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Michael S. Leib DVM, MS, Diplomate ACVIM Professor, Small Animal Medicine Virginia Maryland Regional College of Veterinary Medicine Virginia Tech, Blacksburg, VA 24061 Chronic Vomiting: A Diagnostic Approach
Chronic vomiting (intermittently or continuously for at least 7 days) in dogs and cats is a common and frustrating problem for clients and veterinarians. Because many diseases cause chronic vomiting, a thorough evaluation must be performed to arrive at an accurate diagnosis. Definitive diagnosis of many diseases requires mucosal biopsy. In the past, exploratory laparotomy was necessary to obtain biopsy specimens. However, the increased availability of flexible fiberoptic endoscopy in veterinary medicine has allowed less invasive tissue biopsy. The first step in the approach to the chronically vomiting patient is to determine that vomiting and not regurgitation is present. Vomiting is associated with signs of nausea (depression, salivation, frequent swallowing, and vocalization in some cats) that is followed by abdominal contractions prior to the expulsion of material. Regurgitation is associated with esophageal disorders and occurs passively, usually associated with increased intrathoracic pressure that may be caused by excitement, activity, or changes in body position. Once you have determined vomiting is present the history and physical examination can contain many clues to the etiology. A thorough dietary history should be obtained. In some cases, correcting dietary indiscretion or instituting a highly digestible diet for 3-4 weeks will resolve the vomiting. Dietary indiscretion can be due to a recent diet change, feeding of table scraps, free-roaming behavior allowing ingestion of garbage, ingestion of foreign objects, exposure to toxins (including house plants), excessive ingestion of hair, or feeding a low quality poorly digestible diet. The history may identify the use of drugs, such as NSAIDs, that can cause vomiting due to gastritis or ulceration. The presence of diarrhea or signs of systemic disease may help to rank the rule-out list. Physical examination may be normal or only demonstrate signs of weight loss. An abdominal mass or dilated loop of small bowel may be identified as a cause of high partial small bowel obstruction. If vomiting has recently become more frequent, signs of dehydration may be present (delayed capillary refill time, enophthalmos, decreased skin turgor, tachycardia, pale mucous membranes, and cold extremities). Signs suggesting systemic disease include: polyuria / polydipsia, polyphagia, hepatomegaly, cataract formation, icterus, encephalopathy, ascites, pyrexia, bradycardia, tachycardia, small irregular kidneys, oral ulceration, pale mucous membranes, splenomegaly, or an abdominal mass. Table 1 lists some causes of chronic vomiting in dogs and cats. Systemic diseases can usually be ruled out by a thorough history, careful physical examination and routine laboratory tests (complete blood count, biochemical profile, urinalysis, amylase and lipase, heartworm antibody test, and T4). Correction of dietary indiscretion or a 3-4 week trial with a highly digestible diet should be performed before more invasive testing. Gastrointestinal causes of chronic vomiting may involve either the stomach or orad small intestine. An efficient plan to evaluate gastrointestinal causes includes fecal examination for parasites, survey abdominal radiography, and endoscopic examination with mucosal biopsy. If endoscopy is not available, a barium contrast upper GI series and exploratory laparotomy can be used. Although helpful in some cases, the diagnostic utility of abdominal ultrasound has not yet been fully determined. Abnormalities that can be detected include thickened stomach or small bowel, gastric, small bowel or pancreatic mass, enlarged regional lymph nodes, enlarged hypoechoic pancreas, dilated small bowel, abnormal gastric or small bowel motility, or evidence of an intraluminal foreign body. Survey abdominal radiographs rarely establish a cause for chronic vomiting (unless a radiodense foreign body is seen) and a barium upper GI series is usually indicated. Advantages of contrast radiography versus endoscopy and laparotomy include the following: 1) available in all practices, 2) noninvasive, 3) does not require general anesthesia, 4) always visualizes the duodenum, 5) evaluates gastric size and position, 6) provides a qualitative description of gastric motility and emptying of liquids, and 7) detects extraluminal and submucosal / muscular masses. A barium series is time consuming to perform, costly to the client, and is a source of radiation exposure to the hospital staff. If lesions are identified, tissue biopsy is needed to confirm a diagnosis. If a foreign body is detected, it must be removed via endoscopy or exploratory laparotomy. The upper GI series is insensitive for mucosal lesions. Exploratory laparotomy can be performed in veterinary hospitals and allows visual inspection of serosal surfaces, palpation of the stomach and small intestine, and limited mucosal visualization. It also allows for exploration and biopsy of the pancreas, mesenteric lymph nodes, and the entire small and large intestines. Directed large full-thickness biopsies can be obtained from the stomach and small intestine. Definitive treatment for some conditions (foreign bodies and tumors) can be accomplished. A duodenal aspirate for Giardia can be collected. Disadvantages include the need for general anesthesia, the surgical risk to the patient, post-operative morbidity and the risk for complications, and expense to the client. Endoscopic examination lacks some of the disadvantages of the upper GI series and exploratory laparotomy. Advantages include the following: 1) visual mucosal inspection of the entire stomach and some of the duodenum, 2) directed tissue biopsy, 3) few false-negative procedures (related to the endoscopist's skill), 4) less invasive than laparotomy, 5) quick to perform, 6) the ability to remove foreign bodies, 7) assessment of the feasibility of surgical resection of tumors, and 8) ability to obtain a duodenal aspiration sample for Giardia. Disadvantages include the cost of equipment, the clinical skills necessary to perform endoscopy, the small size of biopsy samples, biopsy of mucosa only, the inability to resect masses, failure to enter the duodenum, evaluation of the orad small bowel only, and the necessity of general anesthesia. Because of the usefulness of endoscopy in cases with chronic vomiting, the author routinely performs endoscopy (and reaches a diagnosis) instead of performing a barium upper GI series or exploratory laparotomy. Thorough endoscopic examination of the stomach and duodenum of the dog and cat can be performed with a flexible fiberoptic gastroscope with an outside tip diameter of <10 mm or less. Four-way control of the tip of the endoscope is necessary. Biopsy channels of 2.8 mm in diameter or greater will provide adequate biopsy samples for histologic evaluation and accept a wide range of foreign body forceps. The endoscopic examination is performed after an overnight fast with the animal under general anesthesia and placed in left lateral recumbency. The endoscope should only be advanced if the gastrointestinal lumen is clearly visible, reducing the possibility of tissue perforation. The endoscope is passed through the lower esophageal sphincter into the cardiac region of the stomach. Initial assessment of the rugal folds should be made before insufflation and gastric distention. Gastric mucosa appears pinker than esophageal mucosa. It is smooth, glistening, and tough. The endoscope is advanced along the greater curvature until the angularis incisura is located. Deflection of the endoscope tip towards the antrum (control knob down) will allow visualization of the antral and pyloric region. Movement of the tip towards the cardia (control knob up) will provide a retroflexed view of the gastric body, fundus and cardia. To enter the duodenum, the scope should be advanced towards the pylorus and gently pushed through. If difficulty is encountered, rolling the animal into dorsal recumbency may allow successful passage. The duodenal mucosa has a more granular appearance than the stomach and is slightly paler. A duodenal aspirate for Giardia should be performed. If abnormalities are found, multiple biopsies of lesions should be taken. If gross abnormalities are not present, biopsies of standard regions should be obtained (cardia, greater curvature, angularis incisura, antrum, pylorus, and duodenum). A biopsy sample should be placed in a rapid urease test to detect the presence of Helicobacter spp. Multiple samples can be placed into the test media, although the author routines places a single biopsy from the angularis into a CLO test (Tri-Med Specialties Inc. 9531 Arden, Lenexa, KS 66215, 800 874 6331). Foreign bodies can be removed with grasping forceps. In addition, brush cytology of lesions may allow rapid diagnosis. By following the diagnostic plan outlined above, most cases with chronic vomiting can be efficiently diagnosed, allowing for development of an appropriate therapeutic plan. Systemic diseases should be thoroughly evaluated before more invasive and expensive tests are performed. Correction of dietary indiscretion or institution of a highly digestible diet may eliminate clinical signs. The use of endoscopy allows a less invasive, more efficient and accurate diagnosis of gastrointestinal causes of chronic vomiting to be reached. Serious complications such as perforation of the stomach are very uncommon and can be avoided with careful endoscopic technique. HELICOBACTER Helicobacter pylori is the single largest cause of chronic gastritis and peptic ulceration in humans. It is also associated with an increased risk of gastric lymphoma and adenocarcinoma. Spiral bacteria were described in 1896 in humans and several animal species. They were rediscovered in 1983 as a cause of peptic ulceration. Helicobacter pylori is a microaerophilic curved spiral gram negative organism with 4 flagella. The organism lives in gastric mucus. It can attach to epithelial cells and may penetrate intercellular junctions. High urease activity cleaves urea to produce ammonia which helps to neutralize the acid environment. The immune system does not remove the organisms. Infection can be life-long without treatment. In some populations as many as 90% of people are infected. Some infections do not cause clinical signs. Diagnosis can be made on serology, cytology of gastric mucus, culture of biopsies, histopathology of biopsies with H&E or Silver stains, C-14 labeled urea breath tests, or the CLO test (biopsy placed in media with urea and a pH indicator). Many treatments have been studied. The gold standard is omeprazole with ampicillin, metronidazole, and Pepto Bismol for 2 weeks. Many species have been identified in dogs and cats: H. felis, H. pylori, and H Heilmannii (Gastrospirillum hominis), H. Salomonis, and H. bizzozeronii have been most common. Experimentally, infection can be established in both dogs and cats. Lymphoid follicular gastritis can be produced. However, clinical signs are absent or very mild. Several surveys of laboratory and pet populations have shown a very high prevalence rate. Peptic ulceration appears to be very rare in dogs and cats. At the present time there are many unanswered questions: 1) What is the role of Helicobacter in clinical cases of chronic gastritis? 2) What is the optimal treatment? 3) Is the organism zoonotic? 4) Does it have a role in other diseases such as gastric cancer and inflammatory bowel disease? In the author's clinic a diagnosis of Helicobacter is based on the following criteria: 1) Clinical signs of chronic vomiting, 2) Gross and histologic evidence of gastritis, 3) absence of other causes of chronic vomiting, i.e.. IBD, and 4) prompt response to therapy. In approximately 25% of cases in which Helicobacter is identified, do I think it is the cause of the clinical signs and needs to be treated. My current therapy is two weeks of omeprazole 0.7 mg/kg SID (or an H2 blocker), amoxicillin 10-20 mg/kg TID, metronidazole 10 mg/kg BID, and Pepto Bismol 1/2-1 tablet TID or 7.5-15 ml TID. Other suggestions include omeprazole with either azithromycin 10-20 mg/kg SID in dogs and 5 mg/kg SID in cats or clarithromycin 7.5 mg/kg BID. Relapses have been seen. It will take many controlled clinical studies before we become comfortable about the role of Helicobacter in dogs and cats and can answer some of the questions I have proposed above. Our patients will benefit from thoroughly evaluating every dog and cat with chronic vomiting and remaining conservative in making the diagnosis. Failure to rapidly respond to treatment suggests that another diagnosis is necessary. Table 1 - Some Causes of Chronic Vomiting
Systemic Gastrointestinal - Stomach Gastrointestinal - Small Intestine VOMITING CASE 1
SIGNALMENT HISTORY PHYSICAL EXAMINATION REGURGITATION OR VOMITING (CIRCLE ONE) DIFFERENTIAL DIAGNOSIS
DIAGNOSTIC PLAN DIAGNOSTIC RESULTS / DIAGNOSIS THERAPY VOMITING CASE 2
SIGNALMENT HISTORY PHYSICAL EXAMINATION REGURGITATION OR VOMITING (CIRCLE ONE) DIFFERENTIAL DIAGNOSIS
DIAGNOSTIC PLAN DIAGNOSTIC RESULTS / DIAGNOSIS THERAPY VOMITING CASE 3
SIGNALMENT HISTORY PHYSICAL EXAMINATION REGURGITATION OR VOMITING (CIRCLE ONE) DIFFERENTIAL DIAGNOSIS
DIAGNOSTIC PLAN DIAGNOSTIC RESULTS / DIAGNOSIS THERAPY Selected References
Giardia Infection in Dogs and Cats
Adopted from Leib MS, Zajac AM. Vet Med 94: 793-802, 1999. Giardia is a flagellate protozoan parasite commonly encountered in small animal veterinary practice. It appears that Giardia isolates from many mammalian hosts are morphologically identical and can be referred to as a single species, Giardia intestinalis. 1, 2 The most common clinical syndrome associated with Giardia is acute small bowel diarrhea, but in some cases acute large bowel diarrhea, chronic small or large bowel diarrhea, or rarely acute or chronic vomiting may occur. Studies throughout the world have found Giardia in 1%-39% of fecal samples from pet and shelter dogs and cats. 3-9 In these studies, many of the Giardia infected animals did not have diarrhea. In most of these surveys younger animals had a higher rate of infection. In addition, Giardia was identified in 11% of fecal samples randomly collected in public parks in Scotland. 10 It appears that various strains posses differing degrees of pathogenicity. 9 Clinical signs may be self-limiting in some patients11 Severe disease may occur in puppies or kittens, animals with other gastrointestinal parasites or diseases, or debilitated animals, but also can occur in otherwise healthy patients. Giardia cysts are not routinely identified by commonly used fecal flotation solutions because cysts become shriveled and cannot be identified. In addition, the numbers of cysts shed in the feces fluctuate over time. 9, 11-14 Many commonly used anthelmintics are not effective against Giardia and the parasite should be considered a zoonotic threat, although this issue is unresolved. This paper will review the important clinical aspects of Giardiasis and will present a practical diagnostic plan, differential diagnosis, and therapeutic plan for the problem of acute diarrhea, and will review the data on the newly approved vaccine for dogs. Biology The life cycle of Giardia is direct15, 16 Cysts may be ingested from contaminated water, but direct animal to animal transmission is also possible, especially where animals are in close contact (cateries or kennels) 9 , 17 Cysts (7-13µ) are oval and contain two trophozoites and two or four nuclei (Figure 1). 13, 16. Excystation occurs in the small intestine and each cyst releases its trophozoites. Maturation and division of the motile trophozoite (12-17µ long and 7-10µ wide) occur in the small bowel (Figure 2). 9, 12 , 13 Trophozoites are teardrop-shaped, have four pairs of flagella, a pair of dark median bodies, are bi-nucleated, and may appear as a "smiling face" when looked at microscopically. 13 , 16, 18 Trophozoites attach to the brush border of the small intestine by means of a ventral disk, where they absorb nutrients1, 13 , 18 Trophozoites multiply by binary fission. 16 Little is known about the mechanism of encystation, but it probably occurs in the ileum or colon. The prepatent period in dogs and cats varies from 5-16 days. Although cysts are susceptible to desiccation, they are hardy and can survive for weeks to months in a cool moist environment. Pathophysiology Little is known about the pathogenesis of Giardia infection in dogs and cats. 2 Studies in laboratory animals and humans have demonstrated malabsorption of nutrients, decreased quantities of intestinal disaccharidases, increased enterocyte turnover, lymphocytic infiltration, and villus atrophy. 1, 9 , 18 , 19 Some of these changes may be secondary to the host's immune response. The wide variation of pathogenicity may be related to the host's immune response or nutritional status, presence of other parasites or gastrointestinal diseases, or strain variation. 1, 16 It appears that both immunoglobulin A and T lymphocytes are involved in the immune response to Giardia. 1, 16, 18 , 20 Giardia-specific IgA may prevent trophozoite attachment to the mucosa. 20 Since younger animals are more commonly affected than older animals, it is possible that some degree of protective immunity develops. 9, 18 Clinical Signs Most dogs and cats infected with Giardia remain asymptomatic. 1, 14-16 When clinical signs occur, acute small bowel diarrhea is most common. 16 Small bowel diarrhea has the following characteristics: liquid to semi-formed feces, moderately increased frequency of defecation, and normal to increased quantity of feces per defecation. 2 The presence of melena (digested blood) is uncommon in cases of Giardiasis . If diarrhea develops, it is usually self-limiting, and has been described as pale, malodorous, and fatty. 16 Severe diarrhea may be accompanied by dehydration, lethargy, and anorexia. However, most affected patients remain bright and alert, afebrile, and maintain a normal appetite. Occasionally acute vomiting may accompany diarrhea. The author has endoscopically observed severe erosion of the duodenum in some cases that resolved following successful treatment for Giardia. 2 A mild eosinophilia occurs in some infected animals. 21 Chronic small bowel diarrhea with weight loss, poor body condition, and intermittent vomiting may also occur. In addition, the authors occasionally have identified Giardia in cases of chronic vomiting. 22 Giardia may be found in dogs and cats that have other gastrointestinal diseases, especially inflammatory bowel disease. In these cases, the clinical signs and laboratory findings reflect the underlying disease. 2 In humans, Giardia may mimic inflammatory bowel disease. 23 Detailed case based descriptions of the clinical signs and laboratory changes associated with spontaneous cases are lacking in the recent veterinary literature. Acute or chronic large bowel diarrhea with hematochezia, excess fecal mucus, and tenesmus may occur on occasion24 In cases of large bowel diarrhea, the frequency of defecation is moderately to greatly increased and quantity of feces per defecation in reduced. Excess fecal mucus is often seen in infected cats. 17, 21 Differential Diagnosis and Diagnostic Plan There are many causes of diarrhea in dogs and cats. 2 Common causes for acute and chronic diarrhea can be found in tables 1-3. A thorough and logical diagnostic plan should be followed to facilitate reaching an accurate diagnosis, minimizing stress to the patient and expense for the owner. The initial step in evaluation of cases with acute diarrhea is to distinguish between self-limiting and life-threatening causes. 2, 25 Most cases are self-limiting and can be diagnosed with a thorough history, careful physical examination, and fecal examination. Life-threatening cases may be associated with some of the following findings: frequent diarrhea, moderate to severe dehydration or abdominal pain, frequent vomiting, or systemic signs such as fever, icterus, lymphadenopathy, coughing, nasal discharge, or dyspnea. Puppies and kittens, especially if unvaccinated, should be suspected of having a life-threatening infectious disease. A recent dietary change, dietary indiscretion, or administration of medication may be identified in the history and suspected as the cause of self-limiting diarrhea. If the history does not identify an underlying problem, a fecal examination should be performed to identify Giardia or other parasites. 2 Appropriate therapy for GI parasites, correction of dietary indiscretion, discontinuing suspect medications, or feeding a low-fat, highly digestible diet will often resolve clinical signs. Animals that are mildly dehydrated may require subcutaneous fluid therapy while those with very frequent diarrhea may benefit from motility modification with narcotics. 26 Failure of the diarrhea to resolve indicates that a more thorough diagnostic approach should be followed. 2 Animals suspected of having a potentially life-threatening problem should receive: fecal examinations for parasites, complete blood count, biochemical profile, urinalysis, and survey abdominal radiographs. 2, 25 Additional procedures may be necessary to confirm specific disorders. Giardia can be identified in animals with either self-limiting or life-threatening acute diarrhea. Because fecal examination should be the initial diagnostic test ordered, a diagnosis can often be reached without performing many unnecessary and expensive diagnostic tests. 2 The diagnostic approach to cases of chronic large bowel diarrhea and acute and chronic vomiting are beyond the scope of this paper and have been recently reviewed. 25, 27-29 Diagnosis of Giardia can usually be made by appropriate fecal examination techniques. If Giardiasis is suspected, but cannot be confirmed, a therapeutic trial maybe indicated. However, cessation of diarrhea after treatment does not confirm a definitive diagnosis of Giardiasis . 2 Microscopic examination of a small amount of fresh diarrheic feces mixed with a drop of normal saline may allow identification of motile trophozoites (Figure 2). 1, 16 Trophozoites can be identified by their rapid "falling leaf" motion and concave ventral surface. Trophozoites may be associated with mucus and the only motility visible may be the flagella. 30 Trichomonads are the only other motile organism similar in size to Giardia. 9, 16 They may be differentiated from Giardia by an undulating membrane, rolling form of motility, lack of a concave surface and single nucleus. 1, 16 One study in dogs showed that examination of fresh feces on 3 separate days identified approximately 40% of dogs infected with Giardia. 31 In that study, Giardia cysts were found in approximately 90% of dogs when three zinc sulfate fecal examinations were done. Trophozoites are rarely found in semi-formed or firm feces. Examination of feces for cysts using zinc sulfate flotation is considered to be the most accurate, practical, rapid, and inexpensive, diagnostic test available. 1 , 9 , 15, 31 In addition to identifying Giardia cysts (Figure 1), eggs of common parasites can also be seen. 16 Approximately 2 gm of feces are mixed with 15 ml of a 33% solution of zinc sulfate (specific gravity 1.18), strained, the tube filled with additional zinc sulfate, and centrifuged for 3-5 minutes at 1500 rpm. If the centrifuge rotor is free-swinging, additional zinc sulfate is added to the tube to create a meniscus and a coverslip placed on the tube. The coverslip can be transferred to a microscope slide for examination after centrifugation. If a fixed-head centrifuge is used, the surface layer of fluid can be transferred to a microscope slide with the bottom of a small glass tube or bacteriologic loop. 1 The microscope slide or coverslip can then be examined for cysts. The sensitivity of the zinc sulfate flotation test is reduced if the centrifugation step is eliminated. Lugol's iodine may be added to the centrifuge tube or slide to stain cysts and make identification easier. 9 However, with experience, cysts can be identified without staining. Yeast can sometimes be confused with Giardia. Most yeast are approximately half as large as Giardia cysts and contain less distinct internal structures. 16 Barium sulfate, several proprietary antidiarrheals, and enemas administered prior to collection of feces may interfere with Giardia detection. Duodenal aspiration of fluid with examination of the sediment for motile trophozoites was at one time considered the gold standard for diagnosis of Giardia in dogs. 32 , 33 Unfortunately this requires either endoscopy or exploratory laparotomy. 34 Ten ml of saline can be infused into the duodenum, through a polyethylene tube passed through the biopsy channel of an endoscope or with a needle and syringe during exploratory laparotomy. The fluid should be aspirated, centrifuged, and immediately examined microscopically for motile trophozoites. An early study comparing duodenal aspiration and zinc sulfate flotation found that duodenal aspiration was positive in 89% of cases while a single zinc sulfate flotation was positive in only 39% of cases. 33 Two more recent studies have contradicted these findings. In a group of research dogs carefully monitored for parasites during a 17 month period, a single zinc sulfate examination identified 77% of infected dogs while a duodenal aspirate identified 67%.35 More recent investigation found that 3 zinc sulfate examinations identified 96% of infected dogs verses 88% with duodenal aspiration. 36 These recent studies support the validity of zinc sulfate flotation as the diagnostic test of choice for Giardia in dogs. A recent review of clinical cases in which duodenal aspiration was performed during upper GI endoscopy, found very few positive tests for Giardia. 22 The reasons why so few Giardia infections were identified were thought to be due to the frequent treatment with metronidazole and the use of zinc sulfate fecal flotation prior to endoscopy. Thus, cases with Giardia were either identified or responded to treatment, avoiding the necessity of endoscopic examination. The authors recommended that duodenal aspiration be performed in cases undergoing upper GI endoscopy if treatment for Giardia has not administered or if zinc sulfate floatation was not performed. Several fecal ELISA tests have been marketed for human use. 1, 16 These tests identify Giardia specific antigens from trophozoites. Preliminary use of one of these tests (Prospect T/Giardia™, Alexon Inc., Mountain View, CA) yielded similar results to zinc sulfate flotation in 84% of examinations in dog feces. 36 However, in 15% of examinations, the ELISA was positive when a single zinc sulfate examination was negative. Giardia was subsequently identified in approximately half of these cases when two additional zinc sulfate flotations were examined. In 1% of fecal samples, the ELISA was negative while the fecal examination was positive. Another report found that a fecal ELISA test was falsely negative in 14% of zinc sulfate positive samples from dogs. 37 This study also found a positive ELISA in 10% of zinc sulfate negative samples. These studies point out that falsely negative ELISA tests occur, and suggest that a negative fecal ELISA does not eliminate the possibility of Giardia infection. In addition, it is possible that the fecal ELISA may help to identify some cases of Giardia missed with zinc sulfate examination. Further investigation is necessary to adequately define the sensitivity and specificity of fecal ELISA testing in dogs and cats. Because of the expense of the fecal ELISA tests, the time required to perform the assay, the lack of identification of other parasite eggs, and the lack of data from cats, the authors recommend using zinc sulfate flotation as the test of choice in identifying animals infected with Giardia. Treatment The authors recommend using either metronidazole or fenbendazole for treating Giardiasis in dogs and cats. The dosage of metronidazole should be 50 mg/kg SID for 5 days. It has been previously suggested to split the dosage and administer it BID. 13 In one study it was effective in 67% of infected dogs at 22 mg/kg BID for 5 days. 38 Tablets should not be divided as the medication is bitter and unpalatable. 1 , 12 , 18 Compounding with tasty flavors, such as tuna or sardine juice, will increase palatability for cats and small dogs that receive less than one tablet. Some authors have found that a lower dosage, 10 mg/kg BID, is effective in cats. 12 Severe neurologic side effects, including seizures and coma, have been reported in dogs receiving higher dosages or prolonged treatment. 39 However, neurologic signs can occur with lower dosages, but are usually reversible if the drug is discontinued. Metronidazole is a potential mutagen and carcinogen, so treatment of pregnant animals should be avoided. 1, 18 Metronidazole enters the parasite by passive diffusion. Under anaerobic conditions, the compound is reduced, forming toxic derivatives that bind to DNA, RNA, and other proteins, leading to denaturation and strand breakage. 40 In humans, metronidazole is metabolized in the liver. Sixty to eighty percent of the metabolites and parent compound is eliminated by the kidney. Approximately 15% is eliminated in the feces. Drug interactions are uncommon, but phenobarbital and prednisone may increase hepatic metabolism while cimetidine may decrease it. Decreased reductive capability has been demonstrated in several metronidazole resistant Giardia strains isolated from human beings. In addition, trophozoites grown in vitro in sublethal concentrations of metronidazole, have developed resistance. 41 This finding could have clinical significance in animals, because dosages used to treat inflammatory bowel disease are lower than those used to treat Giardia. To prevent the potential development of resistance, the authors recommend eliminating the possibility of a Giardia infection by performing 3 zinc sulfate flotations prior to initiating low-dose (10 mg/kg q 12h) long-term metronidazole treatment. Fenbendazole, a drug that has been utilized for many years in dogs and cats without toxicity, has recently been shown to be very effective in treating dogs with Giardia at a dosage of 50 mg/kg SID for three days. 42, 43 Fenbendazole has the advantage of being effective against hookworms, roundworms, whipworms, and some tapeworms. 44 It is poorly soluble in water and rapidly passes through the gastrointestinal tract. It mechanism of action is believed to be binding with the parasite tubulin and inhibiting microtubule assembly. It is safe to administer to pregnant animals. 44 The large animal anthelmintic, albendazole (Valbazen® Suspension, SmithKline Beecham) was reported to be safe and effective in treating dogs with Giardia at a dosage of 25 mg/kg bid for 2 days. 45 However, recent clinical data has demonstrated bone marrow depression can develop in dogs and cats. 46 The authors do not currently recommend the use of albendazole. Furazolidone (Furoxone® Suspension, SmithKline Beecham) is available as a suspension and is convenient to administer to cats and small dogs (4 mg/kg BID for 7 days). It has been shown to be effective in cats. 12 , 17 Quinacrine has been shown to be 100% effective in dogs at 6.6 mg/kg BID For 5 days. 38 Approximately half of the dogs treated developed minor and reversible anorexia, fever, or lethargy. Quinacrine has been shown to improve clinical signs in cats but not to eliminate infection. 21 Unfortunately, quinacrine is not currently available in the United States. Persistent clinical signs or shedding of cysts after treatment may suggest treatment failure, lack of client compliance, reinfection, misdiagnosis, or underlying gastrointestinal disease. 2 Confirming the diagnosis by a different diagnostic test or having a fecal sample evaluated by a commercial laboratory, evaluating client compliance, treating for 10 days, using a different medication, changing the animal's environment, or further diagnostic testing to identify a primary gastrointestinal disorder is indicated. 18 Vaccination Recently, a killed vaccine, GiardiaVaxTM, has been licensed for use in dogs in the United States by Fort Dodge Laboratories. Data presented to the United States Department of Agriculture indicates the vaccine is safe and effective. 47 When vaccinated dogs were challenged and compared to unvaccinated controls in one year duration of immunity studies, they did not develop diarrhea, fewer dogs passed less cysts for shorter periods of time, and trophozoites were not found within the small intestines at the end of the study. In a field study of the vaccine administered to over 750 dogs, no systemic or local reactions were identified. 48 Published reports using a similar vaccine in puppies and kittens 35 days after vaccination showed less diarrhea, fewer animals passing less cysts, and lower numbers of trophozoites within the intestine at the end of the study in the vaccinated animals compared to controls. 49, 50 Although the authors have not developed a firm philosophy regarding the use of this vaccine, we think it may be beneficial in high risk populations (animal research centers, working dog training facilities, military dogs, large breeding kennels etc.), highly endemic areas, and dogs in which reinfection is common. Zoonosis Although controversial, the authors feel that Giardia should be considered potentially zoonotic and adequate precautions taken when contacting feces or infected animals. 1, 16, 18 Attempts to infect dogs and cats with cysts isolated from humans have yielded contradictory results. 14 , 18, 51 , 52 In addition, some laboratory properties of canine and human cysts are different. Some human and animal strains have similar antigenic, genetic, and biochemical properties while others do not. 9, 18 , 51 , 53, 54 Some strains may have a wider host specificity than others. 1, 18 Recently developed molecular biologic tools should allow careful evaluation of strain differences and hopefully will provide conclusive evidence on the zoonotic potential. Infections in humans are often due to water-borne transmission or direct person to person contact. However, it is prudent to consider zoonotic transmission from dogs and cats possible. Additionally, the fecal shedding of cysts by pet dogs and cats may contribute to water contamination. Cysts are very susceptible to drying and many common disinfectants. 1 Quaternary ammonium compounds inactivated cysts more rapidly and at lower concentrations than phenolic or a group of miscellaneous compounds. Phenolic compounds were effective but required longer application times. Many of the miscellaneous disinfectants were effective only at higher temperatures. 55 Dog and cat feces should be disposed of promptly and hands washed immediately after contact with feces or infected pets. 18 If the hair coat is soiled with feces, the pet should be shampooed to remove fecal material. Children and immunocompromised adults should avoid contact with feces. Table 1: Acute Small Bowel Diarrhea - Differential Diagnosis
Table 2: Acute large Bowel Diarrhea - Differential Diagnosis
Table 3: Chronic Small Bowel Diarrhea - Differential Diagnosis
References
Inflammatory Bowel Disease In Dogs And Cats
Inflammatory bowel disease (IBD) is a common cause of chronic vomiting and/or diarrhea in dogs and cats. Since the mid 1980s, the frequency of the diagnosis has vastly increased, paralleling the growth of fiberoptic endoscopy, with the capability of performing minimally invasive mucosal biopsy. The term IBD was adopted from the human medical literature, where it most often refers to two idiopathic conditions, ulcerative colitis and Crohn's disease, each with specific diagnostic criteria. In veterinary medicine, strict diagnostic criteria are lacking and a diagnosis of IBD is made in dogs and cats with chronic gastrointestinal (GI) signs if a mucosal biopsy sample contains increased numbers of inflammatory cells in the absence of a readily detectable primary disorder. When considering a diagnosis of IBD, two concepts must be understood: mucosal inflammation and idiopathic diagnosis. The mucosa of the stomach, small intestine, and large intestine normally contains a population of inflammatory cells that make up a segment of the gastrointestinal immune system. Plasma cells and lymphocytes are found within the epithelium, lamina propria, and mucosal lymphoid follicles. The GI immune system helps protect the body against harmful organisms and prevents their entry into the mucosa and systemic circulation. In addition, the GI immune system minimizes access of normal intraluminal contents (bacteria, bacterial by-products, food antigens, desquamated epithelial cells, and other by-products of the digestive process) to the mucosa and regulates and dampens the inflammatory response to small quantities that do cross the mucosal barrier. Without tolerance (lack of or minimal inflammatory response) to normal GI contents, a continuous and damaging inflammatory response to bacteria and food antigens would occur. Thus, proliferation of inflammatory cells within the mucosa is an appropriate stimulus when harmful antigens or large amounts of normal intraluminal contents gain access to the mucosa. However, even an appropriate localized inflammatory process can result in the recruitment of additional inflammatory cells, release of potent inflammatory mediators, and the development of a self-perpetuating destructive process that results in the clinical signs of vomiting and/or diarrhea. Inflammation damages the mucosal barrier, permitting entry of additional intraluminal antigens across the mucosa, which stimulates further inflammation, damaging the mucosal barrier further, and so on. The division between and control of appropriate and detrimental inflammation is not clear-cut or understood at the present time. Secondly, IBD must be an idiopathic diagnosis, requiring a thorough and complete diagnostic workup. Occult parasites, bacterial and viral infections, metabolic and neoplastic disorders, bacterial overgrowth, and newly described conditions, such as wheat-sensitive enteropathy, need to be eliminated from the differential diagnosis before making a diagnosis of IBD. After eliminating these diagnoses, a group of heterogeneous idiopathic disorders are lumped together under the umbrella diagnosis of IBD. In the future, new syndromes will be described, and these cases will no longer be diagnosed as having IBD. Our concept of idiopathic IBD must be flexible and adapt to new developments. In human beings a vast amount of research has been devoted to IBD. No consistent etiology has emerged; however, much has been learned about the pathophysiology of these conditions. Increased mucosal permeability appears to be a central component of IBD. A breakdown in the mucosal barrier results in increased access of antigens to the mucosa, and the development of a self-perpetuating inflammatory process. Increased permeability may be due to a primary mucosal defect or result from damage secondary to infectious, metabolic, or toxic insults. Alternatively, faulty immunoregulation may occur where normal intraluminal antigens induce an exaggerated immune response that is not dampened and controlled by normal suppressor mechanisms. Which of these underlying mechanisms, if any, occurs in dogs is unknown. The type of inflammatory bowel disease diagnosed depends on the organ affected and the predominant type of inflammatory cells present. Thus, lymphocytic infiltration of the stomach is called lymphocytic gastritis. Eosinophilic inflammation of the colon is termed eosinophilic colitis. Multiple regions of the GI tract can be affected, i.e. enterocolitis. Although the most common form of IBD in dogs and cats is plasmacytic lymphocytic, eosinophilic, suppurative, and histiocytic forms occur. Mixed inflammation is common making it difficult in some cases to label the primary disorder based on the predominant cell type. The distinction between plasmacytic and lymphocytic inflammation with many eosinophils, and eosinophilic inflammation with many plasma cells and lymphocytes may not be clear cut or important as it relates to pathophysiology and treatment. A diagnosis of IBD cannot be made without mucosal biopsy, and yet evaluation of biopsy specimens can be difficult, confusing, contradictory, and frustrating. This is especially true with endoscopic samples which are often less than 2 mm in diameter. Pathologists don't agree on what is considered the normal histopathologic appearance of the mucosa in dogs. Do diet and parasite history effect normal architecture? Histological criteria for IBD have only recently been proposed and are currently being debated. Which are the most important and distinguishing histologic criteria? Are histologic criteria related to differing pathophysiologic mechanisms and varying responses to therapy? Therapeutic recommendations for dogs with IBD are largely based on clinical experience. Controlled clinical trials and research models are lacking. Restricted antigen diets appear to benefit dogs and cats with colitis. Beneficial effects could relate to a primary food allergy or to reduction of antigens crossing a damaged mucosal barrier, resulting in less inflammation. High fiber diets have been effective in cats with colitis. In addition to limited antigen diets, corticosteroids, sulfasalazine, and metronidazole are the mainstays of therapy and control clinical signs by reducing or inhibiting the inflammatory response rather than treating the underlying cause. Drugs with antibacterial activity alter GI flora, probably reducing the number of bacteria crossing a damaged mucosal barrier, diminishing the inflammatory response. Treatment needs to be individualized for each patient, with a trial and error approach, which probably reflects the heterogenicity of disorders lumped together as IBD. In human beings less toxic sulfasalazine derivatives and poorly absorbed or rapidly metabolized corticosteroids have shown benefit in the treatment of IBD and may become part of the veterinarian's therapeutic arsenal. Currently in human beings specific blockers of inflammatory mediators, such as leukotriene B4, are being investigated. If these drugs prove to be safe and effective treatments in people, they will undoubtedly be evaluated in dogs. We have learned a great deal about IBD in dogs and cats during the last decade. However, it is easy to become complacent and erroneously confer a diagnosis of IBD, leading to inappropriate treatment with potent and toxic antiinflammatory drugs for long periods of time. To prevent IBD from becoming an abused and inaccurate diagnosis, complete diagnostic workups and strict evaluation of histologic criteria must be performed. In human beings, infection with Giardia has been shown to mimic IBD. In our patients, have we thoroughly eliminated the possibility of Giardia infection prior to making a diagnosis of IBD? Before its identification in human beings, many people infected with Campylobacter jejuni were erroneously diagnosed as having ulcerative colitis. Have we eliminated the possibility of bacterial enterocolitis causing chronic diarrhea prior to diagnosing IBD? Bacterial overgrowth has recently been associated with plasmacytic lymphocytic enteritis in a dog which histologically improved after resolution of the bacterial overgrowth. Bacterial overgrowth remains a difficult diagnosis to prove; however, measurement of serum B12 and folate can provide supportive evidence for this disorder. Have cases of wheat sensitive enteropathy in Irish Setters been incorrectly placed on lifelong corticosteroid therapy, instead of a wheat-free diet, because intestinal biopsies showed increased numbers of plasma cells and lymphocytes? The concept I would like to leave the reader with is that although a clinical picture of IBD in dogs has emerged, much more needs to be learned. Our patients can benefit from skeptical evaluation of every diagnosis of IBD we make. Are we truly dealing with an idiopathic condition or have we made an error in our diagnostic approach and failed to identify an underlying condition? The following sections are from: Leib MS and Monroe WE. Practical Small Animal Internal Medicine. WB Saunders, Philadelphia, 1997: 709-715. CLINICAL SIGNS The most common clinical signs in dogs and cats with IBD are vomiting, diarrhea, and weight loss. Affected animals may vomit food, water, mucus, or bile stained fluid. Vomiting may not be temporally related to the ingestion of food or water. Diarrhea may have characteristics associated with the small intestine (increased fecal volume per defecation or weight loss), large intestine (increased frequency, reduced fecal volume per defecation, tenesmus, hematochezia, and excess mucus), or both . Appetite is usually normal or depressed, although some animals may exhibit increased appetites. In the early stages of IBD, clinical signs often are mild and intermittent, and may occur cyclically. As the condition progresses clinical signs often gradually increase in frequency and intensity and may become continuous. In some cases the first stool of the day may be normal or near normal, while successive bowel movements become looser. During severe episodes, mild pyrexia, depression, and anorexia may occur. Physical examination may be unremarkable. Weight loss can be present, and may be severe in some cases. Thickened segments of bowel wall or distended bowel with gas and/or fluid may be detected during abdominal palpation. Mild to moderate dehydration may be detected if vomiting and/or diarrhea are severe. Digital rectal examination may produce pain or detect roughened mucosa. Fresh blood may be visible upon the glove after removal from the rectum. DIAGNOSIS The definitive diagnosis of IBD requires histopathologic assessment of GI mucosal samples and elimination of other diseases that result in mucosal inflammation. Mucosal samples may be obtained during endoscopic examination, or if endoscopy is not available, via exploratory surgery. In order to identify other causes of mucosal inflammation, a thorough diagnostic evaluation following the guidelines described under the diagnostic plans for chronic vomiting (see CH 31) and chronic diarrhea must be followed in all cases. ROUTINE LABORATORY EVALUATION Routine laboratory evaluation may be normal in cases of IBD. However, a wide variety of mild and nonspecific hematologic or biochemical abnormalities may occur. No consistent or diagnostic pattern of laboratory abnormalities in animals with IBD has been identified. RADIOGRAPHY Survey abdominal radiographs do not generally contribute to the diagnosis of IBD, but may be helpful in eliminating other causes of vomiting, diarrhea, or weight loss. They may demonstrate gas and/or fluid-filled loops of bowel. Upper and lower barium contrast studies may demonstrate mucosal irregularity and possibly ulceration or thickened intestinal walls, but these findings are not specific for IBD . ENDOSCOPY Endoscopic abnormalities include hyperemia, mucosal hemorrhage, increased mucosal granularity, increased mucosal friability, loss of visualization of colonic submucosal blood vessels, and in some cases ulceration or inability to adequately distend the intestinal lumen. Multiple biopsy samples should always be obtained, even if the mucosa appears normal, because histologic abnormalities can be present. The clinical signs should indicate which portion of the GI tract to examine (vomiting: stomach and duodenum, small bowel diarrhea: duodenum and possibly ileum, and large bowel diarrhea: cecum and colon). Because histologic changes may be present in regions without producing classic clinical signs, some authors recommend examining and obtaining biopsy samples from both the upper and lower gastrointestinal tracts in all cases of suspected IBD. HISTOPATHOLOGY The histologic criteria for establishing a diagnosis of IBD in dogs and cats remain controversial. Classification schemes have recently been proposed which provide some objective criteria that can be applied to the diagnosis of cases of IBD. All diagnostic classification schemes have as central criteria the presence of increased numbers of plasma cells and lymphocytes within the lamina propria. Lesser numbers of eosinophils and scattered neutrophils and macrophages often are found. Other histologic changes that occur in IBD include edematous separation of crypts, increased numbers of intraepithelial lymphocytes, blunting or fusion of villi, obliteration of crypts, cryptal abscessation, basophilia with flattening of surface epithelium, and erosion. The major difficulty in interpreting the histopathologic changes in cases of IBD lies at both ends of the spectrum; mild lesions need to be differentiated from normal and severe lesions from lymphosarcoma. Inflammatory infiltrates commonly are found in close proximity to neoplastic cells in cases of lymphosarcoma. Thus, a small flexible endoscopic forceps biopsy may miss a neoplastic lesion. THERAPY Optimal therapy for dogs and cats with IBD often requires a combination of dietary and pharmacological management that should be modified for each case. If initial therapeutic management does not improve clinical signs, other drugs and drug combinations should be instituted. Compared to administration of a single drug, combination therapy often allows decreased drug dosages to be used, which reduces adverse drug effects. The initial treatment of choice varies greatly among authors with some preferring dietary manipulations while others use sulfasalazine, prednisone, or metronidazole. DIETARY MANAGEMENT Because of the potential role of dietary antigens as either a primary or secondary factor in the pathogenesis of IBD, hypoallergenic diets have been recommended as the initial treatment. Successful management of dogs and cats with plasmacytic / lymphocytic colitis has been documented after feeding either a diet of rice and low fat cottage cheese, or hypoallergenic diets with protein sources of lamb or chicken. A hypoallergenic diet must contain protein and carbohydrate sources novel to the patient. A thorough dietary history should be obtained to determine which ingredients the animal has not been previously exposed to. Many hypoallergenic diets are commercially available and utilize lamb, egg, rabbit, venison, fish, or chicken as a protein source. A homemade diet can be formulated using these protein sources, or others such as cottage cheese or tofu with rice or potatoes as a carbohydrate source. Homemade diets can be deficient in vitamins and minerals. They can be safely fed for trial periods, but must be balanced for long term use. Vitamin and mineral supplements must be carefully selected because many contain extracts and flavorings. The hypoallergenic diet should be fed for four to eight weeks and must be the only nutrient source that the dog or cat receives. Other household pet's food, table scraps, treats, and flavored vitamin and heartworm preventatives must be avoided. Free roaming animals must be strictly supervised to avoid the potential for dietary indiscretion. If the diarrhea resolves when the hypoallergenic diet is fed, the animal should be challenged with its original diet. Diarrhea should rapidly return if dietary hypersensitivity is a component of IBD. The owner can continue feeding the hypoallergenic diet or can pursue antigen identification by adding single ingredients to the hypoallergenic diet for 7-10 days. Although hypersensitivity can occur to any dietary constituent, common offending allergens include beef, cows milk, eggs, fish, wheat, soybeans, oats, or corn. After identifying the ingredient that causes diarrhea, a commercial or homemade ration that lacks the offending antigen can be used. There is some evidence the patient can subsequently develop hypersensitivity to other antigens. Some authors have advocated rotating diets to prevent this from occurring. In addition, use of a "sacrificial" hypoallergenic diet along with anti-inflammatory medications, until the mucosal barrier is repaired, and then switching to a different hypoallergenic diet has be suggested. This recommendation is based on development of hypersensitivity to the newly administered diet while the mucosal barrier is healing. Poorly digestible novel proteins may induce hypersensitivity in patients with increased mucosal permeability because protein digestion usually renders it non-allergenic. Cooked eggs and cottage cheese are assimilated more readily than many meats and may be more hypoallergenic to intestinal mucosa than meat-based diets. Although elimination testing is the current diagnostic procedure of choice, preliminary experience using gastroscopic food sensitivity testing indicates it may be a useful method to identify the offending food antigen in patients with IBD. In addition to hypoallergenic diets other types of diets may be beneficial in the management of IBD. In cats with plasmacytic / lymphocytic colitis a high fiber diet (Prescription diet r/d ®, Hill's Pet Products) or psyllium supplementation (Metamucil®, Proctor and Gamble) has been documented to relieve or improve diarrhea. Even if diarrhea does not completely resolve when feeding a hypoallergenic or high fiber diet, concurrent dietary and medical therapy may achieve control of clinical signs with lower dosages of medication, potentially with fewer side effects, than with medical management alone. If diarrhea continues despite feeding either a hypoallergenic or high fiber diet, the animal may benefit from a highly digestible diet (as described in the section on dietary indiscretion) along with medical management. CORTICOSTEROIDS Corticosteroids are the drugs of choice for cats with colitis and dogs and cats with enteritis that have failed to respond to dietary management. They are used less frequently in dogs with colitis as most cases can be managed utilizing diet, sulfasalazine, or the newer mesalamine products. In dogs showing adverse effects associated with sulfasalazine, adding corticosteroids may allow reduction of the sulfasalazine dosage. The efficacy of corticosteroids is thought to be due to their anti-inflammatory, anti-prostaglandin, anti-leukotriene, and immunosuppressive effects. They inhibit cell membrane phospholipase A, suppressing production of arachidonic acid and subsequently prostaglandin and leukotriene synthesis. Corticosteroids also increase sodium and water absorption and help regulate colonic electrolyte transport. An initial dose of prednisone or prednisolone of 2.0 mg/kg/day often will improve clinical signs within 7-10 days . After normal feces have been produced for approximately four weeks the dosage should be decreased by 50%. As long as diarrhea does not return the dosage can gradually be reduced (at 2-4 week intervals) until the least amount given every other day that controls clinical signs is reached. Typical maintenance therapy is 0.5-1.0 mg/kg q48h. Some animals require long-term treatment whereas in others it is possible to discontinue prednisone within three to four months. When using prednisone with sulfasalazine in dogs, it may be possible to reduce the dosage of sulfasalazine when the prednisone dosage declines to 1.0 mg/kg q48h. Dietary management with a hypoallergenic, high fiber, or highly digestible diet often has a corticosteroid-sparing effect. In cats that cannot tolerate daily oral medication, injectable long-acting methylprednisone acetate, 20 mg subcutaneously, can be administered every 2-4 weeks. Injectable therapy, however has not been as successful as daily medication in controlling clinical signs. Adverse effects of corticosteroids are uncommon in cats. Side effects are common in dogs and often are dosage related. They include polyuria-polydipsia, polyphagia, iatrogenic hyperadrenalcorticism, hypothalamic-pituitary suppression, gastrointestinal bleeding, acute pancreatitis, steroid hepatopathy, and predisposition to bacterial or fungal infections. SULFASALAZINE The treatment of choice for dogs with colitis that do not respond to dietary management is sulfasalazine. Sulfasalazine consists of mesalamine (previously called 5-aminosalicylic acid) linked by an azo bond to sulfapyridine. This linkage prevents absorption by the small intestine and allows delivery of approximately 70% of the drug to the colon. Bacteria in the distal small intestine and the colon break the azo bond liberating both components. Sulfapyridine is absorbed, metabolized in the liver, and excreted by the kidney. It is not thought to have therapeutic effects in IBD and is responsible for some of the adverse reactions associated with sulfasalazine. Mesalamine acts topically in the colon to reduce mucosal inflammation. Although the mechanism of action was once believed to be due to antiprostaglandin activity, recent evidence supports its antileukotriene activity. The recommended dosage range for sulfasalazine in dogs is 20-50 mg/kg to a maximum of 1.0 gm TID. High dosages may be needed in chronic cases. When initially treating a dog a dosage of 20-30 mg/kg TID usually is effective. One of the most common therapeutic mistakes is discontinuation of therapy too soon after resolution of clinical signs, which can lead to diarrhea that may be refractory to the dosage that previously controlled clinical signs. After the dog has normal feces for four weeks the dosing frequency should be reduced to BID. After an additional 2-4 weeks without diarrhea, maintenance dosages should be decreased by 50%, still given BID. If diarrhea returns, the dosage should be increased to the amount that previously controlled clinical signs. In some dogs sulfasalazine can be discontinued while other cases require long-term therapy. Concurrent dietary management with a hypoallergenic or a highly digestible diet may help control clinical signs with a lower dosage of sulfasalazine. In dogs, vomiting and keratoconjunctivitis sicca are common side effects. Vomiting can usually be controlled by administering medication with food or using an enteric-coated preparation. If decreased tear production is detected early, reducing the dosage or discontinuing the drug may result in increased tear production and prevent progression to keratoconjunctivitis sicca. However, if decreased tear production is not detected early, it will become irreversible. The mechanism of action for toxicity is unknown, but sulfapyridine may directly damage the lacrimal and nictitans tear glands, reducing production of the aqueous component of tears. When initiating sulfasalazine treatment, especially with high dosages, tear production should be measured at two-week intervals. If therapy is continued long term, tear production should be measured monthly. Treatment of keratoconjunctivitis sicca associated with sulfasalazine administration with cyclosporine was shown, in a limited number of cases, to be less successful compared to other causes. Sulfasalazine should be used with caution in cats because of their sensitivity to salicylates. Prednisone is the drug of choice for cats with colitis that fail to respond to hypoallergenic, high fiber, or highly digestible diets. Sulfasalazine has been used in cats at 10-20 mg/kg BID-SID. Side effects include anorexia and anemia. The oral suspension (50 mg/ml) allows accurate measurement of doses for cats. NEWER MESALAMINE PREPARATIONS In order to reduce the toxicity associated with sulfasalazine, new drugs have been developed that deliver mesalamine to the colon without linkage to sulfapyridine. These drugs have been shown to be safe and effective in treating human beings with IBD. 181, 182 Two have been approved for use in human beings in the United States. Olsalazine, Dipentum® (Kabi Pharmacia Laboratories), consists of two molecules of mesalamine linked with an azo bond. Asacol® (Procter & Gamble Pharmaceuticals) consists of mesalamine coated with an acrylic resin that dissolves at pH 7 or greater, usually in the terminal ileum and colon. Although there are no established guidelines for using these drugs in dogs with colitis, 10-20 mg/kg TID and 10 mg/kg TID, respectively, have been suggested. These newer agents are less toxic than sulfasalazine as approximately 80-90% of human beings with sulfasalazine intolerance can be treated with these drugs without adverse effects. The most common adverse effect of olsalazine in people is watery diarrhea, which may be minimized by taking the drug with food and gradually increasing the dosage. Although these new drugs have not been used extensively in dogs, keratoconjunctivitis sicca has unfortunately been associated with Asacol® in a limited number of cases. The mechanism of toxicity is unknown. Dipentum® and Asacol® should not be the initial drug used in dogs with colitis, but should to be reserved for patients that develop side effects associated with sulfasalazine. METRONIDAZOLE Metronidazole possesses several properties thought to be beneficial in dogs and cats with IBD. Besides antiprotozoal effects, it is a broad spectrum antibiotic with impressive activity against anaerobic bacteria, it inhibits cell mediated immunity, alters neutrophil chemotaxis, and may have other immunosuppressive effects. Although most veterinary authors suggest that it be used in conjunction with sulfasalazine or prednisone, it can be used to manage dogs and cats with IBD as a single agent. Ten to twenty mg/kg BID-TID have been recommended in dogs and cats. Adverse effects at this dosage are uncommon, but severe neurologic toxicity has been reported with higher dosages. Peripheral neuropathy has been reported in people receiving long term therapy. Combination therapy with metronidazole may have a sulfasalazine or prednisone sparing effect, often resulting in fewer adverse drug reactions. The authors have found that the addition of metronidazole, for 2-4 weeks, to maintenance therapy may be beneficial in dogs or cats that experience an unexplained bout of vomiting and/or diarrhea. AZATHIOPRINE Other immunosuppressive drugs can be used in dogs and cats with IBD. Azathioprine, (Imuran®, Burroughs Wellcome) is the most commonly used drug of this group. Azathioprine is a purine analog that competes with natural purines in the synthesis of DNA and RNA, resulting in nonfunctional nucleic acid strands and preventing proliferation of rapidly dividing cells. Azathioprine is metabolized to 6-mercaptopurine in the liver. Most veterinary authors recommend azathioprine for cases of refractory IBD that have not responded to the previously described treatments. In the authors' experience, azathioprine and other immunosuppressive agents are infrequently needed in cases of IBD. The initial dose in dogs is 2.0 mg/kg SID and in cats 0.3 mg/kg q48h. It may take several months of therapy for this drug to be effective. The dosage can often be reduced to 2 mg/kg q 48h in dogs. Side effects seen in dogs and cats include myelosuppression, hepatic disease, and acute pancreatitis. TYLOSIN Tylosin is a macrolide antibiotic that has been recommended for the treatment of IBD in dogs and cats. Its mechanism of action is unknown. In the authors' experience it is not often beneficial in refractory cases of IBD. The recommended dose range is broad, although 10-20 mg/kg BID is commonly used. It currently is available as a powder for use in poultry, Tylan® Soluble, Elanco, that contains approximately 2.25 gm per teaspoon. Clinical experience suggests it is safe for long-term administration. Tylosin can be used in cases that don't respond to dietary management, sulfasalazine, prednisone, or metronidazole, or when adverse effects to these medications are encountered. PROGNOSIS The prognosis for most cases of PLEC is good. In some animals medication can be discontinued, while others require long-term or life-long treatment. Some cases will develop recurrent clinical signs and need to be retreated. REFERENCES
Chronic Large Bowel Diarrhea in Dogs: What's New?
Chronic large bowel diarrhea is a common problem in dogs. Diarrhea is often accompanied by hematochezia, excess fecal mucus, and tenesmus. The frequency of defecation is increased and the quantity of feces / defecation may be reduced. Weight loss is uncommon. Common causes include highly digestible diet responsive diarrhea, whipworms, Clostridium perfringens enterotoxicosis, irritable bowel syndrome, fiber-responsive large bowel diarrhea, and neoplasia. A thorough diagnostic plan should be followed to reach an accurate diagnosis efficiently. The author's diagnostic plan includes multiple fecal examinations, rectal cytology, elimination of dietary indiscretion, feeding a highly digestible diet for 3-4 weeks, treatment for whipworms, laboratory evaluation consisting of a CBC, biochemical profile, and UA, flexible colonoscopy with multiple mucosal biopsies. After following the above diagnostic plan it is common to identify no abnormalities and hence make the diagnosis chronic idiopathic large bowel diarrhea. In a recent review of dogs with chronic large bowel diarrhea, idiopathic cases were the most common diagnosis and represented 25% of dogs that underwent colonoscopy.1 In the author's experience, these dogs have either irritable bowel syndrome, fiber-responsive large bowel diarrhea, or Clostridium perfringens enterotoxicosis in which rectal cytology has not identified an abnormal number of spores. The purpose of this presentation is to review these three conditions and demonstrate how they can be diagnosed, and successfully treated in practice. Portions of the following discussion are from the author's chapter in Leib MS and Monroe WE (ed.) Practical Small Animal Internal Medicine. WB Saunders, Philadelphia, PA, 1997: 736-738. Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is a commonly diagnosed but poorly described functional disorder of the intestines that occurs in dogs.2 Synonyms include spastic colon, nervous colitis, and mucus colitis.3 Colonic dysfunction exists in the absence of structural, biochemical, or microbiologic abnormalities.4 Diarrhea is often intermittent and hematochezia is uncommon.3 Bloating, nausea, vomiting, and abdominal pain may occur. Often stressors can be identified that are associated with development of cyclic clinical signs. Dogs may be nervous, high-strung, or have abnormal personality traits. The identification of abnormal personality traits or stressors that initiate episodes of diarrhea in a dog with chronic idiopathic large bowel diarrhea is strongly suggestive of IBS. If the dog responds to dietary fiber supplementation, I call the condition fiber-responsive large bowel diarrhea. If the dog does not respond to fiber supplementation, I treat in a trial and error fashion with antispasmodics, CNS sedatives, and opioids and have the owner attempt to reduce stress. The intermittent nature of clinical signs may make assessment of therapy difficult. Pain can often be relieved by antispasmotic agents and the effects of stressors can be reduced by sedatives. Librax® (Roche) contains the sedative chlordiazepoxide (5 mg) and clidinium bromide (2.5 mg), an anticholinergic agent. A suggested dosage is 0.1-0.25 mg/kg of clidinium or 1-2 capsules PO BID-TID.3,5 The drug can be given when the owner first notices abdominal pain or diarrhea or when stressful conditions are encountered, and can usually be discontinued after a few days. Other anticholinergics such as propantheline (Pro-Banthine®, Searle), 0.25 mg/kg PO BID-TID, hyoscyamine (Levsin®, Schwarz Pharma Kremers Urban), 0.003-0.006 mg/kg PO BID-TID, or dicyclomine (Bentyl®, Lakeside Pharmaceuticals), 0.15 mg/kg PO BID-TID have been suggested.3 Anticholinergics can decrease or inhibit GI motility which may worsen diarrhea. In people, side effects include xerostomia, urinary retention, blurred vision, headache, psychosis, nervousness, and drowsiness. The prognosis for cure of IBS in dogs is guarded. Affected dogs may have intermittent clinical signs for years. However, environmental and pharmacologic therapy may result in control or reduction of clinical signs. Dogs that respond to fiber supplementation have a very good to excellent prognosis. Fiber-Responsive Large Bowel Diarrhea The author routinely adds fiber to a highly digestible diet in dogs with chronic idiopathic large bowel diarrhea, even if irritable bowel syndrome has been diagnosed.2,6 In cases of fiber-responsive large bowel diarrhea (FRLBD), chronic intermittent or continuous large bowel diarrhea is usually accompanied by hematochezia, excess fecal mucus, and tenesmus. Abdominal pain and vomiting can occur in some dogs. Nervousness, abnormal personality factors, and stressors have been identified in approximately 40% of cases. However, in some of these cases, a temporal relationship to the diarrhea could not be established. Soluble fiber, psyllium hydrophilic mucilloid (Metamucil®, Procter & Gamble), added to a highly digestible diet (i/d® Hills), has resulted in excellent or very good results in approximately 80% of dogs with chronic idiopathic large bowel diarrhea. In the authors' cases, the median amount of Metamucil® added to the diet was two TBSP / day which was approximately 1.3 g psyllium / kg / day. I have not been able to identify any clinical findings that help to predict whether a dog will respond to fiber supplementation. In some dogs, the amount of fiber added to the diet can be reduced or withdrawn entirely, while in others the highly digestible diet can be replaced with a grocery store brand of food after the diarrhea resolves. Some of the dogs with FRLBD have classic signs of IBS. However, many of the dogs have hematochezia, a clinical sign considered uncommon in dogs with IBS.3,7 In addition, it has been reported that only rarely do dogs with IBS respond to dietary fiber supplementation alone.3 Dietary fiber is a collective term for a wide variety of plant polysaccharides and lignins that are resistant to mammalian digestive enzymes.8,9 There are many types of dietary fiber, each with diverse chemical, physical, and physiologic properties. Water soluble fibers include pectin, gums, mucilages, and some hemicelluloses.8,9 They are found in the parenchymatous portions of fruit and vegetables, and in the seeds of leguminous plants. Water insoluble fibers includes cellulose, lignin, and some hemicelluloses. They are found in cereal grains and seed coats. There are several potential mechanisms by which dietary fiber supplementation may result in clinical improvement in dogs with FRLBD. Soluble fiber adsorbs a large quantity of water, improving fecal consistency. Colonic bacteria, which make up approximately 40-55% of the dry stool mass, ferment soluble fiber, which results in a vast increase in the numbers (but not types) of colonic bacteria and quantity of bacterial byproducts.10,11 Insoluble fiber greatly adds to fecal volume. Thus, dietary fiber can increase fecal bulk which increases colonic distention, the major stimulus for normal colonic motility. With increased colonic distention, an improved motility pattern in dogs with FRLBD may result in resolution of clinical signs. In fact, dietary fiber has been shown to normalize colonic myoelectrical activity and colonic motility in people. Bacterial fermentation of fiber leads to the production of short chain fatty acids, of which butyrate serves as an energy source for colonocytes.10-12 Psyllium comes from the seeds or husks of the plant ispaghul and consists of approximately 90% soluble fiber. Although there are no other reported studies evaluating the use soluble fibers in dogs with diarrhea, there are in human beings. Treatment with psyllium has been shown to be beneficial in children with nonspecific chronic diarrhea of childhood, adults with chronic idiopathic diarrhea, patients with ulcerative colitis in remission, and some with irritable bowel syndrome.13-16 Psyllium has also been shown to improve diarrhea in human burn patients receiving enteral nutrition and in another group of tube-fed patients.17,18 Psyllium also improved fecal consistency in humans with experimentally induced secretory diarrhea and also reduced the acceleration of colonic transport in those with lactulose-induced diarrhea.19,20 Clostridium perfringens Enterotoxicosis Acute and chronic large bowel diarrhea has been associated with Clostridium perfringens type A enterotoxin.21 Vomiting, weight loss, flatulence, and abdominal pain occur less frequently. The disorder occurs most commonly in dogs. Both naturally occurring and hospital acquired cases have been detected.22 Diagnosis is commonly based on finding increased numbers of spores in rectal cytology specimens, or demonstrating the toxin in the feces (which is primarily done at referral hospitals). The reason for including this syndrome within this discussion of chronic idiopathic large bowel diarrhea is that in the author's hospital approximately 25% of toxin positive cases are negative on rectal cytology. Thus, in practices in which toxin is not analyzed, a case of Clostridium perfringens could easily be diagnosed as idiopathic. If fecal toxin cannot be routinely tested in a private practice, it may be indicated to treat a dog with chronic large bowel diarrhea with an appropriate antibiotic as described below to eliminate the presence of C. perfringens enterotoxicosis. Diagnosis can be confirmed by identifying enterotoxin in a fecal sample. Most commonly this was done with a reverse latex agglutination test (PET-RPLA Kit, Oxoid USA, Columbia MO). However, the test is not available at the present time. An ELISA test (Clostridium perfringens Enterotoxin Test, TechLab, Blacksburg, VA) is now being used in the author's hospital, but we have not had enough experience to comment on test results. Diagnosis should be suspected when greater than 3-5 spores per oil immersion field are found in a rectal cytology specimen. The spores are larger than most bacteria and assume a "safety pin" appearance. However, a preliminary study has recently shown a poor relationship between fecal toxin and spores in rectal cytology samples23. A vegetative form of C perfringens is a normal inhabitant of the colon. The enterotoxin is a component of the spore coat and causes intestinal fluid accumulation, mucosal damage, and diarrhea.24 The stimuli for sporulation and enterotoxin production are unknown. Enterotoxin has also been identified in some cases of hemorrhagic gastroenteritis syndrome (HGE), parvovirus, Giardiasis , and IBD.21,25 The author has also demonstrated toxin in the feces of dogs without diarrhea! Acute cases may resolve spontaneously. Chronic cases respond to antibiotic therapy in 3-5 days. Metronidazole at 6 mg/kg BID-TID for 7 days is often effective.21 Ampicillin 22 mg/kg PO TID or amoxicillin 11-22 mg/kg PO BID-TID are also effective treatments. Cases that show intermittent clinical signs require long term therapy. Tylosin can be used in these cases at 10-20 mg/kg BID. Some cases respond to feeding a high fiber diet. The prognosis is excellent. Most affected animals respond to therapy within several days. Clinical findings have not been identified that predict which animals need long-term therapy. TABLE 1 CHRONIC DIARRHEA HISTORY FORM
Date________________ Duration of diarrhea: Continuous / intermittent (circle) If intermittent: Inciting factors (dietary indiscretion, stress, travel, thunderstorms etc.): When diarrhea is present: Weight loss? If present how much? Vomiting? If present: Diet (changes, effects): Meals / day: Maintenance medications: Previous treatments (drug, dose, duration, response): continue on back of form if necessary small bowel large bowel mixed bowel (circle) Answer each question for the average clinical sign. If frequency or severity has progressed, indicate (frequency was 5/day, during last 4 weeks 9/day). TABLE 2: LOCALIZATION OF CHRONIC DIARRHEA
TABLE 3: CHRONIC DIARRHEA - DIFFERENTIAL DIAGNOSIS
CHRONIC SMALL BOWEL DIARRHEA CHRONIC LARGE BOWEL DIARRHEA FIGURE 1: DIAGNOSTIC APPROACH TO CHRONIC DIARRHEA
 CHRONIC DIARRHEA CASE 1
SIGNALMENT HISTORY PREVIOUS THERAPY PAST HISTORY PHYSICAL EXAMINATION LOCALIZATION OF DIARRHEA (CIRCLE ONE) DIFFERENTIAL DIAGNOSIS DIAGNOSTIC PLAN DIAGNOSTIC RESULTS / DIAGNOSIS THERAPY COMMENTS / NOTES CHRONIC DIARRHEA CASE 2
SIGNALMENT HISTORY PREVIOUS THERAPY |