Other chronic intestinal diseases, especially infiltrative ones (Proceedings)

Intestinal biopsy may be accomplished two ways: endoscopy and surgery. CBC, serum chemistry profile, and urinalysis are useful and may point out systemic manifestations of the disease which will aid in correctly diagnosing and prognosing the problem (e.g., hypoalbuminemia due to histoplasmosis), but are also useful as a preanesthetic work up before endoscopy. Ultrasound is useful to look for enlarged mesenteric lymph nodes, focal intestinal/gastric lesions, and loss of mucosal layering. Focal enlargements may suggest a tumor (e.g., alimentary lymphoma or carcinoma), as may lymphadenopathy. However, animals with severe IBD may also have mesenteric lymphadenopathy (as may dogs with histoplasmosis or pythiosis). If the lymph nodes are enlarged, it is reasonable to aspirate them percutaneously with ultrasound guidance. Mesenteric lymph nodes are typically reactive, making it more difficult to interpret cytology from them. However, finding obvious sheets of lymphoblasts or fungal organisms (e.g., histoplasmosis) allows diagnosis. Sonographic examination of the intestines is important (i.e., you may make a diagnosis), but it does not detect intestinal mucosal disease in many patients that are afflicted with such disease. If loss of mucosal layering is seen, then severe infiltration is likely (either inflammatory or neoplastic), but normal-appearing mucosa may have marked disease present. Most of the time, ultrasound's major use is to help you decide whether to perform intestinal biopsy using endoscopy or laparotomy. If there is an obvious lesion where an endoscope cannot reach, it is best to perform laparotomy instead of endoscopy. In contrast, abdominal radiographs (plain or contrast) are rarely helpful or cost-effective in these patients.

For our purposes, inflammatory bowel disease (IBD) will be defined as inflammatory infiltrates in the intestines that cannot be attributed to a specific cause; hence, IBD is idiopathic intestinal inflammation. This is a very important concept. If there are inflammatory infiltrates in the intestines and they subside when the patient is fed an elimination diet, then that patient had dietary intolerance or allergy, not IBD. Likewise, if a patient with inflammatory infiltrates of the intestines responds to antibiotics, then that patient has an antibiotic-responsive enteropathy, not IBD. The important point is that canine and feline IBD is NOT simply a histologic diagnosis. Unfortunately, accurately excluding the other causes of intestinal inflammation is time consuming and can be frustrating to the client who is dealing with ongoing diarrhea/vomiting/weight loss. Additional difficulties involved in diagnosing intestinal inflammation include the lack of agreement among pathologists over what constitutes normal, mild, moderate, and severe inflammation in the intestinal mucosa. Adding to this problem is the fact that many endoscopic biopsies (and a good number of full thickness biopsies) are so hopelessly inadequate that asking a pathologist to make any kind of meaningful statement about them is questionable, at best. This means that one cannot blindly believe pathology reports on intestinal biopsies. However, this makes the situation difficult for the average primary care practitioner who cannot sit down with the pathologist and discuss the slides with a multi-headed scope. A common question is, "When do I doubt a diagnosis or a histologic description?" Perhaps the best guidelines about when to ask for a second opinion center around two questions that should be asked every time a diagnosis is made. The first question is, "Does the diagnosis fit the patient?" (i.e., do the signalment, history, physical examination, laboratory finding and imaging fit the diagnosis?). The second question is, "Does the response to therapy fit the diagnosis?" If the answer to either question is "no", then the diagnosis is suspect.

Dogs with IBD are generally middle aged to older. Any breed may be affected, but some breeds seem to be more commonly affected (i.e., German shepherds, Shar Peis, Basenji's). While it is possible that younger dogs can be affected, that appears to be very uncommon. In the authors' practice, any dog < 4 years of age with a diagnosis of IBD is automatically suspect, and reconsidering the diagnosis is usually one of my first recommendations. Furthermore, isolated IBD of the canine colon is, at least in our practices, extremely uncommon. Even since Clostridial colitis and fiber responsive colonic disease have been discovered, the number of dogs diagnosed with large bowel IBD has dropped precipitously. Most dogs that are ultimately diagnosed with IBD are diagnosed with lymphocytic-plasmacytic IBD. IBD can possibly (probably) be initiated by any number of stimuli. Once sufficient intestinal mucosal inflammation is present, increased intestinal mucosal permeability probably helps the inflammation to become self-perpetuating (i.e., inflammation causes increased permeability which allows immunogenic proteins to enter the mucosa which causes more mucosal inflammation which causes more mucosal permeability which causes ...). The two major stimuli available to start and/or perpetuate intestinal inflammation appear to be diet and bacteria. Therefore, even when treating IBD with anti-inflammatory and/or immunosuppressive drugs, it seems intuitively useful to include dietary and anti-bacterial therapy.

Since IBD is by definition "idiopathic", it makes sense that anti-inflammatory and/or immunosuppressive therapy has been the mainstay therapy. Steroid therapy in particular has been the foundation therapy for IBD for the last 20+ years. This has intuitively made sense because IBD is idiopathic inflammation, and how else do you treat idiopathic inflammation? Prednisolone has been the most commonly used steroid; however, methyprednisolone is more effective for other inflammatory disorders of cats. Steroids are typically administered at a high dose (2-4 mg prednisolone/kg/day or 1.6-3.2 mg methylprednisolone/kg/day). Dexamethasone (e.g., 0.2 mg/kg/day) is sometimes more effective than prednisolone, perhaps because dexamethasone has more anti-inflammatory activity than prednisolone. If high doses of steroid (especially dexamethasone) are used too long, diabetes mellitus and/or iatrogenic hyperadrenocorticism may result.

Budesonide is a steroid that is administered orally and eliminated by first pass metabolism in the liver. It has primarily been used in some cats with IBD that could not tolerate the systemic effects of steroids (e.g., diabetic cats). Despite these pharmacokinetics, we have seen iatrogenic hyperadrenocorticism due to this drug.

Metronidazole has been suggested to have "immunomodulatory" properties that help treat some forms of IBD. However, current thought is that metronidazole is effective because it kills anaerobic bacteria. The dose of metronidazole used for IBD is usually 10-15 mg/kg bid. Adverse reactions to metronidazole are rare when used at this dose, and we do not hesitate to use it for weeks or even months at a time, although there are recent concerns about potential genotoxicity and neoplastic transformation. If CNS toxicity (e.g., seizures, convulsions, disorientation, weakness) occurs due to metronidazole, withdrawal of the drug will usually be associated with clinical remission within 24-48 hours. Vomiting may occur as a minor side effect of metronidazole; if it occurs, it can usually be dealt with quickly by stopping the drug for a day or two and then administering it with food.

Cytotoxic drugs may be used in patients with severe inflammatory infiltrates or those which seem resistant to elimination diets, metronidazole, and corticosteroids. Azathioprine is often recommended, but it is very dangerous in cats. In dogs, 2 mg/kg every day or every other day (preferred) is used in some patients that are resistant to steroid therapy, or that require high doses of steroids that also cause substantial adverse effects. Dogs rarely die from the drug. In cats, 0.3 mg/kg every other day is recommended. In both species, it may take 3-5 weeks before any beneficial effects are seen clinically.

Chlorambucil (Leukeran) is a cytotoxic drug which is much less dangerous than cyclophosphamide or azathioprine in the cat. There are at least two methods of administering chlorambucil to cats. In the first method, the initial dose is 2 mg of chlorambucil/M2 of body surface area given daily for 4-7 days. The dose is then decreased to 1 mg/M2 daily for 7 days. If the clinical signs are lessening, one then starts to administer the drug daily, but only every other week. It is common for these patients to develop anemia (PCV = 18-22%). The second method is to give large cats (i.e., > 7 lbs) 2 mg twice weekly and smaller cats (i.e., < 7 lbs) 1 mg twice weekly. If a clinical response will occur, it should be seen in 4-6 weeks, after which time the drug may be slowly tapered to the lowest effective dose. CBC's should be monitored periodically or anytime the cat seems unwell.

Cyclosporine has been used in dogs with severe or "intractable" IBD. It seems to be effective as fast or faster than other drugs, but have fewer side effects.

Other options that are becoming increasing more interesting are prebiotic and probiotic therapy. In particular, these therapies are being looked at as possible alternatives to protracted antibiotic therapy. Probiotic therapy is the administration of live bacteria, especially but not exclusively Enterococcus, Lactobacillus and Bifidobacteria. These bacteria do not colonize the bowel; rather, they bind to toll-like receptors (TLRs) on the epithelial cells whereby they stimulate specific immune events in the GI tract. The TLRs are part of the innate immune system of the patient, and different TLRs bind to different parts of specific bacteria or their metabolic products. Here in lies the problem we currently face: different bacteria have different effects and we need to determine which bacteria (if any) are beneficial for which problem(s). Hopefully, we will find instances in which probiotics will be helpful, but at this time we are still exploring this issue. In the US there is no FDA regulation of human probiotics, which means that you do not know the quality of what you buy in the grocery store or health food store. If you decided to attempt probiotic therapy, I recommend that you buy products made by major companies that make dog and cat food (which are FDA regulated). Prebiotics are dietary fibers that mammals cannot digest but which certain bacterial can metabolize. The idea is to give prebiotics that preferentially feed "good" bacteria that have a beneficial effect in the GI tract. In general, if the patient responds to prebiotic or probiotic therapy, it seemingly can take up to 4-5 weeks. However, in both cases, any beneficial effect disappears shortly after you stop administering the probiotic or prebiotic.

Lymphoma of the small intestine can obliterate the mucosa and cause malabsorption and protein-losing enteropathy. There may be peripheral involvement (e.g., lymphadenopathy), but the lesion is often limited to the abdomen and does not cause palpable masses. The prognosis is poor, but rare patients live for years after therapy (e.g., surgery and/or chemotherapy). It can be very difficult to differentiate a well-differentiated lymphoma from lymphocytic enteritis, even when you have full thickness biopsies. Some animals with "lymphoma" have been cured with dietary therapy alone, which is to say that it probably was never lymphoma in the first place (regardless of what the biopsy report said). It is common to misdiagnose the lymphoma as IBD is poor, superficial endoscopic biopsies are performed (and this is more common than many realize). Good quality endoscopic biopsies usually allow diagnosis of alimentary tract lymphoma, as long as the endoscope can reach the affected portion of the bowel.