Abstract
Feline inflammatory bowel disease (FIBD) is characterized by persistent gastrointestinal signs, histologic evidence of mucosal inflammation, and responsiveness to immunotherapeutic intervention. Since a concise and comprehensive review of IBD has been recently presented (Jergens 1999), the purpose of this overview is to provide current perspectives on FIBD, and strategies for dealing with patients that fail to respond to routine medical management.
Feline inflammatory bowel disease—current perspectives
Etiopathogenesis
Although the etiology is unclear, new information suggests that IBD results from complex interactions between host susceptibility, mucosal immunity, and the enteric microflora. 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 of IBD. Clinical improvement and decreased intestinal inflammation is observed in humans with IBD when intestinal bacterial concentrations are decreased by antibiotic administration (Sartor 1997, Sutherland et al 1991). Strong serologic antibody activity to several bacterial species is observed in patients with IBD (Peppercorn 1993). Furthermore, experimental colitis generally fails to develop when mice in these laboratory models are maintained in germfree conditions (Brandwein et al 1997).
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 microenviroment has been recently shown to reduce proinflammatory mucosal cytokines (thereby attenuating intestinal inflammation) in humans with Crohn's disease (Rath et al 1996).
Relevant diagnostic testing
A diagnosis of IBD is one of exclusion and requires ruling-out of many other diseases that 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 (MacDonald & Pattersson 2000). 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 (Guilford et al 2001).
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 artifacts inherent in evaluation of endoscopic specimens (Wilcox 1992, Jergens & Moore 1999, Willard 2001). Several histological grading schemes for evaluation of endoscopic specimens from cats with IBD have been described (Dennis 1992, Jergens 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).
We propose a grading system based on the extent of architectural disruption and mucosal epithelial changes (Jergens 1999, Jergens & Moore 1999, Jergens et al 1992). 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 mucosa 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.
Therapeutic strategies in feline IBD
Therapy for FIBD generally includes dietary modification and the use of immunomodulating drugs to reduce mucosal inflammation. Well-designed therapeutic trials have not been performed in cats with IBD, and therapy remains largely empirical, being influenced by the rapidity of clinical remission, the severity of adverse drug effects, client/patient compliance, and drug costs.
There is general agreement that elimination or novel protein, highly digestible diets are beneficial in cats with IBD (Dennis et al 1993, Guilford 1996). A bigger question is which specific dietary components are most important in the pathogenesis or management of this disease. Several dietary constituents of potential relevance in FIBD have been identified (Table 1). Additionally, the benefits of dietary fiber, the use of polyunsaturated fatty acids (n-3 fatty acids), and prebiotic/probiotic supplementation to effect endogenous gut flora have not been fully investigated.
Dietary management alone for IBD is seldom successful and most cats will require pharmacologic therapy (Table 2). 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, azathioprine or chlorambucil, and metronidazole in therapy of FIBD.
Treatment failures in feline IBD
Managing the refractory IBD cat is a relatively uncommon event; however, it may require assessment of numerous potential causes for ‘treatment failure’ as delineated below. (1) Simplistically, I group these scenarios into four major categories: (1) client/patient compliance; (2) severe intestinal disease; (3) intercurrent illness; and (4) misdiagnosis.
Poor client/patient compliance
Poor client compliance with dietary and drug recommendations may predispose to treatment failure. Although most cats respond favorably to elimination or restricted antigen diets, getting these cats changed over to a new ration may favor reduced food intake, prompting clients to feed other less controlled diets. Dietary indiscretion is a major cause for clinical relapse in my experience. Additionally, not all cats are easily medicated (especially those patients requiring combination drug therapy several times daily) which may result in ineffective drug concentrations as originally prescribed. Lastly, it is not uncommon for clients to reduce or discontinue medications prematurely based on rapid clinical improvement with medical therapy. In these instances, inadequate induction drug therapy fails to suppress active intestinal inflammation.
Severe intestinal disease
Cats with severe intestinal inflammation or variants of FIBD (eg, hypereosinophilic syndrome) may not respond to medical therapy. Clinical staging of FIBD is presently problematic, as well defined criteria for assessment of disease activity have not been established as they have in the dog (Jergens 2001). Thus, clinicians predominantly rely on histologic assessment, perhaps coupled with severity of signs and endoscopic appearances for measurement of mild, moderate, or severe FIBD. In this regard, those cats having objective evidence of severe mucosal inflammation including significant villus changes, epithelial immaturity/erosion/necrosis, and/or proprial fibrosis will be more difficult to manage—regardless of the predominant infiltrating cell type. Feline eosinophilic enteritis/colitis, reported by some authors to be refractory to medical therapy (Guilford 1996), is uncommonly encountered but is often responsive to medical management in my experience. Conversely, hypereosinophilic syndrome—characterized by mucosal and multiorgan infiltration with eosinophils—responds poorly to even aggressive pharmacologic therapy (Muir et al 1993).
Intercurrent Illness
Feline IBD associated with other gastrointestinal disorders may also be difficult to manage. Both exocrine pancreatic insufficiency (EPI) and inflammatory hepatobiliary disease may cause exacerbation of signs in patients otherwise appropriately treated. Diagnosis of concurrent EPI is straightforward with determination of subnormal feline TLI concentration; while, hepatopathy may require specific hepatic function testing (e.g. resting ammonia concentration or serum bile acids) and biopsy for confirmation. Practically speaking, feline EPI is uncommon but inflammatory hepatobiliary involvement with FIBD likely is not (Weiss et al 1996). Indeed, mild to moderate elevations of ALT and ALP (less commonly) are observed in cats with active intestinal inflammation. I attribute these hepatic enzyme elevations to an extension of the benign intestinal inflammation. While enzyme activities often normalize with IBD therapy, those cats which continue to exhibit non-specific signs of vomiting, diarrhea, altered appetite, and weight loss with increased enzyme activities may require more critical diagnostic evaluation. Finally, do not hesitate to repeat baseline diagnostic tests in poorly responsive cats to eliminate metabolic disease (renal disease with uremia), infectious disease (toxoplasmosis), and endocrinopathy (hyperthyroidism) which also cause gastrointestinal signs.
Misdiagnosis
Alimentary lymphosarcoma remains the major misdiagnosis in refractory FIBD patients. Well differentiated lymphosarcoma appears very similar morphologically to severe IBD (e.g. lymphocytic-plasmacytic enteritis) confounding accurate interpretation by pathologists (Wilcox 1999, Richter 2001). Even thorough pre-endoscopic examination including serology (FELV testing) and abdominal ultrasonography may fail to discriminate these distinct diseases. Furthermore, as many of these cats are treated with oral glucocorticoids for a variable period prior to the correct diagnosis being made; therapy may ‘mask’ neoplastic infiltrates histologically and render patients minimally responsive to appropriate chemotherapy for their disease. If cats fail to respond following 7–10 days of ‘traditional’ FIBD medical therapy, I repeat endoscopic examination with biopsy or perform a laparotomy with full-thickness biopsies to ruleout lymphosarcoma. Lastly, we rely heavily on endoscopic exfoliative cytology to corroborate histologic findings. Previous studies attest to the complementary utility of this diagnostic technique in identification of feline alimentary neoplasia.(Jergens et al 1998)