Inflammatory Bowel Disease in Small Animals
Idiopathic inflammatory bowel disease (IBD) constitutes a group of GI diseases characterized by persistent clinical signs and histologic evidence of inflammatory cell infiltrate of unknown etiology. The various forms of IBD are classified by anatomic location and the predominant cell type involved. Lymphocytic-plasmacytic enteritis is the most common form in dogs and cats, followed by eosinophilic inflammation. There are occasional reports of inflammation with a granulomatous pattern (regional enteritis). A neutrophilic predominance in the inflammatory infiltrate is rare. A mixed pattern of cellular infiltrate is described on many occasions. Certain unique IBD syndromes occur more often in some breeds, such as the protein-losing enteropathy/nephropathy complex in Soft-coated Wheaten Terriers, immunoproliferative enteropathy of Basenjis, IBD in Norwegian Lundehunds, and histiocytic ulcerative colitis in Boxers.
The etiology of IBD is unknown. Several factors may be involved, such as GI lymphoid tissue (GALT); permeability defects; genetic, ischemic, biochemical, and psychosomatic disorders; infectious and parasitic agents; dietary allergens; and adverse drug reactions. IBD may also be immune mediated. The intestinal mucosa has a barrier function and controls exposure of antigens to GALT. The latter can stimulate protective immune responses against pathogens, while remaining tolerant of harmless environmental antigens (eg, commensal bacteria, food). Defective immunoregulation of GALT results in exposure and adverse reaction to antigens that normally would not evoke such a response. Although dietary allergy is an unlikely cause of IBD (except in eosinophilic gastroenteritis), it may contribute to increased mucosal permeability and food sensitivity.
Current evidence supports the likely involvement of hypersensitivity reactions to antigens (eg, food, bacteria, mucus, epithelial cells) in the intestinal lumen or mucosa. More than one type of hypersensitivity reaction is involved in IBD. For example, type I hypersensitivity is involved in eosinophilic gastroenteritis, whereas type IV hypersensitivity is likely involved in granulomatous enteritis. The hypersensitivity reaction incites the involvement of inflammatory cells, resulting in mucosal inflammation that impairs the mucosal barrier, in turn facilitating increased intestinal permeability to additional antigens. Persistent inflammation may result in fibrosis.
There is no apparent age, sex, or breed predisposition associated with IBD; however, it may be more common in German Shepherds, Yorkshire Terriers, Cocker Spaniels, and purebred cats. The mean age reported for development of clinical disease is 6.3 yr in dogs and 6.9 yr in cats, but IBD has been documented in dogs <2 yr old. Clinical signs are often chronic and sometimes cyclic or intermittent. Vomiting, diarrhea, changes in appetite, and weight loss may be seen. In a retrospective study of cats with lymphocytic-plasmacytic enterocolitis, weight loss, intermittent vomiting progressing to more frequent vomiting on a daily basis, diarrhea, and anorexia were seen most often. Vomiting, melena, and cranial abdominal pain are often seen with gastroduodenal ulceration and erosion. Weight loss, vomiting, diarrhea, ascites, and peripheral edema can be seen in the cases of protein-losing enteropathy. Pulmonary thromboembolism is a rare complication; however, it can occur if there is severe intestinal protein loss (loss of antithrombin III). Clinical signs of large-intestinal diarrhea, including anorexia and watery diarrhea, are not uncommon.
An association between gastric dilation and volvulus (see Gastric Dilation and Volvulus in Small Animals) and IBD in dogs has also been postulated. In this case, inflammation of the bowel may cause alterations in gastric motility and emptying and in GI transit time, thus predisposing to dilation and volvulus.
An association between inflammatory hepatic disease, pancreatitis, and IBD has been reported in cats, although an etiology for this triad of diseases has not been established. However, cats with cholangiohepatitis should also be evaluated for IBD and pancreatitis. Although unproved, it has been suggested that severe IBD in cats may progress to lymphosarcoma.
There are no specific abnormalities on CBC, biochemical evaluations, or radiographs.
Hypoproteinemia due to reduced dietary intake and malabsorption or increased loss via the GI tract may be seen. Hypocalcemia and hypocholesterolemia may be attributed to malabsorption. Increases in serum amylase as a consequence of bowel inflammation have been reported. Hypokalemia secondary to anorexia, potassium loss from vomiting and diarrhea, and mild increases in serum levels of liver enzymes can be expected. Low serum levels of folate and cobalamin because of malabsorption are also documented.
Eosinophilia may be associated with eosinophilic enteritis; however, this is not a sensitive parameter. Microcytic anemia may be present with loss of iron, associated with chronic loss of blood. Nonresponsive anemia, if present, likely reflects anemia of chronic or inflammatory disease.
Erythrocytosis, associated with fluid loss from vomiting and diarrhea, and a stress leukogram may be seen. Radiographic changes may include gas or fluid distention of the stomach and increased total diameter of small-intestinal loops. Contrast films may show diffuse or focal mucosal irregularities suggestive of infiltrative disease. Loss of contrast can be related to ascites.
Fecal examination is important to exclude other causes of mucosal inflammation, such as nematodes, Giardia infection, and bacterial infection. Giardia may be difficult to detect because of intermittent shedding, and empirical treatment with fenbendazole is recommended in all cases.
Abdominal ultrasonography can be used to assess all abdominal organs, examine the entire intestinal tract, and measure wall thickness (although the latter measurement is of no significant value in IBD diagnosis). Small-intestinal hyperechoic mucosal striations are frequently associated with mucosal inflammation and protein-losing enteropathy. Ultrasonography also helps eliminate the possibility of disease in other organs, localize the disease, and determine whether endoscopy would allow biopsy of the site.
Endoscopy allows examination of the esophagus, stomach, duodenum, and sometimes the jejunum, depending on the size of the animal. Colonoscopy allows exploration of the colon. In some cases, gross mucosal lesions may be seen endoscopically, including erythema, friability, enhanced granularity, erosion, and ulceration. In many cases, the endoscopic appearance is normal. However, biopsy samples should always be taken, because the macroscopic and microscopic appearance of the intestinal mucosa are poorly correlated. At least six biopsies of each segment of the GI tract are recommended. Endoscopy is the easiest way to collect biopsy samples, but such samples are superficial and usually can be collected only from the proximal small intestine. One study suggested that ileal biopsies can reveal lesions not apparent in the duodenum and, therefore, should be performed routinely. More specifically, feline lymphoma was much more likely to be found in the ileum than the duodenum. In some cases, exploratory celiotomy and full-thickness biopsy are necessary to reveal histopathologic changes at the level of the mucosa (eg, dilation of the lacteals in lymphangiectasia). However, wound healing can be compromised if there is severe hypoproteinemia or if urgent steroid treatment is needed. For this reason, most clinicians choose to perform endoscopic biopsies unless biopsies of other abdominal organs are required.
Small populations of lymphocytes, plasma cells, macrophages, eosinophils, and neutrophils are normal components of intestinal mucosal tissue. Increased numbers of plasma cells, lymphocytes, eosinophils, and neutrophils in the lamina propria are seen in IBD. However, these morphologic features may also be seen with other causes of GI disease (eg, Giardia, Campylobacter, Salmonella, lymphangiectasia, lymphosarcoma). Although histopathologic assessment of intestinal biopsy material remains the gold standard for diagnosis of many IBDs, it has marked limitations. Specimen quality can vary, pathologic diagnoses are inconsistent, and differentiation between normal specimens and those showing IBD and even lymphoma can be difficult. Biopsy must always be considered in relation to clinical signs, and the animal treated accordingly.
The goals of therapy are to reduce diarrhea and vomiting, promote appetite and weight gain, and decrease intestinal inflammation. If a cause can be identified (eg, dietary, parasitic, bacterial overgrowth, drug reaction, etc), it should be eliminated.
Dietary manipulation by itself may be effective in some cases (eg, in chronic colitis); in other cases, it can enhance the efficacy of concurrent medical therapy, allowing for the drug dosage to be reduced or for drug therapy to be discontinued once clinical signs are in remission. Corticosteroids, azathioprine, sulfasalazine, tylosin, and metronidazole are among the drugs most often used in management of IBD.
Unless the animal is debilitated, it is better to institute therapeutic modalities sequentially. The frequency and nature of clinical signs should be monitored, and therapy adjusted as needed. Treatment should begin with anthelmintic/antiparasitic medication (eg, fenbendazole at 50 mg/kg/day, PO, for 3–5 days). This is followed by dietary modification (preferably with an antigen-limited or hydrolyzed protein diet) for 3–4 wk, then a 3- to 4-wk antibacterial trial (usually tylosin 10 mg/kg, PO, tid, or metronidazole 10 mg/kg, PO, bid), and finally trial immunosuppressive therapy (initially prednisolone, 1 mg/kg, PO, bid).
Dietary modification generally involves feeding a hypoallergenic or elimination diet with a source of protein to which the animal has not been previously exposed (eg, homemade diets of lamb and rice or venison and rice, commercial diets). This diet should be the sole source of food for a minimum of 4–6 wk; no treats of any kind should be fed. Dogs with large-intestinal diarrhea may benefit from diets high in insoluble fiber content (see Colitis in Small Animals). Supplementation of dietary fiber alone is rarely effective in animals with severe inflammatory cell infiltrate.
Sulfasalazine (and related drugs) are often used in dogs when IBD is limited to the large intestine. In the colon, this drug is split to release 5-aminosalicylic acid, which exerts its anti-inflammatory activity in the mucosa. The principal adverse effects in dogs are keratoconjunctivitis sicca and vasculitis. Because of the risk of salicylate toxicity in cats (see Colitis in Small Animals), sulfasalazine is not routinely used in feline colitis. Newer aminosalicylic drugs without some of sulfasalazine’s adverse effects are available, eg, olsalazine (dogs: 10–20 mg/kg, PO, tid) and mesalamine (dogs: 10 mg/kg, PO, tid).
The use of antibiotics can be justified in part by the potential to treat any undiagnosed enteropathogens. Metronidazole (10–20 mg/kg, PO, bid) is the preferred antibacterial for most forms of IBD in small animals. It may have immunomodulatory effects. Tylosin (10 mg/kg, PO, tid) may also have immunomodulatory effects and may have some efficacy in canine IBD. Histiocytic ulcerative colitis of Boxers is responsive to enrofloxacin, which supports the hypothesis that this particular form of IBD is the consequence of an infection with a specific organism.
Corticosteroids may be useful for both small- and large-intestinal disease. Initial dosages are 2 mg/kg/day for prednisone or prednisolone and 0.25 mg/kg/day for dexamethasone. Adverse effects include polyuria, polydipsia, polyphagia, and GI disturbances (eg, vomiting, melena, diarrhea). Dosages should be tapered every 7–10 days to the lowest possible dose required to control clinical signs and, if possible, discontinued altogether. An enteric-coated formulation of the glucocorticoid budesonide has successfully maintained remission in human IBD. A preliminary study has shown apparent efficacy in dogs and cats, but information on use of this drug is limited. It undergoes substantial first-pass elimination via rapid inactivation in the liver; the result is lower systemic bioavailability and reduced effects on the hypothalamic-pituitary-adrenal axis, making iatrogenic hyperadrenocorticism less common than with other glucocorticoids. The optimal dosage in dogs is unknown. Anecdotally, a dosage of 1 mg/m2/day, PO, in dogs, and 1 mg/cat/day, PO, in cats, has been recommended.
In refractory cases, adding an immunosuppressive drug to corticosteroid therapy may be beneficial. Azathioprine (for dogs) and chlorambucil (for cats) can be used. The dosage of azathioprine is 2.2 mg/kg/day, PO. Adverse effects include myelosuppression, pancreatitis, and hepatotoxicity. The dosage of azathioprine can be tapered after several weeks. Typically, the prednisone is tapered first (by 25% every 2–3 wk). After prednisone has been tapered to 0.5 mg/kg every other day without a relapse, then azathioprine is given every other day. If response to steroids is poor, even if combined with azathioprine, cyclosporine can be added at 5–10 mg/kg/day, PO, for at least 8–10 wk. No study has been done to compare cyclosporine and azathioprine. However, one recent study suggested that the combination of chlorambucil-prednisolone was more efficient to treat chronic enteropathy with concurrent protein-losing enteropathy in dogs than the azathioprine-prednisolone protocol.
Azathioprine is not recommended in cats because of sensitivity to adverse effects. Instead, cats are treated with a combination of prednisone and chlorambucil (0.1–0.2 mg/kg or 1 mg/cat). Clinical signs typically improve in 3–5 wk, although 4–8 wk of treatment may be needed. A CBC should be done every 2 wk to monitor for evidence of myelosuppression.
Adjunctive treatment may include ursodeoxycholic acid in cats (10–15 mg/kg/day, PO), cobalamine supplementation (20 mg/kg, SC, every 7 days for 4 wk and then every 28 days for a further 3 mo) in dogs and cats, and other supportive therapy as needed.
The response rate to treatment of IBD is variable. Quality of life tends to be poor, and prognosis is guarded. Hypoalbuminemia is a negative prognostic sign. Prognosis is worse in cases with severe histologic lesions, mucosal fibrosis, eosinophilic enteritis, protein-losing enteropathy, or hypereosinophilic syndrome. Relapses occur and are most often precipitated by dietary indiscretion.