Milk - Soy Protein Intolerance

Background
Soy-based formulas were introduced in infant nutrition 100 years ago, when their use was
recommended for the treatment of summer diarrhea. Eighty years ago, the use of soy-based
formulas was extended to the treatment of cow's milk intolerance. In the 1970s, use of soy-based
formulas became common; in the 1970s and 1980s, US consumption of soy-based formulas was
around 25% of that of cow's milkbased formulas.
In the last few years, interest in soybeans and soybean components has markedly increased,
mainly because of the potential influence of soy on the development of heart disease, cancer,
kidney disease, osteoporosis, and menopause symptoms. Unfortunately, soy protein formulas
(SPFs) can cause allergies and other intolerance reactions. For many years after the first
description by Duke in 1934, soy was considered a weak sensitizing protein based on animal
study findings. In the 1960s, several other authors confirmed the potential allergenicity of soy
protein formulas.
A higher prevalence of soy intolerance has generally been reported in nonimmunoglobulin E
(IgE)-associated enterocolitis and enteropathy syndromes. Authorities have failed to reach
consensus on the risk of feeding allergic or nonallergic infants with soy protein milks.[1, 2] This
divisive clash of opinion is also reflected in the mutually antagonistic stances adopted by 2
important scientific societies, the European Society for Pediatric Gastroenterology, Hepatology,
and Nutrition (ESPGHAN) and the European Society of Pediatric Allergy and Clinical
Immunology (ESPACI).
However, the general agreement is that a significant number of children with cow's milk protein
intolerance develop soy protein intolerance when soy milk is used in dietary management. For
this reason, the American Academy of Pediatrics (AAP) and ESPGHAN recommend the use of
extensively hydrolyzed or free amino acid-based formulae in the treatment of cow's milk protein
allergy.[3] According to ESPGHAN, soy protein formula should particularly not be used in
infants with food allergy during the first 6 months of life.[4]
However, the AAP states that infants with IgE-associated symptoms of cow's milk allergy may
benefit from a soy formula because the risk of cross-reactivity does not appear to be very high.[3]
A Cochrane systematic review confirms that soy formula cannot be recommended for prevention
of allergy or food intolerance in infants.[5]

Pathophysiology
Two heat-stable globulins constitute 90% of the pulp-derived proteins: beta-conglycinin, which
has a molecular weight (MW) of 180,000, and glycinin, which has an MW of 320,000.
Immunoblotting and competitive enzyme-linked immunosorbent assays have identified a 30-kD
glycinin from soybeans that cross-reacts with cow's milk caseins and is composed of 2

polypeptides (A5 and B3) linked by a disulphide bond. The protein's capacity to bind to the
different antibodies relies on the B3 polypeptide.
However, other soy proteins can act as allergens in humans. At least 9 proteins with MW ranging
from 14,875-54,500 were found to react with human IgE in patients with asthma. Moreover, after
enteric digestion, numerous potential antigens are generated at the mucosal surface.
According to some animal study findings, soy proteins appear to be less sensitizing than cow's
milk proteins; however, infants with a previous history of cow's milk protein intolerance have a
greater risk of developing soy protein intolerance. The intestinal mucosa damaged by cow's milk
proteins may allow increased uptake of the potentially allergenic soy proteins.
Antigenicity of soy-based products is strongly influenced by methods of preparation; therefore,
clinical manifestations can be elicited by some soy-based products and not others.

Phytoestrogens
All soybean proteins and foods currently available for human consumption contain significant
amounts of the isoflavones daidzein and genistein, either in the unconjugate form or as different
types of glycoside conjugates.
The isoflavones have structural homology to steroidal estrogens; therefore, they are considered
to be phytoestrogens, but little is known about their biological activity. Unquestionably,
isoflavone ingestion can elicit biological effects; however, isoflavones and their metabolites have
biological properties that are quite separate from classic estrogen action.
Genistein is a potent inhibitor of tyrosine kinases and can interfere with signal transduction
pathways. The threshold intake of dietary estrogens necessary to achieve a biological effect in
healthy adults appears to be 30-50 mg/d.
In soy flours and concentrates, isoflavone concentrations are relatively high (0.5-3 mg/g). In soy
milk and soy-based infant formulas, the concentration of isoflavones is lower (0.3-0.5 mg/g) but
is 10,000-fold higher than the concentration found in breast milk. Moreover, the volume intake
of these products is sufficient to account for a significantly high dietary intake of isoflavones.
Infants fed soy-based formulas have plasma concentrations of isoflavones that are 3000- to
22,000-fold higher than plasma concentrations of estradiol.
Even if these substances have a weak estrogenic activity compared with estradiol, they could
have adverse effects; however, the concerns about the adverse role of phytoestrogens in the first
months of life are exclusively theoretical. At this time, the very limited available evidence from
adult and infant populations indicates that dietary isoflavones in soy-based infant formulas do
not adversely affect human growth, development, or reproduction.
The results of a study that enrolled 48 children (mean age, 37 mo; range, 7-96 mo) suggest that
long-term feeding with soy protein formulas in early life does not produce estrogenlike hormonal
effects.[6] No developmental problems were observed in a cohort of 129 soy proteinbased

formulafed infants.[7] However, according to the Center for the Evaluation of Risks to Human
Reproduction (CERHR), the possibility that adverse effects might occur cannot be dismissed.
Without conclusive findings in humans, ESPGHAN recommends reducing the content of
phytoestrogens in soy protein formulas because of uncertainties regarding safety in infants and
young children.[4]

Epidemiology
Frequency
United States
In a national survey of pediatric allergists, the prevalence rate of soy protein allergy was reported
to be 1.1%, compared with a 3.4% prevalence rate of cow's milk protein allergy.[8]
International
In a prospective study of healthy infants fed soy-based formula, allergic responses to soy were
documented in 0.5% of infants.[9]
In a group of 243 children who were born to atopic parents and who received soy protein
formula for the first 6 months of life to prevent cow's milk allergy, 14 (6%) of the children had
positive skin test prick reactions to soy.[10] Only 1 of these 14 children reacted to the double-blind
placebo-controlled oral food challenge to soy.
The prevalence of food allergy in patients with atopic dermatitis varies with age and the severity
of atopic dermatitis. Different prevalence rates have been reported; however, in most series, 3040% of the patients received a diagnosis of food allergy. In a study from Italy, a positive
radioallergosorbent assay test (RAST) result to soy was found in 25% of children with atopic
dermatitis, but a positive challenge test result to soy was elicited in only 3% of the patients.[6]
Two other studies documented soy positivity in 5% of 204 patients[11] and in 4% of 143
children.[6] See the image below.

Typical atopic dermatitis on the face of an infant.

In a group of 93 children with documented IgE-associated cow's milk allergy who received soy
formula, 14% developed soy allergy.[12] Among 35 children with food-protein enterocolitis
syndrome diagnosed in a single center of Australia during a 16-year period, 34% had soy protein
intolerance.[13]
In 1990, one of the authors reviewed the evidence obtained from 2108 Italian children with
proven cow's milk protein intolerance and nonIgE-associated enterocolitis and enteropathy
syndrome.[14] Forty-seven percent of the patients had to discontinue soy formulas because of
intolerance. A higher prevalence was noted in infants younger than 3 months (53%). Thirty-five
percent of children older than 1 year developed soy intolerance.
A soy-based formula is often substituted for cow's milk in infants recovering from acute
gastroenteritis; however, in a previous study that recruited 18 infants with acute gastroenteritis, 3
(16%) of the children developed a clinical reaction to soy challenge, and 7 (38%) of the children
developed histologic and enzymologic changes after soy challenge.[15]

Mortality/Morbidity
Anaphylactic reactions to soy proteins are extremely rare; however, a population study in
Sweden from 1993-1996 reported 4 deaths caused by soy.[16]

Age

The risk of developing soy protein intolerance decreases with age. Among children with cow's
milk protein intolerance, infants younger than 3 months are at higher risk for developing soy
protein intolerance (53%) compared with children older than 1 year (35%).

History
The typical presentation is that of an infant who develops atopic dermatitis or cow's milk protein
intolerance, which resolves with substitution of a soy-based formula but recurs 1 or 2 weeks
later. Parents may report a recrudescence of dermatitis or GI symptoms. Usually, the infant
presents with watery diarrhea and vomiting.
Soy protein intolerance may cause different clinical syndromes, both immunoglobulin E (IgE)mediated and nonIgE-mediated, ranging from skin, GI, or respiratory tract reactions up to
anaphylaxis. These reactions include the following:

Rhinitis
Urticaria or angioedema
Asthma
Atopic dermatitis
Food proteininduced enterocolitis syndrome (FPIES)
Intestinal villous atrophy (malabsorption syndrome)
Eosinophilic gastroenteritis
Allergic proctocolitis
Constipation
Anaphylaxis (rare)

A European multicenter study, which included both children and adults (mean age, 26.4 y; range
1-69 y), showed that bronchial asthma and seasonal rhinoconjunctivitis are the most frequent
symptoms (65% of patients), followed by atopic dermatitis (33%). In this group of patients, the
first reaction to soy occurred at a mean age of 19 (10) years (range, 3-44 y).[17]
In young children and in infants, soy protein intolerance occurs mainly with dermatological and
GI manifestations. Some children present with atopic dermatitis as a major symptom; however,
most patients present with profuse vomiting and watery diarrhea.
Soy proteins can cause GI manifestations similar to those described in the Medscape Reference
article Protein Intolerance. Although the prevalence of soy protein allergy has been traditionally
considered to be quite high (for cross-reactivity) in infants and children with milk protein allergy
presenting with FPIES, a large epidemiological investigation failed to confirm such high
prevalence.[18]
GI symptoms are very frequent in children with cows milk proctocolitis or enterocolitis who are
fed with soy proteins. Symptoms usually begin within 2 weeks of the infant's first feeding with
soy-derived milk. Sometimes mucus can be present in the stools, but blood is rarely noted. Even
if frank manifestations of colitis are absent, inflammatory changes in the colonic mucosa are
frequently encountered.

Small-bowel atrophy has been documented in different studies. The degree of villous atrophy
may be similar to that found in celiac disease. The mucosal damage may lead to malabsorption,
hypoalbuminemia, and failure to thrive.
Some breast-fed infants can present with red blood mixed in stools as a result of soy allergic
proctocolitis. These infants usually appear healthy, and hematochezia is the only symptom. In
some cases, the syndrome, which can be traced down to maternally ingested soy in about 30% of
cases, does not respond to withdrawal of food allergens from the maternal diet.[19]
A case of recurrent intussusception in an infant with a patch test positive to soy has been
reported. The intussusceptions, which were considered a consequence of lymphoid hyperplasia,
resolved with die and recurred after reintroduction of soy.[20]
Food allergies (including to soy protein) may lead to constipation. Removal of the allergen from
the diet is typically very effective.[21]
The possibility of anaphylaxis occurring in adults ingesting generic drugs containing soybean oil
has also been reported.[22]
In children, approximately 50% of those with soy allergy can outgrow their allergy by age 7
years. Absolute soy IgE levels were useful predictors of outgrowing soy allergy.[23]

Physical
The physical examination findings depend on the clinical picture and the duration of symptoms.

The most frequent presentation is enterocolitis syndrome; therefore, the infant appears
dehydrated, with weight loss and sunken eyes.
In case of proctocolitis, the infant usually appears healthy and has normal weight gain.
In the less frequent case of soy-induced enteropathy, the infant has a low weight-tolength ratio and usually presents with dystrophia.
The signs and symptoms are related to the degree of the malnutrition. For example,
edema is related to hypoalbuminemia, dermatitis enteropathica is related to low zinc
level, and rickets is related to vitamin D deficiency.

Causes
See the list below:

According to some studies in animal models, soy proteins appear to be less sensitizing
than cow's milk proteins. However, because a 30-kD protein in soy may induce crossreactivity to cows milk caseins, infants with a previous history of cow's milk protein
intolerance have a greater risk of developing soy protein intolerance.
The intestinal mucosa damaged by cow's milk proteins may allow increased uptake of the
potentially allergenic soy proteins.

Diagnostic Considerations
GI bleeding
Celiac disease
Malabsorption syndrome
Infectious colitis
Enteropathy
Cow's milk protein intolerance
Autoimmune enteropathy
Intractable diarrhea of infancy
Intestinal infections
Enterocolitis
Intestinal infections
Cow milk protein intolerance
Inflammatory Bowel Disease
Proctocolitis
Anal Fistulas and Fissures
Meckel Diverticulum
Intestinal duplication
Intestinal hemangiomas
Intestinal infections
Cow milk protein intolerance
Inflammatory Bowel Disease

Differential Diagnoses

Emergent Treatment of Gastroenteritis

Pediatric Gastroesophageal Reflux
Ulcerative Colitis Imaging

ther Tests
See the list below:

Soy-induced GI symptoms are not usually immunoglobulin E (IgE)-mediated; therefore,

both skin tests and determination of specific IgE in serum have a low diagnostic value.
Radioallergosorbent assay test (RAST) appears to be of poor predictive value. Many
children with positive results do not react to challenge tests.
Prick tests have little predictive value. The acidic subunits of glycinin and betaconglycinin appear to be present in reduced amounts or absent in some commercial
soybean skin test extracts tested by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE) and immunoblotting. As a consequence, these commercial
extracts are less sensitive than extracts of soy flour.
Patch testing may provide more clinical relevant informations, particularly in children
with eczema.
The role of atopy patch test in children with food allergies (including to soy) presenting
with constipation has also been suggested.[21]
The challenge test with soy proteins, after an elimination diet, is the only reliable method
of evaluating soy protein intolerance.

Procedures
Endoscopy
During the workup for differential diagnoses, upper or lower GI endoscopies are often performed
in patients with soy protein intolerance. However, findings are nonspecific, most commonly
minimal, and, at times, even completely unremarkable. Accordingly, and because of the transient
nature of the disorder, endoscopies are not considered essential.

Esophagogastroduodenoscopy
See the list below:

Macroscopically, only minimal erythematous changes may be observed.

Microscopically, any area (eg, lower esophagus, gastric body, antrum, duodenum) may or
may not show signs of acute inflammation.
In a minority of patients, an infiltrate of eosinophils is observed.
When the clinical presentation is that of a malabsorption syndrome, the duodenal mucosa
may have changes (eg, partial villous atrophy, crypt hyperplasia) indistinguishable from
those of celiac disease.

Colonoscopy
See the list below:

Macroscopically, changes may vary from minimal erythematous segments, most

commonly diffusely involving the distal colon, to severe inflammation with bleeding
ulcers and loss of vascular markings.
Microscopically, nonspecific acute inflammatory changes are observed, typically
indistinguishable from infectious colitis. Rarely, eosinophils predominate in the lamina
propria.

Medical Care
Children affected by soy protein intolerance respond quickly to elimination of soy formula and
introduction of a hydrolyzed protein formula.
Numerous therapeutic strategies have become to be investigated targeting foods that most
frequently provoke severe IgE-mediated anaphylactic reactions (peanut, tree nuts, and shellfish)
or are most common in children, such as cow's milk, soy, and egg. Approaches being pursued are
both food allergenspecific and nonspecific. The former include oral, sublingual, and
epicutaneous immunotherapy (desensitization).[24]

Medication Summary
Drug therapy is not currently a component of the standard of care for soy protein intolerance.

Prognosis
See the list below:

Soy protein intolerance is similar to other food protein intolerances. Its risk peaks during
infancy, and it usually regresses completely during the first 2-3 years of life. Most
children, therefore, can resume consumption of soy proteins by age 5-7 years.[23]

Patient Education
See the list below:

Use of soy protein formula (SPF) during the first 3 months of life does not reduce the
frequency of cow's milk intolerance after the introduction of cow's milk formula.
Routine use of soy protein formula has no proven value in the prevention of atopic
disease.
Routine use of soy protein formula has no proven value in the prevention or management
of infantile colic.