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Contents A. Case study B. More information C. Editors' comments D. References E. CEU questions

Index

A. Case study
A 13-month-old boy presented with gastrointestinal symptoms. After a thorough clinical assessment it was concluded that food allergy was the cause. The mother thought that it may be due to milk, but the reactions to milk were not consistent. The boy was already eating a wide range of foods.

THOUGHT PROCESS:
How does one go about finding the cause of the food allergy?
a. Perform a blood test or skin prick test
b. Ask the mother to keep a food-symptom diary for a period of time to see whether a food-symptom pattern exists
c. Do elimination diet and challenges

DISCUSSION:
a. As the child is eating a wide range of foods, it would be difficult to decide which foods to test for. However, as 95% of children are sensitised to one or more of the 6 main allergens, it would be useful to start by performing a screening test, such as the FX5, which screens for the most common food allergies (cow’s milk, egg, wheat, soy, peanut and fish). This can only be done via a blood test as there are no skin prick screening tests.
b. This may be of use as a pattern between symptoms and food eaten may be identified. However, a screening test may be of more help at this point.
c. An elimination diet is possible; however, deciding which foods to exclude would be challenging as a wide range of foods are eaten with no suspected possible causes. An elimination diet could be tried after the blood test was performed.

Serum was taken from the child and total IgE and FX5 was tested. The results were:
Total IgE: 289 kU/l
FX5: 55 kU/l (class 5)

DISCUSSION:
The total IgE level indicates that the child is very likely to have an IgE-mediated allergy (but always bear in mind that there are causes for an elevated Total IgE). And the FX5 indicated that the child is very likely to be allergic to one or more of the 6 allergens that this test screens for.

It was decided to do serum-specific tests for milk, egg, wheat and soy as the child has not been exposed to the allergens through his diet. The results were:
Milk: 47 kU/l (class 5)
Egg: <0.35 kU/l
Wheat: <0.35 kU/l
Soy: <0.35 kU/l

THOUGHT PROCESS:
What do these results mean?
It is highly unlikely that the boy is allergic to egg, wheat or soy, and very likely to have a clinical reaction to milk.
But the mother felt that the child’s reactions to milk were inconsistent. The mother was asked why she thought her child’s reactions to milk were inconsistent. She said that he reacted to fresh milk, but not warm milk (milk that she had heaten and cooled for him to drink).

Is it possible that the child could react to fresh milk but not warm milk?

DISCUSSION:
The protein in milk, beta-lactoglobulin, is a heat labile allergen, which means that, when it is heated, it is destroyed. Therefore, although the majority of cow’s milk allergic children are sensitised to a number of allergens present in milk, it is possible that the child may be monosensitised to this specific protein only, and could therefore explain why he reacts to fresh milk and not to heated milk.

His serum was tested for beta-lactoglobulin antibodies, and found to have high levels. When the mother only fed her son preheated milk, did he become symptom free.

TIP for Allergy Advisor users: When using the main search function in Allergy Advisor, and "milk - cow's" is chosen, it brings up various pieces of information on milk allergy and allergens. When one selects the Allergen" tab at the top, one can read up on the various milk allergens individually.

B. More information:
Cow's milk is a major cause of adverse reactions in infants, and hidden exposure is common. Reports of prevalence range from 0.5 to 7.5% in infants.¹ Some patients retain the allergy lifelong.²

The Allergens in Milk
Milk contains more than 40 proteins, and all of them may act as antigens.

Cow's milk contains approximately 30 to 35 g/L (3-3.5%) of cow's milk proteins (CMPs), which can be divided into 2 main classes: caseins (80%) and whey proteins (20%). Caseins are precipitated out by chymosin (rennin) or the acidification of the milk to pH 4.6, forming the coagulum (curd). The whey or lactoserum remains soluble in the milk serum. Lactoserum constitutes approximately 20% of the CMPs, and coagulum approximately 80% of the CMPs. Caseins and whey proteins show very different physico-chemical and allergic properties.³

Coagulum contains the casein fraction, comprising 4 proteins: aS1-, aS2-, ß -, and ?-caseins (alphaS1-, alphaS2-, beta -, and kappa-caseins). Lactoserum contains mainly globular proteins, ß-lactoglobulin (beta-lactoglobulin)(BLG) and a- lactalbumin (alpha- lactalbumin)(ALA), followed by minor constituents such as bovine serum albumin (BSA), lactoferrin (LF), immunoglobulins (Ig) and proteosepeptone. BLG and ALA are the major ones and are synthesised in the mammary gland. Others, such as BSA, LF, and immunoglobulins, come from the blood. Proteosepeptone is derived from milk proteins through the action of indigenous enzymes, the most significant of which are the hydrolases, such as the lipoprotein lipase, plasmin, and alkaline phosphatase.⁴ In addition to the above-mentioned proteins, proteolytic fragments of casein and fat globule membrane proteins have been reported to occur in this fraction.⁵

The main characteristics of the major milk proteins are presented in Table 1.^6,7

Table 1. Main Characteristics of the Major Bovine Milk Proteins.⁸

The main characteristics that should be emphasised are the multiplicity and diversity of proteins that are involved in cow's milk allergy (CMA). Polysensitisation to several proteins occurs most often; it is observed in approximately 75% of patients with CMA, and all milk proteins appear to be potential allergens.^8,9 A great variability is observed in the affinity, specificity and magnitude of IgE responses in patients’ sera.^9,10 Most Milk-allergic patients are sensitised to several proteins, including BLG (Bos d 5), Casein (Bos d 8), ALA (Bos d 4), BSA (Bos d 6), Lactoferrin, and Immunoglobulins (Bos d 7).^{11,12,13,14,15,16,17,18,19} A great variability is observed in IgE response.^8,9,20

Casein and BLG, as well as ALA, are major allergens. However, proteins present in very low quantities, such as BSA, immunoglobulins, and especially lactoferrin, also appear to be important since 35% to 50% of patients are sensitized to those proteins and sometimes to those proteins only.^{9,15,18,20,21} In the last few years, sensitivity to casein has increased in terms of both frequency and intensity of IgE response. Sensitizations to casein, BLG, and ALA are closely linked. In contrast, sensitivity to BSA appears to be completely independent, with 50% of the patients being allergic to BSA regardless of their sensitivity to other milk allergens.⁸

The role of various cow's milk proteins (CMPs) in the pathogenesis of CMA is still controversial. Sera from 20 milk-allergic subjects have been used for cow's milk major allergen identification. The prevalence of CMP allergens has been measured as the following: 55% Alpha(s1)-casein, 90% Alpha(s2)-casein, 15% Beta-casein, 50% Kappa-casein, 45% Beta-lactoglobulin, 45% BSA, 95% IgG-heavy chain, 50% Lactoferrin, and 0% Alpha-lactalbumin.²²

The Proteins in Cow’s Milk
Lactoserum (Whey):
ß-lactoglobulin (BLG)
BLG is the most abundant protein in whey, accounting for 50% of total protein in the lactoserum (whey) fraction. It has no homologous counterpart in human milk; i.e., human milk does not contain BLG. Its structure is responsible for the main physic-chemical properties and also for interaction with casein during heat treatments.⁹ The relative resistance of BLG to acid hydrolysis, as well as to proteases, allows some of the protein to remain intact after digestion and increases the probability that intact BLG as well as digested fragments will be absorbed as antigens.^23,24

Heating of beta-lactoglobulin results in changes in the degree of allergenicity of the allergen, but this is dependent on the extent of heating: a slight but significant decreased IgE binding was seen between unheated beta-lactoglobulin solution and beta-lactoglobulin solution heat-treated at 74 degrees C. A more pronounced decrease was found at 90 degrees C. The inhibition of IgE binding of milk after heat treatment at 90 degrees C was also significantly decreased. However, at all heat treatments, a similar total amount of IgE antibodies could be inhibited at a sufficiently high concentration of beta-lactoglobulin.²⁵ BLG also resists pasteurisation.²⁶ Furthermore, heat-denatured proteins can also present new antigenic sites, uncovered by the unfolding process or created by new chemical reactions with other molecules present in the food.²⁷

The IgE binding of beta-lactoglobulin appears to also be significantly impaired in some fermented, acidified milk products such as yogurt, as compared to nonfermented milk.²⁵

a-lactalbumin (ALA)
ALA is a 14.2 kDa protein and one of the major allergens in cow's milk. It represents about 25% of lactoserum (whey) proteins.²⁸

Although some infant formulas closely mimic the ratio of total whey to casein in human milk, the concentration of ALA (the dominant protein in human milk) is relatively low in formula, whereas beta-lactoglobulin, a protein not found in human milk, is the most dominant whey protein in formula.²¹ During ALA’s digestion, peptides appear to be transiently formed that have antibacterial and immunostimulatory properties, thereby possibly aiding in the protection against infection. Cow’s milk also contains ALA, albeit less than human milk (2-5% of total protein in bovine milk), and protein fractions enriched with ALA may now be added to infant formula to provide some of the benefits of human ALA. ²⁹ Whey sources with elevated concentrations of ALA have also become available, which has permitted the development of formulas with increased concentrations of this protein and decreased concentrations of beta-lactoglobulin. ²¹

Bovine serum albumin (BSA)
BSA, a 67 kDa, heat-labile protein, is a major allergen in beef and a minor allergen in Milk.^{9,30,31,32,33,34,35,36,37,38,39} In cow’s milk, BSA accounts for around 5% of the total whey proteins.²⁴

Heating reduces sensitisation to beef and to bovine serum albumin but does not abolish reactivity to BSA under home conditions. However, industrially heat-treated and sterilised homogenised beef and freeze-dried beef may not be allergenic.³³ Heat treatment and chemical denaturation are not able to decrease BSA’s capacity to bind serum-specific IgE. ⁴⁰ Directly heated UHT milks suffer less heat damage than indirectly heated milk. During storage, BSA in directly heat-treated milks decreased significantly, unlike alpha-lactalbumin and beta-lactoglobulin, in which changes were not statistically significant.⁴¹ Pepsin incubation at pH 4.0 was shown to result in a decreased hydrolysis and enhanced residual antigenicity of BSA. ⁴²

Lactoferrin (LF)
LF is an allergen of the whey fraction of Cow's milk.¹⁷ It can be found in the milk of most species at levels lower than 1%.⁴³ LF is present in much higher concentrations in human breast milk (ie, 1 g/L), particularly in colostrum.⁹ Although it is present in very low concentrations in cow's milk, it has been shown to be an important allergen.⁷

Immunoglobulins
The Immunoglobulin (Ig) fraction, which includes IgG and IgE, accounts for about 1% of total milk protein and 6% of whey protein.³ Data on the potential allergenicity of bovine immunoglobulins are very limited. However, some studies propose IgG as another milk allergen due to the observation that IgE from CMA patients specifically binds bovine IgG.²² Bovine IgG has been reported to be a major beef allergen.⁴⁴

Proteose-peptone
The proteose-peptone fraction represents about 1.1% of the total milk protein. It is a heat-stable and acid-soluble protein fraction of milk with important functional properties. This milk component is derived mainly from the proteolysis of beta-casein, and the enzymatic activity of plasmin can over time increase its concentration in milk.³

Coagulum:
Casein
The coagulum consists of the whole casein fraction (i.e., the solid fraction of proteins obtained after coagulation of milk). It is subdivided into a number of families, of which the most important are aS1-, aS2-, ß-, k-, y-caseins (alphaS1 -, alphaS2 -, beta-, kappa-, gamma-caseins).³ Their proportion in the micelles is relatively constant at approximately 37%, 13%, 37%, and 13%, respectively.

Casein is rapidly and extensively degraded by proteolytic enzyme during digestion. Caseins are not significantly affected by severe heat treatments but are very susceptible to all proteinases and exopeptidases. Multisensitisations to the different caseins occur most often in patients sensitised to the whole casein fraction.^7,11

Possible Effects of Processing on Allergenicity
Heat and digestion contribute to the structure and other properties of CMPs, as well as to the IgE-binding epitopes. Casein is thermostable, whereas BLG is thermolabile. However, BLG may be protected through interaction with casein. Thermostability of cow’s milk proteins depends not only on temperature and time spent heated but also on interactions within the food matrix. Heat denaturation, which leads to the loss of organised protein structures, does not always result in a decreased allergenic potential: formation of aggregates may increase the allergenicity of the heated product. When the treatment results in a decrease in the allergenicity, the decrease is always limited. Boiling of milk for a few minutes (2, 5, or 10 minutes) results either in no difference or in a reduction of approximately 50% to 66% of the positive reactions, compared with those to raw milk; similar observations have been reported with raw versus pasteurised or homogenised and pasteurised milk.^{7,8,14,45,46,47} The caseins are heat-stable, and even high pasteurisation (121°C for 20 minutes) only reduces and does not eliminate the allergenicity of the caseins.²²

Hydrolysis of milk proteins is thought to considerably reduce their allergenicity. However, several studies have shown that specific IgE from patients with milk allergy recognised enzymatic digestion products of whey proteins (e.g., BLG and ALA) and casein and that the recognition of peptides may be even better than in the case of the intact molecule.^{48,49,50,51,52} For example, the incidence of reported adverse effects in infants fed partially hydrolysed milk formulae is reported to be approximately 45%, and in those fed extensively hydrolysed milk formulae, either casein or whey, the range is from approximately 65% to 15%, respectively.^53,54,55 Partially hydrolysed formulae may cause allergic reactions due to the presence of residual native protein or of large fragments. Reactions to extensively hydrolysed formulae have been shown to result from short peptidic fragments that still contain the relevant IgE-binding epitopes, which are exposed during the proteolysis.⁸

Ordinary industrial treatment of milk does not remove proteins and only partially reduces the allergenicity. Undegraded allergens are often present in hydrolyzed milk formulas and may cause symptoms in already sensitized subjects.^56,57,58 Intact cow's milk proteins may pass from the gut into the circulation. High concentrations of a-lactalbumin were measured in sera of children with cow's milk allergy⁵⁹ and bovine IgG was found in breast milk from mothers on diets including cow’s milk.⁶⁰

Potential Cross-reactivity
The presence of shared allergens in milk, meat, and dander from cow has been demonstrated. Sensitivity to cow's milk does not usually entail sensitivity to beef or inhaled cow dander. However, the presence of common allergens in milk, meat and dander has been demonstrated.^61,62

There is cross-reactivity between cow's milk and milk from related animals.⁶³ Milk of ruminant species other than cow (e.g., buffalo, sheep, goat, human, and many other species) is constituted from the same or very homologous proteins, which share the same structural, functional, and biological properties. However, human milk does not contain ß-lactoglobulin (beta-lactoglobulin)(BLG).⁹ Human and bovine milk differ substantially in the ratio of whey to casein protein (approximately 60:40 in human milk and approximately 20:80 in bovine milk) and in the proportions of specific proteins.²¹

The same or closely homologous proteins and their variants are present in milk of other ruminant species. However, the polymorphism of milk proteins is genetically determined and of great importance in specifying the origin of milk and in animal breeding. For example, the Variant C of BLG is found only in the Jersey breed of cow.

The gross composition of cow’s, sheep’s and goat’s milk may appear to be very similar, but slight differences in fat, solid (non-fat) and protein fractions result in changes in biological and physico-chemical properties. Sheep’s milk contains almost twice as many solids as cow’s milk and has a higher casein and fat content. The higher proportion of medium- or short-chain saturated fatty acids is believed to lead to greater lactose absorption, which might benefit the mildly lactose intolerant.³

Goat milk proteins have many significant differences in their amino acid composition, compared to the milk proteins of other mammalian species. The relative proportions of the various milk proteins also differ in goat’s and cow’s milk. For example, goat’s milk may contain only trace amounts of the allergenic Casein protein alphaS1-casein, whereas beta-casein represents the most abundant protein in goat’s milk.³

Of particular importance is the fact that the same caseins are present, with high sequence homologies, varying from 80% to more than 90%. As a consequence, a high IgE cross-reactivity among ewe's, goat’s, and cow's milk casein occurs in most patients with CMA.^64,65,66 However, the IgE response may also be specific, with allergic reactions to goat's and ewe's milk without associated CMA,⁶⁷ and with manifestations that occur after ingestion of sheep's and goat's cheese but not cow's milk or other dairy products.⁶⁸

Cross-reacting allergens other than proteins from milk of other species may also exist. Adverse reactions have been reported in milk-allergic patients fed soy-based formulae as cow's milk substitutes. A 30-kDa glycinin-like protein from soybean that cross-reacts with cow's milk casein has been isolated and partially sequenced.¹

C. Comments by our editors

Prof Janice M. Joneja Ph. D., RDN As this review reveals, milk is an extremely complex food with multiple proteins, many of which have the capacity to act as an allergen and elicit an immunological response in a sensitized individual. To increase the complexity of cow’s milk allergy (CMA), different individuals react to different proteins, and there can be considerable differences in the immunological response to each different protein, resulting in several quite distinct clinical presentations of CMA. These factors often lead to problems for doctors in diagnosing the condition in babies and children. Several practitioners have attempted to classify CMA on the basis of immunological mechanism and clinical presentation to aid in diagnosis. A 1995 report identified three distinct types of infant CMA with different symptoms and laboratory findings1: This report highlights some important factors in CMA diagnosis: • Symptoms can develop from minutes to up to 20 hours after ingestion of cow’s milk • Skin prick tests are of very limited value in diagnosing the condition • The prevalence of gastrointestinal symptoms makes the distinction between CMA and lactose intolerance difficult to determine on clinical signs alone Although any adverse reaction experienced after drinking milk is often ascribed to "milk allergy", when the symptoms are localised in the gastrointestinal tract the problem may be lactose intolerance, not an immunologically mediated allergy to milk proteins. It is important to differentiate between lactose intolerance (lactase deficiency) and milk protein allergy as some symptoms such as abdominal pain, diarrhea and vomiting may be common to both conditions. However milk protein allergy can cause inflammation of the gastrointestinal tract which may lead to lactase deficiency, so it is possible for both conditions to exist together. Symptoms in other organ systems such as the respiratory tract and the skin are never symptoms of lactose intolerance, so if these occur as a result of drinking milk it is clear that milk allergy is also a problem. Further details about milk allergy and lactose intolerance, and diagnosis and management of these conditions can be found in reference.2 References: 1. Hill DJ, Hosking CS. The cow milk allergy complex: overlapping disease profiles in infancy. European Journal of Clinical Nutrition 1995;49(Suppl 1):S1-S12 2. Joneja, J.M.Vickerstaff Dealing with Food Allergies in Babies and Children Bull Publishing Company, Boulder, Colorado. October 2007 pp 125-176

Dr. Harris Steinman M.B.Ch.B. This review may at first sight appear to be too detailed: "surely individuals who are allergic to milk have to avoid milk, so there is no need to know details of individual allergens?" Not exactly. Many families cannot afford to replace cow's milk with extensively hydrolysed or other forms of hypoallergenic formulae, and an appreciation of the the characteristics of individual cow's milk allergens and how they contribute to allergic sensitisation, allows the health practitioner to be more precise in selecting alternative milks for these individuals. For example, an individual who is only allergic to heat-labile allergens may be able to tolerate heated milk. With the availability specific IgE testing for many of the individual cow's milk allergens, a degree of "component-resolved diagnosis" can be performed, i.e., one can assess sensitisation to individual allergens of a food. However, the health practioner is reminded that around 30% of immune-mediated adverse reactions to cow's milk are not IgE mediated, and are delayed. Further, lactose intolerance may also cloud the issue and the diagnosis may occassionaly be more complex than at first glance.

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E. CPD Questions (For South African dietitians only. Australian dietitians: where you have relevant learning goals, CEU hours related to this resource can be included in your APD log.)

PLEASE ANSWER ALL THE QUESTIONS
(There is only one correct answer per question.)

1. True or false: All patients with cow’s milk allergy outgrow their allergy
a. True
b. False

2. True or false: Cow's milk proteins can be divided into 2 main classes: caseins (80%) and whey proteins (20%).
a. True
b. False

3. True or false: Polysensitisation to several proteins occurs most often; it is observed in approximately 25% of patients with CMA.
a. True
b. False

4. True or false: The major allergens in cow’s milk are casein, beta-lactoglobulin and lactoferrin.
a. True
b. False

5. True or false: Mainly due to bovine serum albumin, there is cross-reactivity between cow’s milk and beef.
a. True
b. False

6. True or false: Casein is thermostable, whereas beta-lactoglobulin is thermolabile.
a. True
b. False

7. True or false: Thermostability of cow’s milk proteins depends only on temperature and time spent heated.
a. True
b. False

8. True or false: Reactions to extensively hydrolysed formulae have been shown to result from short peptidic fragments that still contain the relevant IgE-binding epitopes, which are exposed during the proteolysis.
a. True
b. False

9. True or false: Human and bovine milk differ only slightly in the ratio of whey to casein protein.
a. True
b. False

10. True or false: There is no cross-reactivity between cow's milk and milk from other ruminant species.
a. True
b. False

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Milk Allergens
CEU Reference number: DT/A01/2008/00006

HPCSA number: DT
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Please make an “X” in the appropriate block for each question

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