Adverse food reactions (Proceedings)

Adverse reactions to food are quite common in both dogs and cats. However, contrary to common believe, only few cases of adverse food reactions are due to true food allergies. Adverse food reactions represent a group of disorders that are defined by gastrointestinal, dermatological, and less commonly respiratory signs in response to ingestion of a certain food. It should be remembered that there are other specific conditions that are either thought to be due to or worsened by diet that are not considered adverse food reactions such as acute pancreatitis, megaesophagus, or portosystemic shunts.

A nomenclature of adverse food reactions has not been agreed upon for veterinary gastroenterology. The following definitions are therefore based on a nomenclature put forth by the American Academy of Allergy and Immunology. In general there are three groups of adverse food reactions: dietary indiscretion, non-immunologic adverse food reactions, and immunologic food reactions.

The most common type of an adverse reaction to food in dogs is dietary indiscretion. Dietary indiscretion is defined as an adverse reaction resulting from such behaviors as gluttony, pica, or ingestion of indigestible materials. Such behavior is commonly seen in puppies and the link between the ingestion of an "indigestible material" such as a ball directly leads to clinical signs such as vomiting, obviously without any involvement of the immune system.

Non-immunologic food reactions or food intolerance includes several types of adverse food reactions such as metabolic food reactions, pharmacologic food reactions, food idiosyncrasies, and food poisoning. Metabolic reactions to food are defined as adverse reactions as a result of an effect of an unusual food component on the physiological metabolism of the animal or as a result of a common dietary component on the defective metabolism of the animal. The former is rather rare in dogs and cats but the latter does occur. The most common example is lactose intolerance, which is present in many adult dogs and cats. This condition is due to lack of the brush border enzyme lactase. Lactose can no longer be digested and will instead be fermented by members of the gastrointestinal microbiota, leading to clinical signs such as bloating, flatulence, and diarrhea. Pharmacologic reactions to food are reactions that are due to a pharmacologic effect in the host. One example of such a reaction is chocolate toxicity in dogs. In these cases the theobromine in the chocolate leads to neurologic, gastrointestinal, and renal malfunction and resulting clinical signs. Food idiosyncrasies are abnormal responses to a food substance or additive that resemble a hypersensitivity response but do not involve an immunologic mechanism. Food idiosyncrasies have been described in human beings but have not been well documented in dogs or cats. Food poisoning is an adverse reaction based on a direct toxic effect of a food. Food poisoning is usually due to toxic substances that have been produced by a microbial contaminant, but can also be due to a toxic principle naturally present in the food. One such example would be onion toxicity in dogs. Finally, food poisoning could also be caused by a toxic substance that has reached a pet food accidentally or through malicious behavior. Such an example would be the melamine scandal a few years ago where rice and wheat gluten from China had been found to have been adulterated with melamine, probably to falsely increase the protein content of said rice or wheat gluten.

Immunologic food reactions include food allergy and food anaphylaxis. Food anaphylaxis should be viewed as a type of food allergy that leads to systemic clinical signs.

Dietary indiscretion

Dietary indiscretion is a common cause for acute gastrointestinal signs such as vomiting and diarrhea. The ingestion of foreign bodies is a special case of dietary indiscretion. Many foreign bodies are radiodense and can be diagnosed by abdominal radiography, while others are radiolucent and maybe more difficult to diagnose. Abdominal ultrasound may prove useful in diagnosing radiolucent foreign bodies or may at least show signs suggestive of intestinal obstruction. In some cases a diagnosis cannot be made non-invasively and an abdominal exploratory is necessary to rule out an intestinal foreign body.

Dietary indiscretion also describes the indiscriminate ingestion of food by a dog and less commonly a cat. These cases most commonly involve the ingestion of human food and often lead to mild cases of acute gastritis and/or pancreatitis that lead to a single episode of vomiting and/or diarrhea and are most commonly not presented to a veterinarian, but resolve without therapy. Another example of dietary indiscretion is the ingestion of excessive quantities of food. Dietary indiscretion is most often easy to diagnose as the owner often is aware of the dietary history of the pet. Single episodes of vomiting and diarrhea, if a dog or cat is presented to a veterinarian for them, and if they are not associated with systemic clinical signs, should be treated with no food for 24 hours followed by the introduction of small quantities of an easily digestible diet if clinical signs have resolved. However, sustained or recurrent clinical signs need to be worked up properly and systemic clinical signs warrant immediate work up and aggressive supportive care.

Diagnosis of food intolerance and food hypersensitivity

A definitive diagnosis of food intolerance and food hypersensitivity is extremely difficult to accomplish and in most cases the diagnosis will remain one of presumption. A definitive diagnosis of an adverse food reaction requires several elimination-challenge feeding cycles. The diet first is changed to a diet that does not contain the assumed offending component and improvement of clinical signs should be observed. Then the patient is challenged with the presumed offending diet and exactly the same clinical signs should be observed as had been previously observed. This cycle is repeated one more time before a definitive diagnosis can be made. However, such a definitive diagnosis is most often of little interest to the pet owner and is more of academic interest. Most pet owners are happy with a presumptive diagnosis and prefer to feed the new diet, even if it is more expensive, rather than risking a relapse of clinical signs. Also, even if a definitive diagnosis of an adverse food reaction can be made a specific diagnosis cannot be reached in most cases by use of an elimination-challenge trial alone.

Thus, the first step in the diagnostic process is a change in diet. Several strategies can be chosen. An easily digestible diet can be chosen if food intolerance is suspected. If food hypersensitivity is suspected a low-antigen or hypoallergenic diet should be used for the elimination trial. The low-antigen diet contains a single protein source that is believed to be novel to the patient. Additionally, the low-antigen diet should contain a single carbohydrate source. While carbohydrates are weak allergens, all carbohydrate sources contain small quantities of proteins that may be sufficient to cause an allergic reaction. Examples of this type of low-antigen diets are duck and potato, venison and potato, rabbit and potato, whitefish and potato, or even kangaroo and some carbohydrate source. It is important to note that these diets are not intrinsically hypoallergenic but limit the exposure of the patient to antigens. The clinical history can often be useful in helping to select an appropriate diet. Some clinicians use radioallergosorbent test (RAST), enzyme-linked immunosorbent assay (ELISA), or intradermal skin testing in order to select an appropriate diet. However, these tests are controversial and are believed to be of little clinical use by some. Intradermal skin testing is probably most useful to identify food allergens that will cause dermatologic signs. However, results have likely little validity in determining food allergens that will cause gastrointestinal signs.

Another approach is the use of diets containing hydrolyzed proteins. It has long been known that small peptides are poor allergens. The principle behind these diets is that the hydrolyzed proteins contained in these diets are too small to act as allergens. This principle has been utilized in humans with food hypersensitivity. A recent study showed that a soy-based hydrolyzed protein diet had a significantly better outcome long-term (12 months and 3 years after diagnosis; response rate 87 and 79%, respectively) than an easily digestible diet (response rate 28 and 12%, respectively) in dogs with chronic small bowel enteropathies. Several diets containing hydrolyzed proteins are available from major pet food manufacturers. The elimination diet should be fed for at least 6 weeks. However, partial response should be expected within the first 2 weeks. If there is no response at all during this period another diet should be tried or further medical work up should be pursued.

Food intolerance (non-immunologic adverse food reactions)

Food intolerance and food hypersensitivity are difficult to distinguish since both can be associated with the same set of clinical signs and both may respond to an elimination feeding trial. One major difference is that food intolerance is a non-immunologic adverse food reaction and as such does not require previous exposure to the inciting substance. Clinical signs may occur upon the first exposure to the offending food. However, clinically this difference cannot be documented and thus a diagnosis of food intolerance remains speculative in most cases.

Metabolic reactions to food

Metabolic reactions to food can either be due to the effect of an unusual dietary component on the normal metabolism of a dog or cat, or more commonly can be due to the effect of a usual dietary component on the defective metabolism of a dog or cat. For example, excessive ingestion of liver by cats may lead to hypervitaminosis A and stomatitis or excessive ingestion of raw egg white may lead to biotin deficiency and bloody diarrhea, but these cases are rare. More common are metabolic reactions to food in animals that have a metabolic defect and therefore do not tolerate certain dietary components. The most common such condition seen in dogs and cats is lactose intolerance. Many adult dogs and cats have little lactase activity in the brush border and develop bloating, flatulence, abdominal discomfort, and diarrhea after ingestion of milk and milk products. Lactose intolerance is also increasingly common in human beings in North America. Many of these cases are suspected to be secondary to an acute viral infection leading to the permanent destruction of the brush border enzyme lactase.

Pharmacologic reactions to food

There are only few examples of pharmacologic reactions to unspoiled foods. The one most commonly observed is chocolate toxicity in dogs. The toxic principle in chocolate is theobromine, a methylxanthine, which can lead to gastrointestinal, neurologic, cardiovascular, and renal abnormalities and resulting clinical signs. A large quantity of chocolate needs to be ingested for clinical signs to develop. Thus the disease is mostly seen in small breed dogs. Most often the dog is presented with a history of chocolate ingestion. Induction of vomiting, activated charcoal administration, and supportive care are usually effective in treating dogs with chocolate toxicity.

Pharmacologic reactions due to ingestion of spoiled foods are more common. Bacteria can produce a variety of vasoactive amines such as tyramine, tryptamine, phenylethylamine, dopamine, norepinephrine, serotonin, and histamine. Tyramine can be found in spoiled cheese, histamine in spoiled tuna, and phenylethylamine in spoiled chocolate.

Food idiosyncrasies

In humans, food additives cause adverse reactions to food. These reactions can be observed after a first exposure, suggesting a non-immunologic pathogenesis of this type of reaction. However, the exact mechanism by which food additives cause idiosyncratic reactions remains unknown. While these types of reactions have been observed in human beings with some frequency, there are few reports of suspected food idiosyncrasies in dogs and cats and they are not well documented.

Food poisoning

Food poisoning is caused by a direct toxic effect of a dietary component (e.g., melamine). Most typically food poisoning involves spoiled or contaminated food. However, food poisoning can also be caused by a toxic principle of a natural food component. Several plants are toxic to dogs and cats and could accidentally reach pet foods. Poisonous mushrooms are classical examples for food poisoning in humans. Other plants may be less toxic than some of the poisonous mushrooms and may only lead to toxic effects if large quantities are ingested. For example, excessive ingestion of onions can cause Heinz body anemia in dogs. Also, large quantities of inadequately cooked lima beans, sorghum sprouts, maize, or chick peas can lead to cyanide toxicity. Finally, grapes and raisins have recently been implicated to cause acute renal failure in dogs.

A more common cause of food poisoning in small animals is the ingestion of spoiled food. Many different bacteria and fungi can grow in feed stuff and are capable of producing toxins that may cause clinical signs. Many of these toxins are produced before the food is prepared and food preparation may kill the microorganism but may not destroy the toxic principle. Aflatoxin, is a mycotoxin produced by Aspergillus flavus, Aspergillus parasiticus, and Penicillium puberulum. Aflatoxin is one of the most potent microbial toxins and can cause clinical signs of hepatic failure and even death in dogs and cats.

Food hypersensitivity (immunologic adverse food reactions)

Pathogenesis

The gastrointestinal wall serves as a barrier against loss of valuable components such as plasma proteins but it also serves as a barrier against entrance of potentially harmful substances. Thus, macromolecular food components, proteins, lipids, and carbohydrates must be digested in the small intestine and only the building blocks, amino acids, fatty acids, cholesterol, mono- and disaccharides, and others can be absorbed. However, a small amount of macromolecular food components are absorbed intact by way of endocytosis, mostly in the small intestine. Proteins that are being absorbed intact can serve as dietary antigens. Most of this protein is being processed through intracellular digestion and rendered non-immunogenic. A small amount escapes lysosomal digestion and reaches the gut-associated lymphoid tissue and normally leads to a cell-mediated suppressor response. Thus, re-exposure to small quantities of the same food antigen should normally not lead to a hypersensitivity response. The GALT also synthesizes IgA that is being secreted onto the luminal surface of the mucosal cells, binding to food antigens and rendering them non-immunogenic. Only if all of these protective mechanisms fail can the food allergen lead to an immunologic response.

There is a vast number of potential food antigens, most of which are glycoproteins and have a molecular weight of 10 – 70 K. Some proteins are more allergenic than others and it seems logical that those proteins that are resistant to heat degradation during cooking or digestion are more allergenic than others. The most common food allergens recognized in dogs are milk, soy, wheat, oats, beef, eggs, horse meat, chicken, corn, pork, and yeast. In cats the most common food allergens are fish and dairy products. However, this profile may change over time as some components become more common in commercial pet foods than they have been in the past. There is also some degree of cross-immunoreactivity. In these cases an animal that is allergic against one protein may also be allergic against a related protein.

Clinical presentation

Dogs and cats of any breed, sex, or age can present with food allergy. Clinical signs of food allergy in dogs and cats are mostly related to the gastrointestinal tract and the skin. Involvement of other organ systems is poorly documented in small animals. Gastrointestinal signs most commonly observed are vomiting and diarrhea, while dermatologic signs commonly observed are pruritus, papules, and erythema.

Diagnosis

The conclusive diagnosis of food allergy is difficult if not impossible. The successful use of a food elimination trial and re-challenge with the offending diet only proves the presence of an adverse food reaction. Several tests have been described to diagnose food hypersensitivity. Skin testing involves the intradermal application of a variety of different potential food allergens. However, as mentioned previously sensitized mast cells may be limited to the gastrointestinal tract and a positive reaction may not be seen even though food allergy is present. Conversely, a positive reaction may be seen in patients that do not have food allergy against that particular food. Thus, overall intradermal skin testing is a poor diagnostic test for food hypersensitivity.

Antibody estimation is another avenue that has been utilized to try to diagnose food allergy. Several different methods have been used to try to estimate the presence of antibodies. Demonstration of IgA or IgG against specific food antigens in serum, demonstration of the presence of fecal IgG against specific food antigens, measurement of IgE concentration against specific food allergens in intestinal juice, and assessment of total serum IgE concentration all have been investigated in human patients with suspected food allergy but none of these tests are particularly sensitive and/or specific. Radioallergosorbent tests (RAST) and enzyme-linked immunosorbent assays (ELISA) both have been used to estimate IgE serum concentrations directed against specific food antigens. However, these tests are controversial. Some investigators believe that these tests are useful to exclude potential food antigens as the lack of IgE against a specific allergen is unlikely associated with food hypersensitivity against this allergen. However, this is only true if the hypersensitivity response is in fact IgE mediated. Also, the presence of IgE against a specific food allergen after challenge with this particular food antigen would suggest the presence of food hypersensitivity, but this would require challenge and follow-up evaluation of IgE concentrations for a specific food antigen. More data is needed before these tests can be recommended for the diagnosis of food allergy in dogs and cats.

Gastroscopic food sensitivity testing involves dripping of a concentrated antigen solution onto the gastric mucosa during gastroscopy and observing the site for erythema, blanching, edema, and petechiation. While this technique has been found to be useful in experimental studies it is time-consuming and tedious and will unlikely become widely used in clinical practice.

Histopathologic evaluation of gastric or intestinal biopsy specimens do not reveal any specific changes in dogs and cats with food hypersensitivity but instead show signs of chronic inflammation and mucosal damage.

Therapy

Elimination of the offending food allergen is the treatment of choice for food allergy in dogs and cats. Unfortunately, conclusive identification of the inciting food allergen is almost impossible. Low-antigen or hypoallergenic diets can be utilized for a feeding trial. Partial response should be observed after 2 weeks, but complete remission of clinical signs could take up to 6 weeks. If home-made diets are utilized care should be taken to balance the diet. After a complete remission has been achieved different ingredients can be slowly added in order to identify other food components that do not elicit a hypersensitivity response.