Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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indirectly (e.g., changing substrate for DNA synthe-

sis, altering energy metabolism, changing physio-

logical integrity of cells, altering the synthesis and

release of cytokines/hormones, or changing the sensi-

tivity of target tissues to various mediators). These

changes have widespread effects on lipid, carbo-

hydrate, and protein metabolism.

0013 Knowledge of the importance of nutrition to the

functioning of the immune system has led to several

practical applications. These include the use of im-

munological tests: as prognostic indexes in surgical

patients, for assessing nutritional status, and for

measuring the efficacy and adequacy of nutritional

therapy. However, our knowledge of the effects of

nutrition on immune function now extends beyond

clinical nutrient deficiency, and there is a growing

body of literature demonstrating the immune benefits

of increasing the intake of specific foods and nutrients.

Nutritional Management of Infectious

Disease

0014 Many interventions are possible to reduce the effect

of infection on morbidity and mortality. Prevention of

disease through sanitation, vector control, promotion

of breast-feeding, and vaccination is crucial. Appro-

priate treatment of infections (e.g., antibiotics) as well

as supportive nutritional therapy during and after

recovery is also important. However, once the stress

response has been activated, and inflammatory

mediators released, it is unlikely that nutritional inter-

vention alone can stop this process. It was not until

1980 that the first prospective randomized clinical

trial was reported that clearly demonstrated that

nutritional intervention could improve patient sur-

vival and reduce infectious incidences. Maintaining

nutritional status is an essential component of the

management of infectious illness. Recent advances

in our understanding of the role of specific nutrients

in modulating immunity and inflammation have

stimulated the development of diets and supplements

aimed at improving recovery from trauma and critical

illness.

0015Even when efforts are made to maintain intake and

nutritional status during illness, the anorexia associ-

ated with infections, even those as mild as those

produced with immunization, is a major obstacle.

As measured by the occurrence of infectious compli-

cations, most clinical studies find that the enteral

(oral) route of providing nutrition is superior to the

parenteral (intervenous) route. Reasons for this phe-

nomenon are not clear, but it appears that enteral

nutrition supports the gut barrier and gut-associated

lymphoid tissue. However, when nutrient intake via

the enteral route is not possible, total parenteral

nutrition (TPN) has become a life-saving therapy to

meet the nutritional needs of patients.

0016In the management of sepsis, the most severe

complication of infectious disease, the effects of the

resulting hypermetabolism can be at least partly

thwarted through delivery of enteral nutrients. The

introduction of hyperalimentation, together with a

diet high in protein content, has been shown to

improve survival by decreasing the number of septic

episodes. General considerations for the nutritional

management of infection are listed in Table 2 and the

need for specific nutrients are discussed below.

Energy

0017During starvation, there is a specific adaptive re-

sponse that is designed to preserve lean body mass.

However, during the stress response, hormones, cyto-

kines, and inflammatory mediators heavily influence

the way in which energy substrates are metabolized.

Energy substrates are mobilized to support inflam-

mation, repair of tissues, and maintenance of immune

function, usually at the expense of lean body tissues.

Lean tissue is broken down to its constituent amino

acids, which provide precursors for the synthesis of

glucose in the liver (gluconeogenesis).

0018Resting energy consumption during sepsis is

reported to increase as much as 30–40%. Thus, pro-

viding additional energy to meet the increased needs

during infection and fever is an essential part of

nutritional management. The energy needs of adult

patients are usually based on estimations of energy

tbl0002 Table 2 General considerations for the nutritional management of infection

Attempts should be made to prevent chronic or multiple bouts of even mild infections. The cumulative effects of repeated infections

result in a greater net energy deficit than one infectious episode

Encourage breast-feeding, as it is a useful and cost-efficient dietary intervention to prevent infections diseases in small children

Begin feeding early in acute infection, as it has been shown to have a significant, positive effect on the course of the disease

Efforts should be made to continue provision of nutrition during mild or moderate episodes of common infections, including diarrhea

Repletion of nutrients lost during the acute phase of infection will require high intakes of most nutrients for extended periods of time.

Above-normal nutrient requirements continue after normalization of the clinical manifestations of infection

After an infectious episode, the energy density of habitual diets should be assessed, to determine if they can sustain recovery

growth after common illnesses. Enrichment or supplementation may be required. Patients with chronic infections and a poor

appetite may require supplemental feeding of high-energy formulas, either orally or by tube

3310 INFECTION, FEVER, AND NUTRITION

expenditure by the Harris–Benedict equation, with

the addition of energy losses or increased require-

ments due to the infection. The metabolic needs of

any other underlying disease and the effects of drugs

used to treat infection should also be considered in

estimating energy requirements. In children, dietary

intake during infection and recovery must be suffi-

cient to sustain rates of growth that may be several

times higher than in healthy children of the same age

(catch-up growth). Most studies have found little

correlation between dietary protein intake at ad-

equate ranges and rate of weight gain, while there is

a clear association between energy intake and

nitrogen accretion.

Protein

0019 Acute infection has a negative impact on nitrogen

balance. It has been estimated that approximately

45 g of protein is required daily during a severe infec-

tion just to support the increased synthetic demand by

immune cells and related tissues. Amino acids from

skeletal muscle, skin and possibly bone are released to

provide substrate for the synthesis of cells and pro-

teins associated with the response to infection. This

biosynthetic response by the host is choreographed by

the cytokines, which both stimulate catabolism of

protein stores and reduce the availability of amino

acids for other processes in the body. The specific

effect of infection on muscle protein loss varies

depending on the causative agent and the initial nu-

tritional status of the host. In the well-nourished host,

mild infection is associated with an increased protein

turnover. However, in a more chronic and prolonged

infection, the modest rise in protein synthesis, is over-

come by the marked increase in the rate of protein

breakdown. Additionally, chronic diarrhea, intestinal

parasitism, and protein-losing enteropathy can result

in additional protein losses.

0020 Most often, the supply of amino acids from the diet

does match the increased demand during an infection,

and this results in depletion of body stores. The in-

hibitory effects of infection upon growth, pregnancy,

and lactation are well recognized. During infection-

induced weight loss, there are reductions in the

plasma concentrations of sulfur amino acids, glycine,

serine, and taurine. These amino acids are found in

high concentrations in many compounds associated

with immune and inflammatory responses, most

notably cytokines, glutathione, metallothionein, and

acute-phase proteins. Early provision of sufficient

calories and protein has proven beneficial and is

now a common feeding protocol in critically ill pa-

tients. However, it has been reported that, apparently,

adequate nutritional support in the presence of a

severe inflammatory stimulus only attenuates the

gluconeogenic process and the breakdown of lean

tissue continues.

Fat

0021Hypertriglyceridemia, resulting from accelerated

fat mobilization from stores, decreased clearance,

increased synthesis, and/or release from the liver, is

characteristic of septic patients. Additionally, studies

have shown fatty acids to undergo inefficient cycling

between organs, which may also contribute to the

elevated metabolic rate. Thus, the energy that, under

normal circumstances, can be obtained from a con-

centrated energy source such as fat is reduced. At

present, there are limited clinical data to support

that providing additional calories in the form of fat

will be beneficial during infections.

0022Metabolic pathways for de novo synthesis of fatty

acids may be impaired during stress states, and sup-

plementation of certain fatty acids in the diet may be

required. The dietary requirements for specific fatty

acids during infection are not known, and this issue is

heavily debated. Studies have demonstrated that feed-

ing specific fatty acids can impact on oxidation, me-

tabolism, and the inflammatory response. At present,

however, the extent to which fatty acid metabolism,

particularly that of the essential fatty acids, is altered

during infection and cancer and the ability to improve

patient outcome with supplementation of fatty acids

in the diet are not known.

0023Extensive studies carried out, mostly with animal

models, feeding different amounts and types of fats

have shown that fatty acid content of the diet affects

most immune functions. In general, fats rich in n-3

polyunsaturated or monounsaturated fatty acids sup-

press inflammation, and fats rich in n-6 polyunsatur-

ated fatty acids exert the opposite effect. The ability

of inflammatory cells, such as macrophages, to pro-

duce cytokines may also be influenced in a similar

manner by feeding different fatty acids. Adding n-3

fatty acids to the diet have been shown to suppress the

thermic (fever) response to experimental infection.

There are a number of levels at which fats may

modify host defense and cytokine biology. Most

relate to the ability of fats to change the fatty acid

composition of membrane phospholipids. Subse-

quently, changes in membrane lipid composition

will change cell signaling, gene expression, and the

synthesis and release of inflammatory mediators,

which will modify the intensity of the inflammatory

response.

Vitamins

0024Vitamins and minerals play widespread and complex

roles in the response to fever and infection. Some of

these micronutrients are incorporated into substances

INFECTION, FEVER, AND NUTRITION 3311

that are released during the response to infection,

others are components of antioxidant defense, while

others support the response by the host.

0025 Vitamin A The role of vitamin A deficiency in vul-

nerability to infection was recognized early in the

twentieth century. The impact of vitamin A deficiency

on increasing the susceptibility to, and severity of,

infections is related to its essential functions in me-

tabolism, glycoprotein synthesis, cellular differenti-

ation, and immune function. Vitamin A deficiency is

associated with impaired T-cell, B-cell, and neutro-

phil function and decreased epithelial defense against

bacterial invasion. Lower serum levels of both carot-

ene (provitamin A) and vitamin A have been reported

during various infections, including hookworm, acute

respiratory infections, gastroenteritis, and measles.

Intestinal infections reduce the absorption of vitamin

A from the diet and can precipitate the clinical

appearance of xerophthalmia and keratomalacia in

those who have a marginal vitamin A status.

0026 The efficacy of vitamin A supplementation during

infections has been examined in randomized, double-

blind, placebo-controlled trials of malnourished

children in various regions of the developing world.

Supplementation with this vitamin is reported to

improve the response to measles vaccines, maintain

the health and barrier function of the intestine, lower

the incidence of respiratory-tract infections, and

reduce mortality associated with diarrhea and

measles. The World Health Organization currently

recommends that vitamin A be given to all individuals

who develop measles in developing countries,

whether or not they have symptoms of vitamin A

deficiency. There are also clinical data suggesting

that vitamin A deficiency in HIV-1-infected individ-

uals contributes to increased mortality, disease pro-

gression, and a higher rate of maternal–infant disease

transfer.

0027 Excessive intakes of vitamin A are potentially toxic

in humans. Although there has been little work on the

relationship to infection in humans, chronic mega-

dosing with vitamin A increases the susceptibility

to infectious organisms, suppressed hematopoiesis,

T-cell proliferation, and antigen-specific antibody

production in animals.

0028 B vitamins A clinical deficiency of thiamin (beriberi)

or niacin (pellagra) is associated with an increased risk

of infections. The B vitamins are involved in energy

and protein metabolism and are needed for cell div-

ision and the formation of both red and white blood

cells. Although there are no specific requirements for

these nutrients determined during infection, the in-

crease in metabolic rate and immune activity that

occurs during an infection would likely increase

their requirement above that of a healthy individual.

0029Vitamin C The essentiality of vitamin C (ascorbic

acid) to protection from infections is most clearly

illustrated during its clinical deficiency disease

(scurvy), where immunosuppression and infections

almost always occur. Poor vitamin C status results

in a loss of integrity of epithelia and impaired bacteri-

cidal capacity of neutrophils. Vitamin C is highly

concentrated in leukocytes and is rapidly utilized

during infection (e.g., to prevent oxidative damage).

Reductions in vitamin C levels in plasma have been

reported during even mild infections such as the

common cold and after immunization against small-

pox and measles. A reduced concentration of this

vitamin in leukocytes is associated with reduced

immune function.

0030The immune system is a major producer of reactive

oxygen radicals and is particularly sensitive to oxida-

tive stress. The actions of vitamin C as a reducing

agent and oxygen-radical quencher are well estab-

lished. If these oxidants are not rapidly neutralized,

they can inhibit chemotaxis, phagocytosis, and other

antimicrobial activities of immune cells. There has

been a long-standing debate concerning the possible

function of high doses of vitamin C in ‘boosting’

immunity to combat infections. Supplementation of

this vitamin was recently reported to reduce the

incidence of respiratory infections in ultramarathon

runners. The results of animal studies and a few

human studies have suggested that the function of

T-cells and neutrophils and antiviral resistance are

increased with large intakes of vitamin C. Since the

early interest and advocacy by Linus Pauling, subse-

quent studies on megadosing with vitamin C have not

unequivocally shown that vitamin C can prevent

and/or treat upper respiratory-tract infections. Some

experts suggest that positive effects of vitamin C sup-

plementation, in early efficacy studies, were compli-

cated by the use of a mixture of antioxidant nutrients,

not controlling for physical stress or studying subjects

with low overall nutritional intakes.

0031Unlike many other dietary antioxidants, even when

consumed at very high levels (5000 mg day

1

), vita-

min C appears to be safe. However, one might still

remain cautious, as some in vitro experiments dem-

onstrate that very high levels of vitamin C suppress

the T-cell and neutrophil response to infectious agents.

0032Vitamin E Vitamin E-deficient rats demonstrate an

enhanced inflammatory response to endotoxins and

addition of the vitamin to their diet suppressed this

effect. Vitamin E supplementation has been shown to

increase T-cell response, reduce the production of

3312 INFECTION, FEVER, AND NUTRITION

some inflammatory/stress cytokines, and improve the

ability of macrophages to destroy bacteria. Although

the data are still limited, there is evidence that vitamin

E may play roles beyond basic nutrition function to

aid in host defense to infection.

Minerals

0033 Dramatic changes in mineral distribution occur at the

outset of infections, with particularly striking shifts

of iron and zinc to intracellular compartments. Be-

cause iron and zinc are essential for growth and repli-

cation of microorganisms, it is possible that the rapid

decrease in circulating iron and zinc during infections

would limit the supply of these essential minerals

for the invading pathogens. The importance of this

nutrient as a host strategy to deprive the invading

pathogens of the essential divalent cationic factors

they need to thrive is controversial, as these nutrients

are also essential to the host.

0034 Iron Experimental and clinical data suggest that

there is an increased risk of infection in the presence

of iron-deficient anemia, although a small number of

reports indicate otherwise. Experimental studies in

laboratory animals uniformly report reversible dele-

terious effects of iron deficiency on most measures of

functional immunity. It is well documented that iron

regulates the function of T-cells, and in most studies

(in vivo and in vitro), a deficiency results in impaired

cell-mediated immunity. Humoral immunity may be

less affected by iron deficiency than cellular immun-

ity. Iron is a component of the cytotoxic enzymes that

are used by neutrophils, macrophages, and natural

killer cells. It has been proposed that the immuno-

surveillance role of macrophages may be mediated in

part by modulation of the iron status in cells. This

sequestration of iron into macrophages has been pro-

posed to be beneficial during the early acute stages of

infectious disease, as it would limit the availability

to microorganisms (particularly intracellular micro-

organisms).

0035 The relationship between iron repletion and infec-

tion is somewhat controversial. The major dilemma

focuses around the studies demonstrating a positive

relationship between iron repletion/supplementation

and increased morbidity from infections. Administra-

tion of parenteral iron during an infection has been

demonstrated to heightened susceptibility to infec-

tion. These clinical observations have been supported

by studies in vitro, in which the rate of microbial

growth diminished when iron was removed from cul-

ture media. Although animal studies have shown that

excess iron promotes the growth of some microorgan-

isms, there is no compelling clinical evidence (except

perhaps for tuberculosis, malaria, and brucellosis)

that this occurs in adult humans receiving oral iron

supplementation. In a recent review, it was concluded

that there is little evidence that oral iron supplemen-

tation or provision of iron fortified foods to iron

deficient individuals inhibits immune function or

increases the susceptibility to most infectious agents

(with the possible exceptions of malaria-related dis-

ease, HIV, and tuberculosis). Thus, the relationship

between iron and infection may depend on the ability

of the infectious organism to acquire iron and the state

of iron nutriture of the host. In conclusion, both iron

deficiency and iron excess exert adverse effects on

immune responses and alter the metabolism and

growth of the pathogens. The balance of these various

effects ultimately will determine clinical outcome.

0036Zinc Zinc is a constituent of key enzymes involved

in cell replication (DNA and RNA polymerase).

Thus, deficiency will impact on any antimicrobial

activity that depends on cellular replication and dif-

ferentiation. Zinc plays a role in regulating the acti-

vation of acute-phase genes (via its ability to bind to

RNA finger loop domains known as ‘zinc fingers’),

such that zinc deficiency impairs translation of genes

normally activated during the acute-phase reaction.

Another essential role of zinc in the immune response

is its binding to certain thymus-derived peptides (thy-

mulin) that appear to function as hormones in the

differentiation and maturation of T-cells. In zinc defi-

ciency, the depletion of mature T-cells heightens sus-

ceptibility to infection. Thus, clinical zinc deficiency

results in thymic involution, lymphoid tissue atrophy,

lymphopenida, decreased cell-mediated immunity,

and impaired natural killer cell activity. Defects in

cell-mediated immunity and increased susceptibility

to infections are well described in the human disease

acrodermatitis enteropathica, an inherited defect of

zinc absorption. Animal studies have confirmed that

zinc deficiency impairs cellular immunity, comprom-

ises B-cell development and antibody production,

inhibits macrophage function, decreases natural

killer activity, and increases the mortality to various

infectious organisms.

0037Plasma zinc decreases during infection, even in

the zinc-sufficient individual. The hypozincemia of

infection is, like iron, part of the acute-phase response

mediated by cytokines, which induce the synthesis of

the intracellular zinc-binding proteins liver, thymus,

and bone marrow. The physiological role of this acute

transfer of zinc from the extracellular to the intracel-

lular compartment is not clear but is hypothesized to

be an attempt to limit viral and bacterial DNA tran-

scription and RNA translation.

0038The impairment in immune response associated with

zinc deficiency is readily reversed by supplementation.

INFECTION, FEVER, AND NUTRITION 3313

A number of experimental trials have illustrated the

efficacy of zinc supplementation to improve immune

function during recovery from infections. For example,

zinc supplementation was reported to reduce the dur-

ation and severity of cold symptoms. Community-

based prospective zinc supplementation of poorly

nourished infants and children, and therapeutic trials

in acutely ill children, suggest a decrease in diarrhea

duration, pneumonia, growth-stunting, acute lower re-

spiratory infections, dysentery altered intestinal per-

meability and improved food intake, and a more

rapid improvement in patients.

0039 Other minerals The diarrhea associated with gas-

trointestinal infections reduces the absorption and

increases the endogenous loss of many of the other

trace minerals, notably copper. It is recommended

that treatment regimens for diarrhea should include

supplementation with copper and other minerals in

addition to zinc. Recently, it was found that elderly

residents in long-term care facilities taking a micro-

nutrient supplement containing zinc and selenium

had up to four times fewer infections than those

taking a placebo. In addition to zinc and iron, other

trace elements are present in several acute-phase

proteins and enzymes associated with antioxidant

defense. These proteins include caeruloplasmin

(copper), superoxide dismutases (manganese, copper,

and zinc), and glutathione peroxidase (selenium).

Deficiencies in these micronutrients alter the ability

of immune cells to respond to inflammatory agents.

Immunonutrients

0040 An immunonutrient is loosely defined as a nutrient

that provides specific benefits to the immune system.

It is hypothesized that, under certain physiological

conditions (e.g., infection), the demand for the nutri-

ent may exceed the ability of the body to synthesize it.

There is growing evidence, from both animal and

human studies of infectious diseases, that immunity

might be improved by providing immunomodulatory

nutrients (e.g., arginine, glutamine, docosahexaneoic

acid, eicosapentanoic acid, gamma linolenic acid,

zinc, and/or nucleotides). Based on these studies,

there are now commercially available enteral and

parenteral solutions that contain mixtures of immu-

nomodulatory nutrients. Complete enteral diets con-

taining combinations of immunonutrients (arginine,

glutamine, nucleotides, o-3 fatty acids), when given

postoperatively to surgical patients, have been

reported to reduce hospital stay, medical treatment

costs and the incidence of wound complications and

infections. The promising experimental evidence of

the metabolic and immune effects of these nutrients

offers therapeutic potential for the future, and

ultimately might help prevent and reduce the mortal-

ity and morbidity associated with infections. Owing

to the inclusion of multiply immune-enhancing nutri-

ents in experimental studies, it is difficult, at present,

to isolate the specific nutrient or combinations re-

sponsible for improvement. Furthermore, one nutri-

ent may work synergistically with others to produce

an effect over and above what would be observed

with a single nutrient alone. At present, more studies

are necessary to find the dosage and duration of the

feeding to obtain the desired clinical outcome.

Conclusions

0041Infectious diseases are on the increase world-wide

and are a major cause of morbidity and mortality

and contribute to malnutrition. Today, protein energy

malnutrition is accepted as a major cause of immuno-

deficiency world-wide. Infections occur frequently in

both the healthy population and with more severe

consequences, in individuals who are immunosup-

pressed through malnutrition. Thus, nutrition plays

an important role in the prevention and treatment of

infections. There are many levels at which nutrient

intake can modify the intensity and characteristics of

the response of animals and humans to inflammatory

stimuli. Recently, it was demonstrated, that for an

RNA virus, the host diet influenced the genetic

make-up of the pathogen and thereby alter its viru-

lence. New knowledge on the interaction between

nutrition and the host immune function and perhaps

also the infectious agent will permit the development

of designer feeding formulas/regimens with selective

ingredients to optimize immunity to reduce the risk of

infection and promote the recovery from infections

and fever.

See also: Elderly: Nutritionally Related Problems; Enteral

Nutrition; Famine, Starvation, and Fasting; Fatty

Acids: Dietary Importance; HIV Disease and Nutrition;

Hypertension: Hypertension and Diet; Malnutrition: The

Problem of Malnutrition; Malnutrition in Developed

Countries; Minerals – Dietary Importance; Nutritional

Surveillance: In Industrialized Countries; Stress and

Nutrition; Trace Elements

Further Reading

Alexander JW (1998) Immunonutrition: the role of omega-

3 fatty acids. Nutrition 14: 627–633.

Bhaskaram P (2001) Immunobiology of mild micronutrient

deficiencies. British Journal of Nutrition 85 (supplement

2): S75–S80.

Field CJ, Johnson IR and Pratt VC (2000) Glutamine and

arginine: immunonutrients for improved health? Medi-

cine and Science in Sports and Exercise 32: S377–S388.

3314 INFECTION, FEVER, AND NUTRITION

Field CJ, Johnson IR and Schley PD (2002) Nutrients and

their role in host resistance to infection. Journal of

Leukocyte Biology 71: 16–32.

Grimble RF (1998) Nutritional modulation of cytokine

biology. Nutrition 14: 634–640.

James MJ, Gibson RA and Cleland LG (2000) Dietary

polyunsaturated fatty acids and inflammatory mediator

production. American Journal of Clinical Nutrition 71:

343S–348S.

Mainous MR and Dietch EA (1994) Nutrition and infec-

tion. Surgical Clinics of North America 74: 659–676.

Mizock BA (2000) Metabolic derangements in sepsis and

septic shock. Critical Care Clinics 16: 319–336.

Schrimshaw NS and SanGiovanni JP (1997) Synergism of

nutrition, infection and immunity: an overview. Ameri-

can Journal of Clinical Nutrition 66: S464–S477.

Shankar AH and Prasad AS (1998) Zinc and immune

function: the biological basis of altered resistance to

infection. American Journal of Clinical Nutrition 68:

447S–463S.

Stephensen CB (1999) Burden of infection on growth fail-

ure. Journal of Nutrition 129: 534S–538S.

Woodward B (1998) Protein, calories, and immune de-

fenses. Nutrition Reviews 56: S84–S92.

INFLAMMATORY BOWEL DISEASE

A Bousvaros, Children’s Hospital Boston, Boston,

MA, USA

Background

0001 Inflammatory bowel disease (IBD) is characterized by

chronic relapsing intestinal inflammation without an

infectious or dietary cause. The term idiopathic IBD is

traditionally limited to the illnesses Crohn’s disease

(CD) and ulcerative colitis (UC), which will be the

focus of this chapter. However, there are many other

conditions (chronic granulomatous disease, BehO

et’s

disease, graft- vs. host-disease, HIV) which may cause

immune-mediated gastrointestinal inflammation.

0002 CD and UC are two separate illnesses that may

share some common genetic background, because a

family history of either disease increases an individ-

ual’s risk of developing both diseases. CD is charac-

terized by a transmural granulomatous intestinal

inflammation, which may occur anywhere in

the intestinal tract from the mouth to the anus; extra-

intestinal granulomas in the lymph nodes, skin, and

genitalia may also be seen. The most common disease

locations include the terminal ileum, cecum, entire

colon, and perianal regions. Intestinal strictures,

fistulae, and abscess are common in CD but not in

UC. Up to 30% of individuals with CD may have

microscopic gastroduodenal inflammation. In con-

trast, ulcerative colitis is characterized by mucosal

inflammation limited to the large intestine. UC

extends from the rectum proximally. Three major

phenotypes of UC have been described: proctitis

(limited to the rectum), left-sided disease (distal

to the splenic flexure), and pancolitis (extending past

the splenic flexure). Pharmacotherapy of both CD and

UC includes the use of aminoslicylates, corticoster-

oids, 6-mercaptopurine, and other immunosuppres-

sive agents. Nutrition may be used as primary

therapy in CD but is only palliative in UC.

0003The precise etiology of these two diseases is un-

known. However, it is hypothesized that an under-

lying genetic mutation involving regulation of the

immune system predisposes an individual to the de-

velopment of CD or UC. When that individual is

exposed to a dietary or infectious antigenic trigger

for the disease, excessive and aberrant intestinal in-

flammation results. In support of this hypothesis,

mutations in an immunomodulator gene (NOD2)

have been identified in a subset of individuals with

CD.

Nutritional Complications in IBD

0004Before determining the extent of evaluation and ther-

apy in a patient with inflammatory bowel disease, the

clinician must ask several questions. First, does

the patient have CD or UC? Nutritional compli-

cations are far more common in patients with CD,

though anemia is common in both. Second, where is

the location of the disease? A patient with CD and

ileal disease is more likely to develop steatorrhea and

vitamin B

deficiency than a patient with disease

limited to the colon. Third, what is the patient’s

age? Children and teenagers with chronic malnutri-

tion from Crohn’s disease are more likely to present

with slowed growth and short stature, whereas adults

present with weight loss. Finally, how active is the

patient’s disease? A patient with IBD and multiple

relapses is at greater risk for nutritional complica-

tions than a patient who has been in remission for

INFLAMMATORY BOWEL DISEASE 3315

years. Nutritional complications of IBD are summar-

ized in (Table 1).

Caloric Deficiency and Growth Failure

0005 Acute severe exacerbations of CD and UC may cause

a sudden cessation of food intake, with weight loss

and dehydration. More commonly, however, low-

grade disease activity causes subtle changes in appe-

tite and growth, especially in CD. Adults with CD

have a significantly lower percent body fat (as deter-

mined by bioelectrical impedance) compared with

patients with UC and controls. In children, growth

failure (decreased height velocity leading to short

stature) results primarily from inadequate caloric

intake. Approximately 50% of children with CD and

10% of children with UC demonstrate decreased

height velocity in childhood and adolescence, with

accompanying pubertal delay. Growth failure may

precede intestinal symptoms of CD in childhood.

The etiology of the decreased intake is multifacto-

rial, and may include gastritis and esophagitis,

cytokine-mediated anorexia, fear of eating secondary

to intestinal inflammation, and decreased taste

sensation secondary to micronutient deficiencies

(e.g., zinc deficiency). Chronic corticosteroid usage,

whether with prednisone or newer agents such as

budesonide, may also impair linear growth. While

levels of growth hormone and IGF-1 may be low in

children, the levels rise with nutritional restitution.

0006 Patients with CD of the small bowel may experi-

ence fat malabsorption and steatorrhea, because

terminal ileal inflammation leads to decreased enter-

ohepatic circulation of bile acids. Steatorrhea is less

common and less severe than in patients with pancre-

atic insufficiency.

0007 In an anthropometric study of 24 children with

moderately active CD, requiring hospitalization, re-

searchers identified a depletion of lean body mass and

expansion of the extracellular water compartment.

The mean resting energy expenditure (REE), as

estimated by indirect calorimetry, was 1250 kcal

per day, which was significantly higher than patients

with anorexia nervosa and similar degrees of

malnutrition. The authors hypothesized that mal-

nourished patients with CD may have a ‘lack of

REE adaptation’ mediated by tumor necrosis factor

and interleukin-6.

Osteoporosis

0008Patients with IBD, especially those treated with

long-term corticosteroids, are at increased risk for

pathologic fractures, including vertebral compression

fractures. The bone mineral density (BMD) of the

lumbar spine, as assessed by quantitative computed

tomography and dual energy X-ray absorptiometry,

demonstrates that approximately 30% of patients

with IBD have a BMD Z-score of less than 1, com-

pared with approximately 15% of age-matched

controls. Patients with CD are at a higher risk of

osteopenia than UC patients. Reports suggest that

up to 70% of children may have a low BMD, but

these reports must be interpreted cautiously because

of the lack of well-established pediatric standards.

The etiologies for osteopenia in IBD are multifactor-

ial and include hypovitaminosis D, decreased calcium

intake, calcium malabsorption from steatorrhea,

corticosteroid effects, and cytokine-medicated bone

resorption. In addition, primary sclerosing cholangi-

tis, an immune-mediated disease causing bile duct

strictures and cholestasis, occurs in 1–4% of IBD

patients and may result in additional impairment of

vitamin D and calcium absorption.

Anemia and Iron Deficiency

0009Anemia in IBD is multifactorial and may reflect iron

deficiency, folate or vitamin B

deficiency, gastro-

intestinal blood loss, impaired utilization of iron, or

myelosuppression caused by medications (e.g., sulfa-

salazine, 6-mercaptopurine). The most common

cause of anemia in IBD is iron deficiency secondary

to impaired iron absorption and intermittent GI

bleeding. Laboratory features include microcytosis,

serum iron levels < 30 mgdl

1

and ferritin levels

<12ngml

1

. Iron indices may be misleading, because

the chronic inflammation may cause a decrease in the

total iron binding capacity and an elevation of serum

ferritin.

Micronutrient Deficiencies

0010While a laboratory studies of micronutrient deficien-

cies are commonly reported in patients with CD and

UC, clinical manifestations of such deficiencies are

fortunately quite rare and largely limited to case

tbl0001 Table 1 Nutritional complications of inflammatory bowel

disease

Global

Inappropriate caloric restriction – anorexia

Weight loss

Growth failure (in children)

Steatorrhea (in Crohn’s disease)

Protein-losing enteropathy

Cholestasis (in primary sclerosing cholangitis)

Osteopenia/low bone density

Com mon mi cro n utri ent defi ci enc i es

Iron-deficiency anemia

Hypoalbuminemia

Vitamin B

deficiency (in ileal Crohn’s disease)

Folate deficiency (especially in patients taking sulfasalazine)

Hypovitaminosis (vitamins A, D, and E)

Zinc and selenium deficiencies

3316 INFLAMMATORY BOWEL DISEASE

reports. Vitamin B

deficiency complicating Crohn’s

ileitis or ileal resection is the most clinically important

vitamin deficiency. In patients with extensive small

bowel CD, vitamin A deficiency causing impaired

dark adaptation and night blindness may occur.

Zinc deficiency causing dermatitis has also been

reported. Studies of IBD patients both with active

disease and in remission have demonstrated reduced

plasma levels of vitamins A, C, D, and E, as well as

selenium, magnesium, and zinc. The risk of micro-

nutrient deficiency may be increased with greater

disease activity. Folic acid deficiency may occur in

individuals taking sulfasalazine. In addition, some of

the newer immunomodulatory agents used to treat

severe UC or CD (e.g., cyclosporine or tacrolimus)

may cause hypocalcemia or hypomagnesemia.

Other Nutritional Complications

0011 CD patients with ileitis or ileal resection may develop

hyperoxaluria and renal stones. Increased gut oxalate

absorption occurs because the luminal bile acid defi-

ciency results in steatorrhea, and the increased intra-

luminal fat binds calcium, so there is no free calcium

to bind oxalate. High levels of homocysteine have

been reported in CD patients from countries where

there is no supplementation of grains with folate.

Nutritional Therapy

Nutritional Therapy of the Acute IBD Patient

0012 Hospitalized patients with IBD are typically severely

ill. A patient with a severe exacerbation of ulcerative

colitis may be passing 15–20 bowel movements per

day and have severe abdominal cramping. Eating and

drinking may exacerbate the pain, so patients tend

not to eat. Thus, while there is no evidence that use of

parenteral nutrition helps heal the colitis, bowel rest

and parenteral nutrition will help forestall weight

loss and may decrease pain. Thus, nutritional support

of these patients is a useful adjunct to medical therapy

(intravenous corticosteroids and/or cyclosporine). If

no response to medical therapy occurs within ap-

proximately 14 days, the patient should be considered

for colectomy.

0013 Hospitalized patients with CD present with small

bowel or colonic mucosal inflammation, abdominal

abscess, or small bowel stricture. While ill patients

commonly require treatment with corticosteroids,

antibiotics, and (in the case of abscess and stricture)

surgery, enteral feeding and/or parenteral nutrition is

once again a useful adjunct. Hospitalized CD patients

who are less ill, whose disease is primarily limited

to the small bowel, whose principal symptoms are

weight loss and diarrhea, and who do not have

stricture or abscess may be candidates for parenternal

nutrition as primary therapy (see below).

Enteral Nutrition as Primary Therapy for CD

0014Multiple randomized controlled trials demonstrate

that in patients with active CD, nutritional therapy

may induce a remission. Such therapy involves cessa-

tion of eating food and exclusive intake of elemental

and/or polymeric formula by mouth, nasogastric

tube, or gastrostomy. The typical elemental formula

has a density of 1 kcal ml

1

, and provides 15% of

calories as free amino acids, 25% as medium-chain

triglyceride, canola or soybean oil, and 63% malto-

dextrin or starch. Polymeric formula has a density of

1–1.5 kcal ml

1

, contains similar fat and carbohy-

drates, but has sodium and calcium caseinate instead

of free amino acids.

0015While the exact mechanism by which formulas

induce remission in CD is unknown, postulated

mechanisms include decreased dietary antigenic load

and modification of the intestinal bacterial flora. In a

metaanalysis of eight studies conducted prior to

1995, the remission rate ranged from 50–80% after

4 weeks of therapy. However, it was concluded that

corticosteroids were more effective than enteral

nutrition at bringing about remission. Trials compar-

ing elemental with polymeric formula as a primary

therapy have not demonstrated any clear benefit of

one over the other. It is therefore reasonable to use a

polymeric formula first, given its lower cost and

greater palatability. While liquid diets have the ad-

vantage of bringing about remission without expos-

ing patients to corticosteroid side-effects, the disease

may relapse within 1–2 months once patients return

to a regular diet. In addition, the passage of the naso-

gastric tube may be uncomfortable for children, and

children who go to school with an indwelling naso-

gastric tube may be stigmatized socially. Enteral

nutrition as a primary therapy is commonly utilized

in Europe, but less so in the USA.

Enteral Therapy for Growth Failure in Children

0016Since growth failure and short stature in children

and adolescents with CD are principally caused by

decreased caloric intake, nocturnal supplementation

with formulas increases the height velocity and im-

proves growth. The advantage of nocturnal supple-

mentation is that a child can eat normally during the

day, and the nasogastric tube can be removed before a

child goes to school. In a typical adolescent or adult,

1000–1500 calories of an elemental or polymeric

formula are delivered overnight at a rate of 100–

150 ml h

1

. In a controlled study of children aged 8–

15 years, nocturnal nastogastric infusion of elemental

INFLAMMATORY BOWEL DISEASE 3317

formula for 1 out of every 4 months for 1 year

resulted in a mean weight gain of 6.9 kg and a height

gain of 7.0 cm. In addition, it has been suggested that

children who respond initially to 4 weeks of exclusive

enteral feeding have a higher probability of staying in

remission if they continue with nocturnal supplemen-

tation after they resume eating.

Home Parenteral Nutrition

0017 While total parenteral nutrition was a commonly util-

ized therapy for CD patients in the 1970s and 1980s,

home parenteral nutrition is infrequently utilized

now. Improvements in medical therapy with the intro-

duction of immunosuppressive agents (azathioprine,

6-mercaptopurine, methotrexate, infliximab) have

decreased the number of patients with chronically

active disease. In addition, surgeons have become

more cautious about resecting bowel in patients with

CD, so there are fewer patients with short bowel

syndrome. Lastly, it is now realized that enteral nutri-

tion is as effective as parenteral nutrition in bringing

about remission in most patients with CD. Home

parenteral nutrition may have a limited role in the

rare patient with CD refractory to other therapies,

intestinal stricture, fistulae, or abscess awaiting sur-

gery. Given that many of these patients are commonly

maintained on immunosuppressive drugs, the risk of

bacterial or fungal sepsis is significant with prolonged

PN.

Nutritional Therapy of Nonmalnourished

Outpatients

0018 Most adults and children with CD and UC feel well,

are not interested in nasogastric tube feeding, and are

either of normal weight or minimally underweight.

While clinically asymptomatic, they remain at risk

for nutritional complications of IBD and desire

dietary counseling. There is no specific diet univer-

sally recommended for patients with CD and UC.

Low-residue, low-fiber diets may be palliative for

patients with narrowed regions of bowel (i.e., CD

patients with inflammatory or fibrotic strictures).

While there are anecdotal reports of elimination

diets (e.g., milk-free, low-carbohydrate) maintaining

remission in some patients, there is not enough

evidence in the literature to encourage patients to

attempt these diets. Studies of fish oil capsules suggest

some efficacy in the treatment of ileocolonic CD and

mild ulcerative colitis. The efficacy of fish oil may be

due to the polyunsaturated fatty acids, which may

decrease the production of leukotriene B4 and inflam-

matory mediator seen in UC.

0019 Given the many studies documenting micronu-

trient and antioxidant deficiencies, patients should

be counseled to take a daily multivitamin. Most

such vitamins contain 400 mg of folic acid, but in

patients receiving sulfasalazine, 1 mg of folate per

day is recommended. Given the risk of osteopenia,

patients should be counseled to take 1200–1500 mg

of total daily calcium, either through their diet or as

supplements. Studies of complementary medicine use

in IBD suggest that 20–40% of CD and UC patients

routinely utilize herbs and/or megavitamins and fail

to tell their physician. Thus, the physician should

specifically inquire about such use and inform the

patient of the potential toxicities of megavitamin

therapy. Patients with chronic ileitis and/or ileal re-

sections should be monitored for vitamin B

defi-

ciency and supplemented with oral or intramuscular

vitamin B

Prevention of IBD

0020Both CD and UC have strong genetic components. It

is estimated that a child born to a parent with CD or

UC has a 5% chance of developing IBD over their

lifetime. However, the fact that IBD varies so dramat-

ically by region suggests that environmental factors

may also confer risk. Environmental factors already

identified include smoking and oral contraceptive

use, both of which increase the risk of CD. Since the

potential exists that food antigens may be a trigger for

the onset of IBD, investigators have tried to identify

modifiable dietary factors that may increase risk.

Unfortunately, because of the low incidence of CD

and UC, prospective cohort studies of risk factors are

nearly impossible. Case-control studies suggest that

patients with UC have higher intakes of sucrose

and fat, and a reduced intake of fructose, fruit, and

vitamin C. Given the limitations of these studies, no

formal recommendation for a preventative diet can be

made at this time.

See also: Anemia (Anaemia): Iron-deficiency Anemia;

Carotenoids: Occurrence, Properties, and

Determination; Physiology; Cobalamins: Properties and

Determination; Physiology; Enteral Nutrition; Folic Acid:

Properties and Determination; Physiology;

Osteoporosis; Parenteral Nutrition; Zinc: Deficiency