Chronic Feline Diarrhea: Key Points on Diagnosis and Management. Abstract. Key Content

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1 Chronic Feline Diarrhea: Key Points on Diagnosis and Management Todd R. Tams, DVM, Diplomate, ACVIM VCA Antech Los Angeles, California Abstract Diarrhea is the hallmark sign of intestinal dysfunction and is a common presenting complaint for cats. There are many potential causes, creating a challenge for the veterinarian to make an accurate diagnosis quickly and thereby enabling the start of effective therapy as early as possible. Possible causes of diarrhea include primary intestinal disease, disorders of the liver or pancreas, and a number of other factors or conditions that adversely affect intestinal function. Whether the diarrhea is persistent or intermittent, initial investigation should include testing for Giardia, Cryptosporidium, Tritrichomonas foetus, and Clostridium perfringens along with evaluating for nematode parasites and dietary causes. Early evaluation of thyroid levels is also recommended in cats 5 years and older along with other baseline blood tests. The author discusses how to approach assessment of cats with chronic diarrhea and focuses on diagnosing the major causes and defining the appropriate treatment for each disorder, including how to manage feline patients with concurrent problems. Key Content The major challenge to veterinarians in assessing cats with chronic diarrhea is in making an accurate diagnosis so that effective therapy can be instituted as early as possible. Giardia, Cryptosporidium, Tritrichomonas foetus, and Clostridium perfringens enterotoxicosis are important problems in cats and, along with nematode parasites and dietary causes, should be investigated early in the course of diarrhea.. Reliance on passive fecal flotation without centrifugation is no longer acceptable or recommended for confirming the presence of nematode parasites or Giardia spp as that assay is far too insensitive. In animals that are known to be chronic carriers of Giardia, supplementing the diet with fiber may be beneficial because increased dietary roughage may make it more difficult for Giardia trophozoites to attach to the small intestinal microvilli. Infection with Cryptosporidium species is much more common than most small animal practitioners recognize. In 2004 the AAFP adopted a position statement recommending that all kittens and adult cats with persistent diarrhea be screened for Cryptosporidium. From Gastrointestinal Diseases, proceedings of a symposium sponsored by Pfizer Animal Health by The Gloyd Group, Inc. All rights reserved. The opinions expressed in this article are those of the author and do not necessarily reflect the official label recommendations and points of view of the company or companies that manufacture and/or market any of the pharmaceutical agents referred to.

2 Tritrichomonas foetus is commonly mistaken for Giardia trophozoites on direct smear exam. To increase the likelihood of finding Tritrichomonas trophozoites on direct smear, it is recommended that multiple direct smears be done on the same day, rather than performing just one. Exocrine pancreatic insufficiency (EPI) is uncommon in cats, but it is recommended that all cats with chronic diarrhea or unexplained weight loss be tested for this condition so that EPI can be definitively ruled out early in the course of diagnostic evaluation. If the patient s signs are consistent with EPI and treatments for any other conditions that have been diagnosed are not resolving those clinical signs, treatment for EPI with digestive enzymes should be instituted. Most cats with EPI have markedly reduced serum cobalamin levels and, less frequently, folate concentrations; thus, serum cobalamin and folate levels should routinely be checked in conjunction with ftli in any cats with suspected EPI. Besides vomiting, diarrhea is a common sign observed in cases of feline inflammatory bowel disease (IBD) and is most likely due to derangement of normal mechanisms of absorption and motility. In most cases, diarrhea is intermittent early but later becomes persistent and usually responds only to specific treatment determined after a definitive diagnosis. Lymphoma is the most common neoplasm and also the most common form of gastrointestinal neoplasia in cats. Endoscopy has been shown to be a very useful modality for diagnosis, especially when multiple biopsies are obtained from the small intestine. Many cats respond favorably to treatment for intestinal lymphoma, therefore, it is strongly recommended that cats with chronic GI signs undergo a biopsy procedure as early as possible, and certainly prior to any corticosteroid therapy, to enable a correct diagnosis and identify the best course of treatment. Causes of Diarrhea in Cats Diarrhea is a common presenting complaint for cats. There are many potential causes, and the challenge to veterinarians is in making an accurate diagnosis so that effective therapy can be instituted as early as possible. Although a variety of signs can be caused by intestinal disorders, diarrhea is the hallmark sign of intestinal dysfunction. It can result from primary intestinal disease (eg, parasitism, infectious or inflammatory disorders, neoplasia), disorders of the liver or pancreas that affect normal intestinal digestive and absorptive processes, and a number of other factors or conditions that adversely affect intestinal function (eg, dietary indiscretion, adverse food reactions, drugs [eg, antibiotics]), and systemic disorders (eg, renal failure, hyperthyroidism). Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 2

3 Diarrhea is often classified according to location (small or large intestinal in origin), mechanism(s) (osmotic decreased solute absorption, secretory hypersecretion of ions, exudative increased permeability, and abnormal motility), and etiology. It is also important to recognize that some cats may have several disorders at the same time (eg, concurrent infection with Giardia and Tritrichomonas foetus), so a thorough diagnostic approach is recommended. Giardia, Cryptosporidium, Tritrichomonas foetus, and Clostridium perfringens enterotoxicosis are important problems in cats. These disorders should be investigated early in the course of diarrhea, whether it is persistent or intermittent, along with nematode parasites and dietary causes of gastrointestinal (GI) signs (Table 1). Hyperthyroidism is always a consideration, and early evaluation of thyroid levels, especially in cats 5 years and older, is recommended along with other baseline blood tests (CBC, complete biochemical profile, urinalysis). Inflammatory bowel disease (IBD) and intestinal lymphoma are considered if there are chronic signs, and intestinal biopsies should be performed before starting trial therapy with corticosteroids whenever possible. Exocrine pancreatic insufficiency (EPI) is uncommon in cats; however, it should be considered in animals with chronic diarrhea. Table 1. Early Diagnostic Screening in Cats with Diarrhea Acute Diarrhea CATS (initial screening) Direct fecal smear(s): fresh sample (perform in less than 1 hour) Zinc sulfate (ZnSO 4 ) centrifugal flotation Giardia species antigen test Later, if Persistent: Repeat all steps above Cryptosporidium species fecal immunofluorescence assay (IFA) Clostridium perfringens enterotoxin assay Large bowel signs? Rule out Tritrichomonas foetus Note: Negative results do not make a rule-out. The practitioner should be persistent, as retesting can be very important in reaching a diagnosis. Giardiasis With the tests available today, diagnosis of Giardia infection has become much more straightforward. The primary diagnostic tests for Giardia include direct saline preparation, centrifugal fecal flotation (zinc sulfate is used most frequently), fecal immunofluorescence assay (IFA), fecal antigen ELISA, and fecal polymerase chain reaction (PCR) assay. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 3

4 These tests can be used alone or in combination. The most commonly used combination of tests includes direct smear, centrifugation assay, and a Giardia antigen test. Many clinicians recommend using a centrifugation assay in conjunction with Giardia antigen testing as 25% to 30% of cases may be missed when only a single zinc sulfate centrifugation assay is performed. Cysts are shed intermittently and their presence does not correlate to clinical signs of disease. Sensitivity increases to greater than 90% if at least three stool specimens are examined via centrifugal flotation within 5 days (both humans and animals). Adding a Giardia antigen test, however, increases sensitivity of evaluation of a single fecal sample significantly (more than 95%), so key information can be conveniently and quickly obtained by running both the centrifugation assay and a Giardia antigen test on a single fecal sample. Reliance on passive fecal flotation without centrifugation is no longer acceptable or recommended as that assay is far too insensitive. Direct Smear Fresh, liquid feces or feces that contain large quantities of mucus should be microscopically examined immediately in the clinic for the presence of protozoal trophozoites of Giardia species (small bowel diarrhea) and Tritrichomonas foetus (large bowel diarrhea). A direct saline smear can be made to potentiate observation of these motile organisms. A 2 mm 2mm 2mm quantity of fresh feces is mixed thoroughly with one drop of 0.9% sodium chloride (NaCl) or water. The surface of the feces or mucus coating the feces should be used as the trophozoites are most common in these areas. After application of a cover slip, the smear is evaluated for motile organisms by examining it under 100 magnification. Culture (T foetus), antigen testing (Giardia species), or PCR (T foetus or Giardia species) can be used to distinguish between specific organisms. Centrifugation Assay Many clinicians currently submit fecal samples to a commercial reference laboratory for the centrifugation assay and performance of a Giardia antigen test. Reasons to have experienced laboratory personnel run the fecal tests are centered on ensuring diagnostic accuracy (consistency in setting up the samples, reading them on time, and correct identification of parasite eggs and cysts). This is best accomplished by experienced, well-trained lab personnel. Treatment Historically, the most common treatment options have included fenbendazole, pyrantel/praziquantel/febantel (the febantel component is effective against Giardia), and metronidazole. Fenbendazole (Panacur Intervet/Schering-Plough Animal Health), well known for its effectiveness against a variety of intestinal parasites, also appears to be highly effective Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 4

5 against Giardia. The same dose that is used to treat roundworms, hookworms, whipworms, and the tapeworm Taenia pisiformis (50 mg/kg orally once daily or in two divided doses for 5 consecutive days [there have been treatment failures occasionally when therapy is given for only 3 days]) is used to treat Giardia. If the infection is not cleared with this regimen, a longer course of therapy is used (7 days). Because of its proven track record for being safe, fenbendazole is believed not to have any teratogenic effects and is therefore the drug of choice for treatment of Giardia in pregnant animals. The agent has also become the preferred treatment for Giardia in cats. The dose of pyrantel, praziquantel, and febantel (Drontal Plus Bayer Animal Health) in cats is 56 mg/kg (based on the febantel component) orally once daily for 5 days. Although metronidazole is less effective and more likely to cause side effects than the other drugs mentioned, it can still be a useful drug for treating Giardia and has the advantage of having antibacterial as well as anti-inflammatory properties. Potential side effects of metronidazole include anorexia, vomiting, and neurologic problems (ataxia, vestibular problems, seizures). The recommended anti-giardia dose is 15 to 25 mg/kg orally every 12 to 24 hours for 5 to 7 days. Some clinicians use metronidazole only as a component of combination therapy (usually with fenbendazole), if there is evidence of a persistent infection not cleared by monotherapy. Dietary Therapy and Supplementation In animals that are known to be chronic carriers of Giardia, supplementing the diet with fiber may be beneficial. Increased dietary roughage may make it more difficult for Giardia trophozoites to attach to the small intestinal microvilli (clinicians can either use commercial diets or simply add a fiber source, such as psyllium fiber (Metamucil Procter & Gamble) to the animal s standard diet). Probiotics Probiotics may be beneficial as adjunctive therapy. Studies in mice and guinea pigs have shown that probiotics offer some benefit. Lactobacillus johnsonii has been shown to inhibit Giardia proliferation in vitro due to alterations in ph from production of lactic acid. In guinea pigs, in vivo, prophylactic feeding of L johnsonii greatly reduced fecal shedding following experimental inoculation with Giardia intestinalis. Enterococcus faecium SF68 fed to mice stimulated an increase in anti-giardia intestinal immunoglobulin A and circulating immunoglobulin G, and increased CD4+ immunocytes (reduced shedding and more rapid clearance of Giardia?). Follow-up Fecal Testing The American Association of Feline Practitioners (AAFP) Advisory Panel on Zoonoses recommends attempting to remove the source of infection during the treatment period. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 5

6 The panel also recommends performing a fecal centrifugal flotation after Giardia species treatment one time, within 2 to 4 weeks following the end of the treatment period (aafponline.org), even if centrifugal flotation was negative while the antigen test was positive when used to establish the initial diagnosis. If the animal is healthy and negative for cysts, then retesting is not indicated again until the next scheduled fecal flotation. Reliance on passive fecal flotation without centrifugation is no longer acceptable or recommended as that assay is far too insensitive. Currently, it is not recommended for any of the Giardia antigen tests to be used as a recheck test in the early posttreatment phase. The length of time that Giardia antigens persist in feces after successful treatment is unknown. Cryptosporidiosis Infection with Cryptosporidium species is much more common than most small animal practitioners recognize. In 2004 the AAFP adopted a position statement recommending that all kittens and adult cats with persistent diarrhea be screened for Cryptosporidium. Cryptosporidium species are coccidians that reside in the GI tract. Infection can be associated with diarrhea in both immunocompetent and immunodeficient hosts. In the past most cases of mammalian cryptosporidiosis were attributed to C parvum. Molecular studies have, however, demonstrated that cats are usually infected with the host-specific C felis, dogs are infected with C canis, and humans are infected with C parvum or C hominus. Cats infected with Giardia or Cryptosporidium species should be considered potentially zoonotic, even though the number of cases in which humans are infected through contact with pets is probably low. Infection in humans is sometimes fatal in the presence of severe immunosuppression. Acute symptoms may include diarrhea, abdominal pain, vomiting, fever, and listless behavior. Infection can also be subclinical in cats. Chronic unresponsive diarrhea has been associated with cryptosporidiosis in cats with serious underlying disease as well as in dogs. Diagnosis Because Cryptosporidium oocysts are quite small (as little as one tenth the size of common Isospora species oocysts) and are usually present in the feces in small numbers, they are very difficult to detect on routine fecal flotation and microscopy. The best test presently available for routine Cryptosporidium testing is a fecal IFA. This test is readily available at commercial laboratories (Merifluor Meridian Bioscience). A negative result does not rule out infection with Cryptosporidium, and the test may need to be repeated. Antigen tests for detecting C parvum in the human species are not sensitive for use in dogs and cats. In time more sensitive tests will be readily available. Serologic testing was developed to measure Cryptosporidium-specific immunoglobulin G in feline sera. Positive tests are a measure of exposure rates but not necessarily active infection or oocyst shedding. The test is used primarily as an epidemiologic Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 6

7 surveillance tool. A nested multiplex fecal PCR assay is also available and can simultaneously distinguish between four zoonotic species: C parvum genotypes 1 and 2, C canis, and C felis. Treatment Many drugs have been tried for treatment of cryptosporidiosis in humans and animals, and few have been found to be effective. Infections in immunocompetent humans are usually self-limiting, and a full recovery usually ensues. Some individuals develop significant GI signs (diarrhea, cramping, weight loss), however, and supportive therapy is essential. The oral aminoglycoside antibiotic paromomycin has been used in both animals (including calves, mice, rats, dogs, and cats) and humans. The treatment course used for dogs and cats has been 5 days (125 to 165 mg/kg orally every 12 hours). If the gut epithelium is injured, significant absorption may occur systemically, with the attendant risk of renal damage or deafness as can occur with other aminoglycosides. Because of concerns about adverse events, paromomycin is not recommended as a first therapy in animals diagnosed with cryptosporidiosis. Azithromycin is currently recommended for initial therapy (cats should receive 7 to 15 mg/kg orally every 12 hours). The duration is variable: 14 to 28 days or longer, if necessary. Tritrichomonas foetus Infection Tritrichomonas foetus is a recently identified (2003) enteric protozoan of cats. It is unknown how long it existed in cats before Infection causes chronic, large bowel, foul-smelling diarrhea (loose stools, presence of blood and mucus, straining to defecate) and is most commonly seen in young cats that have resided in densely populated housing, such as catteries and shelters. Asymptomatic infection in older cats may be common. Trichomonads are transmitted directly from host to host in the form of trophozoites (trichomonads do not form cysts). The associated diarrhea may be intermittent or persistent. Loose stool may dribble out (lack of control), and the anal area may become edematous and inflamed. The organism is present in the ileum, cecum, and colon, causing a chronic lymphoplasmacytic and neutrophilic colitis. As with most dogs that have large bowel diarrhea, cats with T foetus infection often maintain a good appetite and good health and body condition. Diagnosis T foetus is commonly mistaken for Giardia species trophozoites on direct smear exam. All trichomonads possess three to five anterior flagella, an undulating membrane, and a recurrent flagellum attached to the edge of the undulating membrane. All flagella originate from an anterior basal body. An axostyle extends the length of the trichomonad and posteriorly. A cyst stage is not known for this genus. Video clips showing both Giardia and Tritrichomonas trophozoites are available on the North Carolina State University website: cvm.ncsu.edu/docs/personnel/gookin_jody.html. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 7

8 Definitive diagnosis can be made in some cases by direct smear of fresh feces in saline, examined at 200 to 400 magnification. Sensitivity is low, however, for diagnosis by direct smear (only 14% in one study), so results can often be false-negatives. To increase the likelihood of finding Tritrichomonas trophozoites on direct smear, it is recommended that multiple direct smears be done on the same day. Whenever possible, a cat with suggestive signs should be hospitalized for part or all of a day so that each time it defecates, a fecal sample can be obtained and examined quickly via direct saline smear. A commercially available culture system is recommended for use in clinical practice (InPouch TF Biomed Diagnostics, Inc., White City, OR). The InPouch medium does not support the growth of Giardia species or Pentatrichomonas hominis, so presence of organisms is consistent with T foetus. PCR is the most sensitive means for confirming a diagnosis. In one study of 36 cats with T foetus infection, 20 of 36 were positive on the InPouch TF test, and 34 of 36 were positive on PCR. Details on the PCR assay can be reviewed on the North Carolina State University website indicated previously. Until 2005 no effective treatment for T foetus infection had been identified. Unfortunately, some cats with chronic diarrhea and dyschezia were euthanized due to the lack of any therapy that could control the clinical signs. The veterinary community considered it exciting news in 2005 when Dr. Jody Gookin and colleagues at North Carolina State University reported that ronidazole, a nitroimidazole antimicrobial drug, is effective in controlling T foetus. Although the diarrhea eventually resolves over time (months up to 1 to 2 years) in untreated cats, ronidazole is the recommended therapy after a diagnosis has been established so that control of the diarrhea and other clinical signs can be achieved as quickly as possible. Ronidazole is not licensed for any use in the United States but has become more readily available in the US through compounding pharmacies. The drug has mutagenic properties, so it must be compounded in the same way chemotherapy drugs are prepared. It is important that an accurate diagnosis be made so that clients can be counseled appropriately; ie, they should understand that their cat(s) may continue to have abnormal stools for some time or that there may be recurrences. Further, side effects of significant concern can occur related to ronidazole, so this is not a drug that should be used empirically in lieu of testing. Also, it is relatively common for cats to be coinfected with Giardia or Cryptosporidium species, or even both, so a thorough evaluation for parasites is important (the clinician should run a minimum of one zinc sulfate centrifugal flotation and a Giardia antigen test as well as a fecal IFA assay to check for Cryptosporidium). Accurate and thorough testing is essential, and, following identification of any causative agents, they can be treated appropriately for the benefit of the patient and its owner. The original dosage guidance for ronidazole was to administer 30 mg/kg twice daily for 14 days. A 2008 study reported new guidance, however: 30 kg/kg once daily is effective and safer; ie, there is less likelihood of neurologic adverse events at the lower dose. A Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 8

9 capsule preparation is recommended for accurate dosing. The liquid suspension, even if flavored, is very bitter and poorly tolerated by cats. The author and colleagues have seen some cats experience mild neurologic side effects when given ronidazole, similar to those observed with metronidazole. These side effects resolved on discontinuation of the drug. It is expected that fewer instances of neurotoxicity will be reported with the new schedule of 30 mg/kg on a once-daily dosing schedule. It is important that an accurate diagnosis be made so that clients can be counseled appropriately, ie, they should expect that their cat(s) will continue to have abnormal stools for a period until definitive treatment can be administered. Other recommended steps during therapy include isolating cats to decrease the risk of reinfection as well as discarding, after treatment is completed, any litter boxes the cat has used. Follow-up Testing Testing by PCR is recommended at 1 to 2 weeks and 20+ weeks after treatment is completed. Negative results should be interpreted with caution as PCR cannot prove the absence of infection, and prolonged symptomatic carriage of the organism after antimicrobial therapy may be common. Tinidazole is an alternative drug for treating T foetus infection and is also a nitroimidazole antimicrobial. A dosage of 15 to 30 mg/kg once daily can be administered and should be safe but may or may not be effective. Studies have been ongoing; however, results to date have not been impressive. Maldigestive Disease Exocrine pancreatic insufficiency (EPI) is uncommon in cats, but it is recommended that all cats with chronic diarrhea or unexplained weight loss be tested for this condition so that EPI can be definitively ruled out early in the course of diagnostic evaluation. The most sensitive and specific test for EPI is the serum feline trypsin-like immunoreactivity (ftli) assay. This test requires obtaining a serum sample after fasting the animal for 12 hours. Most cats develop EPI as a result of chronic pancreatitis. Other causes include pancreatic acinar atrophy and, rarely, fluke infestation (Eurytrema procyonis). The ftli value may actually be high initially (in association with pancreatitis) and then gradually decreases over time until it reaches a diagnostic range for EPI. It should be noted that occasionally a cat showing signs consistent with EPI does not have an ftli result in the diagnostic range. Usually the ftli will be in the low end of the reference range for normal in such patients. Eventually, these cats reach a stage where the ftli is in the diagnostic range. The main point is that, if there are signs consistent with EPI and treatments for any other conditions that have been diagnosed (eg, IBD, hypocobalaminemia) are not resolving those clinical signs, treatment for EPI with digestive Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 9

10 enzymes should be instituted. A positive response to therapy helps to confirm the presence of EPI. The serum ftli may be in the diagnostic range when it is rechecked 1 to several months after the initial grey zone result. Most cats with EPI have markedly reduced serum cobalamin levels and, less frequently, folate concentrations; thus, serum cobalamin and folate levels should routinely be checked in conjunction with ftli in any cats with suspected EPI. Treatment Pancreatic enzyme supplementation is provided with powdered pancreatic extracts of bovine or porcine pancreas. The initial dose is 0.5 to 1 teaspoon mixed in the food immediately before feeding (preincubation is not indicated). Tablet preparations are often ineffective and should not be used. Standard maintenance diets may be fed. After effective control of clinical signs is achieved, the dose of pancreatic enzymes can be gradually reduced to the minimum level needed to maintain control. Cobalamin supplementation is provided for cats with low serum cobalamin levels (see guidelines described in the Treatment section under Inflammatory Bowel Disease later in this article). If the folate level is low, supplementation is provided with 200 µg of folic acid daily, added to the food for 1 month; and then serum folate levels are assessed once a year. Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is currently recognized as a common and important medical problem in cats. Three general types of clinical presentations have been identified in cats with idiopathic IBD: (1) a clinical course characterized primarily by vomiting, (2) a clinical course characterized primarily by diarrhea, and (3) a clinical course that includes both vomiting and diarrhea as primary signs. Associated clinical signs can include change in appetite (anorexia, inappetence, or ravenousness), weight loss, and lethargy. In some cats, the clinical signs are cyclic, seeming to flare up and then abate in a predictable pattern. Vomiting, among the most frequent clinical signs of IBD in cats, is most often recognized as an intermittent occurrence for weeks, months, or years. As the disorder progresses, an increased frequency of vomiting often leads the owner to seek veterinary attention. In addition to vomiting, diarrhea is a common sign observed in cases of feline IBD and is most likely due to derangement of normal mechanisms of absorption and motility caused by mucosal inflammation. In most cases, diarrhea is intermittent early in the course of the disorder, and there may be a transient response (weeks to several months) to dietary manipulation or any of a variety of medications. Later, the diarrhea becomes persistent and usually responds only to specific treatment, which is determined after a definitive diagnosis is made. Signs of small bowel diarrhea predominate, but signs of large bowel diarrhea may be evident as well, if generalized intestinal tract involvement occurs. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 10

11 Appetite changes in cats with idiopathic IBD vary from decreased appetite to complete anorexia to ravenousness. Inappetence seems to occur more commonly in cats that have vomiting as the primary clinical sign and usually occurs during exacerbation of clinical signs. The three leading differentials to consider in reaching a diagnosis for a cat with a ravenous appetite, diarrhea, and weight loss are IBD, hyperthyroidism, and EPI (uncommon). Some cats with chronic low-grade lymphocytic lymphoma also demonstrate an increased appetite. A definitive diagnosis of IBD can be made based only on intestinal biopsy (endoscopic or full thickness). Tests are run before biopsy to evaluate the overall health status of the patient and to rule out other disorders. Recommended baseline tests include: Complete blood cell count and biochemical profile. Urinalysis. Fecal exams for parasites (clinicians should check routinely for nematodes, Giardia species, and Cryptosporidium species as well as T foetus, if clinical signs are consistent with those seen for that parasite). Serum thyroxine. Serum feline trypsin-like immunoreactivity (ftli). Serum cobalamin and folate. Feline leukemia virus. Feline immunodeficiency virus. Endoscopy for Diagnosis of IBD In a majority of cats with chronic diarrhea that exists with or without associated clinical signs (eg, vomiting, appetite change, weight loss), a definitive diagnosis can be established based on endoscopic examination and biopsies. In most patients with chronic diarrhea, it is preferred that both upper and lower endoscopy be done so that sections from both the small and the large intestine can be evaluated histologically to determine the extent of the disease process as accurately as possible. In addition, in most cats that are well cleansed for colonoscopy a pediatric endoscope can be advanced to the ileocolic orifice, and a biopsy instrument can be extended through the orifice and into the ileum for procurement of ileum samples. Thus, performing complete colonoscopy allows for more detailed evaluation of the small intestine (ie, both upper and lower small intestine are sampled for biopsy). Unlike in cats, in most dogs over 3.5 to 4.0 kg a pediatric endoscope can actually be advanced through the ileocolic orifice and into the ileum for direct visualization of the mucosa. Laparotomy for Examination and Procurement of Biopsy Samples If an exploratory laparotomy is done to obtain intestinal biopsies, the entire bowel should be carefully evaluated. Focally abnormal areas should be biopsied (full-thickness samples) along with one or two normal areas. Many animals with chronic small bowel diarrhea have grossly normal intestine as observed at surgery. Biopsy samples must still be procured. Three full-thickness samples are obtained (duodenum, jejunum, and Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 11

12 ileum). The liver and pancreas, along with any other tissue that appears abnormal (eg, stomach, lymph nodes), should also be biopsied during an exploratory laparotomy. Treatment It is important that the clinician formulate a treatment protocol based on a correlation of clinical course, laboratory and gross findings, and histologic findings rather than relying on histologic changes alone. Corticosteroids are the cornerstone of treatment for idiopathic inflammatory bowel disorders. Mild to moderate cases often respond to prednisone or prednisolone at a starting dosage of 1.0 to 2.2 mg/kg divided twice daily for 2 to 4 weeks followed by a gradual decrease in 50% increments at 2-week intervals. Cats with inflammatory changes graded as mild usually respond quite well to the lower dose, and alternate-day or every-third-day treatment can often be achieved by 2 to 3 months. Occasionally, treatment can be discontinued altogether by 3 to 6 months. If biopsies reveal disease that is moderate to severe, a prednisolone dosage of 2.2 to 4.4 mg/kg divided twice daily is used for the first 2 to 8 weeks or until clinical signs resolve. The author prefers to use prednisolone over prednisone in cats with inflammatory disorders of a moderate to severe nature, as prednisolone may offer improved bioavailability in some cats. This dosage of corticosteroid is usually well tolerated in cats. In these cases a dosage of 1.0 to 2.2 mg/kg daily may be necessary long-term (months to years) to maintain clinical remission. Use of combination drug therapy may also be required at the outset to control clinical signs and prevent progression of the disease. Cats with hypoproteinemia and histologic changes graded as severe often respond quite well when an aggressive therapeutic course is undertaken. Budesonide is a glucocorticoid that is a newer alternative for management of IBD in dogs and cats, especially in severe cases that have proven to be refractory to prednisolone, metronidazole, azathioprine, and dietary management or for patients that are intolerant of the corticosteroids listed. It is one of a group of novel corticosteroids that have been in development for humans in an attempt to make available alternative preparations that will help limit toxicity associated with corticosteroid use. The drug undergoes high first-pass metabolism in the liver, and 90% is converted into metabolites with low corticosteroid activity. Budesonide has minimal systemic availability. The potential for typical corticosteroid side effects is significantly reduced as a result of decreased bioavailability and the resulting limited systemic exposure, which makes this a particularly attractive drug for use in humans and animals that are poorly tolerant of other corticosteroids. Budesonide also has a high receptor-binding affinity in the mucosa. It has been referred to as a locally acting corticosteroid. In general, budesonide is administered to cats and small dogs at 1 mg once daily (the commercially available 3 mg capsule preparation is compounded to a 1 mg capsule). Budesonide can be used in combination with other drugs. As cats tolerate corticosteroids well, there is little indication to use budesonide as initial therapy for IBD; Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 12

13 however, it may be a very attractive option for use in diabetic cats that also have IBD or in patients where conventional therapies have not been sufficiently effective. When combination therapy is indicated, metronidazole (Flagyl Pfizer Inc) is usually the first choice for use in conjunction with prednisolone. Metronidazole s mechanism of action includes an antiprotozoal effect, inhibition of cell-mediated immune responses, and anaerobic antibacterial activity. A dosage of 10 to 20 mg/kg twice daily is used for IBD. Ideally, at least several months of metronidazole therapy is given once it is started. In some cats with severe disease, long-term consecutive use or 1-month to 2-month cycles of treatment with metronidazole may be required. Side effects at this low dosage are uncommon in cats. Occasionally, nausea or vomiting may be seen. Methylprednisolone acetate (Depo-Medrol Pfizer Animal Health) can be used as sole treatment for cats with mild to moderate IBD or as adjunctive therapy when oral prednisolone, metronidazole, or both are used as the primary treatment and flare-ups of clinical signs occur. Consistent control of clinical signs in cats with moderate to severe IBD is more difficult to maintain when methylprednisolone acetate is used alone, however. It is recommended that sole use of methylprednisolone acetate be reserved for situations in which the owner is unable to administer tablet or liquid prednisolone preparations consistently. Initially 20 mg is given subcutaneously or intramuscularly and is repeated at 2-week intervals for two to three doses. Injections are then given every 2 to 4 weeks or as needed for control. If remission cannot be maintained with use of corticosteroids and metronidazole then azathioprine (Imuran GlaxoSmithKline), cyclosporine, or chlorambucil should be considered. Azathioprine is an immunosuppressive drug with a nonspecific effect. Replication of rapidly dividing cells, including immunoblasts, is inhibited. Azathioprine is usually used in cats only when the previously discussed therapeutic measures fail to control the disease. The most important side effect of azathioprine in cats is bone marrow suppression. The author uses a maximum starting dosage in cats of 0.3 mg/kg once every other day. At this low dosage, side effects are uncommon. Alternatively, if clinical signs of IBD do not resolve on the initial azathioprine dosage, then the dose can be increased slightly if there is no evidence of bone marrow suppression. Because of a lag effect, beneficial therapeutic results from azathioprine are often not apparent until 2 to 3 weeks after treatment is started. Azathioprine is generally used for 3 to 9 months in cats. A majority of cats with IBD does not require azathioprine treatment. Complete blood cell counts should be done to monitor for anemia and leukopenia at 3- week to 4-week intervals for the first 2 months and then once monthly. Significant side effects are most often identified during the first 3 to 6 weeks of treatment with azathioprine. There is usually no physical evidence of early azathioprine toxicity in cats. Mild leukopenia (eg, 3,000 to 4,000 cells/mm) is typically the first abnormality that is identified. To administer azathioprine a suspension preparation made by a compounding pharmacy service is used. A major advantage of giving azathioprine in this manner Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 13

14 is that any required increase in dosage can be managed very accurately. If azathioprine is well tolerated and there has been inadequate clinical improvement, the dosage can be increased from 0.3 mg/kg to 0.4 to 0.5 mg/kg once every 48 hours. Another immunosuppressive drug that is used in some cats with severe IBD is chlorambucil (Leukeran GlaxoSmithKline). Some clinicians use chlorambucil as an alternative to azathioprine (the two drugs are not used in conjunction). Chlorambucil is an alkylating agent. Alkylating agents alter DNA synthesis and inhibit rapidly proliferating cells. Chlorambucil is administered initially at 0.1 to 0.2 mg/kg daily in conjunction with prednisolone at 2.2 mg/kg daily. The small pill size of chlorambucil (2 mg) allows for easy dosing. Various dosage schedules for cats have been published, and most cats receive one-half tablet (1 mg) per day. An alternate schedule is 0.15 to 0.3 mg/kg every 72 hours. Toxicities are uncommon in cats but may include anorexia, vomiting, and diarrhea. These problems generally resolve rapidly when chlorambucil is reduced from daily to every-other-day administration. Bone marrow suppression is possible but uncommon and is mild and rapidly reversible when it does occur. After the desired clinical response is achieved, chlorambucil is gradually tapered over several months while prednisolone is continued as the primary maintenance drug. Cyclosporine A (CyA) has been shown to be effective in steroid-resistant IBD in humans and also perianal fistula management in both humans and dogs. Clinical experience in dogs has shown that CyA is an effective option for managing some dogs with steroid refractory IBD. The anti-inflammatory effect of CyA in human IBD is believed to be due to suppression of activated T cells infiltrating the mucosa, thereby decreasing the amount of proinflammatory cytokines and, ultimately, the clinical signs of disease. The recommended dosage is 5 mg/kg once daily. A lag phase of 7 to 10 days has been seen in humans before there are obvious signs of clinical improvement, and a similar finding has been observed in dogs. Cobalamin Therapy in Cats Some animals with GI disease have significant tissue-level cobalamin deficiency. This is usually secondary to a reduced cobalamin absorptive capacity. Therapy for cats involves administering injectable cobalamin according to the following schedule: 250 µg subcutaneously once a week for 6 weeks. Serum cobalamin should be rechecked immediately before the fifth or sixth dose. If the serum cobalamin concentration has normalized, then the dosage schedule can be changed to once monthly. Some owners report, however, that their cat does better on a more frequent dosage schedule (eg, every 2 weeks). Most generic cobalamin preparations contain 1 mg/ml (1,000 µg/ml). It is important to note that injectable multivitamin and B-complex formulations contain significantly lower concentrations of cobalamin, and they also cause pain when injected. Therefore, it is recommended that these preparations not be used for cobalamin supplementation. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 14

15 Unless the intestinal disease is totally resolved, long-term and perhaps lifelong supplementation with cobalamin may be necessary. The frequency of injections on a long-term basis is determined by regular measurement of serum cobalamin concentration. Because dietary allergens may play a role in the cause of IBD, specific dietary therapy may be beneficial. Although moderate to severe degrees of IBD are often either temporarily responsive or only minimally responsive to careful dietary manipulations, some cats with IBD may, in fact, be successfully managed with dietary therapy alone. Long-term control of IBD with as minimal a drug administration schedule as possible may be aided by specific dietary management. Dietary changes should be started as soon as a diagnosis is made and continued as drug therapy is decreased later. The diet should be palatable and offered in small divided feedings (three to four daily, if possible). The main options in dietary selection encompass three major categories of diets, which include a highly digestible diet, an exclusion diet (eg, a hydrolyzed protein diet or a novel protein source diet), and a diet high in fiber. Low-fat diets are not used to manage feline GI disorders. Most commercial exclusion-type diets are also highly digestible, so two major components of dietary therapy can be met through feeding one of these kinds of diets. Hydrolyzed protein diets contain low-molecular protein derivatives, which may be less antigenic. Another characteristic is high digestibility of the protein compo-nents. High-fiber diets are used primarily in cases where there are predominantly large intestinal signs. When cats with IBD respond poorly to treatment, it is usually because of: Inadequate initial or long-term maintenance corticosteroid dosage (and clinicians should consider using prednisolone rather than prednisone). Failure to use ancillary medications (metronidazole, azathioprine, chlorambucil, cyclosporine) in cases where disease is moderate to severe. Failure to recognize and treat a concurrent condition (eg, hyperthyroidism, parasitism [eg, Giardia species, Cryptosporidium species, T foetus, Clostridium perfringens enterotoxicosis]). Treatment only for small intestinal inflammatory disease when colitis is present as well. Some cats with concurrent IBD and colitis may show minimal or no clinical signs of colitis. Failure to recognize and treat low body cobalamin levels (clinicians should measure serum cobalamin in all cats with GI disease). Failure to identify an effective diet. Poor client compliance. Treatment of Intestinal Lymphoma in Cats Lymphoma is the most common feline neoplasm. It is also the most common form of gastrointestinal neoplasia in cats. Gastrointestinal lymphoma is often referred to as either well differentiated (low-grade or lymphocytic), poorly differentiated (high-grade, Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 15

16 lymphoblastic, or immunoblastic), or intermediate (or mixed). Endoscopy has been shown to be a useful modality for diagnosis of intestinal lymphoma in cats, especially when multiple biopsies are obtained using proper technique and instruments that can procure adequate tissue samples. Full-thickness intestinal biopsies may be required in a very limited number of cases to establish the correct diagnosis. Many cats respond favorably to treatment for intestinal lymphoma, especially the lowgrade or chronic lymphocytic type. Clinical signs can be quite similar to those of cats with IBD. Therefore, it is strongly recommended that cats with chronic GI signs undergo a biopsy procedure as early as possible, so that the correct diagnosis can be established and the best course of therapy can be made available for the individual cat. Multi-agent chemotherapy is recommended for all cats with GI lymphoma. Surgery is done only if there is an isolated mass that is causing some degree of luminal obstruction. Survival times in excess of 12 to 18 months are relatively common, but in some cats the response is somewhat shorter (3 to 6 months). The prognosis for longer survival time is much better if the diagnosis is made before clinical signs become chronic and debilitation results. One study has reported excellent results in cats with chronic lymphocytic lymphoma using a protocol of prednisone (orally at 10 mg daily) and chlorambucil (Leukeran) at a dosage of 15 mg/m 2 orally for 4 days, repeated every 3 weeks. Sixty-nine percent of the cats with lymphocytic lymphoma treated with this regimen achieved a complete remission. The median disease-free interval for cats that achieved complete remission was 20.5 months (range: 5.8 to 49 months). The median survival for all cats with lymphocytic lymphoma treated with chemotherapy was 17 months (range: 0.33 to 50 months). Cyclophosphamide (Cytoxan Bristol-Myers Squibb) was used for rescue in some of the cats that were entered in a protocol of 225 mg/m 2 orally every 3 weeks. The protocol that the author has used most often was originally published by S. M. Cotter in Dosage levels have been modified slightly since that time. This protocol uses cyclophosphamide, oncovin, and prednisone or prednisolone (COP) and can easily be managed in any practice setting. Vincristine is administered intravenously at a dosage of 0.5 to 0.75 mg/m 2 once weekly for 4 consecutive weeks and then once every 3 weeks. The initial doses are often decreased by approximately 25% for cats that are inappetent or debilitated. If well tolerated, then the dose can gradually be increased. Care is taken to ensure that none of the vincristine is given extravascularly. The average volume administered is quite low (0.1 to 0.15 ml for many cats, using a vincristine concentration of 1 mg/ml). Cyclophosphamide is given orally at a dosage of 225 mg/m 2 every 3 weeks (50 mg tablets are used with the dose adjusted to the nearest 25 mg on the low side of the calculated dose). Prednisone or prednisolone (preferred) is given orally at 10 mg daily. Although cyclophosphamide and vincristine can be given on the same day, the author often prefers to have the owner administer the cyclophosphamide 2 to 3 days after the oncovin. A complete blood cell count is done several times during the first month and then every Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 16

17 3 weeks to ensure that adequate granulocytes are present before treatment. At least 3,000 granulocytes/µl must be present before cyclophosphamide is given. If the granulocyte count drops to less than 1,000/ µl 5 to 7 days after cyclophosphamide, the dose for subsequent treatments is reduced by 25%. The highest nontoxic dose is most likely to result in the greatest tumor cell kill. The COP protocol is generally well tolerated, although side effects may occur and dosage or interval adjustments may be necessary. Side effects of COP in cats may include anorexia, vomiting, lethargy, and severe tissue irritation if any vincristine is given extravascularly. Also, the haircoat may become thinner, but complete hair loss does not occur. Cats do tend to lose whiskers. Cats should be carefully observed for sepsis especially during the induction phase. Prophylactic antibiotics are not indicated, but any infections that occur should be treated aggressively. Advantages of this protocol include hospital visits at only 3-week intervals after the first 4 weeks, lower cost to the owner, and a treatment interval that allows recovery of normal cells between treatments. The author emphasizes that with careful monitoring and use of a dosage schedule that is tailored to the individual cat, few problems are encountered It is the author s general practice to encourage owners of most cats with GI lymphoma to pursue treatment that includes chemotherapy. Nutritional and metabolic support is also important during treatment. If inappetence is a problem, cyproheptadine can be administered as an appetite stimulant (1 to 2 mg orally every 12 to 24 hours) on an as-needed basis (long-term, if necessary). If there is concurrent renal disease with azotemia or if dehydration is a problem, owners are taught how to administer subcutaneous fluids at home (eg, 100 to 150 ml of lactated Ringer s every 24 to 48 hours, based on their cat s needs). Injections of B-complex vitamins are sometimes helpful as well. Serum cobalamin levels should be checked periodically. Rarely, chemotherapy can be discontinued after 1 year. Therapy is ended only if follow-up endoscopic intestinal biopsies indicate that there is no remaining lymphoma. Most cats remain under treatment for the rest of their lives. If chemotherapy is poorly tolerated and reduced dosages and increased intervals between treatment times are unsuccessful at adequately decreasing side effects, then chemotherapy should be suspended. Prednisone should be continued, however, because it may help maintain remission for a period of time. L-asparaginase can also be used if cyclophosphamide and vincristine are poorly tolerated. Doxorubicin (Adriamycin Pfizer Inc.) can also be used in cats. For clinicians who are inexperienced in administering chemotherapy or have not treated many cats with intestinal lymphoma, it is recommended that a veterinary oncologist or internist be consulted for guidance on protocol selection and ongoing management. Many cats with intestinal lymphoma can be managed successfully for a significant period of time. Conclusion While there are many causes of intermittent or persistent diarrhea in cats, following a systematic diagnostic approach and using the currently available tests will often yield an accurate diagnosis and allow for the most indicated therapy. The quality of readily available Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 17

18 diagnostic testing for parasitic disorders has been enhanced significantly in recent years. It is strongly recommended that efforts be made to obtain intestinal biopsies as early as possible in patients with chronic diarrhea in which the baseline blood, fecal, and imaging tests are not diagnostic; and certainly this should be done before empirical use of corticosteroids, whenever possible. Suggested Reading Barr SC. Cryptosporidiosis and cyclosporiasis. In: Green CE, ed. Infectious Diseases of the Dog and Cat. St. Louis: Elsevier;2006: Barr SC. Giardiasis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. St. Louis: Elsevier; 2006: Gookin JL. Tritrichomonas. In: Bonagura JB, Twedt DC, eds. Current Veterinary Therapy XIV. St. Louis: Elsevier; 2009: Scorza AV, Radecki SV, Lappin MR. Efficacy of a combination of febantel, pyrantel, and praziquantel for the treatment of kittens experimentally infected with Giardia species. J Fel Med Surg. 2006;8:7-13. Tams TR. Chronic diseases of the small intestine. In: Tams TR, ed. Handbook of Small Animal Gastroenterology. Philadelphia, WB Saunders Co; 2003: Williams DA. Feline pancreatic disease. In: Bonagura JB, Twedt DC, eds. Current Veterinary Therapy XIV. St. Louis: Elsevier; 2009: Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 18

19 Diagnosis and Management of Persistent Vomiting Kenneth W. Simpson, BVM&S, PhD, Diplomate, ACVIM, Diplomate, ECVIM-CA Cornell University Ithaca, New York Abstract The clinical importance of vomiting stems from its association with a large and varied group of diseases and the potentially life-threatening consequences of vomiting per se (eg, aspiration pneumonia and fluid and electrolyte depletion). Patient management is directed at detecting and treating the cause and consequences of vomiting. When the cause is undetermined, it is necessary to adopt a rational approach to controlling emesis. Key Content The vomiting center can be stimulated directly, or indirectly via the chemoreceptor trigger zone (CRTZ) situated in the area postrema where the blood-brain barrier is accessible to blood-borne substances, such as toxins or drugs. There are so many potential causes of vomiting that it is easiest to think in broad terms initially, ie, gastric, intestinal, intra-abdominal nongastrointestinal tract, metabolic/endocrine, drugs, toxins, dietary, neurologic, and infectious diseases. The initial plan for vomiting animals is to separate those with problems that are acute and self-limiting from those in need of more thorough investigation and treatment. Most non-gastrointestinal causes of vomiting and gastrointestinal causes, such as a foreign body or intussusception are usually detected, or ruled out, by taking a detailed history, performing a thorough physical examination, routine laboratory tests, and abdominal imaging. Enhancing mucosal cytoprotection and decreasing gastric acid secretion may be beneficial when persistent vomiting is associated with ulceration. Antiemetics are indicated in patients with vomiting that is compromising hydration status, affecting electrolyte and acid-base balance, and in patients at high risk for esophagitis or aspiration pneumonia as well as those distressed by repeated vomiting. Antiemetics are generally contraindicated in patients with gastrointestinal toxicity where they may limit expulsion of the toxic agent. From Gastrointestinal Diseases, proceedings of a symposium sponsored by Pfizer Animal Health by The Gloyd Group, Inc. All rights reserved. The opinions expressed in this article are those of the author and do not necessarily reflect the official label recommendations and points of view of the company or companies that manufacture and/or market any of the pharmaceutical agents referred to.

20 Because antiemetics can effectively mask signs of serious underlying disease, a clinical response to antiemetics should not preclude a search for the underlying cause of vomiting. Antiemetic selection and use in patients with unknown causes of vomiting are based on a best guess, least harmful approach. The treatment of dogs and cats with chronic gastritis is guided by the presence or absence of gastric Helicobacter species. Initiation of Vomiting Vomiting is a reflex act initiated by stimulating the vomiting center in the medulla (Figure 1) (1,2). The vomiting center can be stimulated directly or indirectly via the CRTZ situated in the area postrema where the blood-brain barrier is accessible to blood-borne substances, such as toxins or drugs. Neurologic input from the vestibular nucleus can also stimulate the CRTZ (canine) or the vomiting center. Disease or irritation of the gastrointestinal tract, abdominal organs, or peritoneum and cerebral diseases can directly stimulate the vomiting center via visceral receptors and vagal afferents. Figure 1 Vomiting occurs following stimulation of the vomiting center in the medulla. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 2

21 After the vomiting center is adequately stimulated, a set of visceral events is initiated these events include the sequential inhibition of proximal gastrointestinal motility, a retrograde power contraction in the small intestine, and antral relaxation that enables transfer of intestinal contents to the stomach. This sequence is followed by moderate amplitude contractions in the antrum and intestine and shortening of the intraabdominal esophagus. Dilatation of the cardia and lower esophageal sphincter enables transfer of gastric contents to the esophagus during retching and vomiting. Retching often precedes vomiting and is characterized by rhythmic inspiratory movements against a closed glottis. Negative intrathoracic pressure during retching prevents expulsion of esophageal contents. During vomiting the abdominal muscles contract and the intrathoracic and intra-abdominal pressures are positive, which results in the forceful expulsion of gastric contents from the mouth. Causes of Vomiting There are so many potential causes of vomiting that it is easiest to think in broad terms initially, ie, gastric, intestinal, intra-abdominal nongastrointestinal tract, metabolic/endocrine, drugs, toxins, dietary, neurologic, and infectious diseases, and consider more specific causes when vomiting is localized to one of these groups (Table 1). Patient Evaluation and Diagnostic Approach The initial plan for vomiting animals is to separate those with problems that are acute and self-limiting from those in need of more thorough investigation and treatment (Figure 2). If vomiting is acute and the animal is systemically well, in-depth diagnostic testing is not usually warranted, as vomiting frequently resolves on its own or after short-term symptomatic therapy. If the animal is systemically unwell, has been vomiting for more than a week, or has vomiting associated with hematemesis, bloody diarrhea, or abdominal pain, a more aggressive workup is necessary to define the nature of the problem. Most non-gastrointestinal causes of vomiting and gastrointestinal causes, such as a foreign body or intussusception are usually detected, or ruled out, by taking a detailed history, performing a thorough physical examination, routine laboratory tests (eg, complete blood cell count, profile, urinalysis, and fecal examination, with evaluation of amylase/lipase/pancreatic lipase immunoreactivity [PLI], thyroxine [T 4 ], feline leukemia virus [FeLV], feline immunodeficiency virus [FIV], adrenocorticotropic hormone [ACTH] stimulation where indicated) and abdominal radiographs. Abdominal ultrasound is useful for detecting pancreatic, hepatic, and splenic lesions or GI thickening (focal or diffuse) and for sampling masses and parenchymal abnormalities. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 3

22 Table 1. Causes of Vomiting Dietary Allergy, indiscretion, intolerance, sudden change Drugs Apomorphine, chemotherapy, digoxin, erythromycin, intravenous medications, xylazine Gastric Foreign bodies, gastritis, motility/functional disorders, neoplasia, outflow obstruction, ulceration Infectious Distemper, feline panleukopenia, feline heartworm disease, FeLV, FIP, FIV, infectious canine hepatitis, leptospirosis, parvovirus, salmonellosis Intestinal Bacterial overgrowth/antibiotic-responsive enteropathy, foreign bodies, functional disorders, inflammatory bowel disease, intussusception, neoplasia Intra-abdominal Non-GIT Genitourinary: Nephritis, nephrolithiasis, peritonitis, prostatitis, pyelonephritis, pyometra, urinary obstruction Liver: Biliary obstruction, cholangitis, hepatitis, mucocele Pancreas: Pancreatic neoplasia, pancreatitis Spleen: Torsion Metabolic/Endocrine Diabetic ketoacidosis, hepatic encephalopathy, hypercalcemia, hyperthyroidism, hypoadrenocorticism, septicemia, uremia Neurologic Elevated intracranial pressure, encephalitis, neoplasia, vestibular disease Toxins Ethylene glycol, lead, strychnine Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 4

23 Figure 2 In developing a plan for vomiting animals those with acute, self-limiting problems must be distinguished from those requiring more thorough investigation and treatment. Additional Testing If these tests are negative or show abnormalities compatible with primary gastric or diffuse intestinal disease, then endoscopic examination of the stomach and upper duodenum or contrast radiography are the principal diagnostic options. Endoscopy enables detailed examination and sampling of the gastric and duodenal mucosa, with minimal patient discomfort, and is generally accepted as the best method of evaluating mucosal abnormalities. Radiographic contrast studies (with or without fluoroscopy) are generally restricted to examining functional (emptying) disorders of the stomach and the anatomy and patency of the intestinal tract distal to the duodenum. Patients with evidence of focal intestinal disease or concurrent involvement of multiple organs (eg, liver, pancreas, and intestine in cats with triaditis) are often best evaluated surgically. Overview of Therapy for Vomiting Patient management should be aimed at detecting and treating the cause and consequences of vomiting. Parenteral fluid therapy (usually intravenous) should be Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 5

24 tailored to correct volume depletion and electrolyte and acid-base abnormalities. Dietary alteration in patients with acute vomiting is traditionally to give nothing by mouth for 24 to 48 hours followed by a transition to a bland, carbohydrate-rich diet when vomiting decreases (to facilitate gastric emptying). This notion has been challenged, however, by the results of early enteral nutrition in dogs with parvovirus enteropathy where feeding was associated with decreased duration of hospitalization and reduced intestinal permeability (3). Modified diets may be useful in patients with delayed gastric emptying or chronic gastroenteropathies associated with food intolerance. Gastric protectants (eg, sucralfate) can be used to bind toxins and protect the GI mucosa when vomiting is associated with gastritis or gastric ulceration. Inhibitors of gastric acid secretion (usually H 2 antagonists) are used to limit gastric erosion or ulceration in patients with gastritis, and those considered at risk of developing GI ulceration (eg, shock patients) or esophagitis. Inhibition of gastric acid may also limit the hypochloremia and alkalosis associated with gastric outflow obstruction. Mucosal cytoprotection with prostaglandin E analogs may be beneficial when persistent vomiting is associated with NSAID administration. Analgesics may decrease vomiting associated with acute abdominal conditions, eg, buprenorphine for pancreatitis. Antiemetics are indicated in patients with vomiting that is compromising hydration status, affecting electrolyte and acid-base balance, and in patients at high risk for esophagitis or aspiration pneumonia as well as those distressed by repeated vomiting. Antibiotics are usually limited to suspected infections, acute abdominal conditions, or gastritis associated with Helicobacter species infection. Prokinetic agents are used to promote gastric and intestinal motility in patients with a patent GI tract. Surgery is indicated to remove large foreign bodies, treat some causes of pyloric outflow obstruction, and to obtain biopsies of the GI tract and concurrently diseased organs. Pharmacologic Control of Vomiting Pharmacologic control of vomiting involves antagonizing central and peripheral receptors that regulate emesis and stimulating receptors promoting ordered gastrointestinal motility (1,2,4). The receptor subtypes involved in vomiting and examples of drugs that are commonly used in the management of vomiting are summarized in Figure 3. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 6

25 Figure 3 Summary of receptor subtypes involved in vomiting and examples of drugs that are commonly used to manage vomiting. Some antiemetics have more than one mechanism of action, eg, phenothiazines (eg, chlorpromazine) are antagonists of alpha1-adrenergic and alpha2-adrenergic, H 1 - and H 2 -histaminergic, and D 2 -dopaminergic receptors. Metoclopramide antagonizes D 2 - dopaminergic and 5HT 3 -serotonergic receptors and has cholinergic effects on smooth muscle. Antiemetics are generally contraindicated in patients with gastrointestinal toxicity where they may limit expulsion of the toxic agent. Because antiemetics can effectively mask signs of serious underlying disease, a clinical response to antiemetics should not preclude a search for the underlying cause of vomiting. Nonselective cholinergic receptor antagonists (other than the M 1 -specific antagonist pirenzipine), eg, atropine, scopolamine, aminopentamide, or isopropamide, may cause ileus, delayed gastric emptying, and dry mouth. The recommendation is not to give phenothiazines and the NK 1 antagonist maropitant to hypotensive patients (5). Phenothiazines may also cause unwanted sedation and decrease the seizure threshold in animals with epilepsy (6-8). Maropitant is metabolized by the liver and is heavily Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 7

26 protein bound, hence careful monitoring is suggested in patients with liver disease and hypoproteinemia; maropitant should not be used for more than 5 consecutive days. It can be restarted for another 5-day period after a 1-day washout period, but the onus should be on identifying the cause of vomiting rather than continued antiemetic therapy. Maropitant can prolong the QT interval and is contraindicated in dogs with bradycardia. If maropitant is the drug of choice, however, then ECG monitoring should be increased. When there is suspicion of intestinal obstruction, antiemetics with prokinetic activity, such as metoclopramide, are contraindicated to avoid stimulating contractions. The affected animal s species and age may also impact selection of an antiemetic. Certain antiemetics are not recommended/require caution/are ineffective when used in cats; eg, cats are resistant to apomorphine-induced vomiting, suggesting the D 2 - dopaminergic metoclopramide may have less activity than alpha2-adrenergic antagonists (1,4). Maropitant is currently not licensed for use in dogs less than 16 weeks of age due to the potential for causing dose-dependent bone marrow hypoplasia. Despite the high frequency of antiemetic use in veterinary practice, there is a paucity of controlled studies of antiemetic efficacy in dogs and cats. The comparative efficacy of commonly used antiemetics against vomiting induced by apomorphine (central stimulus) and ipecac (peripheral stimulus) in laboratory dogs indicates that maropitant, chlorpromazine, and metoclopramide have similar activity against apomorphine-induced emesis (all had greater activity than ondansetron), and that ondansetron and maropitant have equal activity against ipecac-induced vomiting (both had greater activity than metoclopramide and chlorpromazine) (9). Two recent clinical trials, one in the United States, the other in Europe, have focused on maropitant. In the US study of 275 dogs, 50% of dogs treated with placebo (32/64) versus 22% (41/188) treated with maropitant vomited at some point after treatment (10). In the European study vomiting was controlled in 97% of 32 dogs receiving maropitant versus 71% of 34 dogs receiving intermittent metoclopramide (0.5 to 1.0 mg/kg /day over 3 doses) (11). Strategies for Managing Persistent Vomiting Uremia Vomiting in uremia is mediated via the effects of uremic toxins on the CRTZ and afferent inputs from the inflamed stomach. Control of vomiting is focused on ameliorating uremia with fluid therapy, antagonizing the effects of uremic toxins on the CRTZ, and limiting potential afferent input from the GI tract, eg, uremic/hypergas-trinemic gastritis. In dogs, CRTZ stimulation can be reduced by administering a D 2 -dopaminergic antagonist, such as metoclopramide (0.2 to 0.4 mg/kg subcutaneously, intramuscularly, or orally four times a day or 1.0 mg/kg continuous intravenous infusion over 24 hours) or maropitant (1.0 mg/kg subcutaneously every 24 hours for no more than 5 days). The peripheral effects are usually addressed with an H 2 antagonist (eg, famotidine at a dosage of 0.5 to 1.0 mg/kg once or twice daily) and mucosal protectant (sucralfate at a dosage of 0.25 to 1.0 g orally three times daily), although a recent study has questioned Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 8

27 the association of uremia and gastric ulceration in dogs (12). Metoclopramide should not be given to patients receiving dopamine to promote diuresis, and may not be an effective centrally acting antiemetic in the cat. Cats, or dogs, with vomiting that is refractory to initial therapy for uremic gastritis may benefit from an alpha2-adrenergic antagonist, such as chlorpromazine (0.2 to 0.4 mg/kg subcutaneously three times daily) or prochlorperazine (0.5 mg/kg subcutaneously or intramuscularly three times daily) after ensuring adequate circulatory status. Gastric Ulceration Vomiting in patients with suspected acute gastritis or gastric ulceration is managed by providing adequate fluid therapy and limiting afferent input from the inflamed gut by decreasing gastric acid secretion (eg, with H 2 antagonists) and providing mucosal protection (eg, sucralfate). A prostaglandin E analog (misoprostol at a dosage of 3 to 5 µg/kg orally three times daily) may be beneficial where persistent vomiting is associated with NSAID administration (13,14). When ulceration is severe and vomiting is not adequately controlled, such antiemetics as metoclopramide, maropitant (dogs), or chlorpromazine/prochlorperazine (if circulating volume is satisfactory) can be used as an adjunct in the short term. In patients with severe or persistent ulceration, more complete inhibition of gastric acid secretion can be achieved with the H + /K + ATPase inhibitor omeprazole (1 mg/kg orally twice daily). This drug may be particularly effective in patients with excessive secretion of gastric acid, eg, gastrinoma. The combination of omeprazole and the long-acting somatostatin analog octreotide (which decreases gastrin release and inhibits gastric acid secretion) effectively reduced vomiting in a dog with gastrinoma (15). Omeprazole has also been shown to decrease gastric ulcers in sled dogs, although diarrhea was an unwanted side effect (16). Mast cell tumors may cause vomiting in dogs via the central effects of histamine on the CRTZ and the peripheral effects of histamine on gastric acid secretion (with resultant hyperacidity and ulceration). Treatment of mastocytosis with H 1 and H 2 histamine antagonists (eg, diphenhydramine and famotidine) may reduce the central and peripheral effects of histamine. Corticosteroids are used to decrease tumor size and release of histamine. Gastritis The treatment of dogs and cats with gastritis is guided by the presence or absence of gastric Helicobacter species. In dogs or cats with chronic vomiting, lymphoid follicular/ lymphocytic gastritis, and gastric colonization by Helicobacter, antibiotics directed against Helicobacter species have produced positive clinical responses. In an uncontrolled trial of antibiotics in dogs and cats with gastritis and Helicobacter infection, clinical signs in 90% of 63 dogs and cats responded to treatment with a combination of metronidazole, amoxicillin, and famotidine (17). Subsequently, 74% of 19 animals in which endoscopy was repeated had no evidence of Helicobacter species in gastric biopsies (17). A recent controlled trial of amoxicillin (15 mg/kg orally twice daily over 14 days), metronidazole (10 mg/kg orally twice daily over 14 days), and bismuth with or Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 9

28 without famotidine in 24 dogs found a similar decrease in vomiting (86.4%) and reduced gastritis scores in dogs that were Helicobacter negative at 6 months (18). The use of famotidine did not improve resolution of clinical signs or eradication of Helicobacter species. Only 43% of dogs were free from Helicobacter at 6 months, which echoes the results of controlled studies in asymptomatic Helicobacter-infected dogs and cats. In another recent study, metronidazole (11 to 15 mg/kg orally twice daily), amoxicillin (22 mg/kg orally twice daily), and bismuth subsalicylate (0.22 ml/kg orally three to 4 times daily) were given to five Helicobacter-infected animals (three dogs and two cats) for 21 days; and resolution of vomiting and long-term eradication of Helicobacter (9 to 38 months) were documented in all animals (19). The author has employed the combination of amoxicillin (20 mg/kg orally twice daily), clarithromycin (7.5 mg/kg orally twice daily), and metronidazole (10 mg/kg orally twice daily) for 14 days to eradicate Helicobacter pylori infection successfully in cats. Taken as a whole, these studies suggest that a longer duration of treatment (21 days) or the use of antibiotics that can eradicate intracellular Helicobacter (eg, clarithromycin) improve eradication; but further studies are required before clear guidelines regarding the treatment of gastric Helicobacter in dogs and cats can be established. The author recommends treating only symptomatic patients that have biopsy-confirmed Helicobacter species infection UandU gastritis. Chronic Gastritis of Unknown Cause Helicobacter-negative lymphocytic plasmacytic gastritis is relatively common in dogs and cats (25% to 40% of cases, according to the author s unpublished observations). The cellular infiltrate varies widely in severity and may be accompanied by mucosal atrophy or fibrosis and, less commonly, hyperplasia. Gastritis may also be accompanied by similar infiltrates in the intestines, particularly in cats (which should also be evaluated for the presence of pancreatic and biliary disease). Patients with lymphoplasmacytic, Helicobacter-negative gastritis are initially treated with diet. The diet is often restricted in antigens to which the patient has been previously exposed, such as a lamb-based diet if the patient has previously been fed chicken and beef, or contains hydrolyzed proteins (usually chicken or soy) that may be less allergenic than intact proteins. Many of these diets are also high in carbohydrates and restricted in fat, which facilitates gastric emptying, and may contain other substances, such as menhaden fish oil or antioxidants, that may alter inflammation. The test diet is fed exclusively for a period of about 2 weeks while vomiting episodes are recorded. If vomiting frequency improves, then a challenge with the original diet is required to confirm a diagnosis of food intolerance. The introduction of a specific dietary component, such as beef, to the test diet is required to confirm sensitivity to that component. If vomiting is unresponsive to the initial test diet, the patient is usually placed on a different diet for the next 2 weeks (usually the limit of client tolerance). If there is no response to dietary manipulation, then the subsequent step is immunomodulation with prednisolone (1 to 2 mg/kg orally per day, tapered to every other day Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 10

29 at the lowest dose that maintains remission over 8 to 12 weeks). Antacids and mucosal protectants are added to the therapeutic regimen if ulcers or erosion are detected during endoscopy or if hematemesis or melena is noted. If gastritis is unresponsive to antibiotics, diet, prednisolone, and antacids, additional immunosuppression may be indicated. It is important, however, to carefully reevaluate the patient record and histopathology (eg, is lymphoma a possibility?) before ramping up immunosuppression. In dogs, immunosuppression is usually increased with azathioprine (orally at 2 mg/kg once daily for 5 days, then every other day, on alternating days, with prednisolone). Chlorambucil may be a safer alternative to azathioprine in cats and has been successfully employed in the management of inflammatory bowel disease and small cell lymphoma (given orally at a dosage of 5 mg per cat every other day). Prokinetic agents, such as metoclopramide, cisapride, and erythromycin, can be used as an adjunct when delayed gastric emptying is present (see following section). Delayed Gastric Emptying Delayed gastric emptying is caused by outflow obstruction or defective propulsion and is usually suggested by the vomiting of food 8 to 12 hours after ingestion (20,21). Other signs include abdominal discomfort, distension, bloating, and intermittent anorexia. Outflow obstruction can be caused by polyps, foreign bodies, tumors, pyloric hypertrophy or stenosis, granulomata, and extraluminal masses, such as pancreatic tumors. Defective propulsion may result from primary gastric diseases, such as gastritis, ulceration, neoplasia, and parasitism, or nongastric disorders, such as stress, trauma, peritonitis, pancreatitis, infectious enteritis, electrolyte and metabolic derangements, drugs, and surgery. Disordered motility may be involved in the initiation of gastric dilatation-volvulus. The finding of hypochloremia, hypokalemia, and metabolic alkalosis, with or without aciduria, should raise the suspicion of an upper GI obstruction or, less commonly, a hypersecretory state, such as gastrinoma or mastocytosis. Radiography is used to investigate vomiting and to confirm delayed gastric emptying (retention of food or fluid more than 16 to 17 hours after a meal, or delayed gastric emptying of liquid barium (30% weight/volume, 12 to 16 ml/kg via stomach tube; the stomach should empty within 15 to 60 minutes in cats and 1 to 2 hours in dogs), barium meal (normal is less than 10 to 15 hours) or barium polyspheres (normal dogs 10, 5 mm and 30, 1.5 mm spheres: 50% empty by 7.5 hours, 75% by 13.1 hours, 90% by 22.5 hours). Endoscopy is useful for confirming gastric outflow obstruction and gastric and duodenal causes of decreased propulsion (eg, ulcers, gastritis). Measurement of gastric ph and serum gastrin may help to determine the cause of gastric ulceration or mucosal abnormalities (15). Treatment of gastric emptying disorders is directed at the underlying cause, eg, surgery for pyloric stenosis or hypertrophic gastropathy, antacids, mucosal protectants, with antibiotics or using antibiotics only, for gastritis. In nonobstructive situations gastric emptying can be enhanced by dietary modification to facilitate gastric emptying (small amounts of semi-liquid, high carbohydrate, protein-restricted, and fat-restricted diets fed Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 11

30 at frequent intervals; intestinal diets blended with water and mixed with an equal volume of boiled rice may also be of benefit) and prokinetic agents, such as metoclopramide (0.2 to 0.5 mg/kg orally or subcutaneously three times daily), cisapride (0.1 to 0.5 mg/kg orally three times daily), or erythromycin ([dog] 0.5 to 1.0 mg/kg orally three times daily) (20-24). In dogs, the H 2 antagonists ranitidine (1 to 2 mg/kg orally twice daily) and nizatidine (2.5 to 5.0 mg/kg orally once daily) have prokinetic activity that appears to be due to their acetyl cholinesteraselike activity (20,21). Pancreatitis Vomiting in dogs with pancreatitis is likely due to direct afferent input to the vomiting center from the inflamed pancreas and adjacent intestines and ileus secondary to inflammation. Analgesia (eg, buprenorphine at a dosage of 0.01 mg/kg subcutaneously twice daily) is used to decrease afferent stimulation of the vomiting center and may also have direct central effects on emesis. The antiemetics traditionally employed in dogs with pancreatitis are metoclopramide (0.2 to 0.4 mg/kg subcutaneously, intramuscularly, or orally four times daily; or 1.0 mg/kg continuous intravenous infusion over 24 hours may have beneficial central and a peripheral effects) and phenothiazines (chlorpromazine or prochlorperazine; ensure adequate volume status). 5HT 3 - receptor antagonists, such as ondansetron, and the NK 1 antagonist maropitant are increasingly used and may offer the additional benefit of decreasing pancreatic or visceral stimulation of emesis. Motion Sickness Stimuli from the vestibular system are thought to be the cause of motion sickness. Motion sickness in dogs can be decreased by the administration of receptor antagonists of NK 1 (maropitant 8 mg/kg orally once daily for 2 days maximum), H 1 -histaminergic (diphenhydramine at 2 to 4 mg/kg orally or intramuscularly three times daily), and M 1 - cholinergic (scopolamine at 0.03 mg/kg subcutaneously or intramuscularly four times daily) receptors (1,25). Motion sickness in the cat does not appear to be controlled by histamine antagonists and can be controlled with chlorpromazine (1). Cancer Chemotherapy The emetic effects of the chemotherapeutic agent cisplatinum in dogs can be decreased by administering butorphanol (0.4 mg/kg subcutaneously 30 minutes prior to cisplatin), 5HT 3 -serotonergic antagonists ([dogs] ondansetron at 0.5 to 1.0 mg/kg orally 30 and 90 minutes after commencing cisplatinum; it is believed that blocking peripheral receptors accounts for the antiemetic effect), and the NK 1 antagonist maropitant (26-31). Metoclopramide has some antiemetic effects against cisplatin, but high, potentially toxic doses may be required. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 12

31 Vet Persistent Vomiting of Undetermined Etiology Symptomatic fluid support, dietary restriction or modification, analgesia, and antiemetic therapy to control vomiting are considered where vomiting is frequent or severe enough to cause derangements of fluid, electrolyte, and acid-base balance. Antiemetic selection and use in patients with unknown causes of vomiting is based on a best guess, least harmful approach, taking into consideration the potential contraindications to antiemetic use in general, eg, ingestion of toxic substances and contraindications for specific agents, including age, hypotension, bradycardia, seizures, and a variety of other factors. Conclusion Vomiting is associated with a wide spectrum of disorders. Patient care should be aimed at detecting and treating the underlying cause. A variety of therapeutic strategies can be used to manage patients with refractory vomiting, eg, fluid support, dietary restriction or modification, acid suppression, gastric cytoprotection, analgesia, antiemetic drugs, and antibiotics; and their use is guided by knowledge of the factors precipitating emesis and the consequences of vomiting. References 1. Washabau RJ, Elie MS. Antiemetic therapy. In: Bonagura JD, Kirk RW, eds. Kirk s Current Veterinary Therapy XII: Small Animal Practice. Philadelphia, PA: W. B. Saunders Company; 1995: Boothe DM. HGastrointestinal pharmacology. H Clin North Am Small Anim Pract. 1999;29: Mohr A J, Leisewitz A L, Jacobson LS, Steiner JM, Ruaux CG, Williams DA. Effect of early enteral nutrition on intestinal permeability, intestinal protein loss, and outcome in dogs with severe parvoviral enteritis. J Vet Intern Med. 2003;17: King GL. Animal models in the study of vomiting. Can J Physiol Pharmacol. 1990;68: HMurphy GPH, HBenson DW H, HSchirmer KAH. Renal response to chlorpromazine in hemorrhagic hypotension: hemodynamic and metabolic changes and adrenolytic effect in dogs. HAnn Surg.H 1966;64: HPisani FH, HOteri G, HCosta CH, HDi Raimondo GH, HDi Perri RH. Effects of psychotropic drugs on seizure threshold. HDrug Safety.H 2002;25: Frank GB, Jhamandas KH. Effects of general depressant drugs on the electrical responses of isolated slabs of cat's cerebral cortex. Br J Pharmacol. 1970;39: Tobias KMH, HMarioni-Henry KH, HWagner RH. A retrospective study on the use of acepromazine maleate in dogs with seizures. HJ Am Anim Hosp Assoc.H 2006;42: Sedlacek HS, Ramsey DS, Boucher JF, Eagleson JS, Conder GA, Clemence RG. Comparative efficacy of maropitant and selected drugs in preventing emesis induced by centrally or peripherally acting emetogens in dogs. J Vet Pharmacol Ther. 2008;31: Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 13

32 J J Semin Vet 10. Ramsey DS, Kincaid K, Watkins JA, et al. HSafety and efficacy of injectable and oral maropitant, a selective neurokinin 1 receptor antagonist, in a randomized clinical trial for treatment of vomiting in dogs. H Vet Pharmacol Ther. 2008;31: De La Puente-Redondo VA, Siedek EM, Benchaoui HA, Tilt N, Rowan TG, Clemence RG. The anti-emetic efficacy of maropitant (Cerenia) in the treatment of ongoing emesis caused by a wide range of underlying clinical aetiologies in canine patients in Europe. J Small Anim Pract. 2007;48: Peters RM, Goldstein RE, Erb HN, Njaa BL. HHistopathologic features of canine uremic gastropathy: a retrospective study. H Vet Intern Med. 2005;19: Murtaugh RJ, Matz M, Labato M, et al. Use of synthetic prostaglandin-e1 (misoprostol) for prevention of aspirin-induced gastroduodenal ulceration in arthritic dogs. J Am Vet Med Assoc. 1993;202: Johnston SA, Leib MS, Forrester SD, Marini M. The effect of misoprostol on aspirininduced gastroduodenal lesions in dogs. J Vet Intern Med. 1995;9: Simpson KW, Dykes NL. HDiagnosis and treatment of gastrinoma. H Vet Med Surg (Small Anim). 1997;12: Davis MS, Willard MD, Nelson SL, et al. Efficacy of omeprazole for the prevention of exercise-induced gastritis in racing Alaskan sled dogs. J Vet Intern Med. 2003;17: Denovo RC, Magne ML. Current concepts in the management of Helicobacterassociated gastritis. Proceedings of the 13 th ACVIM Forum. 1995: Leib MS, Duncan RB, Ward DL. HTriple antimicrobial therapy and acid suppression in dogs with chronic vomiting and gastric Helicobacter spp.h J Vet Intern Med. 2007;21: Jergens AE, Pressel M, Crandell J, et al. Fluorescence in situ hybridization confirms clearance of visible Helicobacter spp associated with gastritis in dogs and cats. J Vet Intern Med. 2009;23: Hall JA, Washabau RJ. HDiagnosis and treatment of gastric motility disorders. H Clin North Am Small Anim Pract. 1999;29: Washabau RJ. HGastrointestinal motility disorders and gastrointestinal prokinetic therapy.h Vet Clin North Am Small Anim Pract. 2003;33: Itoh Z, Suzuki T, Nakaya M, Inoue M, Mitsuhashi S. Gastrointestinal motorstimulating activity of macrolide antibiotics and analysis of their side effects on the canine gut. Antimicrob Agents Chemother. 1984;26: Holle GE, Steinbach E, Forth W. Effects of erythromycin in the dog upper gastrointestinal tract. Am J Physiol. 1992;263:G52-G Burger DM, Wiestner T, Hubler M, Binder H, Keiser M, Arnold S. Effect of anticholinergics (atropine, glycopyrrolate) and prokinetics (metoclopramide, cisapride) on gastric motility in beagles and Labrador retrievers. J Vet Med A Physiol Pathol Clin Med. 2006;53: Benchaoui HA, Siedek EM, De La Puente-Redondo VA, Tilt N, Rowan TG, Clemence RG. Efficacy of maropitant for preventing vomiting associated with motion sickness in dogs. Vet Rec. 2007;161: Schurig JE, Florczyk AP, Rose WC, Bradner WT. Antiemetic activity of butorphanol against cisplatin-induced emesis in ferrets and dogs. Cancer Treatment Rep. 1982;66: Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 14

33 27. Moore AS, Rand WM, Berg J, L'Heureux DA, Dennis RA. Evaluation of butorphanol and cyproheptadine for prevention of cisplatin-induced vomiting in dogs. J Am Vet Med Assoc. 1994;205: Fukui H, Yamamoto M, Sato S. Vagal afferent fibers and peripheral 5-HT3 receptors mediate cisplatin-induced emesis in dogs. Japanese J Pharmacol. 1992;59: Topal A, Kaya M, Gul N. Ondansetron and granisetron in the prophylaxis of nausea induced by cisplatin in dogs. Acta Veterinaria Brno. 2005;74: De La Puente-Redondo VA, Tilt N, Rowan TG, Clemence RG. Efficacy of maropitant for treatment and prevention of emesis caused by intravenous infusion of cisplatin in dogs. Am J Vet Res. 2007;68: Vail DM, Rodabaugh HS, Conder GA. Efficacy of injectable maropitant (Cerenia TM ) in a randomized clinical trial for prevention and treatment of cisplatin-induced emesis in dogs presented as veterinary patients. Vet Comp Oncol. 2007;5: Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 15

34 The Pearls of Feline Liver Disease David C. Twedt, DVM, Diplomate, ACVIM Colorado State University Fort Collins, Colorado Abstract Liver disease is common in the cat, and our veterinary understanding of many conditions has advanced considerably over recent years. The kinds of liver disease as well as interpretation of laboratory tests for feline liver disease are unique and differ greatly from the common liver disorders observed in the dog. This is due in part to specific anatomic and metabolic differences in cats. The author gives an overview of these differences and includes specific pearls of newer information on feline hepatic disease, diagnostic testing, and treatment strategies. Key Content ALP is unique in cats because the half-life of the enzyme is short, and the feline liver is reported to contain only one third of the concentrations found in dogs. Cats with cholangitis usually have higher elevations of GGT than ALP. It is not unusual to find elevations in bilirubin concentrations in cats with inflammatory disease, such as pyothorax, abscesses, or fat necrosis. Cats differ from dogs in the fact that benign tumors are more common than malignant hepatic neoplasia. The diagnosis of idiopathic hepatic lipidosis is made by ruling out all secondary causes and is supported by the clinical history and laboratory findings. In general, dietary fat and protein should not be restricted in cats with idiopathic hepatic lipidosis because calories and protein are so important in providing nutritional balance. A failure to respond to traditional hepatic lipidosis therapy should signal the need to investigate the likelihood of an underlying condition in the patient. Inflammatory liver disease is often associated with concurrent intestinal and pancreatic disease. From Gastrointestinal Diseases, proceedings of a symposium sponsored by Pfizer Animal Health by The Gloyd Group, Inc. All rights reserved. The opinions expressed in this article are those of the author and do not necessarily reflect the official label recommendations and points of view of the company or companies that manufacture and/or market any of the pharmaceutical agents referred to.

35 Primary Liver Disease A study evaluating the utility of liver biochemistries in the diagnosis of feline liver disease found the best predictive tests for primary liver disease include alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), total bilirubin, and bile acids (1). Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values are quite variable, and elevations do not always predict primary inflammatory liver disease (cholangitis) or hepatic lipidosis, both of which cause more cholestatic changes with increases in ALP and GGT rather than hepatocellular damage reflected by increases in ALT and AST. ALP is also unique in cats because the half-life of the enzyme is short (6 hours), and the feline liver is reported to contain only one third of the concentrations found in dogs (2). Consequently, increases in serum ALP due to cholestasis are not expected to increase with the same magnitude as would occur in dogs with a similar disease. Corticosteroids do not induce a steroid isoenzyme of ALP, nor do they cause a steroid hepatopathy. Cats with idiopathic hepatic lipidosis usually have marked increases in ALP and only mild increases in GGT concentrations (3). GGT is a similar to ALP in that GGT increases with cholestasis; however, this enzyme appears to have greater sensitivity for the diagnosis of cholangitis than does ALP. Presumably this is because GGT is found in higher concentrations in the bile ducts than in the hepatocyte, where ALP appears to predominate, and is affected more by intrahepatic cholestasis. Cats with cholangitis usually have higher elevations of GGT than ALP. Clinical Pearl: Elevation of GGT often suggests biliary tract disease, whereas marked increases in ALP occur with lipidosis. Assessing bile acids in cats is most useful in screening for portal systemic shunts. Icterus is a common clinical and laboratory finding, and the old saying that icteric cats have a poor prognosis is no longer true. Feline icterus can occur in association with many causes, of which not all are liver related and many of which are highly treatable. Icterus occurs due to alteration of the normal bilirubin pathway. There are many complexities in bilirubin metabolism, and the ability to conjugate compounds is uniquely affected in the cat. Prehepatic icterus from hemolysis must be ruled out first. For icterus to occur secondary to hemolysis of RBCs, the hemocrit (packed cell volume [PCV]) must fall significantly, usually less than 20%. First, especially treatable causes of hemolytic anemia, such as Mycoplasma spp or hypophosphatemia, should be excluded. Next, causes of altered hepatic bilirubin metabolism should be considered. Several steps are involved in the pathways of bilirubin metabolism before it reaches the bile (Figure 1) (4). This hepatic metabolism can be affected by not only structural damage but also metabolic alterations from inflammatory cytokines or endotoxins or from nutritional alterations due to mobilization of free fatty acids delivered to the liver. In addition, protein deficiencies resulting from starvation or catabolic conditions can lead to depletion of bilirubin-binding proteins, contributing to alterations in metabolism. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 2

36 Figure 1 Diagram showing the hepatic pathway of bilirubin metabolism from uptake, protein binding, conjugation, and then excretion into the bile canuliculi. Cats also have inherent low concentrations of glucuronyl transferase, an enzyme required to convert bilirubin to water-soluble form before hepatic excretion (3). It is these multiple steps in the bilirubin pathway that can result in icterus, often without evidence of significant structural liver disease. The author reviewed a series of cats with elevations in bilirubin and grouped them into either clinically icteric cats (bilirubin greater than 3.0 mg/dl) or those with biochemical icterus (having only icteric serum with bilirubin ranging from 0.5 to 2.9 mg/dl). Cats that were clinically icteric (bilirubin above 3.0 mg/dl) most often had primary hepatobiliary disease when hemolytic disease was ruled out. Clinical Pearl: Icteric cats without hemolysis often have primary liver disease. Cats with biochemical icterus (bilirubin below 3.0 mg/dl) do not always have a primary hepatobiliary disease but could also have other nonhepatic disorders, with the liver being only secondarily affected. For example, it is not unusual to find elevations in bilirubin concentrations in cats with inflammatory disease, such as pyothorax, abscesses, or fat necrosis (5). Clinical Pearl: Cats with biochemical icterus (bilirubin below 3.0 mg/dl) do not always have primary liver disease. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 3

37 Common Liver Diseases in Cats The incidence of liver disease in the cat is unknown, but the disease is considered to be common. In the author s unpublished review of 175 consecutive liver biopsies performed on cats at Colorado State University, several large categories were apparent (Table 1). Four groups composed 87% of the liver biopsies: lipidosis (both idiopathic and secondary, 26%), cholangitis (25%), neoplasia (20%), and reactive hepatopathies (16%). Hepatic cysts are also an occasional finding in some cats but rarely cause problems. Lipidosis and cholangitis were the most common conditions and will be discussed later. Table 1. Approximate Incidence of Feline Liver Disease Based on Histology Reports of 175 Consecutive Liver Biopsies Performed at Colorado State University Histologic Diagnosis Percent Lipidosis 26% Cholangitis 25% Neoplasia 20% Reactive hepatopathies 16% Vascular anomalies 4% Toxic hepatopathies 5% Cystic lesions 2% Miscellaneous 2% Reactive hepatopathies refer to changes in the liver that occur secondary to a primary nonhepatic disorder, such as inflammatory bowel disease, hyperthyroidism, or cardiac disease, to name a few examples. Many cases of secondary reactive hepatopathies also include some degree of secondary lipidosis. Often the leakage enzymes (ALT and AST) are the predominant enzyme abnormality. Hepatic neoplasia is also common, with lymphoma the most common type of cancer observed. Cats differ from dogs in the fact that benign tumors are more common than malignant hepatic neoplasia. Bile duct adenomas (cyst adenomas) were the most common benign tumor and bile duct carcinoma the most common malignant neoplasia noted by the author when hematopoietic tumors (ie, lymphoma) were excluded from the hepatic neoplasia group. Clinical Pearl: Cholangitis and hepatic lipidosis are the most common primary acquired liver diseases in cats. Hepatic Lipidosis Lipidosis by definition is the abnormal accumulation of lipid (most often triglycerides) in the cytoplasm of the hepatocyte (Figure 2). Hepatic lipidosis can occur in cats as either a primary idiopathic disorder or secondary to a number of Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 4

38 other primary disease conditions. The condition is simply the result of nutritional, metabolic, or toxic liver insults that result in abnormal lipid accumulation. This process can be quite variable and is completely reversible (6). Cats appear to be unique when it comes to hepatic lipid accumulation because primary lipidosis in the dog is uncommon. Lipidosis in cats results from many causes. For example, diabetes mellitus is a common secondary cause resulting in significant hepatic triglyceride accumulation. This diagnosis is generally obvious (hyperglycemia and glycosuria), and the lipidosis resolves with appropriate therapy. Figure 2 Yellow liver of a cat that died from idiopathic hepatic lipidosis. Hepatic lipid accumulation can also result secondary to a number of other disease syndromes associated with anorexia and weight loss, including such conditions as pancreatitis, inflammatory bowel disease, or other major organ dysfunction. These secondary conditions are generally associated with less severe lipidosis than occurs with idiopathic hepatic lipidosis (2). The prognosis for secondary hepatic lipidosis is entirely dependent on the primary etiology causing lipidosis. Clinical Pearl: Cats that are sick and anorectic from almost any cause can develop secondary hepatic lipidosis. The etiology of idiopathic hepatic lipidosis is unknown, and many theories have been put forward without substantial documentation. Some suggest that there is a defect in hepatic lipid mobilization resulting in the decreased ability for hepatic fat oxidation, decreased synthesis of apoproteins, and decreased lipoprotein removal from the liver (6). The cause for the rapid mobilization of peripheral fat is as yet unidentified, however. A novel unpublished theory speculated by some is that the disease is one causing a primary central anorexia disorder that then results in fat mobilization and hepatic lipidosis. In any event it is important to investigate all possible secondary conditions leading to anorexia and the hepatic lipidosis. One study reported on a number of cats with acute pancreatitis resembling the classic idiopathic form of hepatic lipidosis (7). Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 5

39 Cats with idiopathic hepatic lipidosis are generally middle-aged or older obese cats with a history indicating a recent stressful episode that is then followed by a period of complete anorexia. There does not appear to be a breed or sex predisposition. Cats present with an acute history of rapid weight loss, depression, and icterus (6). The weight loss is significant (possibly as much as 40% to 60% of body weight occurring over several weeks) and is characterized by significant loss of muscle mass, but abdominal and inguinal fat stores are often spared. The typical neurologic signs commonly associated with hepatic encephalopathy in dogs are uncommon in cats. Complete anorexia, lethargy, and depression may, however, be partly the result of hepatic encephalopathy. Cats with that condition almost always have a total aversion to any type of food. The diagnosis of idiopathic hepatic lipidosis is made by ruling out all secondary causes and is supported by the clinical history and laboratory findings. Icterus is common and is associated with a very high ALP and often normal or a disproportionate increase in GGT. ALT concentrations may be abnormal but quite variable in magnitude of elevation. Clinical Pearl: Elevated ALP with low GGT is often suggestive of hepatic lipidosis. Hypercholesterolemia, hyperammonemia, and abnormal bile acid levels are characteristic. About one third of the cats with idiopathic hepatic lipidosis have a nonregenerative anemia, hypokalemia, and clotting abnormalities; and about one half of the cats demonstrate poikilocytes in the RBCs (2). Finding severe hypokalemia, anemia, or another concurrent disease (ie, pancreatitis) in patients with lipidosis results in a poorer survival rate (2). The liver size may be normal or enlarged on palpation or radiographically and is usually diffusely hyperechoic on ultrasound examination. A definitive diagnosis requires a liver biopsy or hepatic cytology. Fine-needle aspirates of the liver with cytologic evidence of many vacuolated lipid-containing hepatocytes helps support a diagnosis. The reader should be aware, however, that cytologic diagnosis does not always correlate with histology. A needle aspirate is best obtained using ultrasound guidance. Hepatic tissue biopsy confirms the diagnosis of lipidosis but does not differentiate between primary idiopathic lipidosis and lipidosis secondary to other conditions. Care should be taken when obtaining a liver biopsy as some cats may have coagulation abnormalities. Therapy for idiopathic hepatic lipidosis requires aggressive management (8). At the author s hospital approximately an 80% survival rate is expected in cats given appropriate therapy, when no underlying disease is present. Initial therapy requires rehydration with balanced electrolyte solutions. Replacement of potassium deficits is imperative as normokalemia improves survival (2). Some cats may also require magnesium supplementation (8). Administration of glucose-containing solutions may actually cause marked hyperglycemia in these patients and could result in a refeeding syndrome (see later discussion). Cats also have a tendency to develop lactic acidosis and therefore lactate-containing fluids (ie, lactated Ringer s) should be avoided. The practice of adding B vitamins to the fluids should also be avoided because their prolonged exposure to light in the fluid bag could Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 6

40 inactivate them. Parenteral administration is a better option. Adequate nutrition then becomes the most important part of the therapy for hepatic lipidosis. Force feeding or appetite stimulation is generally inadequate to meet caloric needs, and tube feeding is the best way to administer adequate calories (9). Nasogastric tubes can be used, but feeding is limited to liquid diets due to their small size; and they are not tolerated by the patient as well as larger feeding tubes. The author suggests placement of either an esophageal or gastrostomy feeding tube and notes that, in his hospital, staff find esophageal tubes are well tolerated and result in fewer complications than gastric tubes (the author has found that French red rubber feeding tubes are ideal for esophageal feeding). Readers should refer to specific articles on tube placement techniques (8). The nutritional recommendations for idiopathic hepatic lipidosis are completely empirical and poorly documented. There are numerous reports in the literature suggesting various diets (with a variety of protein and fat content recommendations). In general, dietary fat and protein should not be restricted in cats with idiopathic hepatic lipidosis because calories and protein are so important in providing nutritional balance. The author generally feeds a canned nutritional recovery formulation. Caloric requirements should be calculated based on an ideal body weight. At the onset of feeding, cats are given approximately 25% of their caloric needs divided over four to six feedings. Then the amount fed is gradually increased over a week or slightly longer to reach their full caloric requirements. Feeding too much volume or rapid feeding can result in vomiting. Clinical Pearl: Hepatic lipidosis is managed by feeding a balanced diet to meet the cat's caloric requirements. Several authors suggest supplementing with arginine (1,000 mg/day), thiamine (100 mg/day), and taurine (500 mg/day) for 3 to 4 weeks (8,9). There is some evidence (at least in feline weight reduction studies) that L-carnitine supplementation in cats may protect against hepatic lipid accumulation and, consequently, may be an appropriate dietary adjunct for cats with lipidosis (10). Carnitine is required for transport of long-chain fatty acids into the mitochondria for subsequent oxidation and energy production. A deficiency of carnitine may lead to impaired mitochondrial function. It appears that carnitine deficiency could result in liver disease and that supplementation may help protect against encephalopathy, hypoglycemia, and subcellular damage. Studies have failed to show carnitine deficiency in cats with hepatic lipidosis (11). Some authors still suggest giving 250 to 300 mg of carnitine daily during recovery, however. Clinical Pearl: No good data has yet been reported to support the benefit of various dietary supplements. There is evidence to suggest many cats with hepatic lipidosis have or will develop cobalamin (vitamin B12) deficiency (12). Experimental cobalamin deficiency in cats results in lethargy, anorexia, and weight loss the signs observed with lipidosis. Anecdotal reports indicate cats improve faster with high doses of Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 7

41 cobalamin given subcutaneously at 250 µg weekly. It is recommended that serum cobalamin levels first be determined to document the presence of a deficiency and the need for cobalamin supplementation. Note that B-complex vitamins do not contain enough cobalamin in it to correct a deficiency of cobalamin. Some clinicians have suggested administration of S-adensosylmethionine (SAMe), a molecule found in all living organisms and involved in the metabolism of glutathione (GSH) (7). GSH participates in many metabolic processes and plays a critical role in detoxification mechanisms of the cell. Depletion of hepatic GSH can indirectly cause toxic effects in these cells by increasing oxidative stress. Exogenous administered SAMe has been shown to increase intracellular GSH levels in hepatocytes and prevents GSH depletion when exposed to toxic substances, thus acting indirectly as an antioxidant (7). SAMe is also important in hepatocyte membrane integrity and function. Suggested dosage is 100 mg daily. The benefit of SAMe or other antioxidants in hepatic lipidosis is unknown. Another antioxidant hepatoprotectant is milk thistle or its extract silybin (available as a silybinphosphatidylcholine combination that improves GI absorption). The prognosis must be guarded in the recovery from lipidosis; however, with aggressive nutritional therapy, many, if not most, cats recover. Several complications that can occur with therapy include a refeeding syndrome and vomiting. Refeeding syndrome is associated with the development of an often life-threatening electrolyte disturbance that occurs within 24 to 48 hours of enteral feeding (13). This syndrome is well described in humans, occurring with introduction of nutrition and resultant increased insulin levels, driving potassium, phosphorus, and magnesium into the cells and causing a critical depletion of these electrolytes in the blood. Vomiting is also a frequent complication associated with feeding. To avoid these problems, electrolyte abnormalities should be first corrected and then followed by feeding small frequent meals, usually starting out with 25% of the daily calculated caloric needs and gradually increasing the diet volume over 3 to 7 days. If vomiting persists, the author sometimes administers maropitant (Cerenia Pfizer Animal Health) or other antiemetics. Maropitant is metabolized by the liver, but the dosage used by the author for cats with hepatic lipidosis is lower (0.25 to 0.5 mg/kg subcutaneously every 24 hours) than the suggested feline dose of 1.0 mg/kg subcutaneously every 24 hours. When the cat is consuming adequate calories without the need for tube supplementation, the feeding tube can be removed. Tube feeding may extend for up to 4 to 6 weeks. A failure to respond to traditional hepatic lipidosis therapy should signal the need to investigate the likelihood of an underlying condition in the patient. Feline Inflammatory Liver Disease (Cholangitis) Cholangitis is an inflammatory disorder of the hepatobiliary system. It is a disease complex and may be associated with duodenitis, pancreatitis, cholecystitis, cholelithiasis, or a combination. The terminology is somewhat confusing, and pathologists often name the conditions differently. Based on the histologic Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 8

42 classification of the World Small Animal Veterinary Association (WSAVA) Liver Standardization Committee, cholangitis has been separated into three basic histologic groups: neutrophilic cholangitis, lymphocytic cholangitis, and cholangitis associated with liver flukes (Figure 3) (14). Figure 3 Classification scheme of feline cholangitis syndrome based on the WSAVA Liver Standardization Committee recommendations. Neutrophilic Cholangitis. This classification has previously also been referred to as suppurative or exudative cholangitis/cholangiohepatitis and is the most common type of biliary tract disease observed in cats in North America. Neutrophilic cholangitis is thought to be the result of biliary tract infection ascending from the GI tract. In the acute neutrophilic form (ANF), the lesions are exclusively neutrophilic or suppurative, but over time it is believed that cases may progress to a chronic neutrophilic form (CNF) with a mixed inflammatory pattern containing variable numbers of neutrophils, lymphocytes, and plasma cells. The ANF is thought to be the result of an ascending bacterial infection (15). Usually coliforms (Escherichia coli) or Enterococcus spp are most often cultured from the liver or bile. Inflammation can also extend into the hepatic parenchyma causing a cholangiohepatitis. Cats with this syndrome tend to be middle aged or younger and present with acute illness of a week or less in duration. They may have evidence of a fever, anorexia, vomiting, or lethargy. Cats are also frequently icteric. A leukocytosis is generally identified on the CBC. Typically, because of Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 9

43 the primary bile duct involvement, the GGT concentrations are much higher proportionally than the ALP (Figure 4). The ALT and AST increase is variable depending on the amount of inflammation extending into the hepatic parenchyma. Ultrasound should always be performed to rule out pancreatitis and biliary obstruction. Fine-needle aspirate cytology may show suppurative inflammation. In some cases the author also performs an ultrasound-guided cholecystocentesis for cytology and culture. An elevated feline pancreatic lipase immunoreactivity (fpli) supports concurrent pancreatitis. Figure 4 Laparoscopic view of a cat with chronic neutrophilic cholangitis showing the characteristic nutmeg appearance of the liver surface and the gallbladder with dilated cystic and hepatic bile ducts. A liver biopsy is required for histology and confirms the diagnosis. The liver should always be cultured because of the relationship of bacteria and cholangitis. If obstruction is identified, then surgery is indicated to decompress and flush the biliary system. The author always attempts to avoid choosing surgical diversion surgery of the biliary system except as the last resort and suggests to the surgeon to try flushing the extrahepatic biliary system first. Sometimes a temporary biliary stent is placed to maintain patency. Therapy for affected cats includes fluid and electrolyte support as needed, but antibiotics are a critical part of the therapy. Ampicillin, ampicillin-clavulanic acid, cephalosporins, and metronidazole have been suggested as effective antibiotics. Unless a culture and sensitivity directs otherwise, ampicillin or ampicillin-clavulanic acid are the author s choice for antibiotic therapy because of the likelihood of E coli and the fact that both drugs are concentrated in the bile. It is recommended that cats be treated for at least 1 month or even longer with antibiotics. Short duration of therapy may result in recurrence of clinical signs. Ursodeoxycholic acid (Actigall Watson Pharmaceuticals; 10 to 15 mg/kg daily) should be used as well for the benefit of choleresis and hepatoprotection. Abdominal discomfort and Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 10

44 vomiting may be signs of hepatobiliary pain, and buprenorphine or other pain management agents should be administered. Clinical Pearl: Neutrophilic cholangitis is secondary to ascending enteric bacteria and should be treated with appropriate antibiotic therapy. CNF (neutrophilic, mixed, or lymphocytic-plasmacytic) cholangitis may be the result of progression of the acute neutrophilic cholangitis. In the chronic stage the liver lesions are associated with the presence of mixed inflammatory infiltrates in the portal areas consisting of neutrophils, lymphocytes, and plasma cells (14,16). Possibly fibrosis, bile ductular proliferation, or extension of inflammation into the hepatic parenchyma will occur as well. There is a direct relationship between chronic cholangitis and both inflammatory bowel disease and chronic pancreatitis. One study found 83% of affected cats had inflammatory bowel disease and 50% had concurrent chronic pancreatitis (17). The association of the three together has been referred to as feline triaditis. Possibly the common channel theory, where the pancreatic ducts and bile ducts join before entering the duodenum, explains this triad of clinical signs. Ascending bacteria initiate the acute disease and conceivably over time it can become chronic. In a yet to be published study, the author and associates identified bacteria in and around bile ducts in over 68% of cats affected with CNF, suggesting that resident bacteria may be responsible for the chronic inflammation (18). Affected cats are usually middle-aged or older and have a long duration of signs lasting weeks to months. Presenting complaints are often vomiting, lethargy, and anorexia. Signs may wax and wane, and weight loss may occur. Physical findings identify jaundice in most patients, possibly hepatomegaly, and rarely abdominal effusion. The laboratory findings are variable. Most cats are icteric, and there are variable increases in ALP/GGT or ALT/AST. Hyperglobulinemia is observed in more than 50% of the cases. Ultrasound may reveal pancreatic, bile duct, or gallbladder changes. The liver generally has a mixed echogenicity pattern, with prominent portal areas. Cats with concurrent pancreatitis may have an increase in fpli. A liver biopsy confirms the diagnosis. Cultures should always be performed. The traditional treatment usually suggests immunosuppressive therapy using prednisolone at 2 to 4 mg/kg daily and then slowly tapering over 6 to 8 weeks to 0.5 to1.0 mg/kg given once or every other day. This therapy does not always resolve the chronic disease, however, but may slow its progression or minimize the clinical signs. Recent identification of bacteria in many cats having cholangitis indicates a rigorous course of antibiotic therapy for the possibility of a bacterial component would be prudent to consider. Ursodeoxycholic acid is a nontoxic hydrophilic bile acid that, when administered, changes the bile acid milieu. This agent given at a dosage of 10 to 15 mg/kg daily is nontoxic, is suggested for cats having cholangitis, and, in fact, may even be Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 11

45 more beneficial than corticosteroids. The drug is reported to increase bile flow (choleresis), change bile acid concentrations to less toxic concentrations, reduce inflammation and fibrosis, and improve liver enzymes. Other liver support therapy such as SAMe, silybin, or other antioxidants may be of benefit in long-term management. Neutrophilic cholangitis is slow and progressive and is often characterized by periodic flare-ups. Approximately 50% of patients have a prolonged survival. The final stage of this disease complex can be biliary cirrhosis associated with extensive fibrosis and bile duct proliferation that may end with liver failure associated with ascites and hepatic encephalopathy. Clinical Pearl: Always culture a liver biopsy. Lymphocytic Cholangitis. This is a condition (severe lymphocytic portal hepatitis, progressive lymphocytic cholangitis, or nonsuppurative cholangitis) described as a highly chronic lymphocytic inflammatory biliary tract disorder that is progressive over months and years (14). The pathology of the liver is characterized by a consistent moderate to marked infiltration of small lymphocytes predominately restricted to the portal areas and often associated with variable portal fibrosis and biliary duct proliferation. Considerable distortion of liver architecture is seen in the later stages. The bile ducts can also become irregular because of dilation and fibrosis. In some cases lymphocytic infiltrates in the portal areas may be confused with well-differentiated lymphocytic lymphoma. Bacteria are thought not to be primarily involved in the pathogenesis of this syndrome (14). Based on preliminary immunologic studies, it is postulated that lymphocytic cholangitis is the result of immune-mediated mechanisms (19). This syndrome is a slow chronic disease that continues to progress over months to years. It is often first identified in younger animals (20). The most common clinical features observed late in the disease include ascites, jaundice, and hypergammaglobulinemia (in almost all cases). In advanced cases, ultrasonographic examination often demonstrates dramatic changes in the intrahepatic and extrahepatic bile ducts, with marked segmental dilations and areas of stenosis that may lead the operator to believe there is an obstruction. Ascites and hepatic encephalopathy occur late in the disease as a result of acquired portal hypertension and hepatic dysfunction. Treatment for chronic lymphocytic cholangitis involves using anti-inflammatory or immunosuppressive therapy in addition to supportive therapy as described previously for neutrophilic cholangitis. One as yet unpublished study suggests lymphocytic cholangitis patients had a better response when treated with ursodeoxycholic acid than with corticosteroids (20). This finding may not be completely unexpected because ursodeoxycholic acid has been shown to have a positive treatment effect in humans with chronic primary biliary cirrhosis having a very similar histologic pattern to these chronic cases. Clinical Pearl: Lymphocytic Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 12

46 cholangitis is best treated with immunosuppression and ursodeoxycholic acid. Complications of Cholangitis Syndromes. The following conditions are often observed in cases of cholangitis. Bile sludge, cholithiasis, or both frequently occur with inflammatory biliary tract disease. Thick inspissated bile or choleliths are thought to be the result of deconjugation of the normally soluble conjugated bilirubin from the action of bacterial enzymes or inflammatory products present in the biliary tree. Bile sludging is best managed by treating the primary cholangitis, treating any biliary tract infection, and by the use of choleretic agents to increase the flow of bile. Ursodeoxycholic acid should be prescribed at 10 to15 mg/kg daily. Concerns about avoiding use of ursodeoxycholic acid for fear of causing a bile duct obstruction are unfounded in the author's opinion; and, in fact, experimental studies evaluating its use in bile duct obstruction models showed less histologic damage than occurred in the placebo group (21). Corticosteroids have a similar effect on bile flow and may also be useful. Complete obstructions may require surgery, and in rare conditions a cholecystoduodenostomy or cholecystojejunostomy is required. Either procedure should be avoided, if possible, because of the complication of ascending cholangitis. Conclusion The incidence of liver disease in cats is unknown, but the disease is considered to be a common feline disorder. Cats and dogs differ greatly in the kinds of liver disease they develop due in part to specific anatomic and metabolic differences in cats. Interpretation of laboratory tests for feline liver disease is unique and varies widely from interpreting the common liver disorders observed in the dog. Diagnosis and treatment of diseases involving the liver should always take the species and these recognized differences into consideration. References 1. Center SA, Baldwin BH, Dillingham S, et al: Diagnostic value of serum gammaglutamyl transferase and alkaline phosphatase activities in hepatobiliary disease in the cat. J Am Vet Med Assoc. 1986;188: Center SA, Crawford MA, Guida L, et al: A retrospective study of 77 cats with severe hepatic lipidosis. J Vet Intern Med. 1993;7: Sherding RG: Feline jaundice. J Feline Med Surg. 2000;2: Rothuizen J, van den Brom WE, Fevery J. The origins and kinetics of bilirubin in dogs with hepatobiliary and haemolytic diseases. J Hepatol. 1992;15: Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 13

47 5. Ottenjann M, Weingart C, Arndt G, Kohn B: Characterization of the anemia of inflammatory disease in cats with abscesses, pyothorax, or fat necrosis. J Vet Intern Med. 2006;20: Center SA: Feline hepatic lipidosis. In: Richards JR, ed. Veterinary Clinics of North America Small Animal Practice. Philadelphia, PA: WB Saunders Co; 2005: 246, 253, 256, Akol KG, Washabau RJ, Saunders HM, Hendrick MJ. Acute pancreatitis in cats with hepatic lipidosis. J Vet Intern Med. 1993;7: Holan KM. Feline hepatic lipidosis. In: Bonagura JD, Twedt DC, eds. Kirk s Current Veterinary Therapy XIV. St Louis, MO: Saunders/Elsevier; 2008: Griffin B. Feline hepatic lipidosis: treatment recommendations. Compend Contin Educ Pract Vet. 2000;22: Center SA, Harte J, Watrous D, et al. The clinical and metabolic effects of rapid weight loss in obese pet cats and the influence of supplemental oral L- carnitine. J Vet Intern Med. 2000;14: Jacobs G, Cornelius L, Keene B, et al. Comparison of plasma, liver, and skeletal muscle carnitine concentrations in cats with idiopathic hepatic lipidosis and in healthy cats. Am J Vet Res. 1990;51: Simpson KW, Fyfe J, Cornetta A, et al. Subnormal concentrations of serum cobalamin (vitamin B12) in cats with gastrointestinal disease. J Vet Intern Med. 2001;15: Justin RB, Hohenhaus AE. Hypophosphatemia associated with enteral alimentation in cats. J Vet Intern Med. 1995;9: van den Ingh TSGAM, Cullen JM, Twedt DC, et al. Morphological classification of biliary disorders of the canine and feline liver. In: Rothuizen J, Bunch SE, Cullen JM, et al, eds. WSAVA standards for clinical and histological diagnosis of canine and feline liver diseases. Edinburgh: Saunders/Elsevier; 2006: Twedt DC, Armstrong PJ. Feline inflammatory liver disease. In: Bonagura JD, Twedt DC, eds. Kirk s Current Veterinary Therapy XIV. St Louis, MO: Saunders/Elsevier; 2008: Gagne JM, Weiss DJ, Armstrong PJ. Histopathologic evaluation of feline inflammatory liver disease. Vet Pathol. 1996;33: Weiss DJ, Armstrong PJ, Gagne J: Inflammatory liver disease. Semin Vet Med Surg (Small Anim). 1997;12: Twedt DC, Janeczko SD, McCord KW, et al. Culture-independent detection of bacteria in feline inflammatory disease. J Vet Intern Med. 2009;23: Lucke VM, Davies JD. Progressive lymphocytic cholangitis in the cat. J Small Anim Pract. 1984;25: Rothuizen J. Cholangitis in cats a review. Proceedings of the 31st World Small Animal Congress, Prague, Czech Republic. 2006: Frezza EE, Gerunda GE, Plebani M, et al. Effect of ursodeoxycholic acid administration on bile duct proliferation and cholestasis in bile duct ligated rat. Dig Dis Sci. 1993;38:1291. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 14

48 Diseases of the Esophagus The Often Forgotten Organ David C. Twedt, DVM, Diplomate, ACVIM Colorado State University Fort Collins, Colorado Abstract Disorders of the esophagus in the dog are relatively uncommon and, as a result, may be "missed" in the general workup of a case. The clinical sign most often associated with esophageal disease is regurgitation. Regurgitation refers to the passive retrograde expulsion of esophageal contents without retching. The problem in determining regurgitation from the patient history lies in the fact that regurgitation is frequently mistaken for either vomiting or possibly dysphagia. After an esophageal disorder has been identified, evaluation of the esophagus becomes relatively straightforward, using either specialized diagnostic testing, imaging techniques, endoscopy, or a combination. Because motility is the major function of the esophagus, dynamic imaging studies using videofluoroscopic examination may be required to make a definitive diagnosis. This article covers some of the common as well as unique disorders of the esophagus observed in small animals and includes important points to remember about esophageal disease. Key Content If the diagnostic workup of an animal with suggested gastrointestinal disease does not readily identify the condition, the clinician should always re-examine and evaluate for the possibility of esophageal disease. The veterinarian should always look for an underlying cause in cases of megaesophagus. There is no specific therapy for idiopathic megaesophagus other than dietary management and treating secondary complications. Every dog that has a megaesophagus should have an Ach receptor antibody titer and cortisol determination. Esophagitis is more common than previously understood and should not be overlooked in the evaluation of a patient exhibiting esophageal disease. Brachycephalic breeds are prone to gastroesophageal reflux disorders (GERDs). From Gastrointestinal Diseases, proceedings of a symposium sponsored by Pfizer Animal Health by The Gloyd Group, Inc. All rights reserved. The opinions expressed in this article are those of the author and do not necessarily reflect the official label recommendations and points of view of the company or companies that manufacture and/or market any of the pharmaceutical agents referred to.

49 Reflux esophagitis therapy requires proton pump inhibitors to block acid formation and GI prokinetic agents to increase distal esophageal sphincter pressure. Hiatal hernias are difficult to document and should be suspected especially in Shar Peis and brachycephalic breeds with clinical signs. An animal in which regurgitation occurs 1 to 2 weeks following an anesthetic episode should be evaluated for stricture formation. Esophageal foreign bodies should be removed promptly to prevent complications. Rigid hollow esophageal scopes should be considered for removing bones or larger esophageal foreign bodies. Distinguishing Esophageal Disorders Because disorders of the esophagus are relatively uncommon in dogs, they may be "missed" in the general workup of a case. Regurgitation is the clinical sign most often associated with esophageal disease and refers to the passive retrograde expulsion of esophageal contents without retching. Determining regurgitation from the patient history can be difficult because regurgitation is frequently mistaken for either vomiting or possibly dysphagia. Often it is hard for clients, and sometimes even for veterinarians, to differentiate vomiting from regurgitation. To compound matters, some animals with esophageal disease may not have any regurgitation but, rather, have vague signs, such as anorexia, nausea, or salivation. The author has sometimes observed the latter signs with inflammatory esophageal disorders. Animals that have pneumonia from an unexplained cause should always be evaluated for swallowing and esophageal function. After identification of an esophageal disorder, evaluation of the esophagus is relatively clear-cut, using either specialized diagnostic testing, imaging techniques, endoscopy, or a combination. Frequently, it is helpful to watch the animal eat during the physical examination as this observation may aid in localizing the problem. Because motility is the major function of the esophagus, dynamic imaging studies using videofluoroscopic examination may be required to make a definitive diagnosis. Diagnostic Evaluation Radiology is possibly the most important tool for evaluating the esophagus. Routine survey radiographs (including the cervical esophagus and pharynx) may easily demonstrate esophageal abnormalities or foreign bodies. The presence of a small amount of air in the esophagus, although not necessarily considered to be abnormal, is often a clue to an esophageal disorder. In most situations a barium contrast study based on a combination of liquid followed by a barium meal is required using videofluoroscopic examination. Random static barium contrast radiographs may identify gross lesions or foreign bodies but are often inadequate to diagnose less obvious Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 2

50 motility disorders. In cases of suspected esophageal motility disorder, referral to a center that can provide videofluoroscopy is imperative. A major complication in performing contrast studies is the risk of aspiration pneumonia. This risk is less a concern when fluoroscopy is performed because the patient can be carefully monitored during administration of barium, and the barium can be stopped at the first indication of aspiration. Endoscopy is used for visualization, biopsy, or both, of mucosal disorders and obstructions and for foreign body removal. The procedure offers little useful information in the identification of primary megaesophagus or other motility abnormalities in the dog but is useful to detect secondary inflammatory changes or an obscure obstructive condition causing esophageal dilation. In some circumstances mucosal biopsy specimens are obtained; however, the stratified squamous epithelium of the esophagus is very tough and is difficult to biopsy especially when normal. Esophageal disorders can be divided into one of three major categories: (1) motility disorders, (2) obstructions, or (3) inflammatory disorders. In the author s hospital population, esophageal motility disorders make up a majority of the cases seen. Inflammatory disorders may actually be quite common but often go unrecognized unless endoscopy is performed. Table 1 lists some of the common esophageal disorders. Motility Disorders Megaesophagus Table 1. Common Esophageal Disorders Motility disorders Idiopathic megaesophagus Congenital megaesophagus Secondary megaesophagus Obstructions Foreign bodies Strictures Neoplasia Parasitic granuloma (Spirocera lupi) Vascular ring anomaly Esophageal entrapment (neoplastic or inflammatory) Diverticulum Achalasia Inflammatory conditions Esophagitis Reflux esophagitis Hiatal hernia Megaesophagus is a descriptive term that generally refers to esophageal dilation secondary to a hypomotile esophagus (Figure 1) (1). In most cases the prognosis for a Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 3

51 patient with megaesophagus is poor, especially when secondary aspiration pneumonia is present. Consequently, it becomes very important to determine the etiology because some of the causative conditions are potentially treatable. Figure 1 Barium contrast radiograph showing a megaesophagus in a dog with idiopathic megaesophagus. Simply defined, disorders of esophageal motility result from either neural abnormalities or abnormalities in the neuromuscular junction, from esophageal muscular dysfunction, or from a combination of these disorders. Because the esophagus consists almost exclusively of skeletal muscle, systemic myopathies and even neuropathies may also affect the esophagus. The veterinarian should always look for an underlying cause in cases of megaesophagus. See Table 2 for a list of common causes of secondary megaesophagus. Table 2. Conditions Associated with a Secondary Megaesophagus (motility disorders) Myasthenia gravis Hypoadrenocorticism Hypothyroidism Myositis Neuropathies Dermatomyositis Dysautonomia Esophagitis Obstructive lesions Distemper Botulism Poisons (lead, thallium) Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 4

52 Congenital Megaesophagus Congenital megaesophagus occurs in young dogs as an inherited condition or secondary to developmental abnormalities in esophageal innervations (2). The condition has been demonstrated as inherited in the wirehaired terrier and schnauzer breeds, and there is a high incidence in Irish setters, German shepherds, golden retrievers, Shar Peis, Great Danes, Rhodesian ridgebacks, and Labrador retrievers. Clinical signs are often varied in an affected litter, and the prognosis is poor for spontaneous improvement. Adult-Onset Idiopathic Megaesophagus Adult-onset idiopathic megaesophagus occurs spontaneously, most often in dogs from 7 to 15 years of age, with no specific sex or breed predisposition, although the occurrence is more common in larger breed dogs (3). The cause has been shown to be an afferent vagal nerve disorder (possibly involving the afferent nerve, but more likely the lesion is at the level of the brain stem involving certain nuclei), and the treatment is only symptomatic and rarely, if ever, reversible (4). A diagnosis is made by demonstrating esophageal hypomotility without identifying an underlying cause. Animals rarely improve from idiopathic megaesophagus (5). Upright feedings, management of aspiration pneumonia, and placement of a gastric feeding tube are the basic treatments. The author advises owners to try various food consistencies and has, through personal experience, found that canned meatball-type feeding works best. To date no drug therapy has been proven effective. Note that the gastrointestinal (GI) prokinetic agents work on smooth muscle that is only found in the distal esophageal sphincter (DES). In the author s review of 49 idiopathic cases diagnosed at Colorado State University, 73% of patients were either reported dead or were euthanized within 3 months of the diagnosis. Approximately one quarter of the dogs, however, were able to live with megaesophagus involving less severe complications. There is no specific therapy for idiopathic megaesophagus other than dietary management and treating secondary complications. Esophageal Achalasia True achalasia of the DES is defined as a failure of the distal sphincter to open. This is a condition that occurs in humans and results in esophageal dilation, but it is extremely rare in dogs. Achalasia was once believed to be the cause of idiopathic megaesophagus in the dog, but that has been refuted based on manometry studies showing the DES functions normally in dogs with that disorder (6). Reports suggest achalasia can be demonstrated by fluoroscopy showing that the sphincter fails to open (even when the dog is placed in an upright position), and improvement occurs following balloon dilation of the sphincter or surgical cardiomyotomy. There are anecdotal reports of Botox (Allergan; botulinum toxin) injections in the DES resulting in decreased response to acetylcholine relaxing the sphincter. The author believes that some of the suspected achalasia cases may actually be esophageal strictures at the level of the DES. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 5

53 Secondary Megaesophagus Other conditions can directly affect neuromuscular function, including more common disorders, such as myasthenia gravis, adrenocortical insufficiency, systemic lupus erythematosis, polymyositis, hypothyroidism, dysautonomia, and immune-mediated polyneuritis. Focal myasthenia gravis is associated only with esophageal involvement and without generalized muscle weakness (7). In some cases laryngeal and or pharyngeal involvement may also occur. Focal Myasthenia Gravis Focal myasthenia gravis is the most common secondary form of megaesophagus and makes up about 25% to 30% of the cases. Young as well as older dogs are reported to have focal myasthenia gravis, and German shepherds and golden retrievers have been affected most frequently (8). The disorder is an acquired autoimmune destruction of the acetylcholine receptors on the skeletal muscle. Diagnosis of myasthenia gravis is confirmed by identifying positive acetylcholine receptor (Ach) antibodies in the serum. Some dogs may also have concurrent hypothyroidism and may even improve with thyroid administration. The author and colleagues have also seen cases involving third-degree heart block (9). If the patient is found to be Ach receptor negative, then the veterinarian should retest in approximately 1 month, because in some cases the patient may later test positive. Approximately half of the dogs with focal myasthenia gravis have been reported to improve or eventually have remission of clinical signs following therapy. Anticholinesterase therapy using pyridostigmine bromide (Mestinon Valeant Pharmaceuticals) at a dosage of mg/kg two to three times daily is suggested, but other reports recommend steroids or immunosuppressive therapy alone or the combination of both. Remission generally occurs in 3 to 4 months; and, if monitoring Ach receptor antibody titers, those will decline with resolution of signs (10). Hypoadrenocorticism Hypoadrenocorticism has been reported as a cause of reversible megaesophagus in the dog (11). Animals with megaesophagus may present having typical Addison s disease with electrolyte abnormalities, or more often they have atypical Addison's disease without changes in sodium and potassium concentrations. The exact mechanism for the esophageal dysfunction is unknown. Because this disorder is highly treatable with steroids, it is important to reach a diagnosis. Measurement of cortisol levels following both a pre- adrenocorticotropic hormone (ACTH) and post-acth stimulation confirms the diagnosis. Reports suggest that when resting cortisol results are greater than 2.0 µg/dl, hypoadrenocorticism is unlikely. Consequently, in the author s clinic, random cortisol results are often obtained in megaesophagus cases and only if the values are questionable is the follow-through an ACTH stimulation test. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 6

54 Adequate glucocorticoid and, if required, mineralcorticoid replacement results in rapid resolution of the megaesophagus. Every dog with a megaesophagus should have an Ach receptor antibody titer and cortisol determination. Myositis Although uncommon, myositis is sometimes associated with esophageal dysfunction; and clues to the diagnosis include evidence of systemic muscle involvement and creatine kinase elevations (12). Definitive diagnosis requires a muscle biopsy. The author and colleagues have also identified young boxer dogs and other breeds with a muscular dystrophy and esophageal involvement. Some dogs with inflammatory myositis may improve with immunosuppression. Hypothyroidism Hypothyroidism is rarely associated with megaesophagus. Reports suggest, however, that some dogs may improve with appropriate thyroid supplementation (13). Dysautonomia Dysautonomia is a disorder that results from degenerative changes involving neurons of the autonomic nervous system (14). Consequently, the signs of disease are associated with dysfunction of the autonomic nervous system (megaesophagus, dilated pupils, dry eyes, nictitans protrusion, dilated anal sphincter and fecal incontinence, distended urinary bladder and incontinence, and decreased GI motility). The syndrome appears to occur in young, large-breed farm or ranch dogs, suggesting an environmental influence. Many of the cases are referred to the author after a negative abdominal exploratory procedure because of radiographic changes that suggest a GI obstruction. Supporting a diagnosis involves specific ocular testing, a negative Schirmer tear test, lack of response to atropine when testing heart rate, or a negative intradermal histamine skin test. Definitive diagnosis requires histology of autonomic ganglia. Typical lesions are often readily observed in the ganglia on a full-thickness intestinal biopsy. The prognosis for these cases is very guarded. Inflammatory Disorders Esophagitis Inflammation of the esophageal mucosa can range from mild mucosal inflammatory changes to severe ulceration with transmural involvement. The causes of primary esophagitis are most often associated with the direct contact of an irritant or foreign material or from the result of reflux of gastric contents (acid, pepsin, bile, or a combination) into the esophagus (Figure 2) (15). Reflux of gastric contents can occur following anesthesia, secondary to protracted vomiting (such as is associated with parvovirus or GI obstructions), or from a hiatal hernia. Gastrinoma is a rare tumor that produces gastrin, in turn producing high amounts of gastric acid, which results in gastric ulceration Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 7

55 and vomiting. When the very acidic gastric contents come in contact with the esophagus, ulceration occurs. Figure 2 Endoscopic view of the esophagus of a cat with focal esophagitis and ulceration secondary to a doxycycline tablet. Esophageal inflammation causes altered motility, esophageal pain, and regurgitation. Although most animals usually have regurgitation in their histories, some animals may only exhibit such signs as dysphagia, anorexia, nausea, or salivation. Complications, such as aspiration pneumonia, may occur if concurrent pharyngitis and laryngitis are involved in the inflammatory process. Deep ulceration may result in esophageal stricture formation. Videofluoroscopy may show abnormal motility or abnormal peristaltic contractions. Esophagoscopy is usually diagnostic and may show an edematous, reddened, or bleeding esophageal mucosa. Esophagitis is more common than previously understood and should not be overlooked in the evaluation of a patient exhibiting esophageal disease. Gastroesophageal Reflux Disorders Gastroesophageal reflux disorders (GERDs) are probably among the most common causes of esophagitis (16). Gastric acid has long been implicated as the major factor causing mucosal damage; however, acid is not the sole culprit but in combination with pepsin is even more deleterious. Alkaline gastroesophageal reflux also produces inflammatory changes within the esophageal mucosa due to the presence of the pancreatic enzyme trypsin. Trypsin's optimal ph range for proteolytic activity is 5 to 8. The bile salts are also shown to enhance the effect of trypsin when in an alkaline medium. Regardless of the cause, after damage occurs to the DES, its function weakens, triggering a vicious cycle of further gastric reflux causing further mucosal inflammation (17). Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 8

56 Etiologies associated with GERDs in small animals include many factors altering LES pressure, such as general anesthesia, hiatal hernia disorders, and persistent vomiting. In addition, GERDs are associated with disorders of gastric motility or factors increasing abdominal pressure. GERDs are common in brachycephalic dogs with upper airway obstructions resulting in increased negative intrathoracic pressure. The high negative intrathoracic pressure affects the DES function and then promotes continued reflux. Obesity or any condition, such as ascites, causing increased intra-abdominal pressure may also predispose to reflux esophagitis. Brachycephalic breeds are prone to GERDs. Signs of GERD are similar to the signs seen in dogs with esophagitis. Contrast fluoroscopy is usually required to demonstrate gastroesophageal reflux. In suspected cases of GERDs, it is sometimes helpful to apply pressure over the barium-filled stomach, thereby increasing abdominal pressure to demonstrate reflux. Endoscopy is the best diagnostic means of documenting GERDs. The distal esophageal mucosa shows inflammatory changes, and often the DES is open (Figure 3). Esophageal biopsies, although difficult to procure, will show mucosal inflammation. Figure 3 Endoscopic view of the distal esophagus of a dog with reflux esophagitis showing ulceration and an open distal esophageal sphincter. Rational therapy for GE reflux disease depends on specific aims. Those may be medical therapy for alleviating signs or to treat the primary underlying disease. For example, GE reflux may be controlled by: weight reduction in the obese patient, correction of upper airway obstructions, therapy for gastric emptying disorders, or surgical correction of hiatal hernias or an incompetent DES. The aim of medical therapy is to reduce the esophagitis, increase DES pressure, and protect the mucosa against damage from refluxed material (16,18). Therapy should begin with dietary recommendations that include feeding small, frequent meals that are Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 9

57 high in protein and low in fat to maximize distal esophageal pressure and minimize gastric volume. A sucralfate slurry topically binds in ulcers and promotes healing of the esophagus, and protects against mucosal damage from gastroesophageal reflux. Reflux esophagitis is also managed by reducing gastric acid using a proton pump inhibitor, such as omeprazole (0.7 mg/kg daily). The H2 blockers do not completely block all acid and are therefore not recommended (19). Gastric prokinetic agents, such as metoclopramide (Reglan Schwarz Pharma), at a dosage of mg/kg three to four times daily, cisapride given at a dosage of 0.1 mg/kg two to three times daily, or erythromycin given at a dosage of mg/kg two to three times daily, are reported to increase the DES pressure and promote an increase in gastric emptying by increasing gastric contractions. Of these three drugs cisapride is considered to be the most effective agent, with metoclopramide the least effective. Esophageal pain is common and should be managed using either local 2% lidocaine viscous solution or systemic pain management. The prognosis for most animals with GERDs is good following correction of the primary cause. Reflux esophagitis therapy requires proton pump inhibitors to block acid formation and GI prokinetic agents to increase DES pressure. Hiatal Hernias A hiatal hernia is defined as an abnormal protrusion of the abdominal esophagus, gastroesophageal junction (GEJ), or portion of the stomach (or more than one of these) into the thorax through the esophageal hiatus of the diaphragm. In the normal animal a portion of the very distal esophagus and the GEJ lies within the abdominal cavity. The GEJ remains fixed due to the phrenoesophageal ligament and the esophageal hiatus of the diaphragm. For the GEJ to become displaced through the diaphragm into the caudal mediastinum, stretching of the phrenoesophageal ligament must occur, and the esophageal hiatus of the diaphragm must be of sufficient diameter to permit the cranial movement. There appears to be a breed predisposition to hiatal hernias in Shar Peis as well as in some brachycephalic breeds, such as the Boston terrier (18). The author occasionally sees hiatal hernias in cats as well. The signs associated with gastroesophageal reflux also occur with a hiatal hernia (ie, regurgitation, anorexia, hypersalivation, and vomiting). Radiology is sometimes used to make the diagnosis. Survey radiographs often demonstrate esophageal dilation and an increased density in the distal esophagus from the GEJ and stomach within the caudal mediastinum. Barium contrast studies are generally required to diagnose a sliding hiatal hernia (Figure 4). Because hiatal herniation is often intermittent, repeated studies using fluoroscopy may be required to confirm the diagnosis. Applying direct abdominal pressure or manually obstructing the upper airway may improve the likelihood of demonstrating an intermittent sliding hiatal hernia. Endoscopy gives additional evidence for a hiatal hernia and, in fact, may be the best way to confirm its presence. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 10

58 The endoscope should be passed into the stomach and retroflexed to view the DES from the gastric side. When the stomach is insufflated with air, cranial displacement of the DES and cardiac region of the stomach may occur through a weakened or enlarged esophageal hiatus in the diaphragm. Impressions made by the borders of an enlarged esophageal hiatus can be seen on the gastric cardia. Endoscopically observing cranial DES displacement and a large esophageal hiatus as well as distal esophagitis with appropriate clinical signs is suggestive of a hiatal hernia. Figure 4 A barium contrast study of the distal esophagus in a Shar Pei with a hiatal hernia showing esophageal dilation and displacement of the distal esophageal sphincter and proximal stomach into the thorax. When clinical signs occur, medical therapy for reflux esophagitis should first be instituted as described for gastroesophageal reflux. Underlying causes of hiatal hernias should always be treated; these include preexisting upper airway obstructions, obesity, and other causes of increased intraabdominal pressure. Correcting upper airway obstructions in brachycephalic dogs often resolves the clinical signs. In severe cases, or when medical management is unsuccessful, surgical intervention is indicated. Many acquired hiatal hernias respond to medical management, but unresponsive cases require surgical correction. Controversy exists regarding the proper surgical technique for correction of a hiatal hernia. Various combinations of diaphragmatic crural apposition, fixation of the esophagus to the diaphragmatic crus (esophagopexy), and left fundic tube gastropexy are used in the repair of hiatal hernias with good success. Fundoplication procedures are generally unnecessary but have previously been recommended. Surgical outcome for dogs or cats with hiatal hernias is generally favorable with resolution of clinical signs. Hiatal hernias are difficult to document and should be suspected especially in Shar Peis and brachycephalic breeds with clinical signs. Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 11

59 Esophageal Obstruction Obstructive disorders of the esophagus include such conditions as strictures, foreign bodies, vascular ring anomalies, Spirocerca lupi infection, and neoplasia. Neoplasia is uncommon in the dog; however, the author and colleagues have reported on leiomyomas of the DES causing a mechanical obstruction (Figure 5). The prognosis is good with surgical resection of the lesion. Vascular ring anomalies are usually detected in young dogs shortly after weaning, and early identification often results in clinical improvement. The two most common causes of obstruction are esophageal strictures and esophageal foreign bodies. Figure 5 Endoscopic view of the distal esophagus of a dog with a submucosal mass proximal to the distal esophageal sphincter causing esophageal obstruction. The mass was surgically removed and found to be a leiomyoma. Esophageal Strictures Esophageal strictures result following deep submucosal ulceration with subsequent fibrosis (15). For strictures to develop, there must generally be greater than a 180- degree submucosal involvement, whereas focal ulceration is less likely to result in a stricture. In a review of 23 cases of strictures, anesthesia-related gastric reflux occurred in 65% of the cases, 9% of the cases were associated with foreign bodies, and the remainder were due to other causes, such as pill-associated trauma or esophageal tube placement. The association of gastroesophageal reflux and anesthesia is reported to occur in approximately 10% to 15% of dogs that undergo anesthesia for multiple causes so in some patients undergoing anesthesia esophagitis may result and rarely stricture formation could occur. The time between anesthesia and stricture formation is approximately 1 to 2 weeks. Doxycycline and NSAIDs are the most common drugs that result in strictures in Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 12

60 humans; and the author has reported a number of cats that developed esophageal strictures secondary to receiving doxycycline tablets. The doxycycline strictures occur predominantly in the cervical esophagus. Studies in the author s laboratory showed that cats given pills only (without water) experienced delayed passage through the esophagus, with retention of many pills in the cervical esophagus; but, when pill administration was followed directly by giving 3 to 6 ml of water, pills usually passed rapidly into the stomach. Likely in stricture cases the doxycycline tablet fails to leave the esophagus and results in local esophagitis. It is suspected that drug-associated strictures can also occur in dogs. Animals with obstructions caused by strictures classically regurgitate solid food but are often able to hold down liquids. The regurgitation usually occurs immediately or shortly after eating. Liquid barium contrast studies may fail to detect strictures, and all liquid barium contrast studies should be followed by a barium-food mixture. Endoscopy confirms the presence and location of the stricture (Figure 6). Figure 6 Endoscopic view of the distal esophagus of a dog with an esophageal stricture that resulted secondary to an anesthetic episode. Management of esophageal strictures involves either feeding a liquid diet or therapy using balloon dilation. Balloons of increasing size are placed into the stricture and inflated to dilate the lumen of the esophagus mechanically (20). In a review of 23 cases, 84% were considered to have a good outcome following a mean of three separate balloon dilations performed at weekly intervals. The actual number of dilations could be as few as 1 or as many as 10 or more, however. As part of the therapy, the author and colleagues are also injecting 0.1 ml of triamcinolone (10 mg/ml) directly into the stricture using an endoscopic injection needle in three to four sites prior to dilation. The intent is to reduce local inflammation following dilation, which can result in recurrence of stricture formation. Human studies suggest that intralesional steroids are beneficial (21). In severe cases where animals are suffering from malnutrition, the author suggests placing a gastric feeding tube. He also treats all stricture cases with the medical Pfizer Advanced Learning Series 2010 Gastrointestinal Diseases Symposium Proceedings 13