INFLAMMATORY BOWEL DISEASE

IN THE DOG (IBD)

Inflammatory bowel disease (IBD) usually refers to a chronic inflammatory disease anywhere in the gastrointestinal (GI) tract, including the stomach, small intestine (duodenum, jejunum, ileum), and large intestine (colon) The term implies a process of long duration as opposed to sudden onset. Because IBD affects many areas of the GI tract it probably has many different causes. 
More traditionally, IBD has referred to chronic inflammation of the small or large bowel excluding the stomach. The disease is classified by the predominant inflammatory cell found invading the wall of the bowel. Such classification may allude o its cause. However, this method of grouping is not always possible and location of the leison will help its classification. 
IBD is usually found in younger dogs but, it can extend to middle age dogs. There is no strong relationship by breed however, IBD does seem to affect some breeds more often than others. 

The most common form of IBD is lymphocytic-plasmacytic IBD (LPIBD). This term describes the cells that are found microscopically when a biopsy of the leison is examined. Most biopsies are obtained by abdominal surgery or by endoscopy if available. Biopsies are important to rule out other causes such as: dietary hypersensitivity, lymphoma, histoplasmosis (a fungus), bacterial infection or overgrowth, and malassimilation problems. The predominant cell type, lymphocytes and plasma cells represent a chronic stimulation of the immune system. Because of this response, IBD is typically thought of as an immune mediated disease and therefore treated with the various immunomodulating therapies. Current thoughts are that the GI tract has been sensitised by some bacteria or food antigens that determines the ongoing immune response. Complexes are formed from antibodies against food antigens, bacteria or bacterial by-products. These antigen-antibody complexes (ABC) induce the release of destructive chemicals into the area and tissue destruction results. The destruction is indiscriminate. The quantity of ABC¹s produced may influence the long standing nature of the disease.

Signs of IBD are dependent on the location of the problem. Disease in the stomach or upper small intestine are frequently associated with chronic vomiting and weight loss. Diseases of the jejunum, ileum, and colon are associated with chronic diarrhoea, weight loss and infrequent vomiting. Small bowel diarrhoea is often watery with a large volume of faeces and the patient acts sick. Large bowel diarrhoea is associated with straining, some blood, mucus, small volume of faeces and frequent attempts to defecate. 

Once IBD is suspected, strict dietary changes are fundamental for long term results. Often diet will control the disease but in the majority of cases anti-inflammatory drugs are added to quiet the immune system. Often, the use of anti-inflammatory drugs at the beginning is enough with controlled diet to stabilize the chronic inflammation. However, the disease in most cases goes into periods of remission with repeated flare ups. Certain breeds (Wheaton Terriers and Basenjis) are more predisposed to progressive disease.

Diet is chosen to produce the least amount of ABC stimulation. A true hypoallergenic diet should contain a very good single protein source that is highly digestible, so as not to be available for immune stimulation. There are now commercial diets available through veterinarians and some knowledgeable pet food stores that contain only one source of a hypoallergenic protein such as lamb, rabbit, turkey, venison, fish or duck. Many diets listed as hypoallergenic contain other ingredients and caution is order. 
These are usually combined with a good source of carbohydrates such as rice or potatoes. Commercial diets insure that essential vitamins, minerals and fatty acids are included. Fibre is often a vital component of long term care. Quality fibre aids in the development of beneficial colonic flora and enhances the digestive process. In addition, diets free from preservatives and food additives may provide relief for some patients that are sensitive to these chemicals.

Anti-inflammatory therapy involves immunosuppressive drugs, metronidazole, or Salicylates. The mainstay of anti-inflammatory drugs are corticosteroids. Prednisone and methyl prednisolone are powerful anti-inflammatory drugs that can produce impressive results. They have minor short term side effects that include increased drinking, eating and urinating. Long term, these drugs can cause Cushing disease if alternate day therapy can not be achieved for control of IBD. Sulfasalazine is commonly used to control large bowel IBD. It has no long term side effects, however it can cause a dry eye syndrome and occasionally will cause salicylate toxicity. Metronidazole is used because it is anti-inflammatory, anti-protozoan, and is a good 
antibacterial for the small bowel. The only side effect is vomiting. Other drugs that are being tried include cyclosporine and eicosapentaenoic acid, a fatty acid found in fish oil. Eicosapentaenoic acid(Derm Caps) is a drug often used in veterinary medicine to decrease the inflammatory response of inhaled allergies. The only side effects are a shiny coat. 
IBD involves a great deal of patience by the dog owner but most dog will gain relief with some variation of therapies. The disease is life long and will require regular attention.

 
Update from Cornell University College of Veterinary Medicine 

IRRITABLE BOWEL DISEASE IN DOGS


Inflammatory bowel disease: Why the prognosis is often guarded: Inflammatory bowel disease is the term used to describe a diverse group of intestinal disorders in dogs and cats. These disorders are characterized by the abnormal accumulation of inflammatory cells in the mucosa or lining of the intestine. The most common type of inflammatory bowel disease in dogs and cats is called lymphoplasmacytic enteritis. The reason plasma cells and lymphocytes (cells produced in lymphoid tissue) accumulate in the lining of the intestine is not clear but is thought to involve an immunological reaction to antigens present in food, bacteria, or parasites. Veterinarians diagnose lymphoplasmacytic enteritis by ruling out metabolic, parasitic, infectious, and pancreatic causes of small-bowel disorders and also by obtaining biopsies, which demonstrate the abnormal accumulation of inflammatory cells. The exclusion of known causes of intestinal inflammation such as dietary sensitivity and infestation by internal parasites suggests a diagnosis of idiopathic inflammatory bowel disease. The veterinarian evaluates the degree of cellular accumulation and categorizes this as mild, moderate, or severe. The extent of inflammation varies and can range from the duodenum (the first part of the small intestine) to the rest of the small and large bowel. A very severe form of this disease has been found in Basenjis.

Clinical signs
The most frequently observed clinical signs in dogs and cats with lymphoplasmacytic enteritis are chronic diarrhea (large volume) accompanied by weight loss or vomiting. The pet owner can help the veterinarian diagnose the disease by describing the type of diarrhea. Lymphoplasmacytic enteritis of the small intestine is characterized by small bowel disorder, which involves a large volume of stool, a mild increase in frequency of defecation, and little or no straining, mucus, or blood present. The vomit often contains bile, and in cats it frequently contains hairballs. If the large bowel is involved, there may be mucus, blood, and straining at defecation with little matter produced (tenesmus). 
There are other clinical signs such as changes in appetite, excessive burbling noises in the intestine (borborygmi), and abdominal discomfort. It is important for owners to understand that the severity of inflammatory bowel disease is variable, ranging from intermittent diarrhea and vomiting in mild cases to intractable diarrhea, refusal to eat, and weight loss in severe cases. The severity of the disease is believed to reflect the degree of cellular infiltrate into the intestine. 
In addition to these signs, the veterinarian may also note a thickening of the intestine (with or without enlarged lymph nodes), marked weight loss, and the accumulation of fluid in the abdomen (ascites). Animals that have very low plasma protein may also show signs of tissue swelling due to edema formation. 

Treating the disease: dietary factors 
Mild to moderate intestinal inflammation may be associated with dietary sensitivity, food intolerance, parasites (for example, giardia), and even small intestinal bacterial overgrowth. The veterinarian may decide to put the dog or cat on a special diet to determine if dietary sensitivity or intolerance is present. After all factors have been taken into consideration, the pet is usually fed a highly digestible diet that is restricted in tat, is gluten-free, and is limited to a single protein source. Up to six weeks may be required to see a response to this therapeutic trial. 

A trial lasting 21 days of antibiotics may be warranted if small intestine bacterial overgrowth is suspected. (Cat owners should know that dietary modification is seldom effective in cats with inflammatory bowel disease and, furthermore, intestinal bacterial overgrowth has not been recorded in cats.) Dietary factors to consider are additives, preservatives, protein digestibility, protein source, and dietary fiber. Some pet foods are labeled hypoallergenic if they contain no additives and preservatives. Although some pets are allergic to foods with additives and preservatives, there appears to be no hard scientific evidence that most pets react this way, nor is there evidence that additives and preservatives are in and of themselves likely to cause allergic reactions. But weighing in on the side of cautious management, they are excluded from trial diets. 

Pet owners should again be reminded that the mere absence of additives and preservatives does not make a food hypoallergenic. Protein digestibility, meaning that the food contains an adequate amount of highly digestible protein; is important because protein that is poorly digestible may cause antigenic stimulation and may promote inflammatory bowel disease. There are no protein sources that are in and of themselves hypoallergenic. This includes lamb. Much depends on the dietary history of the pet. That is, the protein source in the hypoallergenic diet must be a food that the pet has not encountered before, i.e., tofu, cottage cheese, and lamb, along with rice. The owner is usually advised to use only one of the novel protein sources, and if the pet improves, then switch to a commercially available ration with that protein source. An important piece of advice: check the label and avoid rations that list several protein sources. Fortunately, the market offers an increasingly diverse array of novel protein sources, including rabbit, venison, and duck, along with the more familiar lamb, chicken, and rice. 

Drug therapy for lymphoplasmacytic enteritis 
The administration of immunosuppressives is often required for patients who fail the dietary trials described, for patients with moderate to severe infiltrates, and for patients that develop a condition called hypoproteinemia, a deficiency of protein in the blood due to protein leakage from the gut. Oral prednisone alone is then initial drug of choice. It is usually administered at an immunosuppressive dose for two to three weeks, then decreased by 50 percent every two to three weeks and eventually continued on an alternate day basis for two to three months. The antibiotic tylosin is frequently administered at the same time. If clinical response is poor or if the adverse effects of corticosteroids are troublesome, further immunosuppression can be achieved by adding azathioprine (Imuran) to the regimen. In dogs, azathioprine is usually given every five days and then on a schedule that alternates it with prednisone. Cats are more sensitive to azathioprine and require a reduced dose. The veterinarian will want to monitor the pet's complete blood count every two to four weeks when azathioprine is given. Another drug, metronidazole, can also be used in conjunction with steroids and has effects on bacteria and the immune system. 

Successful treatment is accompanied by a decrease in diarrhea and vomiting followed by weight gain and an increase in plasma proteins. Once a patient has had from two to three months of remission of clinical signs it may be possible to gradually withdraw the immunosuppressive therapy. If signs recur, however, daily medication is continued until they resolve, then the medication is gradually reduced. In patients that respond poorly to therapy or go into relapse after an initial response, the veterinarian, may want to reassess* the patient and consider taking additional intestinal biopsies to rule out the presence of alimentary lymphosarcoma, a malignant tumor of the lymphoid tissue.

What's new in drug therapy 
There has been progress in developing new drugs to treat inflammatory bowel disease and related problems in humans, but unfortunately few of these new drugs are available or practical for use in dogs and cats. Cyclosporine, the extraordinary immunosuppressant that made organ transplantation a lifesaver for thousands of humans, has had moderate success as a treatment for human bowel disease (in this case, Crohn's disease). The drug has serious side effects and is costly, factors that make its use in pets unlikely. The antihypertensive drug clonidine has been used with success in humans, but there is no report of its use in dogs or cats. Finally, the use of the acid found in fish oil for skin diseases in dogs and cats has led to the speculation that fish oil might also benefit pets with inflammatory bowel disease. Although there is a fish oil drug available for humans with inflammatory bowel disease, the drug has not been evaluated in dogs or cats. 

Prognosis 
The owner of a dog or cat with lymphoplasmacytic enteritis should understand that the prognosis for recovery depends on the severity of the condition. Prognosis is also quite variable with many patients requiring prolonged treatment with glucocorticoid and diet modification. In the absence of accurate criteria for predicting response, veterinarians tend to give a guarded prognosis when treating the disease. 

Focus on dietary fiber 
If you believe all the labels you read, you could come away convinced that fiber in the is absolutely necessary for health, well-being and disease-free longevity. But all the hype aside, can an increase in fiber in the diet of a dog or cat either prevent or help manage inflammatory bowel disease? To begin with, the role of fiber has not been well studied, although some experts believe that an increase in fiber is likely to be useful in some cases. But no one claims that fiber can cure a case of inflammatory disease. Dr. Michael D. Willard of Texas A&M notes that some of the known effects suggest some potential benefits. For example fiber increases the activity of the colon and speeds up transit time, increases fecal output and improves stool consistency. This combined action may be of some benefit in certain cases of bowel disease, as has been reported to hap pen with human patients. In spite of this evaluation other experts take more guarded approach. 
Dr. P. J. Markwell and Dr. I. E. Maskell, both of the highly regarded Waltham Centre for Pet Nutrition in Great Britain, say that high fiber diets are not indicated in gastric diseases. However, they agree that fiber may be beneficial in some cases, mainly for the reasons already given. 

Fiber normalizes fecal transit time and fecal water content. Fiber may also increase gastrointestinal tissue weight. The owner of a dog or cat with inflammatory bowel disease is advised not to try to increase fiber content of the pet's diet by, say, giving, it a helping of one of the high-fiber breakfast cereals. That's because most commercial breakfast cereals contain only 2 to 4 grams of fiber per cup, and many contain excessive, sugar and gluten The safest route is to have the veterinarian decide if fiber is of possible benefit in an individual case of inflammatory bowel disease. A homemade high-fiber diet could be prepared by the owner or , a better choice, prescription diet can be such diets are specially formulated with anywhere from 12 to 25 percent more fiber than is in an average commercial food (which usually contains from 1 to 4 percent fiber). In addition prescription diets have the special advantage of being consistent, which is not always the cases with a diet being prepared in the home. 


Cornell University College of Veterinary Medicine 
Animal Health Newsletter (ISSN 0884-092X)

INFLAMMATORY BOWEL DISEASE IN THE DOG AND CAT

OVERVIEW

Inflammatory bowel (IBD) is a chronic gastrointestinal tract disorder of unknown cause and ill-defined pathogenesis. Interactions between the mucosal immune system, host genetic susceptibility, and environmental factors (e.g., normal microflora) have been implicated as causing intestinal inflammation. Two general hypotheses have been proposed: 1) inflammation is due to an abnormal immune response (e.g., host hypersensitivity caused by increased intestinal permeability, defective suppressor function of GALT, and/or other primary immunologic events) and, 2) inflammation is initiated by an appropriate immune response to a normal luminal constituent (dietary antigen or resident enteric flora). With either paradigm, both cellular components (activated intestinal B and T lymphocytes) and molecular elements (complement, prostanoids, leukotrienes, proinflammatory cytokines, leukocyte proteases, nitric oxide, and reactive oxygen species) likely contribute to mucosal inflammation. Clinical signs are attributed to mucosal cellular infiltrates and inflammatory mediators.

RELEVANT DIAGNOSTIC TESTING

A diagnosis of IBD is one of exclusion and requires ruling-out of many other diseases which may cause intestinal inflammation. Systemic diseases, chronic parasitism, dietary sensitivity (e.g., food allergy or intolerance), infectious diseases, and alimentary lymphosarcoma are the major differential diagnoses for IBD. Objective criteria for diagnosis of canine and feline IBD have been described. It is essential that clinical signs be correlated with histologic evidence of gastroenteritis, and that other causes for chronic mucosal inflammation be eliminated by appropriate diagnostic testing. Therapeutic trials using anthelmintics or hypoallergenic diets may be effective in animals having parasitic or dietary causes, respectively, for enterocolitis. One recent study indicates that up to 30% of cats with idiopathic gastrointestinal problems may have food sensitivities.

CLINICAL STAGING OF IBD

The clinical course of IBD is generally characterized by spontaneous exacerbations and remissions, making accurate assessment of disease burden difficult. Determination of degree of illness (e.g., disease activity) is desirable since it serves to gauge initial IBD severity and helps guide therapeutic strategies. There is a paucity of data defining any clinical scoring systems for either canine or feline IBD. We have recently developed a simple numerical scoring system, termed the canine IBD disease activity index (CDAI), which produces very reproducible scores from one clinician to the next. Using this system, six salient gastrointestinal signs are scored 0-3, based upon the magnitude of their alteration from normal in a given IBD patient. Use of this disease activity index has been recently evaluated in a large prospective study. In this investigation, it was shown that the CDAI correlated positively with both histology scores and laboratory markers of intestinal inflammation (e.g., serum haptoglobin and C-reactive protein). Lastly, this same study showed that the CDAI could provide valuable prognostic information when assessing therapeutic responses. 

HISTOLOGIC GRADING CRITERIA

Histologic evaluation of tissue specimens is required for definitive diagnosis of IBD. Unfortunately, no standard microscopic grading system for assessment of biopsy specimens has been established. Biopsy interpretation is notoriously subjective from one pathologist to the next, and is further hampered by the technical constraints of specimen size and procurement or processing artifacts inherent in evaluation of endoscopic specimens. We propose utilization of a grading system based upon the extent of architectural disruption and mucosal epithelial changes. "Mild" IBD lesions are those in which there is no mucosal architectural disruption, glandular necrosis, immaturity or fibrosis in the lamina propria. "Severe" IBD is manifest by architectural distortion of the mucosa as seen with extensive ulceration, necrosis, villus atrophy, glandular loss/hyperplasia, or fibrosis of the lamina propria. Note that in this grading scheme, no attempt is made to quantitate the number of inflammatory cells within the lamina propria. Greater confidence may be placed in a histologic diagnosis of mild IBD when concurrent cytologic lesions of benign mucosal inflammation are observed. Endoscopic exfoliative cytology has been shown to be a useful adjunct to mucosal biopsy for the diagnosis of IBD in the dog and cat.

TREATMENT OF IBD

Dietary Therapy. Patients with IBD may be nutritionally deficient due to decreased food intake, impaired nutrient absorption, and/or increased exudation as seen with protein-losing enteropathy. The most convenient means for dietary manipulation in veterinary patients is with controlled (hypoallergenic) diets. These diets should be formulated with ingredients which the animal has not been fed before (e.g., novel protein source such as venison, rabbit, lamb, whitefish or turkey) or that are unlikely to evoke allergic responses (e.g., potatoes). Controlled diets may have to be fed for several (6-8) weeks to assess their efficacy. Altering the dietary ratio of omega-6 (n=6) to n=3 polyunsaturated fatty acids may affect the inflammatory response of IBD. Diets enriched in n=3 fatty acids are incorporated into biologic membranes resulting in decreased concentrations of pro-inflammatory n=6 fatty acid metabolites (e.g., leukotriene B4 [LTB4], prostaglandins, and interleukin-1). Therapeutic trials assessing the efficacy of dietary fatty acid modification in dogs or cats with IBD have not been published. Fiber-enriched diets are recommended to mitigate signs of large bowel diarrhea and tenesmus. Dietary fiber may increase fecal consistency, bind potential colonic irritants, improve abnormal colonic motility, and produce beneficial short chain fatty acids (e.g., butyrate) which positively influence large bowel structure and function.Commercial high fiber diets or hypoallergenic diets supplemented with moderately fermentable fiber (e.g., psyllium or oat bran) may be fed. 

Pharmacologic Therapy. Dietary management alone for moderate-to-severe IBD is seldom successful and most animals will require pharmacologic therapy. 

Corticosteroids. Prednisone or prednisolone are reasonable first-choice agents for induction therapy of IBD in some dogs and most cats. Beneficial responses are usually observed when dosages of 1-2 mg/kg body weight/day are used in conjunction with dietary therapy. Induction therapy of 2-4 weeks (depending on severity of signs and type of histologic lesion) is generally recommended. Combination drug therapy (e.g., steroids combined with metronidazole, azathioprine, or sulfasalazine) allows a reduced steroid dose for maintenance therapy. Alternative glucocorticoid preparations characterized by high topical anti-inflammatory activity and first pass hepatic metabolism have been recently used in human IBD. They were developed to attain maximal therapeutic effect of conventional steroids while minimizing deleterious systemic effects. These medications are administered rectally (tixcortal pivilate, beclomethasone dipropionate) or orally (budesonide). The efficacy (and potential toxicity) of these new preparations in dogs and cats remains to be proven; although, anecdotal evidence suggests budesonide may be of value in some dogs with lymphocytic-plasmacytic colitis.

Sulfasalazine. Sulfasalazine (SASA) is considered by many clinicians to be the first-choice drug for canine colitis. The recommended dosage range for SASA in dogs is 20-50 mg/kg up to a maximum of 1.0 gm q8h in refractory patients or those having severe disease. I use an initial dosage of 12.5 mg/kg q8h. It is important to continue induction therapy for a minimum of 4 weeks before modifying drug dosage. With resolution of signs, SASA dosages are gradually decreased by 25% at 2 week intervals and eventually discontinued while maintaining dietary management. Caution is advised in using SASA in cats because of their sensitivity to salicylates. 

Newer 5-ASA Preparations. Topical and oral 5-ASA preparations are now used for treatment of human IBD.Two oral preparations of potential use in dogs include olsalazine and mesalamine. Olsalazine (Dipentum) consists of two molecules of mesalamine linked by an azo bond. Various enteric-coated preparations of mesalamine (Pentasa, Asacol) release active drug (5-ASA) in the distal small intestine and colon, respectively.The use of these agents for treatment of canine and feline IBD has not been critically evaluated, but there are substantial anecdotal reports of their efficacy. The proposed dose is approximately one-half that of SASA. 

Metronidazole. Anecdotal reports suggest that metronidazole has beneficial effects in the therapy of canine and feline IBD. Its mechanisms of action might include antiprotozoal action, inhibition of cellular immunity, and bacteriocidal spectrum of activity against anaerobes (e.g., Bacteroides spp). The recommended dosage of metronidazole used in dogs and cats for IBD is 10-20mg/kg q8-12h. Metronidazole is most often combined with corticosteroids or sulfasalazine in patients having moderate-to-severe clinical signs or histologic lesions. It is also effective as a sole agent in animals having mild intestinal inflammation.

Azathioprine. Azathioprine (AZA) is a potent cytotoxic drug occasionally used as adjunctive therapy in severe and refractory IBD. This drug is metabolized in the body to 6-mercaptopurine (6-MP), it's active metabolite, which functions to interfere with antigenic triggering of lymphocytes.Controversy exists concerning the efficacy and safety of AZA and 6-MP in treatment of human IBD. The suggested dosage is 2 mg/kg q24h in dogs and 0.3 mg/kg q48h in cats. A lag time of 3-5 weeks is expected before clinical improvement may be observed. 

Miscellaneous Immunomodulating Drugs. A variety of other drugs (e.g., cyclophosphamide, cyclosporin, tylosin) are occasionally of value in treating refractory IBD. Cyclosporin acts primarily by inhibiting interleukin-2 release from helper T-cells, which prevents T-cell recruitment/amplification and inhibits the release of gamma-interferon. Preliminary observations in humans with IBD suggest that cyclosporine may act synergistically with corticosteroids and produce a more rapid response than classic immunosuppressants. The use of 5-lipoxygenase inhibitor drugs, such as Zileuton, may offer a new type of treatment for IBD.

Summary of Drug Therapy. Most drug therapies interrupt the amplification sequence of inflammation in IBD, explaining why maintenance therapy (via diet and/or drugs) is important. Anecdotal evidence supports the use of oral corticosteroids, sulfasalazine or similar drugs, and metronidazole in therapy of small animal IBD. The added therapeutic benefit of combination drug therapy in dogs and cats has not been established. However, combination drug therapy appears warranted in animals with severe disease, multiorgan involvement, and to reduce systemic effects of corticosteroids.


 Albert E. Jergens, DVM, MS, Diplomate ACVIM 
Iowa State University
Ames, Iowa, USA
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