Diagnosis and Treatment of Enteritis and Inflammatory Bowel Disease

Michelle Henry Barton, DVM, PhD, Diplomate ACVIM Authors Address: College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602. mbarton@vet.uga.edu.

CASE ONE A 13-year-old Tennessee Walking Horse stallion developed acute onset of colic in central Georgia in October. He was found in his stall in the morning with numerous abrasions on his head. The grain and hay that he was offered the previous evening were only partially consumed. The owner witnessed him pawing at the ground. He then became recumbent and rolled. The local veterinarian was called and arrived approximately 45 minutes later. The owner reported that the stallion continued to intermittently paw, flank watch, and roll. His rectal temperature was 101.8oF, heart rate was 60 beats/minute, and respirations were 24 breaths/minute. Mucous membranes were tacky with a toxic line and the capillary refill time was 3 seconds. Gastrointestinal sounds were quiet. A nasogastric tube was passed and 8 liters of brown reflux were obtained. A rectal examination was performed and several loops of mildly distended small intestine were palpable in the midabdomen. The local veterinarian administered 500 mg of flunixin meglumine IV and gave 3 liters of mineral oil and 3 liters of electrolyte solution via the nasogastric tube. The stallion immediately appeared more comfortable and seemed interested in grazing. However, three hours later, he resumes pawing, flank watching, and rolling. He is referred to the Veterinary Teaching Hospital at the University of Georgia for further evaluation. At the time of presentation, the stallion appeared mildly to moderately uncomfortable, as evidenced by pawing and kicking at the abdomen. His rectal temperature was 99oF, heart rate was 64 beats/minute, and respirations were 32 breaths/minute. Mucous membranes were dry and diffusely toxic with a capillary refill time of 4 seconds. Extremities were cold to the touch. Gastrointestinal sounds were absent. Nasogastric intubation yielded 10 liters of oily brown reflux. Rectal examination revealed multiple loops of tightly distended small intestine. A catheter was placed in the jugular vein and isotonic polyionic fluids and 150 mg of xylazine were administered. Blood was submitted for a complete blood count and serum chemistry profile (Table 1). Abdominal fluid was collected and grossly appeared sanguineous (Table 1). The owner wants to know what is wrong with the horse, what is the treatment, and what is the prognosis? Etiology of Enteritis The presence of distended small intestine and gastric reflux are important clues that localize the problem to the small intestine. But what is the underlying etiology? Does this represent transient ileus, an inflammatory, an obstructive, or a strangulating obstructive lesion of the small intestine? The answer to this question is not always

straightforward. In fact, distinguishing between acute inflammatory lesions of small intestine i.e. enteritis and obstructive or strangulating small intestinal lesions can be quite challenging. Enteritis is an acute inflammatory disease of the small intestine. Synonyms for enteritis include anterior or proximal enteritis, gastroduodenojejunitis, and proximal duodenitis-jejunitis. In adult horses, the exact etiology of proximal enteritis is not known. Although it is often speculated that the disease is infectious in nature, specific pathogens are infrequently isolated from affected horses and attempts at reproducing enteritis in adult horses by giving gastric or intestinal contents from affected individuals are largely unsuccessful.1 In some instances, Salmonella and Clostridium spp. can be isolated from the gastric reflux, intestine, or feces; however, outbreaks of enteritis are exceptionally rare in the mature horse.1,2 In contrast, enteritis in neonatal foals is frequently attributed to infectious causes, such as Clostridium spp., rotavirus, Salmonella spp., or septicemia. Unlike mature horses, foals with enteritis are more likely to concurrently have diarrhea.
Table 1. Laboratory values from Case One: the 13 year-old TWH with acute colic.
Parameter PCV (%) Total WBC/l Neutrophils/l (Dohle bodies present) Band neutrophils/l Lymphocytes/l Total protein (gm/dl) Albumin (gm/dl) Creatinine (mg/dl) Bicarbonate mmol/L Abdominal fluid nucleated cell count/l Abdominal fluid protein (gm/dl) Stallion 55 14,900 11,050 900 2,050 8.9 4.3 4.9 18 1,400 4.4 Normal 35-45 5,500-12,000 3,500-8,500 <200 2,000-4,000 5.9-7.7 2.2-3.9 < 2.2 22-30 <5,000 < 2.0

Historically, horses with enteritis often receive grain or pelleted feed in their ration, so it is also speculated that acute enteritis is a noninfectious inflammatory lesion of small intestine caused by mycotoxins or excessive or improper fermentation of carbohydrate.3 Despite lack of a unifying etiology, the gross and histopathologic appearance of the affected small intestine is distinguishing.1 Grossly, the small intestine is distended, mildly to severely edematous, and contains diffuse serosal petechial to ecchymotic hemorrhages. Interspersed streaks of yellow to white serosal discoloration are often present. Histopathologic findings include submucosal edema, neutrophilic infiltration of the submucosal and lamina propria, and villous tip sloughing. In severe cases, transmural edema, mucosal ulceration, extensive hemorrhage, serosal fibrin deposition, and necrosis are present. The lesions most frequently affect the proximal half of small intestine; however, occasionally the entire small intestine and portions of the ascending colon are affected. In this later scenario, diarrhea may also be present. Rarely, only the distal portion of the small intestine is involved.

Diagnosis of Enteritis Various clinical and diagnostic findings of proximal enteritis overlap with obstructive and strangulating lesions of the small intestine.4 Compared to obstructive or strangulating obstructive lesions of small intestine, the following features are more typical of proximal enteritis: mild to severe signs of abdominal pain that subside to depression after gastric decompression; low grade fever (101.5 to 102.5oF); large or persistent volume of malodorous gastric reflux that may be brown; red-brown or orangebrown in appearance; mild to moderately distended small intestine (5 to 7 cm diameter); signs of dehydration and endotoxemia, leukocytosis with mature Neutrophilia; a left shift with toxic neutrophils; metabolic acidosis with an increased anion gap; and increased serum gamma glutamyltransferase activity.1,4,5 The peritoneal fluid protein concentration is typically disproportionately increased to the abdominal fluid nucleated cell count and in fact, the protein concentration (gm/dl) to nucleated cell count (per l divided by 1000) ratio is often > 3. However, in severe cases, the peritoneal fluid may be hemorrhagic with an increased nucleated cell count. Transabdominal ultrasound examination may be helpful. Horses with enteritis have distended loops of small intestine, with normal to diffusely thickened walls (> 3 mm). Corrugated or wavy mucosa is a distinguishing feature from obstructive or strangulating small intestinal lesions (Figure 1). Because the descending duodenum has a distinct location between the liver and the right dorsal colon, this is a particularly important area to examine. If distension is severe and diffuse, an obstructive pattern (i.e. hairpin or U turns) of small intestine may be present, though a focal area of uniformly thickened small intestine with an obstructive pattern is more consistent with a focal strangulating lesion of small intestine. It should be noted, that although proximal enteritis is a medically managed disease, in severe cases, it may not be possible to distinguish proximal enteritis from a strangulating small intestinal lesion.4 In these cases, an exploratory celiotomy should be considered. Although it has been reported that horses that undergo a celiotomy with proximal enteritis have a higher mortality rate, it must also be considered that cases surgically explored were probably more severely affected at the onset. Clearly, it would be better to explore a horse with enteritis than not to explore a horse with a strangulating small intestinal lesion.

Figure 1. Transabdominal ultrasound image of enteritis

This image was obtained in the lower left flank using a 5-2 MHz curvilinear probe set to a depth of 7 cm. The mucosal surface of the small intestine is wavy (arrow head) and the wall is thickened to 1 to 1.5 cm (serosal side of small intestine indicated by the thin arrow; luminal side at mucosa indicated by the arrowhead).

Treatment of Enteritis The key factors in medical management of acute proximal enteritis are fluid therapy, gastric decompression, and anti-inflammatory and anti-endotoxin therapy. Fluid therapy should include correction for dehydration, provide maintenance needs, and address replacement of continued losses from gastric reflux. Isotonic, polyionic fluids are typically sufficient. Depending on the severity of the enteritis, 100 liters or more of IV fluids may be needed on a daily basis. Horses with proximal enteritis may have gastric reflux for days and rarely for one to two weeks. Daily monitoring of creatinine, total protein, and serum electrolyte concentrations are helpful in development of the fluid therapy plan. Horses with proximal enteritis must have their stomach frequently decompressed. Depending on the severity, the patient should be checked for gastric reflux every 2 to 4 hours. Keeping a record of the volume of reflux can serve as a useful guide for fluid therapy, as well as for monitoring trends in the volume of reflux. The horse should be kept strictly NPO. Once gastric reflux has subsided, roughage and water may be gradually re-introduced (typically small amounts are initially offered with a full ration of hay being feed within 3 to 4 days). Too rapid or premature introduction of feed can result in relapse of signs. If enteral nutrition cannot be supplied because of persistent gastric reflux, partial parenteral nutrition should be considered. In neonatal foals, nutritional support is particularly important and total parenteral nutrition is often mandated. Common anti-inflammatory and anti-endotoxin therapies include flunixin meglumine (0.25 mg/kg IV q 8 hour), DMSO (50 to 100 mg/kg diluted to 10% IV q 8 to 12 hours), antibodies to endotoxin (Endoseruma, 1 to 1.5 ml/kg, diluted in 5 to 10 liters of isotonic polyionic fluids, given once), and polymixin B (1,000 to 5,000 IU/kg IV bolus q 8 to 12 hours; contra-indicated in severely azotemic horses). Lidocaine is sometimes administered intravenously as an analgesic, anti-inflammatory, and prokinetic agent (1.3 mg/kg loading bolus, followed by 0.05 mg/kg/minute CRI) for the initial 24 to 48 hours. Laminitis is a frequent complication to proximal enteritis and is reported to develop more commonly in horses with hemorrhagic reflux.6 Heparin therapy (40-110 IU/kg SQ or IV q 8 to 12 hours) significantly reduced the risk of laminitis in one retrospective study of horses with proximal enteritis.6 Antimicrobial therapy is usually not indicated in mature horses with enteritis, as it has not been shown to alter outcome. In contrast, broad spectrum antimicrobial therapy should be given to neonatal foals with enteritis, with special consideration given to the use of metronidazole when Clostridial infection is suspected. By-pass surgery (gastrojejunostomy or duodenojejunostomy) has been described for severe cases of proximal enteritis, though it is rarely performed. The prognosis for proximal enteritis is variable. Overall case survival was reported to be 70% in 1992,7 but it is the authors opinion that the survival rate is considerably higher in the last decade.

Review of Case One: Is this Enteritis? Several features of the above case of the stallion with acute small intestinal disease were consistent with a diagnosis of enteritis: history of fever, repeatedly-obtained large volume gastric reflux, an inflammatory leukogram, signs of endotoxemia (toxic mucous membranes, bands, toxic morphology in the neutrophils), acidosis, dehydration (azotemia, prolonged capillary refill time, dry mucous membranes, increased PCV and total protein), and increased peritoneal fluid protein concentration. The sanguineous peritoneal fluid was worrisome; however, after decompression of the stomach, the stallion remained depressed without overt signs of pain. He was treated with IV fluid therapy, flunixin meglumine, Endoseruma, and frequent gastric decompression. He remained comfortable with a normal heart rate. Hydration improved. Approximately 70 liters of gastric reflux were obtained over the first 48 hours of hospitalization, but then subsided. The nasogastric tube was removed. Over the next 4 days, IV fluid therapy was gradually decreased and water and grass hay were gradually re-introduced. He was discharged on day 6 without complication. CASE TWO A 10 year-old Thoroughbred mare was presented to the Veterinary Teaching Hospital at the University of Georgia in late summer with a 1 month history of low-grade intermittent abdominal pain and weight loss. The mare had been recently purchased 3 months previously and was used as a show jumper. She was eating fescue grass pasture and Coastal-Bermuda hay and 12% protein sweet feed. In the past month the mare had 5 episodes of mild abdominal pain in which she flank watched and repeatedly stretched and pawed. During the first episode, the local veterinarian was called and no physical abnormalities were detected. Mineral oil via a nasogastric tube and 500 mg of flunixin meglumine were administered to the mare. The episode of colic resolved. The 4 subsequent episodes of colic were similar; however, the local veterinarian was not called. The owner gave 500 mg of flunixin meglumine and each episode of colic resolved. The mare was again colicky and was referred without examination for further evaluation. At presentation, the mare was thin with a body condition score of 2/5. The rectal temperature, pulse and respiratory rate are normal. She was quiet, alert, and responsive. She had a diffuse crusting dermatitis. Cool pitting edema was present in the dependent abdomen. Sclerae were mildly injected. Oral mucous membranes were pink and moist. Gastrointestinal sounds were audible. Nasogastric intubation yielded no gastric reflux. A transrectal examination revealed indistinctly thickened sections of small intestine. Feces were cow-patty consistency. Transabdominal ultrasonography confirmed the present of thickened loops (0.8 to 1 cm wall) of small intestine in the left lower flank. A complete blood count was normal. The serum chemistry panel was normal with the exceptions that the total serum protein concentration was 3.9 gm/dl with an albumin concentration of 1.9 gm/dl. An abdominocentesis yielded clear yellow fluid with a nucleated cell count of 1,230/ul and a protein concentration of 1.3 gm/dl. Urine was voided. The urine specific gravity was 1.029 and the dipstick test was negative for

protein, blood, glucose, and bilirubin. The owner wants to know what is the diagnosis, how is it treated, and what is the prognosis. The cool dependent pitting edema is consistent with decreased oncotic pressure, which is confirmed by the reduced serum total protein and albumin concentrations. Approximately equal reduction in the globulin and albumin concentrations is most consistent with protein loss. Lack of significant peritoneal fluid protein and lack of urine protein are suggestive that protein loss is through the gastrointestinal tract: i.e. a protein losing enteropathy. The chronic history of low-grade abdominal pain, weight loss, and protein losing enteropathy, in conjunction with the thickened small intestine are consistent with the diagnosis of inflammatory bowel disease. Etiology of Inflammatory Bowel Disease The exact etiology of Inflammatory Bowel Disease (IBD) in horses is not known though the underlying problem is infiltration of the small intestinal wall (and sometimes large colon) with various inflammatory cells, including eosinophils, plasma cells, lymphocytes, basophils, or macrophages. In general, the clinical signs of IBD are similar. The history and signs present in the above case are typical of IBD: weight loss, with or without recurrent low-grade abdominal pain, lethargy, and dependent edema. Occasionally diarrhea is present. Definitive diagnosis and distinction between different forms of IBD are based on histopathology and the predominant cell present in the intestinal lesions. Several types of IBD have been reported in the horse: granulomatous enteritis, lymphoplasmocytic enteritis, multisystemic eosinophilic epitheliotropic disease, and eosinophilic enteritis.8 Granulomatous enteritis (GE) is one of the most commonly reported forms of IBD in horses and is characterized by the histopathologic presence of diffuse aggregates of macrophages and epithelioid cells with villous atrophy. This form of IBD is most similar to Crohns disease in humans, which has a link to persistent infection with Mycobacterium paratuberculosis, the causative agent of Johnes disease in cattle.9 In horses with GE, bacterial pathogens are not consistently isolated, though acid-fast bacteria have been observed intralesionally. In people, M. paratuberculosis was recently identified by PCR in the buffy coat of 50% of individuals diagnosed with Crohns disease.9 Similar testing may be helpful in determining the etiology of GE in horses. Multisystemic eosinophilic epitheliotropic disease (MEED) is also one of the more commonly reported forms of IBD in horses and is characterized by an eosinophilic infiltration of the intestine, as well as other organs, such as the skin, liver, pancreas, oral cavity, esophagus, lung, mesenteric lymph nodes). The etiology is not known, but the presence of eosinophils is suggestive of type I hypersensitivity reaction, perhaps to inhaled, dietary, or parasitic antigens. Idiopathic eosinophilic enterocolitis (IEC) is an uncommon form of IBD in which eosinophilic infiltration is limited to the intestinal wall. Horses with this form of IBD are

most likely to have a history of colic. Another unusual feature of this disease is that some horses have focal circumferential mural bands of fibrous connective tissue in the intestinal wall.10 Lymphocytic plasmocytic enteritis (LPE) is also reported in the horse and as its name implies, it is characterized by the presence of lymphocytes and plasma cells in the lamina propria. There is less information about this form of IBD in the horse, but in other species this type of IBD often represents a nonspecific intestinal immune response. It may also be an early stage of intestinal lymphosarcoma. Proliferative enteropathy (PE) principally affects foals 3 to 7 months old. It is caused by Lawsonia intracellularis, an obligate intracellular bacterium found in the cytoplasm of proliferative crypt epithelial cells.11 Diagnosis of Inflammatory Bowel Disease A history of weight loss despite an appropriate appetite, recurrent colic, lethargy, diarrhea (most common with MEED), dermatitis (most common with MEED and GE), and dependent edema are suggestive of IBD. Anemia is most commonly reported with GE, though may occur with other forms of IBD. Panhypoproteinemia is most commonly reported in horses with GE and MEED. Protein loss occurs in about half of horses with LPE and is least commonly reported with EEC. In many cases, thickened small intestine may be palpable via rectal examination or may be identified on transabdominal or transrectal ultrasonography (Figure 2). Carbohydrate absorption tests with either glucose or D-xylose most reliably detect malabsorption in horses with GE and LPE. For either test, the patient is fasted for 18 hours and a 10% solution of glucose or D-xylose, 0.5 to 1 gm/kg, is given through a nasogastric tube. Blood for glucose or Dxylose is collected into sodium fluoride or heparin tubes, respectively, at 0, 30, 60, 90, 120, 150, 180, 210, and 240 minutes. Peak plasma levels of glucose or D-xylose should occur between 60 to 120 minutes. Delayed peak or flattened peaks are consistent with a diagnosis of malabsorption.

Figure 2. Transabdominal ultrasound image of Inflammatory Bowel Disease

This image was obtained in the lower left flank using a 5-2 MHz curvilinear probe set to a depth of 15 cm. An isolated short axis view of thickened (1.16 cm) small intestine is visible (arrow). Above and to the right of the thickened segment, several loops of moderately distended, but compressed, small intestine with normal wall thickness are present.

A definite diagnosis of IBD requires histopathologic evidence of infiltrative disease of the small intestine. Unfortunately, an exploratory celiotomy or flank laparotomy would be required to secure a small intestinal biopsy. Rectal mucosal biopsy accurately predicted GE and MEED in about 50% of cases later confirmed to be IBD by small intestinal biopsy or necropsy.8 Silver staining or IFA is needed to detect L. intracellularis on histopathology. Serology and a fecal PCR for L. intracellularis are also available and circumvent the need for an intestinal biopsy. Treatment of Inflammatory Bowel Disease Without knowing the definitive etiology of most forms of IBD in the horse, therapy is principally directed against suspected causes and often includes administration of corticosteroids, larvidical anthelmintics (fenbendazole 10 mg/kg PO q 24 hours for 5 days or moxidectin), antimicrobials, and dietary discretion.8 Many different regimens for corticosteroid therapy have been recommended. The practical advice would be to give corticosteroids (usually dexamethasone at 0.1 mg/kg q 24 hours or prednisolone or prednisone at 1 mg/kg q 24 hours) until a positive response is noted, then taper the amount to achieve a minimally effective dose. The response to steroids is highly variable, but can be curative in some patients. In the face of diffuse intestinal thickening, oral bioavailability of drugs is uncertain, so intravenous or intramuscular administration of corticosteroids may be more appropriate routes earlier in the course of treatment. Though there are reports of spontaneous resolution, antimicrobial therapy is most clearly indicated in young horses with PE. L. intracellularis is sensitive to erythromycin estolate (15-25 mg/kg PO q 6 to 8 hours) alone, or in combination with rifampin (5-10 mg/kg PO q 12 to 24 hours). Chloramphenicol (50 mg/kg PO q 8 hours) may also be effective. Metronidazole has been helpful in some human patients with Crohns disease. If small intestine is grossly thickened, intraluminal obstruction with ingesta may be problematic. Grass pasture or feeding mashes of complete feeds may be better tolerated than hay. If food hypersensitivity is suspected, intradermal skin testing may be helpful in directing dietary changes. If IBD is focal, resection or by-pass of affected intestine can be considered. The prognosis for IBD is variable and depends on the severity and extent of small intestinal and/or large intestinal involvement and the underlying type. The prognosis appears to be most promising for PE and EC and least rewarding for GE and MEED. Review of Case Two: Is this IBD? A skin biopsy was obtained and revealed moderately severe eosinophilic dermatitis. With this finding, MEED was suspected. The mare was larvicidally dewormed with fenbendazole, started on omeprazole (4 mg/kg PO q 24 hours) and 0.1 mg/kg dexamethasone IV q 24 hours. She was offered Equine Seniorb mashes. Within the first

week, the mares attitude gradually improved, feces became formed, and she gained approximately 50 pounds. The dexamethasone was tapered (weekly 25% reduction in total dose). The mare continued to gain weight, the skin lesions and dependent edema resolved, she remained colic-free, thickened small intestine was no longer visible on transabdominal ultrasonography, and the total serum protein reached 6.8 gm/dl. One week after discontinuation of steroids (fives weeks from presentation), the mare became mildly colicky and lethargic. Total protein had decreased to 5.0 gm/dl. Dexamethasone therapy was reinstituted at 0.1 mg/kg per day. Within 3 days, the mares attitude improved and colic resolved. Although the mare had a very positive response to higher doses of dexamethasone, when the dose was decreased, clinical signs reappeared. The owners elected for euthanasia. Histopathology at necropsy confirmed MEED.

References and Footnotes 1. White NA, Tyler DE, Blackwell RB, Allen D. Hemorrhagic fibrinonecrotic duodenitis-proximal jejunitis in horses: 20 cases (1977-1984). J Amer Vet Med Assoc. 1987; 190 (3): 311-315 Arroyo LG, Staempfli H, Rousseau JD Weese JS, Culture evaluation of Clostridium spp in the nasogastric reflux of horses with duodenitis. Proceedings from the Eight International Equine Colic Research Symposium. Quebec City, Canada, August 3-5, 2005. Cohen ND, Murphy E, Roussel A, Minor M, Payne M, Payne F. Is duodenitis=proximal jejunitis associated with high carbohydrate diets? Proceedings from the Eight International Equine Colic Research Symposium. Quebec City, Canada, August 3-5, 2005. Johnston JK; Morris DD. Comparison of duodenitis/proximal jejunitis and small intestinal obstruction in horses: 68 cases (1977-1985). J Am Vet Med Assoc. 1987; 191 (7): 849-854. Davis JL; Blikslager AT; Catto K; Jones SL. A retrospective analysis of hepatic injury in horses with proximal enteritis (1984-2002). 2003; 17 (6): 896-901. Cohen ND; Parson EM; Seahorn TL; Carter GK. Prevalence and factors associated with development of laminitis in horses with duodenitis/proximal jejunitis: 33 cases (1985-1991). J Am Vet Med Assoc. 1994; 204 (2): 250-254. Seahorn TL; Cornick JL; Cohen ND. Prognostic indicators for horses with duodenitis-proximal jejunitis. 75 horses (1985-1989). J Vet Intern Med. 1992; 6 (6): 307-311. Schumacher J; Edwards JF; Cohen N. Chronic idiopathic inflammatory bowel diseases of the horse. J Vet Intern Med. 2000; 14 (3): 258-265. Naser SA, Ghorial G, Romero MS. Culture of M. avium subspecies paratuberculosis from the blood of patients with Crohns disease. The Lancet. 2004; 364: 1039-1014. Southwood LL; Kawcak CE; Trotter GW; Stashak TS; Frisbie DD. Idiopathic focal eosinophilic enteritis associated with small intestinal obstruction in 6 horses. Vet Surg. 2000; 29 (5): 415-419.

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Lavoie JP; Drolet R; Parsons D; Leguillette R; Sauvageau R; Shapiro J; Houle L; Hall G; Gebhart CJ. Equine proliferative enteropathy: a cause of weight loss, colic, diarrhoea and hypoproteinaemia in foals on three breeding farms in Canada. Equine Vet J. 2000; 32 (5): 418-425. a. b. Endoserum, Immvac, Inc, Columbus, MO. Equine Senior, Purina Mills Inc., St. Louis, MO.

_________________________________________________________________________________ American Association of Equine Practitioners - AAEP Focus Meeting, 2005 - Qubec, QC, Canada This manuscript is reproduced in the IVIS website with the permission of AAEP www.aaep.org