| Background and Aims:Crohn’s disease (CD) is a major type of inflammatory bowel disease (IBD), which is characterized by a chronic, segmental transmural inflammation that can occur in any portion of the gastrointestinal (GI) tract, from mouth to anus. CD is quite common in Europe, and its prevalence ranges from 26.0 to 198.5 cases per 100,000 persons, and the incidence rates range from 3.1 to 14.6 cases per 100,000 person-years. The prevalence and incidence rates of CD in China range 2.29 cases per 100,000 persons and 0.848 cases per 100,000 person-years, respectively. Although the prevalence of CD is quite lower in China than that in the western countries, the epidemiological studies have shown that its prevalence in China is on the rise.CD is a chronic inflammatory disease of uncertain etiology and pathogenesis, and it is usually contributed to complex and multi-factorial pathologic processes. Because of the difference of the position, the extent and the degree of disease, the clinical manifestations of CD is complex and diverse, including gastrointestinal symptoms, systemic manifestations, extra-intestinal manifestations and complications. The common gastrointestinal symptoms of CD include abdominal pain, diarrhea and bloody stools.Some CD patients may have systemic manifestations, such as weight loss/emaciation, fever, inappetence, anemia and hypoproteinemia. And some CD patients may also complain extra-intestinal manifestations which include oral ulcer, arthropathy, liver and gallbladder disease, and oculopathy and so on. Fistulization, intestinal obstruction, intra-abdominal abscess and perianal diseases (including perianal abscess, perianal fistula, anal fissure and perianal skin tag) are the common complications of CD. Non-caseating granulomas are the pathological feature of CD, but its endoscopic biopsy positive rate is not high. For no pathological hallmark and definitive criteria, the diagnosis of CD should be based on clinical evaluation and a combination of endoscopic, histological, radiological, and/or biochemical investigations. So far, the disease cannot be cured with easy to relapse, and it has impact on patients’ health-related quality of life (HRQL) to different degrees.CD has a predilection for the ileum, the colon, the rectum, and the perianal regions while the upper gastrointestinal involvement has been rarely described. Upper gastrointestinal involvement of CD (UGCD) may be easy to be misdiagnosis and missed diagnosis. At present, reported incidence of UGCD difference is larger and has a rising trend. The incidence of esophageal CD ranged from 0.3% to 2.0%, while the incidence of stomach and duodenum CD ranged from 0.5% to 4.0%. In 2001, Freeman et al reported that the incidence of UGCD was 11.3%, and Annunziata et al reported that the incidence of UGCD was 16% in 2012. At the same time, some studies suggested that the pathogenesis of IBD was closely related to the heredity and immunity. Hence, the epidemiological characteristics of different ethnic groups may also be a larger difference. In 2004, Leong et al reported that Chinese CD patients in China Hong Kong were characterized by a low proportion of isolated terminal ileal disease (4%) and high proportion of upper gastrointestinal tract disease proximal to the terminal ileum (19%). In 2009, Chow et al also reported that Chinese CD patients were found to have more upper GI tract involvement (22.7%), which predicted the need of operation and further hospitalization. Early literature reports showed that most of the patients with UGCD often required surgical intervention. Even so, there had been a limited number of documented cases reported in the international literature. With the increasing incidence of IBD, the frequent performance of the upper endoscopy and the wide application of endoscopic ultrasonography (EUS) and histological examination, the incidence of UGCD may be more common than it was originally thought. However, the data of UGCD is still limited, especially in China.Based on the above research background, in the present study, a retrospective analysis was performed. And the demographic features (such as gender, age at onset of symptoms, family history), clinical characteristics, Montreal classification, radiologic characteristics, endoscopic and pathological features, management and outcomes of 62 patients who suffered from CD of upper gastrointestinal involvement in Department of Gastroenterology at NanFang Hospital, Southern Medical University, between January 1,2005 and November 30,2014, were analyzed. Our study provided a largest sample study about UGCD and more further studies are required to determine accurate diagnosis, promptly management and better prognosis.Material and methods1. Subjects:The study population consisted of 62 patients who suffered from CD of upper gastrointestinal involvement in Department of Gastroenterology at NanFang Hospital, Southern Medical University, between January 1,2005 and November 30,2014. The diagnosis of CD should be based on clinical evaluation and a combination of endoscopic, histological, radiological, and/or biochemical investigations, according to Chinese Society of Gastroenterology (CSGE), Inflammation Bowel Disease group "The Consensus on Diagnosis and Management of Inflammatory Bowel Disease (Guangzhou,2012)".2. Methods:This study was approved by the ethics committee of NanFang Hospital of Southern Medical University. The medical records of the patients were reviewed by two experienced investigators. Demographic features (such as gender, age at onset of symptoms, family history), clinical manifestation, Montreal classification, imagine, endoscopy, pathology records, therapeutic schedule and outcomes were reviewed and retrospectively analyzed.3. Statistical analysis:Statistical analysis was performed with SPSS 16.0 software by a medical statistician. Descriptive statistics were calculated with means and standard deviations or as medians and interquartile range (IQR), if not normally or log-normally distributed. The enumeration data were calculated with sample number and percentage and compared with Chi-square test. Association significant when p<0.05 is considered.Results:1. During the study period,62 patients were identified with upper gastrointestinal involvement. Among 62 patients,24 (38.7%) patients had simple UGCD, whereas 38 (61.3%) presented with small and/or large bowel disease. Of the total,40 (64.5%) were male and 22 (35.5%) were female. The mean age at onset of symptoms was (33.6±12.5) years (range 15-72 years). Forty-eight patients (77.4%) were diagnosed between the age of 17 and 40 years, and 14 patients (22.6%) were diagnosed older than 40 years. The time of final diagnosis ranged from 1 to 121 months. The median time of final diagnosis for simple UGCD patients was 4 months, while the median time of final diagnosis for the ones presented with small and/or large bowel disease was 8 months.2. During the study period,149575 patients underwent upper endoscopy examination in Digestive Endoscopy Center of NanFang Hospital. Among 149575 patients,85916 (57.4%) patients were male,40 (0.47%o) of 85916 were identified with UGCD. The other 63659 patients were female, and 22 patients (0.35%o) were identified with UGCD. The detection rate of UGCD between genders has no significant difference (x2=1.270,P=0.260).3. During the study period, a total of 62 patients were diagnosed with UGCD. The research showed that 2 patients (3.2%) were diagnosed in 2005,2 patients (3.2%) in 2006,3 patients (4.8%) in 2007,4 patients (6.5%) in 2008,4 patients (6.5%) in 2009, 6 patients (9.7%) in 2010,9 patients (14.5%) in 2011,9 patients (14.5%) in 2012,10 patients (16.1%) in 2013 and 13 patients (21.0%) in 2014. From the above data, the detection rate of UGCD increased year by year.4. Among the patients with UGCD, retrosternal pain (32/46,70.0%), heartburn (24/46, 52.2%), odynophagia (18/46,39.1%) suggesting an esophageal involvement, and abdominal pain (17/21,81.0%), melena (10/21,47.6%), vomiting (10/21,47.6%) suggesting a duodenal and/or gastric involvement, were the main symptoms. Patients suffered isolated UGCD had no systemic manifestations, while the ones who presented with small and/or large bowel disease had common systemic manifestations, including weight loss (18/38,47.4%), fever (6/38,15.8%) and anemia (3/38,7.9%). Patients suffered isolated UGCD had no perianal diseases, but 7 (11.3%) of the ones who presented with small and/or large bowel disease had perianal diseases (including perianal abscess in 2, perianal fistula in 3, and anal fissure in 2 patients). Patients suffered isolated UGCD had complications including esophageal stenosis (1/24,4.2%) and pyloric obstruction (1/24,4.2%), and the ones presented with concomitant small and/or large bowel disease had complications such as obstruction (7/38,18.4%), gastrointestinal bleeding (6/38,15.8%) and fistula formation (2/38,5.3%).5. The Montreal classification of patients with UGCD:(1) Age at diagnosis:1 patient (1.6%) was diagnosed under 16 years of age (A1),40 patients (64.5%) between the age of 17～40 years (A2) and 21 patients aged older than 40 years (A3),1) Isolated UGCD:No one was diagnosed as A1,17 patients (70.8%) as A2 and 7 patients (29.2%) as A3,2) Patients presented with concomitant small and/or large bowel disease:1 patient (2.6%) was diagnosed as A1,27 patients (71.1%) as A2 and 10 patients (26.3%) as A3. (2) Location:27 patients (43.5%) were diagnosed as terminal ileum and upper gastrointestinal disease (L1+L4),2 patients (3.2%) as colon and upper gastrointestinal disease (L2+L4),9 patients (14.5%) as ileocolon and upper gastrointestinal disease (L3+L4),24 patients (38.7%) as isolated upper gastrointestinal disease (L4). (3) Behavior:41 patients (66.1%) had non-stricturing and non-penetrating disease behavior (B1),17 patients (27.4%) having structuring disease behavior (B2),4 patients (6.5%) having penetrating disease behavior (B3), and 7 patients (11.3%) having perianal disease (P).1) Isolated UGCD:22 patients (91.7%) had non-stricturing and non-penetrating disease behavior (B1),2 patients (8.3%) having structuring disease behavior (B2), no patient having penetrating disease behavior (B3) and perianal disease (P),2) Patients presented with concomitant small and/or large bowel disease:19 patients (50.0%) had non-stricturing and non-penetrating disease behavior (B1),15 patients (39.5%) having structuring disease behavior (B2),4 patients (10.5%) having penetrating disease behavior (B3), and 7 patients (11.3%) having perianal disease (P).6. The endoscopic features of the lesions in UGCD were various:(1) esophageal CD: The most common endoscopic findings were ulcers (45/46,97.8%), longitudinal ulcer in 28 (62.2%), crater-like ulcer in 12 (26.7%), irregular ulcer in 7 (15.6%), aphthoid ulcer in 2 (4.4%), and annular ulcer in 1 patient (2.2%). The other lesions such as erosion in 4 (8.7%), irregular ulcer with cobble-stone sign in 1 (2.2%), longitudinal ulcer with polypoid lesion in 1 (2.2%), longitudinal ulcer with esophageal stenosis in 2 patients (4.3%) were detected. (2) gastric CD:ulcer in 5 (50.0%), erosion in 3 (30.0%), pyloric obstruction in 3 (30.0%), cobble-stone sign with gastric fistula in 1 patient (10.0%) were found. (3) duodenal CD:ulcer in 11 (73.3%), erosion in 3 (20.0%), cobble-stone sign in 4 (26.7%), and luminal stenosis in 7 (46.7%) were seen under upper endoscopy. Among 7 patients with luminal stenosis,3 of them had ulcer with luminal stenosis,3 showing cobble-stone sign with luminal stenosis, and 1 having cobble-stone sign, luminal stenosis with fistulization.7. The distribution features of UGCD:(1) esophageal CD:The middle third of the esophagus was involved in 37 patients (80.4%), and the distal, proximal third involvement was identified in 18 patients (39.1%) and 6 patients (13.0%), respectively. (2) gastric CD:There was 1 case (10.0%) in the cardia of stomach,2 cases (20.0%) in the fundus of stomach, and 3 cases each (30.0%) in the body, the antrum of stomach and the pylorus. (3) duodenal CD:The duodenal bulb was involved in 12 cases (80.0%) and the descending part of duodenum was identified in 5 cases (33.3%).8. The pathological features of UGCD:(1) esophageal CD:46 patients underwent endoscopic biopsy, nonspecific inflammation, submucosal inflammatory thickening with a lymphocytic infiltrate in the lamina propria was detected in 45 patients (97.8%), non-caseating granulomas only in 1 case (2.2%), and crack-like ulcer in 11 patients (23.9%). (2) gastric CD:7 patients underwent endoscopic biopsy, all of their pathological findings were chronic inflammation.2 patients underwent distal gastrectomy, and the postoperative pathological findings were stomach and duodenum CD. (3) duodenal CD:11 patients underwent endoscopic biopsy, chronic inflammation was found in 10 (90.9%), and non-caseating granulomas only in 1 patient (9.1%).9.40.3%(25/62) of UGCD cases were misdiagnosed as other diseases. Among them, 18 patients (72.0%) with isolated UGCD were misdiagnosed as esophageal ulcer (11/18,61.1%), esophageal carcinoma (1/18,5.6%), esophageal tuberculosis (2/18, 11.1%), pyloric obstruction (1/18,5.6%) and peptic ulcer (3/18,16.7%).7 patients (28.0%) presented with small and/or large bowel disease were misdiagnosed as gastric lymphoma (1/7,14.3%), pyloric obstruction (2/7,28.6%), peptic ulcer (1/7, 14.3%) and gastrointestinal bleeding (3/7,42.9%).10. Management and outcome of UGCD:(1) Medication treatment:All of our patients were treated with medicine (proton pump inhibitors (PPIs), oral steroids, immune modulators, infliximab (IFX)).80.6%(50/62) of them received oral steroids, 90.3%(56/62) received PPIs,27.4%(17/62), thalidomide,6.5%(4/62), azathioprine (AZA), and 16.1%(10/62) IFX. In addition,38 patients (61.3%) presented with contaminant colon CD received 5-aminosalicylatates. After medication treatment, 85.5%(53/62) of the patients showed clinical improvement. Among 48 patients (77.4%) who underwent follow-up upper endoscopy,81.3%(39/48) achieved mucosal healing. (2) Surgical treatment:4 patients underwent surgical intervention because of complications, and 3 of them (75.0%) were isolated UGCD patients. One patient with esophageal stenosis received esophageal dilatation, but had no improvement. After 3 months, the patient presented with ileocolonic CD, receiving oral steroids and PPI, having clinical improvement, but did not undergo follow-up upper endoscopy and colonoscopy. One patient with gastric fistula underwent surgical repair of the stomach wall, while 2 patients with pyloric obstruction underwent distal gastrectomy, and all of the 3 patients underwent follow-up upper endoscopy showing no recurrence.Conclusions:1. UGCD is more common than it was originally suspected, its detection rate having a trend of increase year by year, with a predilection for young adults, and the detection rate of UGCD between genders has no significant difference. The median time of final diagnosis for simple UGCD patients is longer than the median time of final diagnosis for the ones presented with concomitant small and/or large bowel disease.2. Retrosternal pain, heartburn, odynophagia suggesting an esophageal involvement, and abdominal pain, melena, vomiting suggesting a duodenal and gastric involvement, are the main symptoms. Patients suffered isolated UGCD have no systemic manifestations, while the ones presented with small and/or large bowel disease have common systemic manifestations, including weight loss, fever and anemia. Patients suffered isolated UGCD have few complications, and obstruction, gastrointestinal bleeding and fistula formation are the main complications for the patients presented with small and/or large bowel disease.3. The Montreal classification of UGCD:(1) Age at diagnosis:Most of the UGCD patients, including simple UGCD patients and the ones presented with small and/or large bowel disease, were diagnosed between the ages of 17 and 40 years (A2). (2) Location:Most of the patients presented with small and/or large bowel disease were diagnosed as terminal ileum disease (L1), and then was the ileocolon disease (L3) and colon disease (L2), and the rate of simple UGCD (L4) is not low. (3) Behavior:Most of the UGCD patients, including simple UGCD patients and the ones presented with small and/or large bowel disease, have non-stricturing and non-penetrating disease behavior (B1), and the patients presented with small and/or large bowel disease are more likely to have B2, B3 and P disease behaviors.4. Upper endoscopy examination is essential for the diagnosis of UGCD. The endoscopic features of the lesions in UGCD are various. However, the most commonly described findings on upper endoscopy examination are ulcers. The endoscopic features of the lesions among esophagus, stomach and duodenum are different. The common endoscopic findings for esophageal CD are ulcer, especially longitudinal ulcer and crater-like ulcer, and esophageal stenosis, fistulization are less found. The common endoscopic findings for gastric CD are irregular ulcer, and pyloric obstruction, fistulization can be detected at the late stage. The common endoscopic findings for duodenal CD are ulcer, and cobble-stone sign, obstruction, fistulization are often seen. As for the distribution of lesions, the esophagus, especially the middle third of esophagus is most likely to be involved.5. The presence of granulomas, although highly characteristic of CD, is neither unique to CD with upper gastrointestinal involvement nor universally detected. Histological diagnosis may be suggested by the presence of focally distributed nonspecific and chronic inflammation throughout the submucosa, submucosal inflammatory thickening and crack-like ulcer with or without non-caseating granulomas.6. Isolated UGCD can easily be misdiagnosed, and that may be related to the patients presented with concomitant small and/or large bowel disease having lower gastrointestinal symptoms. Hence, clinicians should not emphasize an auxiliary examination on the diagnosis of UGCD, especially isolated UGCD. The correct diagnosis of CD with upper gastrointestinal involvement needs a combined course that integrates the endoscopic information with all valuable clinical evidences and clues.7. Patients with CD involving upper gastrointestinal tract, especially isolated UGCD, response well to medication treatment, while the ones presented with concomitant small and/or large bowel disease may predicted the need of surgical intervention. |
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