Diagnostic yield of magnetically assisted capsule endoscopy versus gastroscopy in recurrent and refractory iron deficiency anemia

• Abstract
• Introduction
• Methods
• Patients
• Magnetically assisted capsule endoscopy
• EGD
• Ethics
• Statistics
• Results
• Patients
• Diagnostic yield of MACE and EGD
• Magnetically assisted capsule endoscopy
• Upper GI pathology detection
• Small-bowel pathology
• Patient tolerance
• Discussion
• References

Abstract

Background Small-bowel capsule endoscopy is advocated and repeat upper gastrointestinal (GI) endoscopy should be considered for evaluation of recurrent or refractory iron deficiency anemia (IDA). A new device that allows magnetic steering of the capsule around the stomach (magnetically assisted capsule endoscopy [MACE]), followed by passive small-bowel examination might satisfy both requirements in a single procedure.

Methods In this prospective cohort study, MACE and esophagogastroduodenoscopy (EGD) were performed in patients with recurrent or refractory IDA. Comparisons of total (upper GI and small bowel) and upper GI diagnostic yields, gastric mucosal visibility, and patient comfort scores were the primary end points.

Results 49 patients were recruited (median age 64 years; 39 % male). Combined upper and small-bowel examination using the new capsule yielded more pathology than EGD alone (113 vs. 52; P < 0.001). In upper GI examination (proximal to the second part of the duodenum, D2), MACE identified more total lesions than EGD (88 vs. 52; P < 0.001). There was also a difference if only IDA-associated lesions (esophagitis, altered/fresh blood, angioectasia, ulcers, and villous atrophy) were included (20 vs. 10; P = 0.04). Pathology distal to D2 was identified in 17 patients (34.7 %). Median scores (0 – 10 for none – extreme) for pain (0 vs. 2), discomfort (0 vs. 3), and distress (0 vs. 4) were lower for MACE than for EGD (P < 0.001).

Conclusion Combined examination of the upper GI tract and small bowel using the MACE capsule detected more pathology than EGD alone in patients with recurrent or refractory IDA. MACE also had a higher diagnostic yield than EGD in the upper GI tract and was better tolerated by patients.

Introduction

Iron deficiency anemia (IDA) is commonly caused by gastrointestinal (GI) blood loss. [1] [2]. However, first-line endoscopic investigations – esophagogastroduodenoscopy (EGD, gastroscopy) and colonoscopy – fail to identify a cause in approximately 30 % of cases [3]. Small-bowel capsule endoscopy is used for those with recurrent or refractory IDA [4] [5], where diagnostic yield ranges between 44 % and 66 % [6] [7]. Of note, up to 25 % of pathologies detected on capsule endoscopy are benign lesions within reach of EGD [8] [9] [10] [11] [12]. Repeat EGD should therefore also be considered in the investigation of recurrent and refractory IDA [13]. However, EGD is invasive, not without risk, [14] [15], and may not be well tolerated [16] [17]; in addition, pathology detected at EGD is almost always benign [9] [10] [11] [12].

The MiroCam Navi capsule endoscope (Intromedic Ltd., Seoul, Korea) is a modified device that is responsive to magnetic manipulation by an external handheld magnet ([Fig. 1]), permitting a degree of steerability [18]. Live image transmission permits real-time esophagogastric examination on a monitor. An 11-hour battery life also allows follow-on small-bowel examination using the same capsule. Previous studies have demonstrated the feasibility of examining the upper GI tract with the MiroCam Navi [19] [20]. The device might therefore allow the examination of both upper GI tract and the small bowel, as required for full assessment of recurrent and refractory IDA.

The primary aims of the current study were to compare the diagnostic yields and patient comfort of the MiroCam Navi and EGD in patients with recurrent or refractory IDA and to assess gastric mucosal visibility achieved using MACE. Secondary outcomes included a comparison of the Mirocam Navi and EGD in assessment of the esophagus, stomach, and proximal duodenum. The study was executed as an exploratory trial in order to generate a hypothesis for further confirmatory trials.

Methods

Patients

A prospective, single-blinded, cohort study was conducted at Sheffield Teaching Hospitals NHS Trust, UK. All patients aged 18 years or over with recurrent or refractory IDA who were referred for both upper GI tract and small-bowel investigations by EGD and small-bowel capsule endoscopy, respectively, as part of routine clinical investigations were eligible for the study. Capsule endoscopy was performed using the MiroCam Navi, which, prior to entering the small bowel, was used to examine the upper GI tract using the handheld magnet. Patients with pacemakers, intracardiac devices, magnetically or electrically controlled devices or those who were pregnant, had Crohn’s disease or long-term use (> 6 months) of nonsteroidal anti-inflammatory drugs were excluded.

Magnetically assisted capsule endoscopy

Magnetically assisted capsule endoscopy (MACE) was performed using the MiroCam Navi by one of two investigators (H.L.C. or M.F.H.). Patients drank 2 L of Klean Prep (Norgine, Uxbridge, UK) the evening before the procedure, as per standard protocol. Immediately prior to capsule endoscopy, 1 L of water (containing 40 mg of simethicone) was given orally to distend the stomach and optimize gastric views, as previously described [19].

Patients swallowed the capsule in the right lateral position, allowing the esophagus to be viewed, according to the simplified ingestion protocol described by Gralnek et al. [21]. The handheld magnet was placed over the lower sternum to capture, if possible, the capsule before it reached the gastroesophageal junction (GEJ). This was followed by a series of patient positional changes to help carry the capsule to a new location in the flow of swallowed water. The patient was asked to lie supine and the magnet moved through a sequence of positions to view the proximal stomach. Once in position, subtle changes in rotation (altering the polarity) and distance (altering the strength of attraction) of the magnet from the capsule were used to swivel the capsule around its vertical axis to obtain a near 180º view [20]. Similar sequences (described in detail in [Table 1]) were followed with the patient in the left lateral, supine, and right lateral positions in order to examine the proximal stomach, gastric body, and distal stomach, respectively. If necessary, the patient was also examined in the upright seated position.

Visibility at major anatomical landmarks was graded on a 1 – 5 scale (poor to excellent; [Table 2]). A single reporter (M.E.M.) reviewed all capsule videos, reported upper GI pathology, and graded mucosal visibility while blinded to the live MACE findings to avoid interobserver bias. To minimize variation in pathology reporting between MACE and EGD, endoscopists were required to describe pathology using terms selected from a predefined diagnostic list. Once gastric MACE was complete, the capsule was allowed to pass into the small bowel under the action of peristalsis in order to complete small-bowel examination passively.

Standard practice in the unit was followed, such that intramuscular metoclopramide (10 mg; Hameln Ltd., Gloucester, UK) was administered if the capsule endoscope had not traversed the pylorus within 45 minutes of ingestion. The effect of small-bowel preparation was rated overall as good, fair, or poor.

EGD

A member of the study team (accredited by the UK Joint Advisory Group on GI Endoscopy for independent EGD practice) [22], who was blinded to the MACE findings, performed the EGD using Olympus GF-260 gastroscopes (Olympus, Tokyo, Japan). Sedation for EGD was administered according to patient choice. Pathology detected at EGD was documented in a similar fashion to MACE using terms selected from the same predefined diagnostic list.

Patient tolerance of the two modalities was compared using a visual analog scale (VAS) (score 0 – 10, none – extreme) [17] [23].

Ethics

The study was approved and conducted in accordance with the ethical standards of the Yorkshire and The Humber – South Yorkshire NHS Research Ethics Committee (14/YH/1010. ClinicalTrials.gov NCT02282553), and the 1964 declaration of Helsinki and its later amendments.

Statistics

Advice was sought from the University of Sheffield Mathematics and Statistics Resource Centre. Upper GI pathology within reach of EGD is detected in up to 25 % of patients with recurrent or refractory IDA [8] [9] [10] [11] [12]. The diagnostic yield of capsule endoscopy in this cohort is between 44 % and 66 %: a 55 % yield was therefore assumed for the purpose of this study [6] [7]. In order to achieve 80 % power and 5 % two-sided significance, it was estimated that a sample size of 41 patients would be needed to show a difference in diagnostic yield between the two modalities. The study aimed to recruit 50 patients to allow for patient withdrawal from the study between the two examinations.

Statistical analysis was performed using IBM SPSS Statistics for Macintosh, Version 24.0 (IBM Corp., Armonk, New York, USA). Continuous data are presented as a mean (SD) or median with interquartile range (IQR). Categorical variables are expressed as absolute numbers and percentages. Total study population and subgroup analysis was performed with similar statistical methods. Binomial regression was used to compare one or more independent variables with a dichotomous dependent variable. The McNemar’s test was used to compare paired proportions. The Kruskal-Wallis H test was used for rank-based nonparametric comparison. Statistical significance was defined as P < 0.05. All co-authors had access to the data, and reviewed and approved the final manuscript.

Results

Patients

A total of 50 patients (median age 66 years [IQR 15 years]; 39 % male) were consecutively enrolled in the study between December 2014 and August 2017. All patients had previously undergone bidirectional endoscopy after their initial presentation with IDA. Patients had recurrent (n = 40) or refractory (n = 9) IDA. One patient completed MACE but subsequently declined EGD and was excluded from the analysis.

The majority of patients (n = 39, 79.6 %) underwent MACE prior to EGD and 10 (20.4 %) underwent MACE after EGD. The median interval between EGD and MACE was 2 days (IQR 13 days). Mean hemoglobin was 101.1 g/dL (SD 20), mean ferritin was 15.8 μg (SD 15), and mean cell volume was 79.6 fL (SD 7.9). Sedation was given to 38.8 % of EGD patients; mean midazolam and fentanyl doses in these patients were 2.5 mg (SD 0.8) and 50 μg (SD 11.8), respectively.

Diagnostic yield of MACE and EGD

Capsule endoscopy of the upper GI tract using MACE combined with conventional (passive) examination of the small bowel identified more lesions than EGD (113 vs. 52, 95 % confidence interval [CI] 0.41 – 0.53; P < 0.001).

Magnetically assisted capsule endoscopy

Mean examination time for upper GI MACE was 23 minutes (SD 10). The median time for the capsule to traverse the pylorus (gastric transit time) was 62 minutes (IQR 50 minutes). Visualization of upper GI major landmarks was achieved in most cases: esophagus 89.8 %; GEJ 53.1 %; gastric cardia 95.9 %; fundus 98.0 %; greater and lesser curvatures 98.0 % each; anterior and posterior gastric body 98.0 % each; antrum, pylorus, first and second part of the duodenum (D1 and D2), 100 % each ([Fig. 2]). A statistically significant difference was detected, with less visualization of the GEJ by MACE than all other areas (P < 0.001). The MiroCam Navi was magnetically steered into the duodenum in 11 patients (22.4 %). In the remaining patients, passive entry into the duodenum occurred (with or without metoclopramide).

The median visibility scores were: esophagus 4 (IQR 4); GEJ 1 (IQR 3); gastric cardia 5 (IQR 3); fundus 3 (IQR 2); greater curvature 5 (IQR 1); lesser curvature 5 (IQR 0); anterior body 5 (IQR 0.5); posterior body 5 (IQR 0.5); antrum 5 (IQR 0); pylorus 5 (IQR 0); D1 3 (IQR 1); D2 5 (IQR 0). The frequencies of visibility grades for each anatomical landmark are shown in [Table 3]. There was a statistically significant difference between visualization scores of different areas (chi-squared test 209.5, P < 0.05, Kruskal-Wallis H test). Better visualization scores were seen in the greater and lesser curvatures, anterior and posterior body, antrum, pylorus, and D2. Compared with these areas, lower visualization scores were seen in the esophagus, GEJ, cardia, fundus, and D1: apart from the cardia, this difference reached statistical significance with post hoc analysis (P < 0.05, with Bonferroni correction).

Upper GI pathology detection

Both MACE and EGD examinations revealed normal findings in two patients. In the remaining 47 patients, MACE and/or EGD identified a total of 102 lesions that were proximal to the second part of the duodenum ([Table 4]); 38 of these lesions (37.3 %) were identified concomitantly by both modalities. A statistically significant difference was detected, with more overall lesions identified in the upper GI tract (esophagus, stomach, and duodenum up to and including D2) by MACE alone (50 lesions, 49.0 %) ([Fig. 3]) compared with EGD alone (14 lesions [13.7 %]; 95 %CI 0.21 – 0.48; P < 0.001). This difference remained during subgroup analysis, with MACE detecting more total upper GI lesions than EGD, with or without sedation (P = 0.003 and P = 0.003 respectively). More gastric lesions were detected by MACE alone compared with EGD alone (36 vs. 5; P < 0.001) ([Table 5]). No statistically significant difference was seen in lesion detection by MACE alone vs. EGD alone in the esophagus (7 vs. 6; P > 0.99) or duodenum (7 vs. 3; P = 0.18). Subgroup analysis demonstrated similar results: more gastric lesions were detected by MACE than EGD alone, whether EGD was performed with (16 vs. 1 respectively; P < 0.001) or without (19 vs. 4 respectively; P = 0.004) sedation. No statistically significant difference was seen in esophageal or duodenal lesion detection irrespective of whether sedation was given for EGD (P > 0.05 for all).

If only those upper GI lesions that were recognized as possible sources of IDA are included in subgroup analysis ([Table 5]), then 22 pathologies were identified concomitantly by both modalities. MACE alone identified more source lesions than EGD alone (33 vs. 8 respectively; P < 0.001). If only major lesions recognized as likely causes of IDA are included during analysis (esophagitis, altered/fresh blood, angioectasia, ulcers, and villous atrophy), a statistically significant difference persists, with MACE detecting more lesions than EGD (15 vs. 5 respectively (5 detected by both modalities); P = 0.04). No pathologies identified when MACE was performed after EGD were likely to be caused by biopsy trauma. The patient with villous atrophy identified by MACE had this diagnosis subsequently confirmed histologically.

Small-bowel pathology

A total of 41 patients (83.7 %) underwent complete small-bowel examination. There was no statistically significant association between gastric transit time and completion of small-bowel examination (P  = 0.10). The mean small-bowel transit time was 5 hours (SD 2). The bowel preparation was rated good, fair, and poor in 89.8 %, 6.1 %, and 4.1 %, respectively.

In 25 patients, findings on capsule endoscopy beyond the second part of the duodenum were normal. In the remaining 24 patients, pathologies included angioectasia (n = 15), erosions (n = 6), polyps (n = 1), active bleeding (n = 1), small-bowel varices (n = 1), and diverticulum (n = 1). Logistic regression did not detect a statistically significant difference in small-bowel pathology detection by capsule endoscopy with increasing age (P  = 0.55). A total of 17 patients were deemed to have a small-bowel cause (beyond D2) for recurrent or refractory IDA; 15 of these patients also had a concomitant upper GI cause (proximal to D2) identified by MACE, EGD or both. Cases with IDA-associated small-bowel lesions included: 14 patients with angioectasia, one patient with both small-bowel angioectasia and small-bowel varices, one patient with active bleeding but without a visualized focal lesion, and one patient with a bleeding diverticulum.

Patient tolerance

VAS scores for pain (0 [IQR 0] vs. 2 [IQR 3]), discomfort (0 [IQR 0] vs. 3 [IQR 5.5]), and distress (0 [IQR 0] vs. 4 [IQR 5]) were all lower for MACE than EGD (P < 0.001 for all three parameters). A statistically significant difference remained after subgroup analysis irrespective of whether sedation was given (Kruskal-Wallis H test: chi-squared 33.5, 35.9, and 48, respectively; P < 0.05 for all parameters). No complications were seen with MACE or with EGD.

Discussion

Capsule endoscopy using magnetic control (MACE) to examine the upper GI tract followed by passive examination of the small bowel improved the diagnostic yield compared with EGD alone in patients with recurrent or refractory IDA and was better tolerated by patients. This is partly explained by the ability of capsule endoscopy to image the small bowel. But, whereas both modalities missed lesions and overall pathology detection concordance was disappointing, MACE was more sensitive than EGD in the detection of upper GI lesions.

The findings suggest that examination of the upper GI tract and the small bowel might be performed safely and comfortably using a single MACE procedure rather than separate EGD and small-bowel capsule endoscopy in patients with recurrent or refractory anemia. Such an approach would avoid the need for EGD (a test that is not always well tolerated), reduce hospital visits, and may allow cost savings by reducing the number of tests being performed.

The poor diagnostic concordance between the two modalities and the pathology miss rate by EGD – the accepted gold standard – are surprising. The diagnostic yield of EGD for major lesions associated with recurrent and refractory IDA was 20 %, suggesting that no more pathology was being missed by EGD than in other studies of similar patient cohorts [8] [9] [10] [11] [12] [13]. To our knowledge, there are no “back-to-back” or “tandem” studies in which EGD is compared with itself in patients undergoing a second procedure by an endoscopist blinded to the results of the first examination. However, several such studies of colonoscopy performed in expert centers consistently show a miss rate for significant polyps of between 10 % and 20 % [24]. The fact that 11.3 % of patients with upper GI cancers have undergone an EGD within the previous 3 years suggests that important focal lesions are being missed [25]. Spencer et al. showed that there was a significant difference between endoscopists in the rate of reporting for all upper GI pathologies, with the exception of cancer [26]. This might be explained in part by a difference in the terminology used [27], but may also be explained by some endoscopists missing pathology.

The recently published statement on quality standards for upper GI endoscopy acknowledges that endoscopist experience, case volume, and duration of endoscopic examination (with a recommended minimum of 7 minutes) may affect diagnostic yield [22]. The quality of examination may also be affected by patient tolerance, may be incomplete, and may require a repeat examination. It is possible that the better endoscopic control offered by EGD is offset by the better tolerance for capsule endoscopy and a much longer examination time (a mean of 23 minutes).

Other studies also suggest that capsule endoscopy may compare favorably to EGD in terms of upper GI diagnostic yield. Using the MiroCam Navi, our preliminary studies demonstrated that MACE and conventional flexible endoscopy had similar sensitivity in detecting beads sewn inside a porcine stomach model [18]. Olympus and Siemens developed a system akin to magnetic resonance imaging equipment for the purpose of MACE, allowing magnetic steering of the capsule within the stomach. A trial of 189 patients demonstrated 62 % and 89 % sensitivity for major and minor lesions, respectively, compared with EGD [28]. Liao et al. reported a 90.4 % sensitivity in the detection of focal lesions in a multicenter study of 350 patients in China; capsule movement was controlled using a novel system comprising a joystick-controlled large robotic-arm magnet suspended above the patients’ examination couch [29].

The handheld magnet affords a relatively crude level of control of capsule movement. In our experience, despite a magnetic flux density of up to 0.38 T, the handheld magnet was insufficiently powerful to hold the position of the capsule in the presence of strong peristaltic contractions. Movement of the capsule from one region to another is usually achieved within the flow of gastric water that is induced by changing the patient’s position. Relatively small approximations of the magnet toward the abdomen can result in the capsule jumping from posterior to anterior gastric wall. Slow subtle movements of a handheld device weighing 1005 g become more difficult during a prolonged examination as operator fatigue develops. However, once the capsule is in position, magnet rotation alters the polarity resulting in a swivelling of the capsule head and enabling the endoscopist to obtain a near 180º view. Thus, although not helpful in moving the device against peristalsis or through the pylorus, our previous study showed that this level of control was helpful in hastening the identification of landmarks [19] and perhaps, therefore, pathology.

Nonetheless, the data do suggest that visualization of the esophagus, GEJ, fundus, duodenal bulb, and, to a lesser extent, the cardia, could be improved. These data are consistent with experience of other studies of upper GI capsule examination [20] [21] [28] [29] [30]. Liao et al. found that the majority of focal gastric lesions in patients with dyspepsia were located in the body and distal stomach (77 %) rather than the fundus/cardia (23 %) [29]. It may be that the suboptimal visualization of the cardia and fundus by MACE did not impact on the diagnostic yield because of the low prevalence of proximal pathology in this study.

The MiroCam Navi reduces energy consumption by utilizing electric-field propagation (using human tissue as a transmission medium) [31], and image capture seems to be slightly delayed following ingestion, perhaps because of the need for full tissue/water contact. Our experience was that occasionally the magnet failed to capture the capsule in the esophagus and no esophageal images were obtained. Furthermore, the image capture rate is 3 frames per second from one camera compared with 18 frames per second from two cameras (at either end of the capsule) in the ESO-2 esophageal capsule (Medtronic, Dublin, Ireland), which compares very favorably to EGD in esophageal imaging (but has a battery life of only 30 minutes) [30] [32]. Views of the GEJ may be inadequate if the blind end of the capsule is leading, as it will only transmit images from a retrograde perspective as it passes into the stomach, although this often provides excellent views of the cardia. If the camera end of the capsule is leading, GEJ views may be adequate but cardiac views may not be obtained at that point (but may be seen later in the examination).

These problems are likely to be addressed by developing a double-ended capsule with a higher frame rate, although this may require further development of battery technology to power the device for the required time. This is also likely to improve views in the duodenal bulb, through which rapid transit becomes less critical if the image capture rate is high and a double-ended camera allows a near 360º view. Improved fundal views may require further refinements in control. However, this problem may not be confined to MACE; fundal views at EGD require endoscopic retroflexion and insufflation, which is not always possible in patients who cannot retain air.

The study has several limitations. Although villous atrophy identified by MACE was subsequently confirmed histologically, this was not the case with gastritis, gastric atrophy, and Barrett’s esophagus. However, there remained a significant difference in detection rates between the two modalities when these unconfirmed diagnoses were excluded. Nonetheless, the possibility that some pathologies identified by MACE but not by EGD were false-positive diagnoses cannot be excluded. This issue might have been addressed by independent review of photodocumented lesions or by unblinding the endoscopist prior to extubation and allowing repeat examination. Recently published guidelines recommend new quality standards for EGD, which include a minimum examination duration of 7 minutes, inclusion of at least eight photographic landmark images, and routine grading of mucosal visualization quality [22]. These were not routinely assessed in our cohort and should be considered in future comparative studies.

A pragmatic approach of allowing patients to choose whether or not to undergo EGD with sedation means that the study may not have been adequately powered to address any effect of sedation on pathology detection. Finally, there are limited data on the cost-effectiveness of upper GI capsule endoscopy in clinical practice [33], and capsule technology remains purely diagnostic [34]. Follow-up of patients would allow the longer-term outcomes of pathology detection to be assessed. Future studies should consider the cost implications of equipment, capsule video reading time, the training required to perform MACE, and the need for biopsy.

Competing interests

Dr. Hey-Long Ching and Professor Mark E. McAlindon have received research support from Intromedic LTD. for a different study.

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Corresponding author

• References

• 1 Kepczyk T, Kadakia SC. Prospective evaluation of gastrointestinal tract in patients with iron-deficiency anemia. Dig Dis Sci 1995; 40: 1283-1289
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