A Case of Lymphocytic-Plasmacytic Jejunitis Diagnosed by Double-Balloon Enteroscopy in a Dog

Introduction

Advances in endoscopic techniques have made endoscopy an indispensable resource for the diagnosis and treatment of diseases of the esophagus, stomach, duodenum, and colon in human and veterinary medicine. However, the jejunum has been left out of these advances, because it is usually inaccessible by standard endoscopy, despite the fact that this part of the small intestine performs important functions within the gastrointestinal tract.¹ Double-balloon endoscopy (DBE), first described by Yamamoto and colleagues in 2001, is a relatively new endoscopic technique that allows complete visualization of the small intestine, and was recently reported for the first time in dogs. ^2,3 The purpose of this report was to describe the presentation, diagnostic plan, endoscopic findings, and treatment in a dog with lymphocytic-plasmacytic jejunitis diagnosed by DBE.

Case Report

A 17 kg, 3 yr old intact male English setter dog was referred for evaluation of a 6 wk history of intermittent small intestinal diarrhea. The dog passed increased volumes of beige colored semiformed feces, and although mucoid feces were occasionally observed by the owner, there was no tenesmus, vomiting, or blood in the feces. The major clinical signs were poor body condition (body condition score 3/9; ideal weight 5/9) and diarrhea. The dog's diet consisted of standard commercial chow, and he was regularly (every 3 mo; 1 tablet/10 kg body weight) dewormed with a febantel, praziquantel, and pyrantel pamoate combination product^a. Antidiarrheic therapy (metronidazole 20 mg/kg q 12 hr for 2 wk, and loperamide 0.1 mg q 8 hr for 5 days) was previously administered without success. On physical examination, the dog appeared bright and alert, with a moderate level of weight loss (4.5 kg), although no abnormalities were detected on abdominal palpation.

Laboratory data (complete blood count and biochemical profile, and urinalysis) at the time of admission did not reveal significant findings. The serum cobalamine and folate levels were within normal range (385 ng/L, reference range, 249–733 ng/L; 9.5 μg/L, reference range, 6.5–11.5 μg/L, respectively), and no parasites were found on repeated fecal analysis (fresh saline fecal smears and zinc sulfate centrifugal flotation). A Giemsa stained smear of feces was performed, but no white blood cells were observed, and the bacterial populations appeared to be normal. The trypsin-like immunoreactivity (TLI) test showed a normal value (6.2 μg/L, reference range, >5.0 μg/L). Potential dietary sensitivity was analyzed by an 8 wk dietary trial with a commercial novel protein diet,^b but the dog improved only slightly. There was a change in fecal character, and no more mucous feces were found, but fecal production was still above normal, and body condition score remained unchanged. Two weeks after the dietary trial, it was decided to perform both gastroduodenoscopy and colonoscopy to detect possible changes of the intestinal mucosa and obtain biopsy specimens.

Patient preparation for endoscopy included 48 hr fasting (solid food), administration of a senna glycosides oral laxative solution^c the previous day (1 mL/kg), and two enemas 12 and 4 hr before exploration (sodium phosphate solutions)^d. The animal was administered continuous lactated Ringer intravenous blood pressure support infusion, and it was examined under general anesthesia, induced and maintained with isoflurane in oxygen. During the gastroduodenoscopy and colonoscopy, blood pressure and oxygen saturation were monitored. Routine endoscopic examination was performed with a flexible video endoscope^e.

The mucosa was observed to be normal in the whole intestine (duodenum, colon, ileum), and no significant changes were found in the biopsy specimens. Thus, we decided to carry out DBE via both oral and anal approaches, to obtain a more complete intestinal examination. The main advantage of the DBE technique is that it allows examination of portions of the small intestine, which are unreachable with standard endoscopic techniques (gastroduodenoscopy and colonoscopy). DBE has recently been described in the dog, and previously in humans, demonstrating its safety, feasibility, and efficacy.^2–4

The authors used a double-balloon endoscope^f. It mounts a balloon at its distal end, has a working length of 200 cm, an external diameter of 8.5 mm, and the working channel diameter is 2.2 mm. It is equipped with a 145 cm long flexible overtube with an external diameter of 12.2 mm and an internal diameter of 10 mm that also has a balloon at the tip. The two balloons attached at the tip of the enteroscope and the overtube are made of 0.1 mm thick latex, and are very soft (Figure 1). Both are inflated and deflated with air from a one-touch pressure-controlled pump system. The lowest pressure to inflate the balloons sufficiently to grip the intestinal wall is 45 mm Hg.³ This pressure is designed to avoid pain or lesions during balloon dilation.

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DBE is based on an insertion technique in which two balloons, one at the distal end of the endoscope and the other at the distal end of the overtube, are operated in combination, thereby inserting the endoscope while simultaneously shortening the intestine. The double-balloon endoscope advances through the intestine being held alternatively by the balloon on the endoscope and the balloon on the overtube.^3,4 The endoscope and overtube are inserted through the mouth and passed conventionally into the small bowel. Following this, the endoscope is then advanced a short distance in front of the overtube, and the balloon at the end is inflated. The overtube is then advanced along the endoscope and its balloon is inflated. Using the assistance of friction at the interface of the enteroscope and intestinal wall, the small bowel is pleated back to the overtube by slowly pulling together the endoscope and the overtube. The enteroscope balloon is then deflated. The endoscope is advanced while the system is fixed by the overtube balloon (i.e., the bowel is held from the inside), which prevents the distal end of the overtube from pulling out of the intestine. The process is then continued until the entire small bowel has been visualized.² During the insertion process, after the distal end of the overtube has been advanced to the distal end of the endoscope while the intestinal wall is held by the balloon on the scope, both balloons are dilated to hold the intestine, and then both the overtube and endoscope are pulled back slowly to gather and shorten the intestine on the overtube and to simplify the shape of the intestine ahead. The balloons can grip sections of the small intestine and “shorten” the small intestine by pleating it over the endoscope. Sequential shortening of the small intestine over the endoscope and advancement of the endoscope enables a comprehensive examination of the entire small intestine. By this process, the working length of the endoscope can be used effectively, and the endoscope can be inserted once the intestine shape has been simplified for insertion.⁵ It can be inserted through either the mouth or the anus, allowing the observation of the entire gastrointestinal tract.⁵

Fluoroscopy was used on several occasions to control the advancement of the overtube along the endoscope and the pullback of both the endoscope and the overtube during the straightening maneuver, and a plain abdominal radiograph was taken with the animal in supine position (Figure 2). At several depths during oral DBE, the small bowel mucosa was marked with a tattoo by submucosal injection of sterilized ink through an injection catheter (Figures 3A, B). The authors had no difficulties making these submucosal marks. After exploration and while the endoscope and overtube were being pulled back to exit, these submucosal landmarks were found again. Afterward, enteroscopy with the double-balloon technique was carried out using the anal approach. It was possible to examine the entire small intestine because the ink marks were again observed via anal DBE. Biopsy specimens were obtained with biopsy forceps^g at different sites. The biopsies were fixed in formalin, embedded in paraffin, cut in 4 μm thick sections, and stained with hematoxylin and eosin.

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The jejunal mucosa exhibited mild edema and increased granularity in several zones, and appeared friable upon biopsy. Ulcer formation was not noted in any part of the mucosa, and a histopathologic review of biopsy specimens confirmed normal gastric, duodenal, and ileal mucosa. However, after microscopic analysis, a substantial inflammatory reaction was observed in some samples of the jejunal mucosa. Following the classification of Day and colleagues, it was possible to find a moderate increase in the lamina propria lymphocytes and plasma cells. ⁶ The enteric crypts were separated by a diffuse lymphoplasmocitary infiltration that occupied more than 50% of the villous lamina propria. Other histopathologic changes observed in the sections were a mild increase in intraepithelial lymphocytes, and mild to moderate fibrosis with stromal bands of 5–7 fibroblasts in width. Presence of some dilated crypts containing luminal eosinophilic material was also detected (Figure 4).

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A diagnosis of lymphocytic-plasmacytic jejunitis was made at this point. Treatment with prednisone (1 mg/kg per os q 12 hr), metronidazole (12.5 mg/kg per os q 12 hr) and a novel protein diet^b (dividing feedings into two meals) was initiated. After 3 wk, prednisone dosing was gradually decreased (50% reductions at 2 wk intervals and alternate-day treatment), and clinical remission (absence of clinical signs, weight gain) was obtained after 3 mo of therapy. The animal was then kept on the novel protein diet.

Discussion

It is difficult for an endoscope to access the small intestine beyond the duodenum, despite the fact that the duodenum performs some of the most important functions of the gastrointestinal tract.¹ Small intestinal disorders in dogs were investigated by endoscopic biopsy with conventional endoscopes, but they were limited to the descending duodenum and terminal ileum. However, a portion of the jejunum is accessible in small size dogs with a standard endoscope (105 cm) or medium size dogs with longer endoscopes (140 cm). The length of the small bowel, its intraperitoneal location with multiple overlying loops, and its active contractile pattern often make conventional endoscopic and radiographic examinations unsuitable for diagnosis and therapeutic intervention.³ DBE, however, allows complete visualization of the small intestine and is an examination method that takes advantage of the free mobility of the small intestine.¹ The authors agree with others that it offers excellent maneuverability even in the distal small intestine and enables back-and-forth observation and biopsy at any given site.⁵ In dogs, neither endoscopic examination of the entire small intestine with inflammatory bowel disease (IBD), nor diagnosis of plasmacytic-lymphocytic jejunitis by DBE have been reported. The described cases of intestinal inflammatory disease diagnosed by standard endoscopy were related to pathologic changes in the duodenum, ileum, or colon, but not the jejunum. The authors therefore reported the first pathologic finding by DBE diagnosis in this species. In the present case, the use of DBE was justified because the jejunum was inaccessible by standard endoscopy.

The endoscope was advanced under occasional use of fluoroscopy to control loop reduction better. Fluoroscopy is used with DBE in human medicine to control loop reduction and to help ileal intubation during the retrograde approach.⁷ However, in dogs, fluoroscopy has been considered unnecessary for ileal intubation, because the relatively short colon makes the procedure easy.³ In human medicine, at the beginning of the DBE learning curve, examiners need fluoroscopic visualization of the enteroscopic push-and-pull maneuvers in every patient because fluoroscopic control enables inexperienced examiners to understand and learn the mechanical principles of the procedure. As they gain experience, the need for fluoroscopy decreases. By not using fluoroscopy, the depth of insertion into the small bowel is not impaired nor is the examination time extended; therefore, the performance of DBE does not depend on availability of fluoroscopy if the examiner has achieved sufficient procedural competence.⁸ The authors would also recommend the use of fluoroscopy with DBE at the beginning of the learning curve in the dog.

Advantages of this technique are examination and treatment (polypectomy, dilation, removal of foreign bodies, etc.) of the entire area of the small intestine; visualization of high-quality images, and the same maneuverability as that of conventional video endoscopes.⁵ These are reflected by the fact that DBE has enhanced the management of small-intestinal diseases in human medicine.⁹ There are, however, certain limitations to this technique, and in particular, the long time required to visualize the small intestine (a mean of 130 min, in the authors' experience), the use of expensive equipment, the need for additional staffing, and the specific learning of the technique.⁴ In humans, total enteroscopy is possible in 45–86% of cases; however, it is probably indicated in less than 50% of human patients.⁷ Major complications associated with DBE have been described in human medicine, including perforation, pancreatitis, and bleeding.¹⁰ DBE has been associated with a higher complication rate compared with standard endoscopic procedures.¹⁰ Nevertheless, at present, DBE can be described in the vast majority of cases as a safe endoscopic procedure with an overall complication rate of ∼1%.¹¹ Pancreatitis is the most frequent complication for diagnostic DBE and should be taken in consideration in written informed consent.¹¹

Before enteroscopy was available with a high-resolution video endoscope, there were not many references to diseases found in the small intestine in humans as there are currently.¹ However, now that video endoscopy with high image quality can be readily introduced into the organ for examination in humans, various kinds of lesions that were previously undetectable have been found in the small intestine, just as in the stomach and the colon.¹ For example, gastrointestinal hemorrhage is a common and clinically significant health care problem in human medicine; in patients with obscure gastrointestinal bleeding, the diagnostic yield from double-balloon enteroscopy appears to have surpassed other imaging modalities.⁷ Conventional endoscopy and radiographic examinations are often inadequate in identifying the source of bleeding.⁷ DBE is very useful not only for diagnosis (hemorrhage, IBD, polyps, neoplasms, strictures, lymphangiectasia, etc.), but also for endoscopic therapy, such as hemostatic procedure, polypectomy, dilation therapy, or removal of foreign bodies.¹²

The DBE technique has been previously described in the dog, suggesting that it may be an effective tool for the diagnosis and therapeutic intervention of small intestine disorders in dogs, such as tumors, bleeding polyps, inflammatory fibroid polyps, ulcerations and erosions, lymphoma, strictures from tumor or from extrinsic causes, and arteriovenous malformations.³

A retrospective study of the diagnostic value of full-thickness biopsies from the stomach and intestines of dogs with chronic gastrointestinal disease symptoms showed that the jejunum was significantly affected in a number of diseases, including plasmacytic-lymphocytic enteritis, lymphangiectasia, and lymphoma, among others.¹³ The jejunum is the longest region in the canine gastrointestinal tract, as the duodenum, jejunum, ileum, and colon are around 0.4, 4.5, 0.2, and 0.6 m long, respectively.³ Bearing this in mind, and given the patchy distribution of several diseases throughout the gastrointestinal tract, it seems more probable to detect pathologic findings in the jejunum than in other gastrointestinal regions. ¹⁴ Thus, idiopathic IBD confined to the jejunum might occur more often than reported.

IBD localized to the jejunum was diagnosed in this case given the chronic clinical signs, histopathologic findings, and by ruling out other known causes of gastrointestinal inflammation. This was done following the Guidelines of the American College of Veterinary Internal Medicine Consensus Statement, using multiple fecal examinations, biochemical profile, dietary and therapeutic trials, and TLI before enteroscopy. ¹⁵ Immunosuppressive therapy probably played a key role in the dog's responsiveness to a combination therapy, because previous treatment with metronidazole or posterior dietary trial alone obtained no result or only a partial improvement. Corticorteroids are the initial treatment of choice for lymphocytic-plasmacytic enteritis.¹⁴

The intestinal tract was affected by chronic lymphocytic-plasmacytic inflammation at several sites in the jejunum. In the majority of patients with IBD, intestinal involvement is diffuse; duodenal and jejunal changes are often similar in type and degree to those in the ileum. Occasionally, however, there are significant changes in the ileum when duodenal samples from the same patient are either normal or only mildly abnormal.¹⁴ In the authors' case, a normal mucosa was observed in the duodenum and the ileum by standard endoscopy, but abnormal findings were present in several sites of the jejunum, which were detected by DBE. It was also possible to find several degrees of inflammatory infiltrates in different intestinal segments.¹⁴

The jejunal biopsy was collected by DBE, but it could have been collected by other means (i.e., laparotomy or laparoscopy). However, most owners prefer noninvasive diagnostic techniques, like DBE, to surgical procedures. If DBE endoscopes become universally used, a decrease in the price of the DBE endoscopes could be expected in the future. Thus, the price of DBE could be similar to (or lower than) that of obtaining biopsies surgically, with the added advantage of endoscopy being minimally invasive. The cost of DBE is certainly lower than that of capsule endoscopy (the high cost of the capsule itself, equipment, and time-consuming image analysis). As for the learning curve, a significant decrease in overall procedural time and fluoroscopy time after the initial 10 DBE cases was found in human medicine.¹⁶ However, other authors showed that the odds of successful DBE doubled after an endoscopist performed more than 50 examinations.¹⁷

These facts highlight the need to consider performing DBE in animals with gastrointestinal disorders, whose symptoms are not readily explained by routine tests (including conventional endoscopy) and dietary or therapeutic trials.

To the authors' knowledge, this is the first description of a pathologic finding using this technique in the dog. DBE provides a means of thoroughly examining the entire intestine in the dog and allows minimally invasive collection of biopsy samples, without surgical laparotomy or laparoscopy. Increased use of DBE to more accurately investigate diseased animals may improve understanding of the different small bowel disorders of dogs.