The prevalence of upper gastrointestinal (GI) tract involvement in symptomatic patients with Crohn’s disease (CD) varies between 0.5 and 5% [1
]. More recent observational studies, in which esophagogastroduodenoscopy (EGD) was performed as a routine part of the diagnostic evaluation, have demonstrated a higher frequency of both endoscopic and histopathological findings [4
There is no recommendation to perform EGD in asymptomatic adult patients with CD. Studies performed in the pediatric population have demonstrated that the involvement of the upper GI tract has a higher prevalence; it is thus recommended to perform EGD with biopsies of the upper gastrointestinal tract routinely at the time of diagnosis in pediatric patients [6
Similarly to the involvement of the lower digestive tract, endoscopic findings are not specific and include erosions, aphthous ulcers, longitudinal ulcers, strictures, and fistulas [8
]. The main histological findings described are chronic inflammation, lymphoid aggregates, fibrosis, focally enhanced gastritis (FEG), and epithelioid granulomas [9
]. The lower prevalence of H. pylori
infection in patients with CD is a topic that is still debated, with studies showing conflicting results [11
In the non-Caucasian population, these alterations are studied less often [13
]. The aim of the present study was to describe the main endoscopic and histopathological findings of the esophagus, stomach, and duodenum in a sample of patients with CD being treated in a reference outpatient clinic for IBD (inflammatory bowel disease) in Brazil.
3.1. Demographic and Clinical Characteristics
The demographic and clinical characteristics of the subjects included are listed in Table 1
The mean age at the time of EGD was 42.1 (±12.8). The median time of diagnosis was 48 months (1-312). In relation to ethnicity, 10 patients (17.2%) declared themselves as white, 16 patients (27.6%) as black, and 31 patients (53.4%) as mixed race. Poor socioeconomic status was declared by 51 patients (87.9%). Symptoms related to the upper GI tract were present in 39 subjects (67.2%), pyrosis in 21 patients (36.2%), postprandial distress in 18 patients (31%), and epigastric pain in 17 patients (29.3%).
3.2. Endoscopic Findings
EGD showed changes in 51 patients (87.9%). The most frequent macroscopic alterations were edema, erythema, and erosions. The stomach was the site with the highest frequency of lesions, found in 40 patients (69%), compared to the lesions of the esophagus in 30 patients (51.7%) and of the duodenum in 22 patients (37.9%).
In the esophagus, the most frequent diagnosis was erosive esophagitis, present in 25 patients (43.1%) and classified as grade A (Los Angeles) in 21 of 25 patients (84%), grade B in three of 25 patients (12%), and grade C in one of 25 patients (4%). Aphthous ulcers located in the distal third were identified in one patient (1.7%).
In the stomach, gastritis was the most frequent finding, identified in 32 patients (55.2%), with the erosive type in 19 of 32 patients (59.4%), and the erythematous type in 13 of 32 patients (40.6%). The most frequent location of gastritis was the antrum, in 15 of 32 patients (46.9%), followed by concomitant involvement of the body and antrum in 12 patients (37.5%), and, less frequently, the involvement of the body in five patients (15.6%). The intensity was classified as mild in 26 patients (81.2%). Two active gastric ulcers (Sakita A2) and one duodenal ulcer (Sakita H1) were observed during EGD in one H. pylori-positive patient.
There was no association between the presence of erythema and gastric erosion and age, gender, time of diagnosis, smoking, alcohol intake, treatment, location, behavior, or activity of the disease.
The duodenum was the least affected site, presenting with a normal appearance in 36 patients (62.1%). Erosive duodenitis was the most frequent duodenal finding, present in eight patients (13.8%). Duodenal ulcers were identified in three patients (5.2%), two of whom were H. pylori-positive. Ulcer scars were identified in four patients (6.9%), two of whom were H. pylori-positive, and two of whom were H. pylori-negative.
No strictures or fistulas were identified in the esophagus, stomach, or duodenum.
The main endoscopic findings were similar between the patients in remission or active disease states.
The frequency of erosive esophagitis, gastritis, and duodenitis was similar between patients with or without upper GI symptoms. The endoscopic findings in patients with CD according to the presence or absence of upper GI symptoms are listed in Table 2
3.3. Histopathological Findings
Among the 58 subjects included, seven (12.1%) underwent esophageal biopsies due to erosion, aphthous ulcer associated with scars, prolongation of columnar epithelium, and whitish plaques suggestive of Candida esophagitis and eosinophilic esophagitis. Chronic esophagitis was identified in six patients (85.7%), spongiosis in three patients (42.9%), and basal hyperplasia in two patients (28.6%). Just one patient (14.3%) presented normal histopathology.
illustrates the histopathological findings in one patient with aphthous ulcer in distal esophagus.
Chronic gastritis was identified in the body in 52 patients (89.7%) and in the antrum in 51 patients (87.9%), with a predominance of mononuclear cells in 37 patients (63.8%) and discrete infiltrate of the lamina propria in 35 patients (60.3%). Histopathological alterations were present in 18 of 19 patients (94.7%) of the patients with erosive gastritis, and in 13 of 13 patients (100%) with erythematous gastritis. Focally enhanced gastritis (FEG) was identified in four patients (6.9%), all of whom were H. pylori-
negative (Figure 2
), two with erythematous gastritis and two with erosive gastritis. Epithelioid granuloma was not found.
In the duodenum, the main findings were duodenitis in four patients (6.9%), with lymphocytic infiltrate in three patients (5.2%), mild activity in three patients (5.2%), and moderate activity in one patient (1.7%); intraepithelial lymphocytosis in one patient (1.7%), gastric metaplasia in one patient (1.7%), focal fibrosis in one patient (1.7%), and hyperplasia of Brunner glands in four patients (6.9%). Duodenal biopsies were normal in 47 patients (81%).
3.4. Comparison between H. Pylori-Positive and H.-Pylori-Negative Patients
The clinical characteristics were similar between the H. pylori-positive and H. pylori-negative patients.
The main endoscopic and histological findings among the patients positive and negative for H. pylori
are shown in Table 3
and Table 4
Endoscopic findings were compared between the H. pylori-positive and H. pylori-negative patients, with a higher frequency of antral involvement observed in the H. pylori-negative patients and a higher frequency of pangastritis and a greater intensity of gastritis observed in the H. pylori-positive patients, with no statistically significant difference (p > 0.05).
The presence of H. pylori was associated with increased inflammatory activity in the body and antrum, with a predominance of mononuclear and polymorphonuclear cells and permeation of inflammatory cells around the glands, whereas in the H. pylori-negative group, the inflammatory activity was discrete with a predominance of mononuclear cells (p < 0.05).
The presence of upper GI involvement in patients with CD is variable and has been poorly described. Existing studies are heterogeneous regarding the description of upper GI symptoms, the number and location of biopsies, and specific protocols used for histopathological analysis. This is the first study from Latin America to evaluate the clinical, endoscopic, and histopathological aspects of the upper GI tract, exclusively in patients with CD, in a region of high endemicity for H. pylori infection.
Although we observed a high frequency of milder erosive esophagitis, this finding is considered nonspecific [19
]. We identified one patient with an aphthous ulcer located in the distal third with mononuclear inflammatory infiltrate at the time of diagnosis, findings that may suggest an association with CD. Some studies have reported that superficial ulcers and erosions were the most frequent endoscopic findings, with an increase in chronic inflammatory infiltrate [20
]. Therefore, in a patient with CD and esophageal lesions, even if superficial, it is important to perform biopsies, to confirm the involvement and to rule out other conditions such as esophageal reflux disease and infection.
In the stomach and in the duodenum, the most frequent endoscopic findings were edema, erythema, and erosions. Our data are in line with the literature in which gastric nonspecific inflammation was the most common finding described [10
]. Erosions located in the gastric antrum are described at frequencies ranging from 24 to 73% and are difficult to distinguish from erosive gastritis due to other etiologies [16
]. Duodenal lesions are reported at a frequency of 21 to 32.1% and include erosions, ulcers, and a notch-like appearance [23
]. Sakuraba et al. [25
] and Horje et al. [5
] considered the presence of erosions to be a criterion for GI tract involvement when they were associated with suggestive histopathological findings such as FEG, epithelioid granuloma, and crypt distortion [18
]. The finding of gastroduodenal erosions alone in patients negative for H. pylori
does not meet the criteria necessary to define the involvement of these segments, and the correlation between endoscopic and histopathological findings is important [27
In the histopathological analysis, our results demonstrated that all H.-pylori
-negative patients presented with chronic inactive gastritis, characterized by the presence of lymphocytes with no evidence of granulocytes. Although this type of gastritis has been described in patients with CD, chronic active gastritis is more often related. Sonnenberg et al. [28
] demonstrated that both H. pylori-
negative chronic active gastritis and H. pylori-
negative chronic inactive gastritis were more frequent in patients with IBD compared to controls. The finding of chronic inactive gastritis in our sample may be associated with previous treatment for H. pylori
or previous use of PPI, since there may be persistence of the lymphocytic infiltrate in these situations, with no evidence of neutrophils and a higher frequency of H. pylori-
negative chronic inactive gastritis [29
Sonnenberg et al. [28
] demonstrated that FEG had an increased prevalence in patients with IBD when compared to healthy controls. The prevalence of FEG was 43% to 71.4%, according to some authors [5
]. Parente et al. [32
] related a prevalence of 12% in patients with UC and 19% in controls, demonstrating that although this is a frequent finding, it is not specific to CD and can be found in other clinical conditions. The identification of FEG requires multiple gastric biopsies at different sites, which may make its identification difficult in clinical practice [28
]. The few cases observed in our sample, all of them without H. pylori
infection, may be explained by the limited number of biopsies performed. Since H. pylori
may be associated with FEG, it is necessary to rule out this infection before associating this finding with CD.
Giemsa staining was positive for H. pylori
in 32.8% of our patients, which was lower than expected in a population with a high prevalence of this infection. In Brazil, the prevalence is considered high, estimated to be present in 71.2% of the population [33
]. The lower prevalence of this infection in patients with CD could be justified by the frequent use of some medications, such as antibiotics and sulfasalazine, or by immunological mechanisms unknown [30
]. Two meta-analyses, performed by Luther et al. [11
] and Wu X et al. [34
], demonstrated a prevalence of H. pylori
infection of 27.1% and 24.9% in patients with IBD, compared with 40.9% and 48.3% in the control groups without IBD, respectively. The lower prevalence identified in our study may also be associated with prior eradication status, recent use of antibiotics, or the use of only one method to detect the bacteria.
In our study, gastroduodenal granulomas were not identified. The prevalence of granulomas is variable and their identification depends on whether the material is the result of a surgical specimen or biopsy fragments, the biopsied site, and the number of fragments removed [23
]. The finding of granulomas is less frequent in patients taking anti-TNF, since granuloma formation is dependent on inflammatory cytokines and alpha-TNF [4
]. Some studies have demonstrated a correlation between a younger age, short history of disease, and the presence of granulomas [36
]. The time of diagnosis, the age range of the patients included, the use of anti-TNF by almost one-third of the patients, and the conventional histopathological analysis may have influenced the lack of detection of granulomas in our sample.
Recent observational studies have been shown a higher frequency of involvement of the esophagus, stomach, and duodenum, with a prevalence between 16% to 41%. This involvement was more frequently identified when the endoscopy was performed at the time of diagnosis, independent of the presence of gastrointestinal symptoms [4
]. Additional studies are needed to confirm the benefit of EGD to evaluate the extent of disease in adult asymptomatic patients at the time of diagnosis. Despite this greater frequency of endoscopic findings when endoscopy is performed at the moment of diagnosis, many findings are nonspecific with uncertain relevance.
The shortcomings of our study are the small number of patients, the single-center-based design, the absence of a control group without CD for comparison in our results, and the use of only one method for the detection of H. pylori. The majority of patients were in treatment with immunosuppressive or biological therapies at the time of endoscopy, which may have led to underestimation of the presence of more specific findings, such as epithelioid granuloma. Other relevant aspects not evaluated were the recent use of antibiotics, prior eradication status of H. pylori, and identification of chronic users of PPI.
Studies evaluating the frequency of endoscopic and histopathological findings in the upper GI tract in patients with CD are scarce; some have been retrospective and only one was designed to evaluate the prevalence at the time of diagnosis in all adult patients included. Another relevant aspect is that our study used the same endoscopist and pathologist, both blinded to the clinical presentation, reducing the observation bias. Furthermore, the pathologist was blinded to the endoscopic aspects of the study. The absence of more specific findings such as epithelioid granuloma, and the few cases of FEG detected in this sample, may reflect the difficulty of diagnosing upper GI tract involvement in clinical practice via the histopathological study of conventional biopsies from patients under treatment.