Diagnostic and Therapeutic Approach to the Cat with Chronic Diarrhea WSAVA 2002 Congress Stanley L. Marks, BVSc, PhD, Dip. ACVIM (Internal Medicine, Oncology), Dip. ACVN University of California, Davis, School of Veterinary Medicine Davis, California, USA Diarrhea is generally regarded as the most consistent clinical sign of intestinal disease in the cat. The history and physical examination are paramount for determining whether the diarrhea is due to primary disease of the gastrointestinal tract or secondary to extraintestinal diseases such as chronic renal failure or hyperthyroidism. In cats, most chronic diarrheas involve the small-bowel and diarrhea due to maldigestion is relatively uncommon. HISTORY The history can indicate the location, severity, and probable cause of the disease process. An important goal of the history is to categorize the diarrhea into “small bowel” or “large bowel” in origin, because this will have a direct impact on the diagnostic and therapeutic approach to the patient. A careful history should also indicate the presence of extraintestinal disease (renal failure or hyperthyroidism) as the underlying cause of diarrhea or may identify important predisposing factors, such as diet, environmental factors, exposure to parasites, infectious agents, drugs or toxins. The history should focus on the duration of the diarrhea, the patients diet (and diet changes), the appearance of the feces (color, volume, mucus, presence of fresh blood), worming and vaccination history, defecation frequency, aggravating or alleviating factors, and defecation urgency. Adverse reactions to food are a relatively common cause of chronic diarrhea in cats and the history is a simple way to determine incriminating diets or protein sources. PHYSICAL EXAMINATION Physical examination should emphasize the detection of fever, cachexia, dehydration, weakness or depression, pallor (blood loss anemia) and effusions or edema (hypoalbuminemia). The thyroid area should be carefully palpated, and the kidneys and liver examined for changes in size. Intestinal loops should be carefully palpated for masses, thickening (inflammatory or neoplastic infiltration), distension, pain, or associated lymphadenopathy. Palpation of the rectum may reveal rectal masses or thickening of the rectal wall. DIAGNOSTIC APPROACH For undiagnosed chronic diarrhea, the minimum database should include a complete blood count (CBC), a serum biochemistry profile, a urinalysis, a fecal flotation, and a direct smear of saline admixed fresh feces for protozoa. Flotations are excellent for recovering common nematode ova, oocysts of coccidia (including Cryptosporidium spp.), and Giardia cysts. The main limitation of flotations is their inability to float organisms whose diagnostic stage has a specific gravity higher than that of the flotation medium. Most commonly these are the heavy ova of trematodes and acanthocephalans (thorny-headed worms). Fragile cysts and larvae, though recovered, may be too distorted to identify. It is always preferable to use a centrifugation flotation technique. This is probably the single most important change one can institute to improve routine recovery of parasite stages by flotation. Flotation methods that do not utilize a centrifugation technique are often not sensitive enough to recover small numbers of organisms in the feces. Always use a coverslip rather than a loop or glass rod to transfer the meniscus to a slide. If your centrifuge has free-swinging buckets, use a coverslip on the final centrifugation to recover parasites. If your centrifuge has a fixed-angle, carefully add more flotation medium after the final spin to create a meniscus and set the coverslip on top for several minutes before lifting it off for examination. If at this point you are still determined to do standing flotations, use a coverslip to transfer the meniscus. Coverglass improves the optics of any microscope. Check the specific gravity of flotation medium. If possible, switch to zinc sulphate (sg 1.18 or 1.2) in order to improve detection and morphology of Giardia spp. Remember that regardless of the flotation solution all eggs do not float. Choice of flotation solution is less important than the actual method of flotation. Examine preparations as soon as possible after preparing them. Delay will result in distortion of some parasite stages and incorrect or missed diagnoses, especially with delicate cysts and oocysts. Encysted forms of Giardia organisms in a fecal specimen may be detected most reliably with zinc sulfate flotation, as opposed to examination of fresh saline smears.1 Preliminary studies in Giardia-infected cats at the University of California, Davis, have revealed that the ProSpecT® Microplate ELISA Assay (Alexon-Trend, Inc., Ramsey, MN) compares favorably in sensitivity and specificity to the zinc sulfate flotation technique; however, the sensitivity of the ProSpecT® Giardia Rapid ELISA Assay is significantly less than that of the Microplate Assay and zinc sulfate flotation methods. Similar studies have been performed in Cryptosporidium-infected cats at the University of California, Davis, and preliminary findings have revealed that the ProSpecT® Cryptosporidium Microplate Assay is equally sensitive and specific to the modified Ziehl-Neelsen acid-fast staining technique; however, the ProSpecT® Cryptosporidium Rapid Assay is far less sensitive than the former two methods. The importance of evaluating 2 to 3 consecutively obtained fecal specimens cannot be overemphasized as our studies have shown significant increases in sensitivity in all diagnostic tests when more than one stool specimen is examined. Macroscopic examination of a fresh fecal specimen is essential for assessment of bulk, color, consistency, and detection of blood and mucus. Small bowel diarrhea is generally free of grossly visible mucus or red blood, but prominent steatorrhea may cause the feces to appear lighter in color. Acholic or pale feces can also be seen in association with extrahepatic bile duct obstruction causing a lack of the bile pigment stercobilin in the feces. Rapid intestinal transit time can be associated with yellow or green stools due to incomplete metabolization of bilirubin.2 The complete blood count may reveal an eosinophilia secondary to endoparasitism, eosinophilic enteritis, or abdominal mast cell neoplasia. Anemia may result from enteric blood loss or from depressed erythropoiesis caused by systemic disease or chronic inflammation. Underlying systemic diseases such as chronic renal failure or liver disease may be detected on the serum biochemical profile. In addition, panhypoproteinemia (low serum albumin and globulin) may be seen with severe infiltrative bowel diseases such as inflammatory bowel disease, intestinal lymphoma, and Histoplasmosis. The finding of steatorrhea and weight loss in the face of a normal to increased appetite is consistent with a malassimilation disorder such as exocrine pancreatic insufficiency. Although this condition is relatively uncommon in cats, it can be confirmed by performing a serum trypsin-like immunoreactivity assay.3 Cats exhibiting signs of large bowel diarrhea should have a rectal scraping and stained fecal smear performed to evaluate for inflammatory cells or fungal hyphae.4 Serological screening for FeLV and FIV is advised for those cats that have failed to respond to antiparasitic or dietary therapy. Serum thyroxine measurementshould be considered in elderly cats particularly if steatorrhea is observed. Survey abdominal radiographs are a relatively low yield procedure in most patients with chronic diarrhea, but are indicated in cats suspected of having partial obstructions due to foreign bodies, intussusceptions, or masses. Abdominal ultrasound is complimentary to survey abdominal radiographs and is more sensitive for the detection of abdominal masses, intestinal mural thickening, intussusceptions, and mesenteric lymphadenopathy.5 In addition, ultrasound-guided percutaneous biopsy or aspiration of masses is an effective diagnostic procedure. Contrast radiography and fluoroscopy are occasionally indicated for identification of partial obstructions and intestinal motility disorders, respectively. Fecal culture is typically a low-yield procedure in cats with diarrhea because the clinical documentation of enteropathogenic bacteria causing diarrhea is clouded by the presence of these organisms in apparently healthy animals. If bacterial enteritis or enterocolitis is suspected, the feces should be cultured for specific pathogens such as Salmonella, Campylobacter jejuni or Campylobacter upsaliensis, Clostridium perfringens, and Clostridium difficile.6-9 Fecal cultures should be reserved for cats developing diarrhea after kenneling or show attendance, in cats with an acute onset of bloody diarrhea in association with evidence of sepsis, or in diarrhea outbreaks occurring in more than one pet in a household. Caution should be exercised when interpreting the presence of C. perfringens endospores in fecal smears obtained from cats with diarrhea, because healthy cats can harbor large numbers of C. perfringens endospores in their stools. In addition, the currently accepted opinion that $ 2 to 3 endospores/oil immersion field is associated with enterotoxin appears unsubstantiated in light of recent studies documenting a poor correlation between fecal endospore numbers and the presence of enterotoxin.10 The prevalence of C. difficile in fecal specimens from cats who were patients at the University of California Veterinary Medical Teaching Hospital was 9.4% (23 of 245 cats) based on culture on selective media and identification by a latex particle agglutination test.11 Toxin A and B sequences were identified in 8/23 isolates and were confirmed by Southern blot hybridization. All of the cats colonized with toxigenic C. difficile had $ of the risk factors (antibiotic use, antineoplastic therapy) associated with C. difficile infection in human patients. Four of the 8 cats colonized with toxigenic C. difficile were treated with metronidazole and had resolution of the diarrhea and negative fecal culture on subsequent testing. The significance of isolating nontoxigenic C. difficile in asymptomatic human patients is uncertain because the organism is a normal component of the colonic microflora in some individuals. Multiple strains of C. difficile are often isolated during outbreaks of C. difficile-associated diarrhea, and AP-PCR can be utilized to identify the different genotypes of C. difficile within a hospital population. This method has confirmed the potential role of environmental contamination in bacterial transmission by identifying bacteria in the environment with identical genotypes to those isolated from the patient. Cats with no evidence of life-threatening disease, whose diarrhea remains undiagnosed after initial laboratory and imaging procedures, are further evaluated with controlled diets for 2 to 3 weeks. The diet selected should be free of additives and preservatives, and contains a novel protein source that is highly digestible. The protein should be highly digestible because intact proteins are far more antigenic than polypeptides and amino acids. If signs resolve following several weeks of dietary therapy, the diet should be balanced or alternatively a complete and balanced commercial diet with the same novel protein source as the homemade diet should be selected. If signs do not resolve, a more extensive diagnostic approach is warranted. Endoscopy is a valuable procedure for the diagnosis of intestinal mucosal diseases that are associated with morphologic changes. Endoscopy, however, does not differentiate intestinal motility disorders, secretory diarrheas, or brush border enzyme defects, and is likely to miss lesions in the intestinal submucosa and muscularis. In addition, endoscopy is limited by the working length of the scope, limiting endoscopic examination of the jejunum. Rigid proctoscopy is preferred over flexible colonoscopy for the initial evaluation of large bowel disease. Rigid proctoscopy entails less risks, time, and cost than colonoscopy, and is able to diagnose the majority of large bowel disorders because of the diffuse nature of the disease. Flexible colonoscopy is indicated for evaluation of upper colonic disease, including cecal inversion, ileocolic neoplasia, and occult Trichuris infection. Tests for malabsorption do not give a specific causal diagnosis for the diarrhea, and many of these tests are limited by relatively poor sensitivity and specificity. In contrast to the endoscopic procedure, which typically diagnoses abnormal mucosal morphology, malabsorption tests evaluate intestinal function. They identify abnormal carbohydrate or fat assimilation secondary to motility disorders, “bacterial overgrowth,” or brush border enzyme deficiencies.Screening tests of malassimilation include the indirect quantitative analysis of fecal fat, the breath hydrogen analysis and the direct/indirect Sudan stain for fecal fat. The use of the fat absorption test is not recommended due to the frequency of misleading results. PRINCIPLES OF DIARRHEA THERAPY Symptomatic therapy includes restoration and maintenance of fluid and electrolyte balance, dietary modification, and intestinal motility modifiers. Antibiotics and immunosuppressive drugs are introduced based on evidence of inflammatory bowel disease or bacterial enteritis. Motility modifiers are only indicated if the diarrhea is intractable and should not be used if the diarrhea is due to invasive microorganisms. The opiate and opioid narcotic analgesics such as loperamide (Imodium; 0.1-0.2 mg/kg TID, PO) are the most effective motility modifiers for managing diarrhea. Anticholinergic agents are contraindicated because they may cause generalized suppression of all motility and may potentiate ileus. Oral Protectants Oral protectants such as kaolin-pectin, bismuth, activated charcoal, and barium are purported to act locally within the gut lumen to adsorb bacteria and toxins and to provide a protective coating on inflamed mucosal surfaces. Bismuth subsalicylate is the most useful of these agents because it has antienterotoxin, antibacterial, antisecretory, and anti-inflammatory actions. Caution should be exercised with the use of salicylate-containing compounds in cats due to the prolonged elimination of this compound in cats. Bismuth dosed at 0.5 to 1 ml/kg BID for 2 to 3 days is safe in cats. Antibiotics Use of antibiotics as empirical therapy in the management of uncomplicated or noninfectious diarrhea is not recommended because of the adverse effects of the antibiotics on the normal intestinal microflora and their tendency to promote resistant strains of bacteria. Antibiotics are indicated when specific bacterial or protozoan enteropathogens, such as Campylobacter, Clostridium, or Giardia are isolated from the feces (Table 1). In addition, antibiotics should be considered in conditions associated with severe mucosal damage and a high risk of secondary sepsis or endotoxemia.2 Immunosuppressive drugs Immunosuppressive drugs are indicated in cats with inflammatory bowel disease. Oral glucocorticoids should be used at immunosuppressive doses (initially 1.5-2 mg/kg BID) and tapered over a 2-3 month course.12,13 In glucocorticoid resistant cases, the addition of metronidazole14 and azathioprine (Imuran; 0.3 mg/kg q 48 h)12 or chlorambucil (Leukeran; 2 mg q 4 days) may result in remission of disease. Dietary therapy The ideal diet for cats with chronic small bowel diarrhea is based on a highly digestible single protein and carbohydrate source that is gluten and lactose free. There are a limited number of commercial “hypoallergenic” diets currently available that fulfill these requirements, necessitating the use of computer-generated homemade diets in patients failing to respond to the commercial diets. Single protein source diets that are commercially available for cats contain either venison, rabbit, chicken, fish, or lamb. It is important that the ingredients list of a potentially hypoallergenic diet be thoroughly evaluated, because diets with several protein sources (lamb, beef, rice, and wheat) are commonly marketed with a claim to hypoallergenicity. Dietary recommendations for the management of large bowel diarrhea are controversial. The response to dietary therapy can vary dramatically from one patient to another, with some animals showing improvement on low residue, “hypoallergenic” diets, and others improving on less digestible diets containing soluble or insoluble fiber sources.15,16 There is evidence to suggest that some forms of colitis may be associated with a dietary sensitivity similar to that observed with small bowel disease. The theoretical benefit for utilizing highly digestible “hypoallergenic” diets for patients with colitis includes reducing the digestive challenge to the large intestine and minimizing the likelihood of dietary antigens actually reaching the colon, thus lessening the likelihood of an immunological reaction.17 The author recommends feeding a complete and balanced commercial diet containing moderate amounts of a highly digestible single protein source to which the animal has not been previously exposed. The supplementation of fermentable fiber sources such as psyllium or oat bran may be necessary in patients showing partial resolution of their clinical signs. Failure to respond to these recommendations may necessitate selecting a “hypoallergenic” diet with a different novel protein source or adding insoluble fiber to the diet. Table 1. Antibiotics For The Treatment Of Bacterial-Associated Diarrheas Drug Dose Indications Enrofloxacin 5 mg/kg BID, PO Gram negative bacteria Ampicillin 10-20 mg/kg TID, PO Clostridium perfringens Ampicillin 10-20 mg/kg TID, IV, SC Sepsis (use with aminoglycosides) Gentamicin 2.2 mg/kg TID, IV, SC Sepsis Cephalothin 22-44 mg/kg TID, IV, IM Sepsis Metronidazole 10-20 mg/kg BID, PO C. perfringens, C. difficile, IBD Tylosin 20-40 mg/kg BID, PO C. perfringens, IBD Erythromycin 10-15 m
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