Capsule endoscopy for unexplained GI bleeding has shown diagnostic yields of 57–62%,24 with the most common diagnosis being angioectasia (50%), followed by ulcers (26.8%) and tumors (8.8%), as suggested in a recent systematic literature review.14 The present study revealed a detection rate of SB bleeding and lesions using capsule endoscopy of 72.3% (60 of 83 patients), of which NSAID-induced enteropathy accounted for 25 of all 60 SB bleeding cases. The diagnostic yield of small bowel lesions in our study was higher than in a previous nationwide Korean study of capsule endoscopy,25 but the prevalence of ulcerative/erosive lesions was comparable (40/60 vs 106/157). Similar to our results, a Korean study using balloon-assisted enteroscopy found that the most common type of SB lesions associated with obscure GI bleeding were mucosal injury (56%), followed by vascular lesions (18.7%).26 Because of limited availability of data regarding the use of NSAIDs/low-dose aspirin, we could not compare the prevalence of NSAID-induced enteropathy with the results from these studies. However, considering the meaningful association between NSAID use and SB injury presented in previous studies,22, 27 NSAID-induced enteropathy could be the major cause of obscure GI bleeding in Eastern countries. Contrary to previous reports from Western countries, we observed a higher occurrence rate of ulcerative/erosive lesions than angioectasia in patients with obscure GI bleeding, supporting the implication of low-dose aspirin or NSAID medications in the disease etiology. A recent systematic review and meta-analysis suggested that the optical timing of capsule endoscopy would be within 2 days, to improve the diagnostic yield.28 For patients with clear bloody stool in our study, the capsule endoscope was able to start testing within a median of 51 hours (inter-quartile range, 24 to 96 hours). In the case of persistent melena or hematochezia enough to show symptoms, the patients usually visited the emergency room and in these patients, the capsule endoscopy could be performed within at least 48 hours, but if patients showed intermittent blood stool or if symptoms related to bleeding or anemia were not clear, capsule endoscopy would not be conducted within 2 days. In real practice, further improvement is needed in this respect.
NSAIDs are frequently used anti-inflammatory analgesic agents that represent 7.7% of worldwide prescriptions, of which 90% are prescribed to elderly (>65 years) patients.29 The mechanism of NSAID-induced enteropathy is supposed to be mediated through COX inhibition.30 Administration of low-dose aspirin (an irreversible nonselective COX inhibitor) is also associated with SB mucosal injuries; large erosions or ulcers were reported in 60% of healthy volunteers who took 100 mg of low-dose enteric-coated aspirin.31, 32 In the present study, a history of low-dose aspirin or NSAID use was common in patients with obscure GI bleeding (44.6%), showing a higher frequency of SB ulcerative lesions than of other sources of lesions (angioectasia, n=6; upper or lower GI bleeding, n=6).
Prostaglandins (PG) play an important role in regulating GI blood flow and mucus production; therefore, NSAID-induced suppression of PG production has been implicated in SB damage.33, 34 Previously, COX-1 inhibition was regarded to be dominantly related to GI mucosal injuries. However, in a recent animal model study, damage to the SB developed only when both COX-1 and COX-2 were inhibited.35 This result indicates that COX-2-derived PGs also play an important role in the maintenance of tissue integrity and repair of mucosal injury. However, clinical research has shown conflicting results. Several studies have shown an improved GI safety profile with selective COX-2 inhibitors compared to nonselective NSAIDs,36, 37 while others studies indicated no significant differences in SB injuries between these NSAIDs.38, 39 In the current study, among 37 patients with a history of low-dose aspirin or NSAID medications, the 3 treated with selective COX-2 inhibitors had normal stool, suggesting favorable GI outcomes with selective COX-2 inhibitor therapy. Considering that selective COX-2 inhibitors are not completely safe for the SB, further long-term studies with a larger sample size are warranted to establish the safety profile of the drug in the SB.
Furthermore, the impact of capsule endoscopy on clinical outcomes remains controversial despite reports of SB mucosal damage in 70% of patients taking NSAIDs,22, 40 because it remains unclear whether SB mucosal injuries contribute to significant bleeding.41 Although patients with NSAID-induced SB injury show low frequency of severe bleeding in the SB,42 rebleeding rates of 21–35% have been reported in patients with SB ulcerations during a mean follow-up period of 17.1–29.7 months.15, 43 These reports suggest a clinical implication of SB ulcers, which cannot be ignored.
The most effective method of preventing NSAID-induced enteropathy is discontinuation of NSAIDs if possible.12 Previously, there was no strategy to prevent NSAID-induced enteropathy.13, 44 However, a recent study reported the effectiveness of misoprostol in the treatment of SB ulcer bleeding associated with aspirin.45 On the contrary, lesions that induce stenosis, which may not be treated with medication alone, require endoscopic or surgical interventions.46 In the present study, a patient suffering from fibromyalgia developed SB stricture after NSAID medications for >2 years and eventually underwent surgical resection.
This study has several limitations. First, it was a retrospective analysis with a small sample size, with insufficient power to detect a significant effect. Second, because balloon-assisted enteroscopy was not routinely performed, pathological findings could not confirm SB ulcers. Third, the short follow-up period prevented the adequate assessment of risk factors for rebleeding. Finally, the fecal occult blood test could not be performed in 12 of 28 patients who presented with normal stool, thereby limiting the interpretation of the results.