Managing cases of chronic small intestinal diarrhea (Proceedings)

Basic approach to chronic diarrhea

Chronic diarrhea (i.e., that which persists > 2-3 weeks) usually necessitates a systematic diagnostic approach (which may mean classic tests and/or therapeutic trials). The first question in the patient with chronic diarrhea is whether the patient has an obvious problem such as parasites or an obviously inadequate or poor quality diet. At this point, we are not talking about dietary allergy or intolerance; we are simply talking about obviously bad choices or totally erratic diets in which the animal is fed anything and everything. While it is possible that parasites are unlikely in your area, it is always a good idea to check for them; perhaps the dog or cat has been traveling or boarding with an animal that has been traveling where parasites are common. Besides, having intestinal parasites will lower the threshold for diarrhea caused by other problems.

The second question is whether the patient has large intestinal disease or small intestinal disease. It is important to realize that diarrhea is simply increased fecal water. Severe, life-threatening small bowel disease may cause minimal or no diarrhea if the colon can absorb enough water to make the feces firm or solid by the time they are evacuated. In particular, if the patient has been in a cage and unable to exercise (a potent stimulus for defecation), the feces may be normal despite significant intestinal disease. It is only when the colon's water absorbing capacity is exceeded that diarrhea occurs. Even when small bowel disease does cause diarrhea, the weight loss from nutrient malabsorption may precede diarrhea by months.

Use the history to help differentiate large bowel from small bowel disease.

• • Weight loss, especially in the face of a reasonable appetite, strongly suggests nutrient loss from the small intestine. Hepatic disease can closely mimic intestinal disease in this regard, but the intestines are usually a better place to start looking. Weight loss is probably the most important area to look at in differentiating large bowel from small bowel disease. Any animal with chronic small intestinal disease that is clinically significant should have weight loss or loss of condition. Any animal with chronic diarrhea and no loss of weight or condition has large bowel disease until proven otherwise. Some animals with severe large bowel disease will have weight loss, but these usually also have hematochezia, mucus, hypoalbuminemia and/or marked tenesmus.

• • Red blood (hematochezia) comes from the large bowel or the ileum. This finding is specific but insensitive for large bowel diarrhea

• • Mucus in the feces comes from the large intestine or ileum. This finding is specific but insensitive for large bowel diarrhea.

• • Tenesmus and dyschezia suggest large bowel disease; however, any animal with chronic diarrhea can have anal irritation causing tenesmus.

• • Vomiting can occur with either large or small bowel disease.

Once small intestinal disease is diagnosed, the next question is whether there is a protein-losing enteropathy (PLE) or not. Check the serum albumin concentration (NOT the total protein) to make this determination. While it is certainly possible to have PLE and a normal serum albumin concentration (i.e., the disease has not gone on long enough yet to cause hypoalbuminemia), we generally reserve using the term PLE for those dogs which have hypoalbuminemia even though this is not technically correct. If the patient has a serum albumin < 2.0 g/dl that is not caused by renal loss or hepatic insufficiency, then we typically diagnose PLE by default. If you suspect PLE, you should skip down to that section.

Dogs with chronic small bowel diarrhea (not ple)

If the patient does not have PLE, the next step is to eliminate maldigestion. Maldigestion principally means exocrine pancreatic insufficiency (EPI). Cats rarely develop exocrine pancreatic insufficiency, and they are often obviously steatorrhic with a greasy hair coat. I have yet to see classic steatorrhea in a dog with EPI; most of these patients have copious amounts of "oatmeal" consistency diarrhea without blood or mucus. You need to use the serum TLI test to establish the diagnosis; all the other tests (including fat absorption test and therapeutic trials with pancreatic enzymes) have so many false positive and false negative results that they are essentially untrustworthy. Enzyme replacement therapy for EPI will not work in all patients; therefore, you need to establish a diagnosis of EPI with certainty using the TLI test (especially in almost any German shepherd). Failure to use the TLI may mean that you wrongly decide that EPI is not present and go on an do tests that are unnecessary, inappropriate, and costly (e.g., intestinal biopsy) for that patient. Most of the cases of EPI I have seen have been referred for endoscopy and biopsy because EPI was "eliminated" after the animal did not respond to enzymatic supplementation. Conversely, incorrectly diagnosing exocrine pancreatic insufficiency in a dog that does not have that disorder results in prescribing expensive enzyme supplements that are not needed. Dogs may have EPI and not respond to pancreatic enzyme replacement because a) the enzyme product is poorly effective, b) the diet is too high in fat, and c) the dog also has antibiotic responsive enteropathy. Sometimes you need to address all of these issue before the dog with EPI will respond to enzyme supplementation. About 15% of dogs with EPI simply will not respond to therapy, for what reason(s) we do not know. Dogs that are substantially hypocobalaminemic seem to have a more guarded prognosis, and it is not obvious that supplementing cobalamin helps these dogs.

Once maldigestion is eliminated, then malabsorptive diseases must be considered. Malabsorptive small intestinal disease is a common cause of diarrhea. However, a substantial number of dogs (and cats) with malabsorptive small intestinal disease have normal stools despite severe intestinal pathology. This is especially true in cats because they conserve water better than dogs. However, it is common enough in dogs for the practitioner to be acutely aware of the possibility. Small intestinal disease is a major concern in any animal with weight loss despite a normal (and especially an increased) appetite. If the appetite is decreased, one should still explore the possibility of small intestinal disease. In particular, explore the history to find out if the appetite was normal when the problem first began (a strong indication of small intestinal disease or hyperthyroidism).

Once parasites, protein-losing enteropathy, and maldigestion are eliminated (i.e., you have determined that the patient has a non-PLE malabsorptive disease), the question is whether to recommend therapeutic trials or a major diagnostic work up. If the patient can tolerate a possible delay of 4-8 weeks without undue risk, then therapeutic trials are reasonable. If therapeutic trials are performed, they must be designed such that even if they fail, useful information is obtained and the clinician is further ahead than previously. Always ask yourself: "If this therapy fails, will I really know more about what the patient probably has, or will I be as confused as I was before treating it?".

An elimination diet for dietary responsive disease is often useful for non-protein-losing malabsorptive disease. There is no such thing as a commercial diet which is an appropriate elimination diet (i.e., is hypoallergenic and appropriate to look for non-allergic intolerance) for all dogs. We often see cases in which the right thing was done (i.e., an elimination diet was used); but, it was done in such a poorly planned or implemented fashion that the effort was wasted. One must carefully investigate the history and see what the patient has eaten in the past. However, even when you have determined what dietary ingredients the patient has previously been exposed to, it is sometimes difficult to find a diet that works for that particular patient. In some cases, all of our well-planned hypoallergenic diets fail but a chance try at some commercial brand works.

When starting the patient on an elimination diet, one may use a homemade diet or a commercial diet. There are many excellent commercial diets, and they usually work. Home-made elimination diets sometimes work when commercial diets do not; however, this is very uncommon. Therefore, you will have to decide which is most appropriate in the patient that you are treating. The main time I use a home-made diet is when I am first trying to determine if the diarrhea will respond to a diet; but, remember that I often see patients that have been fed numerous commercial diets and have not responded. If feeding a home-made elimination diet resolves the problem, then typically attempt to switch to a completely balanced, more convenient, commercially prepared diet. Regarding commercial elimination diets, the hydrolyzed diets are usually good but are not always the best choice for every patient. Some animals respond better to a novel protein diet than a hydrolyzed diet, and vice-verse. Which ever elimination diet is used, one must be prepared to feed it and it alone for an absolute minimum of 3-4 weeks before its efficacy can be accurately determined. Rare cases need to be feed a diet for 6-8 weeks before they respond, but this is probably well less than 5% of cases. If a diet seems to be effective (i.e., weight gain plus resolution of diarrhea) then continue it for at least another 3-4 weeks to be sure that it was the diet that made a difference as opposed to the patient having some transient improvement due to any number of causes.

Antibiotic-responsive enteropathy (ARE) seems to be a relatively common problem in dogs. It can best be described as a syndrome in which there are substantial numbers of bacteria in the upper small intestines AND the host responds to them in such a manner as to cause intestinal dysfunction. These bacteria are not usually obligate pathogens. Rather, they can be of any species, and E. coli, Staph, Strep, and Corynebacterium are particularly common aerobic/facultative anaerobic bacteria found in the upper small intestines, while Clostridium and Bacterioides are especially common anaerobic bacteria. These bacteria are probably commensals or they may represent contamination from ingested material which is not eliminated by normal host defense mechanisms. The signs they produce, if any, seemingly depend upon at least two factors: a) which bacteria are present and b) how the host responds to them. The relationship of ARE to IBD is unclear, but it seems very possible that bacteria could be responsible for either initiating and/or perpetuating the intestinal inflammation we call IBD. The term "dysbiosis" has been suggested as the bridge between ARE and IBD – that is to say that having bacteria that are somewhat prone to cause problems (i.e., usually enterics such as E. coli) as opposed to having overt pathogens.

Antibiotic-responsive enteropathy is hard to definitively diagnose with laboratory tests. Histopathology and cytology of the intestinal mucosa are extremely insensitive at detecting ARE. Serum cobalamin and folate concentrations have been used for diagnosis, and finding both a low serum cobalamin and an increased serum folate concentration has been considered to be relatively specific for ARE. Measuring serum cobalamin and folate concentrations is relatively insensitive and non-specific for detecting ARE. There are many dogs with chronic GI disease that respond to antibiotic administration but which have normal cobalamin and/or normal folate concentrations. It would seem that treatment for ARE is justified regardless of whether the serum cobalamin and folate concentrations are normal or abnormal, leading one to ask whether there is any benefit to measuring them to diagnose this disorder. Finding hypocobalaminemia or low serum folate levels is beneficial when looking for otherwise occult gastrointestinal disease. Supplementing cobalamin can clearly make cats feel better and diarrhea diminish. In fact, it is almost getting to the point where it is never wrong to give any sick cat cobalamin injections, regardless of blood values of the vitamin. Severe hypocobalaminemia has been suggested to be a poor prognostic signs. While the value of supplementing cobalamin to cats is clear (in fact, it is almost never wrong to give any sick cat supplemental cobalamin), the clinical value of administering cobalamin to dogs with low serum cobalamin concentrations is very uncertain.

Culture of the small bowel was once considered the "gold standard", but this test is fraught with problems. First, it is technically hard to do it correctly. Samples must be obtained without contaminating them with oral secretions. Then they must be processed correctly in an expedient manner so as not to lose any anaerobic bacteria while not allowing the numbers of aerobes to increase. Many investigators have snap frozen fluid samples to culture them later, but such freezing appears to kill large numbers of bacteria, especially anaerobic bacteria. We now know that culture only detects about 30% of the bacteria in the gut; the other 70% cannot be cultured. This makes one seriously question the value of culture unless one is searching for a specific pathogen, and even then there are culture-less methods (e.g., PCR) that may be better. Finally, as has already been said, just culturing bacteria from the small bowel does not allow one to make a diagnosis of a bacterial disease of the small intestines. Large numbers of bacteria (i.e., > 107 CFU/ml) can be present in dogs without any evidence of any clinical disease. For these reasons, we very rarely culture the small intestine of dogs with chronic GI disease. However, there are rare patients that appear to have ARE and yet are resistant to treatment with commonly used antibiotics. Seemingly, these dogs may have one or two very resistant bacteria in their GI tracts, and culture may be required to determine what antibiotic will be effective. However, we have only seen this scenario twice, and we believe it to be very rare.

Because of the apparent difficulty in diagnosing ARE with lab tests, empirical antibiotic therapy is often chosen as a means to diagnosis instead of laboratory tests. The obvious drawbacks to this approach are a) clinical "response" of the patient to the administered antibiotics may be due to the antibiotics or may be due to something else, b) if the patient did not respond to the antibiotic, it may be that you used the wrong antibiotics, and c) even if the patient does have ARE, there may be yet another disease present (e.g., a tumor causing a partial intestinal obstruction) which predisposed the patient to the ARE.

Because any bacteria can be present in the upper small intestine, the species of bacteria in the upper small intestine may change from week to week, and we seldom know which bacteria we are treating, broad spectrum antibiotics designed to lessen bacterial numbers seem to be indicated. You can never sterilize the GI tract. However, because clinical signs are due to a combination of large numbers plus an altered host response, simply lessening the numbers of bacteria often seems beneficial. Oral aminoglycosides were generally considered a poor choice to treat ARE because anaerobic bacteria (which have been suggested to be more of a problem) are resistant to aminoglycosides. However, this opinion is not clearly correct as there are occasional patients that clearly improve when given amikacin orally. Tetracycline is often effective; but, giving tetracycline is inconvenient. Tetracycline must be administered alone (i.e., without any food) and yet be washed down with water to ensure that the capsule to tablet does not stick in the esophagus and cause esophagitis. Tylosin powder has also been useful and is revered by many clinicians. Some clinicians like metronidazole; however, I have not been impressed with the efficacy of metronidazole for ARE. Metronidazole seems to have real benefit in many GI disorders, probably because it is so effective in eliminating many anaerobic bacteria. For patients that are EXTREMELY ill in which we need to know RIGHT NOW whether or not it will respond to antibiotics (i.e., that patient is so ill that you cannot take a chance of being 2-3 weeks from now and not having a response to therapy), I use a combination of enrofloxacin, cephalosporin and metronidazole. I did not say that I used this combination for long periods of time. I use this combination when I absolutely have to know whether or not I will have a clinical response within the next 2-3 weeks or take a chance on losing the patient.

Regardless of which drug is used, such a therapeutic trial should be performed for at least 2-3 weeks before a decision is made as to its efficacy. Remember, you must not only suppress the numbers of bacteria, but you must also allow the intestinal mucosa time to heal. Finally, it appears that concurrently feeding a high quality elimination diet can substantially enhance the efficacy of the antibiotic therapy. Therefore, we now routinely use both in our therapeutic trials.

If the patient appears to respond to this therapeutic trial of elimination diet and antibiotics, then it appears best to continue everything unchanged for an additional 2-4 weeks to be sure that the patient responded to this therapy (as opposed to the patient having some fortuitous, transient response to who-knows-what). If the patient is still doing well at that time, then you either a) stop the antibiotics and see if they diet alone is sufficient to control signs or b) slowly wean the antibiotics to their lowest effective dose (e.g., once a day or even once every other day). It all depends upon how frequently the clinical signs occur. If the signs occur once every 2+ months, then it obviously makes sense to only treat when the patient is symptomatic. If the signs consistently recur within a few days of stopping the antibiotics, then you are probably stuck with treating almost constantly. This latter situation is one of the two times in veterinary medicine that I am aware of in which it is reasonable to look for the lowest effective dose of an antibiotic. Some patients only need antibiotic administration every 2 to 3 days in order to maintain control. In some cases, the patient will breakthrough and re-develop clinical signs after several weeks or months, and a different antibiotic must be used. If the decision is made to stop administering the antibiotics, then the owners should be warned that it is possible that the signs are likely to recur at some point. For ARE to occur, there is probably some defect in host defense mechanisms that allowed the commensal bacteria to cause the clinical signs, and this defect is unlikely to disappear. The question is how severe is the defect (i.e., is the dog likely to have problems continually or only once in a while)?. You should warn the clients that they are likely to have to deal with this problem repeatedly and you need to explain the difference between "cure" and "control".

It may be a good idea to routinely treat all dogs with chronic small intestinal disease for ARE, even if you have histologic evidence of IBD or other disease. I will treat for ARE almost every time I diagnose a dog with a malabsorptive disease since there is no test for ARE that is reliable in ruling this disorder out, including cobalamin and folate determinations.

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 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.