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NSAID Enteropathy
McNally et al. present an exemplary case report of stenosing NSAID-induced damage of the small intestine involving the cooperative use of several diagnostic and therapeutic modalities to obtain a successful long term outcome. In addition, this case queries a number of controversial issues surrounding the approach to the diagnosis and management of this heretofore under-recognized clinical disorder. The noted magnitude of anti-inflammatory use, the high frequency of small bowel pathology in normal volunteers1 and the relative rarity of such severe cases would suggest a spectrum of disease with the majority of patients subclinical and undiagnosed. Some authors have even suggested that NSAID damage of the small intestine may be more clinically relevant than NSAID gastropathy.2
The availability of wireless capsule endoscopy and deep enteroscopy rapidly changed the landscape of our ability to study the entity that we now call “NSAID enteropathy.” Prior to these modalities and actual visualization of the effects from these agents, surrogate information from indirect measurements of small bowel damage, using techniques such as permeability testing of intestinal integrity with Cr-EDTA Indium labeled leukocyte scintigraphy and fecal calprotectin,3 offered some insight into the epidemiology, protein loss and inflammatory component of this entity. Although pathologic features of NSAID damage were long appreciated in rats,4 one of the earliest direct observational studies of small intestinal mucosal damage in humans was performed with a balloon-assisted enteroscope to aid in the diagnosis of chronic blood-loss anemia.5 Subsequent use of intraoperative, push enteroscopy, and double-balloon enteroscopy has added to our knowledge of the pathologic and histologic features of this disorder. Unfortunately, these examinations are cumbersome, time-consuming, invasive and not always readily available.
Therefore, capsule endoscopy has become the mainstay of our diagnostic and research approach to the study of NSAID enteropathy because of its ease of application, patient tolerance and non-invasive nature. The information obtained from a capsule study in this disorder far exceeds that which could be offered by radiologic techniques.6 Unfortunately, the varied findings such as small erosions or minor mucosal breaks to more severe stricturing diaphragms and ulcerations may have unclear clinical implications as the natural history of this entity is still as yet fully understood. The specificity of “pathognomonic” diaphragm disease has proven not as reliable as once thought. A compelling pilot study presented at the 2006 International Conference on Capsule Endoscopy (ICCE) by Bjarnason et al. revealed a 20% incorrect diagnosis rate by four experienced blinded clinicians when reviewing the studies of 18 patients with established Crohn’s disease and 13 patients with NSAID-induced enteropathy.7 (See video quiz below)
Capsule Retention
The risk of capsule retention in diaphragmatic disease, such as in NSAID enteropathy or Crohn’s disease, is fairly high, although complete obstruction is rare.8,9 Capsule retention, as defined arbitrarily as a trapped capsule for at least 2 weeks, has been an area of significant controversy and concern amongst capsule users. Several high risk patients have been defined such as known Crohn’s disease, long term NSAID use, surgical adhesive disease or radiation therapy.10 Unfortunately, radiologic techniques have demonstrated significant inaccuracy at predicting retention after normal exams and even in the setting of tight strictures.11,12 Some investigators have conversely suggested that since retention usually occurs at a site of notable pathology, surgical or endoscopic therapy may be guided by this “complication” to an effective and definitive resolution of the problem.13 Currently, however, most still consider small bowel obstruction or documented stricture a contraindication to capsule endoscopy for the fear of retention and impaction. However, in one series, 19 cases of suspected small bowel obstruction underwent capsule endoscopy with only 4 retentions, none of which caused an acute, high grade small bowel obstruction requiring surgical remediation. These authors concluded that capsule endoscopy can be safely used to identify the etiology and site of a small bowel obstruction.13
Conservative practitioners, who may otherwise avoid the use of a potentially diagnostic capsule endoscopy in high risk patients, may presently use the Agile patency capsule (Given Imaging, Yoqneam, Israel) to assess functional patency of the small bowel (Figure 1). The device is an ingestible and dissolvable capsule made of a lactose/barium body surrounded by dissolvable plugs at each end and containing an internal radiofrequency identification (RFID) tag. The presence in the intestinal tract can be determined by an external scanner or alternatively with standard radiography. Identically sized as the capsule endoscope, the timer plugs at each end are designed to erode after about 30 hours allowing small intestinal fluids into the capsule body resulting in disintegration and passage if retained longer. Initial scanning or radiography is typically performed between 30-36 hours after ingestion. The patient is then followed if patency is unconfirmed by the continued presence of the capsule at first scanning, until it passes for closer examination. Qualitative visual and tactile assessment regarding the condition of the passed capsule body is a critical complimentary assessment of patency which is more important than time of passage. If softening or any deformation of the body is observed, regardless of the travel time through the gastrointestinal tract, patency would be considered highly suspect and capsule endoscopy should probably be avoided (Figure 2).
A recent international, multicenter study by Herrerias et al. investigated the efficacy and safety of the Agile patency system in 106 patients with documented strictures on radiography.14 After ingesting the capsule, patients were scanned or radiographed at 3 intervals: 32-38 hours, 68-72 hours and finally 94-100 hours or until the capsule was excreted and recovered by the patient. The capsule was qualitatively examined for disintegration regardless of time of passage. Patency was established if either the capsule passed “intact” or if the RFID signal was not detected by the 32-38 hour scanning or by radiography. If patency was established, the patient underwent standard capsule endoscopy. If patency could not be established during the first scanning, further determinations were performed at the subsequent intervals or until the capsule was recovered for examination.
Of the 106 patients enrolled, 59 (56%) excreted the capsule intact and underwent a standard capsule study, while 47 (44%) were excreted in a deformed state and were excluded. Interestingly, 73% of the intact capsules were excreted by 60 hours after ingestion and in one patient up to 100 hours. In 26 (44%) of the patients, the capsule was excreted intact prior to the first scheduled scanning. The average passage time was 40 hours. All 59 subjects with intact capsules completed a standard PillCam study with no cases of capsule retention. Significant findings were found in 24 (41%) of the examinations. A total of 17 patients had adverse effects with the Agile capsule with only 3 considered severe consisting of pain and nausea. One of these severe cases was felt unlikely to be related to the Agile capsule.
The authors concluded that the patency system is a safe and useful predictive tool in high risk contraindicated patients, who would otherwise not benefit from the high yield of significant findings obtained on capsule endoscopy, by demonstrating successful passage of a similarly sized capsule.
Several issues are raised by this study in clinical practice. The standard protocol for use of the Agile system dictates scanning close to but not later than 30 hours (Figure 3). If the RFID signal is present at this time, patency is not proven. However, it is clear from this study that passage of intact capsules may take up to 100 hours, most often due to slow transit through the colon. Practitioners using this system should therefore rely more on the qualitative assessment of the passed capsule condition than the time of passage. Otherwise, many patients who would benefit a PillCam study may be excluded. Patients should be strongly encouraged to retrieve the Agile capsule for evaluation despite the potential repulsiveness for some.
In addition, the study didn’t evaluate those with deformed capsules as to the actual incidence of retention or obstruction with subsequent capsule endoscopy. It is possible that many of these patients would pass the PillCam eventually without clinical manifestations or need for invasive intervention. We have all experienced patients with known strictures or high risk manifestations who pass the capsule without any difficulty or may retain for months or longer with the rare need for endoscopic or surgical removal. In fact, as exemplified in the case by McNally et al., retention occurs at a site of significant pathology and can guide an elective approach, whether endoscopic such as balloon-assisted enteroscopy or intraoperative combined procedures for a therapeutic result. My experience has been complete acceptance and consent by patients of the strong potential for retention or even obstruction requiring surgery when fully explained and informed. These patients are desperate to have the exam because of the possibility of a resolution to their often chronic debilitating symptoms. Certainly, a retention requiring invasive intervention for a medically remediable condition would be unfortunate.
Therefore, should we consider capsule retention in a symptomatic patient with stricturing disease a complication or a victory? The consequence of a procedure that can localize pathology where other diagnostics cannot is therapeutically desirable. The case presented by McNally et al. would probably not have had such a successful result if the anticipated and well informed capsule retention had not occurred. Every case should be considered individually, carefully assessing the probability and desirability of capsule retention as a diagnostic tool, possibly using the Agile system, before deciding whether to continue with a high risk exam.
Video Quiz
Two patients are presented here followed by their blinded corresponding capsule images for the reader to match as an exercise in diagnostic acumen. Good luck.
63 year old woman with a long standing history of osteoarthritis involving the cervical spine and hands who has been using Ibuprofen 600mg TID for several years. In the last 2 years, she has developed intermittent melenic stools and postprandial periumbilical cramping. Labs reveal an iron deficiency anemia and hypoalbuminemia with negative endoscopic studies for a bleeding source.
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Figure A1 |
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34 year old man with chronic diarrhea, abdominal bloating and colicky postprandial abdominal pain. During the last several months, he has observed maroon stools, low grade fevers, weakness, nausea and vomiting. An EGD revealed mild gastritis and colonoscopy was significant for mild colitis in the rectosigmoid. An ASCA was positive and the CRP was elevated.
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Figure B1 |
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References:
1. Maiden L, Thjodleifsson B, Theodors A, et al. A quantitative analysis of NSAID-induced small bowel pathology by capsule endoscopy. Gastroenterology 2005;128:1172-1178.
2. Adebayo D, Bjarnason I. Is nonsteroidal anti-inflammatory drug (NSAID) enteropathy clinically more important than NSAID gastropathy? Postgrad Med J. 2006;82:186-191.
3. Davies NM, Saleh JY, Skjodt NM. Detection and prevention of NSAID-induced Enteropathy.
J Pharm Pharmaceut Sci 2000;3(1):137-155.
4. Kent TH, Cardelli RM, Stamler FW. Small intestinal ulcers and intestinal flora in rats given indomethacin. Am J Pathol 1969;54:237-245.
5. Morris AJ, Wasson LA, Mackenzie JF. Small bowel enteroscopy in undiagnosed gastrointestinal blood loss. Gut 1992; 887-889.
6. Costamagna G, Shah SK, Riccioni ME et al. A prospective trial comparing small bowel radiographs and video capsule endoscopy for suspected small bowel disease. Gastroenterology 2002;123:999-1005.
7. Bjarnason I, Voderholzer W, Adler S, Thjodleifsson B, Maiden L. NSAID-induced small bowel damage may be indistinguishable from that of Crohn’s disease by wireless capsule enteroscopy. The 5th International Conference on Capsule Endoscopy, March 6-7, 2006. Boca Raton, Florida.
8. Barkin JS, Friedman S. Wireless capsule endoscopy requiring surgical intervention. The world’s experience [abstract]. Am J Gastroenterol. 2002;97:A-83.
9. Delvaux M, Ben Soussan E, Laurent V et al. Clinical evaluation of the use of the M2A patency capsule system. Endoscopy 2005;37: 801-807.
10. Storch I, Barkin J. Contraindications to capsule endoscopy: do any still exist? Gastrointest Endosc Clin North Am 2006;16: 329-36.
11. Pennazio M, Santussi R, Rondonotti E et al. Outcome of patients with obscure gastrointestinal bleeding after capsule endoscopy: report of 100 consecutive cases. Gastroenterology 2004;126: 643-53.
12. Spada C, Spera G, Riccioni M et al. A novel diagnostic tool for detecting functional patency of the small bowel. Endoscopy 2005;37: 793-800.
13. Cheifetz AS, Lewis BS. Capsule endoscopy retention: is it a complication? J Clin Gastroenterol 2006;40(8):688-91.
14. Herrerias JM, Leighton JA, Costamanga G et al. Agile patency system eliminates risk of capsule retention in patients with known intestinal strictures who undergo capsule endoscopy. Gastroint Endosc 2008;67: 902-909.
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