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When pieces are better than the whole: Hydrolyzed protein diets (Sponsored by Nestlé Purina)
Part of the 2011 Nestlé Purina Veterinary Symposium publication
Clinical signs of food allergy in dogs and cats
Food allergy and food intolerance imply abnormal reactions to a normal food or ingredient. Food allergy is immune-mediated, while food intolerance is considered to be an idiosyncratic reaction. Other forms of adverse reactions to foods can include food intoxication or food poisoning. Unlike food allergy or intolerance, which are abnormal responses to normal foods or ingredients, food poisoning refers to normal, biological reactions to the toxins or infectious agents in foods, rather than to normal foods.
Food allergy may manifest with dermatologic or gastrointestinal (GI) signs, or both. Dermatologic signs of food allergy (Table 1) are similar to those of atopic dermatitis, and both food allergy and atopic dermatitis commonly occur together.1 GI signs can include vomiting, diarrhea, and borborygmus.
Table 1. Common clinical signs of food allergy in dogs and cats4,7,8,21
According to veterinary dermatologists, the majority of dogs and cats with food allergies manifest dermatologic signs, although 15% to 50% are now recognized to also have GI signs.1-4 Moreover, veterinary gastroenterologists recognize that a large percentage of patients with GI signs have some form of food allergy or intolerance.2,5,6 In one study of 70 cats with chronic GI signs, 29% were diagnosed as food allergic based on elimination and challenge testing.5 An additional 20% of cats in the study showed a positive response to diet but did not relapse upon challenge. Similarly, another study demonstrated that 50% of dogs with chronic GI signs were food responsive, although only 20% of these were confirmed by challenge to be food allergic.6
Another study evaluating 128 cats with either pruritus, GI signs, or both, identified 22 (17%) cats that were confirmed food allergic by elimination and subsequent challenge testing.2 Among the cats confirmed to be food allergic, 45% exhibited dermatologic signs, 32% expressed GI signs, and 23% exhibited both signs.
It appears that patients expressing both dermatologic and GI signs are more likely to be diagnosed as food allergic.2-4 In a study of 418,422 dogs in Switzerland, 259 allergic dogs were identified.4 Of these, 65 were identified as food responsive, while 183 were considered atopic. Concurrent GI signs occurred in 31% of the food-responsive dogs, but in only 10% of the atopic dogs. Similarly, cats with both dermatologic and GI signs (42%) were more likely to be food allergic than those with only dermatologic (16%) or GI signs (13%).2
Pathophysiology of food allergy
The exact mechanisms behind food allergy are not fully known, but are thought to involve type I, III, and IV hypersensitivity reactions.7,8 The offending allergens are usually proteins or glycoproteins that can interact with the body's immune system and lead to a hypersensitivity reaction. Interaction between food antigens and the immune system begins in the GI tract, which is the largest immunologic organ in the body.
Role of the GI tract
The GI tract provides numerous means of protecting the body from foreign bacteria, toxic substances, and antigens. It must balance this protective function with the need to absorb and tolerate normal dietary antigens. The primary means of defense against inappropriate allergic responses to dietary antigens include an effective mucosal barrier, efficient digestion of proteins, and oral tolerance developed by the gut-associated lymphoid tissue (GALT).
Complete digestion of proteins destroys the antigenic factors. Under normal circumstances, only trace amounts of intact proteins and large peptides can make it past the mucosal barrier. These proteins are removed by the reticuloendothelial cells of the liver and the mesenteric lymph nodes. When excessive antigens are absorbed, such as with increased mucosal permeability, hypersensitivity may develop.7,9 A critical role is played by the GALT in the development of tolerance to food proteins.10 This function is facilitated by microfold cells (M cells) located on the Peyer's patches. M cells take up antigens from the intestinal lumen and present them directly to lymphocytes within the Peyer's patch. This allows the immune system to develop an appropriate recognition and response to that particular antigen—either to develop a tolerance to a food protein or to mount a defense against an invading organism. Errors in this process can result in development of a food allergy or an infection.
Role of the immune system
Allergic or hypersensitivity reactions are grouped into four types based on the specific mechanisms, immunoglobulins (Ig), and the cells involved. Although type I and III reactions are mediated by IgE or IgG and type IV is a T-cell-mediated reaction, other cells play a role in these reactions.
Advances in the past decade have contributed to a greater understanding of the pathophysiology of allergy: the key lies in CD4+ and CD8+ T cells and related cytokines.10 Two major subsets of CD4+ T cells are the Th1 and Th2 subsets, which are distinguishable on the basis of their expressed cytokines. Th1 cells stimulate cell-mediated immune functions and inhibit IgE synthesis, whereas Th2 cells produce interleukin (IL)-4, which stimulates IgE production by B cells. A proper balance between these cell types is necessary for normal immune function, and a number of immunopathologies have been associated with an exaggerated Th1 or Th2 response. The cytokines IL-10, transforming growth factor-β (TGF-), β and others play an important role in maintaining the Th1-Th2 ratio and promoting allergen tolerance. Increased IL-4, IL-6, and tumor necrosis factor-α (TNF-) α production and a reduced Th1-Th2 ratio associated with increased Th2 cells are found in atopic and food-allergic people.
Immunoglobulin and T-cell responses appear to differ between food allergy and atopy, at least in dogs. One study confirmed an increase in IgE in atopic dogs and an increase in IgG in dogs with food-allergic and other forms of gastroenteritis.11 Though no differences were found in the T-cell status of the GI tract between normal dogs and food-allergic dogs, significant changes occurred within the skin of dogs with cutaneous adverse food reactions.12,13 These changes included a pronounced CD8+ T cell-dependent inflammatory response, and increased expression of IL-4, IL-13, and other genes suggestive of a Th2-skewed immune status.14 These changes remained even after clinical resolution of signs, suggesting a continuing "pre-activated immune status" in dogs with food allergies.14 This is consistent with results from food-allergic children, who have ongoing activation of Th2 cells with increased release of inflammatory cytokines.15
Factors influencing development of allergic conditions
The likelihood of an individual patient developing sensitivity to food depends on permeability of the gut, the presence of allergy to other foods or inhalants, and other factors.9 Heredity is a major predisposing factor in allergic conditions in people. The likelihood of an infant developing atopy or food allergy is 37% if one parent is atopic and 62% if both parents are affected.9 This may also be true in cats and dogs based on breed and familial predisposition, but the mode of inheritance is unknown.
Current evidence suggests that dogs with cutaneous food allergy may be predisposed to developing atopic dermatitis.16 This may be because of an underlying immune (Th1/Th2) imbalance, or it may be a result of compromised GI mucosa. As the GI mucosa is a primary barrier to prevent absorption of potential allergenic proteins, a breach in this barrier increases the likelihood of allergens entering the body and contacting the GALT, thus increasing the risk of sensitization or allergic response.9,10
GI permeability and transmucosal antigen transfer are increased in people with atopy and food allergy, and the absorbed dietary antigens can contribute to clinical signs of allergy. This appears to be associated with clinical or subclinical intestinal inflammation. In cats and dogs, food allergy often manifests with primary GI signs, and up to 30% of patients with cutaneous manifestations also develop GI signs. The percentage with subclinical GI involvement is unknown; thus, it is likely that some degree of GI compromise exists in dogs and cats with food allergies.
Another factor that may influence the manifestation of clinical signs is the pruritic threshold, which refers to the variation in response to a given allergen. It may relate to the concept of "summation," which suggests that multiple allergies or nonallergenic pruritic stimuli are additive in effect. For example, a pruritic dog with concurrent atopy and food allergy may drop below the pruritic threshold by effective control of only one of these conditions. Nonallergenic factors, such as stress, dry skin, and hot weather, can also contribute to pruritus via nonimmunologic means and must be considered in the diagnosis and management of pruritic pets.17
Common food allergens
The vast majority of allergens are proteins or glycoproteins. Since allergies are abnormal or inappropriate reactions of the immune system against a normal protein, allergies can form to any protein. The majority of common food allergens are proteins with a molecular weight between 18 kD and 70 kD.18,19 Smaller proteins are normally too little to elicit an immune reaction, while larger proteins cannot normally access the body across the GI mucosa.
The most commonly identified food allergens in dogs and cats are listed in Table 2. The list reflects commonly fed ingredients. Reactions to carbohydrate sources, such as rice, corn, and potato, have been reported but appear to be much less common. Idiosyncratic reactions to food preservatives or additives also are thought to occur, but evidence to support this idea is lacking.1
Table 2. Most commonly identified food allergens in dogs and cats7
Diagnosis of food allergy
The diagnosis of food allergy is based on physical signs, history, veterinary examination, and results of an elimination diet trial with subsequent challenge. Unfortunately, neither serologic nor intradermal testing is effective for diagnosing food allergies.1,8
Food allergies can occur in animals of any age. A history of chronic, non-seasonal pruritus or otitis externa in dogs or cats, or miliary dermatitis or alopecia in cats, may indicate possible food-allergic dermatitis. GI signs may include vomiting, diarrhea, or borborygmus. Large bowel diarrhea appears to be common in food-allergic dogs.6 The presence of concurrent pruritus or otitis and GI signs should always raise suspicion of food allergy. However, it is necessary to rule out other causes of GI or dermatologic signs that may be confused with food allergies (Table 3). Location and type of skin lesions can help identify or rule out other conditions. For example, lesions predominantly located on the caudal half of the body are more consistent with flea allergy. In nearly 25% of food-allergic dogs, pruritus in the ear region may be the only clinical sign. In pruritic patients, skin cytology should be evaluated for bacterial and Malassezia infections. Unfortunately, medical history does not help differentiate food allergy from atopic disease. The clinical signs of these conditions can be identical, and they may exist concurrently. For patients with GI signs, blood, urine, and feces should be examined to rule out systemic or parasitic causes of vomiting or diarrhea.
Table 3. Differential diagnoses for pruritic dogs and cats
If food allergy is suspected, a dietary trial (Table 4) using an appropriate elimination diet is required. Most patients with dermatologic signs respond within four to eight weeks. If only partial improvement is seen, an additional four to six weeks may be needed for maximum resolution.7,20 If concurrent therapy is provided, such as antibiotics or corticosteroids, the trial must be continued for at least three to six weeks after completion of these therapies. If only GI signs are present, a two- to four-week trial is sufficient.5,7 Improvement in dermatologic signs is typically defined in terms of changes in pruritus. Most studies consider a decrease of 50% or more to be a positive response.7,20,21
Table 4. Conducting a dietary elimination trial to diagnose food allergy
If the patient responds positively to the elimination diet, a provocative challenge with the prior diet is needed to confirm the diagnosis. Though many will occur within 48 hours, allow up to two weeks to document adverse responses during the challenge period.1 A diagnosis of food allergy is confirmed if the patient improves while on the elimination diet, recrudesces during the challenge, and improves again when returned to the elimination diet. If desired, identification of specific protein sources to which the patient is sensitive can be done by challenging with individual ingredients, one at a time, while maintaining the patient on the elimination diet.
The goal in conducting a dietary trial with an elimination diet is to eliminate any exposure to allergens to which the patient may be sensitive. In addition, because the diet may be fed for an extended period of time, it should also provide complete and balanced nutrition and be palatable and convenient for the owner to feed. Controlled intake during the trial period includes the main meal as well as treats, flavored medications, bits of food used to give medications, and access to any other foods.
Homemade novel protein diets
Homemade diets are considered the gold standard for conducting food-allergy trials.7,8,22 The simplest homemade diets include one protein source and one carbohydrate source to which the patient has not previously been exposed. These are typically provided at a volume ratio of 1:1 for dogs and 2:1 for cats (protein:carbohydrate source). for cats. Lack of prior exposure is important as there is nothing inherently hypoallergenic about any particular protein. Therefore, the patient's dietary history must drive the appropriate choice for ingredients to use in the diet.
The advantages of home-prepared diets are the ease of addressing the patient's specific dietary history, enhanced involvement by the owner, and elimination of any types of additives, though sensitivities to additives do not appear to be common.1 Some limitations to home-prepared diets typically used for elimination trials include: labor-intensive preparation (compared with feeding commercial diets); excessive costs; diet acceptance; the possibility of GI upsets; and nutritional completeness.3,7 Because of nutritional imbalances, home-prepared diets are not recommended for use in growing animals nor for long-term use.1,3,7
Published studies using homemade diets suggest a drop-out rate from 15% to 36%, with the most common reasons being patient refusal, difficult preparation, and development of diarrhea.3,21,23 The proportion of dogs enrolled in the elimination-challenge tests that were diagnosed as food allergic in these studies averaged 35.7%.
Commercial novel protein diets
Another approach for managing food-allergic dogs is feeding a commercial novel protein diet. Such a diet contains a limited number of ingredients—usually a single protein and a single carbohydrate source—to which the patient has not been previously exposed. Limiting ingredients reduces the odds that the food contains an allergen to which the patient is hypersensitive.
As with home-prepared diets, the choice of ingredients for commercial novel protein diets should be based on prior exposure considering both protein and carbohydrate sources. While allergies to carbohydrates are uncommon, allergies to the protein contained in these ingredients (e.g., potato, rice, corn, wheat) can occur.5,24,25 Most commercial novel protein diets provide complete and balanced nutrition and they are easy to prepare. Because of this, the proportion of patients completing the elimination study may be increased.2,5 Commercial novel protein diets are recommended when owners do not wish to cook for their pets, when pets do not tolerate home-prepared diets, and when the cost of a home-prepared diet is prohibitive.7
A few published studies have shown that these diets can be used with good success to diagnose food allergy.2,5 However, several studies have documented adverse reactions in 15% to 85% of confirmed food-allergic dogs offered various commercial novel protein diets.8,22,23,26 One study indicated that 22 of 40 dogs reacted only against one of three diets, while an additional eight dogs reacted against two different novel diets.26 Such results confirm the critical importance of a good dietary history prior to selecting a diet for a suspected food-allergic patient. They also are the reason some researchers discourage the use of novel commercial diets during the elimination trial.7,22,26
While there are limitations to using novel protein diets during the diagnostic period, it appears that 84% to 95% of confirmed food-allergic dogs can be maintained on a commercial novel protein diet.22,26 This provides a viable way to control clinical signs while providing complete and balanced nutrition. If the patient's specific allergies are not known, it may be necessary to test several novel protein diets until a suitable diet is found. Unfortunately, it is still possible for the patient to develop a hypersensitivity—even to the novel diet—at a later time.1
Commercial hydrolyzed protein diets
Another option for elimination diets is to use hydrolyzed proteins. The ability of a protein to induce an immune-mediated hypersensitivity is dependent upon the size and structure of the protein. Most food allergens are glycoproteins that range in size from 18 kD to 70 kD.18,19 Proteins of this size are large enough and have sufficient molecular complexity to allow activated T and B cells to recognize the substance as foreign and initiate a response, yet small enough to pass through mucosal membranes and come in contact with elements of the immune system. Hydrolysis, which reduces the proteins to small polypeptides, can create dietary proteins below this size so that they are not recognized by the immune system; thus rendering the proteins non- or hypo-allergenic.
The optimal molecular weight of a protein hydrolysate varies with the type of protein used.7 Soy, an extensively studied dietary protein, contains 21 specific allergens, identified using IgE- or IgG-binding techniques.27,28 The major IgE-producing allergens in soy protein range in size from 20 kD to 78 kD. 27 Thus, if soy protein were hydrolyzed to a molecular weight below 20 kD, these antigens would be destroyed, rendering the protein hypoallergenic. This effect has been confirmed in both in vitro and in vivo studies.19,28-32
In addition to protein hydrolysis, hypoallergenic diets should be formulated using carbohydrate sources containing minimal to no protein to reduce risk of new allergenic responses. While grains are typically considered carbohydrate sources, they also contain varying amounts of intact proteins that could trigger allergic responses.
In recent years, a number of diets made with hydrolyzed proteins have been introduced into the marketplace. If these diets could be used even in dogs allergic to the parent (intact) protein, they could be used as elimination diets without consideration of the dietary history. Several studies specifically designed to look at the impact of hydrolyzed protein diets in dogs allergic to the parent protein documented that the reaction to hydrolyzed proteins is significantly reduced.19,30-33 For example, 10 of 12 confirmed chicken-allergic dogs had at least a 50% reduction in CADESI (Canine Atopic Dermatitis Extent and Severity Index) score when fed a chicken hydrolysate diet.32 In two different studies of dogs with confirmed soy or corn allergies, or both, the reaction to a hydrolyzed soy and corn starch diet was significantly reduced versus intact soy or corn, and no different from the reactions to corn- and soy-free control diets.30,33
Multiple hypersensitivities may occur in one-third to one-half of dogs or cats with food-allergies.7 In one study, most food allergic dogs reacted to two food ingredients while one dog reacted to seven.24 This situation presents a challenge when attempting to develop effective novel protein diets, and becomes less important when a hydrolyzed hypoallergenic diet is used. Furthermore, because the hydrolyzed proteins are truly hypoallergenic, it is less likely that a new allergy will form when these diets are fed long-term. Other advantages of hydrolyzed protein diets are that they can provide complete and balanced nutrition and avoid client concerns about the difficulties in preparing homemade diets.
A further advantage of hydrolyzed protein diets is the effect on digestibility. The use of highly digestible proteins has long been recommended for managing food allergies. One of the natural defenses against food allergy is the breakdown of food allergens during digestion. Under normal circumstances, very little intact protein is absorbed. However, if there is increased GI permeability, or digestive function is compromised, larger peptides and proteins may be absorbed intact, contributing to development or exacerbation of food allergy.9,25 Hydrolysis of a protein enhances digestive efficiency. For example, when soy protein hydrolysates were administered to dogs, the small intestinal absorption rate increased three-fold compared with administration of intact soy protein.34 Thus, feeding hydrolyzed protein diets may avoid aggravation or perpetuation of allergies in animals with compromised GI tracts.
Several studies suggest that about 90% of dogs with food allergy will be detected using hydrolysate diets, although a few dogs or cats might have an adverse reaction to the hydrolyzed diets.18,35 (Sousa C, unpublished data 2001) While this falls short of 100%, it compares favorably with home-prepared or commercial novel diets.
Food allergies may cause dermatological or GI signs, or both. A diagnosis of food allergy is made by performing a dietary elimination trial using an appropriate diet, followed by a food challenge using the patient's prior diet or specific food ingredients. Following diagnosis and identification of the offending allergens, dogs and cats can be maintained on diets that exclude the identified antigens or on commercial novel protein or hypoallergenic diets. As the immune system remains "primed" for an allergic response, it is possible for an allergy to additional proteins to develop over time with recurrence of clinical signs. This risk may be reduced by feeding hydrolyzed protein diets to at-risk patients.
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2. Guilford WG, Markwell PJ, Jones BR, et al. Prevalence and causes of food sensitivity in cats with chronic pruritus, vomiting or diarrhea. J Nutr 1998;128:2790S–2791S.
3. 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 Derm 2006;17:273-279.
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29. Olson ME, Hardin JA, Buret AG, et al. Hypersensitivity reactions to dietary antigens in atopic dogs. In: Reinhart GA, Carey DP, eds. Recent advances in canine and feline nutrition, Vol III, 2000 Iams Nutrition Symposium Proceedings. Wilmington, Ohio: Orange Frazer Press, 2000:69-77.
30. Beale KM, Laflamme DP. Comparison of a hydrolyzed soy protein diet containing corn starch with a positive and negative control diet in corn- or soy-sensitive dogs, in Proceedings. 16th Annual AAVD and ACVD Meeting 2001;12:237.
31. Serra M, Brazis P, Fondati A, et al. Assessment of IgE binding to native and hydrolyzed soy protein in serum obtained from dogs with experimentally induced soy protein hypersensitivity. Am J Vet Res 2006;67:1895-1900.
32. Ricci R, Hammerberg B, Paps J, et al. A comparison of the clinical manifestations of feeding whole and hydrolyzed chicken to dogs with hypersensitivity to the native protein. Vet Derm 2010;21:358-366.
33. 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 Derm 2003;14:181-187.
34. Zhao XT, McCamish MA, Miller RH, et al. Intestinal transit and absorption of soy protein in dogs depend on load and degree of protein hydrolysis. J Nutr 1997;127:2350-2356.
35. Olivry T, Bizikova P. A systematic review of the evidence of reduced allergenicity and clinical benefit of food hydrolysates in dogs with cutaneous adverse food reactions. Vet Derm 2010;21:31-40.