What's new with boxer colitis and other large bowel disorders? (Proceedings)

Anatomy and physiology of the large intestine

The large intestine is comprised of the colon, cecum, rectum, and anal canal, and in dogs and cats comprises roughly one quarter of the total intestinal length. The colon includes the ascending, transverse, and descending components. Blood flow to the colon comes from the cranial and caudal mesenteric arteries, and venous blood drains to the portal vein. Nervous functions of the colon are controlled by parasympathetic, sympathetic, and autonomic innervation. Parasympathetic innervation is from the vagus nerve proximally and the pelvic nerves distally. Sympathetic innervation comes from the paravertebral ganglia, and autonomic innervation comes from intramural nerves running between the layers of muscularis and submucosa. The cecum is an s-shaped blind diverticulum located at the ileocolic junction. Like the small intestine, the large intestine is made up of 4 layers: mucosa, submucosa, muscularis, and serosa. However, compared with the small intestine, the large intestine contains no villi, fewer microvilli, more mucus-producing goblet cells, and slower migration from crypts to the epithelial surface (turnover of colonic cells takes 4-7 days, compared with 1-3 days in the small intestine).

Functionally, the large intestine's major roles include reabsorption of water and electrolytes, microbial fermentation, storage of feces, and coordinated defection. While the majority of water entering the small intestine is reabsorbed within the small intestine (50% efficiency of water extraction in the jejunum, 75% in the ileum), the colon is the most efficient at reabsorbing water, absorbing 90% of water that presents to the colon. This absorptive capacity allows for substantial changes in small intestine flow without causing diarrhea, because the colon can absorb additional water; however, minor changes in colonic absorption can lead to substantial diarrhea. In the colon, sodium reabsorption relies on electrogenic transport (rather than glucose-coupled sodium transport) and is markedly influenced by aldosterone; this helps to explain why addisonian dogs may have diarrhea. In the colon, potassium can be both reabsorbed and secreted, allowing the colon to contribute to close regulation of the body's potassium balance. The colon has abundant goblet cells producing mucus which plays a role in protecting the mucosa from mechanical damage and binding pathogens and enterotoxins to encourage excretion. The colon is highly populated with mostly anaerobic bacteria responsible for bacterial fermentation and production of short chain fatty acids, which can then be used for energy, to stimulate absorption of water and electrolytes and differentiation and proliferation of colonocytes, and to assist in GI motility. Bicarbonate is also excreted in the colon (through a chloride-bicarbonate exchange) and helps neutralize acids produced by bacterial fermentation. Motility in the colon is complex. In the proximal colon, motility is slower, to allow for water and electrolyte absorption and mixing of contents and is predominated by slow rhythmic phasic contractions and retrograde giant contractions. Once feces are ready to be expelled, more forceful giant migrating contractions push feces towards to the rectum.

History and Physical Exam

When a dog or cat is presented with diarrhea, questions to discern large bowel vs. small bowel and acute vs. chronic (>2 weeks) diarrhea are important for developing a logical differential list. Clinical signs of large bowel diarrhea may include increased urgency and frequency of defecation, tenesmus, mucus in feces, and hematochezia. Weight loss is much more characteristic of small bowel than large bowel disease, but weight loss is common with certain infections that primarily affect the large bowel. Historical questions of importance include a description of the frequency, consistency, and character of feces, any changes in diet, recent medications (including parasiticides), recent stressors, travel history, and presence of other systemic signs of illness. A complete physical exam is warranted and may be normal or identify concurrent disease and/or clues to the cause of the large bowel disease. A rectal examination is an important component of the exam to allow evaluation of the rectal canal for masses, strictures, lymphadenomegaly, as well as to allow visualization of the fecal color and consistency.

Diagnostic Approach to Large Bowel Signs

For cases of acute colitis without signs of systemic illness, minimal or no diagnostic tests may be necessary (fecal analysis), and patients may recover with supportive care (fluids), parasiticide therapy, and dietary modification. In chronic cases or those with systemic signs of illness, a minimum database is recommended (CBC, chemistry, urinalysis, fecal float/smear/cytology), and further testing may be indicated (abdominal imaging, colonoscopy).

Histiocytic ulcerative colitis (boxer colitis)

Histiocytic ulcerative colitis is a rare but severe large bowel disorder that is seen primarily in Boxer dogs but has also been reported in the French bulldog, mastiff, Alaskan malamute, and Doberman pinscher breeds. Most affected dogs are young, developing clinical signs before 2 years of age. Male and female dogs appear equally affected. Presenting complaints are typical for large bowel disease and include: mucoid bloody diarrhea, tenesmus and pain on defecation, and increased frequency and urge to defecate. With chronicity, they may lose substantial body weight and appear cachexic. These patients may be extremely painful upon rectal palpation, and the rectal mucosa may feel thickened and produce blood.

The pathophysiology of histiocytic ulcerative colitis has been researched and debated since it was first reported in 1965. It was originally thought to be a severe manifestation of inflammatory bowel disease caused by immune dysregulation; however therapy with novel protein diets, anti-inflammatory (sulfasalazine) or immunosuppressive medications (prednisone, azathioprine) resulted in poor clinical response. Further research has documented the presence of E. coli within intracellular compartments of PAS-positive macrophages in the colonic mucosa of affected dogs. Identified E. coli have had additional virulence properties allowing increased adhesion and invasion of these bacteria within the colonic mucosa and macrophages. E. coli with similar virulence traits have also been identified in a subset of biopsies from humans with Crohn's disease, suggesting a similar etiology and pathophysiology for these conditions. Underlying the E. coli infection may be an inherited genetic defect in the innate immune system of affected dogs; numerous genetic defects have been identified in people suffering from Crohn's disease.

Diagnosis is based on colonoscopy with numerous biopsies taken for histopathology. All dogs should have a fecal examination and deworming and minimal database (CBC, chemistry) to eliminate other causes of colitis prior to colonoscopy. Colonoscopic findings include multifocal superficial ulcers and erosions in the colonic mucosa with intraluminal hemorrhage, hyperemia, irregular nodular and corrugated mucosa surface, edema, and fibrosis. The classic histopathologic finding is presence of large macrophages that stain strongly positive in their cytoplasm with PAS. There is also severe infiltration of the lamina propria and submucosa with neutrophils, macrophages, lymphocytes, mast cells, and plasma cells, as well as loss of goblet cells. Fluorescence in situ hybridization (FISH) can be performed to detect intramucosal colonization of E. coli, and culture and susceptibility of these E. coli is recommended prior to treatment for optimal therapeutic success (http://www.vet.cornell.edu/labs/simpson/).

Recommended treatment for histiocytic ulcerative colitis is antibiotic therapy for 4-8 weeks. Enrofloxacin (5mg/kg PO once daily) has been successful in many cases; however, antimicrobial resistant strains can be seen, and treatment should be based on culture results. Whereas prognosis was considered poor and relapses common with previous therapeutic strategies, response to enrofloxacin has been very promising, with most dogs responding within 3-12 days of starting treatment. Some dogs may have complete clinical response and appear cured after one course of treatment; however others may require longer therapy or even lifetime therapy for management of this disease.

Parasites

Trichuris vulpis

The canine whipworm can cause asymptomatic infections or acute or chronic large bowel diarrhea. Clinical signs may include mucoid feces, hematochezia, or tenesmus. Transmission is through fecal oral ingestion of eggs, which hatch in the small intestine. Larvae migrate to the colon where they attach to the mucosa and mature. Clinical signs depend on worm burden, degree of blood loss, immune and nutritional status of the host, and concurrent infections. Patients may be anemic, and chemistry profiles may show increased BUN from gastrointestinal blood loss, as well as "pseudoaddisonian" electrolytes (elevated potassium and decreased sodium, but normal response to ACTH stimulation). Dogs may shed eggs intermittently, and diagnosis is made by fecal flotation. Effective treatment includes fenbendazole, pyrantel pamoate, febantel, moxidectin, and milbemycin.

Tritrichomonas foetus

These flagellated protozoa are similar to Giardia spp, but they do not form cysts; instead they reproduce by binary fission and are transmitted directly between hosts as trophozoites. T. foetus inhabit the distal ileum and colon of cats, causing lymphoplasmacytic and neutrophilic colitis and chronic large bowel diarrhea. Cats affected most by this parasite are those in highly populated housing, including catteries or shelters. Most symptomatic cats are young. Typical signs include foul-smelling large bowel diarrhea with blood and mucus, which may respond initially to antibiotic therapy but then relapse when discontinued. Diagnosis can be made by direct fecal smear at 40x, visualizing the undulating membrane of T. foetus, which is the approximate size of Giardia spp. without the falling leaf characteristic. T. foetus cannot survive refrigeration and cannot be diagnosed with routine fecal flotation or sedimentation. T. foetus can also be cultured in commercial pouches in-house, by adding 0.05g feces to the pouch and incubating at 37C for 48hr, then assessing with direct microscopy. Culturing using the pouch technique increases both the sensitivity and specificity over direct smears alone for diagnosing T. foetus. PCR is also available at certain laboratories for diagnosing T. foetus and may be superior to fecal culture; specific shipping requirements should be noted for optimal results. Affected cats should be treated specifically for any concurrent parasitic disease or empirically dewormed. A high proportion of cats may show spontaneous resolution of clinical signs (without specific therapy for T. foetus) within 2 years. However, PCR shows most of these cats remain infected even after clinical signs resolve, and they may show relapse with stress, antimicrobial therapy, or dietary changes. Ronidazole has been shown to be effective for feline T. foetus at 30mg/kg PO BID for 14 days. Neurotoxicosis is a potential side effect, suggesting this therapy should be reserved for confirmed cases with informed owner consent.

Heterobilharzia americana

Canine schistosomiasis, caused by the trematode, Heterobilharzia americana, has been diagnosed in Kansas and is a differential diagnosis for large bowel diarrhea. The definitive hosts (mainly raccoons but also dogs, lynx, bobcats and other wildlife) shed eggs in their feces. Eggs hatch when they contact water and release a motile miracidium, which penetrates into the intermediate host, the fresh-water snail. In the snail, it migrates to the digestive gland, develops into a cercaria and is released into fresh water where these cercariae can penetrate the skin of definitive hosts. In the definitive host, migration occurs to the liver where they mature and then to mesenteric veins for mating. Eggs are then released in the mesenteric veins and migrate to the intestinal lumen. The parasite can trigger a granulomatous response in the GI tract, liver, lungs, and pancreas. Affected dogs are usually medium or large breed dogs that are young to middle aged and spend time outdoors with access to fresh surface water with snails. Clinical signs include large bowel diarrhea (blood and mucus), substantial weight loss from malabsorption of food due to granulomatous inflammation, possible vomiting, lethargy, and PU/PD. Intestinal intussusception is also possible. Hypercalcemia is often present, with elevated ionized calcium, normal phosphorus, and in several cases elevated PTHrP despite no evidence of malignancy. Azotemia, hypoalbuminemia, hyperglobulinemia, increased liver enzyme activity, anemia, and eosinophilia may also be seen. Diagnosis cannot be made by fecal flotation; instead fecal sedimentation, fecal PCR, or histopathology may yield a diagnosis. Treatment can be challenging, as these dogs can become reinfected. Fenbendazole (50mg/kg PO q24hrs x 10 days) or praziquantel (25mg/kg PO q8hrs x3 days) may be effective. A fecal sample should be reevaluated 1-2 weeks after treatment, and therapy repeated if still positive.

Histoplasmosis

Both dogs and cats can present with the gastrointestinal form of histoplasmosis, causing large and small bowel diarrhea. Histoplasma capsulatum is a dimorphic fungus found in the soil in endemic regions including Kansas and the Ohio, Missouri, and the Mississippi River valleys. Like other dimorphic fungi, the mycelial form survives in the environment, and the yeast form causes clinical disease in our patients. This organism prefers areas with moist, humid conditions, especially nitrogen-rich organic matter such as bird and bat feces. Infection occurs by inhalation of microconidia, which convert to the yeast phase in the lungs. The incubation period is about 2 weeks. Yeast are phagocytized in the lungs, continue replicating, and can be disseminated within the lymphatics and bloodstream to the GI tract (as well as other organs: lymph nodes, eyes, bone marrow, liver, spleen, skin, bone). Reported cases of GI histoplasmosis without respiratory tract involvement suggests a possible oral route of transmission; however experimental oral administration of H. capsulatum spores has not yielded clinical disease. More likely these patients acquired the infection through inhalation.

While dogs and cats are equally likely to acquire histoplasmosis, GI involvement is more common in dogs. Clinical signs of dogs and cats with GI involvement can include: anorexia, vomiting, cachexia (from malabsorption), and either voluminous watery diarrhea with protein-losing enteropathy from small intestinal infiltration, or tenesmus, mucus, and fresh blood in stool from large bowel infiltration (more common). Patients may be anemic from bone marrow involvement or GI blood loss, and they may have hypoalbuminemia and hyperglobulinemia. A definitive diagnosis is made by cytology or histopathology. In patients with GI signs, evaluating a rectal scrape cytologically may be diagnostic; draining skin lesions and enlarged lymph nodes can also be easy sites to sample for cytology. Diff-Quik or Wright-Giemsa can be used for cytology, and organisms are oval cells 2-5μm in diameter, with a central spherical lightly basophilic body surrounded by a clear halo, usually found intracellularly within macrophages. Abdominal ultrasound shows non-specific thickening of the intestines, along with possible hepatosplenomegaly and lymph node enlargement. Colonoscopy can be used to obtain biopsies for histopathology and may show irregular, thickened, and eroded/ulcerated mucosa. Staging to determine extent of organ involvement is recommended for all cases of GI histoplasmosis (ultrasound, thoracic radiographs, fundic exam). In cases where cytology/histopathology are unrewarding or unsafe to obtain, yet histoplasmosis is a top differential, serology or antigen testing can be considered. Serology is limited in sensitivity and specificity, while antigen testing has been found in humans to have improved sensitivity for diagnosis and therapeutic monitoring of disseminated histoplasmosis.

Although itraconazole (5-10mg/kg PO q 12hrs) is considered the treatment of choice for histoplasmosis, patients with severe small intestinal involvement may not be able to absorb oral medications initially. For these patients, amphotericin B (0.25mg/kg IV q 48hrs) is a more effective option initially. Fluconazole (5-10mg/kg PO q 12 hours) can also be effective for GI histoplasmosis.

Select references

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Gookin JL, Copple CN, Papich MG, et al. Efficacy of ronidazole for the treatment of feline Tritrichomonas foetus infection. J Vet Intern Med 2006;20:536-543.

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Fabrick C, Bugbee A, Fosgate G. Clinical features and outcome of Heterobilharzia americana infection in dogs. J Vet Intern Med 2010;24:140-144.

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Clinkenbeard KD, Cowell RL, Tyler RD. Disseminated histoplasmosis in cats: 12 cases (1981-1986). JAVMA 1987;190:1445-8.