Inflammatory Bowel Disease--More Than a Garbage Can Diagnosis
World Small Animal Veterinary Association World Congress Proceedings, 2007
Stanley L. Marks, BVSc, PhD, DACVIM (Internal Medicine, Oncology), DACVN
University of California, Davis, School of Veterinary Medicine
Davis, CA, USA

The inflammatory bowel diseases (IBD) are the most common causes of chronic vomiting and diarrhoea in dogs and cats, and refer to a group of poorly understood enteropathies characterized by the infiltration of the gastrointestinal mucosa by inflammatory cells.1 The cellular infiltrate is composed of variable populations of lymphocytes, plasma cells, eosinophils, macrophages, neutrophils, or combinations of these cells. Changes in the mucosal architecture characterized by villous atrophy, fusion, fibrosis, and lacteal dilation frequently accompany the cellular infiltrates.

Aetiology of IBD

Although the aetiology of canine and feline IBD is poorly understood, there is provocative evidence from clinical observations and animal models to incriminate normal luminal bacteria or bacterial products in the initiation and perpetuation of canine and feline IBD.Evidence of the role of enteric microflora in the pathogenesis of IBD in people is supported by clinical responses to faecal stream diversion treatment in patients with Crohn's disease (CD)2 and antimicrobial therapy in CD and ulcerative colitis (UC) patients.3 Additionally, there are increases in circulating and intraluminal humoral and T-cell responses to the enteric microflora in human IBD patients. Furthermore, genetic mutations in NOD2/CARD154 and TLR-4 in IBD patients make them less able to detect bacterial components, resulting in defective responses to enteric microflora.5 Studying the composition of the intestinal microflora has been a challenge to researchers; however, recent work has focused closely on the bacteria associated with the mucosal lining. A study of adherent mucosal bacteria in IBD patients concluded that Bacteroides fragilis comprised >60% of the biofilm mass in patients with IBD.6 Dietary factors also appear to play a role in the etiopathogenesis of IBD in dogs and cats based on the clinical response to "hypoallergenic" diets in many of these animals.

Diagnosis of IBD

The diagnosis of inflammatory bowel disease is based on the exclusion of known causes of diarrhoea, vomiting, and weight loss followed by histological confirmation of infiltration of the gastrointestinal mucosa by inflammatory cells and changes in mucosal architecture. The standard work-up for a dog or cat suspected of IBD should include a detailed and accurate history and comprehensive physical examination, followed by a minimum data base consisting of a centrifugation faecal flotation and direct wet preparation, CBC, chemistry panel, and urinalysis. Abdominal ultrasound is a valuable diagnostic tool for evaluating the gastric and intestinal wall for alterations in thickness, alterations in the layering pattern (particularly the mucosa and muscularis layers), assessing changes in mesenteric lymph node size and echo texture, and assessing the ultrasonographic appearance of the liver, pancreas, and adrenal glands. Measurement of serum TLI is warranted in animals suspected of exocrine pancreatic insufficiency. Measurement of serum B12 (cobalamin) and folate is commonly performed by veterinarians to evaluate the absorptive capacity of the ileum and jejunum, respectively, and to detect abnormal changes in the intestinal microflora. The limited diagnostic utility of measurement of serum folate and cobalamin concentrations for diagnosing SIBO has been documented by German et al.7 Additional diagnostic tests that should be performed on a case-based nature include the measurement of serum thyroxin concentration; FeLV and FIV serology; faecal culture for Tritrichomonas foetus; faecal DFA or ELISA for Giardia and/or Cryptosporidium spp., and a faecal enteric panel for enteropathogenic bacteria.

Endoscopy is a valuable procedure for the diagnosis of intestinal mucosal disorders such as IBD that are associated with morphologic changes; however, endoscopy is limited by the working length of the scope, precluding endoscopic examination of the jejunum. Regardless, of the method used to procure intestinal biopsies (endoscopy, laparotomy, laparoscopy), the interobserver variation among histopathologic evaluations of intestinal tissues from dogs and cats is unacceptably high.8 With the support of the WSAVA, the Gastrointestinal Standardization Group has proposed to develop a standardized histologic evaluation system that will be applied to all companion animal gastroenterologic disorders.

Management of IBD

Principles of Nutritional Management

Elimination/Novel Protein Diets

Antigenic determinants on proteins are incriminated in many cases of IBD, implying that the feeding of select protein diets containing a single, highly digestible, novel protein source might be beneficial for managing dogs and cats with IBD.9

Hypoallergenic Diets

The ability to induce an antibody mediated hypersensitivity response appears to be dependent upon the size and structure of the protein. The allergens in soybean protein, for example, are between 20 and 78 kilodaltons, suggesting that soybean proteins with a molecular weight below this threshold would be less likely to illicit an immune-mediated response. Hypoallergenic diets are particularly beneficial as elimination diets for the diagnosis and management of food hypersensitivity, when a patient appears to be allergic to multiple allergens, when a complicated dietary history makes it difficult to identify a "novel" protein, or when a patient has severe IBD.10

Dietary Fiber

The gelling and binding properties of fatty acids and deconjugated bile acids in soluble fibers may be beneficial in certain gastrointestinal diseases. The use of soluble (fermentable) fiber in preference to insoluble (non-fermentable) fiber is generally advocated because most soluble fibers generate butyrate, the principle source of energy for the colonocyte, and other short-chain fatty acids. Short-chain fatty acids may lower the colonic luminal pH, impeding the growth of pathogens.11 The health benefits derived from dietary supplementation of prebiotics have been documented in humans and feeding oligofructose to dogs decreased the concentrations of fecal ammonia and amines and increased the numbers of bifidobacteria in dog feces.12

Polyunsaturated Fatty Acids

Fish oil has been reported to be beneficial in ulcerative colitis and Crohn's disease patients,13 but the results are controversial. Only a few studies found significant decreases in rectal LTB4 concentrations;the others simply reported clinical improvement. There are no published studies in the veterinary literature to date demonstrating the efficacy of n-3 fatty acid supplementation in managing canine or feline patients with IBD.

Fat

Avoiding excessive fat can be instrumental in the management of various gastrointestinal diseases because fat delays gastric emptying in dogs and high-fat foods may contribute to osmotic diarrhoea. Malabsorbed fatty acids are hydroxylated by intestinal bacteria and stimulate colonic water secretion, exacerbating diarrhoea as well as gastrointestinal protein and fluid losses.14

Vitamins and Minerals

Water-soluble vitamins are often depleted by the fluid losses associated with diarrhoea and fat-soluble vitamin loss can be significant in animals with steatorrhea. Magnesium deficiency has been well documented in Yorkshire Terriers with severe inflammatory bowel disease and lymphangiectasia.15 Cats with severe IBD frequently have subnormal serum cobalamin concentrations.

Pharmacologic Management

Most dogs and cats with moderate to severe IBD will require adjuvant pharmacologic therapy in combination with dietary management. It is important to understand that the therapy of IBD must be tailored according to each patient's response.

Oral Corticosteroids

Corticosteroids remain the cornerstone of medical therapy for IBD, despite the lack of published controlled clinical trials documenting their benefit in dogs and cats with IBD. The value of corticosteroids relates to their anti-inflammatory and immunosuppressive properties, although they also increase intestinal sodium and water absorption in the small and large bowel, and regulate basal colonic electrolyte transport.

The dosage and duration of therapy is based on the severity and duration of clinical signs, the severity and type of inflammation, the clinical response, and tolerance to the drug. The initial dosage of prednisone for therapy of IBD in dogs is 1 to 2 mg/kg q 12 hours. Most cats are started at a dose of 5 mg per cat q 12 hours. The drug is gradually tapered over a 6- to 10-week period once clinical remission is attained. Combination therapy with dietary therapy, azathioprine, or metronidazole is undertaken with the goal of reducing the dose of prednisone. Parenteral corticosteroid therapy is reserved for vomiting patients, or animals with severe non-responsive disease.

Budesonide, an orally administered corticosteroid structurally related to 16-hydroxyprednisolone, has high topical anti-inflammatory activity and low systemic activity because of its high affinity to the steroid receptor and rapid hepatic conversion to metabolites with minimal or no steroid activity. The drug is dosed at 1 mg once daily for cats and toy-breed dogs, up to 3 mg BID for a large or giant breed dog.

Azathioprine

Azathioprine is an antimetabolite that is converted to 6-mercaptopurine in the liver and then to thioinosinicacid. The latter compound impairs purine biosynthesis and this biochemical reaction inhibits cellular proliferation and reduces natural killer cell cytotoxicity.16 The onset of these immunological effects is slow, and can require several months for maximal effectiveness. The drug is most useful in dogs as adjunctive therapy in severe or refractory IBD. Azathioprine can also be used for its steroid-sparing effects when the adverse effects of prednisone are unacceptably high. The dose for dogs is 50 mg/m2 or 1-2 mg/kg once daily for 2 weeks, followed by alternate-day administration, whereas cats should receive 0.3 mg/kg q 48 hours. The most significant side effect of azathioprine is bone marrow suppression, particularly in cats. Other side effects include anorexia, pancreatitis, and hepatic dysfunction.

Chlorambucil

The alkylating agent chlorambucil is beneficial for managing refractory cases of IBD, particularly in cats. Haematological monitoring is warranted every 3-4 weeks to assess for neutropenia. Chlorambucil can be administered at 15 mg PO/m2 once per day for 4 consecutive days, and repeated q 3 weeks (in combination with prednisone) or administered at 2 mg per cat q 4 days indefinitely. In dogs chlorambucil is administered at 1.5 mg/m2 every alternate day.

Cyclosporine

Cyclosporine has been demonstrated to be effective in dogs with IBD that were refractory to immunosuppressive doses of prednisone.17 The dose of cyclosporine used was 5 mg/kg q 24 hrs and the drug was well tolerated.

Sulfasalazine

The drug consists of sulfapyridine linked to mesalamine (previously called 5-aminosalicylic acid) by an azo bond that is cleaved by colonic bacteria with subsequent release of the active moiety of the drug, mesalamine. Sulfapyridine is almost completely absorbed in the colon, metabolized in the liver, and excreted in the urine. The mesalamine moiety is locally absorbed and inhibits the formation and degradation of inflammatory mediators, including leukotrienes, prostaglandins, thromboxane, platelet activating factor, histamine, and a number of cytokines. Sulfasalazine is of no value in managing small bowel inflammation because colonic bacterial metabolism is needed to release the active moiety. The usual initial dose in dogs is 20 to 40 mg/kg q 8 hours for 3 weeks, followed by 20 to 40 mg/kg q 12 hours for 3 weeks, and 10 to 20 mg/kg q 12 hours for 3 weeks. The drug should be used with caution and at a lower dose (10-20 mg/kg q 24) in cats because of the salicylate portion of the drug. The most common side-effects of sulfasalazine include anorexia, vomiting, cholestatic jaundice, allergic dermatitis, and keratoconjunctivitis sicca (KCS).

Antimicrobials

Metronidazole (Flagyl), an inhibitor of cell-mediated immunity,18 has been frequently used as an adjunctive agent for the management of IBD. The dose of metronidazole is 10 to 15 mg/kg q 8 to 12 hours. Metronidazole tablets have a sharp, unpleasant, metallic taste when scored that can cause severe salivation. Side-effects are rare, although metronidazole has been associated with a peripheral neuropathy in humans and animals. Less common side effects include inappetence, nausea, vomiting, seizures, and reversible neutropenia. Tylosin (Tylan) is a macrolide antibiotic that has been reported to be effective and safe in managing canine IBD and antibiotic responsive diarrhea (ARD).19 Although the drug's mechanism of action is unknown, it appears to be effective in some dogs' refractory to other forms of therapy. The dose range is 20 to 40 mg/kg q 12 hours.

References

1.  Guilford WG: Idiopathic inflammatory bowel diseases, in Guilford WG, Center SA, Strombeck DR, Williams DA, Meyer DJ (eds): Strombeck's Small Animal Gastroenterology. Third Ed., 1996, pp 451-486.

2.  Winslet MC, et al. Gut 1994;35:236-242.

3.  Gionchetti P, et al. World J Gastroenterol 2006;12:3306-3313.

4.  Hugot JP, et al. Nature 2001;411:599-603.

5.  Franchimont D, et al. Gut 2004;53:987-992.

6.  Swidsinski A, et al. Gastroenterology 2002;122: 44-54.

7.  German AJ, et al. J Vet Intern Med 2003;17(1):33-43.

8.  Willard MD, et al. J Am Vet Med Assoc 2002;15;220(8):1177-82.

9.  Guilford WG, et al. J Vet Int Med 2001;15:7-13.

10. Marks SL, et al. Vet Therapeutics 2002;3:109-118.

11. Brockett M, Tanner GW. Can J Microbiol 1982;28:493-499.

12. Hussein HS, et al. J Nutr 1999;129(7 Suppl):1454S-6S

13. Scheurlen M, et al: Scand J Gastroenterol 1989;24:(suppl 158):100-101.

14. Cummings JH, et al: J Clin Invest 1978;61:953-963.

15. Kimmel SE, et al. J Am Vet Med Assoc 2000;1;217(5):703-6.

16. Brogan M, et al: J Clin Immunol 1985;5:204-211.

17. Allenspach K, et al. J Vet Intern Med 2006;20(2):239-44.

18. Grove DI. Int Arch Allergy Appl Immunol 1977;54(5):422-7.

19. Westermarck E, et al. J Vet Intern Med 2005;19(2):177-86.

Speaker Information
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Stanley L. Marks, BVSc, PhD, DACVIM (Internal Medicine, Oncology), DACVN
University of California, Davis, School of Veterinary Medicine
California, USA


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