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

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other factors such as age, physical exercise, stress, and

coexisting medical problems.

Gastrointestinal Tract

0012 Swelling and tingling of the lips, tongue, and throat

can present as initial symptoms of food allergy occur-

ring as the antigen comes into contact with these

organs. Nausea and vomiting are common acute

symptoms, and abdominal pain and diarrhea also

occur frequently.

0013 The pathological changes in the small intestine

which occur in food allergy have been characterized

from biopsy specimens. It is well documented that

mucosal damage can occur in cows’ milk protein al-

lergy and there is evidence that reactions to soya, egg,

fish, and chicken may also result in mucosal damage.

0014 More extensive intestinal mucosal damage is seen

in celiac disease in response to the ingestion of gluten.

Although abnormal immunological mechanisms are

believed to be partially responsible for this condition,

the exact mechanism remains uncertain. (See Celiac

(Coeliac) Disease.)

0015 Food allergy can also lead to inflammatory changes

in the large bowel and bloody diarrhea (proctocolitis)

in infants. However, in adults there is a lack of

evidence to suggest an immunological basis for large-

bowel disorders. (See Colon: Diseases and Disorders.)

Skin

0016Urticaria (an itchy raised skin rash also known as

nettle rash) and angiedema (swelling of the skin,

mucous membranes, and underlying tissues) are fre-

quently seen as manifestations of food allergy. There

is increasing evidence that food intolerance may be a

cause of eczema but the basic mechanism of the reac-

tion is still unclear. Infantile eczema is certainly more

common in children from atopic families. Such reac-

tions frequently occur in response to cows’ milk pro-

tein and may be ameliorated by dietary manipulation.

Respiratory Tract

0017Sneezing and rhinorrhea (running of the nose) can be

manifestations of food allergy, either in association

with gut or skin symptoms or alone. More rarely,

bronchoconstriction occurs when a food is ingested,

but food allergy is not a common cause of asthma.

Anaphylactic Shock

0018Although the majority of food-allergic reactions are

not life-threatening, a small proportion of reactions

Antigen presentation IgE production

Mast cell

activation

Mediator release Clinical effects

IFN-γ

IL-4, IL-5, IL-6

Cytokines

GM-CSF, TNF-α

IL-8/9, inflammatory

cell activation

IL-3, IL-4,

Preformed

and newly

formed

mediators

Pharmacological effects

Blood vessels, airways, etc.

Cell infiltration and

accumulation

Clinical effects

Hayfever

Asthma

Eczema

Anaphylaxis

Mucosal surface

Processing

and presentation

Antigen

IgE

IL-4

IL-10

TH2

Bε

APC

↑

Overview: induction and effector mechanisms in type I hypersensitivity

fig0002 Figure 2 Innocuous environmental antigens (allergens) enter via mucosal surfaces and are taken up by local antigen-presenting

cells (APCs), which process and present them to TH cells. TH2 cells secrete cytokines that induce B-cell proliferation and favor the

production of an allergen-specific immunoglobulin E (IgE) response. The IgE binds, via Fce receptors (FceRI), to mast cells, thus

sensitizing them. When allergen subsequently reaches the sensitized mast cell, it cross-links surface-bound IgE, causing an increase

in intracellular calcium (Ca

2þ

) that triggers the release of preformed mediators, such as histamine and proteases, and newly

synthesized, lipid-derived mediators such as leukotrienes and prostaglandins. These autocolds produce the clinical symptoms of

allergy. Cytokines are also released from degranulating mast cells and may augment the inflammatory and IgE responses. IL-4,

interleukin-4; IFN-g, interferor-g; GM-CSF, granulocyte – macrophage colony-stimulating factor. Adapted, with permission, from Roitt I,

Brostoff J and Male D (1998) Immunology, 5th edn. Sidcup: Mosby.

2628 FOOD INTOLERANCE/Food Allergies

can lead to anaphylactic shock (anaphylaxis), which

is severe and may be fatal. Anaphylaxis is an acute

allergic (IgE-mediated) reaction of rapid onset and

affecting many organ systems, including the cardio-

vascular system, the respiratory tract, the mouth, the

pharynx, and the skin, either individually or in com-

bination. It is characterized by swelling of the lips

and throat, shortness of breath, a rapid fall in blood

pressure, progressing to cardiovascular collapse and

severe shock. Treatment consists of intramuscular

injection of epinephrine (adrenaline), and without

this anaphylaxis may cause death. Anaphylactic reac-

tions are relatively rare, but there is evidence that

deaths from food-induced anaphylaxis are increasing.

In the UK and Europe, peanut is the most common

food reported to cause anaphylaxis, but other foods

that are known sometimes to cause the condition are

tree nuts, seeds, eggs, milk, and shellfish. Inadvertent

exposure to potential allergens in foods containing, or

contaminated with, minute amounts of the allergen

poses a major risk to the small number of people at

risk of anaphylaxis.

Predisposition to Food Allergies

0019 It is believed that genetic predisposition and immuno-

logical predisposition, notably elevated serum IgE

levels, are the most important determinants of allergic

disease. Environmental factors are secondary but may

still play an important role; they include nondietary

factors such as the level of allergen exposure, which

may be influenced by season of birth, maternal

smoking habit, exposure to pollutants, viral illness,

and the nutritional status of the individual.

0020 The importance of genetic factors in the etiology of

allergic disease and IgE production is evident from the

simple observation that allergic disease is more

common in the children of atopic parents. Children

from families where both parents are atopic have

more than a 50% chance of developing an allergic

disorder; where one parent is atopic, the chance is

about 30%. However, twin studies have shown that

concordance is far less than 100% in monozygotic

(identical) twins, indicating that environmental

factors are also important in the expression of atopic

disease.

0021 Research in atopic families and twins suggests that

total IgE levels are influenced by genetic factors. The

major control of antigen-specific IgE responses is be-

lieved to be linked to the human leukocyte antigen

(HLA) immune response genes. However, HLA-

linked genes do not appear to be responsible for

high IgE levels. There is evidence that general levels

of IgE may be determined by other genes, including

those responsible for cytokine production.

0022Inherited immune deficiency disorders, e.g., defi-

ciencies of complement or IgA, can also predispose

towards allergy. The presence of a specific type of

IgA, secretory IgA, in the gut is believed to reduce

antigen absorption. It might be deduced that IgA

deficiency could lead to increased antigen absorption

and IgE antibody stimulation. However, again the

explanation must be more complex, as not all such

people develop allergy.

0023As ingested food travels through the gut, it presents

the immune system with a vast array of foreign par-

ticles to distinguish. The intestinal mucosa itself is a

barrier which can protect against dietary antigens and

the secretion of mucus from intestinal goblet cells and

the production of secretory IgA are protective mech-

anisms which help to reduce antigen absorption. Dis-

ruption of the intestinal barrier, as occurs after

intestinal infection, and increased permeability of

the barrier, as in premature infants, the newborn, in

malnutrition, and in immune deficiency, may increase

the penetration of antigens.

0024The significance of increased gut permeability in

the etiology of food allergic disease is nevertheless

uncertain. It has been demonstrated that antigens

can cross the gut wall in both allergic and nonallergic

individuals, and that immune complexes may circu-

late in the blood of nonallergic individuals without ill

effect. This underlines the complexity, as well as the

gaps in our understanding, of the ways in which

genetic and environmental factors may interact to

cause allergic disorders.

Vulnerability of the Newborn to Food

Allergy

0025It is evident from clinical experience that the newborn

is vulnerable to food allergens. For example, there is

clear evidence that infants exposed to unmodified

cows’ milk within the first few weeks of life are

particularly susceptible to the development of symp-

toms of allergy to cows’ milk such as eczema. How-

ever, our knowledge of the pathogenesis of food

allergic disease and the relative importance of the

various contributory factors in the neonatal period

is still limited.

0026The immunological response to feeding a ‘foreign

protein’ may result from the immaturity of neonatal

digestive and absorptive functions and early penetra-

tion of the antigens. It has also been suggested that

because newborn infants are temporarily deficient in

IgA – secretory IgA does not appear until the age of

2–4 weeks – the gut mucosa is particularly vulnerable

to antigen penetration.

0027The influence of maternal diet during pregnancy

and lactation, the protective role of breast-feeding,

FOOD INTOLERANCE/Food Allergies 2629

and the timing and introduction of solids at

weaning may all play their part in the pathogenesis

of food allergic disease. The coincident occurrence

of infection with the introduction of a specific

antigen may also be a crucial factor. (See Pregnancy:

Safe Diet.)

0028 The idea that breast-feeding might protect against

allergic disease has existed for some 50 years. Al-

though there are many studies that support this idea,

there are many that do not. Such conflict appears to

result from the difficulty in controlling studies on

infants and differences in methodology. (See Infants:

Breast- and Bottle-feeding.)

0029 On balance, it appears that breast-feeding de-

creases the likelihood of allergic disease in children

who are ‘at risk’ because of family history. To some

extent this is due to the late introduction of foreign

protein but it is also attributable to the presence of

protective immunological factors, such as IgA, in col-

ostrum and breast milk. Breast milk protects against

infection, and breast-feeding should help to maintain

the integrity of the gastrointestinal mucosa in the

neonatal period.

0030 The level of total IgE in umbilical cord blood is

believed to be predictive of allergic disease. The influ-

ence of maternal diet on cord blood immunoglobulin

levels and the placental transfer of antibodies to spe-

cific food proteins in atopic and nonatopic mothers

are subjects of active research at the present time. As

yet the influence of maternal diet on allergic outcome

in the offspring remains uncertain.

0031 The current view is that sensitization in utero does

occur. However, the influence of dietary manipula-

tion of the mother in pregnancy in preventing food

allergy in the infant is contentious and in need of

further research before it can be recommended.

0032 Food antigens pass into breast milk in small

amounts and these are significant in immunological

terms. It is believed that this may lead to sensitization

in susceptible infants. Therefore the exclusion of spe-

cific foods from the mother’s diet during lactation

may be beneficial for at-risk infants. Again, this is

the subject of research.

0033 The potential severity of the reactions associated

with peanut allergy has led to the recommendation, in

the UK, that pregnant and breast-feeding women

from atopic families (whether they are themselves

atopic or if the father or any other sibling has atopic

disease) should avoid peanuts and peanut products in

order to reduce the risk of peanut allergy developing

in their offspring. However, the scientific basis for

this recommendation is still open to debate and

other countries have not made similar recommenda-

tions. (See Food Intolerance: Types.)

0034Particularly important for at-risk infants is the

timing of weaning and the nature of the foods intro-

duced early on. Exclusive breast-feeding, for at least 4

and preferably 6 months, and avoidance of the early

introduction of foods commonly known to cause al-

lergies, e.g., cows’ milk and its products, eggs, wheat,

fish, nuts, and citrus fruits, would seem to be the best

preventive approach. However, more research is

needed on the links between weaning and subsequent

development of food allergic disorders. (See Infants:

Weaning.)

Prevalence of Food Allergies

0035It is difficult to arrive at a precise estimate of the

prevalence of food allergic disease because of the dif-

ferent testing procedures and diagnostic criteria used

in research studies. Figures ranging from 1% to 20%

have been cited, but the true prevalence is currently

estimated to be towards the lower end of this range,

at about 2%. Our present state of knowledge suggests

that food allergy is far less common than food intol-

erances (with a nonimmunological basis), and less

common than allergic reactions to pollen and house

dust. However, as yet there are no systematic data to

permit the accurate calculation of the incidence and

prevalence of food allergic reactions, either in the UK

or elsewhere.

See also: Allergens; Colloids and Emulsions; Colon:

Diseases and Disorders; Food Intolerance: Types;

Immunology of Food; Infants: Breast- and Bottle-

feeding; Weaning; Pregnancy: Safe Diet;

Prostaglandins and Leukotrienes

Further Reading

British Nutrition Foundation (2002) Adverse Reactions to

Food. Report of the British Nutrition Foundation Task

Force. Oxford: Blackwell Science.

Cant AJ (1991) Food allergy and intolerance. In: Mclaren

DS et al. (eds) Textbook of Paediatric Nutrition, 3rd

edn, pp. 204–221. London: Churchill Livingstone.

Food Standards Agency (2000) Adverse Reactions to Food

and Food Ingredients. Report from the Committee on

Toxicity of Chemicals in Food, Consumer Products and

the Environment. London: TSO.

Roitt I, Brostoff J and Male D (1998) Immunology, 5th edn.

Sidcup: Mosby.

2630 FOOD INTOLERANCE/Food Allergies

Milk Allergy

S L Taylor and J Kabourek, University of Nebraska,

Lincoln, NE, USA

Introduction

0001 Cows’ milk is one of the most common causes of

adverse reactions in foods and can occur through

several mechanisms. True cows’ milk allergy (CMA)

occurs through an immunoglobulin E (IgE) mediated

mechanism. The prevalence of allergy to cows’ milk is

reported to be about 2% of the general pediatric

population in developed countries. Treatment of

CMA involves the strict avoidance of cows’ milk

and products containing cows’-milk proteins. Educa-

tion of both the affected child and parents is also vital

to successful management of CMA.

Milk Allergy

0002 Cows’ milk is one of the most common causes of

adverse reactions in foods and can occur through

several mechanisms. True CMA or hypersensitivity

is indicative of an adverse reaction to bovine milk

proteins that produces symptoms and where an im-

munologic mechanism may be implicated. CMA is

mainly an IgE-mediated, type I immediate hypersen-

sitivity reaction, although type III and IV reactions

have also been implicated. CMA is considered the

most severe form of intolerance because the threshold

dose for elicitation of a reaction is low, and symptoms

can be severe in some affected individuals.

0003 Classified by Coombs and Gell, hypersensitivity

reaction mechanisms are divided into four types:

I–IV. The first three types are antibody-mediated,

whereas the fourth type is mediated by T cells and

macrophages.

0004 Type I (anaphylactic) reaction is immediate and

is due to interaction of antigen (allergen) with IgE-

sensitized mast cells and basophils, resulting in

histamine and mediator release from these cells.

0005 Type II (cytotoxic) reaction involves both IgG and

IgM antibodies. A specific cell or tissue is targeted,

activating the complement cascade and causing

cytotoxic cells to damage membranes.

0006 Type III hypersensitivity (immune complex) in-

volves an antigen–antibody complex, causing an

inflammatory response with fixation of complement.

0007 Type IV (cell-mediated) hypersensitivity involves T

cells producing cytokines that recruit phagocytes and

other inflammatory cells. Continued stimulation of

these cells causes tissue damage.

0008In true IgE-mediated CMA, exposure of susceptible

individuals to one or more of several cows’-milk al-

lergens (naturally occurring proteins) elicits the pro-

duction of allergen-specific IgE antibodies. These IgE

antibodies become fixed to the membranes of mast

cells in the tissues and basophils in the blood. This

symptomless process is called allergic sensitization.

Upon subsequent exposure to cows’ milk, the specific

cows’-milk allergen cross-links two IgE antibodies on

the membrane surface of the sensitized mast cells and

basophils. This interaction triggers the release of a

host of bioactive mediators from the mast cells and

basophils, including histamine, leukotrienes, and

prostaglandins. These mediators are responsible for

the range of symptoms experienced in an allergic

reaction.

0009Cows’-milk protein intolerance (CMPI), not to

be confused with IgE-mediated CMA, is generally a

nonimmune-mediated reaction against cows’-milk

proteins. CMPI is probably a cell-mediated inflam-

matory reaction that damages the absorptive function

of the intestinal tract. Symptoms are primarily gastro-

intestinal (nausea, abdominal cramps, and diarrhea)

and delayed, appearing several days after milk inges-

tion. Generally, CMPI is a disorder occurring in

infancy that is frequently outgrown.

0010Lactose intolerance refers to inadequate diges-

tion of lactose, the major carbohydrate found

in milk, usually from a deficiency or low levels

of b-galactosidase (lactase) enzyme. Lactose

intolerance produces gastrointestinal symptoms,

including cramps, bloating, gas, diarrhea, and/or

nausea. In contrast to CMPI and CMA, lactose in-

tolerance primarily affects adults.

Composition

0011Cows’ milk is a nutrient-dense food consisting of

varying amounts of carbohydrate, fat, and protein.

The major constituents of cows’ milk are water

(87.4%) and milk solids (12.6%), which includes

vitamins, minerals, carbohydrate, fat, and protein.

Cows’ milk is known to contain many nutrients,

including varying concentrations of fat and water-

soluble vitamins, minerals, trace elements, and

salts. The principal carbohydrate in milk is lactose.

The lactose content of milk varies by species. Cows’

milk contains about 4.8% lactose (12–12.5 g lactose

per cup), whereas human milk has 7% lactose.

In addition to lactose, minor quantities of glucose,

galactose, and oligosaccharides are present. Milk

fat is a complex lipid existing as an oil-in-water

emulsion. Milk lipids are mainly triacylglycerols

or fatty acid esters with glycerol, of which more

than 400 have been identified. Phospholipids,

FOOD INTOLERANCE/Milk Allergy 2631

sterols, waxes, and free fatty acids have also been

identified.

0012 Cows’ milk is a heterogeneous mixture of at least

20 proteins. Eighty percent of the total protein is

casein proteins and 20% is whey proteins. Caseins

are relatively heat-stable, whereas whey proteins are

more labile. Casein can be fractionated into four

major components: alpha, beta, kappa, and gamma

casein. The whey proteins consist of a-lactalbumin, b-

lactoglobulin, bovine serum albumin, and several

minor proteins, including lactoferrin and lactoper-

oxidase.

0013 Great variability of the human IgE response to

cows’ milk exists. Many patients are allergic to

more than one milk protein. The major allergens of

cows’ milk are a-

casein and b-lactoglobulin. a-

Lactalbumin is also involved in some patients. IgE

antibodies directed to minor cows’-milk proteins,

such as bovine serum albumin and lactoferrin, have

been identified in a few patients but their role in CMA

is not firmly established.

Prevalence

0014 CMA and CMPI are primarily diseases of infancy.

CMA has become one of the most common food

allergies in early childhood since cows’ milk is usually

one of the first foreign antigens encountered in large

quantities in infancy. Most infants develop symptoms

before 1 month of age, often within 1 week of

introduction. Onset of CMA after 1 year of age is

extremely rare. Major risk factors for CMA are a

positive family history of CMA or other atopic dis-

ease and early cows’-milk protein exposure. The

onset of disease in most cases is closely related to

the time of introduction of cows’-milk products.

The prevalence of allergy to cows’ milk is reported

to be about 2% of the general pediatric population in

developed countries. CMA occasionally occurs in

adults, affecting less than 1% of the adult population;

however, good prevalence estimates for CMA in

adults are not available.

Prevention

0015 Because cows’ milk is usually one of the first foreign

antigens encountered in infancy, preventive measures

are ideally employed during this time period, particu-

larly in children of atopic parents. Although conflict-

ing data exist and no single prevention method is

completely effective, protective effects have been

seen with breast-feeding and delaying introduction

of cows’ milk.

0016 Prolonged breast-feeding in all infants is the ideal

source of nutrition, providing immunological factors,

developing intestinal maturation, and enhancing

infant–mother bonding. The protective effect of

breast-feeding may be due, in part, to avoidance

of high doses of cows’-milk proteins or an inherent

protective effect of human milk. Support for the

benefits of breast-feeding in preventing or delaying

the development of CMA has been seen in

prolonged breast-feeding practice of at least 6

months. In addition to breast-feeding, delaying the

introduction of cows’ milk until 6 months of age

also has a preventive effect. If breast-feeding is not

possible or during weaning, an extensively hydro-

lyzed formula in combination with delayed milk

introduction may be protective. Partially hydrolyzed

infant formulas (PHF) are also available. These

formulas appear beneficial in the prevention of

sensitization to cows’ milk and are more palatable

than extensively hydrolyzed formula (EHF). But the

partial hydrolysates can provoke allergic reactions

in previously sensitized infants. There may be a pre-

ventive effect of maternal avoidance of common

allergenic foods during lactation but there has been

no protective effect shown for an altered diet

during pregnancy. Occasionally, CMA seems to de-

velop in exclusively breast-fed infants, ostensibly

from exposure to small amounts of cows’-milk pro-

teins secreted into the breast milk and arising from

the mother’s diet. However, cows’ milk is so import-

ant in the nutrition of lactating women that avoid-

ance of cow’s milk during the lactation period is not

often recommended. Similarly, the practice of cows’

milk avoidance during pregnancy should not be sug-

gested because it may put the health of the mother as

well as the fetus in jeopardy of nutritional compli-

cations or deficiencies.

Symptoms/Manifestation

0017Clinical manifestations and severity of symptoms of

CMA vary widely from one individual to another.

Symptoms arise involving the skin, gastrointestinal

or respiratory tracts. The majority of patients have

greater than two symptoms affecting greater than two

organs/systems. CMA in individuals exhibiting gas-

trointestinal symptoms and/or dermatitis usually re-

solves early in life, whereas individuals with urticaria,

angioedema, respiratory symptoms, or anaphylaxis

may persist with CMA into adult life.

0018Individuals with immediate reactions often exhibit

systemic anaphylaxis and/or dermatological symp-

toms. Anaphylaxis is a systemic, multiorgan reaction

associated with IgE-mediated hypersensitivity. It may

progress slowly or rapidly and can involve hypoten-

sion, bronchospasm, edema, and cutaneous symp-

toms. Treatment for anaphylaxis involves the use of

2632 FOOD INTOLERANCE/Milk Allergy

epinephrine (adrenaline) given intramuscularly, anti-

histamines, and steroids. Although severe reactions to

cows’ milk are rare, deaths have been documented.

Dermatological features may include urticaria,

angioedema, and eczema (dermatitis).

0019 Intermediate reactions occurring from 1 to 24 h

after ingestion may involve gastrointestinal symp-

toms, including vomiting, diarrhea, reflux, colic,

and bleeding.

0020 Symptoms appearing more than 24 h after cows’-

milk ingestion often affect the respiratory tract and

skin. Respiratory symptoms may involve nasal stuffi-

ness, coughing, wheezing, tachypnea, and rhinitis.

Atopic dermatitis is a rather common manifestation

of CMA involving the skin; it can be a chronic

condition.

Diagnosis

0021 Differentiation between CMA and CMPI cannot

be based on clinical symptoms alone, nor is there a

lone clinical test. The first step in evaluation of some-

one with a history of possible adverse reactions is to

take a detailed food history. Along with identifying

the suspected food, the quantity of food needed to

produce symptoms and the frequency with which

reactions occur need to be reported. Physical exams

may be helpful in revealing a chronic skin condition

such as atopic dermatitis. However, other physical

signs, such as respiratory symptoms, may be present

but are not necessarily a result of food hypersensitiv-

ity and may be attributed to other conditions. Gastro-

intestinal complaints, in particular, can have

numerous causes.

0022 Diagnosis is usually based on cows’-milk protein

elimination and challenge tests. Open, controlled

cows’-milk challenges are recommended for in-

fants 0–1 year. In children older than 1 year and

adults, double-blind placebo-controlled challenges

(DBPCFC) are performed. These tests determine if

cows’ milk is the cause of symptoms but do not

identify the mechanism.

0023 Several methods, including skinprick test and radio-

allergosorbent test (RAST), are available as diagnostic

tools in identifying immunological-mediated CMA.

Recent advances in RAST have improved the diag-

nostic value of these tests and lessened the need to

perform DBPCFCs. Milk-specific IgE is seen in some

milk-hypersensitive individuals but not all. CMPI

may be suspected if symptoms are restricted to the

gastrointestinal tract and have delayed onset,

especially in cases where specific IgE antibodies are

absent.

0024 Presently, allergic sensitization to cows’-milk pro-

teins usually occurs during the first few years of life,

often disappearing thereafter. The majority of

children outgrow CMA and CMPI and will acquire

tolerance, with an estimated remission rate of 85–

90% before 3 years of age. However, an early in-

creased IgE response to cows’ milk proteins is associ-

ated with an increased risk of persisting allergy to

cows’-milk proteins, development of asthma or rhi-

noconjuctivitis, or development of atopic disorders

later in life.

Treatment/Management

0025Treatment of CMA and CMPI involves the strict

avoidance of cows’ milk and products containing

cows’-milk proteins. Because even a minute amount

of allergen has the potential to trigger sensitization

and/or symptoms, awareness is key in treatment.

Breast milk is the ideal source of nutrition. If breast-

feeding is not possible, numerous formulas are avail-

able as cows’-milk substitutes.

0026Soy protein formulas can be well tolerated by some

individuals. However, soy is also a commonly aller-

genic food and has been reported to cause symptoms

in some CMA individuals due to the development of

soy allergy.

0027Meat-based formulas from sources such as chicken

or lamb may be used but have also been shown to

cause symptoms on rare occasions. Also, a formula

based on goats’ milk contains b-lactoglobulin and

often causes symptoms in CMA individuals.

0028More commonly, modified-protein formulas are

the treatment of choice. Protein hydrolysates are

classified as PHF or EHF and may be derived from

casein or whey. For the most part, however, these

EHFs are generally tolerated and are a good alterna-

tive for CMA management. A few CMA infants will

respond adversely to trace amounts of milk proteins

or peptides present in EHF.

0029PHF were developed for the purpose of dietary

prevention of CMA and are not recommended for

individuals who already have CMA. EHF have been

in use for over 50 years as a therapeutic diet in

CMA management and are the recommended treat-

ment. However, palatability of EHF is an issue, and

EHF can be quite costly. In severely sensitive indi-

viduals, hypoallergenic, nutritionally complete

infant formula composed of individual amino acids

(elemental formula) may be the only effective substi-

tute.

0030Hypoallergenic formula or breast-feeding should

be the recommended dietary options for infants with

CMA for the first 6 months of life. From 6 months

of age, solid foods may be introduced. Generally,

highly allergenic foods such as egg, soy, peanut, fish,

and wheat are also avoided until the age of 1 year.

FOOD INTOLERANCE/Milk Allergy 2633

Reintroduction of cows’-milk protein may be per-

formed in 3–6-month intervals after the age of

1 year; with infants having severe CMA, pediatric

advice should be sought before attempting reintro-

duction.

0031 Education of both the affected child and parents

is vital to successful management of CMA. Both

the physician and dietitian can provide guidance

and recommend ways for introducing foods in

childhood. This helps guarantee a cows’-milk pro-

tein-free diet as well as a nutritionally complete diet.

Dietitians are also very useful in teaching how to read

labels on food packages and identifying milk-derived

products.

See also: Food Intolerance: Types; Food Allergies;

Lactose Intolerance; Elimination Diets; Infant Foods:

Milk Formulas

Further Reading

American Academy of Pediatrics Committee on Nutrition

(2000) Hypoallergenic infant formulas. Pediatrics 106:

346–349.

Exl B-M, Mu

ller-Teicher G and Vandenplas Y (2000) Pre-

ventative possibilities within the context of cow’s milk

allergy. Allergy and Clinical Immunology International

12: 68–76.

Hosking CS, Heine RG and Hill DJ (2000) The Melbourne

milk allergy study – two decades of clinical research.

Allergy and Clinical Immunology International 12:

198–205.

Novembre E and Vierucci A (2001) Milk allergy/intoler-

ance and atopic dermatitis in infancy and childhood.

Allergy 56(suppl. 67): 105–108.

Pelto L, Salminen S, Lilius E-M, Nuutila J and Isolauri E

(1998) Milk hypersensitivity – key to poorly defined

gastrointestinal symptoms in adults. Allergy 53:

307–310.

Savilahti E, Kuitunen P and Visakorpi JK (1981) Cow’s milk

allergy. In: Lebenthal E (ed.) Textbook of Gastroenter-

ology and Nutrition in Infancy, pp. 689–708. New York:

Raven Press.

Sicherer SH (2000) Determinants of systemic manifest-

ations of food allergy. Journal of Allergy and Clinical

Immunology 106: S251–S257.

Sprikkelman AB, Heymans HS and Van Aslderen WMC

(2000) Development of allergic disorders in children

with cow’s milk allergy or intolerance in infancy. Clin-

ical and Experimental Allergy 30: 1358–1363.

Wal J-M (1998) Cow’s milk allergens. Allergy 53:

1013–1022.

Zeiger RS (2000) Dietary aspects of food allergy prevention

in infants and children. Journal of Pediatric Gastroenter-

ology and Nutrition 30: S77–S86.

Lactose Intolerance

F Suarez, Abbott Laboratories, Columbus, OH, USA

C Shannon, The Toledo Hospital, Toledo, OH, USA

S Hertzler, The Ohio State University, Columbus, OH,

USA

D Savaiano, Purdue University, West Lafayette, IN,

USA

Introduction

0001Lactose intolerance is best defined as the development

of gastrointestinal symptoms after the consumption

of the ‘milk sugar’ lactose. Symptoms of intolerance

can occur in most humans and all mammals if the

amount of lactose consumed exceeds the ability of the

gastrointestinal tract to digest this lactose. Thus, lac-

tose intolerance is intermittent since it depends on

both the dose of lactose and the response of the

gastrointestinal tract. Lactose, a carbohydrate unique

to milks and dairy foods, is a disaccharide composed

of glucose and galactose, synthesized in the mammary

glands of almost all mammals. Young mammals have

a large capacity to digest lactose due to a very high

activity of a digestive enzyme (a lactase) found on the

lining of the small intestine. Most humans and all

mammals exhibit a reduced level of this lactase

enzyme (and thus a reduced capacity to digest lactose)

as they mature past infancy. Interestingly, approxi-

mately 25% of the human population maintains a

high level of lactase activity and therefore a large

capacity to digest lactose throughout life. These indi-

viduals are called lactose-tolerant or lactose digesters.

A more scientific name for this group is lactase-per-

sistent since the enzyme activity is maintained or

persists. The majority of lactose digesters come from

northern European, central African and Middle East-

ern backgrounds. The remaining 75% of the world’s

population, including almost all Asians, Native

Americans, and many Africans and Latinos, are thus

described as lactose-intolerant or lactase-nonpersis-

tent. The regulation of intestinal lactase activity is

under genetic control.

0002The belief that lactase-nonpersistent individuals

will always have abdominal symptoms, such as flatu-

lence, abdominal pain, and diarrhea, following dairy

food consumption has resulted in many individuals

eliminating dairy products from their diet in an effort

to prevent symptoms. However, dairy products pro-

vide key nutrients and the majority of calcium found

in the food supply. The elimination of milk and milk

products from the diet makes it very difficult to obtain

the recommended dietary allowance of calcium

from natural dietary sources. The average American

2634 FOOD INTOLERANCE/Lactose Intolerance

woman consumes only 50–60% of the 1000–1500 mg

recommended for maximum retention of body cal-

cium. Inadequate calcium intake compromises bone

structure and may eventually result in osteoporosis.

Thus, it is important to provide clear dietary manage-

ment that allows lactase-nonpersistent individuals

to consume adequate amounts of essential nutrients,

including calcium, while avoiding symptoms of

intolerance.

0003 Lactose intolerance must not be confused with milk

allergy. Milk allergy is caused when the immune

system reacts against one or more of the proteins

found in milk. Milk allergy usually develops in early

infancy, before 1 year of age. In developed countries,

the incidence in infancy is estimated at 5% and

the remission rate is about 90% before 3 years of

age. Gastrointestinal symptoms are reported in ap-

proximately 50% of infants with milk allergy while

cutaneous symptoms are more common and respira-

tory symptoms less so. In contrast, lactose intolerance

has no immunological bases, only follows the loss of

intestinal lactase activity, which occurs around 3–5

years of age, and is limited to gastrointestinal symp-

toms.

0004 To understand the dietary management of lactose

intolerance, it is important to recognize that multiple

factors affect the body’s ability to digest and tolerate

lactose. These factors include: (1) the amount of lac-

tose ingested; (2) the level of the residual lactase

activity that remains after maturation; (3) gastro-

intestinal transit time; and (4) the capacity of the

colonic microflora to ferment (digest) lactose. This

article will review these factors in order to describe

a dietary approach to eliminate symptoms of intoler-

ance while consuming adequate calcium, as well as to

correct the perception that lactose intolerance is a

frequent and severe problem.

Lactose Digestion and Lactase Activity

0005 Lactose is present in varying degrees in all mamma-

lian milk, with the exception of the milk of the

sea lion. Mammary glands have a unique capability

to synthesize lactose via the enzyme lactose synthe-

tase. Lactose sythetase links the two monosaccharides

(simple sugars) glucose and galactose by a beta 1–4

bond, forming the disaccharide lactose. Cows’ milk

contains about 50 g l

1

of lactose, whereas human

milk contains one of the highest concentrations, up

to 75 g l

1

. Table 1 lists the lactose content of

common dairy foods. Fluid milk products have the

highest concentration of lactose. When cheese is

manufactured, lactose remains with the whey. Thus,

hard cheeses contain very small amounts of lactose

since the whey is removed in the elaboration process.

Lactose may also be found in medications in biologic-

ally insignificant amounts (milligrams) due to its

excellent tablet-forming properties.

0006Dietary lactose cannot be absorbed intact directly

across the small intestinal mucosa; it must first be

hydrolyzed. The enzyme lactase-phlorizin hydrolase

(commonly called lactase), a disaccharidase located

on the brush border of the intestinal epithelium,

breaks the chemical bond between glucose and gal-

actose. These monosaccharides are absorbed across

the intestine and transported to the liver for utiliza-

tion. The lactase enzyme is found must abundantly

in the proximal ileum and specifically only hydrolyzes

lactose. Human infant lactase is the last of the dis-

accharidases to appear during fetal production. The

gene responsible for the synthesis of lactase has been

located in humans on chromosome 2. Lactase activity

can be detected as early as 8 weeks after conception

and increases to that of only one-third of a full-term

infant by 34 weeks’ gestation. During late gestation

(35–38 weeks), lactase activity reaches approxi-

mately three-quarters of that of a full-term infant.

Lactase synthesis and activity are high in nearly all

full-term infants and remain high throughout the first

4 years of life.

0007At some point after weaning, a genetically

programmed reduction of lactase synthesis occurs,

in approximately three-fourths of the world’s

population, to a residual level of 5–10% that of in-

fancy. This loss of intestinal lactase activity is not a

disease, but rather a normal pattern in human physi-

ology and is transmitted by a recessive gene. The

decline in lactase activity is known as lactase-

nonpersistence (LNP) or primary acquired hypo-

lactasia and cannot be modified by continued expos-

ure to milk or lactose.

0008In humans there appears to be a mosaic pattern

of lactase activity in the jejunal enterocytes. In LNP

individuals, some jejunal enterocytes produce high

amounts of lactase while others, even those sharing

the same villus, do not produce lactase. Thus,

rather than a uniform reduction in lactase production

among all enterocytes, a hypolactasic individual

may have a patchy distribution of lactose-producing

enterocytes that are low in number relative to the

nonlactase-producing enterocytes. Current evidence

suggests that the regulation of lactase is accomplished

primarily at the level of transcription, although post-

transcriptional factors may still be elucidated.

0009Congenital lactose intolerance is an extremely rare

inborn error in metabolism in which detectable levels

of lactase are absent at birth (0–10 IU g

1

protein)

and remain abnormal throughout life. An infant

with congenital lactase deficiency will have severe

diarrheal illness beginning a few days after birth.

FOOD INTOLERANCE/Lactose Intolerance 2635

Treatment with a lactose-free diet eliminates symp-

toms and promotes normal growth and development.

0010 Because lactase enzyme protrudes from the mem-

brane of the epithelial cell and the greatest activity is

found at the tip of the intestinal villi, lactase is ex-

tremely vulnerable to intestinal disease or insult. Sec-

ondary hypolactasia is a temporary condition caused

by damage to the enterocytes via disease, poisons

such as alcohol, medications, surgery, or radiation

to the gastrointestinal tract (Table 2). This condition

is relatively common in developing countries, but

most common in Third-World countries where

chronic intestinal infections are prevalent. Once the

causative disease is resolved and the epithelium heals,

lactase activity returns to normal. Total resolution of

the insufficiency may require up to 6 months or more

of diet therapy.

Assessment of Lactase Levels and

Lactose Maldigestion

0011Lactase level can be ascertained with a modest degree

of accuracy simply from the determination of the

subject’s heritage, because prevalence varies among

ethnic and racial groups (Table 3). Individuals of

African, Asian, middle Eastern, Mediterranean

(Jews, southern Italians, Greeks, Arabs), and Native

American origin have a greater than 70% chance of

being LNP. Subjects of Scandinavian and middle

European origin have about a 5% and 15% chance

of being LNP, respectively.

0012The geographical and racial distribution of lactase

persistence has led to the hypothesis that three separ-

ate gene mutations occurred several thousands of

years ago in places where dairy foods had become

tbl0001 Table 1 Lactose and calcium content of selected milks, milk products, and substitutes

Product Serving size Lactose (g perserving) Calcium (mg)

Milk 1 c (237 g) 11 291

Low-fat milk, 2% fat 1 c (237 g) 9–13 297

Lactaid milk, 1% fat, 70% lactose-reduced 1 c (237 g) 3.6 300

Skim milk 1 c (237 g) 12–14 302

Chocolate milk 1 c (237 g) 10–12 280

Sweetened, condensed whole milk 1 c (306 g) 35 868

Dried whole milk 1 c (128 g) 48 1168

Nonfat dry milk, instant 1.5 c (91 g) 46 1120

Buttermilk, fluid 1 c (245 g) 9–11 285

Whipped-cream topping 1 tbs (3 g) 0.4 10

Light cream 1 tbs (15 g) 0.6 14

Half and half 1 tbs (15 g) 0.6 16

Low-fat yogurts 1 c (227–258 g) 11–15 314–415

Cheese

Blue 1 oz (28 g) 0.7 150

Camembert 1 oz (28 g) 0.1 110

Cheddar 1 oz (28 g) 0.4–0.6 204

Colby 1 oz (28 g) 0.7 194

Cream 1 oz (28 g) 0.8 23

Gouda 1 oz (28 g) 0.6 198

Limburger 1 oz (28 g) 0.1 141

Parmesan, grated 1 oz (28 g) 0.8 390

Cheese, pasteurized, processed

American 1 oz (28 g) 0.5 174

Pimento 1 oz (28 g) 0.5–1.7 174

Swiss 1 oz (28 g) 0.4–0.6 219

Cottage cheese 1 c (210 g) 5–6 126

Cottage cheese, low-fat, 2% fat 1 c (226 g) 7–8 155

Butter 2 pats (10 g) 0.1 2

Oleomargarine 2 pats (10 g) 0 1

Ice cream

Vanilla, regular 1 c (133 g) 9 176

French, soft 1 c (173 g) 9 226

Ice milk, vanilla 1 c (131 g) 10 176

Sherbet, orange 1 c (193 g) 4 103

Ice, orange 100 g 0 0

c, cup; tbs, tablespoon.

2636 FOOD INTOLERANCE/Lactose Intolerance

an important component of the adult diet. Darwinian

theory suggests that mutation yielded a survival ad-

vantage to subjects provided they were drinking

milk. Herding animals and the use of mammalian

milk as a human food originated in northern Europe,

the Middle East, and central Africa several thousand

years ago. Interestingly, it is in these populations that

lactase persistence also appeared. Thus, the current

view is that selective advantage in these populations

led to the maintenance of a genetic mutation in each

of these three populations. Inheritance has spread the

persistence trait to other populations. Table 4 shows

that approximately 200 million individuals in the

USA are lactase-persistent.

0013Lactase levels can be measured directly or indir-

ectly. Directly assaying the lactase activity requires a

mucosal biopsy from the jejunum, since the enzyme is

attached to the brush border of the small intestinal

mucosa. Such biopsies can be obtained at endoscopies

or via the use of a variety of tubes equipped with

biopsy capsules. While this test can accurately meas-

ure lactase activity, it is an expensive, invasive, and

time-consuming test and is therefore rarely used clin-

ically. Thus, lactase activity is usually assessed indir-

ectly from measurements of lactose absorption via

blood or breath tests. Digested lactose results in free

glucose, which is absorbed rapidly, and ultimately

tbl00 02 Table 2 Potentialcausesofsecondaryhypolactasia

Diseases

Small-bowelMultisystem

HIVenteropathyCarcinoidsyndrome

Regionalenteritis

(e.g.,Crohn’sdisease)

Cysticfibrosis

Diabeticgastropathy

Sprue(celiacandtropical)Protein-energymalnutrition

Whipple’sdisease

(intestinallipodystrophy)

Zollinger–Ellisonsyndrome

Alcoholism

AscarislumbricoidesinfectionIrondeficiency

Blind-loopsyndrome

Giardiasis

Infectiousdiarrhea

Shortgut

Iatrogenic

Chemotherapy

Radiationenteritis

Surgicalresectionofintestine

Medications

Colchicine(antigout)

Neomycin(antibiotic)

Kanamycin(antibiotic)

Aminosalicylicacid(antibiotic)

Adaptedfrom:SrinivasanRandMinochaA(1998)Whentosuspectlactose

intolerance:symptomatic,ethnic,andlaboratoryissues.Postgraduate

Medicine(1988)104:109–123;ScrimshawNSandMurrayEB(1988)The

acceptabilityofmilkandmilkproductsinpopulationswithahigh

prevalenceoflactoseintolerance.AmericanJournalofClinicalNutrition48:

1083–1159;SavaianoDAandLevittMD(1987)Milkintoleranceand

microbe-containingdairyfoods.JournalofDairyScience70:397–406.

HIV,humanimmunodeficiencyvirus.

tbl00 03 Table 3 Projectionsoflactosemaldigestionaroundtheworld(inmillions)

Area%Lactose

maldigesters

(LM)

199020002020

PopulationLMPopulationLMPopulationLM

Africa756294728056041172879

Asia100318631863688368845784578

Europe 20 721 144 729 146 722 144

Latin America 70 442 309 520 364 645 452

North America 25 278 70 307 77 363 91

Oceania 25 27 7 31 8 38 10

World 5283 4188 6080 4887 7518 6154

(79%) (80%) (82%)

GeoHive,2002ONLINE.Availablehttp://www.geohive.com/global/index.php[2002].

tbl0004 Table 4 Projections of lactose maldigestion in the USA (in millions)

% Lactose

maldigesters

(LM)

19 9 0

millions of

people

millions of

people

2000

millions of

people

millions of

people

2025

millions of

people

millions of

people

African-Americans 75 30 23 34 25.5 44 33

Asian-Americans 100 7 7 11 11 20.5 20.5

Caucasian 20 188 28 197 39.4 209 41.8

Hispanic (all races) 60 22 13 31 18.6 60 36

Native Americans 100 2 2 2 2 2.5 2.5

Total 29 249 72 275 96.5 336 133.8

(% of population) 29% 35% 40%

Source: US Department of Commerce; 1990 census and estimates.

FOOD INTOLERANCE/Lactose Intolerance 2637