of decline is thought insuf-
ficient to reach the global target by 2015. Rural children are almost
twice as likely to be underweight as urban children, and the poorest
quintile is almost 3 times as likely to be underweight as the richest
quintile.
Sustainable Development Goals are expected to follow on from the
MDGs. In addition, in 2012 the World Health Assembly agreed to 6
global nutrition targets to be reached by 2025, measured against a 2010
baseline, and the United Nations Secretary-General launched the Zero
Hunger Challenge with 5 objectives that “would boost economic
growth, reduce poverty and safeguard the environment” and “would
foster peace and stability” (Table 46-1).
disruption, hence the aim to (a) cut fossil fuel use by at least half
of present levels by 2050 so as to reduce CO2 emissions and (b)
change livestock husbandry and agronomic practices to reduce
methane and nitrous oxide emissions.
◆ Increase efficiency of food production: Expanding the area of
agricultural land to any large extent (e.g., by deforestation) is not a
sustainable option because of adverse consequences on ecosystems
and biodiversity, although some expansion of food production
could be achieved by switching good quality land away from
first-generation biofuels. For example, 40% of the U.S. corn
harvest in 2010 went to biofuels. Efforts to increase the intensity of
production need to be environmentally sustainable. These include
optimizing yields by soil and water conservation, removal of
technical and financial constraints faced by farmers, and breeding
resource-efficient crops and livestock that are also climate-resilient
and pest/disease-resistant.
◆ Reduce waste: Some 30-40% of food is wasted, either between
harvesting and the market, or during retail, at home, and in the
food service industry. Better transport and storage facilities in
developing countries, less stringent sell-by dates, lower cosmetic
standards for fruits and vegetables, and ending supersized portions
would help reduce waste.
◆ Change diets: As wealth increases, so does the demand for
processed foods, meat, dairy products, and fish. About one-third
of global cereal production is fed to animals, so reducing
consumption of meat from grain-fed livestock and increasing the
proportion derived from the most efficient sources (pigs and
poultry) would allow more people to be fed from the same
amount of land.

Future Food Security UNDERNUTRITION

Between now and 2050 the world’s population is expected to rise to
around 9 billion, and an increase in food supply of 70-100% will be
needed to feed this larger, more urban, and more affluent populace.
Over this same period, the world’s food supply is expected to diminish
unless action is taken. Accelerating the decline in fertility rates and
reducing overconsumption are basic, but difficult, actions to bridge the
gap between increasing demand and diminishing supply. Equally chal-
lenging actions include limiting climate disruption, increasing the effi-
ciency of food production, reducing waste, and reducing the demand
for meat and dairy foods.
◆ Limit climate disruption: Drought, floods, and other extreme
weather events are becoming more prevalent and destroy crops
and livestock, often on a huge scale. Rising sea levels will lead to
loss of productive land through inundation and salinization.
Acidification of oceans will reduce marine harvests. Curbing
The greatest risk of undernutrition (underweight, stunting, wasting,
and micronutrient deficiencies) occurs in the first 1000 days, from
conception to 24 mo of age, and this early damage to growth and
development can have adverse consequences in later life on health,
intellectual ability, school achievement, work productivity, and earn-
ings. Governments and agencies are therefore advised to focus inter-
ventions on this critical window of opportunity. For folate deficiency,
which increases the risk of birth defects, this particular window of
opportunity is before conception.
Measurement of Undernutrition
The term malnutrition encompasses both ends of the nutrition spec-
trum, from undernutrition to overweight. Many poor nutritional out-
comes begin in utero and are manifest as low birthweight (LBW,
<2,500 g). Preterm delivery and fetal growth restriction are the 2 main
298  Part VI  ◆  Nutrition

Table 46-2 Classification of Undernutrition

CLASSIFICATION INDEX GRADING
Gomez 90-75% of median Grade 1 (mild)
(underweight) weight-for-age
75-60% Grade 2 (moderate)
<60% Grade 3 (severe)
Waterlow 90-80% of median Mild
(wasting) weight-for-height
<70% Severe
Waterlow 95-90% of median Mild
(stunting) height-for-age
90-85% Moderate
<85% Severe
WHO (wasting) <−2 to >−3 SD Moderate
weight-for-height
<−3 Severe Figure 46-3 Measuring mid-upper arm circumference. (Image cour-
WHO (stunting) <−2 to >−3 SD Moderate tesy of Nyani Quarmyne/Panos Pictures.)
height-for-age
<−3 Severe
colored fruits and vegetables and dark green leaves) (see Chapter 48).
WHO (wasting) 115-125 mm mid-upper Moderate The prevalence of clinical deficiency is assessed from symptoms and
(for age group arm circumference signs of xerophthalmia (principally night blindness and Bitot spots).
6-59 mo) <115 mm Severe
Subclinical deficiency is defined as serum retinol concentration
<0.70 µmol/L. Vitamin A deficiency is the leading cause of preventable
blindness in children. It is also associated with a higher morbidity and
mortality among young children.
causes of LBW, with prematurity relatively more common in richer Iodine deficiency is the main cause of preventable mental impair-
countries and fetal growth restriction relatively more common in ment (see Chapter 54). An enlarged thyroid (goiter) is a sign of
poorer countries. deficiency. Severe deficiency in pregnancy causes fetal loss and perma-
Nutritional status is often assessed in terms of anthropometry (Table nent damage to the brain and central nervous system in surviving
46-2). International standards of normal child growth under optimum offspring (cretinism). It can be prevented by iodine supplementation
conditions from birth to 5 yr have been established by the World before conception or during the first trimester of pregnancy. Postnatal
Health Organization (WHO). To compile the standards, longitudinal iodine deficiency is associated with impaired mental function and
data from birth to 24 mo of healthy, breastfed, term infants were com- growth retardation. The median urinary iodine concentration in chil-
bined with cross-sectional measurements of children ages 18-71 mo. dren ages 6-12 yr is used to assess the prevalence of deficiency in the
The standards allow normalization of anthropometric measures in general population, and a median of <100 µg/L indicates insufficient
terms of z scores (standard deviation scores). A z-score is the child’s iodine intake.
height (weight) minus the median height (weight) for the age and sex Iron-deficiency anemia is common in childhood either from low iron
of the child divided by the relevant standard deviation. The standards intakes or poor absorption, or as a result of illness or parasite infesta-
are applicable to all children everywhere, having been derived from a tion (see Chapter 54). Women also have relatively high rates of anemia
large multicountry study reflecting diverse ethnic backgrounds and as a result of menstrual blood loss, pregnancy, low iron intakes, poor
cultural settings. absorption, and illness. Hemoglobin cutoffs to define anemia are
Height-for-age (or length-for-age for children <2 yr) is a measure 110 g/L for children 6-59 mo, 115 g/L for children 5-11 yr, and 120 g/L
of linear growth, and a deficit represents the cumulative impact of for children 12-14 yr. Cutoffs to define anemia for nonpregnant women
adverse events, usually in the first 1,000 days from conception, that are 120 g/L, 110 g/L for pregnant women, and 130 g/L for men.
result in stunting, or chronic malnutrition. A low height-for-age typi- Zinc deficiency increases the risk of morbidity and mortality from
cally reflects socioeconomic disadvantage. A low weight-for-height, or diarrhea, pneumonia, and possibly other infectious diseases (see
wasting, usually indicates acute malnutrition. Conversely, a high Chapter 54). Zinc deficiency also has an adverse effect on linear
weight-for-height indicates overweight. Weight-for-age is the most growth. Deficiency at the population level is assessed from dietary zinc
commonly used index of nutritional status, although a low value has intakes.
limited clinical significance as it does not differentiate between wasting
and stunting. Weight-for-age has the advantage of being somewhat Prevalence of Undernutrition
easier to measure than indices that require height measurements. In It is estimated that approximately 15% of births in low- and middle-
humanitarian emergencies and some field settings, mid-upper arm income countries in 2010 were LBW. Rates of LBW are highest (26%)
circumference is used for screening wasted children (Fig. 46-3). in southern Asia, and are twice those of sub-Saharan Africa. India
Body mass index (BMI) is calculated by dividing weight in kilo- accounts for approximately 40% of the world’s low-weight births. Glob-
grams by the square of height in meters. For children, BMI is age- and ally, in 2011 16% of children <5 yr of age were underweight (weight-
gender-specific. BMI-for-age can be used from birth to 20 yr and is a for-age <−2 SD). The global prevalence of stunting (height-for-age
screening tool for thinness (<−2 SD), overweight (between +1 SD and <−2 SD) has declined from an estimated 40% to 26% over the last 20 yr,
+2 SD), and obesity (>+2 SD). To diagnose obesity, additional mea- with the greatest reductions having taken place in Asia. Stunting preva-
sures of adiposity are desirable as a high BMI can result from high lence is now highest in the African region (36% prevalence). Wasting
muscularity, and not only from excess subcutaneous fat. (weight-for-height <−2 SD) affects 8% of children <5 yr, the prevalence
Micronutrient deficiencies are another dimension of undernutri- having changed little over the past 2 decades. These figures represent
tion. Those of particular public health significance are vitamin A, 101 million underweight children, 165 million stunted children, and
iodine, iron, and zinc. 52 million wasted children.
Vitamin A deficiency is caused by a low intake of retinol (in animal Asia carries 69% of the global burden of underweight children, 58%
foods) or its carotenoid precursors, mainly beta-carotene (in orange- of the global burden of stunted children, and 70% of the global burden
 Chapter 46  ◆  Nutrition, Food Security, and Health  299

of wasted children because of the combination of large population size undernutrition is passed on to the next generation when undernour-
and high prevalence. Africa carries most of the remaining global ished women give birth to LBW babies.
burden. For children <5 yr, the global prevalence is estimated to be Fetal growth restriction and early childhood undernutrition also
33% for vitamin A deficiency, 29% for iodine deficiency, 17% for zinc have consequences for adult chronic illness. LBW is associated with an
deficiency, and 18% for iron-deficiency anemia. Prevalence of micronu- increased risk of hypertension, stroke, and type 2 diabetes in adults.
trient deficiencies tends to be highest in Africa. For pregnant women, The increased risk is thought to reflect “fetal programming,” a process
the estimated prevalence of vitamin A deficiency is 15% and for iron- by which fetal undernutrition leads to permanent changes in the struc-
deficiency anemia 19%. ture and metabolism of organs and systems that manifest as disease in
Rates of clinical deficiency of vitamin A in children <5 yr have been later life. The risk is exacerbated by low weight gain during the first
declining, probably as a result of high-dose vitamin A supplementation 2 yr of life. The increased risk of adult chronic disease emanating from
programs and measles vaccination (as measles leads to sizeable urinary undernutrition in early life is a particular challenge to low-income
loss of vitamin A), but subclinical deficiency remains widespread countries with rapid economic growth.
(more than 90 million children). Large-scale availability of iodized salt Stunting before the age of 3 yr is associated with poorer motor and
has reduced rates of iodine deficiency substantially, and iodized salt cognitive development and altered behavior in later years. The effect is
now reaches an estimated 70% of households. In contrast, progress in
reducing rates of iron-deficiency anemia is slow, and rates remain
largely static. Table 46-3 Global Deaths in Children <5 yr Attributed
to Nutritional Conditions
Consequences of Undernutrition
The most profound consequence of undernutrition is premature death % OF TOTAL
(Table 46-3). Fetal growth restriction together with suboptimal breast- ATTRIBUTABLE DEATHS
feeding in the first month of life contribute to 19% of all deaths in CONDITION DEATHS <5 YR
children <5 yr (1.3 million deaths/yr). When the effects of stunting, (a) Fetal growth restriction 817,000 11.8
wasting and deficiencies of vitamin A and zinc are also considered, (<1 mo)
these 6 items jointly contribute to 45% of global child deaths (3.1
(b) Stunting (1-59 mo) 1,017,000 14.7
million deaths/yr), and many more are disabled or stunted for life.
Anemia contributes to over one-quarter of maternal deaths. (c) Wasting (1-59 mo) 875,000 12.6
The risk of child death from infectious diseases increases even with (d) Zinc deficiency (12-59 mo) 116,000 1.7
mild undernutrition, and as the severity of undernutrition increases,
the risk increases exponentially (Table 46-4). Undernutrition impairs (e) Vitamin A deficiency 157,000 2.3
immune function and other host defenses, consequently childhood (6-59 mo)
infections are more severe and longer lasting in undernourished chil- (f) Suboptimal breastfeeding 804,000 11.6
dren and more likely to be fatal compared with the same illnesses in (0-23 mo)
well-nourished children. Also, infections can adversely affect nutri- Joint effects of (a) + (f ) 1,348,000 19.4
tional status, and young children can quickly enter a cycle of repeated
infections and ever-worsening malnutrition. Even for the survivors, Joint effects of all 6 factors 3,097,000 44.7
physical and cognitive damage as a result of undernutrition can impact From Black RE, Victora CG, Walker SP, et al. Maternal and child undernutrition
their future health and economic well-being. For girls, the cycle of and overweight in low- and middle-income countries, Lancet 382:427–451, 2013.

Table 46-4 Hazard Ratios for All-Cause and Cause-Specific Deaths Associated with Stunting, Wasting, and Underweight
in Children <5 yr
DEATHS
SD Score All Pneumonia Diarrhea Measles Other Infections
Height/length-for-age
<−3 5.5 6.4 6.3 6.0 3.0
−3 to <−2 2.3 2.2 2.4 2.8 1.9
−2 to <−1 1.5 1.6 1.7 1.3 0.9
≥−1 1.0 1.0 1.0 1.0 1.0
Weight-for-length
<−3 11.6 9.7 12.3 9.6 11.2
−3 to <−2 3.4 4.7 3.4 2.6 2.7
−2 to <−1 1.6 1.9 1.6 1.0 1.7
≥−1 1.0 1.0 1.0 1.0 1.0
Weight-for-age
<−3 9.4 10.1 11.6 7.7 8.3
−3 to <−2 2.6 3.1 2.9 3.1 1.6
−2 to <−1 1.5 1.9 1.7 1.0 1.5
≥−1 1.0 1.0 1.0 1.0 1.0
From Black RE, Victora CG, Walker SP, et al. Maternal and child undernutrition and overweight in low- and middle-income countries, Lancet 382:427–451, 2013.
300  Part VI  ◆  Nutrition

6-13 DQ (developmental quotient) points. Iodine and iron deficiencies
also lead to loss of cognitive potential. Indications are that children
living in areas of chronic iodine deficiency have an average reduction
in IQ of 12-13.5 points compared with children in iodine-sufficient
areas. Iron deficiency has a detrimental effect on the motor develop-
ment of children <4 yr and on cognition of school-age children. The
estimated deficit is 1.73 IQ points for each 10 g/L decrease in hemo-
globin concentration.
Undernutrition can have substantial economic consequences for
survivors and their families. The consequences can be quantified in 5
categories: increased costs of healthcare, either neonatal care for LBW
babies or treatment of illness for infants and young children; produc-
tivity losses (and hence reduced earnings) associated with smaller
stature and muscle mass; productivity losses from reduced cognitive
ability and poorer school performance; increased costs of chronic dis-
eases associated with fetal and early child malnutrition; and conse-
quences of maternal undernutrition on future generations. The impact
of nutrition on earnings appears to be independent of the effects of
childhood deprivation.
Key Interventions
Interventions to address child undernutrition can be divided into those
that address immediate causes (nutrition-specific interventions) and
those that address underlying causes (nutrition-sensitive interventions)
(Table 46-5). In the short-term, nutrition-specific interventions (e.g.,
salt iodization) can have substantial impacts even in the absence of
economic growth, and micronutrient interventions (supplementation
and fortification) are consistently ranked by economists of the Copen-
hagen Consensus Center as the most cost-effective investment.
Increased attention is being given to nutrition-sensitive interventions
as the best means of sustainably eliminating malnutrition, and to mul-
tisectoral policies that harness the synergism between the 2 types of
intervention. Cross-sectoral linkages between agriculture, nutrition,
and health are 1 example.
To reduce the adverse consequences of undernutrition on mortality,
morbidity, and cognitive development, interventions must encompass
both fetal and postnatal periods. Preventing LBW is essential, with
emphasis on prevention of low maternal BMI and anemia, and in the
longer term, prevention of low maternal stature. Other measures
include smoking cessation, birth spacing, delaying pregnancy until
after 18 yr of age, and intermittent preventive treatment of malaria. In
the postnatal period, promotion and support of exclusive breastfeeding
is a high priority. Although the Baby Friendly Hospital Initiative has a
marked benefit on rates of exclusive breastfeeding in hospital, postnatal
counseling from community workers or volunteers is needed to facili-
tate continuation of exclusive breastfeeding at home for 6 mo. Most
studies show a lower risk of HIV transmission with exclusive breast-
feeding than with mixed breastfeeding. The risk of transmission of HIV
by breastfeeding is approximately 5-20% depending on duration, but
can be reduced to <2% with antiretroviral drugs. Even without antiret-
roviral drugs, exclusively breastfed children of HIV-infected mothers
in low-income countries have lower mortality than non-breastfed chil-
dren, as the latter are at increased risk of death from diarrhea and
pneumonia.
Interventions to improve infant feeding must be designed for the
local setting and thus require careful formative research during their
development. Messages should be few in number, feasible, and cultur-
ally appropriate. For complementary feeding, nutrient-rich, energy-
dense mixtures of foods, and responsive feeding, are often emphasized.
Where adequate complementary feeding is difficult to achieve and
subclinical deficiencies are common, high-dose vitamin A supplemen-
tation every 6 mo in children <5 yr of age can reduce child mortality
by 5-15% and zinc supplementation can reduce 1-4 yr mortality by
18%, diarrhea incidence by 13%, and pneumonia incidence by 19%.
Monitoring of child growth provides an early alert to a nutrition or
health problem but is only worthwhile if accompanied by good coun-
seling and growth promotion activities. The impact of growth monitor-
ing and promotion will be related to coverage, intensity of contact,
health worker performance and communications skills, adequacy of
resources, and the motivation and ability of families to follow agreed
actions.
Clinical Manifestations and Treatment
of Undernutrition
Treatment of vitamin and mineral deficiencies is discussed in Chapters
48-54. Treatment of low birthweight and intrauterine growth restric-
tion are discussed respectively in Chapter 97.

SEVERE ACUTE MALNUTRITION

Table 46-5 Examples of Nutrition-Specific and
Nutrition-Sensitive Interventions
NUTRITION-SPECIFIC
INTERVENTIONS
• Promotion and support for
exclusive breastfeeding for
6 mo, and continued
breastfeeding for at least 2 yr
• Promotion of adequate,
timely, and safe
complementary feeding from
6 mo
• Increased micronutrient intake
through dietary diversity
• Micronutrient supplements for
pregnant women (iron/folate)
and young children (vitamin A,
iron, zinc) in deficient areas
• Zinc supplements to children
during and after diarrhea
(10-20 mg/day for 2 wk)
• Prevention and treatment of
severe acute malnutrition
• Crop biofortification, food
fortification, salt iodization
• Reduced heavy physical
activity in pregnancy
NUTRITION-SENSITIVE
INTERVENTIONS
• Increased access to
affordable, nutritious food;
smallholder agriculture; credit
and microfinance
• Postharvest food processing
and preservation
• Vaccination against neonatal
and childhood illness; access
to healthcare
• Improved water/sanitation and
hygiene (e.g., handwashing
with soap)
• Education; women’s
empowerment; gender
equality
• Social protection (e.g., cash
transfers)
• Malaria prevention (vector
control/bednets); intermittent
preventive treatment during
pregnancy and in children
3-59 mo
• Birth spacing; delaying
pregnancy until after 18 yr of
age
Severe acute malnutrition is defined as severe wasting and/or bilateral
edema.
Severe wasting is extreme thinness diagnosed by a weight-for-length
(or height) below −3 SD of the WHO Child Growth Standards. In
children ages 6-59 mo, a mid-upper arm circumference <115 mm also
denotes extreme thinness: a color-banded tape (see Fig. 46-3) is a
convenient way of screening children in need of treatment.
Bilateral edema is diagnosed by grasping both feet, placing a thumb
on top of each, and pressing gently but firmly for 10 seconds. A pit
(dent) remaining under each thumb indicates bilateral edema.
This definition of severe acute malnutrition distinguishes wasted/
edematous children from those who are stunted, as the latter (although
underweight) are not a priority for acute clinical care as their deficits
in height and weight cannot be corrected in the short term. The previ-
ous name protein-energy malnutrition is avoided, as it oversimplifies
the complex multideficiency etiology. Other terms are marasmus
(severe wasting), kwashiorkor (characterized by edema), and marasmic-
kwashiorkor (severe wasting + edema).
Children with severe acute malnutrition have had a diet insufficient
in energy and nutrients relative to their needs. The magnitude of the
deficits will differ depending on the duration of inadequacy, quantity
and diversity of food consumed, presence of antinutrients (such as
phytate), individual variation in requirements, and number and sever-
ity of coexisting infections and their duration. Infections can lead to
profound nutrient deficits and imbalances: For example, amino acids
are diverted to form acute-phase proteins and there are losses through
diarrhea of potassium, magnesium, vitamin A, and zinc, and of glycine
and taurine linked to small bowel bacterial overgrowth. Deficits can
 Chapter 46  ◆  Nutrition, Food Security, and Health  301

also arise from increased nutrient utilization in response to noxae (e.g., underneath that is easily infected. The hair is sparse and easily pulled
cysteine and methionine to detoxify dietary cyanogens). Heterogeneity out and may lose its curl. In dark-haired children, the hair may turn
in the extent and nature of the deficits and imbalances, reflecting the pale or reddish. The liver is often enlarged with fat. Children with
diverse pathways to severe acute malnutrition, helps explain why edema are miserable and apathetic, and often refuse to eat.
affected children differ in their clinical presentation and degree of
metabolic disturbance. Children who develop edematous malnutrition Pathophysiology
are more likely than nonedematous children to have been exposed to When a child’s intake is insufficient to meet daily needs, physiologic
noxae that generate oxidative stress and/or to have greater deficits in and metabolic changes take place in an orderly progression to conserve
free radical-scavenging antioxidants (glutathione, vitamins A, C, and energy and prolong life. This process is called reductive adaptation. Fat
E, and essential fatty acids) or cofactors (zinc, copper, selenium). stores are mobilized to provide energy. Later protein in muscle, skin,
and the gastrointestinal tract is mobilized. Energy is conserved by
Clinical Manifestations of Severe Acute reducing physical activity and growth, reducing basal metabolism and
Malnutrition (Table 46-6) the functional reserve of organs and by reducing inflammatory and
Severe wasting (Fig. 46-4) is most visible on the thighs, buttocks, and immune responses. These changes have important consequences:
upper arms, and over the ribs and scapulae where loss of fat and skel- ◆ The liver makes glucose less readily, making the child more prone
etal muscle is greatest. Wasting is preceded by failure to gain weight to hypoglycemia. It produces less albumin, transferrin, and other
and then by weight loss. The skin loses turgor and becomes loose as transport proteins. It is less able to cope with excess dietary
subcutaneous tissues are broken down to provide energy. The face may protein and to excrete toxins.
retain a relatively normal appearance, but eventually becomes wasted ◆ Heat production is less, making the child more vulnerable to
and wizened. The eyes may be sunken from loss of retroorbital fat, and hypothermia.
lachrymal and salivary glands may atrophy leading to lack of tears and ◆ The kidneys are less able to excrete excess fluid and sodium, and
a dry mouth. Weakened abdominal muscles and gas from bacterial fluid easily accumulates in the circulation, increasing the risk of
overgrowth of the upper gut may lead to a distended abdomen. Severely fluid overload.
wasted children are often fretful and irritable. ◆ The heart is smaller and weaker and has a reduced output, and
In edematous malnutrition, the edema is most likely to appear first fluid overload readily leads to death from cardiac failure.
in the feet and then in the lower legs. It can quickly develop into gen- ◆ Sodium builds up inside cells due to leaky cell membranes and
eralized edema affecting also the hands, arms, and face (Fig. 46-5). Skin reduced activity of the sodium/potassium pump, leading to excess
changes commonly occur over the swollen limbs and include dark, body sodium, fluid retention, and edema.
crackled peeling patches (flaky paint dermatosis) with pale skin ◆ Potassium leaks out of cells and is excreted in urine, contributing
to electrolyte imbalance, fluid retention, edema, and anorexia.
◆ Loss of muscle protein is accompanied by loss of potassium,
magnesium, zinc, and copper.
Table 46-6 Clinical Signs of Malnutrition
SITE SIGNS
Face Moon face (kwashiorkor), simian facies (marasmus)
Eye Dry eyes, pale conjunctiva, Bitot spots (vitamin A),
periorbital edema
Mouth Angular stomatitis, cheilitis, glossitis, spongy
bleeding gums (vitamin C), parotid enlargement
Teeth Enamel mottling, delayed eruption
Hair Dull, sparse, brittle hair, hypopigmentation, flag
sign (alternating bands of light and normal color),
broomstick eyelashes, alopecia
Skin Loose and wrinkled (marasmus), shiny and
edematous (kwashiorkor), dry, follicular
hyperkeratosis, patchy hyper- and
hypopigmentation (crazy paving or flaky paint
dermatoses), erosions, poor wound healing
Nails Koilonychia, thin and soft nail plates, fissures, or
ridges
Musculature Muscle wasting, particularly buttocks and thighs;
Chvostek or Trousseau sign (hypocalcemia)
Skeletal Deformities, usually as a result of calcium, vitamin
D, or vitamin C deficiencies
Abdomen Distended: hepatomegaly with fatty liver; ascites
may be present
Cardiovascular Bradycardia, hypotension, reduced cardiac output,
small vessel vasculopathy
Neurologic Global developmental delay, loss of knee and
ankle reflexes, impaired memory
Hematologic Pallor, petechiae, bleeding diathesis
Behavior Lethargic, apathetic, irritable on handling
From Grover Z, Ee LC: Protein energy malnutrition, Pediatr Clin N Am
56:1055–1068, 2009. Figure 46-4 Child with severe wasting.
302  Part VI  ◆  Nutrition
◆ The gut produces less gastric acid and enzymes. Motility is
reduced, and bacteria may colonize the stomach and small
intestine, damaging the mucosa and deconjugating bile salts.
Digestion and absorption are impaired.
◆ Cell replication and repair are reduced, increasing the risk of
bacterial translocation through the gut mucosa.
◆ Immune function is impaired, especially cell-mediated immunity.
The usual responses to infection may be absent, even in severe
illness, increasing the risk of undiagnosed infection.
Figure 46-5 Child with generalized edema.
1. Prevent/treat hypoglycemia
2. Prevent/treat hypothermia
3. Treat/prevent dehydration
4. Correct imbalance of electrolytes
5. Treat infections
6. Correct deficiencies of micronutrients
7. Start cautious feeding
8. Rebuild wasted tissue (catch-up growth)
9. Provide loving care and play
10. Prepare for follow-up
Figure 46-6 The 10 steps of treatment for severe acute malnutrition and their approximate time frames.
◆ Red cell mass is reduced, releasing iron which requires glucose
and amino acids to be converted to ferritin, increasing the risk of
hypoglycemia and amino acid imbalances. If conversion to ferritin
is incomplete, unbound iron promotes pathogen growth and
formation of free radicals.
◆ Micronutrient deficiencies limit the body’s ability to deactivate free
radicals, which cause cell damage. Edema and hair/skin changes
are outward signs of cell damage.
When prescribing treatment it is essential to take these changes in
function into account, otherwise organs and systems will be over-
whelmed and death will rapidly ensue.
Principles of Treatment
Figure 46-6 shows the 10 steps of treatment, which are separated into
2 phases referred to as stabilization and rehabilitation. These steps
apply to all clinical forms and all geographic locations, including North
America and Europe. The aim of the stabilization phase is to repair
cellular function, correct fluid and electrolyte imbalance, restore
homeostasis, and prevent death from the interlinked triad of hypogly-
cemia, hypothermia, and infection. The aim of the rehabilitation phase
is to restore wasted tissues (i.e., catch-up growth). It is essential that
treatment proceeds in an ordered progression and that the metabolic
machinery is repaired before any attempt is made to promote weight
gain. Pushing ahead too quickly risks inducing the potentially fatal
“refeeding syndrome.”
Caregivers bring children to health facilities because of illness, rarely
because of their malnutrition. A common mistake among healthcare
providers is to focus on the illness and treat as for a well-nourished
child. This approach ignores the deranged metabolism in malnour-
ished children and can be fatal. Such children should be considered as
severely malnourished with a complication, and treatment should
follow the 10 steps. Two other potentially fatal mistakes are to treat
edema with a diuretic and to give a high-protein diet in the early phase
of treatment.
◆ Emergency treatment: Table 46-7 summarizes the therapeutic
directives for malnourished children with shock and other
emergency conditions. Note that treatment of shock in these
children is different (less rapid, smaller volume, different fluid)
from treatment of shock in well-nourished children. This
difference is because shock from dehydration and sepsis often
coexist and are difficult to differentiate on clinical grounds. Thus
one has to be guided by the response to treatment: children with
dehydration respond to IV fluid whereas those with septic shock
will not respond. Since severely malnourished children can quickly
succumb to fluid overload, they must be monitored closely.
◆ Stabilization: Table 46-8 summarizes the therapeutic directives for
stabilization steps 1-7. Giving broad-spectrum antibiotics (Table
46-9) and feeding frequent small amounts of F75 (a specially
formulated low-lactose milk with 75 kcal and 0.9 g protein per
Stabilization Rehabilitation
Day 1–2 Day 3–7 Week 2–6
no iron with iron
 Chapter 46  ◆  Nutrition, Food Security, and Health  303

Table 46-7 Emergency Treatment in Severe Malnutrition

CONDITION
Shock
• lethargic or
unconscious and
• cold hands
Plus either:
• slow capillary refill
(longer than 3 sec) or
• weak fast pulse
Hypoglycemia
Blood glucose less than
3 mmol/L
Severe dehydration
Very severe anemia
Hb less than 4 g/dL
Emergency eye care
Corneal ulceration
IMMEDIATE ACTION
1. Give oxygen
2. Give sterile 10% glucose (5 mL/kg) by IV
3. Give IV fluid at 15 mL/kg over 1 hr, using:
• Ringers lactate with 5% dextrose or
• half-normal saline with 5% dextrose or
• half-strength Darrow solution with 5% dextrose
• if all of the above are unavailable, Ringer lactate
4. Measure and record pulse and respirations at the start and every 10 minutes
If there are signs of improvement (pulse and respiration rates fall) repeat IV 15 mL/kg for 1 more hr. Then switch to
oral or nasogastric rehydration with ReSoMal, 5-10 mL/kg in alternate hr (see Table 46-8 step 3)
If there are no signs of improvement assume septic shock and:
1. Give maintenance fluid IV (4 mL/kg/hr) while waiting for blood
2. Order 10 mL/kg fresh whole blood and transfuse slowly over 3 hr. If signs of heart failure, give 5-7 mL/kg packed
cells rather than whole blood
3. Give furosemide 1 mL/kg IV at the start of the transfusion
See Table 46-8 step 1 for treatment
Do not give IV fluids except in shock
See Table 46-8 step 3 for treatment
If very severe anemia (or Hb 4-6 g/dL AND respiratory distress):
1. Give whole blood 10 mL/kg slowly over 3 hr. If signs of heart failure, give 5-7 mL/kg packed cells rather than
whole blood
2. Give furosemide 1 mL/kg IV at the start of the transfusion
If corneal ulceration:
1. Give vitamin A immediately (age <6 mo 50,000 IU, 6-12 mo 100,000 IU, >12 mo 200,000 IU)
2. Instill 1 drop atropine (1%) into affected eye to relax the eye and prevent the lens from pushing out

Table 46-8 Therapeutic Directives for Stabilization

STEP
1. Prevent/treat hypoglycemia
blood glucose <3 mmol/L
2. Prevent/treat hypothermia
axillary <35°C (95°F); rectal
<35.5°C (95.9°F)
3. Prevent/treat dehydration
PREVENTION
Avoid long gaps without food and
minimize need for glucose:
1. Feed immediately
2. Feed every 3 hr day and night
(2 hr if ill)
3. Feed on time
4. Keep warm
5. Treat infections (they compete for
glucose)
Note: Hypoglycemia and
hypothermia often coexist, and are
signs of severe infection
Keep warm and dry and feed
frequently
1. Avoid exposure
2. Dress warmly, including head and
cover with blanket
3. Keep room hot; avoid draughts
4. Change wet clothes and bedding
5. Do not bathe if very ill
6. Feed frequently day and night
7. Treat infections
Replace stool losses
1. Give ReSoMal after each watery
stool. ReSoMal (37.5 mmol Na/L)
is a low-sodium rehydration
solution for malnutrition
TREATMENT
If conscious:
1. 10% glucose (50 mL), or a feed (see step 7), or 1 teaspoon sugar
under the tongue-whichever is quickest
2. Feed every 2 hr for at least the first day. Initially give 14 of feed
every 30 min
3. Keep warm
4. Start broad-spectrum antibiotics
If unconscious:
1. Immediately give sterile 10% glucose (5 mL/kg) by IV
2. Feed every 2 hr for at least first day. Initially give 14 of feed every
30 min. Use nasogastric (NG) tube if unable to drink
3. Keep warm.
4. Start broad-spectrum antibiotics
Actively rewarm
1. Feed
2. Skin-to-skin contact with carer (“kangaroo technique”) or dress in
warmed clothes, cover head, wrap in warmed blanket and provide
indirect heat (e.g. heater; transwarmer mattress; incandescent
lamp)
3. Monitor temperature hourly (or every 30 min if using heater)
4. Stop rewarming when rectal temperature is 36.5°C (97.7°F)
Do not give IV fluids unless the child is in shock
1. Give ReSoMal 5 mL/kg every 30 min for first 2 hr orally or NG tube
2. Then give 5-10 mL/kg in alternate hours for up to 10 hr. Amount
depends on stool loss and eagerness to drink. Feed in the other
alternate hour
3. Monitor hourly and stop if signs of overload develop (pulse rate
increases by 25 beats/min and respiratory rate by 5 breaths/min;
increasing edema; engorged jugular veins)
4. Stop when rehydrated (3 or more signs of hydration: less thirsty,
passing urine, skin pinch less slow, eyes less sunken, moist mouth,
tears, less lethargic, improved pulse and respiratory rate).
Continued
304  Part VI  ◆  Nutrition

Table 46-8 Therapeutic Directives for Stabilization—cont’d

STEP
4. Correct electrolyte
imbalance—deficit of
potassium and magnesium,
excess sodium
5. Prevent/treat infections
6. Correct micronutrient
deficiencies
7. Start cautious feeding
PREVENTION
Minimize risk of cross-infection
1. Avoid overcrowding
2. Wash hands
3. Give measles vaccine to
unimmunized children age >6 mo
Note: Folic acid, multivitamins, zinc,
copper, and other trace minerals
are already added in Nutriset F75
and F100 packets
TREATMENT
1. Give extra potassium (4 mmol/kg/day) and magnesium (0.6 mmol/
kg/day) for at least 2 wk (see Table 46-12)
Note: Potassium and magnesium are already added in Nutriset F75
and F100 packets
Infections are often silent. Starting on the first day, give broad-
spectrum antibiotics to all children.
1. For antibiotic choices/schedule see Table 46-9
2. Ensure all doses are given, and given on time
3. Cover skin lesions so they do not become infected
Note: Avoid steroids as they depress immune function
Do not give iron in the stabilization phase
1. Give vitamin A on day 1 (under 6 mo 50,000 units; 6-12 mo 100,000
units; >12 mo 200,000 units) if child has any eye signs of vitamin A
deficiency or has had recent measles. Repeat this dose on days 2
and 14
2. Folic acid 1 mg (5 mg on day 1)
3. Zinc (2 mg/kg/day) and copper (0.3 mg/kg/day).These are in the
electrolyte/mineral solution and Combined Mineral Vitamin mix
(CMV) and can be added to feeds and ReSoMal
4. Multivitamin syrup or CMV
1. Give 8-12 small feeds of F75 to provide 130 mL/kg/day,100 kcal/kg/
day and 1-1.5 g protein/kg/day
2. If gross edema, reduce volume to 100 ml/kg/day
3. Keep a 24-hr intake chart. Measure feeds carefully. Record leftovers
4. If child has poor appetite, coax and encourage to finish the feed. If
unfinished, reoffer later. Use NG tube if eating 80% or less of the
amount offered
5. If breastfed, encourage continued breastfeeding but also give F75
6. Transfer to F100 when appetite returns (usually within 1 wk) and
edema has been lost or is reduced
7. Weigh daily and plot weight.

Table 46-9 Recommended Antibiotics*

GIVE
If no complications Amoxicillin oral 25 mg/kg twice daily for 5 days
If complications (shock, hypoglycemia, hypothermia, skin lesions, Gentamicin (7.5 mg/kg IV or IM) once daily for 7 days
respiratory or urinary tract infections, or lethargy/sickly) and
Ampicillin (50 mg/kg IV or IM) every 6 hr for 2 days, then oral amoxicillin
(25-40 mg/kg) every 8 hr for 5 days
*Local resistance patterns may require these to be adjusted: Ensure that there is Gram-negative cover.
If specific infections are identified, add appropriate antibiotics.
For persistent diarrhea/small bowel overgrowth, add metronidazole (7.5 mg/kg oral) every 8 hr for 7 days.

100 mL to which potassium, magnesium, and micronutrients are
added), will reestablish metabolic control, treat edema, and restore
appetite. The parenteral route should be avoided; children who
lack appetite should be fed by nasogastric tube, as nutrients
delivered within the gut lumen help in its repair. Table 46-10
gives recipes for preparing the special feeds, and their nutrient
composition. Two recipes for F75 are shown: one requires no
cooking, the other is cereal-based and has a lower osmolality,
which may benefit children with persistent diarrhea. F75 is also
available commercially in which maltodextrins replace some of the
sugar and to which potassium, magnesium, minerals, and vitamins
are already added.
Dehydration status is easily misdiagnosed in severely wasted
children, as the usual signs (such as slow skin pinch, sunken eyes)
may be present even without dehydration. Rehydration must
therefore be closely monitored for signs of fluid overload. Serum
electrolyte levels can be misleading because of sodium leaking
from the blood into cells and potassium leaking out of cells.
Keeping the intake of electrolytes and nutrients constant (see Table
46-9) allows systems to stabilize more quickly than adjusting
intake in response to laboratory results.
Table 46-11 gives a recipe for the special rehydration solution
used in severe malnutrition (ReSoMal). Therapeutic Combined
Mineral Vitamin mix (CMV) contains electrolytes, minerals, and
vitamins and is added to ReSoMal and feeds. If unavailable,
potassium, magnesium, zinc, and copper can be added as an
electrolyte/mineral stock solution (Table 46-12 provides a recipe)
and a multivitamin supplement given separately.
◆ Rehabilitation: The signals for entry to this phase are reduced/
minimal edema and return of appetite.
A controlled transition over 3 days is recommended to
prevent the “refeeding syndrome.” After the transition,
 Chapter 46  ◆  Nutrition, Food Security, and Health  305

Table 46-10 Recipes for Milk Formulas F75 and F100

F75c
F75b (STARTER) F100d
(STARTER) (CEREAL-BASED) (CATCH-UP)
Dried skimmed milk (g) 25 25 80
Sugar (g) 100 70 50
Cereal flour (g) — 35 —
Vegetable oil (g) 30 30 60
Electrolyte/mineral solution (mL)a 20 20 20
Water: make up to (mL) 1000 1000 1000
Content/100 mL
Energy (kcal) 75 75 100
Protein (g) 0.9 1.1 2.9
Lactose (g) 1.3 1.3 4.2
Potassium (mmol) 4.0 4.2 6.3
Sodium (mmol) 0.6 0.6 1.9
Magnesium (mmol) 0.43 0.46 0.73
Zinc (mg) 2.0 2.0 2.3
Copper (mg) 0.25 0.25 0.25
% Energy from protein 5 6 12
% Energy from fat 32 32 53
Osmolality (mOsm/L) 413 334 419
Whisk at high speed to prevent oil from separating out.
a
See Table 46-12 for recipe, or use commercially available therapeutic Combined Mineral Vitamin mix (CMV).
b
A comparable F75 can be made from 35 g dried whole milk, 100 g sugar, 20 g oil, 20 mL electrolyte/mineral solution, and water to 1000 mL; or from 300 mL full
cream cow’s milk, 100 g sugar, 20 g oil, 20 mL electrolyte/mineral solution, and water to 1000 mL.
c
This lower-osmolality formula may be helpful for children with dysentery or persistent diarrhea. Cook for 4 min.
d
A comparable F100 can be made from 110 g dried whole milk, 50 g sugar, 30 g oil, 20 mL electrolyte/mineral solution, and water to 1000 mL; or from 880 mL full
cream cow’s milk, 75 g sugar, 20 g oil, 20 mL electrolyte/mineral solution, and water to 1000 mL.

Table 46-11 Recipe for Rehydration Solution for Table 46-12 Recipe for Concentrated Electrolyte/
Malnutrition (ReSoMal) Mineral Solution*
INGREDIENT AMOUNT INGREDIENT g mol/20 mL
Water 2 L Potassium chloride: KCl 224.0 24 mmol
WHO-ORS One 1-L sachet* Tripotassium citrate 81.0 2 mmol
Sucrose 50 g Magnesium chloride: MgCl2. 6H2O 76.0 3 mmol
Electrolyte/mineral solution† mL Zinc acetate: Zn acetate.2H2O 8.2 300 µmol
ReSoMal contains 37.5 mmol sodium and 40 mmol potassium/L Copper sulfate: CuSO4. 5H2O 1.4 45 µmol
*Sachet contains 2.6 g sodium chloride, 2.9 g trisodium citrate, 1.5 g
potassium chloride, 13.5 g glucose. Water: make up to 2500 mL
†See Table 46-12 for recipe, or use commercially available therapeutic
Add 20 mL when preparing 1 L of feed or ReSoMal.
Combined Mineral Vitamin mix (CMV).
*Make fresh each month. Use cooled boiled water.

unlimited amounts should be given of a high-energy, high-
protein milk formula such as F100 (100 kcal and 3 g protein
per 100 mL), or ready-to-use therapeutic food (RUTF), or
family foods modified to have comparable energy and protein
contents.
To make the transition, for 2 days replace F75 with an equal
volume of F100 and then increase each successive feed by
10 mL until some feed remains uneaten (usually at around
200 mL/kg/day).
After the transition, give 150-220 kcal/kg/day and 4-6 g protein/
kg/day and continue to give potassium, magnesium, and
micronutrients. Add iron (3 mg/kg/day). If breastfed, encourage
continued breastfeeding.
Children with severe malnutrition have developmental delays,
so loving care, structured play, and sensory stimulation during and
after treatment are essential to aid recovery of brain function.
Community-based treatment: Many children with severe acute mal-
nutrition can be identified in their communities before medical com-
plications arise. If these children have a good appetite and are clinically
well, they can be rehabilitated at home through community-based
therapeutic care, which has the added benefit of reducing their expo-
sure to nosocomial infections and providing continuity of care after
306  Part VI  ◆  Nutrition

recovery. It also reduces the time caregivers spend away from home care has 4 main elements: community mobilization and sensitization;
and their opportunity costs, and can be cost-effective for health active case-finding; therapeutic care; and follow-up after discharge.
services. Community-based therapeutic care comprises steps 8-10, plus a
Figure 46-7 shows the criteria for inpatient versus outpatient care. broad-spectrum antibiotic (step 5). RUTF is usually provided, espe-
To maximize coverage and compliance, community-based therapeutic cially in times of food shortage. RUTF is specially designed for reha-
bilitating children with severe acute malnutrition at home. It is high in
energy and protein and has electrolytes and micronutrients added. The
most widely used RUTF is a thick paste that contains milk powder,
peanuts, vegetable oil, and sugar. Pathogens cannot grow in it because
Severe acute malnutrition of its low moisture content. Hospitalized children who have completed
steps 1-7 and the transition can be transferred to community-based
care for completion of their rehabilitation, thereby reducing their hos-
pital stay to about 7-10 days.
With complications Without complications
Bibliography is available at Expert Consult.
Severe edema (+++) Edema (+/++)

OR OR 46.1  Refeeding Syndrome

Robert M. Kliegman
MUAC 115 mm AND MUAC 115 mm
any of the following:
AND Refeeding syndrome can complicate the acute nutritional rehabilita-
Anorexia tion of children who are undernourished from any cause (Table 46-13).
Clinically unwell All of the following: Refeeding syndrome is rare when the WHO recommendations for the
Not alert treatment of malnutrition are followed (see Chapter 46); however, it
Good appetite may follow overly aggressive enteral or parenteral alimentation. Mal-
Clinically well nutrition usually has normal serum electrolytes but is associated with
Alert
intracellular electrolyte depletion. When excessive carbohydrates are
administered, the resultant increase in serum insulin levels may
produce hypokalemia, hypophosphatemia, and hypomagnesemia. The
hallmark of refeeding syndrome is the development of severe hypo-
phosphatemia after the cellular uptake of phosphate during the 1st wk
Inpatient care Outpatient of starting to reefed. Serum phosphate levels of ≤0.5 mmol/L can
therapeutic care produce weakness, rhabdomyolysis, neutrophil dysfunction, cardiore-
spiratory failure, arrhythmias, seizures, altered level of consciousness,
Figure 46-7 Flow diagram for inpatient and outpatient care in or sudden death. Phosphate levels should be monitored during refeed-
the child with severe acute malnutrition. MUAC, Mid upper arm ing, and if they are low, phosphate should be administered during
circumference. refeeding to treat severe hypophosphatemia (see Chapter 55.6).

Table 46-13 Clinical Signs and Symptoms of Refeeding Syndrome

VITAMIN/THIAMINE SODIUM
HYPOPHOSPHATEMIA HYPOKALEMIA HYPOMAGNESEMIA DEFICIENCY RETENTION HYPERGLYCEMIA
Cardiac Cardiac Cardiac Encephalopathy Fluid overload Cardiac
Hypotension Arrhythmias Arrhythmias Lactic acidosis Pulmonary edema Hypotension
Decreased stroke Respiratory Neurologic Death Cardiac compromise Respiratory
volume Failure Weakness Hypercapnia
Respiratory Neurologic Tremor Failure
Impaired diaphragm Weakness Tetany Other
contractility Paralysis Seizures Ketoacidosis
Dyspnea Gastrointestinal Altered mental status Coma
Respiratory failure Nausea Coma Dehydration
Neurologic Vomiting Gastrointestinal Impaired immune
Paresthesia Constipation Nausea function
Weakness Muscular Vomiting
Confusion Rhabdomyolysis Diarrhea
Disorientation Muscle necrosis Other
Lethargy Other Refractory
Areflexic paralysis Death hypokalemia and
Seizures hypocalcemia
Coma Death
Hematologic
Leukocyte dysfunction
Hemolysis
Thrombocytopenia
Other
Death
Data from Kraft MD, Btaiche IF, Sacks GS: Review of RFS, Nutr Clin Pract 20:625–633, 2005. From Fuentebella J, Kerner JA: Refeeding syndrome, Pediatr Clin North
Am 56:1201–1210, 2009.
 Chapter 46  ◆  Nutrition, Food Security, and Health  306.e1
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Ashworth A, Khanum S, Jackson A, et al: Guidelines for the inpatient treatment of
severely malnourished children, 2003, World Health Organization.
Beddington J, Asaduzzaman M, Clark M, et al: Achieving food security in the face of
climate change: Final Report from the Commission on Sustainable Agriculture and
Climate Change, Copenhagen, 2012, CCAFS. http://www.ccafs.cgiar.org/
commission.
Black RE, Victora CG, Walker SP, et al: Maternal and child undernutrition and
overweight in low- and middle-income countries, Lancet 382:427–451, 2013.
http://www.globalnutritionseries.org.
Carvalho NF, Kenney RD, Carrington PH, et al: Severe nutritional deficiencies in
toddlers resulting from health food milk alternatives, Pediatrics 107(4):e–46,
2001.
Engle P, Grantham-McGregor S, Black M, et al: How to avoid the loss of potential
in over 200 million young children in the developing world, Child Health Educ
1(2):58–72, 2009.
FAO, IFAD and WFP: The State of Food Insecurity in the World 2013.The multiple
dimensions of food security, Rome, 2013, FAO. http://www.fao.org/docrep/018/
i33434e.pdf.
Godfray HCJ, Beddington JR, Crute IR, et al: Food security: The challenge of
feeding 9 billion people, Science 327:812–818, 2010.
Gordon-Larsen P, Jones-Smith J: Challenges in ameliorating hunger while
preventing obesity, Lancet 380:787–788, 2012.
Haddad L: Why India needs a national nutrition strategy, BMJ 343:d6687,
2011.
Jay-Russell MT: Raw (unpasteurized) milk: are health-conscious consumers
making an unhealthy choice?, Clin Infect Dis 51:1418–1419, 2010.
Ludwig DS, Blummenthal SJ, Willett WC: Opportunities to reduce childhood
hunger and obesity, JAMA 308(24):2567–2568, 2012.
Shatrugna V, Srivatsan R: The right to food security, BMJ 345:e8273, 2012.
Tierney EP, Sahe RJ, Shwayder T: Kwashiorkor from a severe dietary restriction in
an 8-month infant in suburban Detroit, Michigan: case report and review of the
literature, Int J Dermatol 49:500–506, 2010.
Trehan I, Goldbach HS, LaGrone LN, et al: Antibiotics as part of the management
of severe acute malnutrition, N Engl J Med 368:425–435, 2013.
United Nations Department of Economic and Social Affairs: The Millennium
Development Goals Report 2013, New York, 2013, United Nations. http://
mdgs.un.org.
Valid International: Community-based therapeutic care (CTC): A field manual,
Oxford, 2006, Valid International.
Von Grebmer K, Ringler C, Rosegrant MW, et al: 2012 Global Hunger Index. The
Challenge of hunger: Ensuring sustainable food security under land, water, and
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http://dx.doi/org/10.2499/9780896299429.
Vygen SB, Roberfroid D, Captier V, et al: Treatment of severe acute malnutrition in
infants aged ≤6 months in Niger, J Pediatr 162:515–521, 2013.
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default/WDSContentServer/WDSP/IB/2013/03/13/000333037
_20130313115043/R.
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Chapter 47  Environmental Changes
Overweight and Obesity
Sheila Gahagan
Obesity is an important pediatric public health problem associated
with risk of complications in childhood and increased morbidity and
mortality throughout adult life.
EPIDEMIOLOGY
Obesity is a global public health problem, sparing only dramati-
cally poor regions with chronic food scarcity such as sub-Saharan
Africa and Haiti. In 2008, according to the World Health Organiza-
tion, more than 1.4 billion persons ≥20 yr old were overweight or
obese.
In the United States, 36% of adults are obese, and an additional
35% of adults are overweight. In children, the prevalence of obesity
increased 300% over approximately 40 yr. The National Health and
Nutrition Examination Survey, 2009-2010, found 32% of children,
2-19 yr old to be overweight or obese, and 17% in the obese range.
Children’s risk varies significantly by race/ethnicity. In 2009-2010, 24%
of non-Hispanic Black, 21% of Hispanic, and >20% of American
Indian/Alaskan Native children and adolescents were obese compared
to 14% of white children. Across all racial groups, higher maternal
education confers protection against childhood obesity.
Parental obesity correlates with a higher risk for obesity in their
children. Prenatal factors including high preconceptual weight, gesta-
tional weight gain, high birth weight, and maternal smoking are associ-
ated with increased risk for later obesity. Paradoxically, intrauterine
growth restriction with early infant catch-up growth is associated with
the development of central adiposity and adult-onset cardiovascular
risk. Breastfeeding is only modestly protective for obesity. Infants with
high levels of negative reactivity (temperament) are at risk for obesity.
Better self-regulation is protective.
BODY MASS INDEX
Obesity or increased adiposity is defined using the body mass index
(BMI), which is an excellent proxy for more direct measurement of
body fat. BMI = weight in kg/(height in meters)2. Adults with a BMI
≥30 meet the criterion for obesity, and those with a BMI 25-30 fall in
the overweight range. During childhood, levels of body fat change
beginning with high adiposity during infancy. Body fat levels decrease
for approximately 5.5 yr until the period called adiposity rebound,
when body fat is typically at the lowest level. Adiposity then increases
until early adulthood (Fig. 47-1). Consequently, obesity and over-
weight are defined using BMI percentiles; children >2 yr old with a
BMI ≥95th percentile meet the criterion for obesity, and those with a
BMI between the 85th and 95th percentiles fall in the overweight
range.
ETIOLOGY
Humans have the capacity to store energy in adipose tissue, allowing
improved survival in times of famine. Furthermore, humans innately
prefer sweet and salty foods and reject bitter flavors. Many vegetables
are bitter. These preferences probably reflect evolutionary adaptations
to avoid consuming toxic plants. Nonetheless, repeated exposure to
healthy foods promotes their acceptance and liking, especially in early
life. Simplistically, obesity results from an imbalance of caloric intake
and energy expenditure. Even incremental but sustained caloric excess
results in excess adiposity. Individual adiposity is the result of a
complex interplay among genetically determined body habitus, appe-
tite, nutritional intake, physical activity, and energy expenditure. Envi-
ronmental factors determine levels of available food, preferences for
Chapter 47  ◆  Overweight and Obesity  307
types of foods, levels of physical activity, and preferences for types of
activities.
Over the last 4 decades, the food environment has changed dramati-
cally. Changes in the food industry relate in part to social changes, as
extended families have become more dispersed. Fewer families rou-
tinely prepare meals. Foods are increasingly prepared by a food indus-
try, with high levels of calories, simple carbohydrates, and fat. The price
of many foods has declined relative to the family budget. These changes,
in combination with marketing pressure, have resulted in larger
portion sizes and increased snacking between meals. The increased
consumption of high-carbohydrate beverages, including sodas, sport
drinks, fruit punch, and juice, adds to these factors.
One-third of U.S. children consume fast food daily. A typical fast
food meal can contain 2000 kcal and 84 g of fat. Many children
consume 4 servings of high-carbohydrate beverages per day, resulting
in an additional 560 kcal of low nutritional value. Sweetened beverages
have been linked to increased risk for obesity because children who
drink high amounts of sugar do not consume less food. The dramatic
increase in the use of high-fructose corn syrup to sweeten beverages
and prepared foods is another important environmental change,
leading to availability of inexpensive calories.
Since World War II, levels of physical activity in children and adults
have declined. Changes in the built environment have resulted in more
reliance on cars and decreased walking. Work is increasingly sedentary,
and many sectors of society do not engage in physical activity during
leisure time. For children, budgetary constraints and pressure for aca-
demic performance have led to less time devoted to physical education
in schools. Perception of poor neighborhood safety is another factor
that can lead to lower levels of physical activity when children are
required to stay indoors. The advent of television, computers, and
video games has resulted in opportunities for sedentary activities that
do not burn calories.
Changes in another health behavior, sleep, might also contribute.
Over the last 4 decades, children and adults have decreased the amount
of time spent sleeping. Reasons for these changes may relate to
increased time at work, increased time watching television, and a gen-
erally faster pace of life. Chronic partial sleep loss can increase risk for
weight gain and obesity, with the impact possibly greater in children
than in adults. In studies of young, healthy, lean men, short sleep dura-
tion was associated with decreased leptin levels and increased ghrelin
levels, along with increased hunger and appetite. Sleep debt also results
in decreased glucose tolerance and insulin sensitivity related to altera-
tions in glucocorticoids and sympathetic activity. Some effects of sleep
debt might relate to orexins, peptides synthesized in the lateral hypo-
thalamus that can increase feeding, arousal, sympathetic activity, and/
or neuropeptide Y activity.
Genetics
Genetic determinants also have a role in individual susceptibility to
obesity (Table 47-1). Findings from genome-wide association studies
explain a very small portion of interindividual variability in obesity.
One important example, the FTO gene at 16q12, is associated with
adiposity in childhood, probably explained by increased energy intake
(Table 47-1). Monogenic forms of obesity have also been identified,
including MC4R deficiency, associated with early-onset obesity and
food-seeking behavior. In addition, there are genetic conditions associ-
ated with obesity, such as Prader-Willi syndrome, which results from
absence of paternally expressed imprinted genes in the 15q11.2–q13
region. Prader-Willi syndrome is characterized by insatiable appetite
and food seeking. Epigenetic environmental modification of genes may
have a role in the development of obesity, especially during fetal and
early life.
Endocrine and Neural Physiology
Monitoring of “stored fuels” and short-term control of food intake
(appetite and satiety) occurs through neuroendocrine feedback loops
linking adipose tissue, the gastrointestinal tract, and the central
308  Part VI  ◆  Nutrition

2 to 20 years: Boys NAME

Body mass index-for-age percentiles RECORD #

Date Age Weight Stature BMI* Comments

BMI

35

34

33

32

31

30
95
29

BMI 28
90
27 27
26 85 26
25 25
75
24 24

23 23
50
22 22

21 21
25
20 20
10
19 19
5
18 18

17 17

16 16

15 15

14 14

13 13

12 12

2 2
kg/m AGE (YEARS) kg/m
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Published May 30, 2000 (modified 10/16/00).

SOURCE: Developed by the National Center for Health Statistics in collaboration with
the National Center for Chronic Disease Prevention and Health Promotion (2000).
http://www.cdc.gov/growthcharts

A
Figure 47-1 Body mass index (BMI)-for-age profiles for boys and men (A) and girls and women (B). Developed by the National Center for Health
Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). See www.cdc.gov/growthcharts
 Chapter 47  ◆  Overweight and Obesity  309

2 to 20 years: Girls NAME

Body mass index-for-age percentiles RECORD #

Date Age Weight Stature BMI* Comments

BMI
35

34

33

32

95
31

30

29

BMI 28
90

27 27
26 85 26
25 25

24 75 24

23 23

22 22
50
21 21

20 20
25
19 19
10
18 5
18

17 17

16 16

15 15

14 14

13 13

12 12

2 2
kg/m AGE (YEARS) kg/m
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Published May 30, 2000 (modified 10/16/00).

SOURCE: Developed by the National Center for Health Statistics in collaboration with
the National Center for Chronic Disease Prevention and Health Promotion (2000).
http://www.cdc.gov/growthcharts
B
Figure 47-1, cont’d
310  Part VI  ◆  Nutrition

Table 47-1 Endocrine and Genetic Causes of Obesity

DISEASE SYMPTOMS LABORATORY
ENDOCRINE
Cushing syndrome Central obesity, hirsutism, moon face, hypertension Dexamethasone suppression test
GH deficiency Short stature, slow linear growth Evoked GH response, IGF-1
Hyperinsulinism Nesidioblastosis, pancreatic adenoma, hypoglycemia, Insulin level
Mauriac syndrome
Hypothyroidism Short stature, weight gain, fatigue, constipation, cold TSH, FT4
intolerance, myxedema
Pseudohypoparathyroidism Short metacarpals, subcutaneous calcifications, dysmorphic Urine cAMP after synthetic PTH
facies, mental retardation, short stature, hypocalcemia, infusion
hyperphosphatemia
GENETIC
Alstrom syndrome Cognitive impairment, retinitis pigmentosa, diabetes ALMS1 gene
mellitus, hearing loss, hypogonadism, retinal degeneration
Bardet-Biedl syndrome Retinitis pigmentosa, renal abnormalities, polydactyly, BBS1 gene
hypogonadism
Biemond syndrome Cognitive impairment, iris coloboma, hypogonadism,
polydactyly
Carpenter syndrome Polydactyly, syndactyly, cranial synostosis, mental retardation Mutations in the RAB23 gene, located
on chromosome 6 in humans
Cohen syndrome Mid-childhood-onset obesity, short stature, prominent Mutations in the VPS13B gene (often
maxillary incisors, hypotonia, mental retardation, called the COH1 gene) at locus 8q22
microcephaly, decreased visual activity
Deletion 9q34 Early-onset obesity, mental retardation, brachycephaly, Deletion 9q34
synophrys, prognathism, behavior and sleep disturbances
Down syndrome Short stature, dysmorphic facies, mental retardation Trisomy 21
ENPP1 gene mutations Insulin resistance, childhood obesity Gene mutation on chromosome 6q
Fröhlich syndrome Hypothalamic tumor
FTO gene polymorphism Dysregulation of orexigenic hormone acyl-ghrelin, poor Homozygous for FTO AA allele
postprandial appetite suppression
Leptin or leptin receptor gene Early-onset severe obesity, infertility (hypogonadotropic Leptin
deficiency hypogonadism)
Melanocortin 4 receptor gene Early-onset severe obesity, increased linear growth, MC4R mutation
mutation hyperphagia, hyperinsulinemia
Most common known genetic cause of obesity
Homozygous worse than heterozygous
Prader-Willi Syndrome Neonatal hypotonia, slow infant growth, small hands and Partial deletion of chromosome 15 or
feet, mental retardation, hypogonadism, hyperphagia loss of paternally expressed genes
leading to severe obesity, paradoxically elevated ghrelin
Proopiomelanocortin deficiency Obesity, red hair, adrenal insufficiency, hyperproinsulinemia Loss-of-function mutations of the
POMC gene
Rapid-onset obesity with Often confused with congenital central hypoventilation Unknown genes
hypothalamic dysfunction, syndrome (CCHS), presentation ≥1.5 yr with weight gain, May be a paraneoplastic disorder
hypoventilation, and autonomic hyperphagia, hypoventilation, cardiac arrest, central
dysregulation (ROHHAD) diabetes insipidus, hypothyroidism, growth hormone
deficiency, pain insensitivity, hypothermia, precocious
puberty, neural crest tumors
Turner syndrome Ovarian dysgenesis, lymphedema, web neck, short stature, XO chromosome
cognitive impairment
cAMP, cyclic adenosine monophosphate; FT4, free thyroxine; GH, growth hormone; IGF, insulin-like growth factor; PTH, parathyroid hormone; TSH, thyroid-stimulating
hormone.

nervous system (Fig. 47-2). Gastrointestinal hormones, including cho-
lecystokinin, glucagon-like peptide-1, peptide YY, and vagal neuronal
feedback promote satiety. Ghrelin stimulates appetite. Adipose tissue
provides feedback regarding energy storage levels to the brain through
hormonal release of adiponectin and leptin. These hormones act on
the arcuate nucleus in the hypothalamus and on the solitary tract
nucleus in the brainstem and, in turn, activate distinct neuronal net-
works. Adipocytes secrete adiponectin into the blood, with reduced
levels in response to obesity and increased levels in response to fasting.
Reduced adiponectin levels are associated with lower insulin sensitivity
and adverse cardiovascular outcomes. Leptin is directly involved in
satiety, as low leptin levels stimulate food intake and high leptin levels
inhibit hunger in animal models and in healthy human volunteers.
Adiposity correlates to serum leptin levels among children and adults,
with the direction of effect remaining unclear.
Numerous neuropeptides in the brain, including peptide YY, agouti-
related peptide, and orexin, appear to affect appetite stimulation,
whereas melanocortins and α-melanocortin–stimulating hormone are
involved in satiety. The neuroendocrine control of appetite and weight
involves a negative-feedback system, balanced between short-term
control of appetite and long-term control of adiposity (including
leptin). Peptide YY reduces food intake via the vagal–brainstem–
hypothalamic pathway. Developmental changes in peptide YY are
evident as infants have higher levels of peptide YY than school-age
children and adults. Obese children have lower fasting levels of peptide
YY compared to adults. Weight loss may restore levels of peptide YY
in children even though this does not happen in adults. In addition,
patients homozygous for the FTO obesity risk allele demonstrate poor
regulation of the orexigenic hormone acyl-ghrelin and have poor post-
prandial appetite suppression.
 Chapter 47  ◆  Overweight and Obesity  311

Behavioral and Metabolic Outputs

That Affect Nutrient and
Energy Expenditure

Hypothalamus
Autonomic
Outputs

Brain stem
Pituitary

Metabolic
Regulation
Endocrine Autonomic
Outputs Afferents
Insulin Autonomic
Leptin Ghrelin Outputs
PYY
GLP-1
Fat Autonomic Nutrients
Outputs
Liver
IL-6
Adiponectin Stomach

Adiponectin IL-6
Insulin
Pancreas

Nutrients
Insulin

Autonomic
Outputs
Muscle

Figure 47-2 Regulation of energy homeostasis by the brain–adipose tissue–intestinal axis. Leptin stimulates hypothalamic anorexigenic and
inhibits orexigenic neurons. Adiponectin stimulates hepatic, and muscle glucose utilization and increases insulin sensitivity, while interleukin-6 (IL-6)
contributes to adipose tissue, muscle and hepatic insulin resistance. Peptide YY (PYY) inhibits orexigenic and glucagon-like peptide 1 (GLP-1)
stimulates anorexigenic hypothalamic neurons. GLP-1 also augments glucose stimulated pancreatic insulin secretion and suppresses glucagon
secretion. Insulin stimulates adipose tissue and muscle glucose uptake, enhances lipogenesis, suppresses hepatic glucose production, and has an
inhibitory effect on the hypothalamic anorexigenic system. Ghrelin stimulates the orexigenic hypothalamic pathways. (Modified from Melmed S,
Polonsky KS, Larsen PR, Kronenberg HM: Williams Textbook of Endocrinology, ed 12, Philadelphia, 2011, Saunders. Fig. 35-1.)

COMORBIDITIES immediate comorbidities include type 2 diabetes, hypertension, hyper-

Complications of pediatric obesity occur during childhood and ado-
lescence and persist into adulthood. An important reason to prevent
and treat pediatric obesity is the increased risk for morbidity and
mortality later in life. The Harvard Growth Study found that boys who
were overweight during adolescence were twice as likely to die from
cardiovascular disease as those who had normal weight. More
lipidemia, and nonalcoholic fatty liver disease (Table 47-2). Insulin
resistance increases with increasing adiposity and independently
affects lipid metabolism and cardiovascular health. The metabolic syn-
drome (central obesity, hypertension, glucose intolerance, and hyper-
lipidemia) increases risk for cardiovascular morbidity and mortality.
Nonalcoholic fatty liver disease (NAFLD) occurs in 10-25% of obese
312  Part VI  ◆  Nutrition

Table 47-2 Obesity-Associated Comorbidities

DISEASE POSSIBLE SYMPTOMS LABORATORY CRITERIA
CARDIOVASCULAR
Dyslipidemia HDL <40, LDL >130, total cholesterol >200 Fasting total cholesterol, HDL, LDL, triglycerides
Hypertension SBP >95% for sex, age, height Serial testing, urinalysis, electrolytes, blood urea
nitrogen, creatinine
ENDOCRINE
Type 2 diabetes mellitus Acanthosis nigrans, polyuria, polydipsia Fasting blood glucose >110, hemoglobin A1c, insulin
level, C-peptide, oral glucose tolerance test
Metabolic syndrome Central adiposity, insulin resistance, dyslipidemia, Fasting glucose, LDL and HDL cholesterol
hypertension, glucose intolerance
Polycystic ovary syndrome Irregular menses, hirsutism, acne, insulin Pelvic ultrasound, free testosterone, LH, FSH
resistance, hyperandrogenemia
GASTROINTESTINAL
Gallbladder disease Abdominal pain, vomiting, jaundice Ultrasound
Nonalcoholic fatty liver disease Hepatomegaly, abdominal pain, dependent AST, ALT, ultrasound, CT, or MRI
(NAFLD) edema, ↑ transaminases
Can progress to fibrosis, cirrhosis
NEUROLOGIC
Pseudotumor cerebri Headaches, vision changes, papilledema Cerebrospinal fluid opening pressure, CT, MRI
Migraines Hemicrania, headaches None
ORTHOPEDIC
Blount disease (tibia vara) Severe bowing of tibia, knee pain, limp Knee x-rays
Musculoskeletal problems Back pain, joint pain, frequent strains or sprains, X-rays
limp, hip pain, groin pain, leg bowing
Slipped capital femoral epiphysis Hip pain, knee pain, limp, decreased mobility of Hip x-rays
hip
PSYCHOLOGICAL
Behavioral complications Anxiety, depression, low self-esteem, disordered Child Behavior Checklist, Children’s Depression
eating, signs of depression, worsening school Inventory, Peds QL, Eating Disorder Inventory 2,
performance, social isolation, problems with subjective ratings of stress and depression, Behavior
bullying or being bullied Assessment System for Children, Pediatric Symptom
Checklist
PULMONARY
Asthma Shortness of breath, wheezing, coughing, Pulmonary function tests, peak flow
exercise intolerance
Obstructive sleep apnea Snoring, apnea, restless sleep, behavioral Polysomnography, hypoxia, electrolytes (respiratory
problems acidosis with metabolic alkalosis)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, computed tomography; FSH, follicle-stimulating hormone; HDL, high-density lipoprotein;
LDL, low-density lipoprotein; LH, luteinizing hormone; MRI, magnetic resonance imaging; Peds QL, Pediatric Quality of Life Inventory; SBP, systolic blood pressure.

adolescents. NAFLD is now the most common chronic liver disease in
U.S. children and adolescents. It can present with advanced fibrosis
or nonalcoholic steatohepatitis and may result in cirrhosis and hepa-
tocellular carcinoma. Insulin resistance is commonly associated. Fur-
thermore, NAFLD is independently associated with increased risk of
cardiovascular disease.
Obesity may also be associated with chronic inflammation. Adipo-
nectin, a peptide with antiinflammatory properties, occurs in reduced
levels in obese patients as compared to insulin-sensitive, lean persons.
Low adiponectin levels correlate with elevated levels of free fatty acids
and plasma triglycerides as well as a high BMI, and high adiponectin
levels correlate with peripheral insulin sensitivity. Adipocytes secrete
peptides and cytokines into the circulation, and proinflammatory pep-
tides such interleukin (IL)-6 and tumor necrosis factor-α (TNF-α)
occur in higher levels in obese patients. Specifically, IL-6 stimulates
production of C-reactive protein in the liver. C-reactive protein is a
marker of inflammation and might link obesity, coronary disease, and
subclinical inflammation.
Some complications of obesity are mechanical, including obstructive
sleep apnea and orthopedic complications. Orthopedic complications
include Blount disease and slipped femoral capital epiphysis (see Chap-
ters 677, 678.4).
Mental health problems can coexist with obesity, with the possibility
of bidirectional effects. These associations are modified by gender,
ethnicity, and socioeconomic status. Self-esteem may be lower in obese
adolescent girls compared to nonobese peers. Some studies have found
an association between obesity and adolescent depression. There is
considerable interest in the cooccurrence of eating disorders and
obesity.
IDENTIFICATION
Overweight and obese children are often identified as part of routine
medical care, and the child and family may be unaware that the child
has increased adiposity. They may be unhappy with the medical pro-
vider for raising this issue and respond with denial or apparent lack of
concern. It is often necessary to begin by helping the family understand
the importance of healthy weight for current and future health, espe-
cially because intervention requires considerable effort by the child and
the family. Forging a good therapeutic relationship is important,
because obesity intervention requires a chronic disease management
approach. Successful resolution of this problem necessitates consider-
able family and child effort over an extended period in order to change
eating and activity behaviors.
EVALUATION
The evaluation of the overweight or obese child begins with examina-
tion of the growth chart for weight, height, and BMI trajectories;
consideration of possible medical causes of obesity; and detailed

exploration of family eating, nutritional, and activity patterns. A com-
plete pediatric history is used to uncover comorbid disorders. The
family history focuses on the adiposity of other family members and
the family history of obesity-associated disorders. The physical exami-
nation adds data that can lead to important diagnoses. Laboratory
testing is guided by the need to identify comorbid conditions.
Examination of the growth chart reveals the severity, duration, and
timing of obesity onset. Children who are overweight (BMI in the
85th-95th percentile) are less likely to have developed comorbid condi-
tions than those who are obese (BMI ≥95th percentile). Those with a
BMI ≥99th percentile are even more likely to have coexisting medical
problems. Once obesity severity is determined, the BMI trajectory is
examined to elucidate when the child became obese. Several periods
during childhood are considered sensitive periods or times of increased
risk for developing obesity, including infancy, adiposity rebound (when
body fat is lowest at approximately age 5.5 yr), and adolescence. An
abrupt change in BMI might signal the onset of a medical problem or
a period of family or personal stress for the child. Examination of the
weight trajectory can further expand understanding of how the
problem developed. A young child might exhibit high weight and high
height because linear growth can increase early in childhood if a child
consumes excess energy. At some point, the weight percentile exceeds
the height percentile and the child’s BMI climbs into the obese range.
Another example is a child whose weight rapidly increases when she
reduces her activity level and consumes more meals away from home.
Examination of the height trajectory can reveal endocrine problems,
which often occur with slowing of linear growth.
Consideration of possible medical causes of obesity is essential, even
though endocrine and genetic causes are rare (see Table 47-1). Growth
hormone deficiency, hypothyroidism, and Cushing syndrome are
examples of endocrine disorders that can lead to obesity. In general,
these disorders manifest with slow linear growth. Because children
who consume excessive amounts of calories tend to experience acceler-
ated linear growth, short stature warrants further evaluation. Genetic
disorders associated with obesity can have coexisting dysmorphic
features, cognitive impairment, vision and hearing abnormalities, or
short stature. In some children with congenital disorders such as
myelodysplasia or muscular dystrophy, lower levels of physical activity
can lead to secondary obesity. Some medications can cause excessive
appetite and hyperphagia, resulting in obesity. Atypical antipsychotic
medications often have this dramatic side effect. Rapid weight gain in
a child or adolescent taking one of these medications might require a
discontinuation of that medication. Poor linear growth and rapid
changes in weight gain are indications for evaluation of possible
medical causes.
Exploration of family eating and nutritional and activity patterns
begins with a description of regular meal and snack times and family
habits for walking, bicycle riding, active recreation, television, com-
puter, and video game time. It is useful to request a 24-hr dietary recall
with special attention to intake of fruits, vegetables, and water, as well
as high-calorie foods and high-carbohydrate beverages. When possi-
ble, evaluation by a nutritionist is extremely helpful. This information
will form the basis for incremental changes in eating behavior, caloric
intake, and physical activity during the intervention.
Initial assessment of the overweight or obese child includes a com-
plete review of bodily systems focusing on the possibility of comorbid
conditions (see Table 47-2). Developmental delay and visual and
hearing impairment can be associated with genetic disorders. Difficulty
sleeping, snoring, or daytime sleepiness suggests the possibility of sleep
apnea. Abdominal pain might suggest NAFLD. Symptoms of polyuria,
nocturia, or polydipsia may be the result of type 2 diabetes. Hip or knee
pain can be caused by secondary orthopedic problems, including
Blount disease and slipped capital femoral epiphysis. Irregular menses
may be associated with polycystic ovary syndrome. Acanthosis nigri-
cans can suggest insulin resistance and type 2 diabetes (Fig. 47-3).
The family history begins with identifying other obese family
members. Parental obesity is an important risk for child obesity. If all
family members are obese, focusing the intervention on the entire
family is reasonable. The child may be at increased risk for developing
Chapter 47  ◆  Overweight and Obesity  313
Figure 47-3 Acanthosis nigricans. (From Gahagan S: Child and ado-
lescent obesity, Curr Probl Pediatr Adolesc Health Care 34:6–43, 2004.)
type 2 diabetes if a family history exists. Patients of African-American,
Hispanic, or Native American heritage are also at increased risk for
developing type 2 diabetes. Identification of a family history of hyper-
tension, cardiovascular disease, or metabolic syndrome indicates
increased risk for developing these obesity-associated conditions. If
one helps the family to understand that childhood obesity increases
risk for developing these chronic diseases, this educational interven-
tion might serve as motivation to improve their nutrition and physical
activity.
Physical examination should be thorough, focusing on possible
comorbid conditions (see Table 47-2). Careful screening for hyperten-
sion using an appropriately sized blood pressure cuff is important.
Systematic examination of the skin can reveal acanthosis nigricans,
suggesting insulin resistance, or hirsutism, suggesting polycystic ovary
syndrome. Tanner staging can reveal premature adrenarche secondary
to advanced sexual maturation in overweight and obese girls.
Laboratory testing for fasting plasma glucose, triglycerides, low-
density lipoprotein and high-density lipoprotein cholesterol, and liver
function tests are recommended as part of the initial evaluation for
newly identified pediatric obesity (Table 47-3). Overweight children
(BMI 85th-95th percentile) who have a family history of diabetes mel-
litus or signs of insulin resistance should also be evaluated with a
fasting plasma glucose test. Other laboratory testing should be guided
by history or physical examination findings.
INTERVENTION
There is evidence that some interventions result in modest but signifi-
cant and sustained improvement in body mass. Based on behavior
change theories, treatment includes specifying target behaviors, self-
monitoring, goal setting, stimulus control, and promotion of self-
efficacy and self-management skills. Behavior changes associated with
improving BMI include drinking lower quantities of sugar-sweetened
beverages, consuming higher-quality diets, increasing exercise, watch-
ing less TV, and self-weighing. Most successful interventions have been
family based and take into account the child’s developmental age.
“Parent-only” treatment can be as effective as “parent–child” treat-
ment. Because obesity is multifactorial, not all children and adoles-
cents will respond to the same approach. For example, “loss-of-control”
eating, associated with weight gain and obesity, predicts poor outcome
in response to family-based treatment. Furthermore, clinical-treatment
programs are expensive and not widely available. Therefore there is
interest in novel approaches including Internet-based treatments and
guided self-help.
It is important to begin with clear recommendations about appropri-
ate caloric intake for the obese child (Table 47-4). Working with a
dietitian is very helpful. Meals should be based on fruits, vegetables,
whole grains, lean meat, fish, and poultry. Prepared foods should be
chosen for their nutritional value, with attention to calories and fat.
Foods that provide excessive calories and low nutritional value should
be reserved for infrequent treats.
314  Part VI  ◆  Nutrition

Weight-reduction diets in adults generally do not lead to sustained Psychological strategies are helpful. The “traffic light” diet groups
weight loss. Therefore, the focus should be on changes that can be foods into those that can be consumed without any limitations (green),
maintained for life. Attention to eating patterns is helpful. Families in moderation (yellow), or reserved for infrequent treats (red) (Table
should be encouraged to plan family meals, including breakfast. It is 47-5). The concrete categories are very helpful to children and families.
almost impossible for a child to make changes in nutritional intake This approach can be adapted to any ethnic group or regional cuisine.
and eating patterns if other family members do not make the same Motivational interviewing begins with assessing how ready the patient
changes. Dietary needs also change developmentally, as adolescents is to make important behavioral changes. The professional then engages
require greatly increased calories during their growth spurts, and the patient in developing a strategy to take the next step toward the
adults who lead inactive lives need fewer calories than active and ultimate goal of healthy nutritional intake. This method allows the
growing children. professional to take the role of a coach, helping the child and family
reach their goals. Other behavioral approaches include family rules
about where food may be consumed; for example, “not in the bedroom.”
Increasing physical activity without decreasing caloric intake is
Table 47-3 Normal Laboratory Values for unlikely to result in weight loss. Nonetheless, it can increase aerobic
Recommended Tests fitness and decrease percent body fat even without weight loss. There-
fore, increasing physical activity can decrease risk for cardiovascular
LABORATORY TEST NORMAL VALUE
disease, improve well-being, and contribute to weight loss. Increased
Glucose <110 mg/dL physical activity can be accomplished by walking to school, engaging
Insulin <15 mU/L in physical activity during leisure time with family and friends, or
enrolling in organized sports. Children are more likely to be active if
Hemoglobin A1c <5.7% their parents are active. Just as family meals are recommended, family
AST (age 2-8 yr) <58 U/L physical activity is recommended.
Active pursuits can replace more sedentary activities. The American
AST (age 9-15 yr) <46 U/L Academy of Pediatrics recommends that screen time be restricted to
AST (age 15-18 yr) <35 U/L no more than 2 hr/day for children >2 yr old and that children <2 yr
old not watch television. Television watching is often associated with
ALT <35 U/L
eating, and many highly caloric food products are marketed directly
Total cholesterol <170 mg/dL to children during child-oriented television programs.
LDL <110 mg/dL Pediatric providers should assist families to develop goals to change
nutritional intake and physical activity. They can also provide the child
HDL >45 mg/dL and family with needed information. The family should not expect
Triglycerides (age 0-9 yr) <75 mg/dL immediate lowering of BMI percentile related to behavioral changes
but can instead count on a gradual decrease in the rate of BMI percen-
Triglycerides (age 10-19 yr) <90 mg/dL
tile increase until it stabilizes, followed by a gradual decrease in BMI
AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDL, percentile. Referral to multidisciplinary, comprehensive pediatric
low-density lipoprotein; HDL, high-density lipoprotein. weight-management programs is ideal for obese children whenever
From Children’s Hospital of Wisconsin: The NEW (nutrition, exercise and
weight management) kids program (PDF file). http://www.chw.org/display/
possible.
displayFile.asp?docid=33672&filename=/Groups/NEWKids/NewKidsReferral. There is no effective pharmacotherapy resulting in reversal of excess
PDF. adiposity in children and adolescents. Available medications result in

Table 47-4 Recommended Caloric Intake Designated by Age and Gender

LIFE-STAGE RELATIVELY SEDENTARY LEVEL MODERATE LEVEL OF
GROUP AGE (yr) OF ACTIVITY (kcal) ACTIVITY (kcal) ACTIVE (kcal)
Child 2-3 1,000 1,000-1,400 1,000-1,400
Female 4-8 1,200 1,400-1,600 1,400-1,800
9-13 1,600 1,600-2,000 1,800-2,200
14-18 1,800 2,000 2,400
Male 4-8 1,400 1,400-1,600 1,600-2,000
9-13 1,800 1,800-2,200 2,000-2,600
14-18 2,200 2,400-2,800 2,800-3,200
Adapted from U.S. Department of Agriculture: Dietary guidelines for Americans, 2005. http://www.health.gov/DIETARYGUIDELINES/dga2005/document/html/
chapter2.htm.

Table 47-5 Traffic Light Diet Plan

FEATURE GREEN LIGHT FOODS YELLOW LIGHT FOODS RED LIGHT FOODS
Quality Low-calorie, high-fiber, low-fat, Nutrient-dense, but higher in calories High in calories, sugar, and fat
nutrient-dense and fat
Types of food Fruits, vegetables Lean meats, dairy, starches, grains Fatty meats, sugar, sugar-sweetened beverages,
fried foods
Quantity Unlimited Limited Infrequent or avoided

modest weight loss or BMI improvement even when combined with
behavioral interventions. Various classes of drugs are of interest,
including those that decrease energy intake or act centrally as anorexi-
ants, those that affect the availability of nutrients through intestinal or
renal tubular reabsorption, and those that affect metabolism. The only
U.S. Food and Drug Administration (FDA)-approved medication for
obesity in children <16 yr old is orlistat, which decreases absorption
of fat, resulting in modest weight loss. Complications include flatu-
lence, oily stools, and spotting. This agent offers little benefit to severely
obese adolescents. Because there are multiple redundant neural mech-
anisms that act to protect body weight, promoting weight loss is
extremely difficult. For this reason, there is considerable interest in
combining therapies that simultaneously target multiple weight-
regulating pathways. One example, approved for adults, combines
phentermine, a noradrenergic agent, with topiramate, a γ-aminobutyric
acid (GABA)-ergic medication. This combination resulted in a mean
10.2-kg weight loss compared to 1.4 kg in the placebo group. Side
effects are common and include dry mouth, constipation, paresthesias,
insomnia, and cognitive dysfunction. Another promising example is
the combination of amylin (decreases food intake and slows gastric
emptying) with leptin (which has no anorexigenic effects when given
alone). This combination requires injection and is in clinical trials in
adults. Another FDA approved (for adults) drug is lorcaserin, a selec-
tive serotonin 2C receptor agonist. Establishing long-term safety and
tolerability in children is a challenge as medications of interest have
central nervous system effects or interfere with absorption of nutrients;
teratologic effects must be considered for use in adolescent girls.
In some cases, it is reasonable to refer adolescents for evaluation for
bariatric surgery. The American Pediatric Surgical Association Guide-
lines recommends that surgery be considered only in children with
complete or near-complete skeletal maturity, a BMI ≥40, and a medical
complication resulting from obesity, after they have failed 6 mo of a
multidisciplinary weight management program. Surgical approaches
include the Roux-en-Y and the adjustable gastric band. In obese adults,
bariatric surgery reduces the risk of developing type 2 diabetes melli-
tus. In obese adult patients with existing type 2 diabetes, bariatric
surgery improves the control of diabetes.
PREVENTION
Prevention of child and adolescent obesity is essential for public
health in the United States and most other countries (Table 47-6 and
47-7). Efforts by pediatric providers can supplement national- and
community-level public health programs. The National Institutes of
Health and Centers for Disease Control and Prevention recommend a
variety of initiatives to combat the current obesigenic environment,
including promotion of breastfeeding, access to fruits and vegetables,
walkable communities, and 60 min/day of activity for children. The
U.S. Department of Agriculture sponsors programs promoting 5.5
cups of fruits and vegetables per day. Incentives for the food industry
to promote consumption of healthier foods should be considered.
Marketing of unhealthy foods to children has begun to be regulated.
We expect to see changes in federal food programs including com-
modity foods, the Women, Infant, and Children Supplemental Food
Program, and school-lunch programs to meet the needs of today’s
children.
Pediatric prevention efforts begin with careful monitoring of weight
and BMI percentiles at healthcare maintenance visits. Attention
to changes in BMI percentiles can alert the pediatric provider to
Chapter 47  ◆  Overweight and Obesity  315
increasing adiposity before the child becomes overweight or obese. All
families should be counseled about healthy nutrition for their children
because the current prevalence of overweight and obesity in adults is
65%. Therefore, approximately two-thirds of all children can be con-
sidered at risk for becoming overweight or obese at some time in their
lives. Those who have an obese parent are at increased risk. Prevention
efforts begin with promotion of exclusive breastfeeding for 6 mo and
total breastfeeding for 12 mo. Introduction of infant foods at 6 mo
should focus on cereals, fruits, and vegetables. Lean meats, poultry, and
fish may be introduced later in the 1st year of life. Parents should be
specifically counseled to avoid introducing highly sugared beverages
and foods in the 1st year of life. Instead, they should expose their
infants and young children to a rich variety of fruits, vegetables, grains,
lean meats, poultry, and fish to facilitate acceptance of a diverse and
healthy diet. Parenting matters, and authoritative parents are more
likely to have children with a healthy weight than those who are
authoritarian or permissive. Families who eat regularly scheduled
meals together are less likely to have overweight or obese children.
Child health professionals are able to address a child’s nutritional status
and to provide expertise in child growth and development.
Child health professionals can also promote physical activity during
regular healthcare maintenance visits. Parents who spend some of their
leisure time in physical activity promote healthy weight in their chil-
dren. Beginning in infancy, parents should be cognizant of their child’s
developmental capability and need for physical activity. Because televi-
sion, computer, and video game time can replace health-promoting
physical activity, physicians should counsel parents to limit screen time
for their children. Snacking during television watching should be dis-
couraged. Parents can help their children to understand that television
commercials intend to sell a product. Children can learn that their
parents will help them by responsibly choosing healthy foods.
As obesity is determined by complex multifactorial conditions, pre-
vention will take efforts at multiple levels of social organization. One
example, EPODE (Ensemble Prévenons l’Obésité Des Enfants), is a
multilevel prevention strategy, which began in France and has been
adopted by more than 500 communities in 6 countries. The goal is for
local environments, daycare centers, schools, recreational settings and
families to adopt practices that promote healthy lifestyles for children
from birth to 12 yr old. This initiative relies on 4 necessary compo-
nents: political commitment to change, resources to support social
marketing and changes, support services, evidence-based practices. All
EPODE sites include monitoring and evaluation. Similar efforts are
taking place in the United States. An example of a U.S. community
effort is Shape Up Somerville, a citywide campaign to increase daily
physical activity and healthy eating in Somerville, MA, which has been
ongoing since 2002. This systems intervention focuses on school health
curricula, healthier food in schools and restaurants, safe routes to
school, walkable and bikeable streets and worksite wellness. Commu-
nitywide programs are important because neighborhood environmen-
tal factors (poverty) have been associated with obesity in its residents.
Although these efforts have resulted in lower weight gain in older
children and adolescents, there is considerable interest in focusing
earlier in the life cycle. Beginning obesity prevention during pregnancy
and engaging health systems, early childhood programs, and commu-
nity systems to support healthier life cycles is an approach with
tremendous promise.
Bibliography is available at Expert Consult.
316  Part VI  ◆  Nutrition

Table 47-6 Proposed Suggestions for Preventing Obesity

PREGNANCY
Normalize body mass index before pregnancy.
Do not smoke.
Maintain moderate exercise as tolerated.
In gestational diabetics, provide meticulous glucose control.
Gestational weight gain within the Institute of Medicine (IOM) recommendations.
POSTPARTUM AND INFANCY
Breastfeeding: exclusive for 4-6 mo, continue with other foods for 12 mo.
Postpone the introduction of baby foods to 4-6 mo and juices to 12 mo.
FAMILIES
Eat meals as a family in a fixed place and time.
Do not skip meals, especially breakfast.
No television during meals.
Use small plates, and keep serving dishes away from the table.
Avoid unnecessary sweet or fatty foods and sugar-sweetened drinks.
Remove televisions from children’s bedrooms; restrict times for television viewing and video games.
Do not use food as a reward.
SCHOOLS
Eliminate candy and cookie sales as fundraisers.
Review the contents of vending machines and replace with healthier choices; eliminate sodas.
Avoid financial support for sports teams from beverage and food industries.
Install water fountains and hydration stations.
Educate teachers, especially physical education and science faculty, about basic nutrition and the benefits of physical activity.
Educate children from preschool through high school on appropriate diet and lifestyle.
Mandate minimum standards for physical education, including 60 min of strenuous exercise 5 times weekly.
Encourage “the walking school bus”: groups of children walking to school with adult supervision.
COMMUNITIES
Increase family-friendly exercise and safe play facilities for children of all ages.
Develop more mixed residential-commercial developments for walkable and bicyclable communities.
Discourage the use of elevators and moving walkways.
Provide information on how to shop and prepare healthier versions of culture-specific foods.
HEALTHCARE PROVIDERS
Explain the biologic and genetic contributions to obesity.
Give age-appropriate expectations for body weight in children.
Work toward classifying obesity as a disease to promote recognition, reimbursement for care, and willingness and ability to provide treatment.
INDUSTRY
Mandate age-appropriate nutrition labeling for products aimed at children (e.g., red light/green light foods, with portion sizes).
Encourage marketing of interactive video games in which children must exercise in order to play.
Use celebrity advertising directed at children for healthful foods to promote breakfast and regular meals.
Reduce portion size (drinks and meals).
GOVERNMENT AND REGULATORY AGENCIES
Classify childhood obesity as a legitimate disease.
Find novel ways to fund healthy lifestyle programs (e.g., with revenues from food and drink taxes).
Subsidize government-sponsored programs to promote the consumption of fresh fruits and vegetables.
Provide financial incentives to industry to develop more healthful products and to educate the consumer on product content.
Provide financial incentives to schools that initiate innovative physical activity and nutrition programs.
Allow tax deductions for the cost of weight loss and exercise programs.
Provide urban planners with funding to establish bicycle, jogging, and walking paths.
Ban advertising of fast foods, nonnutritious foods, and sugar-sweetened beverages directed at preschool children, and restrict advertising to
school-age children.
Ban toys as gifts to children for purchasing fast foods.
Adapted from Speiser PW, Rudolf MCJ, Anhalt H, et al: Consensus statement: childhood obesity, J Clin Endocrinol Metab 90:1871–1887, 2005.

Table 47-7 Anticipatory Guidance: Establishing Healthy Eating Habits in Children

Do not punish a child during mealtimes with regard to eating. The emotional atmosphere of a meal is very important. Interactions during
meals should be pleasant and happy.
Do not use foods as rewards.
Parents, siblings, and peers should model healthy eating, tasting new foods, and eating a well-balanced meal.
Children should be exposed to a wide range of foods, tastes, and textures.
New foods should be offered multiple times. Repeated exposure leads to acceptance and liking.
Forcing a child to eat a certain food will decrease the child’s preference for that food. Children’s wariness of new foods is normal and should
be expected. Offering a variety of foods with low-energy density helps children balance energy intake.
Parents should control what foods are in the home. Restricting access to foods in the home will increase rather than decrease a child’s desire
for that food.
Children tend to be more aware of satiety than adults, so allow children to respond to satiety, and stop eating. Do not force children to “clean
their plate.”
Adapted from Benton D: Role of parents in the determination of food preferences of children and the development of obesity, Int J Obes Relat Metab Disord
28:858–869, 2004. Copyright 2004. Reprinted by permission from Macmillan Publishers Ltd.

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Chapter 48  a process that liberates unesterified retinol, for the absorption of
Vitamin A Deficiencies
and Excess
A. Catharine Ross and Libo Tan
OVERVIEW OF VITAMIN A
Vitamin A is a fat-soluble micronutrient that cannot be synthesized de
novo by the mammalian body, thus it is an obligatory dietary factor.
The term vitamin A is generally used to refer to a group of compounds
that possess the biologic activity of all-trans retinol (Fig. 48-1). As a
fat-soluble micronutrient, vitamin A is recognized as being essential
for all vertebrates for normal vision, reproduction, cell and tissue dif-
ferentiation, and functions of the immune system. Vitamin A plays
critical roles in neonatal development. It is required for normal embry-
onic development, hematopoiesis, immune response, metabolism, and
growth and differentiation of many types of cells.
Vitamin A can be obtained from the diet where its main form is as
retinyl esters, such as retinyl palmitate, which are called preformed
vitamin A. They are found primarily in certain foods of animal origin.
Organ meats (especially liver, kidney) are very rich in vitamin A, while
other meats, milk, and cheese contain moderate levels. Other sources
of vitamin A include several provitamin A carotenoids, which are
found naturally in many fruits and vegetables, especially yellow-orange
vegetables (pumpkin, squash, sweet potato), and leafy green vegetables
(chard, spinach, broccoli). One of the most abundant carotenoids is
β-carotene. α-Carotene and β-cryptoxanthin also possess vitamin A
activity at a lower bioactivity. In the body, these precursors are used
for the synthesis of 2 essential metabolites of vitamin A. One is all-trans
retinoic acid, the form of vitamin A required for cell differentiation
and the regulation of gene transcription. It is the most bioactive form
of vitamin A. The other is 11-cis retinal, required for vision. It functions
as the light-absorbing chromophore of the visual pigments rhodopsin
and iodopsin.
Retinol
R = CH2OH, retinol
R = CH2O-fatty acyl group, retinyl ester
A R = COOH, retinoic acid
Dietary Preformed
forms: vitamin A
Intestinal
Absorption: hydrolysis
Esterification
Intracellular and storage
RE Retinol
metabolism: Hydrolysis,
[chylomicron mobilization
transport,
storage in liver,
eyes (RPE), kidneys,
testes, etc.]
B Excretion
Figure 48-1  Vitamin A structures (A) and overview of vitamin A metabolism (B).
Chapter 48  ◆  Vitamin A Deficiencies and Excess  317
METABOLISM OF VITAMIN A
Ingested retinyl esters must first be hydrolyzed in the intestinal lumen,
vitamin A. Most of the retinol is then reesterified in the enterocytes.
The absorption of preformed vitamin A is very efficient. Approximately
70-90% of dietary preformed vitamin A is absorbed as long as there
is ~10 g or more fat in the meal. Chronic intestinal disorders or
lipid malabsorption can result in vitamin A deficiency. Uncleaved
provitamin-A carotenoids in the intestine are also incorporated into
chylomicrons and delivered to various tissues. The estimated absorp-
tion efficiency of carotenoids is approximately 20-50%, and appears to
be more variable among individuals than for preformed vitamin A. The
efficiency of conversion of B-carotene to retinol is much lower than
expected. The carotene cleavage enzyme β-carotene monooxygenase,
present in the enterocyte, exhibits certain single nucleotide polymor-
phisms that reduce the efficiency of conversion of β-carotene to retinol.
Once retinol is esterified in the enterocyte, retinyl ester is then pack-
aged into nascent chylomicrons, which are then secreted into the lym-
phatic vessels and transported via the circulation to the liver or to other
tissues. When vitamin A status is adequate, most mammals, including
humans, store most of their total body vitamin A in the liver, within
stellate cells. When their vitamin A status is deficient, vitamin A stores
can be mobilized; the released retinol can be used by extrahepatic
tissues. Stored vitamin A is released from the liver into the circulation
as retinol bound to its specific transport protein, retinol-binding
protein (RBP), which binds to the thyroid hormone transport protein,
transthyretin (TTR); this complex delivers retinol (as well as the
thyroid hormone) to a large number of vitamin A target tissues. The
major physiologic mediator of retinol uptake by cells in many tissues
is Stra6, a widely expressed multitransmembrane domain protein that
functions as a cell-surface receptor for retinol bound to RBP.
In target tissues, retinol is either esterified into retinyl esters for
storage or oxidized into retinoic acid for function. In the eye, 11-cis-
retinal is formed.
Vitamin A Status in Neonates
Neonates begin life with low levels of vitamin A, in plasma, liver, and
extrahepatic tissues, compared with those in adults. Normal plasma
levels of retinol are 20-50 µg/dL in infants, and increase gradually as
children become older. Median serum retinol values are 1.19 µmol/L
in both boys and girls ages 4-8 yr; 1.4 and 1.33 µmol/L in boys and
-Carotene
-carotene and
provitamin A
carotenoids
Intestinal
cleavage
Oxidation Oxidation
Oxidized
Retinal RA
Reduction metabolites
Conjugation
reactions
Deactivation products
318  Part VI  ◆  Nutrition

girls, respectively, ages 9-13 yr; and 1.71 and 1.57 µmol/L in boys and
girls, respectively, ages 14-18 yr (for conversion, 1 µmol/L = 28.6 µg/
dL). Values of 1.96 and 1.85 µmol/L are found in 19-30 yr old adult
men and women, respectively.
Retinol levels are even lower in neonates in developing countries
where vitamin A intakes may be low and vitamin A deficiency is a
common and significant nutritional problem. Lower vitamin A stores
and plasma retinol concentrations are seen in low birthweight infants
and in preterm newborns. Malnutrition, particularly protein nutrition,
can cause vitamin A deficiency because of the impaired synthesis
of RBP.
Inflammation as a Cause of Low Plasma Retinol
Inflammation is a cause of reduced levels of plasma retinol as a result
of reduced synthesis of RBP and TTR. This condition may mimic a
lack of vitamin A, but will not be corrected by supplementation. In U.S.
adults, those with moderately elevated levels of C-reactive protein,
indicative of mild inflammation, had lower average plasma retinol
levels. The extent to which inflammation is a factor in low plasma
retinol in children is uncertain but it is likely to be significant in acute
infectious diseases such as measles, and possibly in chronic inflamma-
tory conditions such as cystic fibrosis.
FUNCTIONS OF VITAMIN A AND
MECHANISMS OF ACTION
Except for its role in vision, the pleiotropic actions of this micronutri-
ent include many systemic functions that are mediated at the gene level
by all-trans-retinoic acid (RA), which is a ligand for specific nuclear
transcription factors, the retinoid receptors: RARs and RXRs. When
an RAR is activated by the presence of RA, it combines with an RXR,
and the resulting heterodimer binds to specific DNA sequences present
in retinoid responsive genes (RAREs and RXREs, respectively) and
therefore induce or repress the expression of a large number of genes.
In this manner, vitamin A, via its active form, RA, regulates many
genes that are involved in the fundamental biologic activities of cells,
such as cell division, cell death, and cell differentiation. The term reti-
noids includes both natural and synthetic compounds with vitamin A
activity and is most often used in the context of vitamin A action at
the gene level. A large number of synthetic retinoids have been pro-
duced and some have gained clinical acceptance, such as in the treat-
ment of skin disorders and certain cancers.
Retinoic acid is among the most important signaling molecules
in vertebrate ontogenesis. It affects many physiologic processes, includ-
ing reproduction, growth, embryonic and fetal development, and
bone development, in addition to respiratory, gastrointestinal, hema-
topoietic, and immune functions. The role of vitamin A in immune
function and host defense is particularly important in developing
countries, where vitamin A supplementation or therapy reduces the
morbidity and mortality rates of various diseases, such as measles (see
Chapter 246).
Vitamin A plays a critical nongenomic role in vision. The human
retina has 2 distinct photoreceptor systems: the rods, containing rho-
dopsin, which can detect low-intensity light, and the cones, containing
iodopsin, which can detect different colors. The aldehyde form of
vitamin A, retinal, is the prosthetic group on both visual proteins. The
mechanism of vitamin A action in vision is based on the ability of the
vitamin A molecule to photoisomerize (change shape when exposed
to light). Thus, in the dark, low-intensity light isomerizes the rhodop-
sin prosthetic group, 11-cis retinal, to all-trans-retinal, generating an
electrical signal that is transmitted via the optic nerve to the brain and
results in visual sensation.
VITAMIN A DEFICIENCY
If the growing child has a well-balanced diet and obtains vitamin A
from foods that are rich in vitamin A or provitamin-A (Table 48-1),
the risk of vitamin A deficiency is small. However, even subclinical
vitamin A deficiency can have serious consequences.
Deficiency states in developed countries are rare, except in some
impoverished populations (see Chapter 46) or after mistakes in food
preparation or with fad diets, but they are common in many developing
countries and are often associated with global malnutrition (see
Chapter 46). In the clinical setting, vitamin deficiencies can also occur
as complications in children with various chronic disorders or diseases.
Information obtained in the medical history related to dietary habits
can be important in identifying the possibility of such nutritional prob-
lems. Except for vitamin A, toxicity from excess intake of vitamins is
rare. Table 48-1 summarizes the food sources, functions, and defi-
ciency and excess symptoms of the vitamins.
Clinical Manifestations of Vitamin A Deficiency
The most obvious symptoms of vitamin A deficiency are associated with
the requirement of this vitamin for the maintenance of epithelial func-
tions. In the intestines, a normal mucus-secreting epithelium (normal
goblet cell function) is an effective barrier against pathogens that can
cause diarrhea. Similarly, in the respiratory tract, a mucus-secreting
epithelium is essential for the disposal of inhaled pathogens and
toxicants. Characteristic changes as a result of vitamin A deficiency in
the epithelia include a proliferation of basal cells, hyperkeratosis, and

Table 48-1 Vitamin A Characteristics

NAMES AND BIOCHEMICAL EFFECTS OF EFFECTS OF
SYNONYMS CHARACTERISTICS ACTION DEFICIENCY EXCESS SOURCES
Retinol (vitamin A1); Fat-soluble; heat- In vision, as retinal, for Nyctalopia Anorexia, slow Liver, fish liver oils
1 µg retinol = stable; destroyed by synthesis of the visual Photophobia, growth, drying and Dairy products,
3.3 IU vitamin A = oxidation, drying pigments rhodopsin xerophthalmia, Bitot cracking of skin, except skim milk
1 RAE Bile necessary for and iodopsin spots, conjunctivitis, enlargement of Egg yolk, fortified
Provitamins A: the absorption In growth, reproduction, keratomalacia liver and spleen, margarine,
plant pigments α-, Stored in liver embryonic and fetal leading to blindness swelling and pain fortified skim milk
β-, and γ-carotenes Protected by vitamin E development, bone Faulty epiphyseal bone of long bones, Carotenoids from
and cryptoxanthin growth, immune and formation bone fragility, plants: green
have partial retinol epithelial functions, Defective tooth increased vegetables, yellow
activity: 12 µg via retinoic acid as a enamel intracranial fruits, and
β-carotene, or ligand for specific Keratinization of pressure, alopecia, vegetables
24 µg other nuclear transcription mucous membranes carotenemia
provitamin A factors, regulating and skin Fetal abnormalities
carotenoids = 1 µg genes involved in Retarded growth
retinol many fundamental Impaired resistance to
cellular processes infection, anemia,
reproductive failure,
fetal abnormalities
RAE, retinol activity equivalent.

formation of stratified cornified squamous epithelium. Squamous meta-
plasia of the renal pelves, ureters, vaginal epithelium, and the pancreatic
and salivary ducts can lead to increased infections in these areas. In the
urinary bladder, loss of epithelial integrity can result in pyuria and
hematuria. Epithelial changes in the skin caused by vitamin A deficiency
are manifested as dry, scaly, hyperkeratotic patches, commonly on the
arms, legs, shoulders, and buttocks. The combination of defective epi-
thelial barriers to infection, low immune response, and lowered response
to inflammatory stress, all because of insufficient vitamin A, can cause
poor growth and serious health problems in children.
The most characteristic and specific signs of vitamin A deficiency
are eye lesions, but they may be manifest rather late in the progression
of vitamin A deficiency. Lesions caused by vitamin A deficiency
develop insidiously and rarely occur before 2 yr of age. An early
symptom is delayed adaptation to the dark, a result of reduced resyn-
thesis of rhodopsin; later, when vitamin A deficiency is more advanced,
it leads to night blindness as a consequence of the absence of retinal
in the visual pigment, rhodopsin, of the retina. Photophobia is a
common symptom. The pigment epithelium, the structural element of
the retina, keratinizes. When the pigment epithelium degenerates, the
rods and cones have no support and eventually break down, resulting
in blindness.
As vitamin A deficiency progresses, the corneal and conjunctival
epithelial tissues of the eye become severely altered; this change results
from a lack of sufficient RA for normal epithelial cell morphology and
function. The cornea protects the eye from the environment and is also
important in light refraction. In early vitamin A deficiency, the cornea
keratinizes, becomes opaque, is susceptible to infection, and forms dry,
scaly layers of cells (xerophthalmia). The conjunctiva keratinizes and
develops plaques (Bitot spots [Fig. 48-2]). In later stages, infection
occurs, lymphocytes infiltrate, and the cornea becomes wrinkled; it
degenerates irreversibly (keratomalacia and corneal ulceration), result-
ing in blindness. Advanced xerophthalmia (Fig. 48-3) and xerophthal-
mia with permanent damage to the eye (Fig. 48-4) may develop if
untreated. These eye lesions are primarily diseases of the young and
are a major cause of blindness in developing countries. Although rates
of xerophthalmia have fallen, the number of affected children is still
too high.
Other clinical signs of vitamin A deficiency include poor overall
growth, diarrhea, susceptibility to infections, anemia, apathy, mental
retardation, and increased intracranial pressure, with wide separation
of the cranial bones at the sutures. There may be vision problems as a
consequence of bone overgrowth causing pressure on the optic nerve.
Malnutrition, particularly protein deficiency, can cause vitamin A
deficiency by the impaired synthesis of retinol transport protein. In
developing countries, subclinical or clinical zinc deficiency can increase
the risk of vitamin A deficiency. There is also some evidence of mar-
ginal zinc intakes in children in the United States.
Figure 48-2  Bitot spots with hyperpigmentation seen in a 10 mo old
Indonesian boy. (From Oomen HAPC: Vitamin A deficiency, xeroph-
thalmia and blindness, Nutr Rev 6:161–166, 1974.)
Chapter 48  ◆  Vitamin A Deficiencies and Excess  319
Diagnosis
Dark adaptation tests can be used to assess early-stage vitamin A defi-
ciency. Although Bitot spots develop relatively early, those related to
active vitamin A deficiency are usually confined to preschool-age chil-
dren. Xerophthalmia is a very characteristic lesion of vitamin A defi-
ciency. Caution must be exercised to exclude other, similar eye
abnormalities from those associated with vitamin A deficiency. There
are 3 useful indicators for detecting marginal vitamin A status,
although they are mostly limited to research settings: conjunctival
impression cytology, relative dose response, and modified relative dose
response. A diet history can also be useful in suggesting or ruling out
low intake as a cause. There is a relatively high prevalence of marginal
vitamin A status among pregnant and lactating women. The plasma
retinol level is not an accurate indicator of vitamin A status unless the
deficiency is severe and liver stores are depleted, in which case low
plasma retinol is likely to be evident. In children, plasma retinol values
of <0.35 µmol/L are considered to be very deficient, 0.35-0.7 µmol/L
are considered to be deficient, 0.7-1.05 µmol/L are considered to be
marginal, and >1.05 µmol/L are considered to be adequate. It has long
been thought that the liver vitamin A concentration must be 20 µg/g
or higher to support a normal rate of secretion of retinol-RBP into
plasma.
Epidemiology and Public Health Issues
Vitamin A deficiency and xerophthalmia still occur throughout much
of the developing world and are linked to undernourishment and com-
plicated by illness. Programs to provide periodic large doses of vitamin
A have been instituted in many low-income countries in which vitamin
Figure 48-3  Advanced xerophthalmia with an opaque, dull cornea
and some damage to the iris in a 1 yr old boy. (From Oomen HAPC:
Vitamin A deficiency, xerophthalmia and blindness, Nutr Rev 6:161–
166, 1974.)
Figure 48-4  Recovery from xerophthalmia, showing a permanent
eye lesion. (From Bloch CE: Blindness and other disease arising from
deficient nutrition [lack of fat soluble A factor], Am J Dis Child 27:139,
1924.)
320  Part VI  ◆  Nutrition

Table 48-2 Dietary Reference Intakes for Vitamin A in Children

RECOMMENDED DIETARY UPPER LEVEL (UL)
ALLOWANCE (RDA) (µg retinol (µg retinol equivalents
AGE RANGE equivalents per day) per day) COMMENTS
0-6 mo 400 600 The recommended intake for infants is an adequate intake,
7-12 mo 500 600 based on the amount of vitamin A normally present in
breast milk
1-3 yr 300 600 The UL applies only to preformed vitamin A (retinol).
4-8 yr 400 900
9-13 yr 600 1,700
14-18 yr 900 male; 700 female 2,800

A deficiency is still a public health problem. Vitamin A supplementa-

tion is considered part of the strategy of the World Health Organiza-
tion’s Millennium Development Goals to reduce <5 yr mortality. Other
strategies being tested include improving the content of β-carotene in
staple foods through plant breeding (biofortification).

Dietary Reference Intakes for the

Healthy Population
Table 48-2 summarizes the dietary reference intakes for infants and
children. Dietary reference intake values include the estimated average
requirement, which is the mean biologic requirement for the nutrient
in the population; the recommended dietary allowance (RDA), which
is set to cover the needs of >97% of the population (thus the needs of
many people are more than covered by the RDA); and the upper level
(UL), an intake level above which risk of adverse effects may increase;
the UL pertains only to chronic consumption of preformed vitamin A.
The RDA is expressed as retinol activity equivalents (RAEs; 1 RAE =
1 µg all-trans-retinol; equivalents for provitamin-A in foods = 12 µg
β-carotene, 24 µg α-carotene, or 24 µg β-cryptoxanthin). From
infancy to age 18 yr, the RDA increases as a consequence of increased
body size, becoming higher for boys than girls during adolescence.
During pregnancy, the RDA is 750-770 µg, and during lactation, the
RDA is increased to 1,200-1,300 µg to ensure sufficient vitamin A
content during breastfeeding.
It is noteworthy that, especially for young children, the UL is not far
above the RDA, differing by only 2-fold in some age groups. This sug-
gests that for children whose diet is good, care should be taken not to
overuse dietary supplements containing preformed vitamin A and/or
to avoid excessive consumption of foods that are rich in vitamin A,
such as liver. A B

Vitamin A for Treatment of Deficiency
The safety and efficacy of vitamin A supplementation depend on the
patient’s state of health and the regimens of other treatments. A daily
supplement of 1,500 µg of vitamin A is sufficient for treating latent
vitamin A deficiency, after which intake an at RDA level should be the
goal. In children without overt vitamin A deficiency, morbidity and
mortality rates from viral infections, such as measles, have been
reduced by administration of weekly doses equivalent to the RDA level
of vitamin A, or higher doses of 30-60 mg of retinol (100,000-
200,000 IU) given once or twice, under careful monitoring to avoid
toxicity associated with excess vitamin A. Xerophthalmia is treated by
giving 1,500 µg/kg body weight orally for 5 days followed by intramus-
cular injection of 7,500 µg of vitamin A in oil, until recovery.
Vitamin A is also used in preterm infants for improvement of respi-
ratory function and prevention of the development of chronic lung
disease. An analysis of 9 randomized controlled trials of vitamin A
found that vitamin A appears to be beneficial in reducing death or
oxygen requirement with no differences in neurodevelopmental
outcomes.
HYPERVITAMINOSIS A
Chronic hypervitaminosis A results from excessive ingestion of pre-
formed vitamin A (retinol or retinyl ester), generally for several weeks
or months. The cause is often excessive use of vitamin A–containing
Figure 48-5  Hyperostosis of the ulna and tibia in an infant 21 mo of
age, resulting from vitamin A positioning. A, Long, wavy cortical hyper-
ostosis of the ulna (arrow). B, Long, wavy cortical hyperostosis of the
right tibia (arrow), with a striking absence of metaphyseal changes.
(From Caffey J: Pediatric x-ray diagnosis, ed 5, Chicago, 1967, Year
Book, p. 994.)
supplements, or food faddism resulting in excessive intakes of organ
meats. Toxicity can be induced in adults and children with chronic
daily intakes of 15,000 µg and 6,000 µg, respectively. As there is no
antidote for hypervitaminosis A, the prevention of this condition is
most important. Symptoms may subside rapidly on withdrawal of the
vitamin, but the rate of improvement depends on the amount of
vitamin A that has built up in tissues. In extreme cases, hypervitamin-
osis A can be fatal. Signs of subacute or chronic toxicity can include
headache; vomiting; anorexia; dry, itchy desquamating skin; seborrheic
cutaneous lesions; fissuring at the corners of the mouth; alopecia and/
or coarsening of the hair; bone abnormalities; swelling of the bones;
enlargement of the liver and spleen; diplopia; increased intracranial
pressure; irritability; stupor; limited motion; and dryness of the mucous
membranes; desquamation of the palms and the soles of the feet.
Radiographs may show hyperostosis affecting several long bones, espe-
cially in the middle of the shafts (Fig. 48-5). Serum levels of vitamin
A are elevated, mostly as retinyl ester contained in lipoproteins, which
may contribute to membrane damage and symptoms, including release
of liver enzymes into plasma. Hypercalcemia and/or liver cirrhosis may
be present. Hypervitaminosis A is distinct from cortical hyperostosis
(see Chapter 700).
In young children, toxicity is associated with vomiting and bulging
fontanels. An affected child has anorexia, pruritus, and a lack of weight
gain. Acute hypervitaminosis A, such as after consumption of a single
large (30-60 mg dose) of vitamin A may include nausea, vomiting, and
drowsiness; less-common symptoms include diplopia, papilledema,
cranial nerve palsies, and other symptoms suggesting pseudotumor
cerebri.
A syndrome of severe congenital malformations may occur in
infants of mothers who have consumed therapeutic doses (0.5-1.5 mg/
kg) of oral 13-cis-retinoic acid (e.g., Accutane), generally taken for the
treatment of acne or cancer, during the 1st trimester of pregnancy.
These malformations result in a high incidence (>20%) of spontaneous
abortions and birth defects including characteristic craniofacial abnor-
malities. The U.S. Food and Drug Administration has increased the
stringency of prescription of such drugs in women of childbearing age
to attempt to reduce these birth defects.
Excessive intake of carotenoids is not associated with toxicity but
can cause yellow coloration of the skin (carotenodermia) and serum
(carotenemia) that disappears when intake is reduced. Children with
liver disease, diabetes mellitus, or hypothyroidism are more suscepti-
ble. Food faddism including an excessive consumption of carotene-rich
foods may be a cause of this condition.

Bibliography is available at Expert Consult.

 Chapter 48  ◆  Vitamin A Deficiencies and Excess  321.e1
Bibliography
Awasthi S, Peto R, Read S, et al: Vitamin A supplementation every 6 months with
retinol in 1 million pre-school children in north India: DEVTA, a cluster-
randomised trial, Lancet 381:1469–1476, 2013.
Ballew C, Bowman BA, Sowell AL, et al: Serum retinol distributions in residents of
the United States: third National Health and Nutrition Examination Survey,
1988-1994, Am J Clin Nutr 73:586–593, 2001.
Darlow BA, Graham PJ: Vitamin A supplementation to prevent mortality and
short- and long-term morbidity in very low birthweight infants, Cochrane
Database Syst Rev (10):CD000501, 2011.
Erhardt J: Biochemical methods for the measurement of vitamin A deficiency
disorders (VADD), Sight Life Mag 2:5–7, 2003.
Fernandes TF, Figueiroa JN, Grande de Arruda IK, et al: Effect of infant illness of
maternal supplementation with 400,000 IU vs 200,000 IU of vitamin A,
Pediatrics 129:e960–e966, 2012.
Food and Drug Administration. iPLEDGE Information. http://www.fda.gov/Drugs/
DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/
ucm094307.htm.
Grune T, Lietz G, Palou A, et al: Beta-carotene is an important vitamin A source
for humans, J Nutr 140:2268S–2285S, 2010.
Office of Dietary Supplements, National Institutes of Health. Vitamin A Fact Sheet.
http://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/.
Penniston KL, Tanumihardjo SA: The acute and chronic toxic effects of vitamin A,
Am J Clin Nutr 83:191–201, 2006.
Ross AC: Vitamin A. In Ross AC, Caballero B, Cousins RJ, et al, editors: Modern
Nutrition in Health and Disease, ed 11, Baltimore, MD, 2013, Lippincott,
Williams & Wilkins, pp 260–277.
Schmitz J, West KP, Khatry SK, et al: Vitamin A supplementation in preschool
children and risk of hearing loss as adolescents and young adults in rural Nepal:
randomized trial cohort follow-up study, BMJ 344:d7962, 2012.
Sommer A: Vitamin A deficiency and clinical disease: an historical overview,
J Nutr 138:1835–1839, 2008.
Stephensen CB, Gildengorin G: Serum retinol, the acute phase response, and
the apparent misclassification of vitamin A status in the third National
Health and Nutrition Examination Survey, Am J Clin Nutr 72:1170–1178,
2000.
Tanumihardjo S, Vitamin A: biomarkers of nutrition for development, Am J Clin
Nutr 94:658S–665S, 2011.
Tanumihardjo SA: Assessing vitamin A status: past, present and future, J Nutr
134:290S–293S, 2004.
Tielsch JM: Vitamin A supplements in newborns and child survival, BMJ
336:1385–1386, 2008.
Villamor E, Fawzi WW: Effects of vitamin A supplementation on immune
responses and correlation with clinical outcomes, Clin Microbiol Rev 18:
446–464, 2005.
 Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess  321
Chapter 49  noted during critical illnesses.
Vitamin B Complex
Deficiencies and Excess
H.P.S. Sachdev and Dheeraj Shah
Vitamin B complex includes a number of water-soluble nutrients,
including thiamine (B1), riboflavin (B2), niacin (B3), pyridoxine (B6),
folate, cobalamin (B12), biotin, and pantothenic acid. Choline and ino-
sitol are also considered part of the B complex and are important for
normal body functions, but specific deficiency syndromes have not
been attributed to a lack of these factors in the diet.
B-complex vitamins serve as coenzymes in many metabolic path-
ways that are functionally closely related. Consequently, a lack of one
of the vitamins has the potential to interrupt a chain of chemical pro-
cesses, including reactions that are dependent on other vitamins, and
ultimately can produce diverse clinical manifestations. Because diets
deficient in any one of the B-complex vitamins are often poor sources
of other B vitamins, manifestations of several vitamin B deficiencies
usually can be observed in the same person. It is therefore a general
practice in a patient who has evidence of deficiency of a specific B
vitamin to treat with the entire B-complex group of vitamins.
49.1  Thiamine (Vitamin B1)
H.P.S. Sachdev and Dheeraj Shah
Thiamine diphosphate, the active form of thiamine, serves as a cofactor
for several enzymes involved in carbohydrate catabolism such as
pyruvate dehydrogenase, transketolase, and α-ketoglutarate. These
enzymes also play a role in the hexose monophosphate shunt that
generates nicotinamide adenine dinucleotide phosphate (NADP) and
pentose for nucleic acid synthesis. Thiamine is also required for the
synthesis of acetylcholine and γ-aminobutyric acid, which have impor-
tant roles in nerve conduction. Thiamine is absorbed efficiently in the
gastrointestinal (GI) tract, and may be deficient in persons with GI or
liver disease. The requirement of thiamine is increased when carbohy-
drates are taken in large amounts and during periods of increased
metabolism, such as fever, muscular activity, hyperthyroidism, preg-
nancy, and lactation. Alcohol affects various aspects of thiamine trans-
port and uptake, contributing to the deficiency in alcoholics.
Pork (especially lean), fish, and poultry are good nonvegetarian
dietary sources of thiamine. Main sources of thiamine for vegetarians
are rice, oat, wheat, and legumes. Most ready-to-eat breakfast cereals
are enriched with thiamine. Thiamine is water soluble and heat labile;
most of the vitamin is lost when the rice is repeatedly washed and the
cooking water is discarded. The breast milk of a well-nourished mother
provides adequate thiamine; breastfed infants of thiamine-deficient
mothers are at risk for deficiency. Thiamine antagonists (coffee, tea)
and thiaminases (fermented fish) may contribute to thiamine defi-
ciency. Most infants and older children consuming a balanced diet
obtain an adequate intake of thiamine from food and do not require
supplements.
DEFICIENCY
Deficiency of thiamine is associated with severely malnourished states,
including malignancy and following surgery. The disorder (or spec-
trum of disorders) is classically associated with a diet consisting largely
of polished rice (oriental beriberi); it can also arise if highly refined
wheat flour forms a major part of the diet, in alcoholics, and in food
faddists (occidental beriberi). Thiamine deficiency has often been
reported from inhabitants of refugee camps consuming the polished
rice–based monotonous diets. Low thiamine concentrations are also
Thiamine-responsive megaloblastic anemia (TRMA) syndrome is
a rare autosomal recessive disorder characterized by megaloblastic
anemia, diabetes mellitus, and sensorineural hearing loss, responding
in varying degrees to thiamine treatment. The syndrome occurs
because of mutations in the SLC19A2 gene, encoding a thiamine trans-
porter protein, leading to abnormal thiamine transportation and cel-
lular vitamin deficiency. Thiamine and related vitamins may improve
the outcome in children with Leigh encephalomyelopathy and type 1
diabetes mellitus.
Clinical Manifestations
Thiamine deficiency can develop within 2-3 mo of a deficient intake.
Early symptoms of thiamine deficiency are nonspecific, such as fatigue,
apathy, irritability, depression, drowsiness, poor mental concentration,
anorexia, nausea, and abdominal discomfort. As the condition pro-
gresses, more-specific manifestations of beriberi, such as peripheral
neuritis (manifesting as tingling, burning, paresthesias of the toes and
feet), decreased deep tendon reflexes, loss of vibration sense, tender-
ness and cramping of the leg muscles, heart failure, and psychological
disturbances, develop. Patients can have ptosis of the eyelids and
atrophy of the optic nerve. Hoarseness or aphonia caused by paralysis
of the laryngeal nerve is a characteristic sign. Muscle atrophy and
tenderness of the nerve trunks are followed by ataxia, loss of coordina-
tion, and loss of deep sensation. Later signs include increased intracra-
nial pressure, meningismus, and coma. The clinical picture of thiamine
deficiency is usually divided into a dry (neuritic) type and a wet
(cardiac) type. The disease is wet or dry depending on the amount of
fluid that accumulates in the body as a result of factors such as cardiac
and renal dysfunction, even though the exact cause for this edema is
unknown. Many cases of thiamine deficiency show a mixture of both
features and are more properly termed thiamine deficiency with cardi-
opathy and peripheral neuropathy.
The classic clinical triad of Wernicke encephalopathy (mental
status changes, ocular signs, ataxia) is rarely reported in infants and
322  Part VI  ◆  Nutrition
young children with severe deficiency secondary to malignancies or
feeding of defective formula. An epidemic of life-threatening thiamine
deficiency was seen in infants fed a defective soy-based formula that
had undetectable thiamine levels. Manifestations included emesis,
lethargy, restlessness, ophthalmoplegia, abdominal distention, devel-
opmental delay, failure to thrive, lactic acidosis, nystagmus, diarrhea,
apnea, seizures, and auditory neuropathy.
Death from thiamine deficiency usually is secondary to cardiac
involvement. The initial signs are cyanosis and dyspnea, but tachycar-
dia, enlargement of the liver, loss of consciousness, and convulsions
can develop rapidly. The heart, especially the right side, is enlarged.
The electrocardiogram shows an increased Q-T interval, inverted
T waves, and low voltage. These changes, as well as the cardiomegaly,
rapidly revert to normal with treatment, but without prompt treat-
ment, cardiac failure can develop rapidly and result in death. In fatal
cases of beriberi, lesions are principally located in the heart, peripheral
nerves, subcutaneous tissue, and serous cavities. The heart is dilated,
and fatty degeneration of the myocardium is common. Generalized
edema or edema of the legs, serous effusions, and venous engorgement
are often present. Degeneration of myelin and axon cylinders of the
peripheral nerves, with wallerian degeneration beginning in the distal
locations, is also common, particularly in the lower extremities. Lesions
in the brain include vascular dilation and hemorrhage.
Diagnosis
The diagnosis is often suspected on the basis of clinical setting and
compatible symptoms. A high index of suspicion in children present-
ing with unexplained cardiac failure may sometimes be lifesaving.
Objective biochemical tests of thiamine status include measurement of
erythrocyte transketolase activity and the thiamine pyrophosphate
effect. The biochemical diagnostic criteria of thiamine deficiency
consist of low erythrocyte transketolase activity and high thiamine
pyrophosphate effect (normal range: 0-14%). Urinary excretion of thia-
mine or its metabolites (thiazole or pyrimidine) after an oral loading
dose of thiamine may also be measured to help identify the deficiency
state. MRI changes of thiamine deficiency in infants are characterized
by bilateral symmetric hyperintensities of the basal ganglia and frontal
lobe, in addition to the lesions in the mammillary bodies, periaque-
ductal region, and thalami described in adults.
Prevention
A maternal diet containing sufficient amounts of thiamine prevents
thiamine deficiency in breastfed infants, and infant formulas marketed
in all developed countries provide recommended levels of intake.
During complementary feeding, adequate thiamine intake can be
achieved with a varied diet that includes meat and enriched or whole-
grain cereals. When the staple cereal is polished rice, special efforts
need to be made to include legumes and/or nuts in the ration. Thia-
mine and other vitamins can be retained in rice by parboiling, a
process of steaming the rice in the husk before milling. Improvement
in cooking techniques, such as not discarding the water used for
cooking, minimal washing of grains, and reduction of cooking time
helps to minimize the thiamine losses during the preparation of food.
Thiamine supplementation should be ensured during total parenteral
nutrition.
Treatment
In the absence of GI disturbances, oral administration of thiamine is
effective. Children with cardiac failure, convulsions, or coma should
be given 10 mg of thiamine intramuscularly or intravenously daily for
the 1st wk. This treatment should then be followed by 3-5 mg of thia-
mine per day orally for at least 6 wk. The response is dramatic in
infants and in those having predominantly cardiovascular manifesta-
tions, whereas the neurologic response is slow and often incomplete.
Epilepsy, mental disability, and language and auditory problems of
varying degree have been reported in survivors of severe infantile thia-
mine deficiency.
Patients with beriberi often have other B-complex vitamin deficien-
cies; therefore, all other B-complex vitamins should also be adminis-
tered. Treatment of TRMA and other dependency states require higher
dosages (100-200 mg/day). The anemia responds well to thiamine
administration, and insulin for associated diabetes mellitus can also be
discontinued in many cases of TRMA.
TOXICITY
There are no reports of adverse effects from consumption of excess
thiamine by ingestion of food or supplements. A few isolated cases of
pruritus and anaphylaxis have been reported in patients after paren-
teral administration of the vitamin.
Bibliography is available at Expert Consult.
49.2  Riboflavin (Vitamin B2)
H.P.S. Sachdev and Dheeraj Shah
Riboflavin is part of the structure of the coenzymes flavin adenine
dinucleotide (FAD) and flavin mononucleotide, which participate in
oxidation-reduction reactions in numerous metabolic pathways and in
energy production via the mitochondrial respiratory chain. Riboflavin
is stable to heat, but is destroyed by light. Milk, eggs, organ meats,
legumes, and mushrooms are rich dietary sources of riboflavin. Most
commercial cereals, flours, and breads are enriched with riboflavin.
DEFICIENCY
The causes of riboflavin deficiency are mainly related to malnourished
and malabsorptive states, including GI infections. Treatment with
some drugs, such as probenecid, phenothiazine, or oral contraceptives,
can also cause the deficiency. The side chain of the vitamin is photo-
chemically destroyed during phototherapy for hyperbilirubinemia, as
it is involved in the photosensitized oxidation of bilirubin to more
polar excretable compounds. Isolated complex II deficiency, a rare
mitochondrial disease manifesting in infancy and childhood, responds
favorably to riboflavin supplementation and thus can be termed a
dependency state. Brown-Vialetto-Van Laere syndrome (BVVLS), a
rare neurologic disorder characterized by progressive neurologic
deterioration, hypotonia, sensorineural hearing loss, and pontobulbar
palsy responds to treatment with high doses of riboflavin. Mutations
in genes coding for riboflavin transporter proteins have been identified
in children with BVVLS.
Clinical Manifestations
Clinical features of riboflavin deficiency include cheilosis, glossitis,
keratitis, conjunctivitis, photophobia, lacrimation, corneal vasculariza-
tion, and seborrheic dermatitis. Cheilosis begins with pallor at the
angles of the mouth and progresses to thinning and maceration of the
epithelium, leading to fissures extending radially into the skin (Fig.
49-1). In glossitis, the tongue becomes smooth, with loss of papillary
structure (Fig. 49-2). Normochromic, normocytic anemia may also be
seen because of the impaired erythropoiesis. A low riboflavin content
of the maternal diet has been linked to congenital heart defects, but
the evidence is weak.
Diagnosis
Most often, the diagnosis is based on the clinical features of angular
cheilosis in a malnourished child, which responds promptly to ribofla-
vin supplementation. A functional test of riboflavin status is done by
measuring the activity of erythrocyte glutathione reductase (EGR),
with and without the addition of FAD. An EGR activity coefficient
(ratio of EGR activity with added FAD to EGR activity without FAD)
of >1.4 is used as an indicator of deficiency. Urinary excretion of ribo-
flavin <30 µg/24 hr also suggests low intakes.
Prevention
Table 49-1 lists the recommended daily allowance of riboflavin for
infants, children, and adolescents. Adequate consumption of milk,
milk products, and eggs prevents riboflavin deficiency. Fortification of
 Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess  322.e1
Bibliography
Attias J, Raveh E, Aizer-Dannon A, et al: Auditory system dysfunction due to
infantile thiamine deficiency: long-term auditory sequelae, Audiol Neurootol
17:309–320, 2012.
Coats D, Shelton-Dodge K, Ou K, et al: Thiamine deficiency in Cambodian infants
with and without beriberi, J Pediatr 161:843–847, 2012.
Fattal-Valevski A, Azouri-Fattal I, Greenstein YJ, et al: Delayed language
development due to infantile thiamine deficiency, Dev Med Child Neurol
51:629–634, 2009.
Fattal-Valevski A, Bloch-Mimouni A, Kivity S, et al: Epilepsy in children with
infantile thiamine deficiency, Neurology 73:828–833, 2009.
Gupta RK, Yadav SK, Saraswat VA, et al: Thiamine deficiency related
microstructural brain changes in acute and acute-on-chronic liver failure of
non-alcoholic etiology, Clin Nutr 31:422–428, 2012.
Khounnorath S, Chamberlain K, Taylor AM, et al: Clinically unapparent infantile
thiamin deficiency in Vientiane, Laos, PLoS Negl Trop Dis 5:e969, 2011.
Lima LF, Leite HP, Taddei JA: Low blood thiamine concentrations in children
upon admission to the intensive care unit: risk factors and prognostic
significance, Am J Clin Nutr 93:57–61, 2011.
Rao SN, Chandak GR: Cardiac beriberi: often a missed diagnosis, J Trop Pediatr
56:284–285, 2010.
Shamir R: Thiamine-deficient infant formula: what happened and what have we
learned, Ann Nutr Metab 60:185–187, 2012.
Soukaloun D, Lee SJ, Chamberlain K, et al: Erythrocyte transketolase activity,
markers of cardiac dysfunction and the diagnosis of infantile beriberi,
PLoS Negl Trop Dis 5:e971, 2011.
Zuccoli G, Siddiqui N, Bailey A, et al: Neuroimaging findings in pediatric
Wernicke encephalopathy: a review, Neuroradiology 52:523–529, 2010.
 Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess  323

Figure 49-1 Angular cheilosis with ulceration and crusting. (Courtesy Figure 49-2 Glossitis as seen in riboflavin deficiency. (From Zappe
of National Institute of Nutrition, Indian Council of Medical Research, HA, Nuss S, Becker K, et al: Riboflavin deficiency in Baltistan. http://
Hyderabad, India.) www.rzuser.uni-heidelberg.de/%7Ecn6/baltista/ribofl_e.htm.)

Table 49-1 Water-Soluble Vitamins

NAMES TREATMENT
AND EFFECTS OF OF CAUSES OF DIETARY
SYNONYMS BIOCHEMICAL ACTION DEFICIENCY DEFICIENCY DEFICIENCY SOURCES RDA* BY AGE
Thiamine Coenzyme in carbohydrate Neurologic (dry 3-5 mg/day Polished Meat, 0-6 mo: 0.2 mg/
(vitamin B1) metabolism beriberi): irritability, PO thiamine rice–based especially day
Nucleic acid synthesis peripheral neuritis, for 6 wk diets pork; fish; 7-12 mo: 0.3 mg/
Neurotransmitter synthesis muscle tenderness, Malabsorptive liver day
ataxia states Rice 1-3 yr: 0.5 mg/day
Cardiac (wet beriberi): Severe (unmilled), 4-8 yr: 0.6 mg/day
tachycardia, edema, malnutrition wheat 9-13 yr: 0.9 mg/day
cardiomegaly, Malignancies germ; 14-18 yr:
cardiac failure Alcoholism enriched Girls: 1.0 mg/day
cereals; Boys: 1.2 mg/day
legumes
Riboflavin Constituent of flavoprotein Glossitis, 3-10 mg/day Severe Milk, milk 0-6 mo: 0.3 mg/
(vitamin B2) enzymes important in photophobia, PO malnutrition products, day
oxidation-reduction lacrimation, corneal riboflavin Malabsorptive eggs, 7-12 mo: 0.4 mg/
reactions: amino acid, fatty vascularization, poor states fortified day
acid, and carbohydrate growth, cheilosis Prolonged cereals, 1-3 yr: 0.5 mg/day
metabolism and cellular treatment with green 4-8 yr: 0.6 mg/day
respiration phenothiazines, vegetables 9-13 yr: 0.9 mg/day
probenecid, or 14-18 yr:
OCPs Girls: 1.0 mg/day
Boys: 1.3 mg/day
Niacin Constituent of NAD and Pellagra manifesting 50-300 mg/ Predominantly Meat, fish, 0-6 mo: 2 mg/day
(vitamin B3) NADP, important in as diarrhea, day PO maize-based poultry 7-12 mo: 4 mg/day
respiratory chain, fatty symmetric scaly niacin diets Cereals, 1-3 yr: 6 mg/day
acid synthesis, cell dermatitis in Anorexia nervosa legumes, 4-8 yr: 8 mg/day
differentiation, and DNA sun-exposed areas, Carcinoid green 9-13 yr: 12 mg/day
processing and neurologic syndrome vegetables 14-18 yr:
symptoms of Girls: 14 mg/day
disorientation and Boys: 16 mg/day
delirium
Pyridoxine Constituent of coenzymes Irritability, convulsions, 5-25 mg/day Prolonged Fortified 0-6 mo: 0.1 mg/
(vitamin B6) for amino acid and hypochromic anemia PO for treatment ready-to- day
glycogen metabolism, Failure to thrive deficiency with INH, eat cereals, 7-12 mo: 0.3 mg/
heme synthesis, steroid Oxaluria states penicillamine, meat, fish, day
action, neurotransmitter 100 mg IM or OCPs poultry, 1-3 yr: 0.5 mg/day
synthesis IV for liver, 4-8 yr: 0.6 mg/day
pyridoxine- bananas, 9-13 yr: 1.0 mg/day
dependent rice, 14-18 yr:
seizures potatoes Girls: 1.2 mg/day
Boys: 1.3 mg/day
Continued
324  Part VI  ◆  Nutrition

Table 49-1 Water-Soluble Vitamins—cont’d

NAMES TREATMENT
AND EFFECTS OF OF CAUSES OF DIETARY
SYNONYMS BIOCHEMICAL ACTION DEFICIENCY DEFICIENCY DEFICIENCY SOURCES RDA* BY AGE
Biotin Cofactor for carboxylases, Scaly periorificial 1-10 mg/day Consumption of Liver, organ 0-6 mo: 5 µg/day
important in dermatitis, PO biotin raw eggs for meats, 7-12 mo: 6 µg/day
gluconeogenesis, fatty conjunctivitis, prolonged fruits 1-3 yr: 8 µg/day
acid and amino acid alopecia, lethargy, periods 4-8 yr: 12 µg/day
metabolism hypotonia, and Parenteral 9-13 yr: 20 µg/day
withdrawn behavior nutrition with 14-18 yr: 25 µg/day
infusates
lacking biotin
Valproate therapy
Pantothenic Component of coenzyme A Experimentally Isolated Beef, organ 0-6 mo: 1.7 mg/
acid and acyl carrier protein produced deficiency deficiency meats, day
(vitamin B5) involved in fatty acid in humans: irritability, extremely rare poultry, 7-12 mo: 1.8 mg/
metabolism fatigue, numbness, in humans seafood, day
paresthesias (burning egg yolk 1-3 yr: 2 mg/day
feet syndrome), Yeast, 4-8 yr: 3 mg/day
muscle cramps soybeans, 9-13 yr: 4 mg/day
mushrooms 14-18 yr: 5 mg/day
Folic acid Coenzymes in amino Megaloblastic anemia 0.5-1 mg/day Malnutrition Enriched 0-6 mo: 65 µg/day
acid and nucleotide Growth retardation, PO folic Malabsorptive cereals, 7-12 mo: 80 µg/
metabolism as an acceptor glossitis acid states beans, leafy day
and donor of one-carbon Neural tube defects in Malignancies vegetables, 1-3 yr: 150 µg/day
units progeny Hemolytic citrus fruits, 4-8 yr: 200 µg/day
anemias papaya 9-13 yr: 300 µg/day
Anticonvulsant 14-18 yr: 400 µg/
therapy day
Cobalamin As deoxyadenosylcobalamin, Megaloblastic anemia, 1,000 µg IM Vegan diets Organ meats, 0-6 mo: 0.4 µg/day
(vitamin acts as cofactor for lipid irritability, vitamin B12 Malabsorptive sea foods 7-12 mo: 0.5 µg/
B12) and carbohydrate developmental states poultry, day
metabolism delay, Crohn disease egg yolk, 1-3 yr: 0.9 µg/day
As methylcobalamin, developmental Intrinsic factor milk, 4-8 yr: 1.2 µg/day
important for conversion regression, deficiency fortified 9-13 yr: 1.8 µg/day
of homocysteine to involuntary (pernicious ready-to- 14-18 yr: 2.4 µg/
methionine and folic acid movements, anemia) eat cereals day
metabolism hyperpigmentation
Ascorbic Important for collagen Scurvy manifesting 100-200 mg/ Predominantly Citrus fruits 0-6 mo: 40 mg/day
acid synthesis, metabolism of as irritability, day PO milk-based and fruit 7-12 mo: 50 mg/
(vitamin C) cholesterol and tenderness and ascorbic (non–human juices, day
neurotransmitters swelling of legs, acid for up milk) diets peppers, 1-3 yr: 15 mg/day
Antioxidant functions and bleeding gums, to 3 mo Severe berries, 4-8 yr: 25 mg/day
nonheme iron absorption petechiae, malnutrition melons, 9-13 yr: 45 mg/day
ecchymoses, tomatoes, 14-18 yr:
follicular cauliflower, Girls: 65 mg/day
hyperkeratosis, and leafy green Boys: 75 mg/day
poor wound healing vegetables
*For healthy breastfed infants, the values represent adequate intakes, that is, the mean intake of apparently “normal” infants.
INH, isoniazid; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; OCP, oral contraceptive pill; RDA, recommended
dietary allowance.
Source: Dietary Reference Intakes (DRIs): Recommended dietary allowances and adequate intakes, vitamins. Food and Nutrition Board, Institute of Medicine,
National Academies. Available from: http://fnic.nal.usda.gov/dietary-guidance/dietary-reference-intakes/dri-tables.

cereal products is helpful for those who follow vegan diets or who are of this vitamin raises the possibility for some potential risks, limited
consuming inadequate amounts of milk products for other reasons. absorption in high-intake situations precludes such concerns.

Treatment Bibliography is available at Expert Consult.

Treatment includes oral administration of 3-10 mg/day of riboflavin,
often as an ingredient of a vitamin B–complex mix. The child
should also be given a well-balanced diet, including milk and milk
products. 49.3  Niacin (Vitamin B3)
H.P.S. Sachdev and Dheeraj Shah
TOXICITY
No adverse effects associated with riboflavin intakes from food or Niacin (nicotinamide or nicotinic acid) forms part of 2 cofactors, nico-
supplements have been reported, and the upper safe limit for consump- tinamide adenine dinucleotide and NADP, which are important in
tion has not been established. Although the photosensitizing property several biologic reactions, including the respiratory chain, fatty acid
 Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess  324.e1

Bibliography
Allen LH: B vitamins in breast milk: relative importance of maternal status and
intake, and effects on infant status and function, Adv Nutr 3:362–369, 2012.
Bosch AM, Abeling NG, Ijlst L, et al: Brown-Vialetto-Van Laere and Fazio Londe
syndrome is associated with a riboflavin transporter defect mimicking mild
MADD: a new inborn error of metabolism with potential treatment, J Inherit
Metab Dis 34:159–164, 2011.
Haack TB, Makowski C, Yao Y, et al: Impaired riboflavin transport due to missense
mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome, J Inherit
Metab Dis 35:943–948, 2012.
 Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess  325
and steroid synthesis, cell differentiation, and DNA processing. Niacin
is rapidly absorbed from the stomach and the intestines and can also
be synthesized from tryptophan in the diet.
Major dietary sources of niacin are meat, fish, and poultry for non-
vegetarians and cereals, legumes, and green leafy vegetables for vege-
tarians. Enriched and fortified cereal products and legumes also are
major contributors to niacin intake. Milk and eggs contain little niacin
but are good sources of tryptophan, which can be converted to nico-
tinamide adenine dinucleotide (60 mg tryptophan = 1 mg niacin).
DEFICIENCY
Pellagra, the classic niacin deficiency disease, occurs chiefly in popula-
tions where corn (maize), a poor source of tryptophan, is the major
foodstuff. A severe dietary imbalance, such as in anorexia nervosa and
in war or famine conditions, also can cause pellagra. Pellagra can also
develop in conditions associated with disturbed tryptophan metabo-
lism such as carcinoid syndrome and Hartnup disease.
Clinical Manifestations
The early symptoms of pellagra are vague: anorexia, lassitude, weak-
ness, burning sensation, numbness, and dizziness. After a long period
of deficiency, the classic triad of dermatitis, diarrhea, and dementia
appears. Dermatitis, the most characteristic manifestation of pellagra,
can develop suddenly or insidiously and may be initiated by irritants,
including intense sunlight. The lesions first appear as symmetric areas
of erythema on exposed surfaces, resembling sunburn, and might go
unrecognized. The lesions are usually sharply demarcated from the
surrounding healthy skin, and their distribution can change frequently.
The lesions on the hands and feet often have the appearance of a glove
or stocking (Fig. 49-3). Similar demarcations can also occur around
the neck (Casal necklace) (Fig. 49-3). In some cases, vesicles and bullae
Figure 49-3 Characteristic skin lesions of pellagra on hands and
lesions on the neck (Casal necklace). (Courtesy of Dr. J.D. MacLean,
McGill Centre for Tropical Diseases, Montreal, Canada.)
develop (wet type). In others, there may be suppuration beneath the
scaly, crusted epidermis; in still others, the swelling can disappear after
a short time, followed by desquamation (Fig. 49-4). The healed parts
of the skin might remain pigmented. The cutaneous lesions may be
preceded by or accompanied by stomatitis, glossitis, vomiting, and/or
diarrhea. Swelling and redness of the tip of the tongue and its lateral
margins is often followed by intense redness, even ulceration, of the
entire tongue and the papillae. Nervous symptoms include depression,
disorientation, insomnia, and delirium.
The classic symptoms of pellagra usually are not well developed in
infants and young children, but anorexia, irritability, anxiety, and
apathy are common. Young patients might also have sore tongues and
lips, and usually have dry and scaly skin. Diarrhea and constipation
can alternate, and anemia can occur. Children who have pellagra often
have evidence of other nutritional deficiency diseases.
Diagnosis
Because of lack of a good functional test to evaluate niacin status, the
diagnosis of deficiency is usually made from the physical signs of glos-
sitis, GI symptoms, and a symmetric dermatitis. Rapid clinical response
to niacin is an important confirmatory test. A decrease in the concen-
tration and/or a change in the proportion of the niacin metabolites
N1-methyl-nicotinamide and 2-pyridone in the urine provide bio-
chemical evidence of deficiency and can be seen before the appearance
of overt signs of deficiency. Histopathologic changes from the affected
skin include dilated blood vessels without significant inflammatory
infiltrates, ballooning of the keratinocytes, hyperkeratosis, and epider-
mal necrosis.
Prevention
Adequate intakes of niacin are easily met by consumption of a diet that
consists of a variety of foods and includes meat, eggs, milk, and
enriched or fortified cereal products. The dietary reference intake
(DRI) is expressed in mg niacin equivalents (NE) in which 1 mg NE
= 1 mg niacin or 60 mg tryptophan. An intake of 2 mg of niacin is
considered adequate for infants 0-6 mo of age; and 4 mg is adequate
for infants 7-12 mo of age. For older children, the recommended
B
Figure 49-4 Clinical manifestations of niacin deficiency before (A)
and after (B) therapy. (From Weinsier RL, Morgan SL: Fundamentals of
clinical nutrition, St. Louis, 1993, Mosby, p. 99.)
326  Part VI  ◆  Nutrition
intakes are 6 mg for 1-3 yr of age, 8 mg for 4-8 yr of age, 12 mg for
9-13 yr of age, and 14-16 mg for 14-18 yr of age.
Treatment
Children usually respond rapidly to treatment. A liberal and varied diet
should be supplemented with 50-300 mg/day of niacin; in severe cases
or in patients with poor intestinal absorption, 100 mg may be given
intravenously. The diet should also be supplemented with other vita-
mins, especially other B-complex vitamins. Sun exposure should be
avoided during the active phase of pellagra, and the skin lesions may
be covered with soothing applications. Other coexisting nutrient defi-
ciencies such as iron deficiency anemia should be treated. Even after
successful treatment, the diet should continue to be monitored to
prevent recurrence.
TOXICITY
There are no toxic effects associated with the intake of naturally occur-
ring niacin in foods. Shortly after the ingestion of large doses of nico-
tinic acid taken as a supplement or a pharmacologic agent, a person
often experiences a burning, tingling, and itching sensation as well as
flushing on the face, arms, and chest. Large doses of niacin also can
have nonspecific GI effects and can cause cholestatic jaundice or hepa-
totoxicity. Tolerable upper intake levels for children are approximately
double the recommended dietary allowance.
Bibliography is available at Expert Consult.
49.4  Vitamin B6 (Pyridoxine)
H.P.S. Sachdev and Dheeraj Shah
Vitamin B6 includes a group of closely related compounds: pyridoxine,
pyridoxal, pyridoxamine, and their phosphorylated derivatives. Pyri-
doxal 5′-phosphate (PLP) and, to a lesser extent, pyridoxamine phos-
phate function as coenzymes for many enzymes involved in amino acid
metabolism, neurotransmitter synthesis, glycogen metabolism, and
steroid action. If vitamin B6 is lacking, glycine metabolism can lead to
oxaluria. The major excretory product in the urine is 4-pyridoxic acid.
The vitamin B6 content of human milk and infant formulas is ade-
quate. Good food sources of the vitamin include fortified ready-to-eat
cereals, meat, fish, poultry, liver, bananas, rice, and certain vegetables.
Large losses of the vitamin can occur during high-temperature pro-
cessing of foods or milling of cereals, whereas parboiling of rice pre-
vents its loss.
DEFICIENCY
Because of the importance of vitamin B6 in amino acid metabolism,
high protein intakes can increase the requirement for the vitamin; the
recommended daily allowances are sufficient to cover the expected
range of protein intake in the population. The risk of deficiency is
increased in persons taking medications that inhibit the activity of
vitamin B6 (isoniazid, penicillamine, corticosteroids, phenytoin, carba-
mazepine), in young women taking oral progesterone-estrogen contra-
ceptives, and in patients receiving maintenance dialysis.
Clinical Manifestations
The deficiency symptoms seen in infants are listlessness, irritability,
seizures, vomiting, and failure to thrive. Peripheral neuritis is a feature
of deficiency in adults but is not usually seen in children. Electroen-
cephalogram (EEG) abnormalities have been reported in infants as
well as in young adult subjects in controlled depletion studies. Skin
lesions include cheilosis, glossitis, and seborrheic dermatitis around
the eyes, nose, and mouth. Microcytic anemia can occur in infants, but
is not common. Oxaluria, oxalic acid bladder stones, hyperglycinemia,
lymphopenia, decreased antibody formation, and infections also are
associated with vitamin B6 deficiency.
Several types of vitamin B6 dependence syndromes, presumably
resulting from errors in enzyme structure or function, respond
to very large amounts of pyridoxine. These syndromes include
pyridoxine-dependent epilepsy, a vitamin B6–responsive ane­mia,
xanthurenic aciduria, cystathioninuria, and homocystinuria (see
Chapters 85, 456, and 601). Pyridoxine-dependent epilepsy involves
mutations in the ALDH7A1 gene causing deficiency of antiquitin,
an enzyme involved in dehydrogenation of l-alpha-aminoadipic
semialdehyde.
Diagnosis
The activity of the erythrocyte transaminases glutamic oxaloacetic
transaminase and glutamic pyruvic transaminase is low in vitamin B6
deficiency; tests measuring the activity of these enzymes before and
after the addition of PLP may be useful as indicators of vitamin B6
status. Abnormally high xanthurenic acid excretion after tryptophan
ingestion also provides evidence of deficiency. Plasma PLP assays are
being used more often, but factors other than deficiency can influence
the results. Vitamin B6 deficiency or dependence should be suspected
in all infants with seizures. If more common causes of infantile seizures
have been eliminated, 100 mg of pyridoxine can be injected, with EEG
monitoring if possible. If the seizure stops, vitamin B6 deficiency
should be suspected. In older children, 100 mg of pyridoxine may be
injected intramuscularly while the EEG is being recorded; a favorable
response of the EEG suggests pyridoxine deficiency.
Prevention
Deficiency is unlikely in children consuming diets that meet their
energy needs and contain a variety of foods. Parboiling of rice pre-
vents the loss of vitamin B6 from the grains. The DRIs for vitamin B6
are 0.1 mg/day for infants up to 6 mo of age; 0.3 mg/day for ages 6 mo
to 1 yr; 0.5 mg/day for ages 1-3 yr; 0.6 mg/day for ages 4-8 yr; 1.0 mg/
day for ages 9-13 yr; and 1.2-1.3 mg/day for ages 14-18 yr. Infants
whose mothers have received large doses of pyridoxine during preg-
nancy are at increased risk for seizures from pyridoxine dependence,
and supplements during the 1st few weeks of life should be considered.
Any child receiving a pyridoxine antagonist, such as isoniazid, should
be carefully observed for neurologic manifestations; if these develop,
vitamin B6 should be administered or the dose of the antagonist should
be decreased.
Treatment
Intramuscular or intravenous administration of 100 mg of pyridoxine
is used to treat convulsions caused by vitamin B6 deficiency. One dose
should be sufficient if adequate dietary intake follows. For pyridoxine-
dependent children, daily doses of 2-10 mg intramuscularly or
10-100 mg orally may be necessary.
TOXICITY
Adverse effects have not been associated with high intakes of vitamin
B6 from food sources. However, ataxia and sensory neuropathy have
been reported with dosages as low as 100 mg/day in adults taking
vitamin B6 supplements for several months.
Bibliography is available at Expert Consult.
49.5  Biotin
H.P.S. Sachdev and Dheeraj Shah
Biotin functions as a cofactor for enzymes involved in carboxylation
reactions within and outside mitochondria. These biotin-dependent
carboxylases catalyze key reactions in gluconeogenesis, fatty acid
metabolism, and amino acid catabolism.
There is limited information on the biotin content of foods; it is
believed to be widely distributed, thus making a deficiency unlikely.
Avidin found in raw egg whites acts as a biotin antagonist. Signs of
biotin deficiency have been demonstrated in persons who consume
large amounts of raw egg whites over long periods. Deficiency also has
been described in infants and children receiving enteral and parenteral
 Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess  326.e1

Bibliography Piqué-Duran E, Pérez-Cejudo JA, Cameselle D, et al: Pellagra: a clinical,

Brown TM: Pellagra: an old enemy of timeless importance, Psychosomatics
51:93–97, 2010.
Lanska DJ: Chapter 30: historical aspects of the major neurological vitamin
deficiency disorders: the water-soluble B vitamins, Handb Clin Neurol
95:445–476, 2010.
histopathological, and epidemiological study of 7 cases, Actas Dermosifiliogr
103:51–58, 2012.
Steffen C: Pellagra, Skinmed 10:174–179, 2012.
Wan P, Moat S, Anstey A: Pellagra: a review with emphasis on photosensitivity,
Br J Dermatol 164:1188–1200, 2011.
326.e2  Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess
Bibliography
Bowling FG: Pyridoxine supply in human development, Semin Cell Dev Biol
22:611–618, 2011.
Mills PB, Footitt EJ, Mills KA, et al: Genotypic and phenotypic spectrum of
pyridoxine-dependent epilepsy (ALDH7A1 deficiency), Brain 133(Pt 7):
2148–2159, 2010.
Mintzer S, Skidmore CT, Sperling MR: B-vitamin deficiency in patients treated
with antiepileptic drugs, Epilepsy Behav 24:341–344, 2012.
Schmitt B, Baumgartner M, Mills PB, et al: Seizures and paroxysmal events:
symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and
pyridoxine phosphate oxidase deficiency, Dev Med Child Neurol 52:e133–e142,
2010.
 Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess  327
A B
Figure 49-5 Scalp rash (A) Before treatment with biotin, (B) After 3 wk of biotin treatment. (From Ito T, Nishie W, Fujita Y, et al: Infantile eczema
caused by formula milk. Lancet 381:1958, 2013.)
nutrition formula that lack biotin. Treatment with valproic acid may
result in a low biotinidase activity and/or biotin deficiency.
The clinical findings of biotin deficiency include scaly periorificial
dermatitis, conjunctivitis, thinning of hair, and alopecia (Fig. 49-5).
Central nervous system abnormalities seen with biotin deficiency are
lethargy, hypotonia, seizures, ataxia, and withdrawn behavior. Biotin
deficiency can be successfully treated using 1-10 mg of biotin orally
daily. The adequate dietary intake values for biotin are 5 µg/day for
ages 0-6 mo, 6 µg/day for ages 7-12 mo, 8 µg/day for ages 1-3 yr, 12 µg/
day for ages 4-8 yr, 20 µg/day for ages 9-13 yr, and 25 µg/day for ages
14-18 yr. No toxic effects have been reported with very high doses.
Biotin responsive basal ganglia disease is a rare childhood neuro-
logic disorder characterized by encephalopathy, seizures, and extrapy-
ramidal manifestations. Chapter 85.6 describes conditions involving
deficiencies in the enzymes holocarboxylase synthetase and biotini-
dase that respond to treatment with biotin.
Bibliography is available at Expert Consult.
49.6  Folate
H.P.S. Sachdev and Dheeraj Shah
Folate exists in a number of different chemical forms. Folic acid (ptero-
ylglutamic acid) is the synthetic form used in fortified foods and sup-
plements. Naturally occurring folates in foods retain the core chemical
structure of pteroylglutamic acid but vary in their state of reduction,
the single carbon moiety they bear, or the length of the glutamate
chain. These polyglutamates are broken down and reduced in the small
intestine to dihydro- and tetrahydrofolates, which are involved as
coenzymes in amino acid and nucleotide metabolism as acceptors and
donors of 1-carbon units. Folate is important for central nervous
system development during embryogenesis.
Rice and cereals are rich dietary sources of folate, especially if
enriched. Beans, leafy vegetables, and fruits such as oranges and papaya
are good sources, too. The vitamin is readily absorbed from the small
intestine and is broken down to monoglutamate derivatives by mucosal
polyglutamate hydrolases. A high-affinity proton-coupled folate trans-
porter (PCFT) seems to be essential for absorption of folate in intestine
and in various cell types at low pH. The vitamin is also synthesized by
the colonic bacteria, and the half-life of the vitamin is prolonged by
enterohepatic recirculation.
DEFICIENCY
Because of its role in protein, DNA, and RNA synthesis, the risk of
deficiency is increased during periods of rapid growth or increased
cellular metabolism. Folate deficiency can result from poor nutrient
content in diet, inadequate absorption (celiac disease, inflammatory
bowel disease), increased requirement (sickle cell anemia, psoriasis,
malignancies, periods of rapid growth as in infancy and adolescence),
or inadequate utilization (long-term treatment with high-dose nonste-
roidal antiinflammatory drugs; anticonvulsants such as phenytoin and
phenobarbital; and methotrexate). Rare causes of deficiency are heredi-
tary folate malabsorption, inborn errors of folate metabolism (methy-
lene tetrahydrofolate reductase, methionine synthase reductase, and
glutamate formiminotransferase deficiencies), and cerebral folate defi-
ciency. A loss-of-function mutation in the gene coding for PCFT is the
molecular basis for hereditary folate malabsorption. A high-affinity
blocking autoantibody against the membrane-bound folate receptor in
the choroid plexus preventing its transport across the blood–brain
barrier is the likely cause of the infantile cerebral folate deficiency.
Clinical Manifestations
Folic acid deficiency results in megaloblastic anemia and hyperseg-
mentation of neutrophils. Nonhematologic manifestations include
glossitis, listlessness, and growth retardation not related to anemia.
There is an association between low maternal folic acid status and
neural tube defects, primarily spina bifida and anencephaly, and
the role of periconceptional folic acid in their prevention is well
established.
Hereditary folate malabsorption manifests at 1-3 mo of age with
recurrent or chronic diarrhea, failure to thrive, oral ulcerations,
neurologic deterioration, megaloblastic anemia, and opportunistic
infections. Cerebral folate deficiency manifests at 4-6 mo of age with
irritability, microcephaly, developmental delay, cerebellar ataxia, pyra-
midal tract signs, choreoathetosis, ballismus, seizures, and blindness
as a result of optic atrophy. 5-Methyltetrahydrofolate levels are normal
in serum and red blood cells (RBCs), but are markedly depressed in
the cerebrospinal fluid.
 Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess  327.e1

Bibliography Ogundele MO: Question 2. What is the incidence of biotin deficiency in preschool
Imai T, Ebisawa M: Problem of biotin deficiency associated with milk allergic children with global developmental delay, Arch Dis Child 96:895–897, 2011.
child, Arerugi 60:1614–1620, 2011. Tabarki B, Al-Shafi S, Al-Shahwan S, et al: Biotin-responsive basal ganglia disease
Ito T, Nishie W, Fujita Y, et al: Infantile eczema caused by formula milk, Lancet revisited: clinical, radiologic, and genetic findings, Neurology 80:261–267, 2013.
381:1958, 2013.
328  Part VI  ◆  Nutrition
Diagnosis
The diagnosis of folic acid deficiency anemia is made in the presence
of macrocytosis along with low folate levels in serum and/or RBCs.
Normal serum folic acid levels are 5-20 ng/mL; with deficiency, serum
folic acid levels are <3 ng/mL. Levels of RBC folate are a better indica-
tor of chronic deficiency. The normal RBC folate level is 150-600 ng/
mL of packed cells. The bone marrow is hypercellular because of ery-
throid hyperplasia, and megaloblastic changes are prominent. Large,
abnormal neutrophilic forms (giant metamyelocytes) with cytoplasmic
vacuolation also are seen.
Cerebral folate deficiency is associated with low levels of
5-methyltetrahydrofolate in the cerebrospinal fluid and normal folate
levels in the plasma and RBCs. Mutations in the PCFT gene are dem-
onstrated in the hereditary folate malabsorption.
Prevention
Breastfed infants have better folate nutrition than non–breastfed
infants throughout infancy. Consumption of folate-rich foods and
food-fortification programs are important to ensure adequate intake in
children and in women of childbearing age. The DRIs for folate are
65 µg of dietary folate equivalents (DFE) for infants 0-6 mo of age and
80 µg of DFE for infants between 6 and 12 mo of age. (1 DFE = 1 µg
food folate = 0.6 µg of folate from fortified food or as a supplement
consumed with food = 0.5 µg of a supplement taken on an empty
stomach.) For older children, the DRIs are 150 µg of DFE for ages
1-3 yr; 200 µg of DFE for ages 4-8 yr; 300 µg of DFE for ages 9-13 yr;
and 400 µg of DFE for ages 14-18 yr. All women desirous of becoming
pregnant should consume 400-800 µg folic acid daily; the dose is 4 mg/
day in those having delivered a child with neural tube defect. To be
effective, supplementation should be started at least 1 mo before con-
ception, and continued through the first 2-3 mo of pregnancy. There
may be a marginal benefit of periconceptional folate supplementation
in prevention of autistic spectrum disorders. Providing iron and folic
acid tablets for prevention of anemia in children and pregnant women
is a routine strategy in at-risk populations. Mandatory fortification of
cereal flours with folic acid coupled with health-education programs
has been associated with a substantial reduction in incidence of neural
tube defects in many countries.
Treatment
When the diagnosis of folate deficiency is established, folic acid may
be administered orally or parenterally at 0.5-1.0 mg/day. Folic acid
therapy should be continued for 3-4 wk or until a definite hematologic
response has occurred. Maintenance therapy with 0.2 mg of folate is
adequate. Prolonged treatment with oral folinic acid is required in
cerebral folate deficiency, and the response may be incomplete. Treat-
ment of hereditary folate malabsorption may be possible with intra-
muscular folinic acid; some patients may respond to high-dose oral
folinic acid therapy.
TOXICITY
No adverse effects have been associated with consumption of the
amounts of folate normally found in fortified foods. Excessive intake
of folate supplements might obscure and potentially delay the diagno-
sis of vitamin B12 deficiency. Massive doses given by injection have the
potential to cause neurotoxicity.
Bibliography is available at Expert Consult.
49.7  Vitamin B12 (Cobalamin)
H.P.S. Sachdev and Dheeraj Shah
Vitamin B12, in the form of deoxyadenosylcobalamin, functions as a
cofactor for isomerization of methylmalonyl-CoA to succinyl-CoA, an
essential reaction in lipid and carbohydrate metabolism. Methylco-
balamin is another circulating form of vitamin B12, and is essential for
methyl group transfer during the conversion of homocysteine to
methionine. This reaction also requires a folic acid cofactor and is
important for protein and nucleic acid biosynthesis. Vitamin B12 is
important for hematopoiesis, central nervous system myelination, and
mental and psychomotor development.
Dietary sources of vitamin B12 are almost exclusively from animal
foods. Organ meats, muscle meats, sea foods (mollusks, oysters, fish),
poultry, and egg yolk are rich sources. Fortified ready-to-eat cereals
and milk and their products are the important sources of the vitamin
for vegetarians. Human milk is an adequate source for breastfeeding
infants if the maternal serum B12 levels are adequate. The vitamin is
absorbed from ileum at alkaline pH after binding with intrinsic factor.
Enterohepatic circulation, direct absorption, and synthesis by intesti-
nal bacteria are additional mechanisms helping to maintain the vitamin
B12 nutriture.
DEFICIENCY
Vitamin B12 deficiency because of inadequate dietary intake occurs
primarily in persons consuming strict vegetarian or vegan diets. Preva-
lence of vitamin B12 deficiency is high in predominantly vegetarian or
lactovegetarian populations. Breastfeeding infants of B12-deficient
mothers are also at risk for significant deficiency. Malabsorption of B12
occurs in celiac disease, ileal resections, Crohn disease, Helicobacter
pylori infection, and autoimmune atrophic gastritis (pernicious
anemia). Use of proton pump inhibitors and/or histamine 2 receptor
antagonists may increase the risk of deficiency. Hereditary intrinsic
factor deficiency and Imerslund-Gräsbeck disease are inborn errors of
metabolism leading to vitamin B12 malabsorption. Mutations in the
hereditary intrinsic factor gene cause hereditary intrinsic factor defi-
ciency, whereas mutations in any of the 2 subunits (cubilin and amni-
onless) of the intrinsic factor receptor cause Imerslund-Gräsbeck
disease.
Clinical Manifestations
The hematologic manifestations of vitamin B12 deficiency are similar
to manifestations of folate deficiency and are discussed in Chapter
454.2. Irritability, hypotonia, developmental delay, developmental
regression, and involuntary movements are the common neurologic
symptoms in infants and children, whereas sensory deficits, paresthe-
sias, and peripheral neuritis are seen in adults. Hyperpigmentation of
the knuckles (Fig. 49-6) and palms is another common observation
with B12 deficiency in children. Maternal B12 deficiency may also be an
independent risk factor for fetal neural tube defects.
Figure 49-6 Hyperpigmentation of knuckles in an infant with vitamin
B12 deficiency and megaloblastic anemia.
 Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess  328.e1
Bibliography
Berry RJ, Bailey L, Mulinare J, et al; Folic Acid Working Group: Fortification of
flour with folic acid, Food Nutr Bull 31(Suppl 1):S22–S35, 2010.
Breimer LH, Nilsson TK: Has folate a role in the developing nervous system after
birth and not just during embryogenesis and gestation, Scand J Clin Lab Invest
72:185–191, 2012.
Fekete K, Berti C, Cetin I, et al: Perinatal folate supply: relevance in health
outcome parameters, Matern Child Nutr 6(Suppl 2):23–38, 2010.
Gordon N: Cerebral folate deficiency, Dev Med Child Neurol 51:180–182, 2009.
Heseker H: Folic acid and other potential measures in the prevention of neural
tube defects, Ann Nutr Metab 59:41–45, 2011.
Lohner S, Fekete K, Berti C, et al: Effect of folate supplementation on folate status
and health outcomes in infants, children and adolescents: a systematic review,
Int J Food Sci Nutr 63:1014–1020, 2012.
Schmidt RJ, Tancredi DJ, Ozonoff S, et al: Maternal periconceptional folic acid
intake and risk of autism spectrum disorders and developmental delay in the
CHARGE (CHildhood Autism Risks from Genetics and Environment)
case-control study, Am J Clin Nutr 96:80–89, 2012.
Skórka A, Gieruszczak-Białek D, Pieścik M, et al: Effects of prenatal and/or
postnatal (maternal and/or child) folic acid supplementation on the mental
performance of children, Crit Rev Food Sci Nutr 52:959–964, 2012.
Surén P, Roth C, Bresnahan M, et al: Association between maternal use of folic
acid supplements and risk of autism spectrum disorders in children, JAMA
309:570–577, 2013.
Diagnosis
See Chapter 454.2.

Treatment
The hematologic symptoms respond promptly to parenteral adminis-
tration of 250-1,000 µg vitamin B12. Children with severe deficiency
and those with neurologic symptoms need repeated doses; daily or
alternate days in first week followed by weekly for the first 1-2 mo, and
then monthly thereafter. Children having only hematologic presenta-
tion recover fully within 2-3 mo, whereas those with neurologic disease
need at least 6 mo of therapy. Children with continuing malabsorptive
state, and those having inborn errors of vitamin B12 malabsorption
need lifelong treatment. Prolonged daily treatment with high dose
(1,000-2,000 µg) oral vitamin B12 preparations has also been found to
be equally effective in achieving hematologic and neurologic responses
in the elderly, but the data are inadequate in children and young adults.

Prevention
The DRIs are 0.4 µg/day at age 0-6 mo, 0.5 µg/day at age 6-12 mo,
0.9 µg/day at age 1-3 yr, 1.2 µg/day at age 4-8 yr, 1.8 µg/day at age
9-13 yr, 2.4 µg/day at age 14-18 yr and in adults, 2.6 µg/day in preg-
nancy, and 2.8 µg/day in lactation. Pregnant and breastfeeding women
should ensure an adequate consumption of animal products to prevent
the deficiency in infants. Strict vegetarians, especially vegans, should
ensure regular consumption of vitamin B12. Food fortification with
the vitamin helps to prevent deficiency in predominantly vegetarian
populations.

Bibliography is available at Expert Consult.

 Chapter 49  ◆  Vitamin B Complex Deficiencies and Excess  329.e1
Bibliography
Bjørke-Monsen AL, Ueland PM: Cobalamin status in children, J Inherit Metab Dis
34:111–119, 2011.
Boina Abdallah A, Ogier de Baulny H, Kozyraki R, et al: How can cobalamin
injections be spaced in long-term therapy for inborn errors of vitamin B(12)
absorption, Mol Genet Metab 107:66–71, 2012.
CDC: Vitamin B12 deficiency in resettled Bhutanese refugees—United States,
2008-2011, MMWR Morb Mortal Wkly Rep 60(11):343–346, 2011.
Cuffe K, Stauffer W, Painter J, et al: Update: Vitamin B12 deficiency among
Bhutanese refugees resettling in the United States, 2012, MMWR Morb Mortal
Wkly Rep 63:607, 2014.
Favrat B, Vaucher P, Herzig L, et al: Oral vitamin B12 for patients suspected of
subtle cobalamin deficiency: a multicentre pragmatic randomised controlled
trial, BMC Fam Pract 12:2, 2011.
Gräsbeck R, Tammer SM: Juvenile selective vitamin B12 malabsorption: 50 years
after its description—10 years of genetic testing, Pediatr Res 70(3):222–228, 2011.
Honzik T, Adamovicova M, Smolka V, et al: Clinical presentation and
metabolic consequences in 40 breastfed infants with nutritional vitamin B12
deficiency—what have we learned?, Eur J Paediatr Neurol 14:488–495,
2010.
Hudson B: Vitamin B-12 deficiency, BMJ 340:c2305, 2010.
Hunt A, Harrington D, Robinson S: Vitamin B12 deficiency, BMJ 349:g5226,
2014.
Lam JR, Schneider JL, Zhao W, et al: Proton pump inhibitor and histamine 2
receptor antagonist use and vitamin B12 deficiency, JAMA 310:2435–2442,
2013.
Pawlak R, Parrott SJ, Raj S, et al: How prevalent is vitamin B(12) deficiency among
vegetarians, Nutr Rev 71:110–117, 2013.
Stabler SP: Clinical practice. Vitamin B12 deficiency, N Engl J Med 368:149–160,
2013.
Strand TA, Taneja S, Ueland PM, et al: Cobalamin and folate status predicts mental
development scores in North Indian children 12-18 mo of age, Am J Clin Nutr
97:310–317, 2013.
Wang ZP, Shang XX, Zhao ZT: Low maternal vitamin B(12) is a risk factor for
neural tube defects: a meta-analysis, J Matern Fetal Neonatal Med 25:389–394,
2012.

Chapter 50  The early manifestations are irritability, loss of appetite, low-grade
Vitamin C (Ascorbic Acid)
Dheeraj Shah and H.P.S. Sachdev
Vitamin C is important for synthesis of collagen at the level of hydrox-
ylation of lysine and proline in precollagen. It is also involved in neu-
rotransmitter metabolism (conversion of dopamine to norepinephrine
and tryptophan to serotonin), cholesterol metabolism (conversion of
cholesterol to steroid hormones and bile acids), and the biosynthesis
of carnitine. Vitamin C functions to maintain the iron and copper
atoms, cofactors of the metalloenzymes, in a reduced (active) state.
Vitamin C is an important antioxidant (electron donor) in the aqueous
milieu of the body. Vitamin C enhances nonheme iron absorption, the
transfer of iron from transferrin to ferritin, and the formation of tet-
rahydrofolic acid and thus can affect the cellular and immunologic
functions of the hematopoietic system.
DIETARY NEEDS AND SOURCES
Humans depend on dietary sources for vitamin C. An adequate intake
is 40 mg for age 0-6 mo and 50 mg for age 6-12 mo. For older children,
the recommended dietary allowance is 15 mg for age 1-3 yr, 25 mg for
age 4-8 yr, 45 mg for age 9-13 yr, and 65-75 mg for age 14-18 yr. The
recommended dietary allowances during pregnancy and lactation are
85 mg/day and 120 mg/day, respectively. The requirement for vitamin
C is increased during infectious and diarrheal diseases. Children
exposed to smoking or environmental tobacco smoke also require
increased amounts of foods rich in vitamin C. The best food sources
of vitamin C are citrus fruits and fruit juices, peppers, berries, melons,
tomatoes, cauliflower, and green leafy vegetables. Vitamin C is easily
destroyed by prolonged storage, overcooking, and processing of foods.
Chapter 50  ◆  Vitamin C (Ascorbic Acid)  329
Absorption of vitamin C occurs in the upper small intestine by an
active process or by simple diffusion when large amounts are ingested.
Vitamin C is not stored in the body but is taken up by all tissues; the
highest levels are found in the pituitary and adrenal glands. The brain
ascorbate content in the fetus and neonate is manyfold higher than the
content in the adult brain, a finding probably related to its function in
neurotransmitter synthesis.
When a mother’s intake of vitamin C during pregnancy and lacta-
tion is adequate, the newborn will have adequate tissue levels of
vitamin C related to active placental transfer, subsequently maintained
by the vitamin C in breast milk or commercial infant formulas. Breast
milk contains sufficient vitamin C to prevent deficiency throughout
infancy. Infants consuming pasteurized or boiled animal milk are at
significant risk of developing deficiency if the other sources of vitamin
C are also lacking in the diet. Neonates whose feeding has been delayed
because of clinical condition can also suffer from ascorbic acid defi-
ciency. For patients on total parenteral nutrition, a parenteral dose of
80 mg/day is recommended for full-term infants and a parenteral dose
of 25 mg/kg/day is recommended for preterm infants. Children who
choose a limited diet or those on fad diets are at risk for vitamin C
deficiency.
DEFICIENCY
A deficiency of vitamin C results in the clinical presentation of scurvy,
the oldest nutritional deficiency disease to be recognized. Children fed
predominantly heat-treated (ultrahigh-temperature or pasteurized)
milk or unfortified formulas and not receiving fruits and fruit juices
are at significant risk for symptomatic disease. In scurvy, there is defec-
tive formation of connective tissues and collagen in skin, cartilage,
dentine, bone, and blood vessels, leading to their fragility. In the long
bones, osteoid is not deposited by osteoblasts, cortex is thin, and the
trabeculae become brittle and fracture easily.
Clinical Features
fever, musculoskeletal pain, and tenderness in the legs. These signs and
symptoms are followed by leg swelling—most marked at the knees and
the ankles—and pseudoparalysis. The infant might lie with the hips
and knees semiflexed and the feet rotated outward. Subperiosteal hem-
orrhages in the lower limb bones sometimes acutely increase the swell-
ing and pain, and the condition might mimic acute osteomyelitis or
arthritis. A “rosary” at the costochondral junctions and depression of
the sternum are other typical features (Fig. 50-1). The angulation of
scorbutic beads is usually sharper than the angulation of a rachitic
rosary. Gum changes are seen in older children after teeth have erupted
and are manifested as bluish purple, spongy swellings of the mucous
membrane, especially over the upper incisors (Fig. 50-2). Anemia, a
common finding in infants and young children with scurvy, is related
to impaired iron absorption and coexistent hematopoietic nutrient
deficiencies including iron, vitamin B12, and folate. Hemorrhagic
Figure 50-1 Scorbutic rosary. (Courtesy of Dr J.D. MacLean, McGill
Centre for Tropical Diseases, Montreal.)
330  Part VI  ◆  Nutrition
Figure 50-2 Gingival lesions in advanced scurvy. (From Nutrition,
ed 4, Kalamazoo, MI, 1980, The Upjohn Company, p. 80. Used with
permission of Pfizer, Inc.)
Figure 50-3 Perifollicular petechiae in scurvy. (From Weinsier RL,
Morgan SL: Fundamentals of clinical nutrition, St. Louis, 1993, Mosby,
p. 85.)
manifestations of scurvy include petechiae, purpura, and ecchymoses
at pressure points; epistaxis; gum bleeding; and the characteristic peri-
follicular hemorrhages (Fig. 50-3). Other manifestations are poor
wound and fracture healing, hyperkeratosis of hair follicles, arthralgia,
and muscle weakness.
Laboratory Findings and Diagnosis
The diagnosis of vitamin C deficiency is usually based on the charac-
teristic clinical picture, the radiographic appearance of the long bones,
and a history of poor vitamin C intake. The typical radiographic
changes occur at the distal ends of the long bones and are particularly
common at the knees. The shafts of the long bones have a ground-glass
appearance because of trabecular atrophy. The cortex is thin and
dense, giving the appearance of pencil outlining of the diaphysis
and epiphysis. The white line of Fränkel, an irregular but thickened
white line at the metaphysis, represents the zone of well-calcified car-
tilage. The epiphyseal centers of ossification also have a ground-glass
appearance and are surrounded by a sclerotic ring (Fig. 50-4). The
more specific but late radiologic feature of scurvy is a zone of rarefac-
tion under the white line at the metaphysis. This zone of rarefaction
(Trümmerfeld zone), a linear break in the bone that is proximal and
parallel to the white line, represents area of debris of broken-down
bone trabeculae and connective tissue. A Pelkan spur is a lateral pro-
longation of the white line and may be present at cortical ends. Epiph-
yseal separation can occur along the line of destruction, with either
linear displacement or compression of the epiphysis against the shaft
ZD
A B
Figure 50-4 Radiographs of a leg. A, An early scurvy “white line” is
visible on the ends of the shafts of the tibia and fibula; sclerotic rings
(Wimberger sign) are shown around the epiphyses of the femur and
tibia. B, More advanced scorbutic changes; zones of destruction (ZD)
are evident in the femur and tibia. Pelkan spur is also seen at the
cortical end.
(Fig. 50-5). Subperiosteal hemorrhages are not visible using plain
radiographs during the active phase of scurvy. However, during
healing the elevated periosteum becomes calcified and radiopaque
(Fig. 50-5), sometimes giving a dumbbell or club shape to the affected
bone. MRI can demonstrate acute as well as healing subperiosteal
hematomas along with periostitis, metaphyseal changes, and heteroge-
neous bone marrow signal intensity, even in absence of changes in
plain radiographs. Gelatinous transformation of bone marrow, on
aspiration, has been reported in children where the procedure was
done on suspicion of a malignancy.
Biochemical tests are not very useful in the diagnosis of scurvy,
because they do not reflect the tissue status. A plasma ascorbate con-
centration of <0.2 mg/dL usually is considered deficient. Leukocyte
concentration of vitamin C is a better indicator of body stores, but this
measurement is technically more difficult to perform. Leukocyte con-
centrations of ≤10 µg/108 white blood cells are considered deficient
and indicate latent scurvy, even in the absence of clinical signs of
deficiency. Saturation of the tissues with vitamin C can be estimated
from the urinary excretion of the vitamin after a test dose of ascorbic
acid. In healthy children, 80% of the test dose appears in the urine
within 3-5 hr after parenteral administration. Generalized nonspecific
aminoaciduria is common in scurvy, whereas plasma amino acid levels
remain normal.
Differential Diagnosis
Scurvy is often misdiagnosed as arthritis, osteomyelitis, nonaccidental
trauma (child abuse), or acrodynia. The early irritability and bone pain
are sometimes attributed to nonspecific pains or other nutritional defi-
ciencies. Copper deficiency results in a radiographic picture very
 CAL

SH

LD

CE

Figure 50-5 Large subperiosteal hematoma (SH) with areas of calci-

fication (CAL) is seen along the shaft of right femur of a child with
advanced scurvy. Epiphyseal separation is seen in both knees with
linear displacement (LD) in left and compression (CE) against the shaft
in right.

similar to that of scurvy. Henoch-Schönlein purpura, thrombocytope-

nic purpura, or leukemia is sometimes suspected in children present-
ing with hemorrhagic manifestations.

Treatment
Vitamin C supplements of 100-200 mg/day orally or parenterally
ensure rapid and complete cure. The clinical improvement is seen
within a week in most cases, but the treatment should be continued
for up to 3 mo for complete recovery.

Prevention
Breastfeeding protects against vitamin C deficiency throughout
infancy. In children consuming milk formula, fortification with vitamin
C must be ensured. Children consuming heat-treated milk should
consume adequate vitamin C–rich foods in infancy. Dietary or medici-
nal supplements are required in severely malnourished children, and
chronic debilitating conditions such as malignancies and neurologic
disorders.

TOXICITY
Daily intake of <2 g of vitamin C is generally without adverse effects
in adults. Larger doses can cause gastrointestinal problems, such as
abdominal pain and osmotic diarrhea. Megadoses of vitamin C should
be avoided in patients with a history of urolithiasis or conditions
related to excessive iron accumulation such as thalassemia and hemo-
chromatosis. There is a paucity of data regarding vitamin C toxicity in
children. The following values for tolerable upper intake levels are
extrapolated from data for adults based on body weight differences:
age 1-3 yr, 400 mg; age 4-8 yr, 650 mg; age 9-13 yr, 1,200 mg; and age
14-18 yr, 1,800 mg.

Bibliography is available at Expert Consult.


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256:23–25, 2012.
Brennan CM, Atkins KA, Druzgal CH, et al: Magnetic resonance imaging
appearance of scurvy with gelatinous bone marrow transformation, Skeletal
Radiol 41:357–360, 2012.
Carpenter KJ: The discovery of vitamin C, Ann Nutr Metab 61:259–264, 2012.
Choh CTP, Rai S, Abdelhamid M, et al: Unrecognised scurvy, BMJ 340:150–151,
2010.
Geber J, Murphy E: Scurvy in the Great Irish Famine: evidence of vitamin C
deficiency from a mid-19th century skeletal population, Am J Phys Anthropol
148:512–524, 2012.
Chapter 50  ◆  Vitamin C (Ascorbic Acid)  331.e1
Maggini S, Wenzlaff S, Hornig D: Essential role of vitamin C and zinc in child
immunity and health, J Int Med Res 38:386–414, 2010.
Monárrez-Espino J, López-Alarcón M, Greiner T: Randomized placebo-controlled
trial of guava juice as a source of ascorbic acid to reduce iron deficiency in
Tarahumara indigenous schoolchildren of northern Mexico, J Am Coll Nutr
30:191–200, 2011.
Oliveira KF, Cunha DF, Weffort VR: Analysis of serum and supplemented vitamin
C and oxidative stress in HIV-infected children and adolescents, J Pediatr
(Rio J) 87:517–522, 2011.
Schleicher RL, Carroll MD, Ford ES, et al: Serum vitamin C and the prevalence of
vitamin C deficiency in the United States: 2003-2004 National Health and
Nutrition Examination Survey (NHANES), Am J Clin Nutr 90:1252–1263, 2009.
 Chapter 51  ◆  Rickets and Hypervitaminosis D  331

Chapter 51 
Rickets and
Hypervitaminosis D
Larry A. Greenbaum

RICKETS
Bone consists of a protein matrix called osteoid and a mineral phase,
principally composed of calcium and phosphate, mostly in the form of
hydroxyapatite. Osteomalacia is present when there is inadequate min-
eralization of bone osteoid and occurs in children and adults. Rickets
is a disease of growing bone that is caused by unmineralized matrix at
the growth plates and occurs in children only before fusion of the
epiphyses. Because growth plate cartilage and osteoid continue to
expand but mineralization is inadequate, the growth plate thickens.
There is also an increase in the circumference of the growth plate and
the metaphysis, increasing bone width at the location of the growth
plates and causing some of the classic clinical manifestations, such as
widening of the wrists and ankles. There is a general softening of the
bones that causes them to bend easily when subject to forces such as
weight bearing or muscle pull. This softening leads to a variety of bone
deformities.
Rickets is principally caused by vitamin D deficiency (Table 51-1)
and was rampant in northern Europe and the United States during the
early years of the 20th century. Although this problem was largely cor-
rected through public health measures that provided children with
adequate vitamin D, rickets remains a persistent problem in developed
countries, with many cases still secondary to preventable nutritional
vitamin D deficiency. It remains a significant problem in developing
countries, and may be secondary to nutritional vitamin D deficiency
and inadequate intake of calcium.

Etiology
There are many causes of rickets (Table 51-2), including vitamin D
disorders, calcium deficiency, phosphorous deficiency, and distal renal
tubular acidosis.

Clinical Manifestations
Most manifestations of rickets are a result of skeletal changes (Table
51-3). Craniotabes is a softening of the cranial bones and can be
detected by applying pressure at the occiput or over the parietal bones.
The sensation is similar to the feel of pressing into a ping-pong ball
and then releasing. Craniotabes may also be secondary to osteogenesis
imperfecta, hydrocephalus, and syphilis. It is a normal finding in many
newborns, especially near the suture lines, but it typically disappears
within a few months of birth. Widening of the costochondral junctions
results in a rachitic rosary, which feels like the beads of a rosary as the
examiner’s fingers move along the costochondral junctions from rib to
rib (Fig. 51-1). Growth plate widening is also responsible for the
enlargement at the wrists and ankles. The horizontal depression along
the lower anterior chest known as Harrison groove occurs from
pulling of the softened ribs by the diaphragm during inspiration (Fig.
51-2). Softening of the ribs also impairs air movement and predisposes
patients to atelectasis and pneumonia.
There is some variation in the clinical presentation of rickets based
on the etiology. Changes in the lower extremities tend to be the domi-
nant feature in X-linked hypophosphatemic rickets. Symptoms sec-
ondary to hypocalcemia occur only in those forms of rickets associated
with decreased serum calcium (Table 51-4).
The chief complaint in a child with rickets is quite variable. Many
children present because of skeletal deformities, whereas others have
difficulty walking owing to a combination of deformity and weakness.
Other common presenting complaints include failure to thrive and
symptomatic hypocalcemia (see Chapter 572).
332  Part VI  ◆  Nutrition

Table 51-1 Physical and Metabolic Properties and Food Sources of the Vitamins (D, E, and K)
NAMES AND
SYNONYMS
VITAMIN D
Vitamin D3
(3-cholecalciferol),
which is synthesized in
the skin, and vitamin D2
(from plants or yeast)
are biologically
equivalent; 1 µg =
40 IU vitamin D
VITAMIN E
Group of related
compounds with similar
biologic activities;
α-tocopherol is the
most potent and the
most common form
VITAMIN K
Group of
naphthoquinones
with similar biologic
activities; K1
(phylloquinone) from
diet; K2 (menaquinones)
from intestinal bacteria
CNS, central nervous system; GI, gastrointestinal; UV, ultraviolet.
BIOCHEMICAL EFFECTS OF EFFECTS OF
CHARACTERISTICS ACTION DEFICIENCY EXCESS SOURCES
Fat-soluble, stable Necessary for GI Rickets in growing Hypercalcemia, Exposure to sunlight
to heat, acid alkali, absorption of children; which can cause (UV light); fish oils,
and oxidation; calcium; also osteomalacia; emesis, anorexia, fatty fish, egg yolks,
bile necessary for increases absorption hypocalcemia can pancreatitis, and vitamin D–
absorption; of phosphate; direct cause tetany and hypertension, fortified formula,
hydroxylation in the actions on bone, seizures arrhythmias, CNS milk, cereals, bread
liver and kidney including mediating effects, polyuria,
necessary for resorption nephrolithiasis,
biologic activity renal failure
Fat-soluble; readily Antioxidant; Red cell hemolysis in Unknown Vegetable oils, seeds,
oxidized by oxygen, protection of cell premature infants; nuts, green leafy
iron, rancid fats; bile membranes from posterior column vegetables,
acids necessary for lipid peroxidation and cerebellar margarine
absorption and formation of dysfunction;
free radicals pigmentary
retinopathy
Natural compounds Vitamin K–dependent Hemorrhagic Not established; Green leafy
are fat-soluble; proteins include manifestations; analogs (no vegetables, liver,
stable to heat and coagulation factors long-term bone longer used) certain legumes and
reducing agents; II, VII, IX, and X; and vascular health caused hemolytic plant oils; widely
labile to oxidizing proteins C, S, Z; anemia, jaundice, distributed
agent, strong acids, matrix Gla protein, kernicterus, death
alkali, light; bile osteocalcin
salts necessary for
intestinal absorption

Table 51-2 Causes of Rickets Table 51-3 Clinical Features of Rickets

VITAMIN D DISORDERS GENERAL
Nutritional vitamin D deficiency Failure to thrive
Congenital vitamin D deficiency Listlessness
Secondary vitamin D deficiency Protruding abdomen
Malabsorption Muscle weakness (especially proximal)
Increased degradation Fractures
Decreased liver 25-hydroxylase
Vitamin D–dependent rickets type 1 A and B HEAD
Vitamin D–dependent rickets type 2 A and B Craniotabes
Chronic kidney disease Frontal bossing
Delayed fontanel closure
CALCIUM DEFICIENCY Delayed dentition; caries
Low intake Craniosynostosis
Diet
Premature infants (rickets of prematurity) CHEST
Malabsorption Rachitic rosary
Primary disease Harrison groove
Dietary inhibitors of calcium absorption Respiratory infections and atelectasis*

PHOSPHORUS DEFICIENCY BACK

Inadequate intake Scoliosis
Premature infants (rickets of prematurity) Kyphosis
Aluminum-containing antacids Lordosis

RENAL LOSSES EXTREMITIES

X-linked hypophosphatemic rickets* Enlargement of wrists and ankles
Autosomal dominant hypophosphatemic rickets* Valgus or varus deformities
Autosomal recessive hypophosphatemic rickets (1 and 2)* Windswept deformity (combination of valgus deformity of 1 leg
Hereditary hypophosphatemic rickets with hypercalciuria with varus deformity of the other leg)
Overproduction of fibroblast growth factor-23 Anterior bowing of the tibia and femur
Tumor-induced rickets* Coxa vara
McCune-Albright syndrome* Leg pain
Epidermal nevus syndrome* HYPOCALCEMIC SYMPTOMS†
Neurofibromatosis* Tetany
Fanconi syndrome Seizures
Dent disease Stridor due to laryngeal spasm
Distal renal tubular acidosis
*These features are most commonly associated with the vitamin D–deficiency
*Disorders secondary to excess fibroblast growth factor-23. disorders.
†
These symptoms develop only in children with disorders that produce
hypocalcemia (see Table 51-4).
 Chapter 51  ◆  Rickets and Hypervitaminosis D  333

Radiology
Rachitic changes are most easily visualized on posteroanterior radio-
graphs of the wrist, although characteristic rachitic changes can be seen
at other growth plates (Figs. 51-3 and 51-4). Decreased calcification
leads to thickening of the growth plate. The edge of the metaphysis
loses its sharp border, which is described as fraying. The edge of the
metaphysis changes from a convex or flat surface to a more concave
surface. This change to a concave surface is termed cupping and is most
easily seen at the distal ends of the radius, ulna, and fibula. There is
widening of the distal end of the metaphysis, corresponding to the
clinical observation of thickened wrists and ankles, as well as the
rachitic rosary. Other radiologic features include coarse trabeculation
of the diaphysis and generalized rarefaction.
Diagnosis
Most cases of rickets are diagnosed based on the presence of classic
radiographic abnormalities. The diagnosis is supported by physical
examination findings (see Table 51-3) and a history and laboratory test
results that are consistent with a specific etiology.
Clinical Evaluation
Because the majority of children with rickets have a nutritional
deficiency, the initial evaluation should focus on a dietary history,
emphasizing intake of vitamin D and calcium. Most children in indus-
trialized nations receive vitamin D from formula, fortified milk, or
vitamin supplements. Along with the amount, the exact composition
of the formula or milk is pertinent, because rickets has occurred in
children given products that are called milk (e.g., soy milk) but are
deficient in vitamin D and/or minerals.
Cutaneous synthesis mediated by sunlight exposure is an important
source of vitamin D. It is important to ask about time spent outside,
sunscreen use, and clothing, especially if there may be a cultural reason
for increased covering of the skin. Because winter sunlight is ineffective
at stimulating cutaneous synthesis of vitamin D, the season is an addi-
tional consideration. Children with increased skin pigmentation are at
increased risk for vitamin D deficiency because of decreased cutaneous
synthesis.
The presence of maternal risk factors for nutritional vitamin D
deficiency, including diet and sun exposure, is an important consider-
ation when a neonate or young infant has rachitic findings, especially
if the infant is breastfed. Determining a child’s intake of dairy products,
the main dietary source of calcium, provides a general sense of calcium
intake. High dietary fiber can interfere with calcium absorption.
The child’s medication use is relevant, because certain medications,
such as the anticonvulsants phenobarbital and phenytoin, increase
degradation of vitamin D, and aluminum-containing antacids interfere
with the absorption of phosphate.
Malabsorption of vitamin D is suggested by a history of liver or
intestinal disease. Undiagnosed liver or intestinal disease should be
suspected if the child has gastrointestinal (GI) symptoms, although
occasionally rickets is the presenting complaint. Fat malabsorption is

Figure 51-2 Deformities in rickets showing curvature of the limbs,

Figure 51-1 Rachitic rosary in a young infant. potbelly, and Harrison groove.

Table 51-4 Laboratory Findings in Various Disorders Causing Rickets

DISORDER Ca Pi PTH 25-(OH)D 1,25-(OH)2D Alk Phos URINE Ca URINE Pi
Vitamin D deficiency N, ↓ ↓ ↑ ↓ ↓, N, ↑ ↑ ↓ ↑
Chronic kidney disease N, ↓ ↑ ↑ N ↓ ↑ N, ↓ ↓
Dietary Pi deficiency N ↓ N, ↓ N ↑ ↑ ↑ ↓
Tumor-induced rickets N ↓ N N RD ↑ ↓ ↑
Fanconi syndrome N ↓ N N RD or ↑ ↑ ↓ or ↑ ↑
Dietary Ca deficiency N, ↓ ↓ ↑ N ↑ ↑ ↓ ↑
↓, decreased; ↑, increased; ↑↑, extremely increased; 1,25-(OH)2D, 1,25-dihydroxyvitamin D; 25-OHD, 25-hydroxyvitamin D; ADHR, autosomal dominant
hypophosphatemic rickets; Alk Phos, alkaline phosphatase; ARHR, autosomal recessive hypophosphatemic rickets; Ca, calcium; HHRH, hereditary hypophosphatemic
rickets with hypercalciuria; N, normal; Pi, inorganic phosphorus; PTH, parathyroid hormone; RD, relatively decreased (because it should be increased given the
concurrent hypophosphatemia); VDDR, vitamin D–dependent rickets; XLH, X-linked hypophosphatemic rickets.
334  Part VI  ◆  Nutrition
A B
Figure 51-3 Wrist x-rays in a normal child (A) and in a child with rickets (B). The child with rickets has metaphyseal fraying and cupping of the
distal radius and ulna.
A B
Figure 51-4 X-rays of the knees in a 7 yr old girl with distal renal
tubular acidosis and rickets. A, At initial presentation, there is widening
of the growth plate and metaphysical fraying. B, Dramatic improvement
after 4 mo of therapy with alkali.
often associated with diarrhea or oily stools, and there may be signs or
symptoms suggesting deficiencies of other fat-soluble vitamins (A, E,
and K; see Chapters 48, 52, and 53).
A history of renal disease (proteinuria, hematuria, urinary tract
infections) is an additional significant consideration, given the impor-
tance of chronic kidney disease as a cause of rickets. Polyuria can occur
in children with chronic kidney disease or Fanconi syndrome.
Children with rickets might have a history of dental caries, poor
growth, delayed walking, waddling gait, pneumonia, and hypocalcemic
symptoms.
The family history is critical, given the large number of genetic
causes of rickets, although most of these causes are rare. Along with
bone disease, it is important to inquire about leg deformities, diffi­
culties with walking, or unexplained short stature, because some
parents may be unaware of their diagnosis. Undiagnosed disease in the
mother is not unusual in X-linked hypophosphatemia. A history of a
unexplained sibling death during infancy may be present in the child
with cystinosis, the most common cause of Fanconi syndrome in
children.
The physical examination focuses on detecting manifestations of
rickets (see Table 51-3). It is important to observe the child’s gait,
auscultate the lungs to detect atelectasis or pneumonia, and plot the
patient’s growth. Alopecia suggests vitamin D–dependent rickets
type 2.
The initial laboratory tests in a child with rickets should include
serum calcium, phosphorus, alkaline phosphatase, parathyroid hor­
mone (PTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D (1,25-
D), creatinine, and electrolytes (see Tables 51-4 and 51-5 for
interpretation). Urinalysis is useful for detecting the glycosuria and
aminoaciduria (positive dipstick for protein) seen with Fanconi syn-
drome. Evaluation of urinary excretion of calcium (24 hr collection for
calcium or calcium : creatinine ratio) is helpful if hereditary hypophos-
phatemic rickets with hypercalciuria or Fanconi syndrome is sus-
pected. Direct measurement of other fat-soluble vitamins (A, E, and
 Table 51-5 Biochemical Changes in Genetic Causes of Rickets
SERUM BIOCHEMISTRY URINE BIOCHEMISTRY
Phosphate Calcium PTH 250HD 1,250H2D FGF23 Alk Phos Phosphate Calcium OTHER FEATURES
HYPOCALCEMIC VITAMIN D PATHWAY DEFECTS
Vitamin D Low Variable High Low Might be NA Increased Increased Low Variable aminoaciduria
deficiency increased
VDDR1B Low Low High Very low Variable NA Increased Increased Low 250HD does not increase
after vitamin D dosing
VDDR1A Low Low High Normal or high Very low or NA Increased Increased Low 250HD does increase after
ND vitamin D dosing
VDDR2A Low Low High Normal or high High NA Increased Increased Low —
VDDR2B Low Low High Normal or high High NA Increased Increased Low —
HYPOPHOSPHATEMIC RICKETS WITH RAISED FGF23
XLH Low Normal Normal or Normal Low High Increased Increased Variable Urine calcium : creatinine
slightly high used in monitoring therapy
ADHR Low Normal Normal Normal Low High Increased Increased Variable —
ARHR1 Low Normal Normal Normal Low High Increased Increased Variable —
ARHR2 Low Normal Normal Normal Low High Increased Increased Variable —
HYPOPHOSPHATEMIC RICKETS WITHOUT RAISED FGF23
Dent’s Low Normal Normal Normal Normal Normal Increased Increased High Low molecular weight
disease* proteinuria
HHRH Low Normal Normal Normal Normal Normal Increased Increased High No loss of low molecular
weight protein
αKlotho Low Normal Normal Normal Normal Normal Increased Increased Variable —
mutation
OTHER INHERITED RACHITIC DISORDERS
HPP (severe) High High Low Normal Normal Normal Very low Normal or High Raised concentrations of
high mineralization inhibitors
HPP (mild) Normal or Normal Low or Normal Normal Normal Low Normal Variable Raised concentrations of
high or high normal mineralization inhibitors
From Elder CJ, Bishop NJ: Rickets. Lancet 383:1665-1674, 2014.
PTH, parathyroid hormone; 250HD, calcidiol; 1,2SOH2D, calcitriol; FGF23, fibroblast growth factor 23; Alk phos, alkaline phosphatase; NA, data not available; VDDR1B, vitamin D–dependent rickets due to defects in
CYP2R1 encoding vitamin D 25-hydroxylase; VDDR1A, vitamin D–dependent rickets due to defects in CYP27Bl encoding 25-hydroxyvitamin D-1alpha hydroxylase; ND, not detected; VDDR2A, vitamin D–dependent
rickets due to defects in VDR encoding the vitamin D receptor; VDDR2B, vitamin D–dependent rickets due to defects in HNRNPC encoding hnRNPC1 and hnRNPC2; XLH, X-linked hypophosphatemic rickets due to
mutations in PHEX; ADHR, autosomal dominant hypophosphatemic rickets due to mutations in FGF23; ARHR1, autosomal recessive hypophosphatemic rickets due to mutations in DMP1; ARHR2, autosomal recessive
hypophosphatemic rickets due to mutations in ENPP1; HHRH, hereditary hypophosphatemic rickets with hypercalciuria due to mutations in SLC34A3; HPP, hypophosphatasia.
*Dent’s disease is due to mutations in CLCN5.
Chapter 51  ◆  Rickets and Hypervitaminosis D  335
336  Part VI  ◆  Nutrition
K) or indirect assessment of deficiency (prothrombin time for vitamin
K deficiency) is appropriate if malabsorption is a consideration.
VITAMIN D DISORDERS
Vitamin D Physiology
Vitamin D can be synthesized in skin epithelial cells and therefore
technically is not a vitamin. Cutaneous synthesis is normally the most
important source of vitamin D and depends on the conversion of
7-dehydrochlesterol to vitamin D3 (3-cholecalciferol) by ultraviolet B
radiation from the sun. The efficiency of this process is decreased by
melanin; hence, more sun exposure is necessary for vitamin D synthe-
sis in people with increased skin pigmentation. Measures to decrease
sun exposure, such as covering the skin with clothing or applying
sunscreen, also decrease vitamin D synthesis. Children who spend less
time outside have reduced vitamin D synthesis. The winter sun away
from the equator is ineffective at mediating vitamin D synthesis.
There are few natural dietary sources of vitamin D. Fish liver oils
have a high vitamin D content. Other good dietary sources include
fatty fish and egg yolks. Most children in industrialized countries
receive vitamin D via fortified foods, especially formula and milk (both
of which contain 400 IU/L) and some breakfast cereals and breads.
Supplemental vitamin D may be vitamin D2 (which comes from plants
or yeast) or vitamin D3. Breast milk has a low vitamin D content,
approximately 12-60 IU/L.
Vitamin D is transported bound to vitamin D–binding protein
to the liver, where 25-hydroxlase converts vitamin D into 25-
hydroxyvitamin D (25-D), the most abundant circulating form of
vitamin D. Because there is little regulation of this liver hydroxylation
step, measurement of 25-D is the standard method for determining
a patient’s vitamin D status. The final step in activation occurs in
the kidney, where 1α-hydroxylase adds a second hydroxyl group,
resulting in 1,25-D. The 1α-hydroxylase is upregulated by PTH and
hypophosphatemia; hyperphosphatemia and 1,25-D inhibit this
enzyme. Most 1,25-D circulates bound to vitamin D–binding protein.
1,25-D acts by binding to an intracellular receptor, and the complex
affects gene expression by interacting with vitamin D–response ele-
ments. In the intestine, this binding results in a marked increase in
calcium absorption, which is highly dependent on 1,25-D. There is also
an increase in phosphorus absorption, but this effect is less significant
because most dietary phosphorus absorption is vitamin D indepen-
dent. 1,25-D also has direct effects on bone, including mediating
resorption. 1,25-D directly suppresses PTH secretion by the parathy-
roid gland, thus completing a negative feedback loop. PTH secretion
is also suppressed by the increase in serum calcium mediated by
1,25-D. 1,25-D inhibits its own synthesis in the kidney and increases
the synthesis of inactive metabolites.
Nutritional Vitamin D Deficiency
Vitamin D deficiency remains the most common cause of rickets glob-
ally and is prevalent, even in industrialized countries. Because vitamin
D can be obtained from dietary sources or from cutaneous synthesis,
most patients in industrialized countries have a combination of risk
factors that lead to vitamin D deficiency.
Etiology
Vitamin D deficiency most commonly occurs in infancy because of
a combination of poor intake and inadequate cutaneous synthesis.
Transplacental transport of vitamin D, mostly 25-D, typically provides
enough vitamin D for the 1st 2 mo of life unless there is severe mater-
nal vitamin D deficiency. Infants who receive formula receive adequate
vitamin D, even without cutaneous synthesis. Because of the low
vitamin D content of breast milk, breastfed infants rely on cutaneous
synthesis or vitamin supplements. Cutaneous synthesis can be limited
because of the ineffectiveness of the winter sun in stimulating vitamin
D synthesis; avoidance of sunlight because of concerns about cancer,
neighborhood safety, or cultural practices; and decreased cutaneous
synthesis because of increased skin pigmentation.
The effect of skin pigmentation explains why most cases of nutri-
tional rickets in the United States and northern Europe occur in
breastfed children of African descent or other dark-pigmented popu-
lations. The additional impact of the winter sun is supported by
the fact that such infants more commonly present in the late winter
or spring. In some groups, complete covering of infants or the prac-
tice of not taking infants outside has a significant role, explaining the
occurrence of rickets in infants living in areas of abundant sunshine,
such as the Middle East. Because the mothers of some infants can
have the same risk factors, decreased maternal vitamin D can also
contribute, both by leading to reduced vitamin D content in breast
milk and by lessening transplacental delivery of vitamin D. Rickets
caused by vitamin D deficiency can also be secondary to unconven-
tional dietary practices, such as vegan diets that use unfortified soy
milk or rice milk.
Clinical Manifestations
The clinical features are typical of rickets (see Table 51-3), with a sig-
nificant minority presenting with symptoms of hypocalcemia; pro-
longed laryngospasm is occasionally fatal. These children have an
increased risk of pneumonia and muscle weakness leading to a delay
in motor development.
Laboratory Findings
Tables 51-4 and 51-5 summarize the principal laboratory findings.
Hypocalcemia is a variable finding as a result of the actions of the
elevated PTH to increase the serum calcium concentration. The hypo-
phosphatemia is caused by PTH-induced renal losses of phosphate,
combined with a decrease in intestinal absorption.
The wide variation in 1,25-D levels (low, normal, or high) is second-
ary to the upregulation of renal 1α-hydroxylase caused by concomitant
hypophosphatemia and hyperparathyroidism. Because serum levels
of 1,25-D are much lower than the levels of 25-D, even with low levels
of 25-D there is still often enough 25-D present to act as a precursor
for 1,25-D synthesis in the presence of an upregulated 1α-hydroxylase.
The level of 1,25-D is only low when there is severe vitamin D
deficiency.
Some patients have a metabolic acidosis secondary to PTH-
induced renal bicarbonate wasting. There may also be generalized
aminoaciduria.
Diagnosis and Differential Diagnosis
The diagnosis of nutritional vitamin D deficiency is based on the com-
bination of a history of poor vitamin D intake and risk factors for
decreased cutaneous synthesis, radiographic changes consistent with
rickets, and typical laboratory findings (see Tables 51-4 and 51-5). A
normal PTH level almost never occurs with vitamin D deficiency and
suggests a primary phosphate disorder.
Treatment
Children with nutritional vitamin D deficiency should receive vitamin
D and adequate nutritional intake of calcium and phosphorus. There
are 2 strategies for administration of vitamin D. With stoss therapy,
300,000-600,000 IU of vitamin D are administered orally or intramus-
cularly as 2-4 doses over 1 day. Because the doses are observed, stoss
therapy is ideal in situations where adherence to therapy is question-
able. The alternative is daily, high-dose vitamin D, with doses ranging
from 2,000-5,000 IU/day over 4-6 wk. Either strategy should be fol-
lowed by daily vitamin D intake of 400 IU/day if <1 yr old or 600 IU/
day if >1 yr old. It is important to ensure that children receive adequate
dietary calcium and phosphorus; this dietary intake is usually provided
by milk, formula, and other dairy products.
Children who have symptomatic hypocalcemia might need intra-
venous calcium acutely, followed by oral calcium supplements, which
typically can be tapered over 2-6 wk in children who receive adequate
dietary calcium. Transient use of intravenous or oral 1,25-D (cal-
citriol) is often helpful in reversing hypocalcemia in the acute phase
by providing active vitamin D during the delay as supplemental
vitamin D is converted to active vitamin D. Calcitriol doses are
typically 0.05 µg/kg/day. Intravenous calcium is initially given as an
acute bolus for symptomatic hypocalcemia (20 mg/kg of calcium

chloride or 100 mg/kg of calcium gluconate). Some patients require
a continuous intravenous calcium drip, titrated to maintain the
desired serum calcium level. These patients should transition to
enteral calcium, and most infants require approximately 1,000 mg of
elemental calcium.
Prognosis
Most children have an excellent response to treatment, with radiologic
healing occurring within a few months. Laboratory test results should
also normalize rapidly. Many of the bone malformations improve dra-
matically, but children with severe disease can have permanent defor-
mities and short stature. Rarely, patients benefit from orthopedic
intervention for leg deformities, although this is generally not done
until the metabolic bone disease has healed, there is clear evidence that
the deformity will not self-resolve, and the deformity is causing func-
tional problems.
Prevention
Most cases of nutritional rickets can be prevented by universal admin-
istration of 400 IU of vitamin D to infants who are breastfed. Older
children should receive 600 IU/day. Vitamin D may be administered
as a component of a multivitamin or as a vitamin D supplement.
Congenital Vitamin D Deficiency
Congenital rickets is quite rare in industrialized countries and occurs
when there is severe maternal vitamin D deficiency during pregnancy.
Maternal risk factors include poor dietary intake of vitamin D, lack of
adequate sun exposure, and closely spaced pregnancies. These new-
borns can have symptomatic hypocalcemia, intrauterine growth retar-
dation, and decreased bone ossification, along with classic rachitic
changes. More subtle maternal vitamin D deficiency can have an
adverse effect on neonatal bone density and birthweight, cause a defect
in dental enamel, and predispose infants to neonatal hypocalcemic
tetany. Treatment of congenital rickets includes vitamin D supplemen-
tation and adequate intake of calcium and phosphorus. Use of prenatal
vitamins containing vitamin D prevents this entity.
Secondary Vitamin D Deficiency
Etiology
Along with inadequate intake, vitamin D deficiency can develop due
to inadequate absorption, decreased hydroxylation in the liver, and
increased degradation. Because vitamin D is fat-soluble, its absorption
may be decreased in patients with a variety of liver and GI diseases,
including cholestatic liver disease, defects in bile acid metabolism,
cystic fibrosis and other causes of pancreatic dysfunction, celiac
disease, and Crohn disease. Malabsorption of vitamin D can also occur
with intestinal lymphangiectasia and after intestinal resection.
Severe liver disease, which is usually also associated with malabsorp-
tion, can cause a decrease in 25-D formation as a consequence of insuf-
ficient enzyme activity. Because of the large reserve of 25-hydroxlase
activity in the liver, vitamin D deficiency as a result of liver disease
usually requires a loss of >90% of liver function. A variety of medica-
tions increase the degradation of vitamin D by inducing the cyto-
chrome P450 system. Rickets as a consequence of vitamin D deficiency
can develop in children receiving anticonvulsants, such as phenobar-
bital or phenytoin, or antituberculosis medications, such as isoniazid
or rifampin.
Treatment
Treatment of vitamin D deficiency attributable to malabsorption
requires high doses of vitamin D. Because of its better absorption, 25-D
(25-50 µg/day or 5-7 µg/kg/day) is superior to vitamin D3. The dose is
adjusted based on monitoring of serum levels of 25-D. Alternatively,
patients may be treated with 1,25-D, which also is better absorbed
in the presence of fat malabsorption, or with parenteral vitamin D.
Children with rickets as a result of increased degradation of vitamin
D by the cytochrome P450 system require the same acute therapy as
indicated for nutritional deficiency (discussed earlier), followed by
long-term administration of high doses of vitamin D (e.g., 1,000 IU/
Chapter 51  ◆  Rickets and Hypervitaminosis D  337
day), with dosing titrated based on serum levels of 25-D. Some patients
require as much as 4,000 IU/day.
Vitamin D–Dependent Rickets, Type 1
Children with vitamin D–dependent rickets type 1, an autosomal
recessive disorder, have mutations in the gene encoding renal
1α-hydroxylase, preventing conversion of 25-D into 1,25-D. These
patients normally present during the 1st 2 yr of life and can have any
of the classic features of rickets (see Table 51-3), including symptom-
atic hypocalcemia. They have normal levels of 25-D, but low levels of
1,25-D (see Table 51-5). Occasionally, 1,25-D levels are at the lower
limit of normal, inappropriately low given the high PTH and low
serum phosphorus levels, both of which should increase the activity of
renal 1α-hydroxylase and cause elevated levels of 1,25-D. As in nutri-
tional vitamin D deficiency, renal tubular dysfunction can cause a
metabolic acidosis and generalized aminoaciduria.
Treatment
These patients respond to long-term treatment with 1,25-D (calcitriol).
Initial doses are 0.25-2 µg/day, and lower doses are used once the
rickets has healed. Especially during initial therapy, it is important to
ensure adequate intake of calcium. The dose of calcitriol is adjusted to
maintain a low-normal serum calcium level, a normal serum phospho-
rus level, and a high-normal serum PTH level. Targeting a low-normal
calcium concentration and a high-normal PTH level avoids excessive
dosing of calcitriol, which can cause hypercalciuria and nephrocalci-
nosis. Hence, patient monitoring includes periodic assessment of
urinary calcium excretion, with a target of <4 mg/kg/day.
Vitamin D–Dependent Rickets, Type 2
Patients with vitamin D–dependent rickets type 2 have mutations in
the gene encoding the vitamin D receptor, preventing a normal physi-
ologic response to 1,25-D. Levels of 1,25-D are extremely elevated
in this autosomal recessive disorder (see Table 51-4). Most patients
present during infancy, although rickets in less severely affected
patients might not be diagnosed until adulthood. Less-severe disease
is associated with a partially functional vitamin D receptor. Approxi-
mately 50-70% of children have alopecia, which tends to be associated
with a more severe form of the disease and can range from alopecia
areata to alopecia totalis. Epidermal cysts are a less common
manifestation.
Treatment
Some patients respond to extremely high doses of vitamin D2, 25-D
or 1,25-D, especially patients without alopecia. This response is due
to a partially functional vitamin D receptor. All patients with this
disorder should be given a 3-6 mo trial of high-dose vitamin D and
oral calcium. The initial dose of 1,25-D should be 2 µg/day, but some
patients require doses as high as 50-60 µg/day. Calcium doses are
1,000-3,000 mg/day. Patients who do not respond to high-dose vitamin
D may be treated with long-term intravenous calcium, with possible
transition to very high dose oral calcium supplements. Treatment of
patients who do not respond to vitamin D is difficult.
Chronic Kidney Disease (See Chapter 535.2)
With chronic kidney disease, there is decreased activity of
1α-hydroxylase in the kidney, leading to diminished production of
1,25-D. In chronic kidney disease, unlike the other causes of vitamin
D deficiency, patients have hyperphosphatemia as a result of decreased
renal excretion (see Table 51-4).
Treatment
Therapy requires the use of a form of vitamin D that can act without
1-hydroxylation by the kidney (calcitriol), which both permits ade-
quate absorption of calcium and directly suppresses the parathyroid
gland. Because hyperphosphatemia is a stimulus for PTH secretion,
normalization of the serum phosphorus level via a combination of
dietary phosphorus restriction and the use of oral phosphate binders
is as important as the use of activated vitamin D.
338  Part VI  ◆  Nutrition
CALCIUM DEFICIENCY
Pathophysiology
Rickets secondary to inadequate dietary calcium is a significant
problem in some countries in Africa, although there are cases in other
regions of the world, including industrialized countries. Because breast
milk and formula are excellent sources of calcium, this form of rickets
develops after children have been weaned from breast milk or formula
and is more likely to occur in children who are weaned early. Rickets
develops because the diet has low calcium content, typically <200 mg/
day. There is little intake of dairy products or other sources of calcium.
In addition, because of reliance on grains and green leafy vegetables,
the diet may be high in phytate, oxalate, and phosphate, which decrease
absorption of dietary calcium. In industrialized countries, rickets
caused by calcium deficiency can occur in children who consume an
unconventional diet. Examples include children with milk allergy who
have low dietary calcium and children who transition from formula or
breast milk to juice, soda, or a calcium-poor soy drink, without an
alternative source of dietary calcium.
This type of rickets can develop in children who receive intrave-
nous nutrition without adequate calcium. Malabsorption of calcium
can occur in celiac disease, intestinal abetalipoproteinemia, and after
small bowel resection. There may be concurrent malabsorption of
vitamin D.
Clinical Manifestations
Children have the classic signs and symptoms of rickets (see Table
51-3). Presentation can occur during infancy or early childhood,
although some cases are diagnosed in teenagers. Because calcium defi-
ciency occurs after the cessation of breastfeeding, it tends to occur later
than the nutritional vitamin D deficiency that is associated with breast-
feeding. In Nigeria, nutritional vitamin D deficiency is most common
at 4-15 mo of age, whereas calcium-deficiency rickets typically occurs
at 15-25 mo of age.
Diagnosis
Laboratory findings include increased levels of alkaline phosphatase,
PTH, and 1,25-D (see Table 51-4). Calcium levels may be normal or
low, although symptomatic hypocalcemia is uncommon. There is
decreased urinary excretion of calcium, and serum phosphorus levels
may be low as a result of renal wasting of phosphate from secondary
hyperparathyroidism. In some children, there is coexisting nutritional
vitamin D deficiency, with low 25-D levels.
Treatment
Treatment focuses on providing adequate calcium, typically as a dietary
supplement (doses of 700 [1-3 yr age], 1,000 [4-8 yr age], 1,300 [9-18 yr
age] mg/day of elemental calcium are effective). Vitamin D supple-
mentation is necessary if there is concurrent vitamin D deficiency
(discussed earlier). Prevention strategies include discouraging early
cessation of breastfeeding and increasing dietary sources of calcium.
In countries such as Kenya, where many children have diets high in
cereal with negligible intake of cow’s milk, school-based milk programs
have been effective in reducing the prevalence of rickets.
PHOSPHOROUS DEFICIENCY
Inadequate Intake
With the exception of starvation or severe anorexia, it is almost impos-
sible to have a diet that is deficient in phosphorus, because phosphorus
is present in most foods. Decreased phosphorus absorption can occur
in diseases associated with malabsorption (celiac disease, cystic fibro-
sis, cholestatic liver disease), but if rickets develops, the primary
problem is usually malabsorption of vitamin D and/or calcium.
Isolated malabsorption of phosphorus occurs in patients with long-
term use of aluminum-containing antacids. These compounds are very
effective at chelating phosphate in the GI tract, leading to decreased
absorption. This decreased absorption results in hypophosphatemia
with secondary osteomalacia in adults and rickets in children. This
entity responds to discontinuation of the antacid and short-term phos-
phorus supplementation.
Fibroblast Growth Factor-23
Fibroblast growth factor-23 (FGF-23) is a humoral mediator that
decreases renal tubular reabsorption of phosphate and therefore
decreases serum phosphorus. FGF-23, synthesized by osteocytes, also
decreases the activity of renal 1α-hydroxylase, resulting in a decrease
in the production of 1,25-D. Increased levels of FGF-23 cause many of
the renal phosphate-wasting diseases (see Table 51-2).
X-Linked Hypophosphatemic Rickets
Among the genetic disorders causing rickets because of hypophospha-
temia, X-linked hypophosphatemic rickets (XLH) is the most common,
with a prevalence of 1/20,000. The defective gene is on the X chromo-
some, but female carriers are affected, so it is an X-linked dominant
disorder.
Pathophysiology
The defective gene is called PHEX because it is a PHosphate-regulating
gene with homology to Endopeptidases on the X chromosome. The
product of this gene appears to have an indirect role in inactivating
FGF-23. Mutations in the PHEX gene lead to increased levels of
FGF-23. Because the actions of FGF-23 include inhibition of phosphate
reabsorption in the proximal tubule, phosphate excretion is increased.
FGF-23 also inhibits renal 1α-hydroxylase, leading to decreased pro-
duction of 1,25-D.
Clinical Manifestations
These patients have rickets, but abnormalities of the lower extremities
and poor growth are the dominant features. Delayed dentition and
tooth abscesses are also common. Some patients have hypophosphate-
mia and short stature without clinically evident bone disease.
Laboratory Findings
Patients have high renal excretion of phosphate, hypophosphatemia,
and increased alkaline phosphatase; PTH and serum calcium levels are
normal (see Table 51-4). Hypophosphatemia normally upregulates
renal 1α-hydroxylase and should lead to an increase in 1,25-D, but
these patients have low or inappropriately normal levels of 1,25-D.
Treatment
Patients respond well to a combination of oral phosphorus and 1,25-D
(calcitriol). The daily need for phosphorus supplementation is 1-3 g of
elemental phosphorus divided into 4-5 doses. Frequent dosing helps
to prevent prolonged decrements in serum phosphorus because there
is a rapid decline after each dose. In addition, frequent dosing decreases
diarrhea, a complication of high-dose oral phosphorus. Calcitrol is
administered 30-70 ng/kg/day divided into 2 doses.
Complications of treatment occur when there is not an adequate
balance between phosphorus supplementation and calcitriol. Excess
phosphorus, by decreasing enteral calcium absorption, leads to sec-
ondary hyperparathyroidism, with worsening of the bone lesions. In
contrast, excess calcitriol causes hypercalciuria and nephrocalcinosis
and can even cause hypercalcemia. Hence, laboratory monitoring of
treatment includes serum calcium, phosphorus, alkaline phosphatase,
PTH, and urinary calcium, as well as periodic renal ultrasounds to
evaluate patients for nephrocalcinosis. Because of variation in the
serum phosphorus level and the importance of avoiding excessive
phosphorus dosing, normalization of alkaline phosphatase levels is a
more useful method of assessing the therapeutic response than mea-
suring serum phosphorus. For children with significant short stature,
growth hormone is an effective option. Children with severe deformi-
ties might need osteotomies, but these procedures should be done only
when treatment has led to resolution of the bone disease.
Prognosis
The response to therapy is usually good, although frequent dosing can
lead to problems with compliance. Girls generally have less-severe
disease than boys, probably because of the X-linked inheritance. Short
stature can persist despite healing of the rickets. Adults generally do
well with less-aggressive treatment, and some receive calcitriol alone.

Adults with bone pain or other symptoms improve with oral phospho-
rus supplementation and calcitriol.
Autosomal Dominant Hypophosphatemic
Rickets
Autosomal dominant hypophosphatemic rickets (ADHR) is much
less common than XLH. There is incomplete penetrance and variable
age of onset. Patients with ADHR have a mutation in the gene encod-
ing FGF-23 (FGF23). The mutation prevents degradation of FGF-23
by proteases, leading its level to increase. The actions of FGF-23
include decreased reabsorption of phosphate in the renal proximal
tubule, which results in hypophosphatemia, and inhibition of the 1α-
hydroxylase in the kidney, causing a decrease in 1,25-D synthesis.
In ADHR, as in XLH, abnormal laboratory findings are hypophos-
phatemia, an elevated alkaline phosphatase level, and a low or inap-
propriately normal 1,25-D level (see Table 51-4). Treatment is similar
to the approach used in XLH.
Autosomal Recessive Hypophosphatemic
Rickets
Autosomal recessive hypophosphatemic rickets (ARHR), type 1 is an
extremely rare disorder caused by mutations in the gene encoding
dentin matrix protein 1 (DMP1). ARHR, type 2 occurs in patients with
mutations in the ENPP1 gene. Mutations in ENPP1 also cause general-
ized arterial calcification of infancy. Both types of ARHR are associated
with elevated levels of FGF-23, leading to renal phosphate wasting,
hypophosphatemia, and low or inappropriately normal levels of 1,25-D.
Treatment is similar to the approach used in XLH, although monitoring
for arterial calcification is prudent in patients with ENPP1 mutations.
Hereditary Hypophosphatemic Rickets
with Hypercalciuria
Hereditary hypophosphatemic rickets with hypercalciuria is a rare dis-
order that is mainly found in the Middle East.
Pathophysiology
This autosomal recessive disorder is caused by mutations in the
gene for a sodium-phosphate cotransporter in the proximal tubule
(SLC34A3). The renal phosphate leak causes hypophosphatemia, which
then stimulates production of 1,25-D. The high level of 1,25-D increases
intestinal absorption of calcium, suppressing PTH. Hypercalciuria
ensues as a result of the high absorption of calcium and the low level
of PTH, which normally decreases renal excretion of calcium.
Clinical Manifestations
The dominant symptoms are rachitic leg abnormalities (see Table
51-3), muscle weakness, and bone pain. Patients can have short
stature, with a disproportionate decrease in the length of the lower
extremities. The severity of the disease varies, and some family
members have no evidence of rickets but have kidney stones secondary
to hypercalciuria.
Laboratory Findings
Laboratory findings include hypophosphatemia, renal phosphate
wasting, elevated serum alkaline phosphatase levels, and elevated
1,25-D levels. PTH levels are low (see Table 51-4).
Treatment
Therapy relies on oral phosphorus replacement (1-2.5 g/day of elemen-
tal phosphorus in 5 divided oral doses). Treatment of the hypophos-
phatemia decreases serum levels of 1,25-D and corrects the
hypercalciuria. The response to therapy is usually excellent, with reso-
lution of pain, weakness, and radiographic evidence of rickets.
Overproduction of FGF-23
Tumor-induced osteomalacia is more common in adults than in chil-
dren, where it can produce classic rachitic findings. Most tumors are
mesenchymal in origin and are usually benign, small, and located
in bone. These tumors secrete FGF-23 and produce a biochemical
Chapter 51  ◆  Rickets and Hypervitaminosis D  339
phenotype that is similar to XLH, including urinary phosphate wasting,
hypophosphatemia, elevated alkaline phosphatase levels, and low or
inappropriately normal 1,25-D levels (see Table 51-4). Curative treat-
ment is excision of the tumor. If the tumor cannot be removed, treat-
ment is identical to that used for XLH.
Renal phosphate wasting leading to hypophosphatemia and rickets
(or osteomalacia in adults) is a potential complication in McCune-
Albright syndrome, an entity that includes the triad of polyostotic
fibrous dysplasia, hyperpigmented macules, and polyendocrinopathy
(see Chapter 563.6). Affected patients have inappropriately low levels
of 1,25-D and elevated levels of alkaline phosphatase. The renal phos-
phate wasting and inhibition of 1,25-D synthesis are related to the
polyostotic fibrous dysplasia. Patients have elevated levels of FGF-23,
presumably produced by the dysplastic bone. Hypophosphatemic
rickets can also occur in children with isolated polyostotic fibrous
dysplasia. Although it is rarely possible, removal of the abnormal bone
can cure this disorder in children with McCune-Albright syndrome.
Most patients receive the same treatment as children with XLH.
Bisphosphonate treatment decreases the pain and fracture risk associ-
ated with the bone lesions.
Rickets is an unusual complication of epidermal nevus syndrome
(see Chapter 651). Patients have hypophosphatemic rickets due to
renal phosphate wasting and also have an inappropriately normal
or low level of 1,25-D as a consequence of excessive production
of FGF-23. The timing of presentation with rickets varies from infancy
to early adolescence. Resolution of hypophosphatemia and rickets
has occurred after excision of the epidermal nevi in some patients,
but not in others. In most cases, the skin lesions are too extensive
to be removed, necessitating treatment with phosphorus supple­
mentation and 1,25-D. Rickets caused by phosphate wasting is an
extremely rare complication in children with neurofibromatosis (see
Chapter 596.1).
Fanconi Syndrome
Fanconi syndrome is secondary to generalized dysfunction of the
renal proximal tubule (see Chapter 529.1). There are renal losses of
phosphate, amino acids, bicarbonate, glucose, urate, and other mole-
cules that are normally reabsorbed in the proximal tubule. Some
patients have partial dysfunction, with less generalized losses. The
most clinically relevant consequences are hypophosphatemia caused
by phosphate losses and proximal renal tubular acidosis caused by
bicarbonate losses. Patients have rickets as a result of hypophosphate-
mia, with exacerbation from the chronic metabolic acidosis, which
causes bone dissolution. Failure to thrive is a consequence of both
rickets and renal tubular acidosis. Treatment is dictated by the etiology
(see Chapter 529).
Dent Disease (See Chapter 531.3)
Dent disease is an X-linked disorder usually caused by mutations in
the gene encoding a chloride channel that is expressed in the kidney
(CLCN5). Some patients have mutations in the OCRL 1 gene, which
can also cause Lowe syndrome (see Chapter 530.1). Affected males
have variable manifestations, including hematuria, nephrolithiasis,
nephrocalcinosis, rickets, and chronic kidney disease. Almost all
patients have low-molecular-weight proteinuria and hypercalciuria.
Other, less universal abnormalities are aminoaciduria, glycosuria,
hypophosphatemia, and hypokalemia. Rickets occurs in approximately
25% of patients, and it responds to oral phosphorus supplements. Some
patients also need 1,25-D, but this treatment should be used cautiously
because it can worsen the hypercalciuria.
RICKETS OF PREMATURITY (See Chapter 106)
Rickets in very-low-birthweight infants has become a significant
problem, as the survival rate for this group of infants has increased.
Pathogenesis
The transfer of calcium and phosphorus from mother to fetus occurs
throughout pregnancy, but 80% occurs during the 3rd trimester. Pre-
mature birth interrupts this process, with rickets developing when the
340  Part VI  ◆  Nutrition
premature infant does not have an adequate supply of calcium and
phosphorus to support mineralization of the growing skeleton.
Most cases of rickets of prematurity occur in infants with a birth-
weight <1,000 g. It is more likely to develop in infants with lower
birthweight and younger gestational age. Rickets occurs because unsup-
plemented breast milk and standard infant formula do not contain
enough calcium and phosphorus to supply the needs of the premature
infant. Other risk factors include cholestatic jaundice, a complicated
neonatal course, prolonged use of parenteral nutrition, the use of soy
formula, and medications such as diuretics and corticosteroids.
Clinical Manifestations
Rickets of prematurity occurs 1-4 mo after birth. Infants can have
nontraumatic fractures, especially of the legs, arms, and ribs. Most
fractures are not suspected clinically. Because fractures and softening
of the ribs lead to decreased chest compliance, some infants have
respiratory distress due to atelectasis and poor ventilation. This rachitic
respiratory distress usually develops >5 wk after birth, distinguishing
it from the early-onset respiratory disease of premature infants. These
infants have poor linear growth, with negative effects on growth per-
sisting beyond 1 yr of age. An additional long-term effect is enamel
hypoplasia. Poor bone mineralization can contribute to dolichoceph-
aly. There may be classic rachitic findings, such as frontal bossing,
rachitic rosary, craniotabes, and widened wrists and ankles (see Table
51-3). Most infants with rickets of prematurity have no clinical mani-
festations, and the diagnosis is based on radiographic and laboratory
findings.
Laboratory Findings
Because of inadequate intake, the serum phosphorus level is low or
low-normal in rickets of prematurity. The renal response is appropri-
ate, with conservation of phosphate leading to a low urine phosphate
level; the tubular reabsorption of phosphate is >95%. Most patients
have normal levels of 25-D, unless there has been inadequate intake or
poor absorption (discussed earlier). The hypophosphatemia stimulates
renal 1α-hydroxylase, so levels of 1,25-D are high or high-normal.
These high levels can contribute to bone demineralization, because
1,25-D stimulates bone resorption. Serum levels of calcium are low,
normal, or high, and patients often have hypercalciuria. Elevated
serum calcium levels and hypercalciuria are secondary to increased
intestinal absorption and bone dissolution owing to elevation of 1,25-D
levels and the inability to deposit calcium in bone because of an inad-
equate phosphorus supply. The hypercalciuria indicates that phospho-
rus is the limiting nutrient for bone mineralization, although increased
provision of phosphorus alone often cannot correct the mineralization
defect; increased calcium is also necessary. Hence, there is an inade-
quate supply of calcium and phosphorus, but the deficiency in phos-
phorus is greater.
Alkaline phosphatase levels are often elevated, but some affected
infants have normal levels. In some instances, normal alkaline phos-
phatase levels may be secondary to resolution of the bone demineral-
ization because of an adequate mineral supply despite the continued
presence of radiologic changes, which take longer to resolve. However,
alkaline phosphatase levels may be normal despite active disease. No
single blood test is 100% sensitive for the diagnosis of rickets. The
diagnosis should be suspected in infants with an alkaline phosphatase
level that is >5-6 times the upper limit of normal for adults (unless
there is concomitant liver disease) or a phosphorus level <5.6 mg/dL.
The diagnosis is confirmed by radiologic evidence of rickets, which is
best seen on films of the wrists and ankles. Films of the arms and legs
might reveal fractures. The rachitic rosary may be visible on chest
x-ray. Unfortunately, x-rays cannot show early demineralization of
bone because changes are not evident until there is >20-30% reduction
in the bone mineral content.
Diagnosis
Because many premature infants have no overt clinical manifestations
of rickets, screening tests are recommended. These tests should
include weekly measurements of calcium, phosphorus, and alkaline
phosphatase. Periodic measurement of the serum bicarbonate concen-
tration is also important, because metabolic acidosis causes dissolution
of bone. At least 1 screening x-ray for rickets at 6-8 wk of age is appro-
priate in infants who are at high risk for rickets; additional films may
be indicated in very high risk infants.
Prevention
Provision of adequate amounts of calcium, phosphorus, and vitamin
D significantly decreases the risk of rickets of prematurity. Parenteral
nutrition is often necessary initially in very premature infants. In the
past, adequate parenteral calcium and phosphorus delivery was diffi-
cult because of limits secondary to insolubility of these ions when their
concentrations were increased. Current amino acid preparations allow
higher concentrations of calcium and phosphate, decreasing the risk
of rickets. Early transition to enteral feedings is also helpful. These
infants should receive either human milk fortified with calcium and
phosphorus or preterm infant formula, which has higher concentra-
tions of calcium and phosphorus than standard formula. Soy formula
should be avoided because there is decreased bioavailability of calcium
and phosphorus. Increased mineral feedings should continue until the
infant weighs 3-3.5 kg. These infants should also receive approximately
400 IU/day of vitamin D via formula and vitamin supplements.
Treatment
Therapy for rickets of prematurity focuses on ensuring adequate deliv-
ery of calcium, phosphorus, and vitamin D. If mineral delivery has
been good and there is no evidence of healing, then it is important to
screen for vitamin D deficiency by measuring serum 25-D. Measure-
ment of PTH, 1,25-D, and urinary calcium and phosphorus may be
helpful in some cases.
DISTAL RENAL TUBULAR ACIDOSIS
(See Chapter 530)
Distal renal tubular acidosis usually manifests with failure to thrive.
Patients have a metabolic acidosis with an inability to acidify the
urine appropriately. Hypercalciuria and nephrocalcinosis are typically
present. There are many possible etiologies, including autosomal reces-
sive and autosomal dominant forms. Rickets is variable, and it responds
to alkali therapy (see Fig. 51-4).
HYPERVITAMINOSIS D
Etiology
Hypervitaminosis D is secondary to excessive intake of vitamin D. It
can occur with long-term high intake or with a substantial, acute inges-
tion (see Table 51-1). Most cases are secondary to misuse of prescribed
or nonprescription vitamin D supplements, but other cases have been
secondary to accidental overfortification of milk, contamination of
table sugar, and inadvertent use of vitamin D supplements as cooking
oil. The recommended upper limits for long-term vitamin D intake are
1,000 IU for children <1 year old and 2,000 IU for older children and
adults. Hypervitaminosis D can also result from excessive intake of
synthetic vitamin D analogs (25-D, 1,25-D). Vitamin D intoxication is
never secondary to excessive exposure to sunlight, probably because
ultraviolet irradiation can transform vitamin D3 and its precursor into
inactive metabolites.
Pathogenesis
Although vitamin D increases intestinal absorption of calcium,
the dominant mechanism of the hypercalcemia is excessive bone
resorption.
Clinical Manifestations
The signs and symptoms of vitamin D intoxication are secondary
to hypercalcemia. GI manifestations include nausea, vomiting, poor
feeding, constipation, abdominal pain, and pancreatitis. Possible
cardiac findings are hypertension, decreased Q-T interval, and arrhyth-
mias. The central nervous system effects of hypercalcemia include
lethargy, hypotonia, confusion, disorientation, depression, psychosis,
hallucinations, and coma. Hypercalcemia impairs renal concentrating
mechanisms, which can lead to polyuria, dehydration, and hypernatre- Avoidance of sun exposure, including the use of sunscreen, is prudent.
mia. Hypercalcemia can also lead to acute renal failure, nephrolithiasis, The patient should also restrict calcium intake.
and nephrocalcinosis, which can result in chronic renal insufficiency.
Deaths are usually associated with arrhythmias or dehydration. Prognosis
Most children make a full recovery, but hypervitaminosis D may be
Laboratory Findings fatal or can lead to chronic kidney disease. Because vitamin D is stored
The classic findings in vitamin D intoxication are hypercalcemia and in fat, levels can remain elevated for months, necessitating regular
extremely elevated levels of 25-D (>150 ng/mL). Hyperphosphatemia monitoring of 25-D, serum calcium, and urine calcium.
is also common. PTH levels are appropriately decreased owing to
hypercalcemia. Hypercalciuria is universally present and can lead to Bibliography is available at Expert Consult.
nephrocalcinosis, which is visible on renal ultrasound. Hypercalcemia
and nephrocalcinosis can lead to renal insufficiency.
Surprisingly, levels of 1,25-D are usually normal. This may be a result
of downregulation of renal 1α-hydroxylase by the combination of low
PTH, hyperphosphatemia, and a direct effect of 1,25-D. There is evi-
dence indicating that the level of free 1,25-D may be high, owing to
displacement from vitamin D–binding proteins by 25-D. Nephrocalci-
nosis is often visible on ultrasound or CT scan. Anemia is sometimes
present; the mechanism is unknown.

Diagnosis and Differential Diagnosis

The diagnosis is based on the presence of hypercalcemia and an ele-
vated serum 25-D level, although children with excess intake of 1,25-D
or another synthetic vitamin D preparation have normal levels of 25-D.
With careful sleuthing, there is usually a history of excess intake of
vitamin D, although in some situations (overfortification of milk by a
dairy) the patient and family may be unaware.
The differential diagnosis of vitamin D intoxication focuses on
other causes of hypercalcemia. Hyperparathyroidism produces hypo-
phosphatemia, whereas vitamin D intoxication usually causes hyper-
phosphatemia. Williams syndrome is often suggested by phenotypic
features and accompanying cardiac disease. Idiopathic infantile
hypercalcemia occurs in children taking appropriate doses of vitamin
D. Subcutaneous fat necrosis is a common cause of hypercalcemia in
young infants; skin findings are usually present. The hypercalcemia of
familial benign hypocalciuric hypercalcemia is mild, asymptomatic,
and associated with hypocalciuria. Hypercalcemia of malignancy is an
important consideration. High intake of calcium can also cause hyper-
calcemia, especially in the presence of renal insufficiency. Questioning
about calcium intake should be part of the history in a patient with
hypercalcemia. Occasionally, patients are intentionally taking high
doses of calcium and vitamin D.

Treatment
The treatment of vitamin D intoxication focuses on control of hyper-
calcemia. Many patients with hypercalcemia are dehydrated as a result
of polyuria from nephrogenic diabetes insipidus, poor oral intake, and
vomiting. Rehydration lowers the serum calcium level via dilution and
corrects prerenal azotemia. The resultant increased urine output
increases urinary calcium excretion. Urinary calcium excretion is also
increased by high urinary sodium excretion. The mainstay of the initial
treatment is aggressive therapy with normal saline, often in conjunction
with a loop diuretic to further increase calcium excretion.
Normal saline, with or without a loop diuretic, is often adequate for
treating mild or moderate hypercalcemia. More significant hypercal-
cemia usually requires other therapies. Glucocorticoids decrease intes-
tinal absorption of calcium by blocking the action of 1,25-D. There is
also a decrease in the levels of 25-D and 1,25-D. The usual dosage of
prednisone is 1-2 mg/kg/24 hr.
Calcitonin, which lowers calcium by inhibiting bone resorption, is
a useful adjunct, but its effect is usually not dramatic. There is an excel-
lent response to intravenous or oral bisphosphonates in vitamin D
intoxication. Bisphosphonates inhibit bone resorption through their
effects on osteoclasts. Hemodialysis using a low or 0 dialysate calcium
can rapidly lower serum calcium in patients with severe hypercalcemia
that is refractory to other measures.
Along with controlling hypercalcemia, it is imperative to eliminate
the source of excess vitamin D. Additional sources of vitamin D such
as multivitamins and fortified foods should be eliminated or reduced.

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Ahmed SF, Franey C, McDevitt H, et al: Recent trends and clinical features of
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Beck-Nielsen SS, Brixen K, Gram J, et al: Mutational analysis of PHEX, FGF23,
DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets,
J Hum Genet 57:453–458, 2012.
Belenchia AM, Tosh AK, Hillman LS, et al: Correcting vitamin D insufficiency
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Carpenter TO: The expanding family of hypophosphatemic syndromes, J Bone
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 Chapter 52  ◆  Vitamin E Deficiency  341

Chapter 52 
Vitamin E Deficiency
Larry A. Greenbaum

Vitamin E is a fat-soluble vitamin and functions as an antioxidant, but

its precise biochemical functions are not known. Vitamin E deficiency
can cause hemolysis or neurologic manifestations and occurs in pre-
mature infants, in patients with malabsorption, and in an autosomal
recessive disorder affecting vitamin E transport. Because of its role as
an antioxidant, there is considerable research on the potential role of
vitamin E supplementation in chronic illnesses.

PATHOGENESIS
The term vitamin E denotes a group of 8 compounds with similar
structures and antioxidant activity. The most potent member of these
compounds is α-tocopherol, which is also the main form in humans.
The best dietary sources of vitamin E are vegetable oils, seeds, nuts,
green leafy vegetables, and margarine (see Table 51-1).
The majority of vitamin E is located within cell membranes, where
it prevents lipid peroxidation and the formation of free radicals. Other
antioxidants, such as ascorbic acid, enhance the antioxidant activity of
vitamin E. The importance of other functions of vitamin E is still being
delineated.
Premature infants are particularly susceptible to vitamin E defi-
ciency, because there is significant transfer of vitamin E during the last
trimester of pregnancy. Vitamin E deficiency in premature infants
causes thrombocytosis, edema, and hemolysis potentially causing
anemia. The risk of symptomatic vitamin E deficiency was increased
by the use of formulas for premature infants that had a high content
of polyunsaturated fatty acids (PUFAs). These formulas led to a high
content of PUFAs in red blood cell membranes, making them more
susceptible to oxidative stress, which could be ameliorated by vitamin
E. Oxidative stress was augmented by aggressive use of iron supple-
mentation; iron increases the production of oxygen radicals. The inci-
dence of hemolysis as a result of vitamin E deficiency in premature
infants decreased secondary to the use of formulas with a lower content
of PUFAs, less-aggressive use of iron, and provision of adequate
vitamin E.
Because vitamin E is plentiful in common foods, primary dietary
deficiency is rare except in premature infants and in severe, generalized
malnutrition. Vitamin E deficiency does occur in children with fat
malabsorption secondary to the need for bile acid for vitamin E
absorption. Although symptomatic disease is most common in chil-
dren with cholestatic liver disease, it can occur in patients with cystic
fibrosis, celiac disease, short-bowel syndrome, or Crohn disease. The
autosomal recessive disorder abetalipoproteinemia (see Chapter 86)
causes fat malabsorption, and vitamin E deficiency is a common
complication.
 In ataxia with isolated vitamin E deficiency (AVED), a rare
autosomal recessive disorder, there are mutations in the gene for
α-tocopherol transfer protein (TTPA). Patients with this disorder are
unable to incorporate vitamin E into lipoproteins before their release
from the liver, leading to reduced serum levels of vitamin E. There is
no associated fat malabsorption, and absorption of vitamin E from the
intestine occurs normally.
Children at risk for vitamin E deficiency as a result of malabsorption
should be screened for deficiency and given adequate vitamin E sup-
plementation. Vitamin preparations with high content of all of the
fat-soluble vitamins are available.
Bibliography is available at Expert Consult.

CLINICAL MANIFESTATIONS
A severe, progressive neurologic disorder occurs in patients with pro-
longed vitamin E deficiency. Clinical manifestations do not appear
until after 1 yr of age, even in children with cholestasis since birth.
Patients may have cerebellar disease, posterior column dysfunction,
and retinal disease. Loss of deep tendon reflexes is usually the initial
finding. Subsequent manifestations include limb ataxia (intention
tremor, dysdiadochokinesia), truncal ataxia (wide-based, unsteady
gait), dysarthria, ophthalmoplegia (limited upward gaze), nystagmus,
decreased proprioception (positive Romberg test), decreased vibratory
sensation, and dysarthria. Some patients have pigmentary retinopathy.
Visual field constriction can progress to blindness. Cognition and
behavior can also be affected. Myopathy and cardiac arrhythmias are
less-common findings.
In premature infants, hemolysis as a result of vitamin E deficiency
typically develops during the 2nd mo of life. Edema may also be
present.

LABORATORY FINDINGS
Serum vitamin E levels increase in the presence of high serum lipid
levels, even when vitamin E deficiency is present. Hence, vitamin E
status is best determined by measuring the ratio of vitamin E to serum
lipids; a ratio <0.8 mg/g is abnormal in older children and adults;
<0.6 mg/g is abnormal in infants <1 yr. Premature infants with hemo-
lysis caused by vitamin E deficiency also often have elevated platelet
counts.
Neurologic involvement can cause abnormal somatosensory evoked
potentials and nerve conduction studies. Abnormalities on electroreti-
nography can precede physical examination findings in patients with
retinal involvement.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Premature infants with unexplained hemolytic anemia after the 1st mo
of life, especially if thrombocytosis is present, either should be empiri-
cally treated with vitamin E or should have serum vitamin E and lipid
levels measured. Children with neurologic findings and a disease
that causes fat malabsorption should have their vitamin E status
evaluated.
Because children with AVED do not have symptoms of malabsorp-
tion, a correct diagnosis requires a high index of suspicion. Friedreich
ataxia has been misdiagnosed in some patients (see Chapter 597.1).
Children with unexplained ataxia should be screened for vitamin E
deficiency.

TREATMENT
For correction of deficiency in neonates, the dose of vitamin E is 25-50
units/day for 1 wk, followed by adequate dietary intake. Children with
deficiency as a result of malabsorption should receive 1 unit/kg/day,
with the dose adjusted based on levels; ongoing treatment is necessary.
Children with AVED normalize their serum vitamin E levels with high
doses of vitamin E and require ongoing treatment.

PROGNOSIS
The hemolytic anemia in infants resolves with correction of the vitamin
E deficiency. Some neurologic manifestations of vitamin E deficiency
may be reversible with early treatment, but many patients have little or
no improvement. Importantly, treatment prevents progression.

PREVENTION
Premature infants should receive sufficient vitamin E via formula or
breast milk fortifier and formula without a high content of PUFAs.

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supplementation increases markers of haemolysis in sickle cell anaemia patients:
a randomized, double-blind, placebo-controlled trial, Br J Haematol 160:688–
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Breidenassel C, Valtuena J, Gonzalez-Gross M, et al: Antioxidant vitamin status
(A, E, C, and beta-carotene) in European adolescents-the HELENA Study, Int J
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Kositamongkol S, Suthutvoravut U, Chongviriyaphan N, et al: Vitamin A and E
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Chapter 52  ◆  Vitamin E Deficiency  342.e1
Shneider BL, Magee JC, Bezerra JA, et al: Efficacy of fat-soluble vitamin
supplementation in infants with biliary atresia, Pediatrics 130:e607–e614, 2012.
Stagnaro-Green A, Pearce EN: Iodine and pregnancy: a call to action, Lancet
382:292–293, 2013.
Su HJ, Chang CH, Chen HL: Effects of vitamin C and E intake on peak expiratory
flow rate of asthmatic children exposed to atmospheric particulate matter, Arch
Environ Occup Health 68:80–86, 2013.
Vos MB, Colvin R, Belt P, et al: Correlation of vitamin E, uric acid, and diet
composition with histologic features of pediatric NAFLD, J Pediatr Gastroenterol
Nutr 54:90–96, 2012.
342  Part VI  ◆  Nutrition

Chapter 53 
Vitamin K Deficiency
Larry A. Greenbaum

Vitamin K is necessary for the synthesis of clotting factors II, VII, IX,
and X; deficiency of vitamin K can result in clinically significant bleed-
ing. Vitamin K deficiency typically affects infants, who experience a
transient deficiency related to inadequate intake, or patients of any age
who have decreased vitamin K absorption. Mild vitamin K deficiency
can affect long-term bone and vascular health (see Chapters 103.4 and
480).

PATHOGENESIS
Vitamin K is a group of compounds that have a common naphthoqui-
none ring structure. Phylloquinone, called vitamin K1, is present in a
variety of dietary sources, with green leafy vegetables, liver, and certain
legumes and plant oils having the highest content. Vitamin K1 is the
form used to fortify foods and as a medication in the United States.
Vitamin K2 is a group of compounds called menaquinones, which are
produced by intestinal bacteria. There is uncertainty regarding the
relative importance of intestinally produced vitamin K2. Menaqui-
nones are also present in meat, especially liver, and cheese. A mena-
quinone is used pharmacologically in some countries.
Vitamin K is a cofactor for γ-glutamyl carboxylase, an enzyme that
performs posttranslational carboxylation, converting glutamate resi-
dues in proteins to γ-carboxyglutamate (Gla). The Gla residues, by
facilitating calcium binding, are necessary for protein function.
The classic Gla-containing proteins involved in blood coagulation
that are decreased in vitamin K deficiency are factors II (prothrombin),
VII, IX, and X. Vitamin K deficiency causes a decrease in proteins C
and S, which inhibit blood coagulation, and protein Z, which also has
a role in coagulation. All of these proteins are made only in the liver,
except for protein S, a product of various tissues.
Gla-containing proteins are also involved in bone biology (e.g.,
osteocalcin and protein S) and vascular biology (matrix Gla protein
and protein S). Based on the presence of reduced levels of Gla, these
proteins appear more sensitive than the coagulation proteins to subtle
vitamin K deficiency. There is evidence suggesting that mild vitamin
K deficiency might have a deleterious effect on long-term bone strength
and vascular health.
Because it is fat soluble, vitamin K requires the presence of bile
salts for its absorption. Unlike other fat-soluble vitamins, there are
limited body stores of vitamin K. In addition, there is high turnover
of vitamin K, and the vitamin K–dependent clotting factors have a
short half-life. Hence, symptomatic vitamin K deficiency can develop
within weeks when there is inadequate supply because of low intake
or malabsorption.
There are 3 forms of vitamin K–deficiency bleeding (VKDB) of the
newborn (see Chapter 103.4). Early VKDB was formerly called classic
hemorrhagic disease of the newborn and occurs at 1-14 days of age.
Early VKDB is secondary to low stores of vitamin K at birth as a result
of the poor transfer of vitamin K across the placenta and inadequate
intake during the 1st few days of life. In addition, there is no intestinal
synthesis of vitamin K2 because the newborn gut is sterile. Early VKDB
occurs mostly in breastfed infants as a consequence of the low vitamin
K content of breast milk (formula is fortified). Delayed feeding is an
additional risk factor.
Late VKDB most commonly occurs at 2-12 wk of age, although
cases can occur up to 6 mo after birth. Almost all cases are in breastfed
infants because of the low vitamin K content of breast milk. An addi-
tional risk factor is occult malabsorption of vitamin K, as occurs in
children with undiagnosed cystic fibrosis or cholestatic liver disease
(e.g., biliary atresia, α1-antitrypsin deficiency). Without vitamin K pro-
phylaxis, the incidence is 4-10/100,000 newborns.
The third form of VKDB of the newborn occurs at birth or shortly
thereafter. It is secondary to maternal intake of medications (warfarin,
phenobarbital, phenytoin) that cross the placenta and interfere with
vitamin K function.
VKDB as a result of fat malabsorption can occur in children of any
age. Potential etiologies include cholestatic liver disease, pancreatic
disease, and intestinal disorders (celiac sprue, inflammatory bowel
disease, short-bowel syndrome). Prolonged diarrhea can cause vitamin
K deficiency, especially in breastfed infants. Children with cystic fibro-
sis are most likely to have vitamin K deficiency if they have pancreatic
insufficiency and liver disease.
Beyond infancy, low dietary intake by itself never causes vitamin K
deficiency. However, the combination of poor intake and the use of
broad-spectrum antibiotics that eliminate the intestine’s vitamin K2-
producing bacteria can cause vitamin K deficiency. This scenario is
especially common in the intensive care unit. Vitamin K deficiency can
also occur in patients who receive total parenteral nutrition without
vitamin K supplementation.
CLINICAL MANIFESTATIONS
In early VKDB, the most common sites of bleeding are the gastroin-
testinal (GI) tract, mucosal and cutaneous tissue, the umbilical stump,
and the postcircumcision site; intracranial bleeding is less common.
GI blood loss can be severe enough to require a transfusion. In con-
trast, the most common site of bleeding in late VKDB is intracranial,
although cutaneous and GI bleeding may be the initial manifestation.
Intracranial bleeding can cause convulsions, permanent neurologic
sequelae, or death. In some cases of late VKDB, the presence of an
underlying disorder may be suggested by jaundice or failure to thrive.
Older children with vitamin K deficiency can present with bruising,
mucocutaneous bleeding, or more serious bleeding.
LABORATORY FINDINGS
In patients with bleeding as a result of vitamin K deficiency, the pro-
thrombin time (PT) is prolonged. The PT must be interpreted based
on the patient’s age, because it is normally prolonged in newborns (see
Chapter 476). The partial thromboplastin time is usually prolonged,
but it may be normal in early deficiency; factor VII has the shortest
half-life of the coagulation factors and is the first to be affected by
vitamin K deficiency, but isolated factor VII deficiency does not affect
the partial thromboplastin time. The platelet count and fibrinogen level
are normal.
When there is mild vitamin K deficiency, the PT is normal, but there
are elevated levels of the undercarboxylated forms of the proteins that
are normally carboxylated in the presence of vitamin K. These under-
carboxylated proteins are called proteins induced by vitamin K absence
(PIVKA). Measurement of undercarboxylated factor II (PIVKA-II) can
be used to detect mild vitamin K deficiency. Determination of blood
vitamin K levels is less useful because of significant variation based on
recent dietary intake; levels do not always reflect tissue stores.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
The diagnosis is established by the presence of a prolonged PT that
corrects rapidly after administration of vitamin K, which stops the
active bleeding. Other possible causes of bleeding and a prolonged PT
include disseminated intravascular coagulation (DIC), liver failure,
and rare hereditary deficiencies of clotting factors. DIC, which is most
commonly secondary to sepsis, is associated with thrombocytopenia,
low fibrinogen, and elevated D-dimers. Most patients with DIC have
hemodynamic instability that does not correct with restoration of
blood volume. Severe liver disease results in decreased production
of clotting factors; the PT does not fully correct with administration
of vitamin K. Children with a hereditary disorder have a deficiency in
a specific clotting factor (I, II, V, VII, X).
Coumarin derivatives inhibit the action of vitamin K by preventing
its recycling to an active form after it functions as a cofactor for
γ-glutamyl carboxylase. Bleeding can occur with overdosage of the
commonly used anticoagulant warfarin or with ingestion of rodent
poison, which contains a coumarin derivative. High doses of salicylates
also inhibit vitamin K regeneration, potentially leading to a prolonged
PT and clinical bleeding.
TREATMENT
Infants with VKDB should receive 1 mg of parenteral vitamin K. The
PT should decrease within 6 hr and normalize within 24 hr. For rapid
correction in adolescents, the parenteral dose is 2.5-10 mg. In addition
to vitamin K, a patient with severe, life-threatening bleeding should
receive an infusion of fresh-frozen plasma, which corrects the coagu-
lopathy rapidly. Children with vitamin K deficiency as a consequence
of malabsorption require chronic administration of high doses of oral
vitamin K (2.5 mg twice/wk to 5 mg/day). Parenteral vitamin K may
be necessary if oral vitamin K is ineffective.
PREVENTION
Administration of either oral or parenteral vitamin K soon after birth
prevents early VKDB of the newborn. In contrast, a single dose of oral
vitamin K does not prevent a substantial number of cases of late VKDB.
However, a single intramuscular injection of vitamin K (1 mg), the
current practice in the United States, is almost universally effective,
except in children with severe malabsorption. This increased efficacy
of the intramuscular form is thought to be the result of a depot effect.
Concerns about an association between parenteral vitamin K at birth
and the later development of malignancy are unsubstantiated.
Discontinuing the offending medications before delivery can prevent
VKDB attributable to maternal medications. If this is not possible,
administration of vitamin K to the mother may be helpful. In addition,
the neonate should receive parenteral vitamin K immediately after
birth. If parenteral vitamin K does not correct the coagulopathy rapidly,
then the child should receive fresh frozen plasma.
Children who are at high risk for malabsorption of vitamin K should
receive supplemental vitamin K and periodic measurement of the PT.
Bibliography is available at Expert Consult.

Bibliography
Anderst JD, Carpenter SL, Abshire TC, et al: Evaluation for bleeding disorders in
suspected child abuse, Pediatrics 131:e1314–e1322, 2013.
Bauman ME, Black K, Bauman ML, et al: Warfarin induced coagulopathy in
children: assessment of a conservative approach, Arch Dis Child 96:164–167,
2011.
Busfield A, Samuel R, McNinch A, et al: Vitamin K deficiency bleeding after NICE
guidance and withdrawal of Konakion Neonatal: British Paediatric Surveillance
Unit study, 2006-2008, Arch Dis Child 98:41–47, 2013.
Krzyzanowska P, Ksiazyk J, Kocielinska-Klos M, et al: Vitamin K status in patients
with short bowel syndrome, Clin Nutr 31:1015–1017, 2012.
Chapter 53  ◆  Vitamin K Deficiency  343.e1
Mager DR, Qiao J, Turner J: Vitamin D and K status influences bone mineral
density and bone accrual in children and adolescents with celiac disease, Eur J
Clin Nutr 66:488–495, 2012.
Shneider BL, Magee JC, Bezerra JA, et al: Efficacy of fat-soluble vitamin
supplementation in infants with biliary atresia, Pediatrics 130:e607–e614,
2012.
Vanakker OM, De Coen K, Costrop L, et al: Functional polymorphism in
gamma-glutamylcarboxylase is a risk factor for severe neonatal hemorrhage,
J Pediatr 159:347–349, 2011.
Chapter 54  ◆  Micronutrient Mineral Deficiencies  343

Chapter 54 
Micronutrient Mineral
Deficiencies
Larry A. Greenbaum

Micronutrients include vitamins (see Chapters 48-53) and trace ele-

ments. By definition, a trace element is <0.01% of the body weight.
Trace elements have a variety of essential functions (Table 54-1). With
the exception of iron deficiency, trace element deficiency (see Table
54-1) is uncommon in developed countries, but some deficiencies
(iodine, zinc, selenium) are important public health problems in a
number of developing countries. Because of low nutritional require-
ments and plentiful supply, deficiencies of some of the trace elements
are extremely rare in humans and typically occur in patients receiving
344  Part VI  ◆  Nutrition

Table 54-1 Trace Elements

ELEMENT PHYSIOLOGY EFFECTS OF DEFICIENCY EFFECTS OF EXCESS DIETARY SOURCES
Chromium Potentiates the action of insulin Impaired glucose tolerance, Unknown Meat, grains, fruits,
peripheral neuropathy, and and vegetables
encephalopathy
Copper Absorbed via specific intestinal Microcytic anemia, osteoporosis, Acute: nausea, emesis, Vegetables, grains,
transporter neutropenia, neurologic abdominal pain, coma, and nuts, liver, margarine,
Circulates bound to symptoms, depigmentation of hepatic necrosis legumes, corn oil
ceruloplasmin hair and skin Chronic toxicity (liver and brain
Enzyme cofactor (superoxide injury) occurs in Wilson
dismutase, cytochrome disease (see Chapter 357.2)
oxidase, and enzymes involved and secondary to excess
in iron metabolism and intake (see Chapter 357.3)
connective tissue formation)
Fluoride Incorporated into bone Dental caries (see Chapter 312) Chronic: dental fluorosis Toothpaste,
(see Chapter 307) fluoridated water
Iodine Component of thyroid hormone Hypothyroidism (see Chapters Hypothyroidism and goiter Saltwater fish, iodized
(see Chapter 564) 566 and 568) (see Chapters 566 and 568); salt
maternal excess can cause
congenital hypothyroidism
and goiter (see Chapter 568.1)
Iron Component of hemoglobin, Anemia (see Chapter 456), Acute (see Chapter 63): nausea, Meat, fortified foods
myoglobin, cytochromes, and decreased alertness, impaired vomiting, diarrhea, abdominal Deficiency can also
other enzymes learning pain, and hypotension result from blood
Chronic excess usually loss (hookworm
secondary to hereditary infestation,
disorders (see Chapters 463.9 menorrhagia)
and 357.4); causes organ
dysfunction
Manganese Enzyme cofactor Hypercholesterolemia, weight Neurologic manifestations, Nuts, meat, grains, tea
loss, decreased clotting cholestatic jaundice
proteins*
Molybdenum Enzyme cofactor (xanthine Tachycardia, tachypnea, night Hyperuricemia and increased Legumes, grains, liver
oxidase and others) blindness, irritability, coma* risk of gout
Selenium Enzyme cofactor (prevents Cardiomyopathy (Keshan Nausea, diarrhea, neurologic Meat, seafood, whole
oxidative damage) disease), myopathy manifestations, nail and hair grains, garlic
changes, garlic odor
Zinc Enzyme cofactor Decreased growth, dermatitis of Abdominal pain, diarrhea, Meat, shellfish, whole
Constituent of zinc-finger extremities and around orifices, vomiting grains, legumes,
proteins, which regulate gene impaired immunity, poor Can worsen copper deficiency cheese
transcription wound healing, hypogonadism,
diarrhea
Supplements beneficial in
diarrhea and improve
neurodevelopmental outcomes
*These deficiency states have been reported only in case reports associated with parenteral nutrition or highly unusual diets.

unusual diets or prolonged total parenteral nutrition without adequate
delivery of a specific trace element. They can also occur in children
with short bowel or malabsorption. Excess intake of trace elements (see
Table 54-1) is uncommon, but it can result from environmental expo-
sure or overuse of supplements.
For a number of reasons, children are especially susceptible to trace
element deficiency. First, growth creates an increased demand for
most trace elements. Second, some organs are more likely to sustain
permanent damage because of trace element deficiency during child-
hood. The developing brain is particularly vulnerable to the conse-
quences of certain deficiency states (iron, iodide). Similarly, adequate
fluoride is most critical for dental health during childhood. Third,
children, especially in the developing world, are more prone to gastro-
intestinal disorders that can cause trace element deficiencies because
of malabsorption.
A normal diet provides adequate intake of most trace elements.
However, the intake of certain trace elements varies significantly in
different geographic locations. Iodide-containing food is plentiful near
the ocean, but inland areas often have inadequate sources, leading to
goiter and hypothyroidism. Iodine deficiency is not a problem in the
United States because of the widespread use of iodized salt; however,
symptomatic iodine deficiency (goiter and hypothyroidism) is common
in many developing countries. Selenium content of the soil and con-
sequently of food is also quite variable. Dietary selenium deficiency
(associated with cardiomyopathy) occurs in certain locations, such as
some parts of China.
The consequences of severe isolated trace mineral deficiency are
illustrated in certain genetic disorders. The manifestations of Menkes
disease (see Chapters 357.5 and 599) are caused by a mutation in the
gene coding for a protein that facilitates intestinal copper absorption.
This mutation results in severe copper deficiency; subcutaneous copper
is an effective treatment. The recessive disorder acrodermatitis entero-
pathica (see Chapter 671) is secondary to malabsorption of zinc. These
patients respond dramatically to zinc supplementation.
Children can have apparently asymptomatic deficiencies of certain
trace elements but still benefit from supplementation. As an example,
zinc is highly effective in treating children before or during diarrheal
illnesses in the developing world.

Zinc deficiency is quite common in the developing world and is
often associated with malnutrition or other micronutrient deficiencies
(iron). Chronic zinc deficiency is associated with dwarfism, hypogo-
nadism, dermatitis, and T-cell immunodeficiency. Diets rich in phy-
tates bind zinc, impairing its absorption. Zinc supplementation in
at-risk children reduces the incidence and severity of diarrhea,
Chapter 54  ◆  Micronutrient Mineral Deficiencies  345
pneumonia, and possibly malaria. In developing countries, children
who have diarrhea may benefit from zinc supplementation, especially
if there is underlying malnutrition.
Bibliography is available at Expert Consult.