Abstract
Etiopathogenesis
Inflammatory bowel (IBD) is a chronic gastrointestinal tract disorder of unknown cause and ill-defined pathogenesis. Although the aetiology is unclear, new information suggests that these diseases result from complex interactions between host susceptibility, mucosal immunity, and the enteric microflora. A variety of pathogenic mechanisms for IBD have been proposed, including an appropriate immune response to a luminal pathogen or abnormal luminal substance, autoimmunity, or an aberrant immune response to normal luminal constituents such as dietary antigens or resident intestinal bacteria (Sartor 1997). In susceptible animals, IBD may arise because of a breakdown in the regulatory constraints on mucosal immune responses (loss of tolerance) to enteric bacteria. Both clinical observations and animal models implicate the resident bacterial flora as an essential cofactor in driving the inflammatory response to IBD. Clinical improvement and decreased intestinal inflammation is observed in humans with IBD when intestinal bacterial concentrations are decreased by antibiotic administration (Sutherland et al 1991, Peppercorn 1993). Strong serological antibody activity to several bacterial species is observed in patients with IBD (Brandwein et al 1997). Furthermore, experimental colitis generally fails to develop when mice in these laboratory models are maintained in germfree conditions (Rath et al 1996).
Since intestinal inflammation occurs against this ‘background’ of crosstalk between the resident bacterial flora and the mucosal immune response, it seems reasonable that therapeutic strategies aimed at altering the flora may influence mucosal immunophysiology. Modulation of the enteric micro-environment has been recently shown to reduce pro-inflammatory mucosal cytokines (thereby attenuating intestinal inflammation) in humans with Crohn's disease (Shanahan 2001).
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 (eg, food allergy or intolerance), infectious diseases, and alimentary lymphosarcoma are the major differential diagnoses for IBD. Objective criteria for diagnosis of feline IBD have been described (Jergens et al 1992). It is essential that clinical signs be correlated with histological 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 (eg, 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 (Jergens). 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, and showed excellent correlation to both histology scores and serological markers of intestinal inflammation (eg, haptoglobin and C-reactive protein). Scoring indices may also provide valuable prognostic information when assessing therapeutic responses. At present, there is no clinical scoring index for assessment of feline IBD activity.
Histologic grading criteria
Histological examination of mucosal biopsy specimens is essential for diagnosis of IBD. Unfortunately, uniform and objective morphological criteria of IBD lesions have not been established. Biopsy interpretation is notoriously subjective from one pathologist to the next, and microscopic interpretation is further hampered by the technical constraints of small specimen size and procurement/processing artefacts inherent in evaluation of endoscopic specimens (Wilcox 1992, Jergens & Moore 1999, Willard). Several histological grading schemes for evaluation of endoscopic specimens from dogs and cats with IBD have been described (Jergens et al 1992, Dennis et al 1993, Jacobs et al 1990). Most studies have relied on subjective evaluation of lamina proprial cellularity while excluding more objective parameters of mucosal inflammation including increased intraepithelial lymphocytes, altered mucosal structure, and changes in the surface epithelia (Wilcox 1992).
This author uses a grading system based on the extent of architectural disruption and muscosal epithelial changes (Jergens et al 1992, Jergens & Moore 1999). In this grading scheme, ‘mild’ lesions are those in which there is no mucosal architectural disruption, glandular necrosis, immaturity, or fibrosis of the lamina propria. ‘Severe’ IBD is manifested by architectural distortion of the mucosal such as seen with extensive erosion, necrosis, villus atrophy, glandular loss or severe glandular hyperplasia, or fibrosis of the lamina propria. ‘Moderate’ lesions have microscopic changes of severity between these two extremes. Note that in this IBD grading scheme, no attempt is made to quantitate the number of inflammatory cells within the lamina propria. Rather, increases in mucosal immune cell populations may reflect altered, but normal, immunologic responses to diverse dietary and microbial stimuli. Changes in mucosal cellularity alone, without other evidence of inflammation or enterocyte injury, should be interpreted cautiously and are unlikely to be IBD.
Treatment of IBD Nutritional Therapy
Patients with IBD may be nutritionally deficient due to decreased food intake, impaired nutrient absorption, and/or increased excudation as seen with protein-losing enteropathy. The most convenient means for dietary manipulation in veterinary patients with with highly digestible diets. These diets should be formulated with ingredients which the animal has not been fed before (eg, novel protein source such as venison, rabbit, lamb, whitefish or turkey) or that are unlikely to evoke allergic responses (eg, potatoes). Controlled diets may have to be fed for several (six to eight) weeks to assess their efficacy. Altering the dietary ratio of omega-6 (n=6) to n=3 polyunsaturated fatty acids may effect the inflammatory response of IBD. Diets enriched in n=3 fatty acids are incorporated into biological membranes resulting in decreased concentrations of pro-inflammatory n=6 fatty acid metabolites (eg, 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. Fibre-enriched diets are recommended to mitigate signs of large bowel diarrhoea and tenesmus. Dietary fibre may increase faecal consistency, bind potential colonic irritants, improve abnormal colonic motility, and produce beneficial short chain fatty acids (eg, butyrate) which positively influence large bowel structure and function.
The use of prebiotic and probiotic therapy to modify intestinal bacterial populations may reduce intestinal inflammation of IBD. Fructooligosaccharides (FOS) are carbohydrates (pre-biotics) which resist enzymatic digestion and are metabolised by bacteria in the distal small bowel and colon. Supplementation of FOS to healthy cats (Sparkes et al) and dogs with bacterial overgrowth (Willard et al 2000) has demonstrated altered bacterial populations; however, the clinical significance of these observations is unknown. Probiotics are live microbial food ingredients that alter the enteric flora and have a favourable effect on health. A variety of organisms have been utilized in animal models of IBD including lactobacilli, bifidobacteria, and other non-pathogenic bacterial strains with encouraging results (Mao 1996, Madsen et al 1999). However, rigorous evaluation of probiotic therapy in humans and animals with IBD has not been performed.
Pharmacologic therapy
Dietary management alone for moderate-to-severe IBD is seldom successful and most animals will require pharmacological therapy.
Corticosteroids
Prednisone or prednisolone are reasonable first-choice agents for induction therapy of IBD in 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 two to four weeks (depending on severity of signs and type of histological lesion) is generally recommended. Combination drug therapy (eg, steroids combined with metronidazole, azathioprine, or others) allows a reduced steroid dose for maintenance therapy. Alternative glucocorticoid preparations characterised by high topical anti-inflammatory activity and first pass hepatic metabolism have been recently used in human IBD. The efficacy (and potential toxicity) of these new drugs remains to be proven; although, anecdotal evidence suggests budesonide may be of value in some dogs with lymphocytic-plasmacytic colitis.
Sulfasalazine/Newer 5-ASA preparations
Caution is advised in using sulfasalazine (SASA) in cats because of their sensitivity to salicylates. Topical and oral 5-ASA preparations are now used for treatment of human IBD. 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.
Metronidozole
Clinical observations suggest that metronidazole has beneficial effects in the therapy of feline IBD. Its mechanisms of action might include anti-protozoal action, inhibition of cellular immunity, and bacteriocidal spectrum of activity against anaerobes (eg, Bacteroides spp). The recommended dosage of metronidazole for IBD is 10–20 mg/kg q8–12 h. It is most often combined with corticosteroids or sulfasalazine in patients having moderate-to-seveere clinical signs or histological 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 metabolised in the body to 6-mercaptopurine (6-MP), its active metabolite, which functions to interfere with antigenic riggering of lymphocytes. The suggested dosage is 0.3 mg/kg q48 h in cats. A lag time of three to five weeks is expected before clinical improvement may be observed.
Miscellaneous immunomodulating drugs
A variety of other drugs (eg, 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.
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 been established. However, combination drug therapy appears warranted in animals with severe disease, multiorgan involvement, and to reduce systemic effects of corticosteroids.