Introduction
Celiac disease is an immune-mediated gluten-dependent enteropathy that affects the
small bowel [1]. While reports of prevalence vary, celiac disease is estimated to affect 0.5 % to
1 % of the United States population [2]
[3]
[4]. Gluten is a ubiquitous protein present in foods like wheat, barley, and rye [1]
[5] Celiac disease, often called gluten-sensitive enteropathy, can result in symptomatic
malabsorption and may present with a breadth of symptoms including diarrhea, bloating,
and fatigue. If untreated, celiac disease may lead to iron deficiency anemia, vitamin
D deficiency, vitamin B12 deficiency, and intestinal lymphoma, thus signifying a need
to ensure an accurate diagnosis [1]
[6].
Despite the need to ensure appropriate identification, diagnosis of celiac disease
is often challenging and delayed as there is a considerable overlap between celiac
disease and other gastroenterological disorders such as irritable bowel syndrome [7]. Diagnosis includes serologic testing, typically via tissue transglutaminase antibody
(TTG-IgA), with or without the use of duodenal biopsy. Duodenal biopsy is generally
performed if serologic testing is positive, if there is a high pre-test probability
for celiac disease, or if there are discordant results of serologic testing [7]. Pathologic diagnosis is established or confirmed according to the modified Marsh-Oberhuber
classification, which accounts for the number of intraepithelial lymphocytes, crypt
hyperplasia, and villous atrophy [8]
[9].
As celiac disease may result in patchy histologic changes in the small bowel, the
site and number of duodenal biopsies becomes of considerable importance. Biopsies
were classically obtained from the distal duodenum (i. e., sections duodenal stage
2 [D2] through D4). However, there have been an increasing number of studies that
have evaluated biopsy of the duodenal bulb (i. e., section D1) for diagnosis of celiac
disease in the adult and pediatric populations [7]
[10]
[11]
[12]. When compared to distal duodenal biopsies alone, duodenal bulb biopsies may increase
the diagnostic yield; however, studies to date have shown varied results.
The primary aim of this study was to perform a systematic review and meta-analysis
to evaluate the feasibility, efficacy, and tolerability of duodenal bulb biopsy for
the diagnosis of celiac disease in the adult and pediatric populations. We hypothesized
that duodenal bulb biopsy would improve the diagnostic yield of celiac disease as
compared to distal duodenal sampling alone.
Methods
Literature search
A comprehensive search of the literature was performed to identify articles that examined
endoscopic duodenal biopsy for the diagnosis of celiac disease. We followed previously
cited recommendations for search strategies to identify diagnostic accuracy studies
[13]. Systematic searches of PubMed, EMBASE, Web of Science, and the Cochrane Library
databases were performed from 2001 through December 31, 2017. The search terms included:
“endoscopic duodenal biopsy”, “celiac disease”, “gluten-sensitive enteropathy”, “celiac
sprue”, “non-tropical sprue”, “endemic sprue”, and “duodenal bulb”.
All relevant articles irrespective of language, year of publication, type of publication,
or publication status were included. The titles and abstracts of all potentially relevant
studies were screened for eligibility. The reference lists of studies of interest
were then manually reviewed for additional articles by cross checking bibliographies.
Two reviewers (TRM and CRO) independently screened the titles and abstracts of all
the articles according to predefined inclusion and exclusion criteria. Any differences
were resolved by mutual agreement and in consultation with the third reviewer (TR).
In the case of studies with incomplete information, contact was attempted with the
principal authors to obtain additional data.
Study selection criteria
Only studies investigating use of endoscopic biopsy for the diagnosis of celiac disease
were included. Only human subject studies were considered in the analysis. A study
was excluded if deemed to have insufficient data, as were review articles, editorials,
and correspondence letters that did not report independent data. Case series and reported
studies with fewer than five patients were excluded. Participants included patients
of any age in whom the presence of celiac disease was suspected based upon clinical
symptoms alone or positive serologic markers were included. The Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) statement outline for reporting
systematic reviews and meta-analyses was used to report findings [14].
Outcome measures
The primary outcome measurement in this study was efficacy of endoscopic duodenal
bulb biopsy in patients with suspected celiac disease. Location of biopsy within the
duodenum was defined as duodenal bulb (i. e., section D1) versus distal duodenal (i. e.,
sections D2 through D4). Secondary measured outcomes in addition to location of biopsy
included mean number of biopsies performed, confirmatory diagnosis of celiac disease
as defined by the modified Marsh-Oberhuber classification, and type and number of
alternative diagnoses potentially identified (i. e., Brunner gland hyperplasia, peptic
duodenitis, gastric metaplasia, or other). Information on type and year of study,
average patient age (years), and gender were also collected. Sensitivity and subgroup
analyses were also performed for only high-quality studies (i. e., inclusion of only
randomized controlled trials or prospective studies), diagnostic yield as stratified
by pediatric and adult populations, and number of small bowel biopsies.
Statistical analysis
This meta-analysis was performed by calculating pooled proportions. After appropriate
studies were identified through systematic review, the individual study proportion
was transformed into a quantity using the Freeman-Tukey variant of the arcsine square
root transformed proportion. Then the pooled proportion was calculated as the back
transform of the weighted mean of the transformed proportions, using inverse arcsine
variance weights for the fixed effects model and DerSimonian-Laird weights for the
random effects model [15]
[16].
Measured outcomes comparing site of duodenal biopsy were obtained. From this, standardized
mean difference was calculated and transformed to the natural logarithm before pooling,
and the variance was calculated. Fixed-effects models were applied to duodenal bulb
and distal duodenal biopsy data to determine effect size and corresponding 95 % confidence
intervals (CIs). Since this was a cumulative meta-analysis, publication bias was not
assessed. Combined weighted proportions, and meta-regression were determined by use
of the Stata 13.0 software package (Stata Corp LP, College Station, TX).
Results
Patient characteristics of included studies
This meta-analysis included a total of 17 studies [10]
[11]
[12]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]. A PRISMA flow chart of search results is shown in [Fig. 1]. A total of 4050 patients (males n = 1707; 42.15 %) were included in this study.
Mean age of all patients included was 35.07 ± 20.66 years. Both adult and pediatric
populations were included in this study as well. Adult patients made up the vast majority
(n = 2684; 66.27 %) of enrolled patients in this systematic review and meta-analysis.
Mean age of adults and pediatric patients was 46.70 ± 2.69 and 6.33 ± 1.26 years,
respectively. All but two studies commented on the number of bulb biopsies performed;
however, many included “at least one” or “at least two” and other studies ranged from
one to five samples taken. Fourteen prospective and three retrospective studies were
included. All three retrospective studies examined pediatric populations [18]
[21]
[22]. No randomized controlled trials were found and included in this systematic review
and meta-analysis. Further baseline patient and study characteristics are highlighted
in [Table 1].
Fig. 1 Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow
chart of search results for duodenal bulb biopsy.
Table 1
Characteristics of included studies to assess duodenal bulb biopsy for celiac disease.
|
Author
|
Year
|
Study design
|
Number of patients
|
Mean age (years)
|
Number of males
|
Minimum number of bulb biopsies
|
Distal confirmation
|
Bulb confirmation
|
|
Adult study population
|
|
Stoven et al.
|
2016
|
Prospective
|
679
|
50
|
324
|
Bulb (n = 2); Distal (n = 4)
|
17/18
|
18/18
|
|
Mooney et al.
|
2016
|
Prospective
|
1378
|
50.3
|
661
|
Bulb (n = 4); Distal (n = 4)
|
242/268
|
268/268
|
|
Caruso et al.
|
2013
|
Prospective
|
55
|
35.67
|
11
|
Bulb (n = 4); Distal (n = 4)
|
25/38
|
27/38
|
|
Kurien et al.
|
2012
|
Prospective
|
28
|
48
|
9
|
Bulb (n = 4); Distal (n = 4)
|
23/28
|
26/28
|
|
Nenna et al.
|
2012
|
Prospective
|
43
|
35.2
|
10
|
Bulb (n = 2); Distal (n = 3)
|
42/43
|
43/43
|
|
Evans et al.
|
2011
|
Prospective
|
461
|
51
|
161
|
Bulb (n = 1); Distal (n = 4)
|
132/211
|
148/211
|
|
Gonzalez et al.
|
2010
|
Prospective
|
40
|
45
|
30
|
Bulb (n = 2); Distal (n = 4)
|
35/40
|
40/40
|
|
Pediatric study population
|
|
Mansfield-Smith et al.
|
2014
|
Retrospective
|
60
|
8.42
|
19
|
–
|
42/60
|
54/60
|
|
Sharma et al.
|
2013
|
Retrospective
|
101
|
8.21
|
33
|
Bulb (n = 1); Distal (n = 4)
|
93/101
|
99/101
|
|
Tanpowpong et al.
|
2012
|
Retrospective
|
103
|
8.5
|
40
|
–
|
83/103
|
79/103
|
|
Levinson-Castiel et al.
|
2011
|
Prospective
|
96
|
6
|
31
|
Bulb (n = 1); Distal (n = 4)
|
81/87
|
86/87
|
|
Mangiavillano et al.
|
2010
|
Prospective
|
47
|
8.1
|
14
|
Bulb (n = 4); Distal (n = 4)
|
42/47
|
47/47
|
|
Rashid et al.
|
2009
|
Prospective
|
35
|
8.1
|
14
|
Bulb (n = 2); Distal (n = 4)
|
31/35
|
33/35
|
|
Prasad et al.
|
2009
|
Prospective
|
52
|
6.4
|
33
|
Bulb (n = 2); Distal (n = 2)
|
52/52
|
52/52
|
|
Bonamico et al.
|
2008
|
Prospective
|
665
|
5.25
|
237
|
Bulb (n = 1); Distal (n = 4)
|
649/665
|
665/665
|
|
Ravelli et al.
|
2005
|
Prospective
|
112
|
6.4
|
43
|
Bulb (n = 4); Distal (n = 4)
|
110/110
|
110/110
|
|
Bonamico et al.
|
2004
|
Prospective
|
95
|
6.9
|
37
|
Bulb (n = 1); Distal (n = 4)
|
11/16
|
16/16
|
Duodenal biopsy findings
Of the total patients included in this systematic review and meta-analysis, 47.46 %
(n = 1922) were diagnosed with celiac disease based upon a positive biopsy result
from any location in the duodenum. Fourteen studies found biopsy of the duodenal bulb
to increase the diagnostic yield of celiac disease [10]
[11]
[12]
[17]
[18]
[19]
[20]
[22]
[23]
[24]
[25]
[27]
[29]
[30] A total of three included studies demonstrated no improvement in diagnostic accuracy
of celiac disease with duodenal bulb biopsy [21]
[26]
[28].
Overall, the diagnosis of celiac disease was histologically confirmed in 97 % (95 %
CI: 91 to 100; P < 0.001) of biopsy samples obtained from the duodenal bulb ([Fig. 2]). From the distal duodenum, histologic confirmation of celiac disease was reported
in 89 % (95 % CI: 81 to 94; P < 0.001) of biopsy samples ([Fig. 3]) The sampling for the duodenal bulb demonstrated an overall increase of 5 % (95 %
CI: 3 to 9; P < 0.001) in the diagnostic yield of celiac disease ([Fig. 4]). Non-celiac histologic diagnoses including Brunner gland hyperplasia and peptic
duodenitis were reported more commonly in the duodenal bulb as compared to the distal
duodenum with an increase in diagnostic yield of 4 % (95 % CI: 3 to 5; P < 0.001) and 1 % (95 % CI: 1 to 2; P < 0.001) ([Supplemental Fig. 1] and [Supplemental Fig. 2]).
Fig. 2 Overall diagnostic accuracy of duodenal bulb biopsy for diagnosis of celiac disease
Fig. 3 Overall diagnostic accuracy of distal duodenal biopsy for the diagnosis of celiac
disease.
Fig. 4 Overall diagnostic yield increase of duodenal bulb biopsy versus distal duodenal
biopsy for the diagnosis of celiac disease.
Supplemental Fig. 1 Diagnostic yield increase of duodenal bulb biopsy versus distal duodenal biopsy for
the diagnosis of Brunner gland hyperplasia.
Supplemental Fig. 2 Diagnostic yield increase of duodenal bulb biopsy versus distal duodenal biopsy for
the diagnosis of peptic duodenitis.
Sensitivity and subgroup analyses
Sensitivity analysis including only high-quality manuscripts (i. e., prospective studies)
demonstrated a similar increased diagnostic yield of duodenal bulb biopsy as compared
to our cumulative meta-analysis results, 5 % (95 % CI: 3 to 8; P < 0.001) ([Supplemental Fig. 3]). When stratified by pediatric and adult populations, duodenal bulb biopsy demonstrated
a 4 % (95 % CI: 1 to 9) and 8 % (95 % CI: 6 to 10) increase in the diagnostic yield
of celiac disease, respectively (P < 0.001) ([Supplemental Fig. 4] and [Supplemental Fig. 5]). Further breakdown of our results by number of biopsies revealed that two studies
performed less than the recommended number of biopsies from the distal duodenum [12]
[26]. When these studies were excluded, biopsy of the duodenal bulb increased the diagnostic
yield of celiac disease by 6 % (95 % CI: 3 to 10; P < 0.001) ([Supplemental Fig. 6]). More biopsies of the duodenal bulb (i. e., > 2 bulb biopsies) did not significantly
improve diagnostic yield of celiac disease as compared to overall results – increase
yield of 6 % (95 % CI: 1 to 14; P < 0.001) versus 5 % (95 % CI: 3 to 9; P < 0.001), respectively.
Supplemental Fig. 3 Overall diagnostic yield increase of duodenal bulb biopsy versus distal duodenal
biopsy for the diagnosis of celiac disease – prospective, high-quality studies only.
Supplemental Fig. 4 Diagnostic yield increase of duodenal bulb biopsy versus distal duodenal biopsy for
the diagnosis of celiac disease among pediatric patients.
Supplemental Fig. 5 Diagnostic yield increase of duodenal bulb biopsy versus distal duodenal biopsy for
the diagnosis of celiac disease among adult patients.
Supplemental Fig. 6 Overall diagnostic yield increase of duodenal bulb biopsy versus distal duodenal
biopsy for the diagnosis of celiac disease among studies following American College
of Gastroenterology guidelines.
Discussion
Based upon results from our systematic review and meta-analysis, biopsy and histologic
examination of duodenal bulb during routine upper endoscopy appears to increase diagnostic
yield and aid in the diagnosis of celiac disease. Among all patients, duodenal bulb
biopsy improved diagnostic yield of celiac disease by 5 %. This is concordant with
results identified in other trials [19]
[24]
[25]. Even when stratified by pediatric and adult populations, endoscopic bulb biopsy
was shown to be an effective strategy to improve diagnostic accuracy. Importantly,
this general practice of duodenal bulb sampling appears to increase diagnostic yield
for both adult and pediatric patients. Therefore, gastroenterologists and endoscopists
should consider sampling the duodenal bulb, in addition to the distal duodenum, to
improve histologic diagnosis of celiac disease.
Celiac disease is an autoimmune enteropathy elicited by ingestion of gluten [31]. While the disease was traditionally thought to affect individuals of Northern European
ancestry, celiac disease has now become increasingly recognized and reported in people
of various racial/ethnic and geographical distributions including Asian andAfrican
as well [32]. Within the last five decades, prevalence of celiac disease has increased five-fold
affecting approximately 1 % of individuals in many populations [33]. This global increase in prevalence reflects a true increase in incidence and has
been shown to not be a result of increased awareness or screening efforts [31] However, even with a rising prevalence, evidence has suggested that the ratio of
knownto unknown diagnosed celiac disease patients was one in seven, signifying that
a substantial number of individuals may be unaware of their disease [34].
Current American College of Gastroenterology (ACG) guidelines recommend small bowel
biopsy to confirm the diagnosis of celiac disease in patients with a positive serology
and in those with a high probability of celiac disease (i. e., typically considered
≥ 5 %), regardless of the serology [7]. Supported by a high level of evidence, the ACG also highlights upper endoscopy
with small-bowel biopsy as a critical component of the diagnostic evaluation for persons
with suspected celiac disease and to confirm the diagnosis suggesting multiple biopsies
be obtained from the duodenum with one or two from the bulb at least four biopsies
from the distal duodenum. Additional international and national pediatric and adult
guidelines echo this statement but do not provide specific sites of the small intestine
to sample [35]
[36]
[37]
[38] Classically, histologic features of celiac disease may range from mild alterations
characterized by increased intraepithelial lymphocytes to a flat mucosa with villous
atrophy, enhanced epithelial apoptosis, and crypt hyperplasia [39]
[40]
[41]
[42]
[43]
[44]. For this reason, small-intestinal biopsy has been central to confirmation of the
diagnosis of celiac disease since the 1950s [45].
Despite this general statement regarding a role for biopsy in diagnosis of celiac
disease, in the last decade there has been debate regarding the optimal biopsy sampling
strategy with regards to location and number of biopsies. Current ACG guidelines recommend
multiple biopsies of the duodenum (one or two biopsies of the bulb and at least four
biopsies from the distal duodenum) to confirm the diagnosis of celiac disease – strong
recommendation, high level of evidence [7]. All studies included with the exception of two trials specifically followed these
recommendations when evaluating the role for duodenal bulb biopsy and celiac disease
diagnosis [12]
[26]. Importantly, more than two biopsies from the duodenal bulb did not appear to increase
the diagnostic yield of celiac disease, suggesting that providers need not over-sample
the bulb. These results reaffirm and strengthen the current ACG guidelines.
Despite our results questioning the utility of more than two duodenal bulb biopsies
and possibly suggesting duodenal bulb biopsy alone may improve the diagnosis of celiac
disease, it remains very important for providers to sample both the duodenal bulb
and distal duodenum when entertaining the diagnosis of celiac disease. The varying
degree of histology combined with a heterogeneous or patchy distribution within the
small bowel necessitates a sampling strategy that includes the duodenal bulb [10]
[20]. The rationale as to why some patients may have villous atrophy exclusively in either
the bulb or distal duodenum remains unknown; however, it is plausible to assume this
may simply reflect the patchy distribution of the celiac disease-associated lesions
[17]
[27]
[46]
[47]. Another explanation may be that ingestion of gluten may cause localized tissue
damage in the bulb as this portion of the intestine is rich in lymphatic structures;
it is also the initial duodenal site to be exposed to gluten before it is digested
[48].
Traditionally, the diagnosis of celiac disease has relied upon multiple endoscopic
biopsies collected from the more distal segments of the duodenum. This has been in
large part due to concern regarding presence of Brunner glands in the proximal duodenum
and fear of interference with evaluation of the villous to crypt ratio [17]
[49]
[50]
[51]. However, in addition to an improved diagnostic accuracy, duodenal bulb sampling
resulted in an increase in diagnostic yield of non-celiac etiologies. The most prominent
of these diagnoses were Brunner gland hyperplasia and peptic duodenitis (i. e., increased
yield of 4 % and 1 %, respectively). Therefore, the opportunity to improve the diagnostic
efficacy of celiac disease and establish further non-celiac diagnoses is further validation
that biopsy of the duodenal bulb is a useful strategy to evaluate select patients.
Limitations of the current study include the inherent heterogeneity bias of pooled
systematic reviews and meta-analyses. This current study relies heavily upon observational
studies, with no included randomized trials. While publication bias was not formally
assessed, sensitivity analysis was performed through inclusion of prospective studies
only. Although these studies may be superior to retrospective studies, we cannot discount
the overall quality of evidence is less than ideal and may have an effect on the findings
of the review. Furthermore, analysis unit problems, inclusion of correlated observations,
are not uncommon in clinical research and present a challenge to the reliability of
the findings. Other limitations of our study include the inability to define specific
patient and biopsy characteristics to further guide practice habits. In accordance
with current American College of Gastroenterology guidelines, both serology and biopsy
should be performed on patients who consume a gluten-containing diet [7]. Included studies in this systematic review and meta-analysis do not specifically
separate patient populations by those adherent or nonadherent to a gluten-free diet.
This information would be useful in providing insight as to whether bulb biopsy would
be influenced by gluten-free adherence. Pathologic diagnosis of the included studies
was as defined by the modified Marsh-Oberhuber classification and did not utilize
the more recent, simplified Corazza classification [9]
[41]
[52]. Furthermore, histology of patients with celiac disease is different in adults as
compared to pediatric patients with a higher occurrence of villous atrophy in pediatric
populations and milder histologic changes in adults. While this limitation is addressed
in our subgroup analysis, biopsy-associated factors were also important limitations.
Based upon the study data, we were unable to determine size, number, quality, and
orientation of biopsies for all included studies – all of which may affect the histological
analysis and influence the identification of celiac disease. This is an important
and clinically relevant question to clinicians that requires further study.
Despite these limitations, our study has several strengths. Most importantly, our
meta-analysis methodologically summarizes all available data to evaluate the efficacy
of duodenal bulb biopsy for the diagnosis of celiac disease. Importantly, our results
and confirmation of celiac disease on histology were determined based upon a reproducible
and reliable grading system (i. e., the modified Marsh-Oberhuber classification).In
addition, the inclusion of both pediatric and adult patients provides a comprehensive
answer to the scope of the diagnostic dilemma and easily translates to a wide and
diverse practice setting, suggesting that updated guidelines may specifically address
this question in both populations. Furthermore, to these authors’ knowledge, this
is the first study to demonstrate a more beneficial role for duodenal bulb biopsy
for adults as compared to children. These results also reaffirm current ACG guidelines
for diagnosis of celiac disease and suggest that there is no improvement in diagnostic
yield for more than two biopsies from the duodenal bulb. Importantly, our results
are in accordance with previous studies demonstrating small-bowel biopsy is also useful
for differential diagnosis of other malabsorptive disorders [53]. In our study, duodenal bulb biopsy not only increased the diagnostic yield of celiac
disease, but also improved the diagnosis of alternative non-celiac associated gastrointestinal
disorders.
Conclusion
In conclusion, endoscopic sampling of the duodenal bulb in addition to the distal
duodenum is recommended to improve histologic diagnosis of celiac disease.While previous
studies and results have suggested that patients with high suspicion of celiac disease
and positive serum antibodies may not require biopsy sampling in both the bulb or
distal duodenum to identify celiac disease-associated lesions, the 5 % increase in
diagnostic yield suggests that both biopsy sites are important to confirm the diagnosis.
Ultimately, biopsy and histologic examination of duodenal bulb during routine upper
endoscopy in evaluation of patients with suspected gluten-sensitive enteropathy appears
to increases the diagnostic yield of celiac disease.
