Introduction
Evaluation of gastrointestinal bleeding with standard endoscopic and radiographic
methods reveals an identifiable source in 90 % to 95 % of patients [1]
[2]. Up to 75 % of the remaining cases of suspected small bowel bleeding (SSBB) are
thought to originate in the small bowel [3]
[4]. Investigation of suspected small bowel bleeding often relies on persistent anemia
identified on full blood count analysis and requires access to specialist centers
and diagnostic techniques. Development of novel technology has provided noninvasive
means of assessing small bowel pathology. However, access to these tests may be restricted
by increasing demand and limited resources.
Small bowel capsule endoscopy (SBCE) uses wireless video technology to provide noninvasive
endoluminal imaging of the small bowel, without need for insufflation of air or sedation.
It is generally well tolerated by patients, and more sensitive than push enteroscopy,
cross-sectional imaging and as good as device-assisted enteroscopy (DAE) in identifying
small bowel pathology [5]
[6]
[7]. The European Society for Gastrointestinal Endoscopy (ESGE) recommends small bowel
video capsule endoscopy as the first-line investigation in patients with SSBB, when
small-bowel evaluation is indicated after a negative upper and lower endoscopy [7].
Diagnostic yield of SBCE is affected by delays between the suspected bleeding episode
and time of investigation. Patients with ongoing overt or occult bleeding (fecal occult
blood [FOB] positivity or unexplained iron deficiency anemia) are more likely to have
pathology identified on SBCE. Conversely, diagnostic yield of SBCE has been reported
to be reduced in patients who have experienced time delays between the investigation
and diagnosis of SSBB [8]
[9]
[10]. It is therefore imperative that patients referred for investigation of suspected
small bowel bleeding are triaged efficiently to maximize potential diagnostic yield
and to guide further management.
Fecal immunochemical test (FIT) has an established role in investigating large bowel
bleeding and is incorporated into several national bowel cancer screening programs
[11]. It detects only human globin, which makes it more sensitive for colorectal lesions
than guaiac tests, but theoretically less sensitive for proximal gastrointestinal
lesions due to degradation of globin in transit [12].
Importantly, however, a positive FIT has been observed in 40 % to 60 % of patients
who did not present with colorectal lesions upon subsequent investigation [13]. These data suggest that the source of the positive FIT may instead arise from small
bowel pathology, perhaps due to incomplete globin degradation during gastrointestinal
transit. FIT may, therefore, represent an opportunity as a useful screening biomarker
to optimize triage and potentially filter inappropriate referrals for SBCE. It is
also readily available in outpatient and GP settings, and could be easily incorporated
into an SBCE referral algorithm.
Thus, the aim of this study was to investigate whether FIT could help predict likelihood
of small bowel bleeding or other significant small bowel pathology at the time of
SBCE. In doing so, we sought to contribute to the available body of data and to postulate
whether FIT, alone or in combination with serum hemoglobin (Hb), could be used to
triage patients referred for investigation of suspected small bowel blood loss.
Patients and methods
Patient selection criteria
We conducted a prospective pilot study in a tertiary referral center in Dublin, Ireland.
Candidates were invited to participate if they were adults (≥ 18 years) referred for
investigation of suspected small bowel bleeding following negative esophagogastroduodenoscopy
(EGD) and colonoscopy. This included investigation for other possible causes of ferropenic
anemia. These included duodenal biopsies and serology for identification of celiac
disease; Campylobacter-like organism (CLO) test or urea breath test to identify Helicobacter pylori; or gastric biopsies and serology to determine presence of autoimmune gastritis.
SSBB was subclassified according to ACG guidelines as overt small bowel bleeding (melena
or hematochezia with a source identified in the small bowel) or occult (iron-deficiency
anemia with or without guaiac-positive stools who are found to have a small bowel
source of bleeding). Exclusion criteria included those under 18 years of age and those
who declined or were unable to participate. Ethics was approved via the SJH/AMNCH
Research Ethics Committee (REC Reference: 2017 – 08).
Study materials
The FIT collecting tubes (OC-Sensor, EIKEN CHEMICAL, Tokyo, Japan) were quantitatively
analyzed according to manufacturer’s guidelines using latex agglutination immune-turbidimetry.
A cut-off of 45 ug Hb/g feces (equivalent to 225 ng Hb/mL buffer) was chosen for our
study, above which a FIT was deemed positive. This value was chosen as it is the standard
cut-off used in the Irish National Bowel Screening Programme and is supported by international
data as a cost-effective cut-off level [14]
[15]
[16].
SBCE investigations were performed using PillCam SB3 (Medtronic, Dublin) technology
and analyzed by a single experienced gastroenterologist using Rapid Reader Version
8 software (Medtronic, Dublin). The reader is a professor in Gastroenterology with
decades of experience in standard and capsule endoscopy. The reader was blinded to
the FIT result. SBCE were deemed positive if potential sources of bleeding were identified,
including angiodysplasia, neoplasms, ulcerative enteritis, or if visualized blood
was observed. Anemia was defined based on local laboratory ranges for hemoglobin (< 13 g/dL
for males and < 12 g/dL for females).
Study protocol
Two trained technicians who routinely perform SBCE were briefed on the study protocol.
Prior to attending for their capsule endoscopy, patients were advised to take their
last solid meal at lunchtime the day prior to the study, with clear fluids until midnight.
Subjects then fasted until their procedure. On the day of their SBCE, patients were
offered the opportunity to take part in the study. The purpose of the study, the specific
protocol and alternatives to participation were clearly explained by the technicians.
If willing to proceed, the patient was given a study-pack including an information
leaflet, consent form, clinical questionnaire, FIT collecting tube and instructions.
Eight sensors were placed on the abdominal wall and subjects were provided with a
wireless recording device. Simethicone was given, they then swallowed the capsule
and the wireless recorder was checked to ensure proper function. The recorder was
worn for 8 hours during which time the patient could move freely and eat a light diet
after 5 hours. The recording device was then returned to the gastroenterology department,
along with the completed clinical questionnaire, FIT tube, and consent. Patients were
then invited to provide a full blood count for analysis of serum hemoglobin. FIT samples
were transferred immediately to the laboratory when received and stored at 0C, thereby minimizing time potential for degradation.
Data collection
Data were anonymized after collection and stored on a central data file on a single
computer in a single hospital. Patients were assigned a study number to which the
results of the relevant investigations were assigned. Clinical data collected included
age, gender, use of medications including anti-platelets and iron supplementation,
recent gastrointestinal bleeding, and relevant past medical history. Hb and FIT results
were accessed using the electronic laboratory system and recorded under the study
ID.
Endpoints
The primary endpoint was correlation between FIT and clinically significant findings
on SBCE. Secondary endpoints included correlation between anemia and findings on SBCE;
and between a combination of anemia plus FIT (Hb + FIT) and SBCE findings.
Statistical analysis
Continuous variables were expressed as medians (range). Correlation analysis using
Pearson coefficient was used to identify possible associations between variables.
Chi-squared test was used to assess differences between groups as appropriate. Mann
Whitney U test was performed to assess non-parametric samples. Associations were evaluated
using univariate logistic regression analysis. Multivariate analysis was performed
when two or more variables were significantly associated during univariate analysis.
P < 0.05 was considered significant in all analyses. Receiver operating curve (ROC)
was calculated to evaluate the primary endpoint, and area under the curve (AUC) was
calculated. Sensitivity, specificity, positive predictive value (PPV) and negative
predictive value (NPV) were calculated. Statistical analysis was performed using SPSS
(Build 16.0.0, IBM, New York, United States).
Results
A total of 54 patients were enrolled in the study. Fifty-one subjects were included
in the final study cohort. The other three subjects were excluded due to inadequate
luminal views in one case; one patient did not return a FIT; and one study was not
performed as the patient could not swallow the capsule. FITs were returned within
48 hours in all cases, and immediately stored in a refrigerator at 0 °C until processed.
88.2 % returned a Hb, and 66.6 % completed the questionnaire (relevant analysis was
completed on available data only).
Median age was 60 years (18 – 85 years), 37.3 % were male and 41.2 % of patients were
≥ 65 years old ([Table 1]). 38.9 % (n = 22) reported overt gastrointestinal bleeding (melena or hematochezia)
within the 3 months prior to testing, while 61.1 % (n = 29) had been referred with
suspected occult small bowel bleeding. Previous requirement for blood transfusion
was reported by 30.6 %, 38.9 % reported recent (within 3 months) use of oral or intravenous
iron supplementation, and 27.8 % were taking one or more antiplatelet agents at time
of testing. No patients were taking warfarin, and one patient was taking direct oral
anticoagulants.
Table 1
Patient Characteristics.
|
Characteristics
|
Result
|
|
Demographics
|
|
|
60 (18 – 85 years)
|
|
|
37.3 %
|
|
Medications
|
|
|
38.9 %
|
|
|
27.8 %
|
|
|
2.8 %
|
|
|
0 %
|
|
Clinical characteristics
|
|
|
2.8 %
|
|
|
38.9 %
|
|
|
30.6 %
|
|
Biochemical characteristics
|
|
|
455 ug Hb/g (0 – 4820 ug Hb/g)
|
|
|
13.0 g/dL (7.1 – 15.7 g/dL)
|
FIT, fecal immunochemical test
Median hemoglobin for the cohort at the time of SBCE was 13.0 g/dL (7.1 – 15.7 g/dL),
and 33 % were anemic based on local laboratory parameters (< 13 g/dL for males and
< 12 g/dL for females). Of the patients, 29.4 % had FIT scores more than the predetermined
cut-off of ≥ 45 ug Hb/g. 33.3 % of patients with positive FIT were male, and 60 %
of positive results were from patients ≥ 65 years.
Of the patients, 25.5 % had clinically significant findings on SBCE ([Fig. 1]). These included four new diagnoses of ulcerative enteritis; three cases of angiodysplasia;
three small-bowel neoplasms; and two findings of blood with no clear source ([Table 2]). Of the patients, 53.8 % with SB pathology were ≥ 65 years old, 69.2 % were female
and 33.3 % reported overt bleeding within the last 3 months.
Fig. 1 Findings on small bowel capsule endoscopy. Findings considered to be potential causes
for suspected small bowel bleeding are shown.
Table 2
Findings according to likelihood of causing SSBB
|
Variable
|
N
|
|
Probable causes
|
|
New ulcerative enteritis
Established Crohn’s enteritis
Neoplasm
Visible blood of unknown source
|
4
3
3
2
|
|
Possible causes
|
|
Non-bleeding angiodysplasia
Gastritis or gastric erosions
Gastric angiodysplasia
Portal hypertensive gastropathy
|
3
2
3
1
|
SSBB, suspected small bowel bleeding
Regression analysis revealed a statistically significant correlation between positive
FIT (≥ 45 ug Hb/g) and findings on SBCE (R = 0.51, P = 0.0001). Positive FIT had a PPV of 60 % and NPV of 88.9 % in predicting SB pathology
(OR 12, 95 % CI [2.77 – 51.96], P = 0.001) ([Table 3]). There was a statistically significant reduction in mean FIT scores between patients
with and without SB pathology (1300.85 [SEM ± 439.81 ug Hb/g] versus 168.59 [SEM ± 129.85 uh Hb/g],
P = 0.0001) ([Fig. 2]). There were four false-negative results, which included an ulcerated submucosal
mass, inflammatory distal ileal mass, proximal and jejunal angiodysplasia, and ulcerated
anastomosis.
Table 3
Correlations of variables in predicting pathology on small bowel capsule endoscopy.
|
Variable
|
PPV
|
NPV
|
P value
|
|
Endpoints
|
|
|
60 %
|
88.9 %
|
0.001[*]
|
|
|
40 %
|
83 %
|
0.09
|
|
|
66.7 %
|
82.1 %
|
0.025[*]
|
|
Other variables
|
|
|
20.0 %
|
73.1 %
|
0.514
|
|
|
21.4 %
|
72.7 %
|
0.506
|
|
|
50.0 %
|
90.9 %
|
0.014[*]
|
* Denotes statistically significant variables (P < 0.05). Chi-squared and univariate logistic regression used for analysis. PPV, positive
predictive value; NPV, negative predictive value; FIT, fecal immunochemical test
Fig. 2 Mean ± SEM FIT values. Mean FIT Values: Positive SBCE = 1300.8 (± 439.8 uh Hb/g);
Negative SBCE = 168.6 (± 129.9 ug Hb/g). *** P = 0.0001.
Sensitivity and specificity for FIT ≥ 45 ug Hb/g in predicting SB pathology were 69.2 %
and 88.9 %, respectively. Calculation of ROC showed AUC to be 0.84, suggesting this
is a useful test (95 % CI [0.70 – 0.97], P = 0.0003) ([Fig. 3]). Sensitivity and specificity varied with FIT cut-off points, as would be expected.
Sensitivity for FIT > 20 ug Hb/g, > 45 ug Hb/g, > 135 ug Hb/g, and > 200 ug Hb/g was
84.6 %, 69.2 %, 69.2 %, and 61.5 %, respectively; while specificity was 60.5 %, 88.9 %,
89.5 %, and 89.5 %, respectively ([Table 4]).
Fig. 3 ROC of varying FIT values in prediction of pathology on SBCE.
Table 4
Sensitivity and specificity of FIT values in Predicting SB pathology
|
FIT Value (ug Hb/g)
|
Sensitivity
|
Specificity
|
|
–1
|
100 %
|
100 %
|
|
10
|
92.3 %
|
39.5 %
|
|
20
|
84.6 %
|
60.5 %
|
|
45
|
69.2 %
|
88.9 %
|
|
135
|
69.2 %
|
89.5 %
|
|
200
|
61.5 %
|
89.5 %
|
|
400
|
53.8 %
|
97.4 %
|
FIT, fecal immunochemical test; SB, small bowel
A combination of anemia and positive FIT was also statistically significant in predicting
small bowel pathology on SBCE (R = 0.39, P = 0.009). Hb + FIT had a PPV for SB pathology of 66.7 %, and an NPV of 82.1 % (OR
9.14, 95 % CI [1.39 – 60.12], P = 0.025).
Anemia at time of SBCE had a PPV for predicting SB pathology of 40 %, and an NPV of
83 % (OR 3.33, 95 % CI [0.81 – 13.66], P = 0.09). Multivariate analysis of statistically significant variables (FIT ≥ 45 ug Hb/g;
Hb + FIT) using multivariate linear regression revealed persistent statistical significance
(P < 0.001).
Recent use of oral or intravenous iron was significantly associated with findings
on SBCE (P = 0.005). There was no significant correlation between positive SBCE and concurrent
use of antiplatelet medications, recent overt bleeding, or prior blood transfusion.
We found no significant correlation between antiplatelet use and positive FIT ([Table 3]).
SBCE revealed pathology proximal to the small bowel potentially accounting for SSBB
in six further cases. These included gastritis (4 cases), angiodysplasia in the stomach
(1 case), and portal hypertensive gastropathy (1 case) ( [Fig.4]). Including these cases increased the diagnostic yield of our SBCE to 37.3 %. Evaluation
of endpoints in these cases alone did not reveal any significant correlations.
Fig. 4 Findings on SBCE (including outside of SB).
Discussion
Investigation of suspected small bowel bleeding requires significant amounts of time
and resources. The role of SBCE in diagnosis of SSBB has been well recognized in international
guidelines, not only in identifying lesions potentially suitable for intervention,
but also as negative tests have been shown to be associated with a lower risk of subsequent
rebleeding [14]. Increasing awareness of the utility of SBCE has increased demand and therefore
created a need for efficient methods of triaging referrals. Unfortunately, no validated
selection tool for SBCE referral yet exists. A biomarker with strong positive predictive
value would help prioritize patients who may require further intervention and management.
Similarly, a biomarker with good negative predictive value may help screen inappropriate
referrals, reduce costs and decrease the burden on busy departments.
FIT has been proven to be useful in detecting colorectal pathology, however a significant
proportion of false positives raises the possibility that it may also be useful in
detection of small bowel lesions [13]. There is limited data on this topic, however a recent meta-analysis of six publications
suggested FIT is not a good predictor of findings on SBCE [15] . In the meta-analysis, sensitivity and specificity of FIT in prediction of SB pathology
were 0.48 and 0.60 respectively, both considerably lower than our trial (0.69 and
0.89 at > 45 ug Hb/g). The studies included differed significantly from our trial,
which may have contributed to this discrepancy. First, there were significant delays
between analysis of FIT and completion of SBCE, in some cases up to 4 months [15]. In the meta-analysis, time between FIT to SBCE ranged between 3 days to 4 months,
with an average lag of 1 to 2 weeks. Our average delay between FIT to SBCE was 24
hours. As has previously been reported, time between bleeding episode and SBCE can
affect diagnostic yield, therefore we maximized the potential correlation by minimizing
delay [8]
[9]
[10]. This was a major strength of our study and supports the argument that to maximize
efficacy of this resource, a positive FIT at time of referral should ensure urgent
access to SBCE. Second, all studies in the meta-analysis used a FIT cutoff value of
100 ng/mL (20 ug Hb/g), whereas a cutoff value of 45 ug Hb/g was used in the current
study. There is a significant variation in cutoff values between centers and countries
(many of which use a cutoff of 10 ug Hb/g) which remains a source of confusion. Results
are difficult to standardize as different countries and hospitals use differing commercial
products and analytical methods [16]. Optimal cutoffs may therefore vary from country to country, with further data required
to identify an international standard. Despite this, our chosen cutoff value is used
by the Irish BowelScreen programme and supported by data obtained by other groups
[17]
[18]
[19]. Our study suggests that FIT ≥ 45 ug Hb/g correlates well with findings on SBCE,
and that a higher cutoff value results in better specificity (84.2 % in our study
vs 60 % in the meta-analysis). This gives strength to the idea of FIT as a screening
biomarker prior to SBCE.
Referral for SBCE is recommended for patients with iron deficiency anemia lacking
an identifiable source following upper and lower gastrointestinal endoscopy. As mentioned
above, there is often a significant delay between detection of anemia – frequently
in the community setting – and completion of SBCE. We examined the relationship between
Hb and SB pathology in our cohort. Anemia trended towards but did not reach statistical
significance in predicting findings on SBCE (PPV 40 %, NPV 83 %, P = 0.09). However, when we combined FIT > 45 ug Hb/g and anemia, this proved statistically
significant in predicting pathology (PPV = 66.7 % (P = 0.025), NPV = 82.1 % (P = 0.004).
Incorporating a combination of FIT and Hb into the referral pathway could therefore
be a useful tool in triaging referrals for SBCE. Adding FIT to the SBCE referral pathway
would be relatively simple given its convenience and ready availability in the community.
In the case of a positive FIT, our findings suggest a referral for urgent SBCE should
be made. However, with a negative FIT, repeating an FBC to check for resolution of
anemia may negate need for SBCE referral. If anemia is identified, referral could
then be completed ([Fig. 5]). Through use of such an algorithm, there is potential to streamline the referral
pathway for SBCE.
Fig. 5 Suggested algorithm for SBCE referral based on FIT use.
Utilization of FIT as a screening biomarker may also generate significant financial
savings. According to an economic analysis by Palimaka et al, the average cost of
a capsule endoscopy is approximately $950 CAD (approximately €633 at 2015 exchange
rate) [20], while the cost of FIT stands at approximately €20 to €30 [21]. Applying these data to our cohort, use of FIT > 45 ug Hb/g as a screening tool
could have saved our department approximately €19,456 over the course of the study
period, with four false-negative cases as described above.
Limitations of this study include relatively low numbers of patients. We are seeking
to remedy this by developing a larger analysis to challenge our findings. Our study
also revealed a relatively low diagnostic yield for SBCE versus some other studies.
Our pathology detection rate was 25.5 %, considerably lower than in some studies included
in the meta-analysis, some of which reached 63 % [22]. This may reflect the lack of standardization when reporting capsule studies. Our
figure reflected clinically significant findings as determined by a consultant gastroenterologist
with expertise in SBCE, whereas some studies included all SB findings, some of which
may be considered less likely to contribute to gastrointestinal bleeding [10]. The diagnostic performance in our study may also reflect inclusion of overt and
occult bleeding cases within the same cohort, as overt bleeding has been shown to
increase diagnostic yield. The average age of patients in the studies included in
the meta-analysis was 64.1 years, whereas our patient cohort was younger, with an
average age of 56.6 years, which may also have affected SBCE findings.
While our study supports use of FIT in detection of small bowel pathology, it does
not support its use in identifying more proximal pathology. When including findings
proximal to the small bowel, e. g. gastric pathology, our SBCE diagnostic yield increased
to 37.3 % which is in line with other publications. However, this resulted in disappearance
of significant correlations, which may have been a factor in outcomes of previous
studies. This supports the hypothesis that more proximal pathology may result in denaturing
of Hb, but suggests FIT is still a useful tool in detection of SB pathology.
Conclusion
There is an established need for a biomarker to aid in investigation of suspected
small intestinal bleeding. We found FIT to be sensitive and specific in predicting
small bowel pathology on SBCE. Our findings suggest that FIT, possibly in conjunction
with serum hemoglobin, is a useful and cost-effective screening tool for selection
of patients who would benefit from this procedure.
