Managing chronic enteropathies in dogs (Sponsored by Nestle Purina)

Managing chronic enteropathies in dogs

Dogs with intestinal disease typically present with clinical signs such as diarrhea, weight loss, or vomiting. Diarrhea that has lasted three weeks or more is usually considered chronic. The initial diagnostic approach to chronic diarrhea is based on determining the nature and severity of the diarrhea and the presence of specific or localizing clinical findings. The presence of additional clinical signs often points to the underlying cause (see Table 1). This information is integrated to determine whether diarrhea is most likely due to large bowel disease (dyschezia, tenesmus, increased frequency of defecation, small volume of feces with mucus and blood) or a consequence of small intestinal disease or exocrine pancreatic insufficiency (large volume of diarrhea, weight loss, possible vomiting). In patients with abdominal pain, dehydration, frequent vomiting, or localizing findings such as an abdominal mass, these problems are pursued ahead of an in-depth workup for chronic diarrhea. In patients with chronic diarrhea and no obvious cause, it is best to adopt a systematic approach, determined by the localization of diarrhea to the small or large bowel. Patients with signs of large or small bowel involvement are usually evaluated for diffuse GI disease. This presentation will review the diagnosis and management of dogs with chronic enteropathies that are predominantly associated with small bowel diarrhea.

Table 1. Potential underlying causes of chronic diarrhea and commonly associated clinical signs

Investigation of chronic small bowel diarrhea

The initial diagnostic approach to patients with chronic small bowel diarrhea is summarized in Table 2.

Table 2. Initial diagnostic approach to chronic small bowel diarrhea

After the exclusion of infectious and parasitic agents, non-GI disorders, exocrine pancreatic insufficiency, and intestinal structural abnormalities requiring surgery, the most common group of intestinal conditions associated with chronic small bowel diarrhea are idiopathic inflammatory bowel disease (IBD), diet-responsive enteropathy, antibiotic-responsive enteropathy, and lymphangiectasia.

The diagnostic approach to this group of patients is usually determined by the severity of clinical signs and the presence or absence of hypoalbuminemia, intestinal thickening, or mesenteric lymphadenopathy. In patients with any of these abnormalities, intestinal biopsy is required to define the cause (e.g., IBD, lymphangiectasia, lymphoma) and to optimize therapy. Controlled studies have shown that hypoalbuminemia is associated with a poor outcome in dogs with chronic enteropathy.1 , 2 Evaluation of hemostatic function is recommended to determine if hypo- or hyper-coagulability have arisen as a consequence of enteric protein loss.

The clinical severity of intestinal disease can be quantified by determining the canine IBD activity index (CIBDAI) through evaluation of attitude, activity, appetite, vomiting, stool consistency, stool frequency, and weight loss.3 Measurement of serum C-reactive protein (CRP) has been shown to correlate with CIBDAI and implies that severe clinical disease is accompanied by a systemic inflammatory response.3 Measurement of CIBDAI or CRP can also serve as a baseline for determining the response to treatment.

In stable patients with chronic diarrhea (i.e., good attitude, appetite, mild weight loss, normal serum proteins, and no intestinal thickening or lymphadenopathy), measurement of serum cobalamin and folate help evaluate disease severity, aid in localization of intestinal disease, and determine if supplementation is required. Low-serum cobalamin concentration (< 200ng/L) has also been associated with a negative prognosis.2 Intestinal biopsy is indicated in dogs with low serum cobalamin concentrations to determine the nature of the intestinal disease. In stable patients with chronic diarrhea and normal serum cobalamin concentrations, the client can be given the option of empirical treatment (see below). Failure to respond to empirical therapy or worsening of disease is an indication for intestinal biopsy.

Intestinal biopsy

Intestinal biopsies can be acquired endoscopically or surgically. In patients without an indication for surgery (e.g., intestinal masses, anatomic or structural disease, or perforation), the authors prefer to perform diagnostic endoscopy to visually inspect the esophageal, gastric, and intestinal mucosa, and to procure endoscopic biopsies. Guidelines for biopsy acquisition have recently been published.4 Operator experience and biopsy quality and number are key in enabling effective histopathologic evaluation. Surgical biopsy is usually performed where intestinal disease is suspected to involve the submucosa or muscularis, and where the results of endoscopic biopsies do not adequately explain the clinical picture.

Unfortunately, the histopathologic interpretation of GI biopsies varies considerably among pathologists.5 To try to correct this problem, a working group established by the World Small Animal Veterinary Association has created a series of images to standardize the evaluation of intestinal histopathology.6 The ability of this scheme to increase agreement between pathologists, and the clinical relevance of the criteria it evaluates, remain to be determined, but it is a step in the right direction.

The most common histopathologic diagnoses in dogs with chronic diarrhea are IBD, lymphangiectasia, and lymphoma. The most commonly described histopathologic lesion in the intestines of dogs is increased cellularity of the lamina propria that is usually referred to as being consistent with IBD. The extent of inflammation is variable and ranges from focal to diffuse involvement of the small and large intestine. The degree of inflammatory cell accumulation is also variable and is subjectively categorized as normal, mild, moderate, or severe.

Increased numbers of lymphocytes and plasma cells, described as lymphoplasmacytic enteritis, is the most frequently reported form of IBD. Moderate to severe lymphoplasmacytic enteritis is often described in association with a protein-losing enteropathy. Predisposed breeds include basenji, Norwegian lundehund, and Chinese Shar-Pei. However, recent studies have called into question the appropriateness and clinical relevance of the term "lymphoplasmacytic" enteritis. Dogs have similar numbers of CD3+ T lymphocytes before and after clinical remission,7 and cats with and without signs of intestinal disease have similar numbers of lymphocytes and plasma cells.8

The presence of moderate to large numbers of eosinophils in intestinal biopsies, which is often accompanied by circulating eosinophilia, suggests possible parasitic infestation or dietary intolerance. Moderate to high numbers of macrophages and neutrophils raise the possibility of an infectious process, and culture and special stains are indicated.

Changes in mucosal architecture, such as villus atrophy and fusion, are less frequently commented on than cellularity, but appear to be important indicators of disease severity. A recent study in cats with signs of GI disease measured mucosal cytokines levels to identify histologic correlates of mucosal inflammation. In this study, villus atrophy and fusion correlated with severity of clinical signs and degree of pro-inflammatory cytokine up-regulation in the duodenal mucosa.9

Dilatation of lymphatics and the presence of crypt abscesses and crypts cysts are most commonly encountered in dogs with protein-losing enteropathies, and often are accompanied by lymphoplasmacytic inflammation of varying severity.5 , 10

Treatment

The clinical severity of disease, the nature and severity of histopathologic lesions, and the presence or absence of hypoalbuminemia guides treatment. For dogs with low clinical disease activity, normal intestinal histopathology, and serum albumin concentrations >2.0g/dl, the following empirical treatment protocol can be followed.

Table 3: Options for dietary trials

1. Empirical treatment for Giardia and endoparasites if not already performed (e.g., fenbendazole 50mg/kg by mouth for five days).

2. Dietary trial (see Table 3). A positive response suggests diet-responsive enteropathy. If a good response, continue diet, consider re-challenge, and defining basis of dietary intolerance.

3. Antibiotic trial: tylosin (1 0 to 15mg/kg by mouth three times daily), oxytetracycline (20mg/kg by mouth three times daily),

or metronidazole (10mg/kg by mouth twice daily). A positive response suggests antibiotic-responsive enteropathy, maintain on antibiotics for 28 days then discontinue. If a good response, consider transition to probiotics.

4. For poor response, reappraise, then consider other treatments.

Inflammatory bowel disease

Treatment of any disease is ideally directed at the underlying cause, which is problematic for IBD as the etiopathogenesis is unclear.

IBD in people and animals is increasingly considered a consequence of uncontrolled intestinal inflammation in response to a combination of elusive environmental, enteric luminal constituents (principally microbial and dietary), and immunoregulatory factors in genetically susceptible individuals.

In people, genetic susceptibility is linked increasingly to defects in innate immunity exemplified by mutations in the innate immune receptor NOD2/CARD15, which in the presence of the enteric microflora may lead to upregulated mucosal cytokine production, delayed bacterial clearance, and increased bacterial translocation, thereby promoting and perpetuating intestinal inflammation.11 While the mucosa-associated flora is implicated frequently as a pivotal factor in the development of IBD in people and animals, the specific bacterial characteristics that drive the inflammatory response have remained elusive. The clinical responses of some dogs with idiopathic chronic diarrhea to antibiotics such as tylosin or oxytetracycline, and the predisposition of certain breeds, (e.g., German shepherd), points to a similar interaction of host susceptibility and microflora in dogs.12 " As the numbers of cultivable aerobic and anaerobic bacteria in the duodenal fluid of dogs that respond to antibiotics is similar to dogs that respond to food or immunosuppression, it is plausible that dogs with antibiotic responsive enteropathy are more susceptible to their resident microflora, but this remains to be determined.14, 15

Recent advances in molecular microbiology have enabled the analysis of complex bacterial communities without bacterial culture. Culture-independent analyses of bacterial 1 6S rDNA libraries in people reveal that only 30 percent of the fecal flora appears cultivable, and there is significant variation in the flora in different gastrointestinal segments and luminal contents versus the mucosa of healthy individuals.16 The application of these culture-independent techniques to people, dogs, and cats has revealed that intestinal inflammation is associated with a floral shift from gram-positive Firmicutes to gram-negative bacteria, predominantly Enterobacteriaceae.9, 17, 18 It is noteworthy that increased numbers of Enteobacteriaceae have been found to correlate with mucosal inflammation and clinical signs in cats with signs of GI disease,9 and a novel group of adherent and invasive Esherichia coli (AIEC) have been associated with intestinal inflammation in people and boxer dogs with granulomatous or histiocytic ulcerative colitis.17 , 19 While it remains to be determined if these floral alterations are a cause or a consequence of the inflammation, their discovery has provided new opportunities for therapeutic intervention.

There is also growing evidence to support an important role diet plays in the development of canine IBD. In a controlled study of 65 dogs with diarrhea of at least six weeks duration, 39 of 65 dogs responded to dietary modification (10 days of Purina Veterinary Diets LA Limited Antigen [now known as DRM Dermatologic Management®]), and the remaining dogs were treated with corticosteroids (2mg/kg orally once daily for 1 0 days followed by a tapering dose over 1 0 weeks).20 The CIBDAI and histopathologic scores were similar (> 70 percent moderate to severe in each group) in dogs that did and did not respond to diet. Dogs that responded to diet tended to be younger and have higher serum albumin than dogs that did not respond to diet. Dogs that did not respond to diet were subsequently treated with steroids. Interestingly, intestinal histopathology results did not differ in either diet-responsive or steroid-responsive dogs before and after treatment.

Taken as a whole, the results of studies in dogs with chronic diarrhea have, to date, provided reasonable evidence that various subsets of dogs will respond to treatment with specific antibiotics, diet modification, or immunosuppressive therapy. At present there is no reliable means for predicting which dogs will respond to which treatment, and treatment consists of a series of therapeutic trials.

Standardized treatment protocol for canine IBD

The authors are prospectively evaluating a standardized treatment protocol for dogs with IBD:

• Mild to moderate disease activity, mild to moderate histopathologic abnormalities (lymphocytes and plasma cells are the predominant cell type), serum albumin > 2.0g/dl:

1. Empirical treatment for Giardia and helminths, if not already performed.

2. Dietary trial with a hydrolyzed soy diet for two weeks. If a good response then maintain on diet, consider re-challenge, and defining basis of dietary intolerance.

3. Antibiotic trial with tylosin for two weeks. If a good response, maintain on antibiotics for 28 total days then discontinue. Consider transition to probiotics.

4. Immunosuppression with glucocorticoids or azathioprine.

• For dogs < 70lbs: 2mg/kg prednisolone orally once daily for 21 days, 1.5mg/kg orally once daily for 21 days, 1 mg/kg orally once daily for 21 days.

• For dogs > 70lbs: 2mg/kg azathioprine orally once daily for five days, then 2mg/kg orally once daily every other day.

5. If poor response, reappraise before considering escalating immunosuppression (e.g., adding azathioprine, or substituting with cyclosporine21 if already on azathioprine).

6. If good response taper immunosuppression, then stop antibiotics.

• Moderate disease activity, moderate to severe intestinal histopathologic abnormalities (villus atrophy and fusion, lymphocytes and plasma cells are the predominant cell type), serum albumin < 2.0g/dl:

1. Empirical treatment for Giardia and helminths if not already performed.

2. Concurrent dietary modification to a hydrolyzed soy diet, antibiotics (tylosin), and immunosuppression (glucocorticoids or azathioprine).

• The use of elemental (monomeric) diets and partial parenteral nutrition may be required in some dogs with severe protein-losing enteropathy.

• Concurrent therapy with ultra low dose aspirin (0.5mg/kg orally once daily) may be indicated in patients considered at risk for thromboembolic disease.

• Concurrent judicious use of diuretics (furosemide 0.5 mg/kg once or twice daily for 2 to 3 days, and spironolactone 0.5-1.0 mg/kg by mouth twice daily) is often recommended in patients with significant ascites. Monitor for hypokalemia and metabolic alkalosis.

3. Reappraise if poor response before considering escalating immunosuppression.

• Consider failure to absorb oral prednisolone and switch to injectable corticosteroids.

• Dexamethasone may be preferable to prednisolone in patients with ascites to avoid increased fluid retention.

4. If good response taper immunosuppression, then stop antibiotics. The authors are evaluating this approach in an ongoing prospective clinical trial: To date, in 16 dogs with a histopathologic diagnosis of IBD, 1 0 dogs were diet-responsive, three steroid-responsive, and three were partially responsive to a combination of food and antibiotics.

Lymphangiectasia

Intestinal lymphangiectasia is characterized by the abnormal distension of lymphatic vessels within the mucosa. Intestinal lymphangiectasia is a consequence of a localized or generalized lymphatic abnormality or increased portal pressure (e.g., right-sided heart failure, caval obstruction, or hepatic disease). Lymphatic abnormalities are often associated with lipogranulomatous inflammation that is visible as small white granules on the intestinal mesentery. Tumor infiltration of lymphatics or lymph nodes can also cause lymphangiectasia. In some cases, lymphangiogra-phy reveals a generalized lymphatic abnormality. Dilatation of lymphatics is associated with the exudation of protein rich lymph into the intestine and severe malabsorption of long chain fats. Crypt cysts and crypt abscesses may also be observed in intestinal biopsies. Yorkshire terriers (10-fold relative risk), soft coated wheaten terriers (frequently with concurrent proteinuria), and Norwegian lundehund seem to be over represented, supporting a familial cause in some dogs.5 , 10 ,22

Clinical findings: The clinical findings are essentially a consequence of the intestinal loss of protein and can include weight loss, chronic diarrhea, ascites, edema, and chylothorax.

Diagnosis: Lymphangiectasia usually presents with clinical signs of a protein-losing enteropathy. It appears endoscopically as white blebs on the mucosa (dilated lymphatics). Endoscopic biopsies are often adequate. Surgical biopsy should be undertaken carefully with appropriate precautionary measures to avoid dehiscence.

Treatment: The underlying cause of lymphangiectasia is not usually determined. Treatment is supportive and symptomatic.

1. Dietary recommendations are similar to those for the other causes of chronic small bowel diarrhea listed, but fat restriction may have to be more severe.

• Medium chain triglyceride (e.g., coconut oil 0.5 to 2ml/kg body weight per day added to food) can be added to the diet, or a diet already containing them (e.g., Purina Veterinary Diets EN Gastroenteric® canine formula) can be fed to provide an easily assimilable source of calories.

2. Treatment with prednisolone is often necessary (1 to 2mg/kg by mouth twice daily) and may work by decreasing lipogranulomatous inflammation or concurrent mucosal inflammation. The authors try to avoid high-dose, long-term immunosuppression with corticosteriods due to risk of sepsis in these patients. Prednisolone is tapered to the lowest effective dose once remission is achieved.

• In patients with severe mal-absorption, parenteral glucocorticoids may be required, and a switch to dexamethasone may be made in patients with ascites or edema.

3. Escalation of immunosuppression may be tried if unresponsive.

4. Adjunctive therapy with metronidazole or tylosin is often employed to decrease the risk of bacterial translocation through the markedly impaired gut.

5. Ultra low-dose aspirin and diuretic therapies are employed as in treatment of IBD with albumin < 2.0g/dl).

Prognosis: The response to therapy is variable, with some dogs staying in remission for several years while others pursue a path towards fulminant hypoproteinemia or thromboembolic disease. The prognosis is always guarded.

Acknowledgements:

We gratefully acknowledge the support of the Morris Animal Foundation and Nestlé-Purina for studies of inflammatory bowel disease in dogs.

Disclosure:

K. Simpson is a member of the Nestle Purina Advisory Council.

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