Management of inflammatory bowel disease (Proceedings)

Article

Idiopathic inflammatory bowel disease (IBD) is characterized by chronic gastrointestinal signs associated with diffuse accumulation of lymphocytes and plasma cells in the lamina propria and morphologic abnormalities of the intestinal mucosa and epithelium.

Idiopathic inflammatory bowel disease (IBD) is characterized by chronic gastrointestinal signs associated with diffuse accumulation of lymphocytes and plasma cells in the lamina propria and morphologic abnormalities of the intestinal mucosa and epithelium. Lymphocytic-plasmacytic mucosal inflammation may be diffuse or selectively involve the stomach, small intestine or colon; and is the most common endoscopic abnormality found in dogs and cats with chronic vomiting and diarrhea.

Etiopathogenesis

The etiology of IBD in dogs and cats is unknown, but the pathogenesis is believed to involve genetic factors, interactions of dietary antigens and enteric microflora with the mucosal immune system, and altered permeability of the mucosal barrier. In IBD the intestinal mucosal immune system seems to be reacting inappropriately to antigenic stimulation from dietary constituents and commensal bacterial flora.  Chronic inflammation of the bowel may become uncontrolled and self-perpetuating when loss of mucosal integrity and increased permeability allow bacterial and dietary antigens to enter the lamina propria where they incite ongoing immune stimulation and inflammation. Studies in naturally occurring IBD in dogs and cats have found altered subpopulations of mucosal immune cells, increased proinflammatory cytokines, increased acute phase proteins, altered mucosal permeability, and changes in bacterial microflora. However, it is unclear whether some of these observations reflect primary causal abnormalities or the nonspecific consequences of chronic GI inflammation.

Clinical signs

The most common clinical signs of IBD in are vomiting, diarrhea, and weight loss. The signs vary with the regions of the GI tract affected and the severity of mucosal disease. The clinical signs typically wax and wane over periods ranging from a few weeks to years. Animals of all ages are susceptible. Chronic episodic vomiting is the most frequent sign of IBD in cats, and is usually related to lesions in the duodenum. Vomiting is often unrelated to eating and it may be the only sign of IBD, although it can be accompanied by a history of chronic diarrhea in some cats. The vomitus usually consists of clear or bilious fluid or foam. Vomiting of undigested or partially digested food occurs less often. Chronic unresponsive diarrhea of small bowel origin (i.e., lymphocytic-plasmacytic enteritis) is seen in both dogs and cats with IBD. Feces may vary from soft and semiformed feces to profuse watery diarrhea. Diarrhea of large bowel origin (i.e., lymphocytic-plasmacytic colitis) is characterized by increased frequency of defecation, urgency, tenesmus, increased fecal mucus, and hematochezia. Fecal consistency varies. In cats, a loss of litter training can also be seen. The physical examination is unremarkable in most animals with IBD until progressive weight loss causes poor body condition with advanced disease. Intestinal loops are sometimes palpably thickened and firm on abdominal palpation.

Diagnosis

Precise criteria for the definitive diagnosis of IBD in dogs and cats have not been established. In general, the presumptive diagnosis of idiopathic IBD is based on (1) chronic GI signs greater than 3 weeks in duration; (2) characteristic lesions of IBD in mucosal biopsies; (3) incomplete response to dietary trials, anthelmintics, and antibiotics; and (4) exclusion of identifiable causes of chronic inflammation of the GI tract based on thorough diagnostic evaluation. This last criterion recognizes that lymphocytic-plasmacytic inflammation is a nonspecific lesion, and only a thorough diagnostic work-up can establish that it is truly idiopathic and not merely an inflammatory response to an undiagnosed condition. In addition to endoscopic mucosal biopsy of the intestines, diagnostic evaluations should be directed toward exclusion of parasitic and infectious diseases, extraintestinal diseases (e.g., organ failure, hypoadrenocorticism, or hyperthyroidism), and diet-responsive disease. Well planned dietary trials are required to diagnose dietary hypersensitivity.

Laboratory evaluations

Routine CBC, urinalysis, and serum biochemistries are normal in most cases; however, some animals have mild nonspecific laboratory abnormalities such as mild anemia, stress leukogram (mature neutrophilia, lymphopenia), stress hyperglycemia (cats), hypoproteinemia (hypoalbuminemia, hypoglobulinemia, or both), hypokalemia, and mildly elevated serum liver enzymes. Hypoproteinemia from intestinal protein loss (protein-losing enteropathy) may indicate a more severe form of the disease. Cats with IBD can have concurrent cholangitis and/or pancreatitis, or so-called triaditis, which may increase serum liver enzymes and feline pancreatic lipase (fPL). Eosinophilia is found in some cats with IBD. To ruleout endocrinopathies that can mimic IBD, a baseline cortisol level screens for hypoadrenocorticism in dogs and a serum T4 screens for hyperthyroidism in cats. Exocrine pancreatic insufficiency as a cause of chronic diarrhea and weight loss should be diagnosed by a trypsin immunoassay (TLI). Serum vitamin levels (cobalamin, folate, vitamin K) can be decreased, presumably from malabsorption. Cats with chronic GI disease are especially susceptible to hypocobalaminemia; thus, a baseline cobalamin level is important to determine if parenteral cobalamin therapy is needed. Bleeding and abnormalities of hemostasis (e.g., prolonged PIVKA coagulation times) attributable to vitamin K deficiency have been reported complications of feline IBD. Fecal examinations may be needed to exclude helminths, Giardia, Tritrichomonas, and other parasitic and infectious agents, many of which can cause GI inflammation that can be mistaken for IBD. Cats should be retrovirus tested.

Radiography and ultrasonography

In IBD abdominal radiography is unremarkable and does not aid in the diagnosis. Some cases have nonspecific distension of bowel loops with fluid and gas on survey radiographs, and barium-contrast radiography occasionally demonstrates diffuse mucosal irregularity. Animals with IBD occasionally develop complicating intussusception. Ultrasonography can be used to assess intestinal thickness, layering, and echogenicity as indicators of infiltrative disease, while also allowing identification of potential abnormalities in other abdominal structures, especially the mesenteric lymph nodes, liver, and pancreas. Cats with IBD have increased risk for concurrent cholangitis and pancreatitis. Mild to moderate intestinal thickening with mucosal hypoechogenicity are nonspecific findings indicative of an infiltrative lesion, but intestinal thickening is not consistently found in IBD. Focal or severe mural thickening with loss of layering is suggestive of lymphoma, and should prompt a recommendation for fine-needle aspiration cytology of the region and possibly full-thickness biopsy.

 

Endoscopic examination and biopsy

Histopathologic evaluation is the gold standard for diagnosis of IBD. Standards for describing and grading the histopathologic lesions of IBD in endoscopic biopsies have recently been established by World Small Animal Veterinary Association Gastrointestinal Standardization Group. In most cases, endoscopic mucosal biopsy is the most practical and least invasive means of confirming the presence and assessing the severity of mucosal inflammation in IBD; however, full-thickness biopsy by laparotomy or laparoscopy is considerably more accurate for differentiating between IBD and lymphoma, because of access to submucosal layer and the jejunum and ileum regions, which are preferential sites for lymphoma. Willard has shown that the diagnostic value of endoscopic biopsies is affected by the number and quality the of tissue specimens as well as the experience of the pathologist; and that substantial interobserver variation occurs between pathologists interpreting endoscopic biopsies, which can adversely affect diagnosis and treatment decisions. The most reliable results occur when an experienced endoscopist submits an adequate number (at least 8 tissue samples from each region of the GI tract) of high quality biopsy specimens to a pathologist that is experienced with endoscopic GI histopathology.

In IBD the clinical signs do not always correlate with the region of greatest cellular infiltration, especially in cats. It is not uncommon to find significant involvement of the colon in cats that present for vomiting. Conversely, cats with hematochezia or other colonic signs may have unexpected gastroduodenal lesions. Therefore it may be advisable to routinely obtain biopsies from the stomach, duodenum, colon, and ileum (if the ileocolic sphincter can be navigated during colonoscopy) in all cats suspected of IBD.

Endoscopically, the mucosa in IBD may appear to be normal or it may have any of the following abnormalities: erythema, petechiae, increased mucus, increased friability, increased surface granularity, thickened or increased folds, erosions/ulcers, or lack of distensibility. In the colon the submucosal vessels may be less visible. In many animals with IBD, the mucosal lesions are only apparent microscopically and a normal endoscopic appearance does not rule out the disease; thus, biopsies should always be taken even when no endoscopically-visible lesions are found.

The histopathologic lesions of IBD are characterized by diffuse infiltration of the lamina propria with mature lymphocytes and plasma cells in association with morphologic evidence of mucosal damage (e.g., villous blunting, fusion, or fibrosis; crypt distortion) and epithelial abnormalities. The inflammation occasionally includes other types of inflammatory cells (neutrophils, eosinophils, macrophages). The cellular infiltrate is usually confined to the mucosa; thus, a marked infiltrate that extends deeper into the submucosa should raise suspicion of lymphoma and full-thickness biopsy may be advisable. When lymphoma is a possibility, it may be important to consider additional methods of assessing biopsies, such as immunohistochemistry, flow cytometry, or T-cell clonality assay.

Treatment

Treatment of IBD is focused on modifying the diet and intestinal flora to decrease the antigenic stimulation of the GI tract, and medical therapy to modulate the local immune response and control inflammation. In most IBD cases, an underlying cause cannot be identified, and the most effective treatment approach is a sequential series of therapeutic trials beginning first with a fenbendazole trial to exclude undetected Giardia or helminth infections; then if signs persist, a diet trial using a novel protein or hydrolyzed protein diet to exclude dietary hypersensitivity; then if signs persist, an antibiotic trial using metronidazole or tylosin to modify the intestinal flora; and then finally if signs persist, an antiinflammatory regimen of a corticosteroid  is initiated, usually combined with dietary modification (e.g., commercial GI diet, novel protein diet, or hydrolyzed protein diet). If diet and corticosteroids fail to control the disease, metronidazole or tylosin may be added for antibacterial and potential immunomodulatory activity. Metronidazole can also be used as a single drug to induce or maintain remission in mild cases. For refractory large bowel involvement, sulfasalazine or mesalamine may be used for local antiinflammatory effects in the colon. For the most refractory cases, immunosuppressive agents such as chlorambucil (cats), azathioprine (dogs), or cyclosporine can be combined with a corticosteroid. Adjunctive therapy includes cobalamin, probiotics, omega-3-fatty acids, and environmental enrichment (indoor cats).

Dietary therapy

Various strategies for dietary modification have been used for treatment of IBD, including single novel protein diets, hydrolyzed protein diets, fiber-enriched diets, and diets with adjusted fatty acid levels. In some animals with IBD, dietary modification produces a complete or partial resolution of the signs and sometimes regression of the lesions. Potential explanations for a beneficial response to dietary modification include the effects of the diet on composition of the microflora, mucosal morphology and function, and exposure to foodborne antigens or additives.

Dietary hypersensitivity or food allergy is an immunologically mediated adverse reaction to a protein component in food. A well-controlled dietary trial using a protein elimination diet is the basis for diagnosis of dietary hypersensitivity as a cause of IBD. The diet is changed to a well-defined, additive-free, digestible diet that contains hydrolyzed protein or a single novel source of protein not found in the patient's normal diet. Hydrolyzed protein diets consist of minimally antigenic oligopeptides instead of intact proteins. Alternatively, novel protein sources can be used, such as turkey, duck, lamb, rabbit, venison, fish, or tofu. Novel protein diets can be home-prepared diets or commercial single-source novel protein diets, which are more convenient and balanced for long-term feeding. Intake of all other foods and sources of antigen must be completely eliminated throughout the feeding trial, including table scraps, treats, and medications with antigenic additives, such as probiotics and flavored vitamin supplements. The goal is to feed the trial diet for a minimum of 4 weeks. One study using commercial novel protein diets in a strict dietary elimination trial followed by antigen challenge testing found that 29% of cats with chronic idiopathic gastrointestinal problems had dietary hypersensitivity, most commonly involving beef, corn, and wheat.

Cobalamin therapy

Cobalamin deficiency can occur with IBD, especially in cats, presumably the result of malabsoption of the vitamin in the ileum, and cobalamin deficiency can impair intestinal mucosal regeneration and cause mucosal atrophy, exacerbating diarrhea and making the patient refractory to the usual anti-inflammatory therapy. Hypocobalaminemia (serum cobalamin <200 ng/L) is treated with subcutaneous injections of cobalamin (cats/small dogs- 250 mg; medium dogs- 500 mg; large dogs- 1000 mg), given weekly for at least 6 weeks, then every other week for 6 weeks, and then monthly.

Metronidazole and tylosin

Metronidazole (10 to 15 mg/kg PO q12h) and tylosin (10 to 20 mg/kg PO q12h) are sometimes beneficial for IBD as single agents or in combination with corticosteroids. The beneficial effects might be attributable to intraluminal antibacterial action (reduction of bacterial-derived antigens) or to the immunomodulating effects of these drugs. Metronidazole tablets have an unpleasant bitter taste and provoke salivation, nausea, and sometimes vomiting. A liquid formulation of metronidazole benzoate is better tolerated by cats, or tablets can be split and placed in gel capsules. Dosages of metronidazole exceeding 50 mg/kg/day, especially for prolonged periods (weeks), have occasionally caused signs of reversible central nervous system toxicity (weakness, ataxia, disorientation, seizures, cortical blindness).

Corticosteroids

For initial medical therapy of IBD, oral prednisone and prednisolone are the most consistently effective and preferred therapy: in dogs at 1 to 2 mg/kg q24h; and in cats at 2 to 4 mg/kg q24h, or 5 mg total dose/cat q12h, PO. Prednisolone is the active form of the steroid and preferred over the prodrug prednisone in cats. Clinical improvement using this dosage should be noted within 1 to 2 weeks. After 2 weeks of remission, the dosage is tapered in 2- to 4-week increments to the lowest effective alternate-day dosage (usually 0.5 to 1.0 mg/kg). Dexamethasone (0.2 mg/kg PO q12-24h) is sometimes more effective than prednisone or prednisolone. In cats that are impossible to medicate orally, periodic injections of methylprednisolone acetate (20 mg IM or SC q2-4 wk) may be substituted for oral treatment.

Budesonide (Entocort; total daily dose of 1 to 3 mg PO for dogs and 0.5 to 1 mg for cats) is an alternative corticosteroid for refractory cases. Budesonide has selective mucosal anti-inflammatory activity with less steroidal side effects due to first-pass liver metabolism. In dogs, enough budesonide is absorbed to suppress the hypothalamic-pituitary-adrenal axis, but steroidal side effects are generally less than with conventional steroids.

Corticosteroid therapy may be discontinued on a trial basis after 8 to 12 weeks of remission; however, continuous alternate-day therapy is often required indefinitely to prevent relapse. In animals refractory to corticosteroids alone, combination with metronidazole, tylosin, or an immunosuppressive drug may be necessary.

 

Mesalamine and 5-aminosalicylic acid derivatives

Orally administered 5-ASA derivatives (sulfasalazine, olsalazine, mesalamine) are designed to be minimally absorbed during passage through the small intestine, which allows them to reach the colon where they have a targeted nonsteroidal anti-inflammatory effect. Because they have limited activity in the upper GI tract, they are only beneficial in animals with colonic IBD (colitis). In general, these drugs are not as effective as corticosteroids for controlling IBD in dogs and cats.

Chlorambucil in cats with refractory IBD

In cats with IBD that is refractory to prednisolone alone, combining prednisolone with the alkylating agent chlorambucil (Leukeran; 2 mg total dose per cat, PO q48-72h; or 20 mg/m2 once every 2 to 3 weeks) may provide greater immunosuppression and be more effective for inducing remission of the disease. In addition to treating refractory IBD, the addition of chlorambucil may enable use of a lower dose of corticosteroid to control the disease, thereby minimizing steroidal side effects. The chlorambucil-prednisolone combination is also an effective treatment for low-grade small cell lymphoma; thus, this combination can be used in cats where histopathologic differentiation between IBD and small cell lymphoma is inconclusive. The CBC should be monitored periodically in cats on chlorambucil. Chlorambucil is preferred over azathioprine in cats because azathioprine can be associated severe myelotoxicity in cats.

Azathioprine and cyclosporine in dogs with refractory IBD

In dogs with refractory IBD, azathioprine (1 to 2 mg/kg PO q24-48h) can be added to the corticosteroid regimen. The CBC and liver enzymes should be monitored periodically in dogs on azathioprine. Cyclosporine (Atopica; 5 mg/kg PO q24h), a potent immumnosuppressive drug that inhibits interleukin-2 and T-cell recruitment, has been found to be effective for controlling steroid-refractory IBD in dogs. Transient inappetance and vomiting are common side effects of cyclosporine, but these typically resolve within 1 to 2 weeks.

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