Inflammatory bowel disease in dogs and cats

IBD refers to a spectrum of chronic gastrointestinal diseases associated with idiopathic inflammation in the stomach, small intestine or large intestine. It is a common clinical problem in small animal practice.

The most useful way to define IBD is

1. Chronic or intermittent gastrointestinal signs (> 3weeks)
2. Evidence of mucosal inflammation on gastrointestinal biopsies
3. Absence of other causes of gastrointestinal inflammation
4. Inadequate response to antiparasitic, dietary, and antibiotic treatments alone
5. Clinical response to immunosuppressive treatment

The term IBD is useful because owners can understand it easily but it is probably often overused. “Chronic enteropathy” is a better term for many animals with chronic vomiting and diarrhoea.

As can be seen from the way IBD is defined, it is not simply diagnosed based on gastrointestinal biopsies. Exclusion of other causes and response to treatment are also needed for diagnosis. “IBD” can be thought of as one form of chronic enteropathy that is distinguished from food-responsive enteropathy and antibiotic-responsive enteropathy by its responsiveness to anti-inflammatory drugs.

PATHOGENESIS

The cause is unknown. IBD is thought to be the result of an inappropriate immune response to antigens within the lumen of the GI tract. This is thought to result from disturbances in one (or a combination) of the mucosal barrier, the mucosal immune system, or the microbes in the lumen.

PRESENTATION

Clinical signs in IBD are not specific. They can include any combination of vomiting, small or large bowel diarrhoea, weight loss, excessive borborygmi, flatulence, abdominal pain or discomfort, increased or reduced appetite, and signs of hypoproteinaemia such as ascites or subcutaneous oedema. Vomiting seems to be more common in cats and diarrhoea more common in dogs. Signs sometimes wax and wane.

The diagnosis is most commonly made in middle-aged animals. IBD is rare in young animals; adverse reactions to food and antibiotic-responsive diarrhoea are much more common causes of gastrointestinal signs in animals less than 2 years of age.

There is no apparent gender association. Breed predispositions are recognised in Basenjis, German Shepherds, Soft-Coated Wheaten Terriers, Shar-peis, and Siamese cats, but any breed can be affected.

DIFFERENTIAL DIAGNOSIS

• Non gastrointestinal disease
  • Exocrine pancreatic insufficiency
  • Pancreatitis
  • Liver disease
  • Kidney disease
  • Hypoadrenocorticism
  • Congestive heart failure
• Infectious causes
  • Campylobacter spp. (often found in healthy dogs)
  • Salmonella spp.
  • Clostridium perfringens(often found in healthy dogs)
  • Clostridium difficile(often found in healthy dogs)
  • E. coli(often found in healthy dogs)
  • Parasites: Roundworms, Hookworms, Whipworms, Isospora spp., Cryptosporidium spp., Giardia spp.
• Adverse reaction to food/dietary intolerance/ food-responsive enteropathy
• Antibiotic-responsive diarrhoea/ antibiotic-responsive enteropathy
• Breed specific enteropathy
  • Basenji enteropathy
  • Familial protein-losing enteropathy of Soft Coated Wheaten Terriers
  • Gluten sensitive enteropathy in Irish setters
• Granulomatous colitis of boxers, French bulldogs and related dogs
• Lymphangiectasia
• Neoplasia (Lymphoma, adenocarcinoma, others)
• Irritable bowel syndrome (chronic idiopathic large bowel diarrhoea)
• Partial obstruction
  • Foreign body
  • Intussusception

DIAGNOSTIC APPROACH

By definition, IBD is chronic and not self-limiting and so investigation is required.

History and physical examination

History is important, for finding out about toxin or foreign body ingestion, worming status, travel history, poor quality diet or scavenging, the presence of signs in in-contact animals, the presence of systemic signs, or things that indicate severity, such as weight loss. Physical examination could reveal poor body condition or abnormalities consistent with some important differentials for chronic GI signs such as hypoadrenocorticism, hyperthyroidism, or lymphoma. In protein-losing enteropathy with severe hypoalbuminaemia there could be ascites or peripheral oedema. Abdominal palpation can reveal organomegaly, masses, foreign bodies, intussusception, thickened or distended loops of intestine, ascites, or areas of pain.

Initial investigation

Firstly, in a dog or cat with chronic GI signs, systemic disease, parasitism, and exocrine pancreatic insufficiency (EPI) must be excluded. The following tests are useful:

• Haematology may reveal anaemia of inflammatory disease, or anaemia caused by GI blood loss. Neutrophilia could be present, reflecting inflammation. Eosinophilia may be seen in hypoadrenocorticism or in parasitism (and sometimes in IBD with eosinophilic intestinal inflammation). Lymphopenia may be seen in protein-losing enteropathy (PLE).
• Biochemistry (including electrolytes) and ideally urinalysis should be performed. This helps to rule out hepatic and renal disease. Intestinal disease can cause a “reactive hepatopathy”, with elevated liver enzymes but normal liver function. Biochemistry may indicate protein-losing enteropathy (PLE). In PLE, serum albumin and globulin are usually both reduced (globulins may be high in basenji enteropathy). There may also be low serum cholesterol, calcium and magnesium in PLE. Liver function testing (bile acids) and urine protein: creatinine ratio should be performed to exclude other causes of hypoalbuminaemia. Faecal alpha-1 protease inhibitor assay may be a useful marker for PLE and may be more sensitive than serum albumin, especially early in the disease process.
• Serum T4 measurement should be considered in cats.
• FeLV and FIV testing should also be considered in cats.
• Basal cortisol assay or ACTH stimulation test should be performed to exclude hypoadrenocorticism.
• Serum trypsin-like immunoreactivity (TLI) assay is very important, to exclude exocrine pancreatic insufficiency, an important differential that requires specific management. Serum TLI should be measured in all cases: a normal result excludes EPI with a high degree of confidence.
• Faecal culture and examination for parasites is usually performed. Ideally test a pooled sample of 3 faeces samples collected over a 5-day period. A Giardia antigen test could be performed. Even if no parasites are detected, it is sensible to give a 3-5 day course of fenbendazole to exclude parasites including Giardia (Giardia in particular may only shed intermittently, with no pattern).
• In cats, faecal examination for Tritrichomonas foetus (PCR is most sensitive) should be performed.
• Serum folate and cobalamin assays may give evidence of malabsorption, and may help localise the disease to proximal or distal small intestine, helping to guide subsequent biopsy collection (folate is absorbed in the proximal small intestine and cobalamin is absorbed in the distal small intestine). It is important to supplement cobalamin if it is low, and some evidence suggests that response to treatment for intestinal disease may be inadequate until cobalamin deficiency is corrected. Low serum cobalamin may also be prognostic in canine IBD. Folate and cobalamin assays are not useful in the diagnosis of small intestinal bacterial overgrowth or antibiotic response diarrhoea (results do not correlate with antibiotic responsiveness).

Further investigation

At this stage of the work-up, further investigations could involve imaging (radiography, ultrasound) and GI biopsy. This may not be appropriate for every case. In many cases of chronic enteropathy, the signs are mild, the animal is stable and not unwell, does not have PLE or low cobalamin, and has no abnormalities on initial work up or abdominal palpation. In this situation, biopsy may not be very useful and may not alter management, so therapeutic trials may be performed. IBD cannot be diagnosed on biopsy alone and well-designed therapeutic trials are an important part of the diagnosis (see definition of IBD above).

Therapeutic trials

These trials should be performed in this order:

1. Antiparasitic trial: even if no infectious agent is found on faecal analysis, a course of fendendazole (50 mg/kg once daily for 5 days) should be prescribed, in case the dog or cat has occult parasitism including Giardia infection.
2. Dietary trial. Diet must be antigen limited and highly digestible, and moderately fat-restricted. There are several suitable diets (e.g. hydrolysed protein diet, proprietary single source protein diet, home-cooked single source protein diet). Sometimes more than one may be need to be tried. A hydrolysed protein diet is often a suitable choice.  As well as being “hypoallergenic”, these diets are highly digestible. The diet should be changed over a few days, and then fed exclusively. A beneficial response should be seen within 2 weeks. Laboratory testing for dietary sensitivity is not recommended
3. Antibiotic trial. One of tylosin, oxytetracycline, or metronidazole is prescribed and given for 2 weeks in combination with the diet already prescribed.

As well as being therapeutic, if properly performed these trials help to categorise the disease as being “food-responsive” or “antibiotic-responsive”.

Imaging

Radiography does not often add much diagnostic information in chronic enteropathy but it helps identify surgical diseases such as intussusception and foreign body. Ultrasonography is more useful in investigating chronic enteropathy and can give information about all abdominal organs. It is useful for identifying obstruction, intussusception (Fig. 1), focal lesions (guiding subsequent fine needle aspiration or biopsy), loss of the normal 5-layered appearance, thickening of intestinal walls, and effusion. Knowing whether focal or diffuse disease is present helps choose the most suitable method of biopsy (endoscopic or surgical).

Biopsy

Biopsies can be collected via endoscopy or coeliotomy (or laparoscopy if available). Endoscopy is had advantages as it is minimally invasive, allows inspection of the mucosa, allows the identification of some abnormalities such as ulceration and lymphangiectasia, allows collection of multiple biopsies, with targeted biopsy of affected areas, and allows steroid treatment to be started early if desired. In some studies, endoscopic appearance correlated with outcome better than the results of histopathology (Figs 2 and 3). However, endoscopy cannot get access to lesions that are out of reach of the scope or in the deeper layers (e.g., some cases of lymphoma or lymphangiectasia), and it is easy to obtain poor quality samples that are mostly just tips of villi. Multiple (at least 6) biopsies should be taken from each area. Good quality samples improve the diagnostic sensitivity of endoscopic biopsy. If possible, the ileum should be biopsied, as there is some evidence that ileal biopsies are more likely to be diagnostic than duodenal biopsies. Standardised endoscopic reporting forms should be used such as the ones endorsed by the Comparative Gastroenterology society available at the WSAVA website. 

Surgical biopsies are better if disease involving the deeper layers of the intestine is suspected following ultrasound. Exploratory surgery allows the collection of large, full thickness biopsies from the whole GI tract, but does not allow inspection of the mucosa, so patchy lesions could be missed. It is more invasive and there may be a risk of wound dehiscence and peritonitis, particularly in hypoproteinaemic patients. The ability to biopsy other abdominal organs (liver, pancreas) may be valuable in cats, because intestinal disease is often concurrent with liver or pancreatic disease in cats.   

Limitations of intestinal biopsies
It is very important to have a realistic expectation of what can be achieved by intestinal biopsy. Biopsy is important in the diagnosis of neoplasia and disorders with characteristic histopathology (such as granulomatous colitis), and is useful for documenting inflammation s part of a diagnosis if IBD. But, there are major limitations including:

• Sample quality can vary
• Interpretation is difficult: in one important study, poor agreement between pathologists was shown and the same slide could be interpreted differently by different pathologists. For example, some intestinal samples from normal, healthy dogs were even wrongly given a diagnosis of lymphoma
• It is impossible to correlate histological appearance to clinical severity
• What treatment the patient will respond to cannot be determined from the results of biopsy
• Food-responsive diarrhoea, antibiotic-responsive diarrhoea, and IBD may look the same on biopsy
• Several causes of chronic diarrhoea could be normal on biopsy (e.g. antibiotic-responsive diarrhoea, adverse reaction to food, and several others)
• There is much overlap between the different types of inflammation recognised in IBD (lymphocytic/plasmacytic, eosinophilic, neutrophilic)
• Differentiating severe lymphocytic inflammation from small cell lymphoma is very difficult and may be impossible

Pathologists should ideally report on the quality of biopsies and evaluate them according to a standardised classification system, for example the one proposed by the WSAVA GI standardization group.

Clinical Activity Index

These can be used to quantify the severity of IBD, to help assess response to treatment, and to allow comparison between published studies. Canine and feline IBD activity indices are published (CIBDAI, FIBDAI). A Canine Chronic Enteropathy Clinical Activity Index has been proposed (CCECAI); this includes serum albumin, ascites and pruritus as factors.

MANAGEMENT OF IBD

Where lymphocytic/plasmacytic or eosinophilic inflammation is documented
If clinical signs persist following proper antiparasitic, dietary and antibiotic trials, an immunosuppressive trial is started using prednisolone (dogs, 1-2 mg/kg/day, cats, 2-4 mg/kg/day). If prednisolone alone is unsuccessful or if steroid side effects are a problem, another drug can be added.

Some dogs that are refractory to prednisolone may respond to ciclosporin at 5 mg/kg/day.

Chlorambucil can be used in dogs and cats at 2-6 mg/m_² once daily, tapering the dose to a maintenance dose of 2-3 mg/m_² every other day. Haematology should be monitored.

Azathioprine can be used in dogs only (1-2 mg/kg daily for one week followed by 1-2 mg/kg every other day). Onset of activity may take 10 days, often longer, and haematology should be monitored. 

A prospective trial showed that prednisone and metronidazole gave no benefit over prednisone alone in IBD in dogs.

Where neutrophilic or granulomatous inflammation is documented
Fluorescence in-situ hybridisation (FISH) analysis is recommended, using a probe directed against eubacterial DNA, in an attempt to identify invasive bacteria such as E. coli as a cause of the inflammation. Immunosuppression should not be done until infectious agents have been excluded.

PROGNOSIS

Usually considered good, but not all dogs respond well to immunosuppression. Negative prognostic indicators include more severe disease (based on clinical activity index or endoscopic score), low serum cobalamin, and low serum albumin. The prognosis for cats appears better than for dogs although there are some that do not respond to treatment.

Suggested readings

1. Allenspach, K., S. Rufenacht, S. Sauter, A. Grone, J. Steffan, G. Strehlau, and F. Gaschen. "Pharmacokinetics and Clinical Efficacy of Cyclosporine Treatment of Dogs with Steroid-Refractory Inflammatory Bowel Disease." [In eng]. J Vet Intern Med 20, no. 2 (Mar-Apr 2006): 239-44.
2. Allenspach, K., B. Wieland, A. Grone, and F. Gaschen. "Chronic Enteropathies in Dogs: Evaluation of Risk Factors for Negative Outcome." Journal of Veterinary Internal Medicine 21, no. 4 (2007): 700-08.
3. Casamian-Sorrosal, D., M. D. Willard, J. K. Murray, E. J. Hall, S. S. Taylor, and M. J. Day. "Comparison of Histopathologic Findings in Biopsies from the Duodenum and Ileum of Dogs with Enteropathy." [In eng]. J Vet Intern Med 24, no. 1 (Jan-Feb 2010): 80-3.
4. Day, M. J., T. Bilzer, J. Mansell, B. Wilcock, E. J. Hall, A. Jergens, T. Minami, 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." [In eng]. J Comp Pathol 138 Suppl 1 (Feb-Apr 2008): S1-43.
5. Garcia-Sancho, M., F. Rodriguez-Franco, A. Sainz, C. Mancho, and A. Rodriguez. "Evaluation of Clinical, Macroscopic, and Histopathologic Response to Treatment in Nonhypoproteinemic Dogs with Lymphocytic-Plasmacytic Enteritis." [In eng]. J Vet Intern Med 21, no. 1 (Jan-Feb 2007): 11-7.
6. Hall, E. J., and A. J. German. "Diseases of the Small Intestine." In Textbook of Veterinary Internal Medicine, edited by S. J. Ettinger and E. C. Feldman. 1526-72. St Louis: Saunders, 2010. Reprint, NOT IN FILE.
7. Jergens, A. E., J. M. Crandell, R. Evans, M. Ackermann, K. G. Miles, and C. Wang. "A Clinical Index for Disease Activity in Cats with Chronic Enteropathy." Journal of Veterinary Internal Medicine 24, no. 5 (2010): 1027-33.
8. Jergens, A. E., J. Crandell, J. A. Morrison, K. Deitz, M. Pressel, M. Ackermann, J. S. Suchodolski, J. M. Steiner, and R. Evans. "Comparison of Oral Prednisone and Prednisone Combined with Metronidazole for Induction Therapy of Canine Inflammatory Bowel Disease: A Randomized-Controlled Trial." [In eng]. J Vet Intern Med 24, no. 2 (Mar-Apr 2010): 269-77.
9. Jergens, A. E., C. A. Schreiner, D. E. Frank, Y. Niyo, F. E. Ahrens, P. D. Eckersall, T. J. Benson, and R. Evans. "A Scoring Index for Disease Activity in Canine Inflammatory Bowel Disease." [In eng]. J Vet Intern Med 17, no. 3 (May-Jun 2003): 291-7.
10. Washabau, R. J., M. J. Day, M. D. Willard, E. J. Hall, A. E. Jergens, J. Mansell, T. Minami, and T. W. Bilzer. "Endoscopic, Biopsy, and Histopathologic Guidelines for the Evaluation of Gastrointestinal Inflammation in Companion Animals." J Vet Intern.Med. 24, no. 1 (2010): 10-26.
11. Willard, M. D., A. E. Jergens, R. B. Duncan, M. S. Leib, M. D. McCracken, R. C. DeNovo, R. G. Helman, M. R. Slater, and J. L. Harbison. "Interobserver Variation among Histopathologic Evaluations of Intestinal Tissues from Dogs and Cats." [In eng]. J Am Vet Med Assoc 220, no. 8 (Apr 15 2002): 1177-82.
12. Willard, M. D., J. Mansell, G. T. Fosgate, M. Gualtieri, D. Olivero, P. Lecoindre, D. C. Twedt, et al. "Effect of Sample Quality on the Sensitivity of Endoscopic Biopsy for Detecting Gastric and Duodenal Lesions in Dogs and Cats." [In eng]. J Vet Intern Med 22, no. 5 (Sep-Oct 2008): 1084-9.