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Topic #8: Inflammatory Bowel Disease (IBD) The basics – the dog with vomiting, diarrhea, weight loss, and unhappy owners Inflammatory bowel disease is an immune­related disorder in which the intestines are chronically or intermittently inflamed. A synonym, with the same abbreviation (IBD), is ‘irritable bowel disease’. Canine patients may experience vomiting, diarrhea, weight loss or a combination of any (or all) of these signs. There is a great deal of individual variation in the severity, duration, response to therapy, and long­term effects of having IBD. IBD can come in different forms, but the most common is called lymphocytic­ plasmocytic enteritis (LPE) and is named for the main immune cell types that are found in biopsies of the affected sections of the small intestine. Also very common is a form in which there are mixed inflammatory cells (Craven, et al, 2004). Lymphocytes are cells that typically function to detect and kill viruses, fungi, and even tumor cells. When they are exposed to infectious agents, including bacteria and some complex molecules like foreign proteins and complex carbohydrates, they can transform into antibody­producing plasma cells. Lymphocytes also interact with other immune and inflammatory cells to create a very active defense system of the body, protecting people, dogs, and other animals against disease. Other types of IBD include lymphocytic­plasmocytic colitis (LPC), which primarily affects the colon (a portion of the large intestine) and granulomatous enteritis/gastritis, where there can be lesions in the small intestines and/or stomach. Granulomatous enteritis/gastritis is very rare. Canine IBD, especially granulomatous enteritis/gastritis, is similar in some respects to the human disorder, known as Crohn’s disease. Humans experience many of the same symptoms as dogs with IBD and are often cared for with the same treatments. Much of our veterinary knowledge of IBD comes from research on Crohn’s disease using dogs and other animals with spontaneous and experimental disease as translational animal models. Crohn’s disease is thought to have a genetic component and researchers are looking into this possibility in dogs. How does your dog develop IBD? It is not fully known why some dogs get inflammatory bowel disease and so it is another “idiopathic” condition. (A running joke among medical and veterinary medical professionals is that ‘idiopathic’ really means ‘the idiots treating me don’t have a clue about why I’m sick!). Different theories on the cause of this disease have been popular over time, including pre­existing problems with blood vessels causing disruption in the intestines, overproduction of mucus, a simply overactive
gut, an infectious agent, or a dog with the equivalent of ‘hyperactivity disorder’. (We are sure this last theory applied strictly to Jack Russell terriers, not Westies). (We apologize to owners of Jack Russell terriers for this joke at their expense. JRTs are wonderful dogs!). Currently, it is understood that IBD is an immune related disorder. In a healthy dog, the small and large intestines, which includes the colon, have their own local part of the immune system. This gastrointestinal portion of the immune system is meant to protect the body from viruses, bacteria or other antigens (unwelcome outsider proteins and complex molecules) that may be consumed in food and water. The healthy intestinal tract is, fortunately, inhabited by friendly bacteria at all times. This friendly bacteria, or normal flora, help keep antigens out simply by occupying all the good living space in the intestines. Under normal circumstances, the intestinal immune system does not react to the friendly bacteria, allowing the many species of these beneficial bacteria an environment do to their job. It is thought that in animals with IBD, a problem has developed in one of three areas: the local intestinal immune system or its regulation (the body may be attacking itself or friendly bacteria), the integrity of the intestines themselves (through some injury), or the disruption of the balance of normal flora in the intestines. Any one of these problems can trigger an unwanted immune response that gets out of control and becomes self­perpetuating. Much of the current research in the pathogenesis (what causes IBD and how it develops) is devoted to understanding the role of the immune system (See Current research in the pathogenesis and treatment of IBD, below) What are the signs that IBD may be developing? The major clinical sign in IBD is small bowel diarrhea. (Yes, veterinarians can tell from diarrhea if there’s a problem with the small or large intestines.) If it’s the earliest part of the small intestines that’s affected, vomiting may be the most prominent sign and there may be no diarrhea at all. Dogs with LPC will suffer from large bowel diarrhea, developing soft stools which may have blood or mucus in them. Often the signs come and go seemingly randomly. In early stages of IBD, dogs may appear perfectly healthy except for a change in stool consistency and frequency. As time goes on and if the disease is undiagnosed or left untreated, some dogs may loose weight because of the loss of nutrients in the stool. Eventually, any patient can develop vitamin and mineral deficiencies which manifest as malnutrition. Another long­term problem that can occur is lymphangiectasia (the dilation of lymphatic vessels) which can eventually result in the development of one or more masses in the affected area.
How is IBD diagnosed? IBD is a diagnosis made by ruling out other diagnoses. Dogs can exhibit similar signs (vomiting and diarrhea) from problems with intestinal parasites, food allergies, dietary changes, stresses associated with moving/traveling/boarding, and even changes in household occupants (like the arrival of new babies). In many affected dogs, a definitive diagnosis of IBD is made by examining a section or sections of the intestines taken from a biopsy. These procedures are time­ consuming, require sedation/anesthesia, are invasive (biopsies are ‘snipped’ from the surface of the gastrointestinal tract), and can be expensive (Allenspach, et al, 2004). Veterinary pathologists examine the sections for an overpopulation of immune cells. Unfortunately, the determination of too many immune cells is a subjective one and can be confused with lymphocytic lymphoma, a form of intestinal cancer. When a veterinarian suspects IBD, he or she may perform a number of diagnostic tests to rule out other diseases. A fecal test will help rule out parasites. Blood work will reveal a high count of immune­related cells, indicating inflammation. In some cases, x­rays may be taken after the patient has received a barium enema, which will highlight the colon on the x­ray. Ultrasound and regular x­rays are not usually as helpful in the diagnosis of IBD, but may reveal other problems. The most important diagnostic test is a thorough examination of the intestines with an endoscope. An endoscope is a camera that can be inserted into the intestines of a patient in order to allow a veterinarian to view the health of the intestinal tissue and to take a biopsy, if necessary. Shown in Figure 1, Dr. Michael Leib, an expert in the diagnosis and therapy of small animal gastrointestinal diseases, examine the inside of a dog’s colon with the endoscope in his left hand and looking at the monitor on the right of Figure 1..
Figure 2, on the left, shows an endoscopic view of inflamed intestine (red spots and rough surface). The endoscopist may biopsy these areas through the endoscope and put these small biopsy pieces in fixative for preparation of microscope slides. A veterinary pathologist will examine the biopsy sample under a microscope and determine what type of disease process is going on. An unexplained inflammatory process is likely to be IBD. A major differential diagnosis in dogs with some of these signs is intestinal canine malignant lymphoma, and it requires a skilled pathologist, working with the clinical veterinarian, to be sure the correct diagnosis is made. The appearance of intestinal canine malignant lymphoma in endoscopic biopsies is an increased number of abnormal lymphocytes present. A major differentiating feature of IBD is the presence of mixed populations of normal lymphocytes, plasma cells, and sometimes cells like neutrophils and eosinophils (Craven, et al, 2004). If there is any doubt about the diagnosis, it is an excellent idea to request a second opinion on the biopsy diagnosis. A veterinarian may also employ the canine IBD activity index (CIBDAI) to “score” a patient’s clinical signs and determine the severity of the disease (Jergens; Jergens et al, 2002, 2003, 2004). The veterinarian assigns a number from one to three to each of six clinical signs: attitude/activity, appetite, vomiting, stool consistency, stool frequency and weight loss. The scores are added up and the total determines if the disease is considered clinically insignificant, mild, moderate or severe. This index is based on others designed to quantify Crohn's disease in humans and can be used to asses the progress a patient is making. Simple blood tests generally aren’t very helpful for diagnosing IBD specifically. However, a very small number of affected dogs (2.5% in one study) had decreased numbers of circulating platelets (Ridgway, et al, 2001). Treatment of these dogs for IBD resolved this problem (thrombocytopenia). Another case report study found two dogs with anemia, presumably due to blood loss through the gastrointestinal tract (Ristic, et al, 2002). Foster and co­workers (Foster, et al, 2003) studied serum antibodies (IgE and IgG) in three populations of dogs – normal dogs, dogs with allergies and dogs with one of four types of gastrointestinal disease. The four types of gastrointestinal disease were small bowel bacterial overgrowth, IBD, food­ responsive disease, and infectious diarrhea. They found no difference in antibody levels between dogs with any of the types of gastrointestinal disease but there was a statistically significant increase in IgG levels of dogs with gastrointestinal disease, compared to either normal dogs or those with allergies.
Treatment of IBD – sometimes frustrating for owners Unfortunately, there is little data on the effectiveness of particular treatments for IBD so treatment is based on empirical evidence and the clinical experience of the veterinarian. Treatment of IBD is usually multifaceted and will likely include a combination of diet change, antibiotics and immunosuppressive drugs, including the use of corticosteroids such as prednisone, all described in more detail below. Management with drugs alone is not recommended and usually has limited value in stopping IBD. Diet. Initial treatment of an acute bout of IBD may require complete resting of the intestines by withholding food and providing IV nutrients. For long­term care, feeding a special diet is one of the most important things that can be done to manage IBD. An ideal diet should include limited sources of highly digestible protein and carbohydrates. Often, it is necessary to provide a novel protein source, one the animal hasn’t had before and so will not have developed an allergy to. A veterinarian can explain how to create an appropriate homemade diet and some commercial prepared diets may work as well. (Figure 3. at left – home cooking of diets may be a useful part of managing IBD). Commercial diets with hydrolyzed proteins (proteins with a molecular weight smaller than is thought to be recognized by the body as an antigen) are now available but little data exists as to their effectiveness. Other diet changes such as increasing fiber content (to decrease diarrhea), changing levels of omega­3 and omega­6 fatty acids (to reduce inflammation), and feeding probiotics (such as Lactobacillus) may also be tried. A very comprehensive review of nutritional therapy in gastrointestinal disease in dogs was recently published (Zoran, 2003). Antibiotics. Antibiotics are thought to suppress the numbers both friendly and unfriendly bacteria in the intestines. A lowered number of bacteria and the antigens associated with them are thought to allow the patient to reduce its immune response to bacterial antigens, reduce inflammation and reduce signs associated with IBD. For many years, the most commonly used antibiotic in cases of IBD has been sulphasalazine (Azulfidine) because it is thought to have both antibiotic and anti­inflammatory properties. The most common side effect from the use of sulphasalazine is dry eyes. Other common drugs used included the antibiotics metronidazole and tylosin (Craven, et al, 2004). Immunosuppressive drugs. Corticosteroids are given to suppress the immune system, but carry dangerous potential side effects when given over long periods
of time, such as hyperadrenocorticism, gastrointestinal ulceration and pancreatitis. Azathioprine, an immunosuppressive drug sometimes used to treat autoimmune diseases and cancer, is often given in conjunction with corticosteroids in order to reduce the doses of corticosteroids needed and avoid side­effects as much as possible. Bone marrow suppression is the most common side­effect of azathioprine. Managing canine IBD requires a life­long commitment from owners. The prognosis for a dog with IBD depends on the severity of the disease and the progression at the time of diagnosis. A change in diet and close monitoring of the patient may be all that’s needed to manage many cases of IBD. For others, only minimal medication must be added. However, if an animal is in very poor body condition, it is harder for it to recover. Dogs with LPC do better than those with LPE and dogs with granulomatous enteritis/gastritis are thought to not fare well, although not much data is available. The good or moderately good news is that with a combination of therapies, many dogs with IBD will improve. Data published in a retrospective case study review of 80 dogs with IBD, by Craven and co­workers (Craven, et al, 2004) showed the following:
· 21/80 dogs went into disease remission with therapy (median observation time 14 months)
· 40/80 dogs had intermittent signs of disease (median observation time 17 months) Unfortunately, these authors also found in their study that 3/80 dogs had disease that could not be controlled by therapy and 10/80 dogs were euthanized due to failure to improve. Good follow­up was not found on the remainder of dogs in this study. Current research in the pathogenesis and treatment of IBD Much of the current research on IBD is focused in two main areas:
· understanding characteristics and functions of immune cells found in biopsies of dogs with IBD
· novel diagnostic methods to detect IBD or response to therapy of IBD
· testing of new therapies for treatment of IBD Characteristics and functions of mucosal immune cells In a series of papers, Allenspach and colleagues, (Allenspach, et al, 2004, 2006a, 2006b, 2006c; Luckschander, et al, 2006) looked for markers of immune cell activity or responsiveness in dogs with IBD. They found that roughly half of dogs studied had circulating perinuclear antineutrophilic cytoplasmic antibodies (PANCAs) in their serum, indicating reactivity to inflammatory cells. These antibodies had been detected in people with IBD, ulcerative colitis, and also in
those with systemic lupus erythematosus. They looked for antibodies against a common yeast (Saccharomyces cerevisiae) (ASCAs), which are known to be seen in people with Crohn’s disease, and found them in 17/39 dogs studied. They did not consider the levels of ASCAs significant in IBD dogs. They found that dogs with IBD that had relatively low levels of a cellular protein, p­ glycoprotein (p­gp), were more likely to respond to drug therapy than dogs with high levels of p­gp. German and co­workers (German, et al, 2000a, 2000b, 2001, 2003) studied biopsies from the duodenum from dogs with IBD. They found increased numbers of IgG+ plasma cells, CD3+ t­lymphocytes, CD4+ lymphocytes, macrophages and neutrophils, using a variety of special cell stains. Of interest, they noted a decreased number of mucosal mast cells, this differing from findings of Locher and co­workers (Locher, et al, 2001). German and his colleagues found that in Boxer dogs with the histiocytic variant of ulcerative colitis, there were also increased numbers of IgG+ plasma cells, CD3+ t­lymphocytes, and periodic acid Schiff’s positive macrophages. Not only were increased numbers of immune effector cells present, but inflammatory cytokines (IL­2, IL­5, IL­12p40, TNF alpha, and TGF beta) produced by these cells were seen over expressed in German Shepherd dogs with IBD. However, McCann and his co­workers (McCann, et al, 2007) did not feel that serum TNF alpha levels were good indicators of disease severity in IBD. Greger and his colleagues (Greger, et al, 2006) also noted increased expression of peroxisome proliferator associated receptor alpha (PPAR alpha) in mucosal samples of dogs with IBD. They interpreted this as an indication of increased nuclear receptor activity mediating mucosal inflammation. Likewise, Spichiger and co­workers (Spichiger, et al, 2005) found increased expression of growth hormone receptors, IGF­1, and IGF­2 in samples of inflamed gastrointestinal tract. They, too, felt that the presence of these mediators was indicative of cycles of inflammation and healing in dogs with IBD. Novel diagnostic methods Gaschen and co­workers (Gaschen, et al, 2005) used Doppler blood flow measurements of two of the main arteries (the celiac and cranial mesenteric arteries) that supply blood to the gastrointestinal tract. Of significant interest, they found attenuated blood flow during several fasting and feeding intervals in dogs with IBD not seen in normal dogs. This may indicate that changes in blood flow, coupled with changes in motility of gut segments, may contribute to the development and progression of IBD and signs associated with it. New therapies for IBD Some dogs do not respond well to therapies for IBD. Dogs treated with corticosteroids like prednisone are prone to development of gastric ulcers and to
have excessive thirst (polydipsia), excessive and sometimes uncontrolled urination (polyuria) and excessive hunger (polyphagia). Long­term use of corticosteroids is associated with increased chance of infection and may increase the risk for developing cancer (this has been shown in people). Veterinarians have looked for new drugs to help dogs that may not tolerate corticosteroids. Allenspach and co­workers (Allenspach, et al, 2006) administered the immunosuppressive drug, cyclosporine A, to dogs not responding well to corticosteroid therapy. Improvement in clinical signs was seen in 12/14 dogs treated and biopsies of the intestinal tract showed decreased mucosal t­ lymphocytes in responding dogs. Tumulty and colleagues (Tumulty, et al, 2004) studied the effect of the centrally acting hormone mediator, budesonide, on clinical signs in dogs with IBD. No beneficial effect of this drug was seen. In summary, research into the causes and treatments of IBD is very active in the past few years. An increasing understanding of the critical role that immune reactivity plays in the development of IBD is possible with new molecular techniques. This knowledge will help in the design of molecular therapies in the near term and understanding why Westies, as a breed, may be predisposed to develop IBD. References used and resources for further study Allenspach K, Bergman PJ, Sauter S, Gröne A, Doherr MG, Gaschen F, “P­ glycoprotein expression in lamina propria lymphocytes of duodenal biopsy samples in dogs with chronic idiopathic enteropathies” Journal of Comparative Pathology: 134(1):1­7, 2006a. Allenspach K, Luckschander N, Styner M, Seibold F, Doherr M, Aeschbach D, Gaschen F, “Evaluation of assays for perinuclear antineutrophilic cytoplasmic antibodies and antibodies to Saccharomyces cerevisiae in dogs with inflammatory bowel disease” American Journal of Veterinary Research: 65(9):1279­83, 2004. Allenspach K, Rüfenacht S, Sauter S, Gröne A, Steffan J, Strehlau G, Gaschen F, “Pharmacokinetics and clinical efficacy of cyclosporine treatment of dogs with steroid­refractory inflammatory bowel disease” Journal of Veterinary Internal Medicine: 20(2):239­44, 2006b. Allenspach K, Steiner JM, Shah BN, Berghoff N, Ruaux C, Williams DA, Blum JW, Gaschen F, “Evaluation of gastrointestinal permeability and mucosal absorptive capacity in dogs with chronic enteropathy” American Journal of Veterinary Research: 67(3):479­83, 2006c.
Cave NJ, “Chronic inflammatory disorders of the gastrointestinal tract of companion animals” New Zealand Veterinary Journal: 51(6):262­74, 2003 Cave NJ, “Hydrolyzed protein diets for dogs and cats” Veterinary Clinics of North America. Small Animal Practice: 36(6):1251­68, 2006. Craven M, Simpson JW, Ridyard AE, Chandler ML, “Canine inflammatory bowel disease: retrospective analysis of diagnosis and outcome in 80 cases (1995­ 2002)” Journal of Small Animal Practice: 45(7):336­42, 2004. Foster AP, Knowles TG, Moore AH, Cousins PD, Day MJ, Hall EJ, “Serum IgE and IgG responses to food antigens in normal and atopic dogs, and dogs with gastrointestinal disease” Veterinary Immunology and Immunopathology: 92(3­ 4):113­24, 2003. Gaschen L, Kircher P, Lang J, Gaschen F, Allenspach K, Gröne A, “Pattern recognition and feature extraction of canine celiac and cranial mesenteric arterial waveforms: normal versus chronic enteropathy­­a pilot study” Veterinary Journal: 169(2):242­50, 2005. German AJ, Hall EJ, Day MJ, “Chronic intestinal inflammation and intestinal disease in dogs” Journal of Veterinary Internal Medicine: 17(1):8­20, 2003. German AJ, Hall EJ, Day MJ, “Immune cell populations within the duodenal mucosa of dogs with enteropathies” Journal of Veterinary Internal Medicine: 15(1):14­25, 2001. German AJ, Hall EJ, Kelly DF, Watson AD, Day MJ, “An immunohistochemical study of histiocytic ulcerative colitis in boxer dogs” Journal of Comparative Pathology: 122(2­3):163­75, 2000a. German AJ, Helps CR, Hall EJ, Day MJ, “Cytokine mRNA expression in mucosal biopsies from German shepherd dogs with small intestinal enteropathies” Digestive Diseases and Sciences: 45(1):7­17, 2000b. Greger DL, Gropp F, Morel C, Sauter S, Blum JW, “Nuclear receptor and target gene mRNA abundance in duodenum and colon of dogs with chronic enteropathies” Domestic Animal Endocrinology:31(4):327­39, 2006. Jergens AE, “Clinical assessment of disease activity for canine inflammatory bowel disease” Journal of the American Animal Hospital Association: 40(6):437­ 45, 2004 Jergens AE, “Underestimating gastrointestinal inflammation­­implications for therapy” Journal of Feline Medicine and Surgery: 4(3):179­82, 2002.
Jergens AE, Schreiner CA, Frank DE, Niyo Y, Ahrens FE, Eckersall PD, Benson TJ, Evans R, “A scoring index for disease activity in canine inflammatory bowel disease” Journal of Veterinary Internal Medicine:17(3):291­7, 2003 Locher C, Tipold A, Welle M, Busato A, Zurbriggen A, Griot­Wenk ME, “Quantitative assessment of mast cells and expression of IgE protein and mRNA for IgE and interleukin 4 in the gastrointestinal tract of healthy dogs and dogs with inflammatory bowel disease” American Journal of Veterinary Research: 62(2):211­6, 2001. Luckschander N, Allenspach K, Hall J, Seibold F, Gröne A, Doherr MG, Gaschen F, “Perinuclear antineutrophilic cytoplasmic antibody and response to treatment in diarrheic dogs with food responsive disease or inflammatory bowel disease” Journal of Veterinary Internal Medicine: 20(2):221­7, 2006. McCann TM, Ridyard AE, Else RW, Simpson JW, “Evaluation of disease activity markers in dogs with idiopathic inflammatory bowel disease” Journal of Small Animal Practice: Jun 30 2007 [Epub ahead of print]. Peters IR, Helps CR, Calvert EL, Hall EJ, Day MJ, “Cytokine mRNA quantification in duodenal mucosa from dogs with chronic enteropathies by real­ time reverse transcriptase polymerase chain reaction” Journal of Veterinary Internal Medicine: 19(5):644­53, 2005. Münster M, Hörauf A, Bilzer T, “[Assessment of disease severity and outcome of dietary, antibiotic, and immunosuppressive interventions by use of the canine IBD activity index in 21 dogs with chronic inflammatory bowel disease]” Berliner und Münchener tierärztliche Wochenschrift: 119(11­12):493­505, 2006. Ridgway J, Jergens AE, Niyo Y, “Possible causal association of idiopathic inflammatory bowel disease with thrombocytopenia in the dog” Journal of the American Animal Hospital Association: 37(1):65­74, 2001. Ristic JM, Stidworthy MF, “Two cases of severe iron­deficiency anaemia due to inflammatory bowel disease in the dog” The Journal of Small Animal Practice: 43(2):80­3, 2002. Rudorf H, van Schaik G, O'Brien RT, Brown PJ, Barr FJ, Hall EJ, “Ultrasonographic evaluation of the thickness of the small intestinal wall in dogs with inflammatory bowel disease” The Journal of Small Animal Practice: 46(7):322­6, 2005. Spichiger AC, Allenspach K, Ontsouka E, Gaschen F, Morel C, Blum JW, Sauter SN, “Abundance of mRNA of growth hormone receptor and insulin­like growth factors­1 and ­2 in duodenal and colonic biopsies of dogs with chronic
enteropathies” Journal of Veterinary Medicine A, Physiology, Pathology, Clinical Medicine: 52(10):491­7, 2005. Strombeck DR, “Chronic inflammatory bowel disease” In: Strombeck DR, (ed.) Small Animal Gastroenterology, Davis, CA: Stonegate Publishing, 1979:240­ 261. Tumulty JW, Broussard JD, Steiner JM, Peterson ME, Williams DA, “Clinical effects of short­term oral budesonide on the hypothalamic­pituitary­adrenal axis in dogs with inflammatory bowel disease” Journal of the American Animal Hospital Association: 40(2):120­3, 2004. Zoran D, “Nutritional management of gastrointestinal disease” Clinical Techniques in Small Animal Practice: (4):211­7, 2003.