INFLAMMATORY BOWEL DISEASE

• 1. Define inflammatory bowel disease.

  Inflammatory bowel disease (IBD) is a group of idiopathic, chronic gastrointestinal (GI) tract disorders characterized by infiltration of the lamina propria by inflammatory cells. The cellular infiltrate may be lymphocytes, plasma cells, eosinophils, neutrophils, macrophages, or combinations of these.

• 2. What causes IBD?

  The cause of IBD is probably multifactoral. It appears to involve host hypersensitivity responses to antigens (food, bacterial, or self) within the bowel lumen or mucosa. Genetic and psychosocial factors also may be involved. Increased permeability allows luminal antigens to cross the mucosa, leading to inflammation and further mucosal damage, which in turn further increase permeability. Mucosal inflammation occurs in a diverse group of disorders, including bacterial, viral, protozoal, and parasitic infections, bacterial overgrowth, metabolic disease, neoplasia, pancreatitis, and cholangiohepatitis. These conditions should be excluded from the differential list before a cat is assumed to have IBD due to dietary hypersensitivity.

• 3. Describe the pathophysiology of IBD.
  IBD is an abnormal mucosal immune response, which results in the recruitment of inflammatory cells to the intestine. The immune response itself leads to tissue destruction and impairment of digestive and absorptive capabilities. Damage results from the following factors:

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    Arachidonic acid metabolites
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    Proinflammatory cytokines
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    Leukotrienes, produced in the lipoxygenase pathway, that act as chemotactic agents, increase vascular permeability, and induce smooth muscle contraction
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    Prostaglandins from the cyclo-oxygenase pathway, which result in pain, vasodilation, increased vascular permeability, and increased secretion of water and electrolytes
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    Platelet-activating factor, which is chemotactic and increases vascular permeability
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    Interleukins. which regulate the mucosal immune system
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    Oxygen-derived free radicals and nitric oxide, which damage the mucosa
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    GI peptides, including substance P, vasoactive intestinal peptide, and somatostatin
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    Clonal expansion of activated intestinal B and T lymphocytes.
• 4. Describe the typical signalment for cats with IBD.

  There is no age, sex, or breed predilection, although purebred cats may be at increased risk for lymphocytic-plasmacytic enteritis. Although most affected cats are middle aged (6–8 years) or older, about one-third of the patients are 2 years old or younger. IBD has been diagnosed as early as 5 months of age.

• 5. What are the common clinical signs of IBD?

  Chronic vomiting and diarrhea are the most common clinical signs and may occur alone or in combination. Vomiting often is not associated with eating and should be differentiated from regurgitation (see Chapter 26). Diarrhea may contain mucus or blood, indicating large bowel involvement. Anorexia, weight loss, lethargy, loss of litter training, abdominal pain, and hematemesis also may be seen. The clinical signs are generally intermittent or cyclical and reflect the predominant sites of disease. Clinical signs are similar among the various histologic forms. Symptoms vary from mild to severe. Exacerbations and spontaneous remissions are common.

• 6. What characteristic abnormalities are found on physical examination?

  No physical examination findings are pathognomonic, but several findings may suggest IBD. Cranial abdominal discomfort may be present and is more noticeable in cats with concurrent pancreatitis. Intestinal bowel loops may be thickened. Cats with “triaditis”—the combination of inflammatory bowel disease, pancreatitis, and cholangiohepatitis—may be icteric and have a palpable liver. Many cats are ill kempt, and emaciation may be noted, particularly if malabsorption is occurring.

• 7.
  What are the primary differential diagnoses for IBD?

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    Endocrine diseases (hyperthyroidism, exocrine pancreatic insufficiency)
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    Food intolerance
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    Bacterial enteritis (Helicobacter spp., Salmonella spp., Campylobacter spp., Clostridium perfringens, Escherichia coli; see Chapter 20)
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    Parasites (helminths, cestodes, protozoans; see Chapter 19)
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    Fungal enteritis (Histoplasma capsulatum; see Chapter 22)
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    Neoplasia (lymphosarcoma, adenoma, adenocarcinoma; see Chapter 24)
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    Viral enteritis (feline leukemia virus [FeLV], feline immunodeficiency virus [FIV], feline enteric coronavirus, feline panleukopenia; see Chapter 21)
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    Obstruction
• 8. How is IBD diagnosed?

  IBD is diagnosed by combining histologic evidence of inflammation with exclusion of other causes of GI inflammation. Baseline laboratory tests should include complete blood count (CBC), serum biochemical profile, FeLV antigen test, FIV antibody test, serum total T4 concentration (for cats at risk for hyperthyroidism), urinalysis, fecal parasite examination (zinc sulfate flotation and direct smear), fecal wet mount, Cryptosporidium spp. screening, rectal cytology, and survey abdominal radiographs (see Chapter 18). Fecal culture is indicated in cats with suspected bacterial enteritis (see Chapter 20).

• 9. What CBC abnormalities support the diagnosis of IBD?

  The CBC may show increased eosinophils. However, parasitic diseases and hypoadrenocorticism also induce this abormormality. Microcytic anemia may develop if IBD is severe and results in iron deficiency due to chronic blood loss. Plasma protein concentration decreases if protein-losing enteropathy is present.

• 10. How do serum biochemical abnormalities aid in the diagnosis of IBD?

  The primary benefit of serum biochemical testing is to exclude other causes of vomiting and diarrhea. Panhypoproteinemia is consistent with protein-losing enteropathy, which may occur with some forms of IBD. Some cats (25%) with lymphocytic-plasmacytic enteritis are reported to have mildly increased serum alanine transferase (ALT), aspartate transferase (AST), and alkaline phosphatase (ALP) activities. Liver function tests are usually normal; in some cats, however, histologic examination of the liver reveals periportal inflammatory infiltrates. Because the pancreatic and biliary ducts are shared in cats and empty into the duodenum, IBD may result in concurrent pancreatitis and cholangiohepatitis (see Chapters 29 and 36). This syndrome has been called “triaditis” and may explain serum biochemical evidence of hepatic and pancreatic involvement. Triaditis may be due to translocation of bacteria from the diseased GI tract into the portal circulation. Cobalamin, folate, and vitamin K levels may be decreased as a result of malabsorption.

• 11. What is the diagnostic benefit of imaging procedures?

  Survey and contrast films of the abdomen have a low likelihood of showing abnormalities (masses or increased small intestinal diameter). Barium studies may show flocculation of barium contrast material, irregular mucosal-barium interface, delayed transit time, or persistent adherence of barium to mucosa. Ultrasound may show small intestinal abnormalities, including altered echogenicity, small intestinal wall thickening, or poor small intestinal wall definition. However, results of imaging procedures are not specific for IBD and are used primarily to exclude other causes of vomiting or diarrhea.

• 12. How should tissues be obtained for histologic evaluation?

  Endoscopically obtained or full-thickness surgical biopsies may be used for histologic evaluation. Endoscopic mucosal biopsy is less invasive than surgery but provides small samples (usually 2.8 mm in diameter at most) that include mucosa only. Samples are easily obtained from the stomach, duodenum, rectum, and colon; the jejunum and ileum are less commonly sampled. Samples often have crush artifact, which makes histologic characterization difficult. Because only mucosa is obtained, deeper inflammation or neoplasia may be missed, and it is difficult to document the presence of lymphangectasia. It is important to obtain samples even if the mucosal surface appears normal. Multiple samples should be obtained from each site. In dogs, duodenal aspirates are performed to assess for Giardia spp. and bacterial overgrowth. In cats, however, Giardia spp. reside more distally in the small bowel, and normal cats have extremely variable numbers of bacteria in the duodenum. Thus the diagnostic benefit of these tests is limited. If gastritis is suspected, samples should be collected from the cardia and placed on a urea slant to assess for the presence of urease activity, which supports the diagnosis of helicobacteriosis (see Chapter 20).

  If endoscopic biopsies are nondiagnostic in a cat with clinical signs of IBD and other causes of vomiting and diarrhea have been ruled out, surgical, full-thickness biopsies are warranted. Surgery has the additional benefit of allowing visualization and biopsy of the pancreas and liver in cats with suspected triaditis. Because endoscopically obtained biopsies are occasionally falsely negative, require specialized equipment, and limit testing to the mucosal surface, exploratory laparotomy may be the preferred procedure for clients with limited budgets.

• 13. In what forms does IBD occur?

  IBD is classified by the area of the GI tract that is affected and the predominant type of inflammatory cell:

  Lymphocytic-plasmacytic enterocolitis is the most common type of IBD diagnosed in cats. The lamina propria is infiltrated with lymphocytes and plasma cells. The disease may progress to diffuse intestinal lymphoma.

  Eosinophilic enterocolitis and hypereosinophilic syndrome are rare forms of IBD characterized by diffuse or focal infiltration of mature eosinophils into one or more layers of the intestinal tract. Usually they are accompanied by peripheral eosinophilia. Although eosinophilic enterocolitis is confined to the GI tract, hypereosinophilic syndrome may involve the liver, spleen, lymph nodes, bone marrow, lung, pancreas, adrenal glands, or skin. Hypereosinophilic syndrome responds poorly to glucocorticoids, is considered a preneoplastic condition, and has a high mortality rate.

  Regional granulomatous enterocolitis is less common. It is characterized by transmural granulomatous inflammation, usually of the ileum and colon, that causes stenosing, mass-like thickening of a region of bowel wall. Regional lymph nodes and adjacent mesentery also may be involved.

  Other rare forms (all treated as lymphocytic-plasmacytic IBD) include neutrophilic (suppurative) colitis, granulomatous colitis, histiocytic colitis, necrotic colitis, and angiopathic colitis with vasculitis and ischemic ulcers.

• 14. How is IBD treated?

  The basic concepts of treatment are to remove the antigenic source of inflammation and then suppress the cell-mediated inflammatory response in the GI tract. The goals are remission of clinical signs, control with dietary management, and use of metronidazole and/or prednisolone. Relapses often occur and require drug therapy. Severe and refractory IBD may require the use of potent immunosuppressive drugs. Some cats require indefinite drug administration for control.

• 15. Describe dietary management of IBD.

  The diet should contain a single, highly digestible, novel protein (one that the cat has not eaten before) and reduced amounts of food additives. It also should be gluten-free; use rice or potato as a carbohydrate source. High-fat diets should be avoided. If colitis is present, consider high-fiber diets containing either insoluble (cellulose) or soluble (psyllium) fiber. When a homemade diet is used for initial treatment, many cats find baby rice cereal more palatable than cooked white rice. Some people advocate a “sacrificial protein” for the first 6 weeks of treatment, on the theory that the cat is more likely to develop dietary sensitivity during the time that the gut is inflamed. Protein hydrolysates have reduced molecular weights (< 10,000 daltons) that should decrease antigenicity.

  Commercially Available Hypoallergenic Diets

  Lamb	Venison
  Hill's Prescription Diet D/D (canned)	Innovative Veterinary Diets (canned or dry)
  Innovative Veterinary Diets (dry or canned)	Waltham Select Protein (canned)
  lams Eukanuba Response Formula (canned)	Duck
  Rabbit	Innovative Veterinary Diets (dry)
  Innovative Veterinary Diets (canned)	Hydrolyzed proteins
  Nature's Recipe Rabbit (canned)	Hills Prescription Diet Z/D (dry)

  Hill's Pet Nutrition, Topeka, KS; Innovative Veterinary Diet, Nature's Recipe Co., Newport, KY; lams Company, Dayton, OH; Waltham USA, Vernon, CA.
• 16. What dietary supplements are commonly recommended?
  Various nutritional deficiencies secondary to IBD require supplementation. In addition, some nutritional supplements may have anti-inflammatory effects or promote healing of the intestinal tract. Controlled studies of these supplements for treatment of feline IBD are lacking.

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    Vitamin B12 (cobalamine) and folate concentrations are often reduced by malabsorption.
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    Vitamin K deficiency due to malabsorption of fats may be severe enough to cause bleeding and abnormal hemostasis.
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    N-acetyl glucosamine has shown promise in the treatment of inflammatory disorders, including IBD, colitis and Crohn's disease in people.
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    Glutamine can be supplemented as an energy source for mucosal cells of the digestive tract.
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    Vitamin C scavenges free radicals, enhances immune function, has anti-inflammatory properties, and may reduce stress.
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    Lactobacillus acidophilus is a probiotic that may help to restore normal intestinal flora.
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    Dimethylglycine modulates production of lymphocytes and antibodies. It is theorized to decrease the allergic response.
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    Proanthocyanidin complex is a bioflavinoid that theoretically works with vitamin C to reduce inflammation, strengthen capillaries, scavenge free radicals, and improve immune function. Antiviral activity also has been proposed.
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    Vitamin E, vitamin A, and selenium are antioxidants that may protect cells from free oxygen radical-induced damage.
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    Zinc is thought to potentiate immune system response and enhance healing.
  Dietary Supplements for Management of IBD

  SUPPLEMENT	PROPOSED DOSE
  Cobalamine	125–250 mg/wk SC or IM for 6–8 weeks
  Dimethylglycine	50–250 mg/cat PO, indefinitely
  Folate	0.5 mg/day PO for 1 month
  Glutamine	250–5000 mg/cat PO, indefinitely
  N-acetyl glucosamine	250–1500 mg/cat PO, indefinitely
  Lactobacillus acidophilus	50–500 million microorganisms/cat PO, until stool returns to normal consistency
  Proanthocyanidin complex	10–200 mg/cat PO, indefinitely
  Selenium	15 mg/day PO, indefinitely
  Vitamin A	1000–5000 IU/day PO as beta caroline, indefinitely
  Vitamin C	250–300 mg/cat PO, indefinitely.
  Vitamin E	200 IU/day PO as alpha tocopherol daily, indefinitely.
  Zinc	7.5 mg/day PO, indefinitely

  SC = subcutaneously, IM=intramuscularly, PO =orally.
• 17. What drugs are used to manage IBD?

  DRUG	PROPOSEDDOSE
  Chlorambucil	2 mg PO every other day or 2 mg/M2/day for 7 days; then 1 mg/M2/day for 7 days; then taper to lowest effective maintenance dose
  Cyclophosphamide	50 mg/M2 PO 4 times/wk: during remission, use chlorambucil
  Cyclosporine	0.5–8.5 mg/kg PO every 12–24 hr, indefinitely
  Methylprednisolone	10–20 mg/cat IM every 2 wk until controlled; then as needed
  Metronidazole	10–20 mg/kg PO every 8–12 hr for 2–4 wk; then gradually taper off over 1–2 mo
  Prednisolone	1–2 mg/kg PO every 12–24 hr for 2–4 wk; then reduce dose by half every 2 weeks until lowest effective maintenance dose is found.
  Azathioprine	0.3 mg/kg PO every 48 hr, indefinitely.
  Sulfasalazine	10–20 mg/kg PO every 24 hr for 7–10 days

  PO =orally, IM=intramuscularly.
• 18. Describe the effects of metronidazole.

  This antibiotic is one of the antiprotozoal drugs of choice for Giardia spp. in cats. Because it has an excellent anaerobic spectrum, it may aid in the treatment of secondary bacterial overgrowth. It is proposed to inhibit cell-mediated immunity and to alter neutrophil chemotaxis and thus may be an effective adjunct to glucocorticoids. Side effects include salivation (due to bad taste), anorexia, vomiting, central nervous system abnormalities (seizures), and neutropenia.

• 19. Discuss the role of glucocorticoids.

  Prednisolone is used most frequently, but if the cat cannot or will not take oral medications, methylprednisolone can be used. Control seems to be more difficult with parenteral depository glucocorticoids. Transdermal dosing of prednisolone also may be helpful when oral drugs cannot be administered. Glucocorticoids should not be prescribed until the diagnosis of IBD is confirmed by histology. Common side effects include polyuria, polydipsia, polyphagia, skin disease, weight gain, and type 2 diabetes mellitus (see Chapter 54).

• 20. How does azathioprine work?

  The mechanism of immunosuppression has not been determined, but it is thought to depend on several factors. Azathioprine antagonizes purine metabolism, resulting in inhibition of RNA, DNA synthesis, and mitosis. Incorporation into nucleic acids may cause chromosome breaks, and inhibition of coenzyme function may disrupt cellular metabolism. Azathioprine has a greater effect on cellular immunity and delayed hypersensitivity than on humoral antibody responses. It is thought to take at least 1–3 weeks to become fully effective, and clinical response may require 6 weeks. It is used most often in cases of IBD that cannot be controlled by diet modifications and glucocorticoids or in cats that glucocorticoids make ill. Side effects may include bone marrow suppression, pancreatitis, hepatic damage, and anorexia. CBC should be monitored once or twice weekly for 10–14 days after starting, then monthly.

• 21. What is the mechanism of action of sulfasalazine?

  The mechanism of action is not known. It is thought that after colonic bacteria cleave sulfasalazine into sulfapyridine and 5-aminosalicylic acid (5-ASA), the antibacterial (sulfapyridine) and anti-inflammatory (5-ASA) activity modify the course of the disease. Levels of both drugs are higher in the colon when the compound is used than with separate administration. Dosing in cats may be difficult without compounding. Primary side effects include anorexia, vomiting, and anemia; in dogs sulfasalazine has induced keratoconjunctivitis sicca.

• 22. How do cyclophosphamide and chlorambucil work?

  The metabolites of cyclophosphamide act as alkylating agents, interfering with DNA replication, RNA transcription and replication, and nucleic acid function. The phosphorylating activity of cyclophosphamide also enhances its cytotoxic properties. The mechanism of action for its immunosuppressive activity on T-cells and antibody production is unknown. The drug is associated with bone marrow suppression and hemorrhagic cystitis (rarely). It should not be used over the long term. If it is effective during the induction phase, the related drug chlorambucil should be used for chronic management.

  The mechanism of action of chlorambucil is cross-linking with cellular DNA. It is cytotoxic and cell cycle-nonspecific. Side effects include myelosuppression, resulting in anemia, leukopenia, and thrombocytopenia. It can also result in anorexia, vomiting, and diarrhea. A complete blood count with platelets should be done weekly until the cat is stable, then every other week.

• 23. Describe the mechanism of action of cyclosporine.

  The mechanism of action is impedance of calcium-dependent signal transduction in the cytosol of lymphocytes. Cyclosporine stimulates secretion of transforming growth factor beta, which inhibits interleukin 2-stimulated T-cell proliferation and generation of antigen-specific cytotoxic lymphocytes. The primary side effects in people and dogs include inappetence, GI irritation, and gingival hyperplasia. Blood levels should be measured 24–48 hours after starting therapy to ensure adequate levels and periodically during therapy. The goal is a 12-hour whole-blood trough level of 250–500 ng/ml. Gelatin capsules may be needed for administration because of the unpleasant taste.

• 24. What is the prognosis for cats with IBD?

  The prognosis depends on the form of IBD. In general, although the condition cannot be cured, the prognosis for control is good.