These have been evidenced by human, mouse, canine, and feline models.1\u201313<\/sup><\/p>\n The genetic component believed to be associated with an increased risk of IBD is well documented in humans and involves mutations in pattern recognition receptors such as nucleotide binding oligomerized domain 2, Toll-like receptors (TLRs), and interleukin-23.1,3,5,8\u201310,12,14<\/sup> These receptors sense pathogen-associated molecular patterns in the region of the immediate cell surface or intracellular environment.<\/p>\n Specific breeds of dogs are recognized as being prone to chronic enteropathies, which likely suggests a genetic component (TABLE 1<\/strong>).<\/p>\n Although a genetic component is not as well recognized in cats, Siamese and other oriental breeds have been suggested to be more predisposed to developing IBD.22,23<\/sup> In our experience, this has not necessarily been the case, as domestic shorthaired and longhaired breeds account for most cats presenting and diagnosed at our facility.<\/p>\n The pathophysiology behind breed predispositions is not well understood, but triggers have been identified in some breeds. In boxers with granulomatous colitis, genome analysis has identified disease-associated single-nucleotide polymorphisms (SNPs) that may affect killing of pathologic Escherichia coli<\/em>. The presence of these adherent and invasive E coli <\/em>within mucosal macrophages of specifically boxers, and this organism\u2019s eradication with tailored antibiotic implementation further suggests a breed-specific association relative to disease pathogenesis as well as clinical response.8,15-18,24,25<\/sup><\/p>\n Genetic analysis of German shepherds has shown that several SNPs in the TLR 4 and TLR 5 genes are significantly associated with the incidence of lymphocytic\u2013plasmacytic IBD.26<\/sup> These TLRs are a class of proteins of the innate immune system that span the membrane of sentinel cells, such as macrophages and dendritic cells, and are important in the recognition of lipopolysaccharide of gram-negative bacteria, lipoteichoic acid of gram-positive bacteria, and bacterial flagellin.<\/p>\n TLR 2 mRNA expression, which has been correlated with the clinical severity of IBD, has been noted to be higher in the duodenum of affected dogs compared with healthy dogs.1<\/sup> In mouse models, TLR 2 has been implicated in the homeostasis of intestinal tissue after injury.1,27,28<\/sup><\/p>\n The mucosal immune system, immune tolerance, and other innate and adaptive immune processes also play roles in the development of chronic inflammation of the GI tract.<\/p>\n Immunoglobulin A (IgA), important in the mucosal defense system, provides a barrier to keep luminal bacteria from crossing the luminal epithelial cells. Loosely and tightly adherent mucus produced by goblet cells and tight junctions between luminal epithelial cells also provide an immediate barrier. Any irregularity in these barriers can lead to the transposition of GI pathogens and commensals and result in chronic inflammation.<\/p>\n The focus of inflammation can exacerbate the degradation of tight junctions. T helper 1 cells and complementary T cell subsets are involved in the secretion of proinflammatory cytokines, whereas T regulatory cells antagonize proinflammatory states for appropriate homeostasis of the gut adaptive immune system. In IBD, this balance is lost.29<\/sup><\/p>\n Intensive and hyperresponsive states of inflammation result from aggressive T-cell responses to antigens and pathogens with upregulation of inflammatory mediators, as well as defects in microbial extermination and downregulation of inflammatory control mediators.13,23<\/sup><\/p>\n Environmental factors encompass a number of possible etiologies. In humans with chronic enteropathies, etiologies include stress, diet, and previous exposure to pharmaceuticals, including antibiotics.9,29,30<\/sup> Although stress has not been well established in the literature as an etiology in dogs and cats, stressful events for cats have been associated with other inflammatory diseases, such as feline idiopathic cystitis and recrudescence of feline upper respiratory tract infections.31 <\/sup><\/p>\n There is a diet-responsive component to IBD, as noted in humans.8,12,23,29<\/sup> Some cats and dogs respond favorably to novel protein and\/or hydrolyzed protein diets. Because multiple dietary components are recognized by the GI immune system as foreign antigens,32<\/sup> the thought is that decreasing the load of antigens decreases inappropriate immune responses.<\/p>\n Dysbiosis, or alteration of the normal microbial ecosystem within the intestine, is also observed in IBD.1<\/sup> This has been demonstrated via fluorescence in situ hybridization analysis (FIGURE 1<\/strong>). Reported common changes in the normal commensals include decreases in Firmicutes <\/em>(eg, clostridia, bacilli), decreases in Bacteroidetes<\/em>, reduced Clostridium <\/em>diversity, and increases in Enterobacteriaceae <\/em>(such as E coli <\/em>and Pseudomonas <\/em>strains).2<\/sup><\/p>\n FIGURE 1. Three-color fluorescence in situ hybridization identifies Cy-3-labeled Clostridia species (labeled orange) localized within adherent mucus of a colonic biopsy specimen obtained from a dog with IBD. The mucus is also occupied by other bacteria (total bacteria labeled green with FITC-Eub). The dark blue structures are nuclei (note some epithelial cells sloughed into the mucus) stained with DAPI. Courtesy of Angela Bryan.<\/em><\/p><\/div>\n Although dysbiosis would explain the occasional response to antibiotics, a number of these organisms are also found in healthy dogs and cats. Therefore, the combined action of the microbiome ecosystem and environmental factors, not solely the presence of these microflora, likely determines progression to IBD.<\/p>\n Alteration of the microbiota by manipulation of commensals, and restricting the diet to one containing fewer structural carbohydrates and more fat, results in decreased production of short-chained fatty acids needed for overall gut health, providing further evidence for the interplay between the factors predisposing to IBD.2,8,23<\/sup><\/p>\n Clinical signs of IBD can include vomiting, diarrhea, melena, hematochezia, weight loss, and hyporexia to anorexia, in any combination. Some patients also present with clinical signs of disease progression, such as subcutaneous edema, pleural effusion, and ascites associated with hypoalbuminemia due to a related PLE.33<\/sup><\/p>\n The presence of ongoing clinical signs lasting more than 3 weeks is the basis of classification of a chronic enteropathy.34<\/sup> It is important to get a full history, which includes:<\/p>\n This comprehensive medical history ensures proper consideration of differentials with similar presentation and an appropriate diagnostic plan.<\/p>\n A clinical diagnosis of IBD is based on7,33<\/sup>:<\/p>\n A diagnosis of IBD is primarily one of exclusion and requires elimination of IBD mimics through complete clinical examination, laboratory testing, and specialized instrumentation. Differentiation of severe IBD from well-differentiated (small cell) lymphoma may be especially problematic in cats.35,36 <\/sup><\/p>\n After the exclusion of infectious and parasitic agents, nongastrointestinal disorders, exocrine pancreatic insufficiency, and intestinal structural abnormalities requiring surgery (BOX 1<\/strong>), the most common diagnoses of chronic enteropathy include food-responsive enteropathy (FRE), antibiotic-responsive diarrhea (ARD), and idiopathic IBD.<\/p>\n Parasites<\/strong><\/p>\n Pathogenic bacteria <\/strong><\/p>\n Fungi and algae <\/strong><\/p>\n Neoplasia<\/strong><\/p>\n Anatomic and functional disorders <\/strong><\/p>\n Other<\/strong><\/p>\n Viruses<\/strong><\/p>\n Organ dysfunction <\/strong><\/p>\n Other<\/strong><\/p>\n <\/div><\/div>\n Fecal examination by direct wet mount or flotation techniques can rule out parasitic causes for mucosal inflammation (BOX 1<\/strong>).<\/p>\n Giardia <\/em>and Cryptosporidium <\/em>infections are best detected using indirect fluorescent antibody tests.<\/p>\n Cats with chronic large bowel diarrhea should be screened for Tritrichomonas foetus <\/em>infection by polymerase chain reaction.37<\/sup><\/p>\n Routine hematology may reveal nonregenerative anemia reflective of chronic inflammation or enteric blood loss. Neutrophilia with or without a left shift <\/strong>is associated with erosive\/ulcerative intestinal lesions. Eosinophilia <\/strong>is seen with some forms of IBD such as eosinophilic enteritis.1,4,38,39<\/sup><\/p>\n Results from biochemical analysis rarely provide definitive evidence for IBD, but they do facilitate the recognition of abnormalities in other organs that may cause GI signs.<\/p>\n In cats with IBD, hyperproteinemia <\/strong>and mild elevation in liver enzymes <\/strong>(alanine aminotransferase and alkaline phosphatase) are often reported.7,22,40 <\/sup><\/p>\n Dogs with PLE frequently have hypoalbuminemia <\/strong>and hypoglobulinemia<\/strong>, which may be accompanied by hypocholesterolemia <\/strong>and hypocalcemia<\/strong>. The presence of hypoalbuminemia correlates with a negative outcome in dogs.33,38<\/sup><\/p>\n Cats with IBD may have increased serum pancreatic lipase <\/strong>concentrations (suggestive of pancreatitis). This association does not appear to influence clinical outcome, based on a recent report.41<\/sup> However, increased serum pancreatic lipase concentrations in dogs with IBD have been associated with a poorer clinical outcome.42<\/sup><\/p>\n Dogs and cats with chronic small bowel disease may have decreased serum cobalamin <\/strong>concentrations secondary to cobalamin malabsorption. Failure to recognize and correct hypocobalaminemia can delay clinical recovery, even with specific therapy for IBD.43<\/sup> Hypocobalaminemia has also been correlated with a poor prognosis in dogs with chronic enteropathies.33<\/sup><\/p>\n Abdominal radiographs <\/strong>can be used to assess the following:<\/p>\n FIGURE 2. Lateral abdominal radiograph of a dog with pancreatitis. Note the loss of abdominal detail in the cranioventral abdomen with caudal displacement of the small intestine. Courtesy of Dr. Eric Van Eerde<\/em>.<\/p><\/div>\n FIGURE 3. Lateral abdominal radiograph of a dog with hepatocellular carcinoma. Note the increase in soft tissue opacity (mass effect) in the cranioventral abdomen. Courtesy of Dr. Eric Van Eerde<\/em>.<\/p><\/div>\n Abdominal ultrasonography <\/strong>is superior to abdominal radiography in defining diffuse GI mucosal disease, intestinal wall thickness (FIGURE 4<\/strong>), and mesenteric lymphadenopathy seen with IBD as well as other infiltrative (eg, lymphoma) disorders.44<\/sup><\/p>\n FIGURE 4. Ultrasound images showing jejunal muscularis thickening in a cat with IBD. (A) Cross-sectional image showing thickened small intestinal wall (0.44 cm). (B) Longitudinal section demonstrating a similar thickened appearance (0.38 cm). Normal small intestinal wall thickness in cats is reported as 0.16 to 0.36 cm.24 Courtesy of Dr. Jacob Ewing.<\/p><\/div>\n Ultrasonographic examination allows fine-needle aspiration of focal wall thickening and enlarged lymph nodes to provide samples for cytologic analysis.<\/p>\n Cats with ultrasonographic evidence of muscularis propria thickening are more likely to have lymphoma than IBD.45<\/sup><\/p>\n Endoscopic examination with mucosal biopsy is essential to confirm a diagnosis of IBD and determine the extent of disease. The most widely reported endoscopic abnormalities seen with canine and feline IBD include mucosal friability, increased granularity, and mucosal erosions (FIGURE 5<\/strong>).7,33,46 <\/sup><\/p>\n FIGURE 5. Endoscopic images of dogs with IBD consistent with (A) increased small intestinal friability, (B) increased small intestinal granularity, and (C) intestinal mucosal erosions. (D) Endoscopic image showing the advancement of biopsy forceps to obtain partial-thickness biopsy samples in a dog with inflamed GI mucosa and IBD. Courtesy of Dr. Albert Jergens<\/em>.<\/p><\/div>\n The association between endoscopic lesions and disease activity in small animal IBD has been investigated to a limited extent. In separate investigations, endoscopic abnormalities of the duodenum of dogs with IBD did not always correlate with clinical indices of inflammation.33,47<\/sup> The presence of severe mucosal lesions of the duodenum, but not the colon, was associated with a negative outcome in one study.33<\/sup><\/p>\n In contrast to dogs, cats with IBD have endoscopic abnormalities that correlate to both clinical disease activity and histopathologic lesions at diagnosis.6<\/sup><\/p>\n Standard mucosal biopsies of the stomach and duodenum alone may miss more distal sites (eg, ileal mucosa) of cellular infiltration. Ileal biopsies should be obtained in all dogs and cats to increase diagnostic yield whenever gastroduodenoscopy or colonoscopy is performed, especially as lymphoma is an important differential diagnosis in cats.36<\/sup><\/p>\n The need to perform ileoscopy may be guided by the presence or absence of hypocobalaminemia, because cobalamin is absorbed in the ileum.<\/p>\n Definitive diagnosis requires histopathologic evaluation of biopsy specimens. The microscopic findings in IBD consist of minimal to pronounced inflammatory cell infiltration, often accompanied by varying degrees of mucosal architectural disruption. Unfortunately, biopsy interpretation is notoriously subjective, suffering from extensive interobserver variability, the technical constraints of specimen size, and procurement\/processing artifacts inherent in evaluation of endoscopic specimens.48<\/sup><\/p>\n One recent effort to standardize the assessment of GI inflammation resulted in a histopathologic monograph that defines numerous morphologic and inflammatory features in endoscopic biopsies.39<\/sup> However, even with this standardized scheme, there was very poor agreement between pathologists,49<\/sup> resulting in the design of a simplified model for IBD, currently under review.50<\/sup><\/p>\n Recent studies indicate that changes in mucosal architecture, such as villous morphology and goblet cell mucus content, are related to the presence and severity of GI disease. These studies have used quantitative, observer-independent variables (eg, inflammatory cytokines, intestinal mucus) to identify histopathologic correlates of disease.6<\/sup><\/p>\n In cats with signs of GI disease, villous atrophy and fusion correlate with the severity of clinical signs and degree of proinflammatory cytokine upregulation in the duodenal mucosa.6<\/sup> Architectural changes in the gastric mucosa correlate with cytokine upregulation in dogs with lymphocytic gastritis.51<\/sup> In the colon, loss of mucus and goblet cells correlates with the severity of disease in dogs with lymphoplasmacytic and granulomatous colitis.52<\/sup><\/p>\n IBD patients with mild to moderate clinical disease activity and normal serum albumin concentrations are first treated sequentially with dietary and antibiotic trials. If they fail to respond to either of these trials, immunosuppressive therapy is initiated.<\/p>\n A positive response to a dietary trial allows the patient\u2019s disease to be classified as FRE, a term that includes both dietary allergy and intolerance. The primary option for a dietary trial is switching to a diet that leads to antigenic modification (eg, novel protein source, protein hydrolysate). The diet must be palatable and introduced in gradually increasing amounts over 4 to 7 days.<\/p>\n In dogs with FRE, a clinical response is usually observed within 1 to 2 weeks of changing the diet. In one study, dogs that responded to diet were younger and had higher serum albumin concentrations and predominant signs of large bowel diarrhea compared with dogs that did not respond to diet.33<\/sup><\/p>\nGenetics<\/h3>\n
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<\/a><\/strong><\/p>\nMucosal Immune System and Immune Responses<\/h3>\n
Environmental Factors<\/h3>\n
Microbial Factors<\/h3>\n
<\/a>Clinical Signs<\/h2>\n
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Differential Diagnosis<\/h2>\n
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GASTROINTESTINAL<\/h3>\n
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EXTRA-GASTROINTESTINAL<\/h3>\n
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Diagnostics<\/h2>\n
Fecal Examination<\/h3>\n
Hematology<\/h3>\n
Serum Biochemistry and Specialized Serologies<\/h3>\n
Diagnostic Imaging<\/h3>\n
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<\/a>\n
<\/a><\/a>Endoscopy and Mucosal Biopsy<\/h3>\n
<\/a>Histopathology<\/h3>\n
Treatment<\/h2>\n
Diet<\/h3>\n
Antibiotics<\/h3>\n