Inflammatory bowel disease is a collective term that describes a group of disorders characterized by persistent or recurrent gastrointestinal signs and histologic evidence of intestinal inflammation on biopsy material. The disease bears little resemblance to inflammatory bowel disease (Crohn’s disease and ulcerative colitis) of humans, and indiscriminate use of the term “IBD” is no more useful than a dermatologist making a diagnosis of “chronic dermatitis. Although a number of recognized diseases are associated with chronic intestinal inflammation (Box Causes of Chronic Small Bowel Inflammation), the cause of idiopathic inflammatory bowel disease is, by definition, unknown. Variations in the histologic appearance of the inflammation suggest that idiopathic inflammatory bowel disease is not a single disease entity, and the nomenclature reflects the predominant cell type present. Lymphocytic-plasmacytic enteritis (lymphocytic-plasmacytic enteritis) is the most common form reported; eosinophilic (gastro-) enteritis (EGE) is less common; and granulomatous enteritis is rare. Neutrophilic infiltration is a feature of human inflammatory bowel disease but is infrequent in idiopathic inflammatory bowel disease of dogs and cats.
Causes of Chronic Small Bowel Inflammation
- Giardia sp.
- Histoplasma sp.
- Toxoplasma sp.
- Mycobacteria sp.
- Pathogenic bacteria (Campylobacter, Salmonella spp., pathogenic Escherichia coli)
Small bowel inflammation associated with other primary gastrointestinal diseases
- Lymphocytic-plasmacytic enteritis (lymphocytic-plasmacytic enteritis)
- Eosinophilic gastroenterocolitis (EGE)
- Granulomatous enteritis (same as regional enteritis?)
Idiopathic inflammatory bowel disease is a common cause of chronic vomiting and diarrhea in dogs and cats, but its true incidence is unknown. In reality it is often overdiagnosed because of difficulties in interpretation of histopathologic specimens and failure to eliminate adequately other causes of mucosal inflammation. No apparent gender predisposition occurs in dogs and cats, but in both species inflammatory bowel disease is most common in middle-aged animals. gastrointestinal signs, which may have been variably controlled by dietary manipulation, are sometimes seen from an earlier age. Although inflammatory bowel disease can potentially occur in any dog or cat breed, certain predispositions are recognized, such as lymphocytic-plasmacytic enteritis in German shepherds and Siamese cats, lymphoproliferative enteropathy in basenjis, and protein-losing enteropathy / protein-losing nephropathy (protein-losing enteropathy / PLN) in soft-coated wheaten terriers. Shar Peis often have a severe lymphocytic-plasmacytic enteritis with hypoproteinemia and extremely low serum cobalamin concentrations. In cats an association, called triaditis, has been reported for inflammatory bowel disease, lymphocytic cholangitis, and chronic pancreatitis.
Clinical Signs Associated with Inflammatory Bowel Disease
Vomiting of bile with or without hair in cats and grass in dogs
Small intestinal — type diarrhea
- Large volume
Thickened bowel loops
Large intestinal — type diarrhea
- Mucoid stool
- Frequency and tenesmus
Abdominal discomfort / pain
Excessive borborygmi and flatus
- Decreased appetite / anorexia
- Eating grass
Hypoproteinemia / ascites
Vomiting and diarrhea are the most common clinical signs, but an individual case may show some or all of the signs in Box Clinical Signs Associated with Inflammatory Bowel Disease.Sometimes an obvious precipitating event (e. g., stress, dietary change) is present in the history, but clinical signs may wax and wane. The nature of signs crudely correlates with the region of the gastrointestinal tract affected: gastric signs are more common if gastric or upper small intestine inflammation is present; in cats, vomiting is often the predominant sign of small intestinal IBD; and Li-type diarrhea may be the result of colonic inflammation or may result from prolonged small intestine diarrhea. The presence of blood in the vomit or diarrhea is associated with more severe disease, especially eosinophilic inflammatory infiltrates. Severe disease is associated with weight loss and protein-losing enteropathy, with consequent hypoproteinemia and ascites. Appetite is variable; polyphagia may be present in the face of significant weight loss, whereas anorexia occurs with severe inflammation. Milder inflammation may not affect appetite, although postprandial pain can be significant even without other signs. Systemic consequences of inflammatory bowel disease can occur, although reports are sparse.
Etiology and Pathogenesis
The underlying etiology of small animal inflammatory bowel disease is unknown, and comparisons have been made with similar human conditions. In this regard, the breakdown of immunologic tolerance to luminal antigens (bacteria and dietary components) is thought to be critical, perhaps resulting from disruption of the mucosal barrier, dysregulation of the immune system, or disturbances in the intestinal microflora. Therefore antigens derived from the endogenous microflora are likely to be important in disease pathogenesis, and a potential role for diet-related factors is suggested by the clinical benefit of dietary therapy in some cases of canine inflammatory bowel disease.
Genetic factors are likely to contribute to the pathogenesis of inflammatory bowel disease, and in humans the strongest associations are with genes of the human MHC (human leukocyte antigen [HLA]). Furthermore, some human patients with Crohn’s disease have a mutation in the NOD2 gene on chromosome 16. This gene’s product detects bacterial lipopolysac-charide and can activate the proinflammatory transcription factor NF-kB. Such a link may explain the development of aberrant immune responses to bacteria in certain individuals. Genetic factors are also likely in dogs, given the recognized breed predispositions, although studies are lacking
Intestinal biopsy is necessary for a definitive diagnosis of inflammatory bowel disease, although the clinical signs and physical findings may be suggestive (see Box Clinical Signs Associated with Inflammatory Bowel Disease). The term idiopathic inflammatory bowel disease is limited to cases in which histologic evidence of inflammation is found without an obvious underlying cause. All other etiologies, including infectious, diet-responsive, and antibacterial-responsive conditions, should be excluded. Therefore before intestinal biopsy is undertaken, laboratory evaluation and diagnostic imaging are performed. Such tests cannot provide a definitive diagnosis of inflammatory bowel disease, but they can help eliminate the possibility of anatomic intestinal disease (e. g., tumor, intussusception), extraintestinal disease (e. g., pancreatitis), and known causes of intestinal inflammation. Furthermore, by determining whether focal or diffuse intestinal disease is present, the clinician can choose the most appropriate method of intestinal biopsy.
Hematology Occasionally neutrophilia, with or without a left shift, is noted. Eosinophilia may suggest EGE, but it is neither pathognomonic nor invariably present. Anemia may reflect chronic inflammation or chronic blood loss.
Serum biochemistry No pathognomonic changes are seen in 1BD, but diseases of other organ systems should be recognized and excluded. Hypoalbuminemia and hypoglobulinemia” are characteristic of protein-losing enteropathy, whereas hypocholesterolemia may suggest malabsorption. Intestinal inflammation in dogs may cause a “reactive hepatopathy, ” with mild elevations in liver enzymes (alanine aminotransferase (ALT] and alkaline phosphatase [ALP]). In contrast, because of the shorter half-lives of liver enzymes in cats, increases are more likely to be the result of hepatocellular or cholestatic disease.
Fecal examination Fecal examination is most important for eliminating other causes of mucosal inflammation, such as nematodes (e. g., Trichuris, Uncinaria, Ancylostoma, and Strongyloides spp.), Giardia infection, and bacterial infection (e. g., Salmonella or Campylobacter spp. or clostridia). Given that fecal parasitology may not always detect Giardia organisms, empirical treatment with fenbendazole is recommended in all cases.
Increased fecal alphap1-PI concentrations would be expected in dogs with inflammatory bowel disease, as well as significant intestinal protein loss even before hypoproteinemia develops (see above).
Folate and cobalamin Serum concentrations of both these vitamins are affected by intestinal absorption, therefore proximal, distal, or diffuse inflammation can result in subnormal folate concentrations (proximal inflammation) or cobalamin concentrations (distal inflammation) or both (diffuse inflammation). Although such alterations are not pathognomonic for inflammatory bowel disease, deficiencies may require therapeutic correction. Measurement of serum folate and cobalamin is now commercially available for cats, and cobalamin deficiency associated with inflammatory bowel disease has been documented. Cobalamin deficiency has systemic metabolic consequences, and anecdotal evidence suggests that deficient cats with inflammatory bowel disease require parenteral supplementation to respond optimally to immunosuppression.
Diagnostic imaging Imaging studies document whether focal or diffuse disease is present and whether other abdominal organs are affected. Such information, in conjunction with specific clinical signs, allows the clinician to choose the most appropriate method of biopsy. Plain radiographs may be useful for detecting anatomic intestinal disease; contrast studies rarely add further information. Ultrasonographic examination is superior to radiography for documenting focal anatomic intestinal disease and is particularly useful in cats with inflammatory bowel disease. Ultrasonography permits evaluation of intestinal wall thickness and can document mesenteric lymphadenopathy. Ultrasound-guided fine needle aspiration (FNA) can provide samples for cytologic analysis, which may aid in diagnosis.
Intestinal biopsy Intestinal biopsy is necessary to document intestinal inflammation. Endoscopy is the easiest method of biopsy, but it has limitations, because samples are superficial and in m6st cases can be collected only from the proximal small intestine. In some cases exploratory laparotomy and full-thickness biopsy are necessary, although the procedures are more invasive and can be problematic if severe hypoproteinemia is present. These techniques may be more suitable for cats, given the tendency in this species for multiorgan involvement.
Histopathologic assessment of biopsy material remains the gold standard for inflammatory bowel disease diagnosis, and the pattern of histopathologic change depends on the type of inflammatory bowel disease present. However, the limitations of histopathologic interpretation of intestinal biopsies are recognized. The quality of specimens can vary, agreement between pathologists is poor, and differentiation between normal specimens and those showing inflammatory bowel disease and even lymphoma can be difficult. Grading schemes for the histopathologic diagnosis of inflammatory bowel disease have been suggested, but these have not yet been widely adopted.
IBD activity index In humans, activity indices are used to quantify the severity of inflammatory bowel disease; this helps practitioners to assess the response to treatment and to make a prognosis by allowing comparisons between published studies in the literature. Recently an activity index was suggested for canine inflammatory bowel disease, and this may aid disease classification in the future.
Other diagnostic investigations Given the limitations of histopathology, other modalities are required. One approach would be the use of immunohistochemistry or flow cytometry to analyze immune cell subsets. However, such techniques are labor intensive and poorly standardized and are unlikely to be generally available in the foreseeable future.
Whatever the type of inflammatory bowel disease, treatment usually involves a combination of dietary modification and antibacterial and immunosuppressive therapy. Unfortunately, objective information on efficacy is lacking, and most recommendations are based on individual experience. The authors usually recommend a staged approach to therapy whenever possible; initial treatment involves antiparasiticides to eliminate the possibility of occult endoparasite infestation. Thereafter, sequential treatment trials with an exclusion diet and anlibacterials are pursued; immunosuppressive medication is used only as a last resort. However, in some cases, clinical signs or mucosal inflammation is so severe that early intervention with immunosuppressive medication is essential. If clinical signs are intermittent, the owners should keep a diary to provide objective information as to whether treatments produce genuine improvement.
Dietary modification The diets recommended for patients with inflammatory bowel disease are antigen limited, based on a highly digestible, single-source protein preparation. An exclusion diet trial should be undertaken to eliminate the possibility of an adverse food reaction, and most clients are happy to try this, given concerns over the side effects of immunosuppressive drugs. An easily digestible diet decreases the intestinal antigenic load and thus reduces mucosal inflammation. Such diets may also help resolve any secondary sensitivities to dietary components that may have arisen from disruption of the mucosal barrier. After the inflammation has resolved, the usual diet often can be reintroduced without fear of an acquired sensitivity.
Well-cooked rice is the preferred carbohydrate source because of its high digestibility, but potato, corn starch, and tapioca are also gluten free. Fat restriction reduces clinical signs associated with fat malabsorption. Modification of the n3 to n6 fatty acid ratio may also modulate the inflammatory response and may have some benefit both in treatment and in maintenance of remission, as in human inflammatory bowel disease. However, no direct studies have been done to prove a benefit in canine inflammatory bowel disease. Supplementation with oral folate and parenteral cobal-amin is indicated if serum concentrations are subnormal.
Antibacterial therapy Treatment with antimicrobials can be justified in inflammatory bowel disease, partly to treat secondary small intestinal bacterial overgrowth and partly because of the importance of bacterial antigens in the pathogenesis of inflammatory bowel disease. Ciprofloxacin and metronidazole are often used in human inflammatory bowel disease, and metronidazole is the preferred drug for small animals. The efficacy of metronidazole may not be related just to its antibacterial activity, because it may exert immunomodulatory effects on cell-mediated » immunity. Furthermore, other antibacterials (e. g., tylosin) may also have immunomodulatory effects and have efficacy in canine inflammatory bowel disease.
Immunosuppressive drugs The most important treatment modality in idiopathic inflammatory bowel disease is immunosuppression, although this should be used only as a last resort. In human inflammatory bowel disease, glucocorticoids and thiopurines (e. g., azathioprine, 6-mercaptopurine) are used most widely. In dogs, glucocorticoids are used most frequendy, and prednisone and prednisolone are the drugs of choice. Dexamethasone should be avoided, because it may have deleterious effects on enterocytes. In severe inflammatory bowel disease, prednisolone can be administered parenterally, because oral absorption may be poor. The initial dosage of 1 to 2 mg / kg given orally every 12 hours is given for 2 to 4 weeks and then tapered slowly over the subsequent weeks to months. In some cases therapy can be either completely withdrawn or at least reduced to a low maintenance dose given every 48 hours.
Signs of iatrogenic hyperadrenocorticism are common when the highest glucocorticoid dose is administered. However, signs are transient and resolve as the dosage is reduced. If clinical signs of inflammatory bowel disease consistently recur when the dosage is reduced, other drugs can be added to provide a steroid-sparing effect. Budesonide, an enteric-coated, locally active steroid that is destroyed 90% first-pass through the liver, has been successful in maintaining remission in human inflammatory bowel disease with minimal hypothalamic-pituitary-adrenal suppression. A preliminary study showed apparent efficacy in dogs and cats, but limited information is available on the use of this drug.
In dogs, azathioprine (2 mg / kg given orally every 24 hours) is commonly used in combination with prednisone / prednisolone when the initial response to therapy is poor or when glucocorticoid side effects are marked. However, azathioprine may have a delayed onset of activity (up to 3 weeks) and, given its myelosuppressive potential, regular monitoring of the hemogram is necessary. Azathioprine is not recommended for cats; chlorambucil (2 to 6 rag / m given orally every 24 hours until remission, followed by drug tapering) is a suitable alternative. Other immunosuppressive drugs are methotrexate, cyclophosphamide, and cyclosporine. Methotrexate is effective in the treatment of human Crohn’s disease, but it is not widely used in companion animals; it often causes diarrhea in dogs. Cyclophosphamide has few advantages over azathioprine and is rarely used. However, cyclosporine may show promise for the future, given its T lymphocyte-specific effects and efficacy in canine anal furunculosis. Unfortunately, it is expensive, and studies in human inflammatory bowel disease have shown variable efficacy and toxicity.
Novel therapies for inflammatory bowel disease Novel therapies are increasingly used for human inflammatory bowel disease in an attempt to target more accurately the underlying pathogenetic mechanisms. These therapies include new immunosuppressive drugs, monoclonal antibody therapy, cytokines and transcription factors, and dietary manipulation (Table Novel Therapies for Human Inflammatory Bowel Disease). In the future, such therapies may be adopted for small animal inflammatory bowel disease.
Novel Therapies for Human Inflammatory Bowel Disease
||Mechanism Of Action
||Inhibits lymphocyte proliferation; reduces IFN-gamma production
|Leukotriene antagonists (zileuton, verapamil)
||Inhibit arachidonic acid cascade
|Prostaglandin (PG) targeting agents
||Mucosal protection from PC analogs; anti-inflammatory effects from PC antagonists
|Thromboxane synthesis inhibitors
||Inhibits TNF-αlpha expression
||Inhibits TNF-αlpha and IL-12 expression; reduces leukocyte migration; impairs angiogenesis
|Bone Marrow and Stem Cell Transplantation
|Bone marrow grafts
||Unknown; immunomodulation (?)
|Protein hydrolysate diets
|Fish oil therapy
||Diverts eicosanoid metabolism to LTB5 and PGE3
|Short chain fatty acid therapy
||Provides nutrition for enterocytes
|Probiotics and prebiotics
||Antagonize pathogenic bacteria; immunomodulatory effects
|Anti-IL-2 monoclonal antibody (MAb)
||Counteracts proinflammatory effects
|Anti-IL-2R (CD25) MAb
||Inhibits IL-2 effects
||Counteracts proinflammatory effects
||Downregulates TNF-alpha and IL-1beta
||Anti-inflammatory; antiviral (?)
||Immunomodulatory effect on Th 1 cells
||Counteracts proinflammatory effects; induces inflammatory cell apoptosis
|Endothelial Cell Adhesion Molecules and Their Manipulation
|ICAM-1 (antisense oligonucleotide)
||Reduces immune cell trafficking
|Anti-alpha4 / beta7 MAb
||Reduces immune cell trafficking
|Other Immune System Modulations
||Saturates Fc receptors; other (?)
|NF-kB antisense oligonucleotide
||Inhibits proinflammatory cytokine expression
|ICAM-1 antisense oligonucleotide
||Reduces immune cell trafficking
IFN, interferon; IL, interleukin; ICAM, intercellular adhesion molecule; LTB, leukotriene B; MAb, monoclonal antibody; PG, prostaglandin; PGE, prostaglandin E; Th 1, T helper 1; TNF, tumor necrosis factor
Mycophenolate mofetil recently has been used to treat human inflammatory bowel disease, although its efficacy is variable. Drugs that target TNF-α (e. g., thalidomide and oxpentifylline) may be suitable for the treatment of canine inflammatory bowel disease because of the importance of this cytokine in disease pathogenesis. Human open-label trials have demonstrated a beneficial effect for thalidomide in refractory Crohn’s disease. Oxpentifylline has shown efficacy in studies in vitro, but clinical results have been less rewarding. Anti-TNF-alpha monoclonal antibody therapy, which has also undergone trials in human inflammatory bowel disease, has the additional beneficial effect of inducing apoptosis in inflammatory cells. Species-specific monoclonal antibodies will be needed for canine and feline inflammatory bowel disease.
Finally, modulation of the enteric flora with probiotics or prebiotics may have benefits in targeting the pathogenesis of inflammatory bowel disease. A probiotic is an orally administered living organism that exerts health benefits beyond those of basic nutrition. In addition to having direct antagonistic properties against pathogenic bacteria, they modulate mucosal immune responses by stimulating either innate (e. g., phagocytic activity) or specific ( e. g., secretory IgA) immune responses. However, care should be taken to select the most appropriate organisms, which are likely to vary between host species.
Prebiotics are selective substrates used by a limited number of “beneficial” species, which therefore cause alterations in the luminal microflora. The most frequently used prebiotics are nondigestible carbohydrates, such as lactulose, inulin, and FOS. Both probiotics and prebiotics can reduce intestinal inflammation in mouse models of inflammatory bowel disease. Preliminary placebo-controlled trials with probiotics and prebiotics in human inflammatory bowel disease patients have shown promising results, although similar trials in canine and feline inflammatory bowel disease are still awaited.
A severe, hereditary form of lymphocytic-plasmacytic enteritis has been well characterized in basenjis, although the mode of inheritance is unclear. It has been likened to immunoproliferative small intestinal disease (IPSID) in humans, because both conditions involve intense intestinal inflammation. However, IPSID is characterized by an associated gammopathy (alpha heavy chain disease) and a predisposition to lymphoma. Affected basenjis often have hyper-globulinemia but not alpha heavy chain disease and may be predisposed to lymphoma. The intestinal lesions in basenjis are characterized by increases in CD4+ and CD8+T cells.
Signs of chronic intractable diarrhea and emaciation are most rommon Lymphocytic-plasmacytic paslritis, with hypergasirmemia and mucosal hyperplasia, may be seen in addition to the enteropathy. Protein-losing enteropathy often occurs, with consequent hypoalbuminemia, although edema and ascites are not common. Clinical signs are usually progressive, and spontaneous intestinal perforation may occur.
The approach to diagnosis is the same as before, and ultimately depends on histopathological examination of biopsy specimens.
Treatment generally is unsuccessful, with dogs dying within months of diagnosis. However, early, aggressive combination treatment with prednisolone, antibiotics, and dietary modification may achieve remission in some cases.
Familial Protein-Losing Enteropathy and Protein-Losing Nephropathy in Soft-Coated Wheaten Terriers
Recendy a clinical syndrome unique to soft-coated wheaten terriers was characterized. Affected dogs present with signs of protein-losing enteropathy or PLN or both. A genetic basis is likely, and although the mode of inheritance is not yet clear, pedigree analysis of 188 dogs has demonstrated a common male ancestor. The disease is probably immune mediated, given the presence of inflammatory cell infiltration. A potential role for food hypersensitivity has been suggested, because affected dogs have demonstrated adverse reactions during provocative food trials and alterations in antigen-specific fecal IgE concentrations.
Signs of protein-losing enteropathy tend to develop at a younger age than PLN. Clinical signs of the protein-losing enteropathy include vomiting, diarrhea, weight loss, and pleural and peritoneal effusions. Occasionally, thromboembolic disease may occur.
Preliminary laboratory investigations, as in most dogs with protein-losing enteropathy, demonstrate panhypoproteinemia and hypocholesterolemia. In contrast, hypoalbuminemia, hypercholesterolemia, proteinuria, and ultimately azotemia are seen with PLN, Histopathologic examination of intestinal biopsy material reveals evidence of intestinal inflammation, villus blunting, and epithelial erosions, as well as dilated lymphatics and lipogranulomatous lymphangitis.
Treatment and Prognosis
The treatment for protein-losing enteropathy is similar to that described for general inflammatory bowel disease, but the prognosis is usually poor.
Other Forms of Inflammatory Bowel Disease
Granulomatous enteritis is a rare form of inflammatory bowel disease characterized by mucosai infiltration with macrophages, resulting in the formation of granulomas. The distribution of inflammation can be patchy. This condition is probably the same as “regional enteritis,” in which ileal granulomas have been reported. Granulomatous enteritis has some histologic features in common with human Crohn’s disease, but obstruction, abscessation, and fistula formation are not noted. Conventional therapy is not usually effective, and the prognosis is guarded, although a combination of surgical resection and anti-inflammatory treatment was reported to be successful in one case. In cats, a pyogranulomatous transmurai inflammation has been associated with FIPV infection.
Proliferative enteritis is characterized by segmental mucosal hypertrophy of the intestine. Although many species can be affected, the condition is most common in pigs. A similar but rare condition has been reported in dogs. There have been suggestions of an underlying infectious etiology, and Lawsonia intracellularis has been implicated, although this has not yet been proved. Other infectious agents with a proposed link are Campylobacter spp. and Chlamydia organisms