Introduction
There is interest in factors associated with the underdiagnosis of celiac disease
[1]. An accurate diagnosis relies on combining clinical, serological, and histological
data, with a greater emphasis recently being placed on histological data [2]. Therefore, the final diagnostic component of celiac disease rests with the endoscopist
and the pathologist.
To diagnose celiac disease, the most recent American College of Gastroenterology (ACG)
guidelines recommend multiple biopsies of the small bowel: one or two biopsies of
the bulb and at least four of the distal duodenum [3]. These guidelines differ from those issued by the American Gastroenterological Association
in 2006, which only recommended four to six samples from the distal duodenum [4]. Despite these recommendations, the sensitivity of duodenal biopsy may be decreased
by the patchy distribution of disease [5], quality of the biopsy specimen [6], and the variability in pathological interpretation [7]. Biopsies are performed on patients because of abnormal serology, high index of
suspicion, routine duodenal biopsy at endoscopy for disease indications other than
celiac disease or endoscopic visualization of villous atrophy [8]
[9]. A recent survey revealed a discrepancy between the number of biopsies recommended
and real-life practice, showing that 63 % of patients had fewer than four duodenal
biopsies [10].
In the current study, we investigated the yield of celiac disease diagnosis with respect
to the number of samples collected. Subsequently, we evaluated patient and endoscopist
factors that affected the number of samples obtained.
Patients and methods
Institutional Review board approval was obtained (404688-1). In this retrospective
study, we reviewed the records from two community hospitals in Michigan, United States:
St. John Providence Hospital and Medical Center, in Southfield and St. John Providence
Park Hospital and Medical Center, in Novi, Michigan. Both inpatient and outpatient
endoscopies were evaluated between 1 January 2008 and 11 February 2013. Patients were
included in the study according to International Classification of Diseases – ninth
revision (ICD-9) codes for endoscopy indications ( [Table 1]). The ICD-9 codes were selected according to all possible gastrointestinal manifestations
of celiac disease, as defined by the ACG [3]. Patients who did not meet inclusion criteria were excluded ( [Fig. 1]). Patients were also excluded if there was a pre-endoscopy explanation for the ICD-9
codes chosen, and thus, a low pretest probability for celiac disease.
Table 1
Pre-endoscopy International Classification of Diseases – ninth revision diagnosis
codes.
|
Indication
|
ICD-9 code
|
Grouping
|
Patients, n
|
|
Abdominal pain, other specified site
|
|
Abdominal pain, unspecified site
|
789.00
|
0
|
1600
|
|
Abdominal pain generalized
|
|
Anemia unspecified
|
285.9
|
|
|
|
Iron deficiency anemia
|
280.9
|
1
|
1294
|
|
Chronic blood loss anemia
|
280.00
|
|
|
|
Nausea with vomiting
|
780.71
|
|
|
|
Vomiting
|
787.03
|
2
|
901
|
|
Nausea
|
787.02
|
|
|
|
Diarrhea
|
787.91
|
3
|
209
|
|
Epigastric abdominal pain
|
789.06
|
4
|
1105
|
|
Abnormal weight loss
|
783.21
|
5
|
204
|
|
Right upper quadrant abdominal pain
|
789.01
|
6
|
128
|
|
Periumbilical abdominal pain
|
789.05
|
7
|
16
|
|
Right lower quadrant abdominal pain
|
789.03
|
8
|
19
|
|
Left upper quadrant abdominal pain
|
789.02
|
9
|
33
|
|
Left lower quadrant abdominal pain
|
789.04
|
10
|
23
|
|
Celiac disease (unconfirmed pre-endoscopy)
|
579.0
|
11
|
13
|
|
Dyspepsia and other specified
|
536.8
|
12
|
261
|
|
Other symptoms involving the digestive system
|
787.99
|
13
|
178
|
|
Flatulence eructation and gas pain
|
787.3
|
14
|
21
|
|
Transaminasemia
|
790.14
|
15
|
0
|
ICD, International Classification of Diseases.
Fig. 1 Exclusion criteria. EGD, esophagogastroduodenoscopy.
A total of 39 endoscopists were reviewed, three of whom were pediatric endoscopists.
Their expertise ranged from 1 year to more than 30 years of clinical practice. Trainees
were from all 3 years of a fellowship program (three per year).
Monitored anesthesia care with deep propofol sedation was used in all adult and pediatric
patients. Two types of gastroscopes were used in the adult population: Olympus GIF160
and GIF180 (Olympus, Tokyo, Japan). The Olympus GIF-XP160 gastroscope was used in
pediatric patients. White-light endoscopy with a two-bite technique was used for all
sample collections.
Endoscopic features were grouped into three categories: normal features with no gross
pathology, classic celiac disease features, and all other appearances. Classic celiac
disease features were findings in the endoscopy reports that were defined by previous
studies by Lee and Green in 2005 [11]: loss or reduction in duodenal folds, mosaic mucosal pattern, scalloped configuration
of the duodenal folds, micronodular pattern or increased vasculature pattern in the
duodenum.
Pathological diagnoses by seven general pathologists, with more than 5 years of experience,
were categorized as no celiac disease (NCD), celiac disease, or possible celiac disease
(PCD). In cases of doubt, intradepartmental consultation was obtained. Celiac disease
was defined according to the modified Marsh criteria [12]: shortening of villi and crypt hyperplasia with a villous to crypt ratio of less
than 3:1, presence of intraepithelial lymphocytosis (IEL), more than 40 IELs. If lesions
were less than the original Marsh – Oberhuber 3a classification [13], they were categorized as PCD; this group included Marsh I and II lesions, and villous
atrophy that did not fulfill Marsh criteria (villous atrophy without increased IELs).
Statistics
Statistical analysis was performed on the data using univariate, multivariate with
one-way between-groups analysis of variance, t tests, and chi-squared analysis using SPSS 15 (SPSS Inc., Chicago, Illinois, USA).
Results
A total of 8127 patients were reviewed and 5997 met the criteria for analysis ([Fig. 1]). Patients were categorized into three cohorts as determined by pathology. Of the
5997 patients, 41 patients (0.7 %) were diagnosed with celiac disease and 62 (1.0 %)
were classified as PCD ([Table 2]). Of all patients, 4038 (67.3 %) were female and 5530 (92.2 %) were over the age
of 20 years. Of the 4844 patients for whom race was documented, 2854 (58.9 %) were
Caucasian. Endoscopies were performed in the outpatient setting in 4656 patients (77.6 %),
and trainees were involved in 2045 procedures (34.1 %).
Table 2
Patient demographic details. Due to limited number of samples, patients with more
than six biopsies have not been included.
|
Diagnosis
|
NCD, no. of patients
|
Celiac disease, no. of patients
|
PCD, no. of patients
|
|
Race, n
|
|
|
2793
|
28
|
33
|
|
|
1916
|
4
|
10
|
|
|
43
|
0
|
0
|
|
|
12
|
1
|
0
|
|
|
4
|
0
|
0
|
|
|
1126
|
8
|
19
|
|
Sex, n
|
|
|
3965
|
34
|
39
|
|
|
1929
|
7
|
23
|
|
Age, mean, years
|
55
|
39
|
42
|
|
Patients < 20 years, n
|
445
|
8
|
14
|
|
No. of biopsies, n (%)
|
|
|
3660 (62.1)
|
0 (0)
|
0 (0)
|
|
|
331 (5.6)
|
1 (2.4)
|
8 (12.9)
|
|
|
975 (16.5)
|
6 (14.6)
|
27 (43.5)
|
|
|
465 (7.9)
|
10 (24.4)
|
15 (24.1)
|
|
|
243 (4.1)
|
4 (9.8)
|
8 (12.9)
|
|
|
109 (1.8)
|
2 (4.9)
|
1 (1.6)
|
|
|
111 (1.9)
|
18 (43.9)
|
3 (4.8)
|
|
Total diagnosis
|
5894
|
41
|
62
|
NCD, no celiac disease; PCD, possible celiac disease.
The frequency of celiac disease diagnosis increased with increasing sample number
( [Fig. 2]). Using chi-squared analysis, the prevalence of celiac disease diagnosis was 0.3 %
when fewer than four specimens were collected compared with 4.7 % when four or more
were collected (chi-squared = 139.7, P < 0.001). The prevalence of celiac disease diagnosis increased to 12.8 % when six
or more specimens were collected compared with 0.4 % when fewer than six were collected
(chi-squared = 304.22, P < 0.001). The percentage of patients diagnosed with PCD from only one sample was
2.3 % and peaked at 3.1 % for four specimens.
Fig. 2 Diagnostic yield based on number of biopsies.
A total of 508 patients (8.5 %) had four or more biopsies performed. Four or more
specimens were obtained with increased frequency during the study, with 20 cases in
2008 and 126 cases in 2012. A similar pattern was seen for six biopsies, with 9 cases
in 2008 and 44 cases in 2012. Of the patients diagnosed with celiac disease, 43.9 %
had six specimens collected, 9.8 % had four biopsies, and 14.6 % were diagnosed from
two specimens. The likelihood of having a diagnosis of PCD was more common with two
samples (43.5 %), with the diagnosis of PCD falling to 4.8 % in patients with six
samples.
Each variable was assessed for its number of biopsies in relation to final diagnosis.
Supplemental [Fig. 1] demonstrates the mean number of biopsy samples in relation to indication. Diagnoses
for all types of ICD-9 abdominal pain codes were combined. Diarrhea for the celiac
disease group had a mean of 5.0 specimens, whereas anemia had a mean of 4.0 samples.
When celiac disease was suspected as the indication, a mean of 4.0 biopsies were performed.
In the NCD and PCD cohorts, there was a statistically significant difference between
the indications using an unpaired t test (P < 0.001 and P = 0.001, respectively). Owing to the limited sample size, only indications for abdominal
pain, anemia, and diarrhea were used in the PCD group for this analysis. No difference
was observed in the celiac disease group (P = 0.59).
Analyzing the three groups for endoscopic features, patients with classic endoscopic
celiac features had more samples collected ( [Fig. 3]). Differences were seen in the NCD, PCD, and celiac disease cohorts for mean number
of samples collected in relation to endoscopic features (P = 0.001, P = 0.04, P = 0.06, respectively).
Fig. 3 A box-whisker plot revealing the distribution of the mean number of samples collected
for each diagnosis cohort and their respective endoscopic features. NF, normal features;
CDF, classic disease features; NCCDF, nonclassic celiac disease features; PCD, possible
celiac disease; CD, celiac disease; NCD, no celiac disease.
When endoscopy was performed in the inpatient setting, 5 out of 1341 patients (0.4 %)
were diagnosed with celiac disease, and 16 (1.2 %) with PCD. A mean of 0.46 specimens
were collected within the inpatient group compared with 1.17 in the outpatient setting
(P = 0.001). No difference in mean specimen number was observed for celiac disease and
PCD (P = 0.11 and P = 0.48, respectively).
When a pediatric gastroenterologist performed endoscopy (compared with an adult gastroenterologist),
a greater median number of biopsies was obtained for all three cohorts. Only three
pediatric gastroenterologists were reviewed, and 468/5997 patients were under the
age of 18 years. Supplemental [Fig. 2] shows that pediatric patients with celiac disease had a narrower range of biopsy
sample number compared with adult patients with celiac disease. Using an unpaired
t test, no difference was observed for pediatric patients in the celiac disease and
PCD cohorts compared with the adult cohorts (P = 0.35 and P = 0.63, respectively). A difference was observed for the NCD cohort (P < 0.001).
With regard to patient demographic details and trainee presence, the three cohorts
were aggregated before analysis was performed. With respect to sex, female patients
had a statistically greater mean number of specimens collected – 1.07 compared with
0.96 specimens collected for male patients (P = 0.004). Only 4844 patients identified their race: 2854 (58.9 %) were Caucasian,
1930 (39.8 %) were African American, 43 (0.9 %) were Asian, and 13 patients (0.3 %)
were of Middle-Eastern descent. Only Caucasian and African American patients were
compared owing to the small number of patients in the other groups. Caucasian patients
had a mean of 1.2 specimens collected compared with 0.6 for African American patients
(P < 0.001). With respect to age, mean biopsy number generally decreased with advancing
age, and this decline was significant for the no celiac disease group (P < 0.001) ( [Fig. 4]). In the presence of a trainee, on average fewer specimens were collected – 0.9
compared with 1.1 without a trainee (P < 0.001).
Fig. 4 Mean number of biopsy samples by age.
Discussion
The results of this study have confirmed previous studies demonstrating that celiac
disease diagnosis is dependent on the number of biopsies taken. Patient factors, such
as endoscopic features, indication, and demographic details, and endoscopist factors
such as absence of a trainee, type of gastroenterologist (pediatric vs. adult), and
the endoscopy setting (inpatient vs. outpatient) appear to determine whether an adequate
number of biopsies are taken.
We saw a significant increase in celiac disease diagnosis when six or more samples
were collected. This may be due to a small sample size; however, this observation
was not noted with four and five specimens compared with two and three specimens as
seen in previous studies [14]. Overall, 499 patients (8.3 %) with suspected celiac disease had four or more specimens
obtained; however, the percentage of patients with six or more specimens submitted
increased annually. Our results are comparable to previous studies that showed patients
undergoing esophagogastroduodenoscopy (EGD) with celiac disease as a differential
diagnosis often do not undergo duodenal biopsy, nor are the recommended number of
specimens collected [14]
[15].
We found that patient factors that can influence whether an adequate number of biopsies
are taken include endoscopic features and demographic details. Demographic details
include the patient’s age (pediatric vs. young adult vs. older adult), race, and sex.
The mean number of biopsies increased for classic endoscopic features of celiac disease,
for Caucasian patients vs. African American patients, for female vs. male patients,
and for younger vs. older patients. Other patient factors include the indication for
endoscopy. For classic celiac disease symptoms and manifestations, mean biopsy number
was greater than for nonspecific celiac disease symptoms. Additionally, for endoscopist
factors, the mean number of biopsies was greater when a trainee was not present, when
a pediatric rather than an adult gastroenterologist performed the procedure, and when
the patient was seen in an outpatient setting rather than as an inpatient.
More biopsies were performed when classic celiac disease endoscopic features were
present, even though these features have a poor sensitivity and positive predictive
value when applied to the dyspeptic population [16]. Moreover, the reliability of endoscopic features in celiac disease diagnosis has
been disappointing [16]. In our study, 74 % of patients with celiac disease had classic endoscopic features;
however, about 70 % of the PCD cohort did not have classic celiac disease features,
which probably led to the lower number of biopsies obtained in this group. Therefore,
biopsy number should not be influenced by gross examination. It is important to note,
that an endoscopist might have a greater suspicion of celiac disease from gross appearance
with newer diagnostic techniques [17], which might lead to a greater number of samples collected.
Patient demographic factors significantly influenced sample number. A higher index
of suspicion, as reflected in the number of biopsy samples collected, diminished after
the age of 60 years. This can be problematic because celiac disease can present after
the age of 60 [18]. Our study demonstrated a similar reported pattern to that observed within the United
States for biopsy disproportion with respect to ethnicity and race [19]. More biopsies were performed in Caucasian patients than in African American patients
or other minority groups. This is likely to be due to a lower index of suspicion,
as a lower prevalence of celiac disease has been reported in minority groups [20]. In our study, the suspicion for celiac disease in nonwhite patients was lower,
leading to fewer biopsy samples. This suggests that celiac disease may be overlooked
in minority groups [19].
In the examination of sex differences, the NCD cohort revealed a statistically significant
discrepancy in biopsy number. This agrees with multiple epidemiological studies showing
that women are more likely to be diagnosed [21]; however, serological screening reveals a more equal sex difference. Lebwohl et
al. demonstrated that men are less likely to undergo duodenal biopsy than women for
the same indication [19].
Manifestations of celiac disease such as chronic diarrhea, chronic anemia, or osteoporosis
require outpatient evaluation. When patients present to the hospital and warrant endoscopic
evaluation, their symptoms are typically more acute and severe. There were statistically
significantly fewer samples obtained in the inpatient setting owing to a lower index
of suspicion for celiac disease. However, fewer samples may have been obtained, as
hospitalized patients are typically more ill and may have had clearer endoscopic signs
requiring fewer samples, as biopsy would be targeted to the affected areas. The majority
of celiac disease diagnoses were made in outpatients. Nonetheless, we cannot conclude
that celiac disease should mainly be investigated in the outpatient setting because
there was a disproportionate number of patients evaluated in this setting. Knowing
the significant variation for celiac disease presentation and multiple disease associations
that can be seen in a hospital setting, such as myocarditis, inflammatory bowel disease,
sarcoidosis, IgA nephropathy, and epilepsy [22], it is essential that guidelines are adhered to regardless of the patient setting.
We delineated a group as PCD given the uncertainty regarding celiac disease among
those with histological abnormalities that did not include villous atrophy with concomitant
IEL. This group had significantly fewer biopsies. It is possible that some members
of this group may have had celiac disease. The differential diagnosis of these more
minor changes of increased IELs with normal villous height and villous abnormalities
includes, as well as celiac disease, Helicobacter pylori-associated gastritis, medications (primarily nonsteroidal anti-inflammatory drugs),
infections, bacterial overgrowth in the small intestine, and immune dysregulation
[23]. Unless more specimens are evaluated, the pathologist could not confidently label
patients with a definitive celiac disease diagnosis. The diagnosis of those labeled
as PCD becomes challenging to manage, as a definitive therapeutic option cannot be
offered for the patient’s symptoms.
Classic celiac disease symptoms are diarrhea, steatorrhea, and weight loss due to
malabsorption [3]. This notion is consistent with our observation: celiac disease was considered highly
likely when the indication was diarrhea, as this indication had the greatest number
of samples collected in the celiac disease cohort. Interestingly, it was nonspecific
gastrointestinal symptoms and abdominal pain indications that had the most samples
collected in the PCD cohort. Newer reports suggest that the clinical presentation
of celiac disease for adults has changed over time, and typical presentation should
not be expected in the adult population [24]. Thus, it becomes important to appropriately investigate the broader spectrum of
symptoms and adhere to the guidelines irrespective of the indication.
Our initial suspicion was that the presence of a trainee would increase compliance
with ACG recommendations. Previously, it has been demonstrated that the involvement
of a trainee increased the detection rate of polyps during screening colonoscopies
[25]. The results of this study did not support this hypothesis.
This study strongly demonstrates the importance of following guidelines in order to
maximize the yield of celiac disease diagnosis during endoscopic evaluation. Following
guidelines will also minimize the number of patients who are classified as PCD or
who are misdiagnosed with no celiac disease. Previous studies demonstrated that a
proportion of patients were diagnosed with celiac disease only after repeat EGD or
in some instances multiple EGDs [1]. This reiterates the importance of collecting six samples. In addition to collecting
the appropriate quantity of samples, targeting biopsies in the duodenal bulb, at the
9- or 12-o’clock position, may improve the yield [5]. It has been shown in several studies that celiac disease-related histological lesions
are present in the bulb, with isolated mucosal abnormalities seen in up to 13 % of
celiac disease cases [26]
[27]. Furthermore, histopathological abnormalities of celiac disease are patchy, and
orientation of biopsy specimens can be variable, with crush biopsy artifacts [13]
[15]. Poor orientation and other technical processes render about 10.7 % of biopsies
inadequate [28]. The orientation of the specimen can be influenced by the number of bites during
the forceps pass [29]. In addition, sample clumping, small biopsies, and incorrect preparation should
be considered [30], as they may affect the final pathological reading. Interpretations of histological
artifacts can be minimized by using the Corazza-Villanacci grading system rather than
the Marsh criteria, to reduce the possible disagreement in gluten-sensitive enteropathy
[31].
The strengths of our study include a large cohort examined over a 5-year time frame.
The study was performed within a community setting, making the data clinically applicable,
and multiple variables were simultaneously investigated. No previous studies have
looked at the presence of a trainee or endoscopy clinical setting, and their impact
on the number of samples collected. Limitations of our study include the retrospective
design. Pertinent clinical data that would affect the pretest probability of detecting
celiac disease, such as family history, human leukocyte antigen tissue transglutaminase
antibody serology, and gluten-free diet response, were not incorporated, particularly
in patients in the PCD cohort. Our finding of a higher yield of celiac disease diagnosis
with higher specimen submission might be due to reverse causality, that is, patients
who are most likely to have celiac disease may have more specimens submitted due to
the underlying suspicion of celiac disease by the endoscopist. The post-EGD diagnosis
(i. e. the final diagnosis in the NCD cohort) was not assessed, and the endoscopist
may have been justified in not taking adequate samples for celiac disease if the definitive
diagnosis was reached. Multiple pathologists were involved in the study, all of whom
were general pathologists. PCD cases were not sent for outside expert pathology interpretation.
Trainees from all three years of a fellowship program were included, and their degree
of experience and grade of participation were not assessed. Furthermore, the location
of the biopsy and the orientation within the duodenum were not assessed.
In summary, the yield of celiac disease diagnosis significantly improved with six
biopsy samples. Adherence to guidelines when celiac disease is suspected is still
not at goal, although there has been improvement in recent years. If celiac disease
is considered in the differential diagnosis, it is critical that guidelines are followed
to maximize the yield of the procedure.
Supplemental Fig. 1 Mean number of samples collected for each diagnosis cohort with regard to indication.
PCD, possible celiac disease; CD, celiac disease; NCD, no celiac disease.
Supplemental Fig. 2 A box-whisker plot illustrating the distribution of the mean number of samples collected
for pediatric patients compared with adult patients for each diagnosis cohort. NCD,
no celiac disease; CD, celiac disease PCD; possible celiac disease.
