Inflammatory bowel disease: Diagnostic and treatment approaches (Proceedings)

Inflammatory bowel disease is a somewhat loosely defined term that describes chronic gastrointestinal (GI) tract signs in dogs and cats, especially weight loss, vomiting and diarrhea. The term inflammatory bowel disease is often used to define a picture of intestinal mucosal inflammation from a variety of cell types, most commonly lymphoplasmacytic, without apparent cause. Because some animals with intestinal inflammation will respond to changes in diet, or to administration of antibiotics, some clinicians term the clinical syndrome chronic enteropathy and subdivide the syndrome into food responsive, antibiotic responsive, and steroid responsive disease. This presentation will primarily address the diagnostic and treatment considerations of inflammatory bowel disease /chronic enteropathy in dogs and cats.

Clinical signs

Inflammatory bowel disease should be considered a differential diagnosis for any dog or cat with a chronic history of weight loss, vomiting or diarrhea. Appetites in affected animals can range from good to poor. In severe cases, there can be enough enteric protein loss to cause peripheral edema, or thoracic or abdominal effusions. Clinical signs can be cyclic with spontaneous waxing and waning, particularly early in the clinical course.

Diagnostic approach

Most patients will have had a laboratory data base (CBC, biochemical profile, urinalysis) at some point in the clinical evaluation. There are no pathognomic clinical pathology features. Affected animals can have anemia of inflammatory disease, inflammatory or stress leukograms; thrombocytosis is a relatively common hematologic abnormality and is attributed to chronic inflammation. Biochemical profile abnormalities can include increases in liver enzyme activity, which are typically mild to moderate, hypoalbuminemia/ panhypoproteinemia, or hyperglobulinemia. There are no urinalysis abnormalities that specifically suggest gastrointestinal disease, but a urinalysis can exclude the urinary tract as a source of protein loss in hypoalbuminemic patients. Comprehensive fecal examinations are important to exclude gastrointestinal parasites as the cause of clinical signs. Fecal floats, direct smears and wet mounts allow for a thorough assessment of stool samples for intestinal parasitism. Before embarking on an expensive diagnostic or treatment protocol, it may well be worth empiric treatment with fenbendazole or other broad-spectrum anthelmintic.

Other readily available diagnostic tests that can be important in the evaluation of the inflammatory bowel disease candidate are serum trypsin-like immunoreactivity (TLI), folate and cobalamin concentrations. Exclusion of exocrine pancreatic insufficiency is an important early step in the evaluation of animals (both dogs and cats) with signs compatible with chronic small bowel disease, thus a TLI should be performed early in the diagnostic process. High serum folate and low cobalamin concentrations can indicate the presence of bacterial overgrowth, which can complicate inflammatory bowel disease, or cause intestinal inflammation. If bacterial overgrowth is suspected, a search for an underlying cause such as, for example, exocrine pancreatic insufficiency, partial intestinal tract obstructions, or motility disorders is warranted.

The author is an advocate of abdominal imaging in candidates for inflammatory bowel disease. Abdominal imaging can help rule out partially obstructive diseases, which in some patients can have overlap in clinical features with those of inflammatory bowel disease, can help raise or lower the index of suspicion for gastrointestinal neoplasia. Imaging approaches that are useful include abdominal radiography (with contrast as needed) or abdominal ultrasonography, which is often the author's preferred imaging approach. Abdominal ultrasonography can be very helpful in assessment of intra-abdominal lymph nodes, which if large, can be aspirated under ultrasound guidance for cytologic examination. This is an advantage as intestinal lymphoma is a competing differential for inflammatory bowel disease, and the diagnosis of intestinal lymphoma can be established by cytological examination precluding the need for more aggressive biopsy approaches. In some parts of the country infectious diseases, such as Pythium or Histoplasma, can cause disease similar to inflammatory bowel disease and these agents can be found on cytological samples as well. Abdominal ultrasound can also help exclude focal disease as a cause of clinical signs, an important consideration as many patients that are suspects for inflammatory bowel disease are eligible for endoscopic biopsies, and endoscopic examinations may be of limited use in patients with focal disease. Abdominal ultrasonography also helps evaluate other organs, which can provide important staging information for patients with gastrointestinal neoplasms, for which clinical signs may be similar to those of inflammatory bowel disease.

The diagnosis of inflammatory bowel disease is established largely on results of intestinal tract biopsy. A guideline for the histologic assessment of endoscopic biopsies has recently been offered in an attempt to standardize the evaluation of these biopsy samples. The guidelines consider a number of features of the biopsy sample including epithelial integrity, the degree of lymphocyte infiltration into the epithelium, villus atrophy, crypt dilation, lacteal prominence, and cellularity of the lamina propria. For all of these elements to be adequately evaluated requires good quality biopsy samples. For endoscopic biopsies to be of most value, the biopsy should extend to the submucosa so that crypt and villous anatomy can be better assessed. Biopsies that contain only villous tips are generally inadequate for the diagnosis of inflammatory bowel disease. Occasionally, there is a risk that severe inflammatory bowel disease will be mistaken as intestinal lymphoma, or vice versa, in endoscopic biospsies. This is particularly true in cats for which small cell intestinal lymphoma can be confused with lymphocytic enteritis; the risk is minimized with good quality biopsy samples. Endoscopic examination allows a good examination of the accessible gastrointestinal mucosa, which could be important for targeting biopsy efforts.

Intestinal biopsies can also be acquired surgically, particularly if there is no access to endoscopic biopsies. In some patients, accurate diagnosis may require a surgical biopsy if endoscopic biopsies were not helpful. Irregular distribution of lesions may also limit endoscopic biopsies. Properly acquired surgical biopsies are likely to allow evaluation of all needed elements of the intestinal tract. An exploratory laparotomy that is performed with the initial intention of acquiring biopsies of the intestinal tract should not be completed without biopsies of the intestinal tract; enlarged lymph nodes and other visceral lesions can be biopsied, but the intestinal biopsies are crucial for complete assessment.

There are many histological features of inflammatory bowel disease, and this presentation is not intended to detail those features. Inflammatory infiltrates that most commonly characterize inflammatory bowel disease are lymphocytes and plasma cells, or eosinophils, or a mix of lymphocytes, plasma cells and eosinophils; some patients have other inflammatory cell types. There is no currently available means of reliably distinguishing, based on intestinal histopathology, animals with food responsive inflammation from idiopathic intestinal inflammation.

Treatment considerations

Dietary manipulations, antibiotics and immunosuppressive therapy tend to be the cornerstones of therapy for patients with chronic enteropathy/inflammatory bowel disease. Some patients with histologically documented intestinal inflammation can have resolution of clinical signs with dietary changes alone; such patients have been termed food responsive enteropathies. The younger the patient with clinical features of inflammatory bowel disease, the more likely it is to have a food-responsive enteropathy as food responsive intestinal inflammation is considered more common in young animals, while older animals are more likely to have non-food (steroid) responsive inflammation. Diets employed in patients with predominantly small bowel disease are usually comprised of a novel protein and carbohydrate, ideally each from a single-source (i.e. single protein source, single carbohydrate source); a variety of pet food manufacturers make such diets. Hydrolyzed protein diets can be suitable approaches for some animals. For patients with large bowel signs predominating, there is no real consensus as to what constitutes the best initial dietary therapy. Options include higher fiber diets, especially soluble fiber, low residue diets, and novel protein/carbohydrate diets; basically, if one diet approach is ineffective, another should be tried. It is important to recognize that multiple diet types may be need to be tried before concluding that the patient does not have food-responsive disease. The author has also resorted to having owners home cook meals with novel protein and carbohydrate sources on the possibility that preservatives or other additives to commercial preparations contribute to intestinal inflammation. It is generally agreed by most veterinary internists that for the patient that is clinically stable, a dietary trial should be the first step taken in a patient with chronic enteropathy. Responses can be seen within 10-14 days in many food-responsive patients, although several weeks of feeding are suggested to have confidence that the new diet is ineffective.

For those patients that do not have a response to dietary manipulation, a usual next step in the treatment of inflammatory bowel disease is the administration of an antibiotic such as metronidazole (15 mg/kg PO q12h) or tylosin (10 mg/kg PO q24h). Responses to antibiotics in responsive patients are usually prompt, often within 24-72 hours. Some animals require longer term (2-4 weeks) or repeated administration of antibiotics for long-term control of clinical signs.

The last step up in medical therapy for the patient with chronic enteropathy is usually immunosuppressive therapy. There are a number of drugs that can be used for immunosuppressive treatment of inflammatory bowel disease patients. The most commonly used drugs for treating animals with inflammatory bowel disease are glucocorticoids and cyclosporine; azathioprine is often used as an adjunct to glucocorticoids in dogs. Immunosuppressive drugs can be used singly, or in combination. Glucocorticoids have a long history in the treatment of inflammatory bowel disease with most papers demonstrating efficacy in improvement or resolution of clinical signs in a large proportion of treated animals. Prednisone is commonly used as a first-line immunosuppressive treatment in dogs and cats with inflammatory bowel disease, with dosages of prednisone given at 1-2 mg/kg PO q12h; the author often doses cats at 10 mg/cat/day for the average 3-4 kg cat. For dogs with poor responses to prednisone, azathioprine can be added at a dosage of 1-2 mg/kg PO q24h for 10-14 days, after which the dose interval is usually extended to every 48 hours; cats with poor responses to prednisone are often treated with cyclosporine, chlorambucil, or budesonide as the next line therapy. Cyclosporine dosage is 5 mg/kg PO q24h. There is relatively little literature evidence that supports the use of azathioprine in dogs with inflammatory bowel disease, but there is strong anecdotal support for its use. A relatively recent paper reported that administration of cyclosporine at 5 mg/kg PO once daily was of benefit in improving clinical signs in dogs with inflammatory bowel disease refractory to glucocorticoids and other medical therapy. Cyclosporine is typically reserved for those patients that are refractory to other therapy because of the relative expense of cyclosporine compared to other drugs.

Budesonide is an orally administered glucocorticoid that is purported to have local (topical) activity but less systemic effects than other glucocorticoid formulations. Studies have shown that budesonide does alter the hypothalamic pituitary axis in healthy dogs and dogs with inflammatory bowel disease, but without owner perceptions of the other usual side effects of systemically active glucocorticoids. There is anecdotal evidence that budesonide helps many, but not all, patients with inflammatory disease when oral prednisone has not, or when the side effects of prednisone are unbearable to owners. Budesonide has been empirically dosed at 1 mg PO for small dogs and cats, 2 mg for medium sized dogs, and 3 mg for large dogs although larger doses may be needed for any given patient. Budesonide is a much more potent glucocorticoid than prednisone, thus administration of budesonide with other glucocorticoids, or NSAIDs, is not advised.

For patients that have low serum cobalamin concentrations, administration of cobalamin is recommended. Cobalamin treatment may be important for some patients in restoration of normal gastrointestinal epithelial integrity and function, while untreated deficiency may blunt responses to other therapeutic interventions.

Prognosis

Responses to therapy can be variable, but the primary goal of treatment is control of clinical signs first, and resolution of laboratory abnormalities (especially hypoalbuminemia) as a secondary goal. One theme that has emerged from several of the recent papers of inflammatory bowel disease in dogs is that just as there is no correlation between severity of clinical signs and severity of intestinal inflammation, there is no correlation between clinical improvement and resolution of intestinal inflammation. These findings suggest that in patients with poor clinical response, there is little to be gained from repeating intestinal biopsies unless it is believed that the initial biopsies were not representative of the disease process.

Not all animals will respond to therapy. Prior studies have noted that approximately 20% of dogs with inflammatory bowel disease will not respond to dietary and immunosuppressive therapy. In the paper that described the use of cyclosporine in dogs that had failed other medical therapy, 2/14 treated animals still showed no clinical improvement. Some factors that have predicted poor response include more severe clinical signs (including ascites and edema), low serum albumin and low serum cobalamin concentrations. Still, some patients with these negative prognostic indicators can show clinical improvement so treatment should not be withheld simply because of the existence of these indicators.

References

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Burgener IA, et al. Upregulation of toll-like receptors in chronic enteropathies in dogs. J Vet Int Med 2008; 22:553-560.

Day MJ, et al. Histopathological standards for the diagnosis of gastrointestinal inflammation in endoscopic biopsy samples from the dog and cat: a report from the World Small Animal Veterinary Association Gastrointestinal Standardization Group. J Comp Pathol 2008; 138:S1-S43.

Garcia-Sancho M, et al. Evaluationof clinical, macroscopic, and histopathologic response to treatment in nonhypoproteinemic dogs with lymphocytic-plasmacytic enteritis. J Vet Int Med 2007; 21:11-17.

Schreiner NMS, et al. Clinical signs, histology and CD-3 positive cells before and after treatment of dogs with chronic enteropathies. J Vet Int Med 2008; 22:1079-1083.