Hydrolysed Protein Diets
World Small Animal Veterinary Association World Congress Proceedings, 2013
Nick Cave, BVSc, MVSc, PhD, DACVN
Massey University, Palmerston North, New Zealand

Introduction

The primary aim of a hydrolysed protein diet is to sufficiently disrupt the proteins within the diet so as to remove any existing allergens and prevent recognition by a patient sensitized to the intact protein. A secondary aim might be to disrupt the proteins to such an extent that there are no longer any antigens capable of eliciting an immune response and leading to sensitization in a naïve individual. Ideally, hydrolysis will prevent mast cell degranulation that would occur in response to the intact protein, and it will enable a patient hypersensitive to the protein to ingest the hydrolysate without clinical signs.

The term "hypoallergenic diet" should be reserved for diets that have a substantial reduction in antigenicity and preferably have been shown to be tolerated by the vast majority of patients known to be hypersensitive to the intact source protein.1-3 However, defining at which point in the reduction in antigenicity or clinical reactivity a diet could be considered "hypoallergenic" is arbitrary, and the use of the term is discouraged.

Although the majority of the known food allergens are proteins or glycoproteins, non-protein molecules can function as allergens. Certain carbohydrates, free of proteins, such as pneumococcal polysaccharides and highly crosslinked dextran, have been demonstrated to induce allergic reactions in man, and some carbohydrates (e.g., inulin) can function as haptens or as the antigenic part of glycoproteins. They are also claimed to be responsible for crossreactivity between plant allergies and are incriminated in false-positive serum IgE ELISA allergy tests.11 However, in cases where a dietary carbohydrate is suspected as an allergen, it is more likely that there is a protein allergen within the carbohydrate source than there is the existence of a true hypersensitivity to the carbohydrate molecules. Maize zeins, which are 20 to 23 kDa proteins, have been detected in hydrolysed casein formulae when corn starch is used as the carbohydrate source.4 Similarly, lipophilic protein allergens have been isolated in refined vegetable oils.5 Thus, the carbohydrate and lipid ingredients in hydrolysed protein diets may be an important source of protein allergens since they are not subjected to enzymatic hydrolysis and should be considered when evaluating diets.

Although type 1, IgE-mediated hypersensitivities are thought to be present in some cases of food hypersensitivity, it is likely that other mechanisms exist in a subset of cases, especially in cases where only GI signs are present. The degree of hydrolysis needed to prevent an adverse reaction may be different when adverse, non-IgE-mediated immune responses are present.

Commercial Hydrolysed Protein Diets

Initial selection of a commercial hydrolysed protein diet for a particular patient should probably be based upon the protein source. None of the currently available diets are sufficiently hydrolysed to guarantee the complete absence of any allergens. Therefore, it is prudent to select a diet that does not contain a protein source that the patient is known or suspected to be sensitized to. Secondary consideration should be given to the sources of carbohydrate and lipid, as sources of potential allergens.

Problems with Hydrolysates

The most significant problem that manufacturers of hydrolysate formulae face is persistent immunogenicity. In the initial stages of an enzymatic hydrolysis, it is common for previously hidden antigenic sites to become exposed and for the product to increase in allergenicity, which is only reduced with further hydrolysis. Many well-documented examples of hypersensitivity to hydrolysed infant formulae have been published.6-9 Only very small amounts of intact allergenic epitopes are required to elicit significant and even fatal responses in sensitized individuals.10 The best guarantee of producing a truly nonallergenic diet resides in the production of purified amino acids and small peptides.

Preserving palatability for humans is difficult with the more extensively hydrolysed products. Peptides and amino acids produce a variety of flavours. Bitterness offers the greatest hurdle to palatability. The bitter taste of peptides is a product of their amino acid composition. Hydrophobic side chains are exposed when a protein is hydrolysed, and these can be tasted; as hydrolysis proceeds, bitterness tends to increase, peaking in hydrolysed soy between 4 to 2 kDa, then declining as the peptide fragments decrease in size further.11,12 The starting protein source greatly influences the final taste of the hydrolysed product. However, the taste of a hydrolysate is dependent on the mixtures of peptides and cannot be assumed to be any one flavour, or easily predicted from the protein source of known hydrophobicity. Indeed, protein hydrolysates have long been used to enhance the palatability of commercial dog and cat foods. Based on data published to date then, the rate of acceptance by dogs fed hydrolysed protein diets as elimination diets is similar to those fed conventional select protein diets.13,14

Hydrolysis significantly increases osmolarity, and feeding high-osmolarity solutions (800 mOsm/L) causes diarrhoea in humans.15 Even higher osmolarities can cause sloughing of enterocytes.16 Enteral solutions of ≤ 250 mOsm/L improve rehydration, cause lower stool volume, and less vomiting compared with a solution of 311 mOsm/L in children with enteritis.17

The osmolarity of three hydrolysate diets was determined to be 182, 293, and 623 mOsm/L when mixed 1:4 wt:wt with water, compared with 93 mOsm/L for a standard intact protein maintenance diet.18 Therefore, it is conceivable that the high osmolarity could be detrimental in some dogs.

Use and Evidence of Efficacy in Food Hypersensitivity

The primary role for the use of hydrolysed protein diets is for the diagnosis or management of food hypersensitivity. The identification of a truly novel protein in patients presented for evaluation of dietary hypersensitivity can be difficult. Hydrolysed protein diets allow greater confidence in the instigation of an elimination trial where a dietary history is either uncertain or reveals prior exposure to multiple proteins. Protein hydrolysate diets have been reported to be effective and well tolerated when used as elimination diets for the diagnosis of adverse food reactions in dogs.13,14,19 In those studies, owner compliance was excellent, whereby 73% to 97% of dogs completed the 6- to 8-week trial periods. The high completion rates are similar or superior to those reported by authors utilizing home-cooked or commercial novel-protein diets (64–80%) for elimination diet trials.19-22

The protein sources incriminated in the adverse reactions were not reported in either study by Loeffler et al. (2004, 2006); therefore, it is impossible to comment on the efficacy of that diet in cases where the patient is sensitized to the intact source protein. However, in a study using the Royal Canin soy hydrolysate diet, 2 dogs that did not improve when fed the soy and chicken-based hydrolysate did improve when fed either a home-prepared soy-based diet or a commercial rabbit and rice diet.23 Those findings suggest either sensitization to the chicken or other protein fraction within the hydrolysate diet, or the creation of novel dietary antigens as the result of the food processing, as has been demonstrated to occur.24 It is predicted that the recently introduced and more highly hydrolysed Royal Canin feather protein diet will have a superior efficacy.

The Nestle-Purina HA soy-based hydrolysate diet was fed for 2 weeks to 14 crossbreed dogs that were known to be allergic to soy and/or corn.25 Of the 14 dogs, 3 reacted adversely to the hydrolysed soy diet, all of which were hypersensitive to both soy and corn, so it is uncertain to what fraction the dogs were reacting to. This study demonstrated for the first time, that a commercially available hydrolysate diet can be fed to the majority of dogs sensitized to the intact source protein without eliciting clinical signs. However, it also indicated that a significant proportion (21%) of dogs sensitized to the intact compounds will still react adversely to the hydrolysed diet. This re-emphasizes the limitations of the currently available hydrolysed protein diets. For maximum confidence in performing an elimination diet trial, it is still important - even when using a hydrolysed protein diet - to obtain an accurate dietary history and to choose a diet that contains ingredients the patient is unlikely to be sensitized to.

When considering reports of the efficacy of hydrolysate diets, it should be remembered that nutritional factors other than the hydrolysis of the protein component may be responsible for reported clinical improvements. Nutritional variables that could affect clinical responses include dietary digestibility, correction of vitamin or mineral deficiencies, a lowered n-6:n-3 fatty acid ratio, and the potential for an immunomodulatory effect of soy isoflavones (e.g., genistein) within the diet, especially in cases of intestinal disease. A study that would definitively demonstrate the efficacy of protein hydrolysis alone would compare two diets in which the only difference is that one of the diets has the protein component hydrolysed.

Conclusion

Although true food hypersensitivity is relatively uncommon in both dogs and cats, it is a commonly considered differential. Hydrolysed protein diets are a convenient and proven option for the diagnosis and management of food hypersensitivity. As experience with hydrolysed protein diets in veterinary medicine increases, so will our appreciation for the range of their benefits in diseases such as IBD and acute enteritis. Comparing the currently available hydrolysate diets beyond basic ingredients is difficult because of the absence of standard evaluations. Determining the optimal degree of hydrolysis is even more difficult and will likely differ according to protein, patient, and disease process. The degree of hydrolysis currently employed in veterinary diets may be ideal from nutritional and palatability perspectives, but it cannot guarantee an absence of intact allergens. As such, the use of hydrolysed protein diets does not expunge the need for a detailed dietary history when dietary hypersensitivity is suspected.

References

1.  Kleinman RE, Bahna SL, Powell GF, et al. Use of infant formulas in infants with cow milk allergy: a review and recommendations. Pediatr Allergy Immunol. 1991;4:146–155.

2.  Cave NJ, Guilford WG. A method for in vitro evaluation of protein hydrolysates for potential inclusion in veterinary diets. Res Vet Sci. 2004;77:231–238.

3.  Jackson HA, Jackson MW, Coblentz L, et al. Evaluation of the clinical and allergen specific serum immunoglobulin E responses to oral challenge with cornstarch, corn, soy and a soy hydrolysate diet in dogs with spontaneous food allergy. Vet Dermatol. 2003;14:181–187.

4.  Frisner H, Rosendal A, Barkholt V. Identification of immunogenic maize proteins in a casein hydrolysate formula. Pediatr Allergy Immunol. 2000;11:106–110.

5.  Zitouni N, Errahali Y, Metche M, et al. Influence of refining steps on trace allergenic protein content in sunflower oil. J Allergy Clin Immunol. 2000;106:962–967.

6.  Cantani A, Micera M. Immunogenicity of hydrolysate formulas in children (part 1). Analysis of 202 reactions. J Investig Allergol Clin Immunol. 2000;10:261–276.

7.  Cantani A, Micera M. Immunogenicity of hydrolysate formulas in children (part 2): 41 case reports. J Investig Allergol Clin Immunol. 2001;11:21–26.

8.  Businco L, Cantani A, Longhi MA, et al. Anaphylactic reactions to a cow's milk whey protein hydrolysate (Alfa-Re, Nestle) in infants with cow's milk allergy. AnnAllergy. 1989;62:333–335.

9.  Saylor JD, Bahna SL. Anaphylaxis to casein hydrolysate formula. J Pediatr. 1991;118:71–74.

10. Oppenheimer JJ, Nelson HS, Bock SA, et al. Treatment of peanut allergy with rush immunotherapy. J Allergy Clin Immunol. 1992;90:256–262.

11. Cho MJ, Unklesbay N, Hsieh FH, et al. Hydrophobicity of bitter peptides from soy protein hydrolysates. J Agric Food Chem. 2004;52:5895–5901.

12. Adler-Nissen J. A review of food protein hydrolysis-specific areas. In: Enzymic Hydrolysis of Food Proteins. New York: Elsevier Applied Science Publishers Ltd; 1986:427.

13. Loeffler A, Lloyd DH, Bond R, et al. Dietary trials with a commercial chicken hydrolysate diet in 63 pruritic dogs. Vet Rec. 2004;154:519–522.

14. Nguyen PG, Dumon HJ, Siliart BS, et al. Effects of dietary fat and energy on body weight and composition after gonadectomy in cats. Am J Vet Res. 2004;65:1708–1713.

15. Ladas SD, Isaacs PE, Sladen GE. Post-prandial changes of osmolality and electrolyte concentration in the upper jejunum of normal man. Digestion. 1983;26:218–223.

16. Altaf W, Perveen S, Rehman KU, et al. Zinc supplementation in oral rehydration solutions: experimental assessment and mechanisms of action. J Am Coll Nutrition. 2002;21:26–32.

17. Hahn S, Kim Y, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration due to diarrhoea in children: systematic review. BMJ. 2001;323:81–85.

18. Chauvet B, Mougeot I, Cave NJ, et al. Osmolality of a new highly hydrolyzed feather-protein based diet. In: 2012.

19. Loeffler A, Soares-Magalhaes R, Bond R, et al. A retrospective analysis of case series using home-prepared and chicken hydrolysate diets in the diagnosis of adverse food reactions in 181 pruritic dogs. Vet Dermatol. 2006;17:273–279.

20. Chesney CJ. Food sensitivity in the dog: a quantitative study. J Small Anim Pract. 2002;43:203–207.

21. Tapp T, Griffin C, Rosenkrantz W, et al. Comparison of a commercial limited-antigen diet versus home-prepared diets in the diagnosis of canine adverse food reaction. Vet Ther. 2002;3:244–251.

22. Roudebush P, Schick R. Evaluation of a commercial canned lamb and rice diet for the management of adverse reactions to food in dogs. Vet Dermatol. 1994;5:63–67.

23. Biourge VC, Fontaine J, Vroom MW. Diagnosis of adverse reactions to food in dogs: efficacy of a soy-isolate hydrolysate-based diet. J Nutrition. 2004;134:2062S–2064S.

24. Cave NJ, Marks SL. Evaluation of the immunogenicity of dietary proteins in cats and the influence of the canning process. Am J Vet Res. 2004;65:1427–1433.

25. Jackson HA, Jackson MW, Coblentz L, et al. Evaluation of the clinical and allergen specific serum immunoglobulin E responses to oral challenge with cornstarch, corn, soy and a soy hydrolysate diet in dogs with spontaneous food allergy. Vet Dermatol. 2003;14:181–187.

  

Speaker Information
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Nick Cave, BVSc, MVSc, PhD, DACVN
Massey University
Palmerston North, New Zealand


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