Chronic Enteropathies in Small Animals
Inflammatory Bowel Disease
Chronic enteropathies (CEs) are characterized by the presence of GI clinical signs (diarrhea, vomiting, anorexia) for more than 3 weeks. CE can be subdivided into 4 categories: food-responsive enteropathy, antibiotic-responsive enteropathy, immunosuppressant-responsive enteropathy (including steroid-responsive diarrhea) and nonresponsive enteropathy. Protein-losing enteropathy is a fifth type of CE. It include small animals that lose proteins across the gut and is usually associated with a more guarded prognosis.
Historically the term 'inflammatory bowel disease' has been used to describe CE. However, most dogs with chronic GI signs will not need immunosuppressant treatment, so this term was misleading. For this reason, idiopathic inflammatory bowel disease (IBD) should only be used to describe CE 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 chronic enteropathy is poorly understood in small animals.
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. CE 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 CE (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 CE. 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.
Recent studies suggest that microbiome dysregulation and motility disorders may be associated with CE in small animals. However, further investigations are necessary to confirm these hypotheses.
There is no apparent age, sex, or breed predisposition associated with chronic enteropathy; IBD 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 years in dogs and 6.9 years in cats, but CE has been documented in dogs <2 years old. Dogs with food-responsive enteropathy are typically younger than dogs with immunusuppresant-responsive enteropathy and present with signs of large bowel disease. Dogs with antibiotic-responsive enteropathy are usually younger dogs of large breeds, and German Shepherds are over-represented. Granulomatous colitis has been reported in Boxers and French Bulldogs.
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 and CE 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 CE 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 CE and pancreatitis. Although unproved, it has been suggested that severe CE in cats may progress to lymphosarcoma.
Chronic enteropathies are diagnosed by excluding other causes of GI signs such as gastric foreign bodies or lymphoma. Diagnosis is often based on the history, clinical signs, and physical examination. Laboratory and imaging studies are normal in most cases. Food-responsive enteropathy and antibiotic-responsive are usually diagnosed based on response to a treatment trial. In poor responders endoscopic or surgical examination with biopsies are recommended to diagnose more specific enteropathies, followed by immunosuppressive treatment if necessary. Histology does not help to differentiate food-responsive enteropathy from antibiotic- or immunosuppressant-responsive enteropathy. For this reason, endoscopic or surgical biopsies are recommended when the patient does not respond to a diet change or antibiotic trial. If serum proteins are low or the patient is debilitated, diet change and antibiotic trials are skipped and further investigations are performed. Other exceptions include dogs with high suspicion of neoplasia or infection (eg, granulomatous colitis in Boxers).
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.
Cobalamin supplementation has been reported to be beneficial in hypocobalaminemic cats with CE. Although there is no evidence currently to support a benefit of cobalamin in dogs with CE, measurement of cobalamin in dogs with CE and supplementation of hypocobalaminemic dogs may be worthwhile.
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 CE 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 CE. 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 CEs, it has marked limitations. Specimen quality can vary, pathologic diagnoses are inconsistent, and differentiation between normal specimens and those showing CE and even lymphoma can be difficult. Biopsy must always be considered in relation to clinical signs, and the animal treated accordingly.
Clonality testing (PCR for antigen receptor rearrangement [PAAR]) is recommended in cases where lymphoma is suspected on histology. A positive PAAR suggests small-cell lymphoma.
Fluorescence in situ hybridization (FISH) is recommended to identify bacteria in formalin-fixed tissues in cases with granulomatous or neutrophilic inflammation. It is a more convenient and sensitive method than culture.
Capsule endoscopy has been used recently in small animals to detect GI bleeding. A capsule equipped with a camera is administered as a pill to the patient (more than 7 kg) and travels through the GI tract for approximately 15 hours, on average. This allows visualization of the GI mucosa throughout the GI tract. It can detect GI bleeding from the mouth to the rectum. However, examination may be incomplete because insufflation of the stomach can't be performed, and biopsies and examination may be incomplete if the capsule is retained in the stomach. This examination should not replace endoscopic examination. Its indication is limited to GI bleeding or lesions between the duodenum and the distal ileum.
Unless the animal is debilitated or serum proteins are low, sequential treatment trials are recommended. Dietary change followed by an antibiotic trial are recommended first. If not successful, further investigation including endoscopic examination and biopsies to confirm immune-mediated origin is followed by steroid therapy with or without cytotoxic drugs (eg, azathiaprine, cyclophosphamide, cyclosporine). Typically, patients with suspected protein-losing enteropathy are treated more aggressively because of their guarded prognosis. Endoscopic biopsies are followed by treatment with both dietary change and early immunosuppressive treatment.
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.
The canine IBD activity index (CIBDAI) and the canine CE clinical activity index (CCECAI) are scoring systems that have been validated to evaluate clinical response to treatment.
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 weeks, then a 3- to 4-week antibacterial trial (usually tylosin, 10 mg/kg, PO, three times daily, or metronidazole 10 mg/kg, PO, twice daily), and finally trial immunosuppressive therapy (initially prednisolone, 1 mg/kg, PO, twice daily). Ideally, the latter should be started based on histologic analysis of GI biopsies.
Dietary modification resolves clinical signs in more than 50% of cases of CE; 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.
Dietary modification generally involves feeding an 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). Novel antigen diets (new carbohydrate and protein source) or hydrolyzed diets (containing smaller proteins [peptides] to reduce antigenic reaction) have both been effective in dogs with CE. The specific diet should be the sole source of food for a minimum of 4–6 weeks; 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 a severe inflammatory cell infiltrate. Most dogs with food-responsive enteropathy respond within a few days to 2 weeks. Several studies have reported a good longterm response after diet change in dogs with CE (up to a 65% success rate over 3 years). Cooperation of the owner is essential in the treatment of dogs with CE. Some dogs (31%–75%) can be fed their initial diet after 3 months of the diet trial.
Dietary trials are usually not started alone in dogs with protein-losing enteropathy, so limited data are available on their effects in these cases. Success was reported with an ultra-low-fat diet in dogs with primary lymphangiectasia in one study. However, steroids are usually necessary because of intestinal inflammation secondary to lymph leakage, and they are usually used concurrently to control clinical signs. Another study reported success with dietary change alone in management of Yorkshire Terriers with protein-losing enteropathy.
If dietary change is not efficient at improving clinical signs, antibiotic treatment is recommended. Oxytetracycline, metronidazole, and tylosin are generally used. Their effects are incompletely understood but could include modification of the gut flora and modulation of the immune system.
Sulfasalazine (and related drugs) are often used in dogs when the large intestine is affected. 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, three times daily) and mesalamine (dogs: 10 mg/kg, PO, three times daily).
The use of antibiotics can be justified in part by the potential to treat any undiagnosed enteropathogens. Oxytetracycline (10 mg/kg, PO, three times daily), metronidazole (10 mg/kg, PO, twice daily), tylosin (5 mg/kg, PO, once daily, or up to 20 mg/kg three times daily) or enrofloxacin (10–15 mg/kg, once daily) can be used to treat CE in dogs. It may have immunomodulatory effects. Tylosin was reported to resolve diarrhea within days in a double-blinded prospective clinical trial. Histiocytic ulcerative colitis of Boxers is responsive to enrofloxacin, which supports the hypothesis that this particular form of antibiotic-responsive enteropathy is the consequence of an infection with a specific organism (E coli). Dogs on enrofloxacin should be reassessed every 2 weeks. Usually, a total of 8 weeks treatment is sufficient. Relapses are frequent, but restarting antibiotic is usually successful. Prevention with probiotics and steroids have not been successful. There are no reports on the use of antibiotics alone to treat protein-losing enteropathy in small animals. In Yorkshire Terriers with protein-losing enteropathy and crypt abscesses, FISH did not detect any bacteria.
Antibiotic treatment is recommended while waiting for the FISH results if biopsies reveal granulomatous or neutrophilic inflammation.
If an antibiotic trial has not been successful within 2 weeks, reassessment of the patient is suggested, and immunosuppressants may be indicated.
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. One study showed a >80% response rate of dogs with CE (after exclusion of FRE and ARE) treated with prednisolone for 21 days. The response rate was similar to the group treated with budesonide.
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 weeks). 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 weeks.
Studies evaluating efficacy of cyclosporine on CE in dogs showed conflicting results (reported success 25% vs 79%) and included only a few patients. The response to cyclosporine is usually short-lived in dogs with CE, but cyclosporine may play a role as a rescue treatment. However, one recent study suggested that the combination of chlorambucil-prednisolone was more efficient to treat CE with concurrent protein-losing enteropathy in dogs than the azathioprine-prednisolone protocol. Cyclosporine has also been reported to be successful in treating PLE in dogs.
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 weeks, although 4–8 weeks of treatment may be needed. A CBC should be done every 2 weeks 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 weeks and then every 28 days for a further 3 months) in dogs and cats, and other supportive therapy as needed.
The response rate to treatment of CE is variable. Negative prognostic factors for dogs with CE include: marked endoscopic changes in the duodenum, hypocobalaminemia, hypoalbuminemia, hypovitaminosis D, and a high CIBDAI score. Relapses occur and are most often precipitated by dietary indiscretion. A poor outcome has been reported for dogs with protein-losing enteropathy, with a median survival time of less than 6 months, except for Yorkshire Terriers (median survival time of 44 months). Dogs with protein-losing enteropathy with large cell lymphoma have the worst prognosis (median survival time of less than 100 days).
In most studies, 15% to 40% of dogs do not respond to all therapies described above in the short term. In addition, longterm treatment seems to be adequate only for dogs with food-responsive enteropathy. In nonresponders, the diagnosis should be reconsidered first. Motility disorders are underestimated in small animals. It is possible that some CE in small animals might be associated with motility disorders rather than infection or inflammation. Manipulation of the GI microbiome seems to be promising, but insufficient data is available about probiotic treatment to recommend its use at this stage. Fecal transplantation has been reported to be successful to treat refractory Clostridium difficile in people and seems promising in treating GI diseases in small animals.
CE is subdivided into 4 categories based on response to medical treatment (food-responsive, antibiotic-responsive, immunosuppressant-responsive, nonresponsive).
Most small animals with CE respond to dietary modification.
Sequential treatment using dietary modification, antibiotic trials, and steroid therapy is recommended. For debilitated or hypoproteinemic patients, a more aggressive approach is advised.