Clinical Utility of Capsule Endoscopy and Double-Balloon Enteroscopy in the Management of Obscure Gastrointestinal Bleeding

Obscure gastrointestinal bleeding (OGIB) is defined as gastrointestinal (GI) bleeding of unknown origin that persists despite esophagogastroduodenoscopy (EGD) and colonoscopy. OGIB can be categorized into overt OGIB in patients with clinically evident bleeding (hematemesis, melena, or hematochezia) or occult OGIB, which manifests as iron-deficiency anemia or a positive fecal occult blood test. Overt OGIB is sometimes further categorized into ongoing and previous.

OGIB is a common but embarrassing problem for gastroenterologists. Although missed lesions from EGD and colonoscopy may occur, OGIB evaluations usually focus on visualizing the small intestine. Although most OGIB-associated lesions are considered to be present within the small intestine, bleeding lesions cannot be identified for long periods of time because of the clinical difficulty of accessing the small intestine. Due to this urgent need, new small bowel endoscopies including capsule endoscopy (CE) and double-balloon enteroscopy (DBE) were developed and these modalities have enabled diagnosis and have evolved to become approaches to treating OGIB during the past decade.

The development of wireless CE led to the easy viewing of the entire small intestine in a single examination. Two types of CE for the small intestine were released, Pill Cam SB (Given Imaging, Ltd., Yoqneam, Israel) in 2001 and Endo Capsule (Olympus Medical Systems, Tokyo, Japan) in 2005. Because CE is minimally invasive and has a high diagnostic yield in evaluating patients with OGIB, it is currently used as the best initial diagnostic modality for OGIB after negative EGD and colonoscopy. According to a meta-analysis comparing the diagnostic yield of CE to those of push enteroscopy and small bowel barium radiography for OGIB, CE was superior to the other modalities [1].

Although CE is a noninvasive and safe procedure, the chief adverse event is capsule retention, in which a capsule remains in the GI tract for ≥2 weeks. Known risk factors for the retention are previous abdominal surgery, abdominal radiation therapy, and small intestinal type of Crohn’s disease. The pooled retention rate of CE was 1.4% for OGIB in a systematic review on CE [2]. To assess the small intestinal patency and predict the retention, a dissolving Pill Cam patency capsule was released in 2012. Its tolerability in children has not been guaranteed yet though the safety is confirmed in adults [3]. The limitation of CE is its inability to obtain biopsies and provide endoscopic treatments. Thus, CE is preferred in cases in which only a visual diagnosis of the bleeding lesion is required in OGIB.

Bleeding lesions in the small intestine confirmed via CE include erosions/ulcers, vascular lesions, tumors, and others. Erosions/ulcers are most commonly found in the small intestine and sometimes cause severe active bleeding. Typical images of erosion and active bleeding collected on CE are shown in Figure 1a and b. Vascular lesions include angioectasia, Dieulafoy’s lesion (arterial bleeding), and arteriovenous malformation. Acquired von Willebrand syndrome due to aortic valve stenosis causes angioectasia and GI bleeding. In patients with multiple angioectasias in the GI mucosa and skin, the possibility of hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) should be considered. Tumors in the small intestine include leiomyoma, gastrointestinal stromal tumor, neuroendocrine tumor, adenocarcinoma, and lymphoma. The other lesions include Crohn’s disease and Meckel’s diverticulum, and we should understand the possibility of infrequent diseases such as hemosuccus pancreaticus and hemobilia.

There are several risk factors for the presence of bleeding lesions considered to be positive in CE. Age, anticoagulant therapy, and liver cirrhosis are significant predictors of positive CE findings in patients with OGIB [4]. Low hemoglobin levels and severe comorbidities are also associated with the positive findings [5]. The frequency of positive CE findings is reported to be higher in patients with overt OGIB than in those with occult OGIB (59.5 vs. 46.2%, respectively; p = 0.03) [6]. The other related risk factors are the presence of chronic renal failure, a history of non-steroidal anti-inflammatory drug (NSAID) and low-dose aspirin (LDA) use, and proton pump inhibitor use [7]. Angioectasia is associated with the pathogenesis of liver cirrhosis, chronic renal failure treated with hemodialysis, and heart valve syndrome. NSAID and LDA often cause erosions/ulcers, and Watanabe et al. [8] confirmed the utility of CE in the assessment of LDA-induced small intestinal erosions/ulcers. Proton pump inhibitor may induce dysbiosis of intestinal microbiota and exacerbate the small intestinal damage such as erosions/ulcers. We consider that intestinal microbiota plays a crucial role in NSAID-induced small intestinal damage [9]. Novel therapy modulating the composition of the intestinal microbiota could be developed for such small intestinal damages [10].

CE induction in the early stage of OGIB is considered to enhance the diagnostic yield. Bresci et al. [11] reported that the diagnostic yield was increased when CE was performed within a few days after the occurrence of bleeding, possibly within 2 weeks. Pennazio et al. [12] examined the clinical outcomes of patients undergoing CE for ongoing overt OGIB, previous overt OGIB, and occult OGIB with resolved bleeding ratios of 86.9, 41.4, and 69.2% respectively. They insisted that the diagnostic yield of CE was the highest when performed in the early stage of OGIB and that CE should be performed as soon as possible to enable an accurate diagnosis.

Positive CE findings that lead to therapeutic intervention should have beneficial effect on the clinical outcome. It was reported that positive CE findings led to a specific therapy that resolved the underlying disease or improved the clinical condition in 71.4% of OGIB patients after a mean follow-up time of 11.8 months [13]. Lai et al. [14] suggested that the re-bleeding rate in OGIB patients with negative CE findings was significantly lower than that in patients with positive CE findings (5.6 vs. 48.4%, respectively; p = 0.03). Endo et al. [15] reported that the re-bleeding rate of OGIB patients who received therapeutic intervention was significantly lower than that of those who did not receive therapeutic intervention among patients with positive CE findings (9.5 vs. 40.0%, respectively; p = 0.046) [15]. Thus, CE should be performed early in the workup course of OGIB, and positive CE findings that lead to effective therapeutic intervention will have a beneficial impact on the clinical outcomes of OGIB patients.

Previously, push enteroscopy was widely used to manage OGIB because it enabled the biopsy and therapeutic intervention of lesions at the proximal small intestine. Thereafter, several types of device-assisted enteroscope system were released, such as DBE (Fujifilm Corp., Tokyo, Japan) in 2004, single-balloon enteroscopy (SBE; Olympus Medical Systems, Tokyo, Japan) in 2007, and spiral enteroscopy (SE; Spirus Medical, LLC, West Bridgewater, MA) in 2007. These devices enabled the examination of the deeper small intestine through a combination of a 200-cm-long enteroscope and an overtube. SBE has one and DBE has 2 inflatable balloons that enable the insertion of the enteroscope by fixing and shortening the small intestine. SE consists of an overtube with a raised helix at the distal end (Endo-Ease) and a conventional scope, and clockwise rotation of the overtube advances the enteroscope into deeper lesions. Among these modalities, DBE has provided the most clinical evidences to date.

The main advantages of DBE are its ability to be inserted into the deeper intestine, obtain biopsies for pathological diagnosis, and perform therapeutic interventions. Patients with actively bleeding lesions should undergo therapeutic DBE such as hypertonic saline epinephrine injection, argon plasma coagulation, and hemostatic clipping. The marking of a clip for subsequent angiography and the submucosal injection of a tattoo for subsequent surgery are also possible. Typical images of bleeding lesions and therapeutic procedure collected on DBE are shown in Figure 1c–i.

It should be noted that DBE sometimes causes severe adverse events. The prevalence of adverse events associated with DBE is reportedly 3.2%, and the major adverse events are acute pancreatitis (0.9%), intestinal bleeding (1.3%), and intestinal perforation (0.2%) [16]. These rates of adverse events are higher than those associated with conventional EGD and colonoscopy. These adverse events tend to occur after a therapeutic procedure and in patients with ulcers with small bowel disease such as Crohn’s disease [17]. Limitations of DBE are that it sometimes fails to achieve total enteroscopy, even if both oral and anal examinations are performed, and it requires long-term sedation and hospitalization.

Kakiya et al. [18] reported the utility of DBE in patients with previous overt OGIB. If therapeutic DBE is successful, patients in clinically stable condition may be observed depending on the situation. Fujita et al. [19] reported that the re-bleeding rate after DBE varied depending on the source of bleeding and patients with treatable lesions had good clinical outcomes after a follow-up period of 41.4 months. In contrast, further treatments such as angiography with interventional radiology or surgery should be considered in patients with evidence of persistent recurrent OGIB.

CE and DBE currently play a major role in the evaluation of small bowel diseases, and they are considered to have complementary roles in the diagnosis and treatment of OGIB. CE is minimally invasive and can view the entire small intestine in a single examination with a high diagnostic yield. Because DBE requires oral and anal route examination, while CE can evaluate the entire small intestine in a single pass, the diagnostic yield of CE is generally considered to be higher than DBE in a single examination. Its inability to obtain biopsies or administer interventional therapy is made possible with DBE. The American College of Gastroenterology clinical guideline recommended that CE is first considered to determine the source of OGIB [20]. Kameda et al. [21] demonstrated that CE yielded more abnormal findings (erosions/ulcers, angioectasias, tumors, and hemorrhagic polyps) than DBE in patients with OGIB in a prospective study (90.6 vs. 65.6%, respectively; p = 0.03). In addition, Nakamura et al. [22] showed that CE should be selected for the initial diagnosis because it was superior to DBE at detecting small erosions and angioectasias and stated that DBE should be selected to treat or histologically diagnose the condition after the bleeding site is detected on CE [22]. Okamoto et al. [23] reported that initial CE was recommended more than DBE in patients with occult OGIB and overt OGIB who had no strong risk factors related to the presence of bleeding lesions.

Teshima et al. [24] performed a meta-analysis comparing CE and DBE that focused specifically on OGIB and showed that the diagnostic yield of DBE performed after a previously positive CE was higher than that of DBE performed in all patients (75.0 vs. 55.5%; OR 1.79; 95% CI 1.09–2.96; p = 0.02). In contrast, the diagnostic yield for DBE performed after a previously negative CE was only 27.5%. They clarified that the proper sequence for examining patients with OGIB, using CE prior to DBE, significantly enhanced the diagnostic yield of DBE [24]. Similarly, Kaffes et al. [25] showed that the diagnostic yield of DBE after obtaining positive findings on CE was 75.0% with significant reductions in recurrent bleeding and blood transfusion requirements (p < 0.001) in patients with OGIB in a prospective study. These observations indicate that positive CE findings improve the diagnostic yield of subsequent DBE and that CE findings may indicate patients who are likely to benefit from subsequent DBE. Furthermore, CE could serve as a guide for predicting the appropriate insertion route of DBE. In a study using a time index to estimate the approximate location of CE, anal route enteroscopy was indicated if capsule transit time from capsule ingestion to the lesion was ≥75% of the total time from ingestion to cecum [26].

Considering the above evidences, the sequence to perform CE prior to DBE is a rational approach to detect the bleeding lesion in the management of OGIB. In addition to these modalities, dynamic contrast-enhanced CT is useful to detect the bleeding portion, extraluminal lesion, and the small intestinal stricture unless patients have renal failure or a previous allergy to the contrast agent [27]. If dynamic CT can detect the bleeding portion, DBE should be considered subsequently. Otherwise we believe that CE should be performed first prior to DBE whenever possible to visualize the entire small intestine. If CE detects a positive finding that requires biopsy or endoscopic intervention, DBE is indicated subsequently.

There are no clear guidelines for further investigations of patients with negative findings in the first CE, and no strategies have been established to date. Considering the low re-bleeding rate after negative CE [14], some patients in stable general condition could avoid further invasive investigations and may only require follow-up. However, further examinations should be considered in patients with recurrent bleeding and progressing anemia. Repeated CE, DBE, scintigraphy, and angiography should be available to identify the bleeding parts and lesions. Technetium-99 m human serum albumin diethylenetriamine pentaacetic acid (^{99 m}Tc-HSAD) scintigraphy is a noninvasive technique that can detect GI bleeding at a rate of 0.05 mL/min. Although it can scan images chronologically, it sometimes misidentifies pooled blood as bleeding lesion. Angiography can detect bleeding at a rate of 0.5 mL/min, and it has the advantage of administering specific embolization therapy. An appropriate approach that considers each advantage and shortfall should be chosen in cases of OGIB that is difficult to diagnose.

DBE or Meckel’s scintigraphy is recommended if there are no abnormal findings in CE and further workup is necessary in clinical practice guideline for enteroscopy by Japan Gastroenterological Endoscopy Society [28]. On the other hand, there are some reports that repeated CE was beneficial due to its high diagnostic yield. Bar-Meir et al. [29] revealed that 20% of patients with severe iron-deficiency anemia in whom the first CE was negative had positive findings on repeated CE. Viazis et al. [30] suggested that patients with negative CE findings would benefit from repeated CE if the hemoglobin level dropped to ≥4 g/dL. We compared the positive finding rate between repeated CE and DBE for OGIB patients with negative CE findings in a preliminary study, and the rate of positive findings in repeated CE group was significantly higher than that in DBE group (73.2 vs. 39.6%, respectively; p = 0.001). Therefore, we consider that CE should be repeated prior to DBE for patients with OGIB even if the first CE is negative. Randomized controlled trial will be necessary to clarify this point in the future.

From the findings above, we propose a management flow for OGIB in Figure 2.

CE and DBE have complementary roles in the management of OGIB, and the precise timing and proper sequence may be important for the approach to treating OGIB. CE should be performed early in the workup course of OGIB. Positive CE findings lead to effective therapeutic DBE and have a beneficial impact on the clinical outcomes of OGIB patients. On the contrary, the management of negative CE findings is currently undefined. There is a possibility that repeated CE is useful to detect positive findings in patients with evidence of sustained bleeding and progressing anemia. Further studies are needed to establish the best strategy for evaluating OGIB.

The authors declare that there are no conflicts of interest regarding this review article.