Gastroenterology Today Spring 2022

Volume 32 No. 1
Spring 2022
The Perfect Pair...
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CONTENTS
CONTENTS
4 EDITORS COMMENT
6 FEATURE Gastric polyps: a 10-year analysis of 18,496
upper endoscopies
14 FEATURE Endoscopic retrograde appendicitis therapy
versus laparoscopic appendectomy versus open
appendectomy for acute appendicitis: a pilot study
22 FEATURE An extremely dangerous case of acute massive
upper gastrointestinal bleeding: a case report
26 NEWS
31 COMPANY NEWS
This issue edited by:
Hesam Ahmadi Nooredinvand
c/o Media Publishing Company
Greenoaks
Lockhill
Upper Sapey, Worcester, WR6 6XR
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COVER STORY
At Diagmed Healthcare our mission is to provide our Customers with innovative products
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types of polyps in multiple sizes (including diminutive and large) and features the following:
• Features a shield shape design that maximises its width for control and placement
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• 33% thinner wire diameter than traditional braided wires allowing for stiffness and
fl exibility due to its thin, seven braided wire confi guration
• Reduces polyp “fl y away” from the resection site making it possible tocollect specimen
for pathology 2
Designed by GI nurses, the eTrap polyp trap supports retrieval of multiple specimens,
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• Two removable polyp specimen collector strainer trays allowing for retrieval of multiple
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• A measurement guide designed to aid in specimen sizing
For more information on our complete offering of polypectomy solutions, visit
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1) Horiuchi A, Hosoi K. “Prospective, Randomized Comparison of 2 Methods of Cold Snare Polypectomy for Small
Colorectal Polyps.” Gastrointestinal Endoscopy (2015): 1-7.
2) Din S, Ball A. “Cold Snare Polypectomy: Does Snare Type Infl uence Outcomes?” Digestive Endoscopy (2015): 1-6.
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the Publisher, the Editors or Media
Publishing Company.
Next Issue Summer 2022
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GASTROENTEROLOGY TODAY - SPRING 2022
3

EDITORS COMMENT
EDITORS COMMENT
GASTROENTEROLOGY TODAY - SPRING 2022
“COVID-19
pandemic
appears to
be shifting
towards an
endemic
disease
with most
healthcare
services
gradually
returning
to normal,
the positive
impact of
which will
certainly
be felt by
patients.”
Disruption to the health service during the last couple of years as a result of the
pandemic has undoubtedly had a detrimental impact on certain aspects of patient care.
A recent healthcare survey by Crohn’s and Colitis UK highlights how a delay in diagnosis,
difficulty in accessing specialist advice and disruption to surgery and endoscopy services
have had a negative impact on both physical and mental wellbeing of many patients with
Inflammatory Bowel Disease (IBD).
There is however light at the end of the tunnel. COVID-19 pandemic appears to be shifting
towards an endemic disease with most healthcare services gradually returning to normal,
the positive impact of which will certainly be felt by patients.
We have a number of fascinating articles included in this Spring edition of Gastroenterology
Today including,
• Role of Endoscopic Retrograde Appendicitis Therapy (ERAT) as an alternative to surgical
appendectomy in acute uncomplicated appendicitis
• Scientists in Munich explore the mechanism that triggers problematic interaction between
intestinal bacteria and cells in intestinal mucus layer in patients with IBD which could offer
targets for development of new drug therapy
• Coeliac UK highlights the role of the Rare Disease Collaborative Network in supporting
with diagnosis and management of patients with refractory coeliac disease
• Retrospective study looking at the frequency of gastric polyps and their association with
certain factors
• An interesting case report of massive gastrointestinal bleeding secondary to a fish bone!
Hesam Ahmadi Nooredinvand,
St George’s Hospital
4

Prescribe Entocort ® CR by brand
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Entocort ® CR* 1
• ~50% fewer corticosteroid-associated side effects
than prednisolone 2,3
• Unlike Entocort ® CR, prednisolone increases
susceptibility to, and severity of, infections †2,4
• Entocort ® CR is the only controlled-release
oral budesonide indicated for Crohn’s disease 2
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*Remission was defined as a score of ≤150 on the Crohn’s disease activity index.
†Entocort ® CR should be used with caution in patients with infections where the use of glucocorticosteroids may have unwanted effects. 2
ENTOCORT CR 3mg Capsules (budesonide) - Prescribing
Information
Please consult the Summary of Product Characteristics (SmPC) for full
prescribing Information
Presentation: Hard gelatin capsules for oral administration with an
opaque, light grey body and an opaque, pink cap marked CIR 3mg in black
radial print. Contains 3mg budesonide. Indications: Induction of remission
in patients with mild to moderate Crohn’s disease affecting the ileum and/or
the ascending colon. Induction of remission in patients with active
microscopic colitis. Maintenance of remission in patients with microscopic
colitis. Dosage and administration: Active Crohn’s disease (Adults): 9mg
once daily in the morning for up to eight weeks. Full effect achieved in 2-4
weeks. When treatment is to be discontinued, dose should normally be
reduced in final 2-4 weeks. Active microscopic colitis (Adults): 9mg once
daily in the morning. Maintenance of microscopic colitis (Adults): 6mg once
daily in the morning, or the lowest effective dose. Paediatric population: Not
recommended. Older people: No special dose adjustment recommended.
Swallow whole with water. Do not chew. Contraindications:
Hypersensitivity to the active substance or any of the excipients. Warnings
and Precautions: Side effects typical of corticosteroids may occur. Visual
disturbances may occur. If a patient presents with symptoms such as
blurred vision or other visual disturbances they should be considered for
referral to an ophthalmologist for evaluation of the possible causes.
Systemic effects may include glaucoma and when prescribed at high doses
for prolonged periods, Cushing’s syndrome, adrenal suppression, growth
retardation, decreased bone mineral density and cataract. Caution in
patients with infection, hypertension, diabetes mellitus, osteoporosis,
peptic ulcer, glaucoma or cataracts or with a family history of diabetes or
glaucoma. Particular care in patients with existing or previous history of
severe affective disorders in them or their first degree relatives. Caution
when transferring from glucocorticoid of high systemic effect to Entocort
CR. Chicken pox and measles may have a more serious course in patients
on oral steroids. They may also suppress the HPA axis and reduce the stress
response. Reduced liver function may increase systemic exposure. When
treatment is discontinued, reduce dose over last 2-4 weeks. Concomitant
use of CYP3A inhibitors, such as ketoconazole and cobicistat-containing
products, is expected to increase the risk of systemic side effects and
should be avoided unless the benefits outweigh the risks. Excessive
grapefruit juice may increase systemic exposure and should be avoided.
Patients with fructose intolerance, glucose-galactose malabsorption or
sucrose-isomaltase insufficiency should not take Entocort CR. Monitor
height of children who use prolonged glucocorticoid therapy for risk of
growth suppression. Interactions: Concomitant colestyramine may
reduce Entocort CR uptake. Concomitant oestrogen and contraceptive
steroids may increase effects. CYP3A4 inhibitors may increase systemic
exposure. CYP3A4 inducers may reduce systemic exposure. May cause low
values in ACTH stimulation test. Fertility, pregnancy and lactation: Only
to be used during pregnancy when the potential benefits to the mother
outweigh the risks for the foetus. May be used during breast feeding.
Adverse reactions: Common: Cushingoid features, hypokalaemia,
behavioural changes such as nervousness, insomnia, mood swings and
depression, palpitations, dyspepsia, skin reactions (urticaria, exanthema),
muscle cramps, menstrual disorders. Uncommon: anxiety, tremor,
psychomotor hyperactivity. Rare: aggression, glaucoma, cataract, blurred
vision, ecchymosis. Very rare: Anaphylactic reaction, growth retardation.
Prescribers should consult the summary of product characteristics in
relation to other adverse reactions. Marketing Authorisation Numbers,
Package Quantities and basic NHS price: PL 36633/0006. Packs of 50
capsules: £37.53. Packs of 100 capsules: £75.05. Legal category: POM.
Marketing Authorisation Holder: Tillotts Pharma UK Ltd, The Stables,
Wellingore Hall, Wellingore, Lincoln, LN5 0HX. Date of preparation of PI:
February 2020
Adverse events should be reported.
Reporting forms and information can be
found at https://yellowcard.mhra.gov.uk.
Adverse events should also be reported to
Tillotts Pharma UK Ltd. Tel: 01522 813500.
References: 1. Campieri M et al. Gut 1997; 41: 209–214. 2. Entocort ®
CR 3 mg capsules – Summary of Product Characteristics. 3. Rutgeerts
P et al. N Engl J Med 1994; 331: 842–845. 4. Prednisolone 5 mg tablets
– Summary of Product Characteristics.
Date of preparation: August 2021. PU-00572.

FEATURE
GASTRIC POLYPS: A 10-YEAR
ANALYSIS OF 18,496 UPPER
ENDOSCOPIES
Haythem Yacoub 1,2* , Norsaf Bibani 1,2 , Mériam Sabbah 1,2 , Nawel Bellil 1,2 , Asma Ouakaa 1,2 , Dorra Trad 1,2 and Dalila Gargouri 1,2
Yacoub et al. BMC Gastroenterology (2022) 22:70 https://doi.org/10.1186/s12876-022-02154-8
Abstract
Background/aims
Gastric polyps (GPs) are usually asymptomatic lesions of the upper
gastrointestinal tract observed in 1–3% of esophagogastroduodenoscopies
(EGD). Most GPs are benign. The aim of this study was to precise the
frequency of different types of gastric polyps in our population, and to
analyze their possible association with other factors.
Materials and methods
A total of 18,496 consecutive patients undergoing EGD over a
10-year period (between 2007 and 2018) in a tertiary hospital were
retrospectively reviewed. Eighty-six patients diagnosed with gastric
polyps were analysed. Demographics, medical history of the patients,
and indication for gastroscopy were collected. Morphological,
histological characteristics of polyps, and therapeutic management data
were also collected.
fundic gland are the most common in our country. The high frequency of
Helicobacter pylori infection in our patients and in our area may explain
the high frequency of HP.
Keywords
Stomach, Polyp, Polypectomy, Endoscopic mucosal resection
Introduction
Gastric polyps (GPs) are defined as luminal projections above
the plane of the adjacent mucosa regardless of its histological
type [1]. Gastric polyps are usually discovered incidentally during
esophagogastroduodenoscopies (EGD) and their prevalence is
estimated from 0.5 to 23% of all upper gastrointestinal endoscopies [2].
Some polyps can occasionally present with bleeding, anemia, or gastric
outlet obstruction [3].
GASTROENTEROLOGY TODAY - SPRING 2022
Results
GPs were found in 86 out of 18,496 (0.46%) reviewed EGD,
corresponding to a total of 141 polyps. There were 64 female (74.4%)
and 22 male patients (25.6%) with a sex ratio (M/F) of 0.34. The
average age was 58.1 years. One hundred and forty one polyps were
included, and histopathology was obtained on 127 GPs. The most
common location was the fundus (59.6%) and 48.9% were smaller than
5 mm. The polyp was unique in 75.6% of cases. According to Paris
classification, 80% of the polyps were sessile (Is). Hyperplastic polyps
were the most common (55.9%), followed by sporadic fundic gland
polyps observed in 23 patients (18.1%), 7 (5.5%) were adenomas and
4 (3.1%) were neuroendocrine tumors type 1. The following factors
were associated with hyperplastic polyps: anemia (p =0.022), single
polyp (p=0.025) and size≥5 mm (p=0.048). Comparing hyperplastic
polyps’ biopsies to resected polyps, no difference was found in the
evolutionary profile of the 2 groups. A size less than 10 mm (p =0.013)
was associated with fundic gland polyps. Sixty polyps (47.2%) were
treated by cold forceps, 19 (15%) treated by a mucosal resection and
15 (11.8%) with diathermic snare. Five procedural bleeding incidents
were observed (3.9%). Only the use of anticoagulant treatment was
associated with a high bleeding risk (p=0.005). The comparative
histological study between specimens of biopsied GPs and endoscopic
polypectomy led to an overall agreement of 95.3%.
Conclusion
In our study, the GPs frequency was 0.36%. Hyperplastic polyps and
The majority of polyps are benign (> 85% of cases). The risk of
malignancy or malignant transformation of gastric polyps depends on
their histological nature. GPs have been associated with multiple factors,
such as H. pylori infection for hyperplastic polyps and adenomas,
proton-pump inhibitor (PPI) use for fundic gland polyps [4, 5].
The aim of this study was to precise the frequency of different types of
gastric polyps in our population and to analyze their possible association
with other factors to evaluate the results of curative endoscopic
resection of gastric polyps and to study the evolutionary status of
unresected gastric polyps.
Methods
Study design
A retrospective study in which all consecutive patients with GPs were
enrolled was performed at a tertiary-level hospital (Habib Thameur
Hospital of Tunis) from 2008 to 2017. A total of 18,496 consecutive
EGD over a 10-year period were retrospectively reviewed. Eightysix
patients diagnosed with gastric polyps were analysed. Follow-up
gastroscopies performed on the same patient were not excluded. This
study was performed according to the Declaration of Helsinki, following
the guidelines for good clinical practice. Habib Thameur Hospital ethics
committee approved the study protocol.
6
*Correspondence: yacoubhaythem@hotmail.com
1
Gastroenterology and Hepatology Department, Habib Thameur Hospital, Tunis, Tunisia
©The Author(s) 2022

FEATURE
All cases of gastric polyps were identified from endoscopy reports.
All data regarding patients were obtained from the electronic medical
record. Demographic data (sex, age), relevant pathological history
(colorectal cancer or hereditary polyposis syndrome, colon polyp,
cirrhosis), routine hemograms, as well as data related to the EGD
indication of gastroscopy, number and size of GPs, location, histological
type, and the presence of chronic gastritis or H. pylori infection using
the Hematoxylin eosin staining) were collected. The polyp size was
estimated by comparing it with the opening size of the used biopsy
forceps. In patients with multiple polyps, we collected the endoscopic
characteristics of the four largest polyps. GP recurrence following
resection were also collected (number, location, size, histological type
and, recurrence interval after polypectomy) Patients whose hemoglobin
levels were less than 13 g/dl in males and 12 g/dl in females were
considered with anemia.
was based on endoscopic findings; the most common localization
for gastric polyps was the fundus, followed by the antrum and the
corpus (Table 2).
Histopathologic diagnosis of polyps was obtained for 127 polyps.
The histological study showed hyperplastic polyps in 71 of the polyps
(55.9%), followed by fundic gland polyps (n=23, 18.1%) (Table 3). The
“other” category included pancreatic heterotopias, lipoma and polypoid
foveolar hyperplasia.
H. pylori infection identification was carried out with the hematoxylin
eosin staining in 64 patients (patients with gastric mucosa
abnormalities). H. pylori infection was detected in 45 patients
(62.3%). H. pylori was positive in 30 of the 49 (61.2%) of patients with
hyperplastic polyps.
Ethics approval and consent to participate
This study was performed according to the Declaration of Helsinki,
following the guidelines for good clinical practice. “Habib Thameur
Hospital ethics committee” approved the study protocol. All methods
were carried out in accordance with relevant guidelines and regulations.
Informed consent to participate in the study was obtained from
participants.
Statistical analysis
The data were analyzed on the Statistical Package for the Social
Sciences (SPSS) version 23, IBM SPSS Inc.; Chicago, IL, USA). Results
for the continuous variables that followed a normal distribution were
expressed as mean±standard deviation and range while variables that
did not follow a normal distribution were presented in median and the
interquartile range.
For comparisons, Student’s t-test was used for quantitative variables.
A univariate analysis was conducted to identify the possible associated
factors with the different histological types of GPs. A multivariate analysis
was carried out with variables that achieved statistical significance. The
level of statistical significance was established with a p value ≤ 0.05.
The factors independently associated with hyperplastic polyps were
the presence of anemia, being a single polyp, and sized≥5 mm. The
associated variable for fundic gland polyps, was only size 70 years. Age distribution of the patients with
GPs was summarized in Fig. 1.
More than the three-quarters of the patients had single polyps.
The average polyp diameter was 6 mm (range: 2–30 mm). The
diameters of the polyps were < 5 mm in 69 of cases (48.9%), 5–9
mm in 53 (37.6%) patients, 10–19 mm in 15 (10.7%) patients,
and ≥ 20 mm in 4 (2.8%) patients (Table 2). The location of GPs
Age (median years),(range, years) 58.1 ± 15.4, (18–84)
Gender
Male 22 (25.6)
Female 64 (74.4)
Personal history
GERD 26 (30.2)
Anemia 36 (44.2)
Colon polyps 2 (2.3)
Cirrhosis 11 (12.8)
Gastrectomy 3 (3.5)
Hereditary polyposis syndrome 0 (0)
Indication
Epigastric pain 30 (34.9)
Dyspepsia 16 (18.6)
Anemia 21 (24.4)
UGIB 2 (2.3)
Monitoring of PHT 13 (15.1)
Other 4 (4.7)
GP gastric polyps, GERD gastro-esophageal reflux disease, PHT portal
hypertension, UGIB upper gastrointestinal bleeding
GASTROENTEROLOGY TODAY - SPRING 2022
7

FEATURE
Anticoagulant or anti-aggregating medication was significantly correlated
with the onset of bleeding (p=0.002).
Twenty-one polyps were biopsied and then resected. A comparison of
the histological results between biopsy specimen and polypectomy was
made.
Adenomas analysis showed a 100% agreement between primary and
final results. The agreement rate was 93% for hyperplastic polyps
(13 polyps out of 14). The comparative histological study between
specimens of biopsied GPs and endoscopic polypectomy led to an
overall agreement of 95.3% (Table 7).
Discussion
One hundred and twenty-seven specimens, corresponding to eightysix
patients, of the total of 18,496 upper gastrointestinal endoscopic
procedures, taken from gastric polypoid lesions (0.46%) were reported.
In the literature, a great variability was observed in the prevalence of
GPs, ranging from 0.5 to 6.35% [2, 6, 7]. In our study, the prevalence
of GPs is lesser than reported in literature. This can be explained by
the fact that follow-up EGD performed on the same patient was not
excluded.
This is the first study that evaluates the GPs frequency in Tunisia. In our
study, we found that the most common symptoms in patients with GPs
were epgastric pain and anemia. We also found that GPs were localized
mostly in the fundus, and mostly Is according to Paris classification and
the hyperplastic type was the most common.
Table 2 Morphological and histological characteristics of the
141 polyps
Parameter n (%)
Table 2 Morphological and histological characteristics of the
Patient with GPs 86 (100)
141 polyps
Single 65 (75.6)
Parameter Multiple n (%) 21 (24.4)
Location
Patient with GPs 86 (100)
Fundus 51 (59.3)
Single 65 (75.6)
Body 5 (5.8)
Multiple 21 (24.4)
Antrum 28 (32.6)
Location
Multiple location 2 (2.3)
Fundus 51 (59.3)
Size in mm
Body 5 (5.8)
1–4 mm 69 (48.9)
Antrum 28 (32.6)
5–9 mm 53 (33.6)
Multiple location 2 (2.3)
10–14 mm 8 (5.7)
Size in mm
15–19 mm 7 (5)
1–4 mm 69 (48.9)
> 20 mm 4 (2.8)
5–9 mm 53 (33.6)
Paris classification
10–14 mm 8 (5.7)
Ip 17 (12)
15–19 mm 7 (5)
Is 112 (80)
> 20 mm 4 (2.8)
IIa 11 (8)
Paris classification
IIb, IIc 0 (0)
Ip 17 (12)
Is GP gastric polyps
112 (80)
IIa 11 (8)
IIb, IIc 0 (0)
Hyperplastic polyps and fundic gland polyps together make up to 90%
GP gastric polyps
[6,7,8] followed by adenomas and other histological type, which are
much less common. These rates are similar to those observed in our
population with a predominance of hypeplastic type.
GASTROENTEROLOGY TODAY - SPRING 2022
Fig. 1 The age distribution of patients with gastric polyps
Fig. 1 The age distribution of patients with gastric polyps
8

FEATURE
Table Table 3 3 Histological analysis analysis of the of the 127 127 GP GP
Table Table 5 5 Univariate analysis analysis of of associated factors factors with with fundic fundic
Table 3 Histological analysis of the 127 GP
gland Tablepolyps 5 Univariate analysis of associated factors with fundic
Histological Table 3 type Histological type analysis of the 127 GP
gland
n (%) n (%) Tablepolyps 5 Univariate (n=127) analysis of associated factors with fundic
gland polyps (n=127)
Histological type n (%)
Parameter gland polyps (n=127)
Histological type n (%)
Fundic Fundic gland gland polyps polyps Non-fundic p value p value
Hyperplastic 71 (55.9) 71 (55.9)
Parameter Fundic gland polyps gland Non-fundic gland polyps polyps
Parameter Fundic gland polyps Non-fundic p value p value
Fundic Hyperplastic Fundic Hyperplastic gland gland polyps polyps 23 71 (18.1) (55.9) 23 71 (18.1) (55.9)
n (%) n (%) gland n (%) gland n (%) polyps polyps
Adenoma Fundic Adenoma Fundic gland gland polyps polyps 237 (5.5) (18.1) 237 (5.5) (18.1)
n (%) n (%) n (%) n (%)
Age Age (years) (years) 53.3 53.3 ± 21.3 ± 21.3 58.8±14.1 0.303 0.303
Adenoma Neuroendocrine Adenoma neoplasia neoplasia 47 (3.1) (5.5) 47 (3.1) (5.5)
Age Gender (years) 53.3 ± 21.3 58.8±14.1 0.303 0.289
Xanthelasmaneoplasia 14 (0.8) (3.1) 1 (0.8) Age Gender (years) 53.3 ± 21.3 58.8±14.1 0.289 0.303
Neuroendocrine neoplasia 4 (3.1)
Male Gender Male 1 (11.1) 19 (27.5) 0.289
Xanthelasma Inflammatory fibroid fibroid polyp polyp 91 (7.2) (0.8) 9 (7.2) Gender 1 (11.1) 19 (27.5) 0.289
Xanthelasma 1 (0.8)
Male Female 18 (11.1) (88.9) 19 50 (27.5) (72.5)
No Inflammatory true No true polyp polyp fibroid polyp 79 (5.5) (7.2) 7 (5.5) Male Female 18 (11.1) (88.9) 19 50 (27.5) (72.5)
Inflammatory fibroid polyp 9 (7.2)
Female 8 (88.9) 50 (72.5) 0.170
Other No true Other polyp 57 (3.9) (5.5) 5 (3.9) Female Single/multiple 8 (88.9) 50 (72.5) 0.170
No true polyp 7 (5.5)
Single/multiple 5 (55.6) 53 (76.8)
GP Other gastric polyps
5 (3.9)
Single/multiple 5 (55.6) 53 (76.8) 0.170 0.170
GP Other gastric polyps
5 (3.9)
Single Multiple Single Multiple 54 (55.6) (44.4) 54 (55.6) (44.4) 53 16 (76.8) (23.2) 53 16 (76.8) (23.2)
GP gastric GP gastric polyps polyps
GERDMultiple 4 (44.4) 4 (44.4) 16 (23.2) 16 (23.2) 0.7 0.7
Table Table 4 4 Univariate analysis analysis of of associated factors factors with with
GERDYes GERD 5 (55.6) 5 (55.6) 20 (29) 20 (29) 0.7 0.7
Table hyperplastic Table 4 Univariate 4 polyps Univariate polyps (n analysis = (n 127) analysis = 127) of of associated associated factors factors with with Yes No Yes No 54 (55.6) (44.4) 54 (55.6) (44.4) 20 49 (29) (71) 20 49 (29) (71)
hyperplastic polyps (n = 127)
Parameter hyperplastic polyps Hyperplastic (n = 127) polyps polyps Non-
Nonhyperplastic
p value p value No Anemia No Anemia 4 (44.4) 4 (44.4) 49 (71) 49 (71) 0.115 0.115
p value Yes Anemia 8 (88.9) 43 (62.3) 0.115
Parameter Hyperplastic polyps Nonhyperplastic
polyps
Parameter Hyperplastic polyps Nonhyperplastic
Yes No Yes No 81 (88.9) (11.1) 81 (88.9) (11.1) 43 26 (62.3) (37.7) 43 26 (62.3) (37.7)
p value
Yes Anemia 8 (88.9) 43 (62.3) 0.115
polyps
n (%) n (%) n polyps (%) polyps n (%)
No Location No Location 1 (11.1) 1 (11.1) 26 (37.7) 26 (37.7)
n (%) n (%) n (%) n (%)
Age Age (years) (years) 57.7 57.7 ± 13.4 ± 13.4 58.8 58.8 ± 17.4 ± 17.4 0.7 0.7 Fundus Location Fundus Location 23 (100) 23 (100) 56 (53.9) 56 (53.9)
Age Gender Age Gender (years) (years) 57.7 57.7 ± 13.4 ± 13.4 58.8 58.8 ± 17.4 ± 17.4 0.7
0.7
Fundus Non Fundus Non fundus fundus 23 0 (0) (100) 23 0 (0) (100) 56 48 (53.9) (46.1) 56 48 (53.9) (46.1)
Male Gender Male Gender 12 (24.5) 12 (24.5) 8 (27.6) 8 (27.6) 0.7 0.7
Non Size Non Size in fundus mm in fundus mm 0 (0) 0 (0) 48 (46.1) 48 (46.1) 0.013 0.013
MaleFemale 37 12 (75.5) (24.5) 37 12 (75.5) (24.5) 21 8 (27.6) (72.4) 21 8 (27.6) (72.4)
< Size 5 mm < Size in 5 mm in mm 14 (60.9) 14 (60.9) 55 (53) 55 (53) 0.013 0.013
Female Single/multiple Female 37 (75.5) 37 (75.5) 21 (72.4) 21 (72.4) 0.05 0.05 < ≥5 mm < ≥5 mm 14 9 (39.1) (60.9) 14 9 (39.1) (60.9) 55 49 (53) (47) 55 49 (53) (47)
Single/multiple Single/multiple 40 (81.6) 40 (81.6) 11 (38) 11 (38) 0.05 0.05
≥Paris 5 mm ≥Paris 5 mm classification 9 (39.1) 9 (39.1) 49 (47) 49 (47)
Multiple Single Multiple Single 940 (18.4) (81.6) 940 (18.4) (81.6) 18 11 (62) (38) 18 11 (62) (38)
Ip Paris Ip Paris classification classification 3 (13) 3 (13) 12 (11.5) 12 (11.5) 0.524 0.524
GERD Multiple GERD Multiple 9 (18.4) 9 (18.4) 18 (62) 18 (62) 0.7 0.7 Ip Is Ip Is 316 (13) (69.5) 316 (13) (69.5) 12 85 (11.5) (81.7) 12 85 (11.5) (81.7) 0.524 0.273 0.524 0.273
GERDYes GERD 15 (30.6) 15 (30.6) 10 (34.5) 10 (34.5) 0.7 0.7
Is IIa Is IIa 16 4 (17.5) (69.5) 16 4 (17.5) (69.5) 85 7 (6.8) (81.7) 85 7 (6.8) (81.7) 0.273 0.105 0.273 0.105
No Yes No Yes 34 15 (69.4) (30.6) 34 15 (69.4) (30.6) 19 10 (65.5) (34.5) 19 10 (65.5) (34.5)
IIa IIb, IIc IIa IIb, IIc 40 (17.5) (0) 40 (17.5) (0) 70 (6.8) (0) 70 (6.8) (0) 0.105 – 0.105 –
Anemia No Anemia No 34 (69.4) 34 (69.4) 19 (65.5) 19 (65.5) < 10 < –3 10 –3 GP: IIb, IIc gastric GP: IIb, IIc gastric polyps, polyps, GERD: GERD: 0 (0) 0 gastro-esophageal (0) reflux reflux disease 0 (0) disease 0 (0) – –
Yes Anemia Yes Anemia 28 (57.2) 28 (57.2) 3 (10.3) 3 (10.3) < 10 < –3
10 –3 Significant GP: gastric Significant GP: gastric polyps, p value polyps, p value GERD: < 0.05 GERD: < 0.05 are in gastro-esophageal are bold in bold reflux reflux disease disease
No Yes Yes No 21 28 (42.8) (57.2) 21 28 (42.8) (57.2) 26 3 (10.3) (89.7) 26 3 (10.3) (89.7)
Significant Significant p value p value < 0.05 < 0.05 are in are bold in bold
Location No Location No 21 (42.8) 21 (42.8) 26 (89.7) 26 (89.7) 0.009 0.009
Table Table 6 Risk 6 Risk value value for the for the significant variables variables in the in the multivariate
Antrum Location Antrum Location 34 (47.9) 34 (47.9) 43 (76.8) 43 (76.8) 0.009 0.009
analysis Table analysis Table 6 Risk 6 Risk value value for the for the significant significant variables variables in the in the multivariate multivariate
Non Antrum Non Antrum antrum antrum 37 34 (52.1) (47.9) 37 34 (52.1) (47.9) 13 43 (23.2) (76.8) 13 43 (23.2) (76.8)
analysis
Size Non Size in antrum mm in mm 37 (52.1) 13 (23.2) 0.002 0.002 Variable Variable analysis
Non antrum 37 (52.1) 13 (23.2)
Odds Odds ratio ratio 95% 95% CI CI p value p value
< Size 5 mm < Size in 5 mm in mm 30 (42.3) 30 (42.3) 39 (69.6) 39 (69.6) 0.002 0.002
Variable Variable Hyperplastic polyps polyps
Odds Odds ratio ratio 95% 95% CI CI p value p value
≥< 5 mm ≥< 5 mm 41 30 (47.7) (42.3) 41 30 (47.7) (42.3) 17 39 (30.4) (69.6) 17 39 (30.4) (69.6)
Anemia Hyperplastic Anemia Hyperplastic polyps polyps 4.28 4.28 (1.39–13.17) 0.022 0.022
Paris ≥ 5 mm Paris ≥ 5 mm classification 41 (47.7) 41 (47.7) 17 (30.4) 17 (30.4)
Single Anemia Anemia Single 2.85 4.282.85 (1.39–13.17) (0.95–8.59) (1.39–13.17) 0.025 0.022 0.025 0.022
Ip Paris Ip Paris classification classification 10 (14) 10 (14) 5 (8.9) 5 (8.9) 0.371 0.371
Size≥5 Single Size≥5 Single mm mm 2.851.85 (0.95–8.59) (1.29–2.67) (0.95–8.59) 0.048 0.025 0.048 0.025
Is Ip Is Ip 58 10 (81.7) (14) 58 10 (81.7) (14) 43 5 (8.9) (76.8) 43 5 (8.9) (76.8) 0.496 0.371 0.496 0.371 Fundic Size≥5 Fundic Size≥5 mmgland polyps polyps 1.85 1.85 (1.29–2.67) (1.29–2.67) 0.048 0.048
IIa Is IIa Is 358 (4.3) (81.7) 358 (4.3) (81.7) 843 (14.3) (76.8) 843 (14.3) (76.8) 0.055 0.496 0.055 0.496 Size Fundic Size Fundic < 5gland mm < 5gland mm polyps polyps 2.31 2.31 (1.37–4.11) < 0.001 < 0.001
IIb, IIa IIc IIb, IIa IIc 03 (0) (4.3) 03 (0) (4.3) 08 (0) (14.3) 08 (0) (14.3) – 0.055 – 0.055 Size GP gastric GP Size < 5gastric mm < polyps, 5 mm polyps, GERD GERD gastro-esophageal 2.31 2.31 (1.37–4.11) reflux (1.37–4.11) reflux disease disease < 0.001 < 0.001
GP IIb, gastric IIc GP IIb, gastric IIcpolyps, polyps, GERD GERD 0 (0) 0 gastro-esophageal (0) reflux reflux disease 0 disease (0) 0 (0) – –
GP gastric GP gastric polyps, polyps, GERD GERD gastro-esophageal reflux reflux disease disease
Significant GP gastric Significant GP gastric polyps, p value polyps, p value GERD < 0.05 GERD < 0.05 are gastro-esophageal in are bold in bold reflux reflux disease disease
Significant Significant p value p value < 0.05 < 0.05 are in are bold in bold
are the most common [9,10,11,12,13]. It has been suggested that
the prevalence of hyperplastic polyps could be related to the high
Argüello et al. reported the frequency of GP as 42.8% for
hyperplastic polyps, and 37.7% for fundic gland polyps. The
mean age of the patients was 65.6 years and 38% were males
[9]. Carmack et al. found the incidence of GP as 6.3% in 121.564
EGD. Fundic gland polyps were the most frequent polyp type,
which accounted for 77% of all polyps of all polyps [6]. Fundic
gland polyps were the second most common type (18.1%) of GPs
lesions in our study. In the majority of series, hyperplastic polyps
prevalence of H. pylori infection in our population (62.3%). Freeman
et al. reported tendency of fundic gland polyps to arise in H. pylori
-free stomachs [14] (OR 0.007, 95% CI 0.003–0.015). The same
findings were also reported in Carmack et al. study (OR 0.007,
95% CI 0.003–0.016) [6]. Fundic gland polyps tend also to arise
in patients who receive long-course PPI treatment [14, 15]. The
widespread of PPIs use and the low H. Pylori infection rate may be
the most important reasons behind the large frequency of fundic
GASTROENTEROLOGY TODAY - SPRING 2022
9

FEATURE
gland polyps reported in American studies [6, 14]. Although in three
Spanish series, hyperplastic polyps were the most common which
is comparable to our study [8, 9, 16].
Hyperplastic polyps are associated with chronic gastritis such
as H. pylori gastritis, and particularly autoimmune gastritis.
Patients with hyperplastic polyp have an increased risk of gastric
adenocarcinoma [1, 17, 18].
In our study, adenomas were detected in seven patients (5.5%).
The majority of cases we reported were low-grade intestinal-type.
These polyps constitute less than 10% and have a malignant
potential. They are more common in communities where gastric
cancer is frequent [19]. Malignant potential of adenomas is variable
(6.8% − 55.3%) [20]. Risk factors for malignancy transformation are:
high-grade dysplasia, and size of the lesion [19].
It has been reported that between 16 and 37.5% of cases, and
despite the endoscopic appearance of a polyp, the final histological
study shows normal mucosa [6, 16]. In our study the percentage of
biopsies with normal mucosa was 5.5%.
Although the majority of GP do not cause symptoms, they can be
the cause of bleeding and gastric obstruction. Frequently, GP are
detected during EGD performed to study gastrointestinal symptoms
not attributable to polyps or asymptomatic patients examined for
other reasons [6, 21].
In our study, an association between hyperplastic polyps and
anemia, single polyps and size > 5 mm. It has been described in
the literature between anaemia and hyperplastic polyps, while the
gastrointestinal reflux was associated with fundic gland polyps [22].
A total of 94 polyps were resected with snare. Five patients had
hemorrhage requiring endoscopic treatment and bleeding was
60
53
Table 7 Agreement between polypectomy and biopsy
specimen in different histological types
Histological type
Biopsy
Polypectomy
Table 7 Agreement between
specimen (n)
polypectomy
(n)
and biopsy
specimen Adenomas in different histological types
Histological With low grade typedysplasia Biopsy 4 Polypectomy
4
With high grade dysplasia specimen 1 (n) (n) 1
Fundic gland polyps
Adenomas
1 1
Hyperplastic polyps
With low grade dysplasia
13
4
14
4
Type I neuroendoscrine tumor
With high grade dysplasia
1
1
1
1
Inflammatory mucosa
Fundic gland polyps
1
1
0
1
Hyperplastic polyps 13 14
Type I neuroendoscrine tumor 1 1
controlled Inflammatory by mucosa endoscopic procedures. 1 Perforation did 0not occur in
any of our patients. In the literature, bleeding as a complication of
gastric polypectomy was reported in 3.5% [23].
Relationship between long-term PPIs use and fundic gland polyps’
occurring has not yet been fully established. Jalving et al. [4] found
in their study a significant association only in the subgroup of
patients treated with PPI for over 1 year. Our data do not support a
relationship between PPI and fundic gland polyps.
In patients with GP, evaluating H. pylori infection state by obtaining
biopsies of the surrounding gastric mucosa is recommended and
treatment is required if present [24, 25].
Hyperplastic polyps should be biopsied according to the British
society of gastroenterology and an examination of the whole
stomach should be made. H pylori infection should be detected and
eradicated when present [24]. GP of the non-adenomatous type
are at a low risk of malignant transformation, therefore endoscopic
resection is not necessary.
GASTROENTEROLOGY TODAY - SPRING 2022
50
60
53
40
50
30
40
14 14
20
7
30
10
14
1
14
20
7
0
10
Cold snare Hot snare
1
EMR
Monoblock Piece-meal
0
Fig. 2 The distribution of polypectomy. EMR endoscopic mucosal resection
Cold snare Hot snare EMR
Monoblock Piece-meal
Fig. 2 The distribution of polypectomy. EMR endoscopic mucosal resection
5
5
10

FEATURE
Guidelines on management of hyperplastic polyps, recommend
resection of polyps greater than 5 mm [26, 27].
Complete removal of the adenoma should be performed when safe to
do according to the British recommendations [24].
Polypectomy is not required for sporadic fundic gland polyps. Biopsy of
probable fundic gland polyps is recommended to exclude dysplasia. In
patients with multiple fundic gland polyps who are under 40 years-old,
or where biopsies specimens show dysplasia, colonoscopy should be
performed to exclude familial adenomatous polyposis [24].
Szaloki et al. reported that there were important disagreements in 12
cases of examined forceps biopsy specimens. In 14 neoplastic, and
1 hyperplastic polyps, the degree of dysplasia seen on histological
examination of the forceps biopsy specimens differed from that
observed for the resected specimens. Complete agreement between
the histological results on ectomized polyp, and the forceps biopsy
was observed in only 55.3% of the cases [28]. In our study, Adenomas
analysis showed a 100% agreement between primary and final results.
The agreement rate was 93% for hyperplastic polyps (13 polyps out of
14). The overall agreement was of 95.3%.
Ethics approval and consent to participate
This study was performed according to the Declaration of Helsinki,
following the guidelines for good clinical practice. “Habib Thameur
Hospital ethics committee” approved the study protocol. All methods
were carried out in accordance with relevant guidelines and regulations.
Informed consent to participate in the study was obtained from
participants.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Gastroenterology and Hepatology Department, Habib Thameur
Hospital, Tunis, Tunisia. 2 Faculty of Medicine of Tunis, El Manar
University, Tunis, Tunisia.
Received: 8 July 2021 Accepted: 7 February 2022
Published online: 19 February 2022
Our study included the greatest number of EGD with patients diagnosed
with GP in our country.
Conclusion
Gastric polyps’ frequency in our study was low (0.46%). Hyperplastic
polyps are the most common gastric polyps in our country. In case of
single polyps, biopsies are recommended to rule out a diagnosis of
adenoma or hyperplastic polyps with dysplasia. Good knowledge of
practical guidelines is important for the management of GP.
Acknowledgements
Not applicable.
Authors’ contributions
H.Y.: concept, design, definition of intellectual content, literature
search, manuscript preparation, manuscript editing, manuscript review.
N.B.: concept, design, definition of intellectual content, manuscript
preparation, manuscript review. M.S.: definition of intellectual content,
manuscript preparation. N.B.: design. A.O.: design, manuscript
review. D.T.: manuscript review. D.G.: definition of intellectual content,
manuscript review. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
The data that support the findings of this study are available on
request from the corresponding author, [HY]. The data are not publicly
available due to [restrictions e.g. their containing information that could
compromise the privacy of research participants].
Declarations
References
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3. Barbosa SHB, Lazaro GCF, Franco LM, Valenca JTJ, Nobre
SMA, Souza M. Agreement between different pathologists in
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4. Jalving M, Koornstra JJ, Wesseling J, Boezen HM, Jong DE,
Kleibeuker SJH. Increased risk of fundic gland polyps during
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spectrum of gastric polyps: a 1-year national study of over 120,000
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7. Morais DJ, Yamanaka A, Zeitune JM, Andreollo NA. Gastric polyps:
a retrospective analysis of 26,000 digestive endoscopies. Arq
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JR, Vazquez Sequeiros E, Boixeda de Miquel D. Gastric polyps:
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Esp Enferm Dig. 2011;103(8):416–20.
9. Argüello Viúdez L, Córdova H, Uchima H, Sánchez Montes C, Ginès
À, Araujo I, et al. Gastric polyps: retrospective analysis of 41,253
upper endoscopies. Gastroenterol Hepatol. 2017;40(8):507–14.
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10. Bassene ML, Diallo S, Thioubou MA, Diallo A, Gueye MN, Diouf ML.
Gastric polyps in a digestive endoscopy center in Dakar. Open J
Gastroenterol. 2017;7(10):279–86.
11. Olmez S, Sayar S, Saritas B, Savas AY, Avcioglu U, Tenlik I, et
al. Evaluation of patients with gastric polyps. North Clin Istanb.
2018;5(1):41–6.
12. Ljubicic N, Kujundzic M, Roic G, Banic M, Cupic H, Doko M, et al.
Benign epithelial gastric polyps-frequency, location, and age and sex
distribution. Coll Antropol. 2002;26(1):55–60.
13. Sivelli R, Del Rio P, Bonati L, Sianesi M. Gastric polyps: a clinical
contribution. Chir Ital. 2002;54(1):37–40.
14. Freeman HJ. Proton pump inhibitors and an emerging epidemic
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2008;14:1318–20.
15. Raghunath AS, O’Morain C, McLoughlin RC. Review article: the
long-term use of proton-pump inhibitors. Aliment Pharmacol Ther.
2005;22(11):55–63.
16. Macenlle García R, Bassante Flores LA, Fernández Seara J. Pólipos
gástricos epiteliales. Estudio retrospectivo 1995–2000. Rev Clin
Esp. 2003;203(8):368–72.
17. Abraham SC, Singh VK, Yardley JH, Wu TT. Hyperplastic polyps of
the stomach: associations with histologic patterns of gastritis and
gastric atrophy. Am J Surg Pathol. 2001;25(4):500–7.
18. Scoazec JY. Les polypes gastriques: pathologie et génétique. Ann
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19. Hattori T. Morphological range of hyperplastic polyps and
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20. Stolte M. Clinical consequences of the endoscopic diagnosis of
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21. Gencosmanoglu R, Sen Oran E, Kurtkaya Yapicier O, Avsar E, Sav
A, Tozun N. Gastric polypoid lesions: analysis of 150 endoscopic
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2003;9(10):2236–9.
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25. Sharaf RN, Shergill AK, Odze RD, Krinsky ML, Fukami N, Jain R, et
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26. Evans JA, Chandrasekhara V, Chathadi KV, Decker GA, Early DS,
Fisher DA, et al. ASGE guideline: the role of endoscopy in the
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27. Han AR, Sung CO, Kim KM, Park C, Min B, Lee JH, et al.
Theclinicopathological features of gastric hyperplastic polyps with
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28. Szaloki T, Toth V, Tiszlavicz L, Czako L. Flat gastric polyps: results
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12

FASTER DIAGNOSIS OF GASTRIC CANCER
FEATURE
Gastric cancer is typically diagnosed at a very late stage,
leading to a poor prognosis for the patient, and the strain
on healthcare services through the COVID-19 pandemic
has only made things worse. However, detection of precancerous
conditions – such as atrophic gastritis (AG) and
gastric intestinal metaplasia (GIM) – before endoscopy could
potentially support diagnostic pathways, allowing doctors
in primary care to identify and prioritise patients for whom
endoscopy would be useful, streamlining NHS resources and
improving patient outcomes.
What are AG and GIM?
AG is a chronic inflammatory condition of the gastric mucosa.
It can be an autoimmune disorder, but most commonly arises
following prolonged inflammation caused by Helicobacter
pylori
infection. This disrupts the mucus barrier that helps
to protect the cells of the stomach lining from digestive
juices, causing them to be slowly destroyed. AG significantly
increases the risk of stomach cancer, with 18 % of cases
progressing to cancer within 10 years. However, studies
suggest that in some cases the progression of AG can be
halted, and even improved, reinforcing the importance of early
diagnosis and monitoring. 1
GIM is common in cases of AG and occurs when the cells
of the stomach lining are replaced with cells similar to the
lining of the intestines. Again, H. pylori is often implicated in
this process, which predisposes individuals to intestinal-type
gastric adenocarcinoma and neuroendocrine tumours (NETs).
Patients with GIM are often over 50 years of age, and the risk
is further increased by factors such as smoking or having a
first-degree relative with gastric cancer.
Challenges of diagnosis
The current gold standard for diagnosing AG and GIM is
gastroscopy with targeted biopsies, which relies on referral
of patients from primary care. However, AG and GIM are often
asymptomatic – or present with very general symptoms such as
stomach pain, loss of appetite, nausea or vomiting, anaemia and
stomach ulcers – making them hard to detect. Tests for
H. pylori infection, along with blood tests for levels of
pepsinogens and gastrin-17, may help to identify some patients
for whom a referral would be beneficial. However, current
practice is not to actively look for AG and GIM cases before
endoscopy, and so patients may remain undiagnosed in primary
care for prolonged periods if they do not qualify for referral.
Rapid detection of AG and GIM
GastroPanel from BIOHIT is a simple, non-invasive blood test
that can be used in primary care settings for effective diagnosis
of AG and GIM. It gives detailed information on the structure
and function of the stomach mucosa, by quantifying pepsinogen
I, pepsinogen II and gastrin-17, and can also differentiate the
cause of AG by identifying IgG antibodies to H. pylori. Using
GastroPanel in targeted groups of at-risk patients could help to
direct referrals more effectively. As well as detecting cancers
at an earlier and more curable stage, reducing the number of
gastroscopies in lower risk patients would reduce both the cost
and volume burden on healthcare resources, without adversely
affecting patient care.
For more information about GastroPanel
contact: info@biohithealthcare.co.uk
1 . Kong YJ, Yi HG, Dai JC, Wei MX. Histological changes of gastric mucosa after Helicobacter pylori eradication: A systematic review and meta-analysis. World J Gastroenterol 2014; 20(19): 5903-5911
For the early diagnosis
of gastric cancer risk
Reduce endoscopy waiting lists and
improve the diagnostic pathway for
patients, through an earlier, faster
and more cost-effective approach.
GASTROENTEROLOGY TODAY - SPRING 2022
www.biohithealthcare.co.uk
13

FEATURE
ENDOSCOPIC RETROGRADE APPENDICITIS
THERAPY VERSUS LAPAROSCOPIC
APPENDECTOMY VERSUS OPEN APPENDECTOMY
FOR ACUTE APPENDICITIS: A PILOT STUDY
Zhemin Shen 1 , Peilong Sun 1*† , Miao Jiang 2† , Zili Zhen 1 , Jingtian Liu 1 , Mu Ye 1 and Weida Huang 1
Shen et al. BMC Gastroenterology (2022) 22:63 https://doi.org/10.1186/s12876-022-02139-7
GASTROENTEROLOGY TODAY - SPRING 2022
14
Abstract
Background
An increasing number of studies have shown the merits of endoscopic
retrograde appendicitis therapy (ERAT) in diagnosing and treating acute
uncomplicated appendicitis. However, no related prospective controlled
studies have been reported yet. Our aim is to assess the feasibility and
safety of ERAT in the treatment of acute uncomplicated appendicitis.
Methods
In this open-label, randomized trial, participants were randomly allocated
to the ERAT group, laparoscopic appendectomy (LA) group and open
appendectomy (OA) group. The primary outcome was the clinical success
rate of the treatment. Intention-to-treat analysis was used in the study.
Results
The study comprised of 99 patients, with 33 participants in each
group. The clinical success rate was 87.88% (29/33), 96.97% (32/33)
and 100% (33/33) in the ERAT, LA and OA group, respectively. In the
ERAT group, 4 patients failed ERAT due to difficult cannulation. In LA
group, 1 patient failed because of abdominal adhesion. There were no
significant differences among the three treatment groups regarding the
clinical success rate (P=0.123). The median duration of follow-up was
22 months. There were no significant differences (P =0.693) among the
three groups in terms of adverse events and the final crossover rate of
ERAT to surgery was 21.21% (7/33).
Conclusion
ERAT can serve as an alternative and efficient method to treat acute
uncomplicated appendicitis.
Trial registration The study is registered with the WHO Primary Registry-
Chinese Clinical Trial Registry (ChiCTR1900025812).
Keywords
Acute appendicitis, Endoscopic retrograde appendicitis therapy,
Appendectomy, Randomized controlled trial
Introduction
Acute appendicitis is one of the most common causes of acute
abdominal pain clinically [1]. Appendectomy has long been standard
treatment for acute appendicitis. However, there are a series of potential
*Correspondence: sunpeilong@fudan.edu.cn
†
Peilong Sun and Miao Jiang contributed equally in the trial
1
Department of General Surgery, Jinshan Hospital, Fudan University, Shanghai, China
©The Author(s) 2022
postoperative complications, such as postoperative bleeding, wound
infection and intestinal obstruction [2, 3], and the overall complication
rate has been reported to be 8.2–31.4% [1]. Moreover, negative
appendectomy is also a nonnegligible problem [4]. As previous studies
suggested that perforation may not be an inevitable consequence of
acute appendicitis, there is a division of opinions on performing surgery
on patients with acute uncomplicated appendicitis [5]. Thus, developing
a safe and efficient nonoperative method has been an agenda for
treating acute uncomplicated appendicitis.
Endoscopic retrograde appendicitis therapy (ERAT) was firstly
reported by Liu et al. as being inspired by endoscopic retrograde
cholangiopancreatography (ERCP) [6]. ERAT is a novel, nonoperative and
minimally invasive method of treating acute uncomplicated appendicitis.
Recently, there has been additional studies of the use of ERAT for
treating acute uncomplicated appendicitis [7,8,9]. The results of these
3 trials indicated the clinical value of ERAT, including both diagnostic
and therapeutic aspects. Thus, ERAT has the potential to become an
alternative treatment method for acute appendicitis, especially in patients
who are deemed as high-risk candidates for surgery. However, these
previous studies were all retrospective, and no prospective study has
been reported yet. To address this issue, we conducted a prospective
randomized controlled trial to compare ERAT with laparoscopic
appendectomy (LA) and open appendectomy (OA), and evaluated the
feasibility and safety of ERAT in treating acute uncomplicated appendicitis.
Method
Patients
The period of patient enrollment was between January 2018 and August
2019. A prospective, open-label, randomized controlled study was
conducted at Jinshan Hospital, Fudan University. Patients diagnosed
with acute uncomplicated appendicitis were enrolled in the study.
The inclusion criteria were as follows: (1) patient age over 18 years and
under 80 years; (2) Alvarado score >5 [1]; (3) suspicious (or could not
be excluded) acute appendicitis diagnosed by an abdominal CT scan,
which was indicated by a dilated appendix with a diameter greater than
6 mm, a thickened cecal wall, and periappendiceal fat inflammation, with
or without an appendicolith [10].
Exclusion criteria were as follows: (1) suspected acute complicated
appendicitis with perforation or gangrene; (2) appendiceal diameter

FEATURE
Fig. 1 Procedures of endoscopic retrograde appendicitis therapy (ERAT). a Congestion and edema around the mucosa of appendix orifice. b The
endoscopic retrograde appendicography (ERA) fluoroscopy showed filling defect in the appendix lumen (arrows), which indicated the presence
of appendicoliths. c Cannulation of catheter along the guidewire with sand-like appendicoliths excretion and pus drainage inside the appendix
lumen, confirming acute appendicitis. d Retracting the appendicoliths by the extraction basket. e After appendicolith being retracted, the appendix
lumen was fully filled with contrast media under ERA. f Stenting for keeping pus drainage
greater than 15 mm, which usually indicates malignancy [11]; (3)
patients under the age of 18 years or over 80 years; (4) patients
with the following contradictions for receiving colonoscopy, surgery
or anesthesia: (a) severe cardiopulmonary insufficiency, psychiatric
dysfunction or coma; (b) acute diffuse peritonitis, which is defined
as diffuse abdominal tenderness, rebound tenderness and muscular
tension; (c) acute gastroenteritis (dysentery, explosive ulcerative colitis);
(d) concurrent menses; (e) intestinal obstruction; (f) acute gastrointestinal
hemorrhage; (g) recent gastrointestinal or pelvic operation or
radiotherapy; (h) allergy to contrast medium; (i) hemorrhagic tendency
because of long-term use of corticosteroids or anticoagulant treatment;
(5) patients undergoing any other clinical trial.
Written informed consent was obtained from all participants. The study
was conducted according to the Declaration of Helsinki and approved
by the Ethics Committee of Jinshan Hospital, Fudan University (No.
2017–24) on May 17th, 2017. The study is registered with the WHO
Primary Registry-Chinese Clinical Trial Registry (ChiCTR1900025812)
(09/09/2019).
Randomization was conducted by a computer-generated randomization
number (1:1:1) by statisticians. The final allocation was concealed in
an opaque envelope. The allocation was reported to the doctors and
patients immediately prior to the intervention.
Preintervention preparation
All patients intravenously received antibiotic treatment (1.5 g cefuroxime
with 100 ml normal saline, 0.5% metronidazole 100 ml) immediately
after being clinically diagnosed. In the ERAT group, the patients orally
took 328.8 g polyethylene glycol (PEG) electrolyte solution with 2000 ml
water before ERAT for bowel preparation. When the excrement became
a clear liquid, the patients were well prepared to undergo ERAT.
ERAT procedure
Similar to that in previous studies [7,8,9], the ERAT procedure was
performed as follows (Fig. 1):
First, a full and careful examination of the large intestine was performed
by a colonoscope (CF-H260AI, Olympus, Japan) with a transparent cap.
Then, the colonoscope was located to the appendiceal orifice to check
the appendiceal mucosa to determine whether there was inflammation
or any other abnormalities. With the help of a transparent cap, the tip
of the catheter (BDC-12/55–7/1810/55–7/18, Micro-Tech Co. Ltd.,
Nanjing, China) was placed in the appendiceal orifice, and a 0.035-inch
GASTROENTEROLOGY TODAY - SPRING 2022
15

FEATURE
guidewire (MTN-BM-89/45-A, Micro-Tech Co. Ltd., Nanjing, China) was
gently and deeply inserted into the appendiceal lumen over the catheter.
Finally, the catheter moved forward into the appendiceal lumen along
the guidewire. To make a definite diagnosis, the appendiceal lumen
was filled with contrast medium (ioversol) for endoscopic retrograde
appendicography (ERA) fluoroscopy. Next, the appendiceal lumen was
flushed repeatedly with gentamicin (240,000 units with 100 ml normal
saline) and 0.5% metronidazole 100 ml to clear pus and other infectious
contents, such as sand-like appendicoliths. Then, an extraction basket
(SEB-A- 30/55–7/200, Micro-Tech Co., Ltd., Nanjing, China) was used
to extract the remaining appendicoliths if necessary. Finally, a plastic
stent (SPSOF7-7, Cook, USA) was placed routinely in the appendiceal
orifice to maintain pus drainage.
Surgical treatment
All operations were performed by surgeons from a same team. In the
LA group, the three-port technique (umbilical, 10 mm; suprapubic, 5
mm; right lower abdomen, 10 mm) was chosen. In the OA group, a
McBurney muscle-splitting incision technique was used.
and CRP level; the duration of diet resumption; the length of hospital
stay (LOS); the total cost of the primary hospital stay; adverse events
during follow-up period and final crossover rate of ERAT to surgery.
Definition
The clinical success of ERAT is defined as successful appendix
cannulation with complete resolution of symptoms and normalization
of inflammatory markers, including WBC count, neutrophil percentages
and CRP. Difficult appendix cannulation is defined as failure to achieve
successful appendix cannulation within 15 min. The assessment of
abdominal pain degree is based on visual analog scales (VAS). In the
VAS, scores of 0 and 10 represent no pain and most severe pain,
respectively. Complete relief of abdominal pain refers to a VAS score of
0.
The diagnostic criteria of acute appendicitis by ERAT mainly consist
of ERA fluoroscopy images, inflammation of the appendiceal mucosa
observed under endoscopy and the presence of pus or appendicoliths
inside the appendiceal lumen [8].
GASTROENTEROLOGY TODAY - SPRING 2022
16
Postintervention management
After ERAT or surgery was performed, patients were sent back to the
ward and monitored carefully. Patients continued to receive antiinflammatory
therapy when necessary. In the ERAT group, patients
were given a soft diet later on the same day and resumed a normal diet
when the soft diet was tolerated. In the LA and OA groups, a soft diet
was started 24 h after surgery, and a normal diet was given when the
soft diet was completely tolerated. All patients were asked about their
clinical presentation every day. Routine blood tests, including the white
blood cell (WBC) count, neutrophil percentages and C-reactive protein
(CRP) level, were performed on day 1, 3, and 5 in a similar fashion after
ERAT or surgery. Patients were discharged when all symptoms were
completely relieved and inflammatory markers (including the WBC count,
neutrophil percentages, and CRP level) returned to normal. If ERAT
failed or abdominal pain persisted after ERAT, LA or OA was performed
immediately.
Follow-up
Fourteen days after ERAT, all patients in the ERAT group were scheduled
for outpatient services to inform doctors of their symptoms after
discharge. Patients then received an abdominal X-ray to check the
status of the stent. If the stent was not discharged spontaneously with
defecation, colonoscopy was recommended to retrieve the stent.
Follow-up was performed by telephone interview every 3 months for
the first half year, and then every 6 months till November 2020. In
the ERAT group, recurrence of abdominal pain or appendicitis after
ERAT, including the relevant treatment, was mainly investigated. In the
LA group and OA group, the survey mainly included postoperative
complications such as wound infection, persistent incision pain and
intestinal obstruction. Follow-up was performed until the end of the
study period.
Outcomes
The primary outcome was the clinical success of the treatment. The
secondary outcomes were as follows: the duration of complete relief of
abdominal pain and body temperature; the duration of normalization of
inflammatory markers including the WBC count; neutrophil percentages
In the ERAT group, adverse events mainly indicated the recurrence of
acute appendicitis. In the LA and OA groups, adverse events suggested
postoperative complications.
Statistical analysis
As this was a pilot trial, we did not perform a power calculation. On the
basis of our yearly caseload of approximately 240 cases and estimated
recruitment of one fifth of eligible cases, we aimed to enroll at least
96 patients within a 2-year period. Qualitative data are expressed as
numbers (n) and percentages (%) and were compared by using the χ 2
test or Fisher’s exact test when appropriate.
Quantitative data are expressed as the mean ±standard deviation
(SD) or median with 25th and 75th percentiles, as appropriate. For
normally distributed quantitative data (such as age, temperature, WBC
count), one-way analysis of variance (ANOVA) was used to compare
the differences among the three groups. For nonnormally distributed
quantitative data (neutrophil percentages, CRP, Alvarado scores, VAS
scores, the duration of normalization of inflammatory markers, the
duration of normal diet and body temperature, total cost and length of
hospitalization), the Kruskal–Wallis test followed by all pairwise multiple
comparisons was used to detect statistical significance. Bonferroni’s
correction was used for multiple hypothesis testing. The data were
analyzed by IBM SPSS software version 22 (SPSS, Chicago, Illinois,
USA). A P value

FEATURE
Fig. 2 Trial profile
Appendicoliths were present in 12 patients (36.36%) in the ERAT group,
16 patients (48.48%) in the LA group and 11 patients (33.33%) in the
OA group. There were no significant differences in appendicoliths among
the three groups (p =0.516).
Treatment success rate and efficacy of ERAT
Table 2 shows the clinical outcomes of the three groups. Successful
treatment was achieved in 29 patients (87.88%) in the ERAT group,
32 patients (96.97%) in the LA group and 33 patients (100%) in the
OA group. No significant differences were observed among the three
groups (P=0.123). Among the three groups, ERAT failed in four patients
(12.12%) due to difficult cannulation, and LA was performed in these
patients later on the same day, with uneventful recoveries. All these
four patients were found appendicoliths before ERAT. Appendicoliths
of the other 8 patients who were found to have appendicoliths by CT
scan were removed by ERAT. Stents were placed in 29 patients with
successful ERAT. In the LA group, a 63-year-old patient failed LA due
to extensive abdominal adhesion caused by surgical reduction for
intussusception 3 years ago. The patient was later converted to OA
successfully.
Among 29 patients who underwent successful ERAT, most achieved
complete abdominal pain relief immediately after the procedure. The
duration of normalization of inflammatory markers, including the WBC
count, neutrophil percentages and CRP level, did not significantly differ
among the ERAT, LA and OA groups (P =0.351, P=0.607, P=0.147,
respectively). The overall cost in the LA group was significantly
higher (P

FEATURE
Table 1 Basic characteristics
ERAT group (n=33) LA group (n=33) OA group
(n=33)
P value
Age, mean (SD), years 44.12±16.95 43.24±15.41 45.45±18.04 0.866
Male, n (%) 18 (54.55) 17 (51.52) 19 (57.58) 0.967
Abdominal surgery history, n (%) 8 (24.24) 8 (24.24) 7 (21.21) > 0.999
Symptoms
Migrated right lower abdominal pain, n (%) 29 (87.88) 22 (66.67) 25 (75.76) 0.142
Nausea, n (%) 22 (66.67) 23 (69.70) 17 (51.52) 0.285
Vomiting, n (%) 5 (15.15) 4 (12.12) 9 (27.27) 0.345
Anorexia, n (%) 33 (100) 32 (96.97) 32 (96.97) > 0.999
Fever, n (%) 18 (54.55) 13 (39.39) 17 (51.52) 0.532
Temperature (℃) 37.37±0.77 37.13±0.57 37.22±0.58 0.317
Signs
Right lower abdominal tenderness, n (%) 33 (100) 33 (100) 33 (100)
Rebound tenderness, n (%) 17 (51.52) 15 (45.45) 20 (57.58) 0.654
Laboratory examination
WBC count (× 10 9 /L) 11.78±3.84 11.87±3.80 13.64±3.87 0.091
Neutrophil percentages, median (25th, 75th percentile) 0.84 (0.78, 0.87) 0.81 (0.76,0.85) 0.83 (0.76, 0.90) 0.233
CRP (mg/L) 0.749
0–20 18 (54.6) 20 (60.6) 25 (75.76)
21–50 7 (21.2) 7 (21.2) 6 (18.18)
> 50 8 (24.2) 6 (18.2) 2 (6.06)
CT scan
Local Cecal Wall thickening, n (%) 4 (12.12) 0 (0) 1 (3.03) 0.123
Periappendiceal fat inflammation, n (%) 25 (75.76) 27 (81.82) 29 (87.88) 0.496
Intraluminal appendicolith, n (%) 12 (36.36) 16 (48.48) 11 (33.33) 0.516
Alvarado scores, median (25th, 75th percentile) 8 (7, 9) 8 (6, 9) 8 (7, 9) 0.127
VAS scores, median (25th,75th percentile) 6 (5, 7) 7 (6, 7) 6 (6, 7) 0.054
ERAT, endoscopic retrograde appendicitis therapy; LA, laparoscopic appendectomy; OA, open appendectomy; SD, standard deviation; WBC, white blood cell; CRP,
C-reactive protein; VAS, visual analog scale
GASTROENTEROLOGY TODAY - SPRING 2022
9 patients only received colonoscopy for one time. Moreover, for the 4
patients who failed ERAT, they also received two-times intervention since
they underwent both ERAT and LA. Table 3 summarizes the adverse
events which arose in the three groups. No significant differences
(P =0.693) were found among the three treatment groups. In the ERAT
group, three patients (9.09%) reported right lower abdominal pain and
were diagnosed with recurrent acute appendicitis. The recurrence time
was 4, 6 and 11 months, respectively. Two of them were found to have
intraluminal appendicoliths during primary hospitalization. These three
patients received LA later at the same day. Thus, there were totally 7
patients in the ERAT group who crossed over to the LA group, and
the final crossover rate is 21.21% (7/33). In the LA group, one patient
(3.03%) was found to have a fluid collection around the ileocecal
junction and the fluid collection gradually diminished later on. In the
OA group, three patients (9.09%) were found to have postoperative
complications. Two of them exhibited wound infections within one
month after surgery. Another patient complained of occasional incision
pain one month after OA, especially on rainy days.
Discussion
In this pilot RCT, we have shown that ERAT is feasible and safe for
treating acute uncomplicated appendicitis. Overall, nearly 25% of
patients accepted to participate the trial, suggesting the potential
clinical extension of ERAT since it is a brand-new treating method and
no patient has ever heard of it before. Appendicoliths and infection are
considered as important causes of acute appendicitis and ERAT could
treat acute uncomplicated appendicitis by appendicolith extraction, pus
drainage and intraluminal pressure reduction to relieve the syndromes
and ultimately treat acute appendicitis [7, 12, 13]. Although this pilot trial
was not adequately powered to detect differences in treatment efficacy,
the results are useful to inform future clinical application of ERAT.
Although there are some complications associated to colonoscopy,
the adverse event rates were less than 1% and 0.2% for bleeding and
perforation respectively and there were no any adverse events related
to colonoscopy among the patients underwent ERAT treatment in our
study [14]. Moreover, ERAT compares favorably with the results of
surgery in terms of the postintervention recovery of patients. Regarding
the period of body temperature normalization, inflammatory markers
(including the WBC count, neutrophil percentages and CRP level)
and the length of hospitalization, our data did not indicate significant
differences among the three groups (P =0.194, P=0.351, P=0.607,
P=0.147, P=0.054, respectively), which showed that the clinical
efficacy of ERAT was similar to that of surgery. As for different surgical
methods, LA showed a similar clinical efficacy as OA, while LA yielded
18

FEATURE
Table 2 Clinical outcome
ERAT group
(n = 33)
LA group
(n=33)
OA group
(n=33)
P value ERAT-LA ERAT-OA LA-OA
Treatment Success, n (%) 29 (87.88) 32 (96.97) 33 (100) 0.123
Definite acute uncomplicated appendicitis, n (%) 33 (100) 33 (100) 33 (100)
Appendicoliths removal, n (%) 8 (66.67) NA NA
Stent d rainage, n(%) 29 (87.88) NA NA
Failed cannulation, n (%) 4 (12.12) NA NA
Transferred to surgery, n (%) 4 (12.12) NA NA
Normalization of WBC count, days 0.351
0–1 16 12 17
1–3 5 12 9
> 3 2 0 2
Normalization neutrophil percentages, days 0.607
0–1 15 11 7
1–3 11 14 19
> 3 4 2 2
Normalization of CRP, days 0.147
0–1 3 1 3
1–3 5 10 2
> 3 7 2 3
Normalization of temperature, median (25th, 75th 2 (1, 3) 1 (1, 2) 2 (1, 3) 0.194
percentile), days
LOS, median (25th, 75th percentile), days 5 (4, 6) 4 (3, 5) 4 (3, 5) 0.054
Total cost, median (25th, 75th percentile), RMB 10,983.25
(10,210.26,
13,028.25)
14,517.22
(12,991.05,
15,528.25)
8246.82
(6819.71,
9530.22)
< 0.001 0.001 < 0.001 < 0.001
ERAT, endoscopic retrograde appendicitis therapy; LA, laparoscopic appendectomy; OA, open appendectomy; NA, not applicable; WBC, white blood cell; CRP,
C-reactive protein; LOS, length of hospital stay
Table 3 Follow-up
ERAT group
(n=33)
LA group
(n=33)
OA group (n=33)
P value
Stent discharged, n (%) 29 (87.88) NA NA
Spontaneously discharged, n (%) 9 (31.03) NA NA
Retrieved, n (%) 20 (68.97) NA NA
Adverse events, n (%) 3 (9.09) 1 (3.03) 3 (9.09) 0.693
Recurrence, n (%) 3 (9.09) NA NA
Patients with appendicolith at first admission, n (%) 2 (6.06) NA NA
Patients without appendicolith at first admission, n (%) 1 (3.03) NA NA
Crossover rate (%) 21.21 3.03 NA
Complications
Wound infection, n (%) NA 0 2 (6.06)
Abdominal or incisional pain, n (%) NA 0 1 (3.03)
Abdominal fluid collection, n (%) NA 1 (3.03) 0
Obstructive symptoms, n (%) NA 0 0
ERAT, endoscopic retrograde appendicitis therapy; LA, laparoscopic appendectomy; OA, open appendectomy; NA, not applicable
fewer complications, although there was no statistical significance
(P =0.693) in the current study. OA, as the traditional treatment method,
is the most reliable therapy for acute appendicitis. However, OA seems
to cause more adverse events, such as wound infection, which reduces
the quality of life of patients.
protect beneficial or commensal microorganisms from contamination
with pathogenic organisms [15]. In addition, evidence has shown that
appendectomy may slightly increase the incidence of Crohn’s disease
[16]. In patients with acute uncomplicated appendicitis, ERAT may
preserve the function of the appendix with a satisfactory therapeutic
effect. To some extent, ERAT may be essential for intestinal immune
A previous study suggested that the appendix could preserve and function, which is another strength of the treatment.
GASTROENTEROLOGY TODAY - SPRING 2022
19

FEATURE
GASTROENTEROLOGY TODAY - SPRING 2022
Difficult biliary cannulation is defined as the inability to achieve selective
cannulation within 10 min or 5 attempts by a recent ERCP guideline
[17]. Taking the ERCP guideline as a reference, in our study, we set
the difficult appendix cannulation time to within 15 min regardless of
the number of cannulation attempts. In the present study, 4 patients
(12.12%) failed ERAT treatment. All of these failures were due to difficult
cannulation caused by a swollen mucosa and narrow lumen of the
appendix. In these patients, the guidewire failed to pass through the
swollen and convoluted appendiceal lumen. Unfortunately, difficult
appendiceal cannulation remains an unsolved issue. We believe that
there may be two ways to assist appendiceal cannulation in this
situation. One is to find new equipment that can overcome the severe
edema of the appendix mucosa. The other is to prolong the pre-ERAT
duration to acquire more sufficient anti-inflammatory effect by antibiotics
and thereby maximally reduce the inflammation of the appendiceal
mucosa. However, the second method would definitely increase the
overall hospitalization duration of patients. Subsequent studies will be
conducted to address difficult appendiceal cannulation. In the current
study, 4 patients who failed ERAT were found to have appendicoliths.
However, the reason of failure was due to the mucosal edema instead
of the obstruction of the appendicoliths. Apart from the 4 patients,
the other 8 patients with appendicoliths had a smooth recovery by
receiving ERAT alone. Hence, appendicolith should not be considered
as a contraindication of ERAT. Same as previous study [18], we think
the key to remove appendicoliths was based on the quality of the stone
and the technique of the endoscopist. A fragile stone, regardless of
its size, is more likely to be removed by the combination of irrigation
and extraction basket. If the stone is hard and large, the success of
retraction is more dependent on the experience and the technique of
the endoscopist. When a giant and irregular appendicolith is observed,
it is also feasible to squeeze the appendix and let the stone fall into
the intestine cavity. After that, the appendicolith can be removed via
the intestine by a stone basket. Previous studies showed that the
recurrence rates of acute appendicitis patients treated with ERAT ranges
from 6.1 to 15% [7,8,9]. In the present study, 3 patients (9.09%) had
recurrent appendicitis. This recurrence rate was consistent with previous
findings. The recurrence of acute appendicitis may be associated with
the appendiceal morphology since long and curved appendix is also
risk factor of acute appendicitis. Other factors, such as genetic and
environmental factors, may also have impact on recurrence. The final
crossover rate of ERAT group was 21.21%, which means more than 3/4
of all patients recovered successfully by receiving ERAT alone and those
who crossed over to surgery did not experience any adverse outcomes
due to the delay in appendectomy. However, the final crossover rate
may be underestimated due to short-term follow-up period and a
long-term follow-up is needed to be done in the future. Moreover, in a
previous study, spontaneous discharge of the stents was considered as
an adverse event [9]. However, in current study, the stents of 9 patients
spontaneously discharged and these 9 patients did not show symptoms
during the 14-day period. Thus, from our point of views, if the patients
do not show any discomfort, spontaneous discharge of the stents
should be considered as a benefit and convenience since these patients
will not have to undergo colonoscope a second time.
Another advantage of ERAT is its ability to facilitate a precise diagnosis
of acute appendicitis. Generally, endoscopy can serve as a diagnostic
tool for numerous diseases, such as ulcerative colitis and Crohn’s
disease [19, 20]. A previous study indicated that colonoscopy can
diagnose acute appendicitis with 100% sensitivity and 99% specificity
[21]. Li et al. further described the key points of diagnosing acute
appendicitis by ERAT by observing both the appendiceal mucosa
morphology and the appendiceal lumen imaging by fluoroscopy [8].
In our study, 33 patients with acute uncomplicated appendicitis in
the ERAT group were all confirmed by ERAT. In the future, ERAT may
become an essential diagnostic method for patients suspicious for acute
appendicitis who have atypical clinical manifestations.
One feature of our study was that an abdominal CT scan was performed
in all participants. Although CT scan is not a necessary diagnostic
criterion for acute appendicitis, using CT can enhance the accuracy of
diagnosing acute appendicitis and minimize the negative appendicitis
rate. Similar to this view, some previous trials showed that their study
design was limited due to the lack of CT scans performed in suspicious
patients [7]. Based on former experiences, all participants had to be
examined by abdominal CT scan in our study. Thus, we could accurately
enroll the patients with acute uncomplicated appendicitis in our trial by
both clinical manifestation and CT scan confirmation.
The study has several limitations. First, the success rate of ERAT largely
depends on the skills of endoscopists. Although our endoscopists are
experienced doctors, the lack of ERAT guidelines was still the main
problem when faced with difficult cannulation. Second, since this was
an RCT, we tried to perform ERAT on the first day of hospital admission,
which was similar to the timing of emergency surgery. The downside of
this strategy is that it may cause insufficient anti-inflammatory treatment
in patients, which may increase the difficulty of appendiceal cannulation.
Third, in the current study, the power was not calculated and the study
is more likely to commit a type II error. However, in this pilot study,
the safety and feasibility of ERAT were preliminarily estimated. Thus,
future studies involved with larger sample size are needed to be done.
Fourth, a double-blinded trial cannot be conducted due to the nature
of the study. Last, the need to prepare for colonoscopy in patients with
abdominal pain requires further study and is another limitation of the
study.
In conclusion, ERAT was demonstrated to be a feasible and safe
treatment for acute uncomplicated appendicitis. However, difficult
appendiceal cannulation and acute appendicitis recurrence are the main
problems that remain to be solved. In the future, large-scale multicenter
RCTs are needed to further address the current challenges.
Abbreviations
ERAT: Endoscopic retrograde appendicitis therapy; LA: Laparoscopic
appendectomy; OA: Open appendectomy; PEG: Polyethylene glycol;
SD: Standard deviation; ERA: Endoscopic retrograde appendicography;
WBC: White blood cell; CRP: C-reactive protein; LOS: Length of
hospital stay; VAS: Visual analog scales; ANOVA: Analysis of variance;
ITT: Intention-to-treat; CT: Computed tomography; RCT: Randomized
controlled trial; EMR: Endoscopic mucosal resection
Acknowledgements
We would like to thank American Journal Experts (https://www.aje.com/)
for English language editing. We also appreciate all members from the
Department of General Surgery, Jinshan hospital, Fudan University, for
helping with the study.
20

FEATURE
Authors’ contributions
PLS and MJ proposed the study and were accountable for all aspects of
the work. ZMS contributed to the article in the aspects of drafting work
as well as collecting, analyzing and interpreting the data; ZLZ, JTL, MY
and WDH all made essential contribution to the manuscript. All authors
read and approved the final manuscript.
Funding
This study was supported by Project of Shanghai Municipal Health
Commission of China (No. 201740041). All the funding was used to
conduct this trial.
Availability of data and materials
The datasets supporting the conclusions of this article are available in the
the ResMan original data sharing platform (IPD sharing platform) of the
Chinese Clinical Trial Registry, which can be viewed at the following website:
http://www.medresman.org.cn/pub/cn/proj/projectshow.aspx?proj=5600.
We expect to release the original data on December 2022.
Declarations
Ethics approval and consent to participate
All procedures performed in studies involving human participants
were in accordance with the ethical standards of Ethics Committee of
Jinshan Hospital, Fudan University (No. 2017-24) on May 17th, 2017
and also with the 1964 Helsinki declaration and its later amendments
or comparable ethical standards. The experimental protocol was also
approved by Shanghai Municipal Health Commission and Project of
Shanghai Municipal Health Bureau in China (No. 201740041). Written
informed consent was obtained from all participants. The study is
registered with the WHO Primary Registry-Chinese Clinical Trial Registry
(ChiCTR1900025812).
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interest.
Author details
1
Department of General Surgery, Jinshan Hospital, Fudan University,
Shanghai, China. 2 Department of Gastroenterology, Jinshan Hospital,
Fudan University, Shanghai, China.
Received: 29 June 2021 Accepted: 3 February 2022
Published online: 13 February 2022
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principles of surgery. 9th ed. New York: McGraw-Hill; 2010. p. 1074–5.
14. Su YK, Kim HS, Hong JP. Adverse events related to colonoscopy:
global trends and future challenges. World J Gastroenterol.
2019;25(02):190–204.
15. Randal Bollinger R, Barbas AS, Bush EL, Lin SS, Parker W. Biofilms
in the large bowel suggest an apparent function of the human
vermiform appendix. J Theor Biol. 2007;249:826–31.
16. Kaplan GG, Pedersen BV, Andersson RE, Sands BE, Korzenik
J, Frisch M. The risk of developing Crohn’s disease after an
appendectomy: a population-based cohort study in Sweden and
Denmark. Gut. 2007;56:1387–92.
17. Liao WC, Angsuwatcharakon P, Isayama H, Dhir V, Devereaux B,
Khor CJ, et al. International consensus recommendations for difficult
biliary access. Gastrointest Endosc. 2017;85:295–304.
18. Song MY, Liu ZH, Zhao LX, Liu BR. Endoscopic retrograde
appendicitis therapy for treating a giant hard appendicolith
embedded in the appendiceal orifice: a case report. Asian J Surg.
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Sands BE. ACG clinical guideline: management of crohn’s disease in
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GASTROENTEROLOGY TODAY - SPRING 2022
21

FEATURE
AN EXTREMELY DANGEROUS CASE OF
ACUTE MASSIVE UPPER GASTROINTESTINAL
BLEEDING: A CASE REPORT
Zhiqiang Yi 1† , Cheng Chen 2† , Biguang Tuo 1 , Taolang Li 3 and Xuemei Liu 1*
Yi et al. BMC Gastroenterology (2022) 22:67 https://doi.org/10.1186/s12876-022-02138-8
Abstract
Background
Upper gastrointestinal (GI) bleeding is a severe acute disease of
gastroenterology department. Fish bone is the most common foodrelated
foreign body. However, fish bone piercing the esophagus,
causing the mediastinal abscess that corroded the left subclavian artery,
resulting delayed but high-risk massive upper gastrointestinal bleeding
is very rare.
Case presentation
A 54-year-old man was admitted to the hospital with a chief complaint
of hematemesis for 2 h. The color of hematemesis was bright red, and
the volume was over 1000 ml. He also had symptoms of palpitations,
fatigue and sweating. He had been on long-term glucocorticoids or
nonsteroidal anti-inflammatory drugs (NSAIDs) for gout for 3 years
before admission, had no previous history of liver disease or GI bleeding
disease, and had a history of drinking.
GASTROENTEROLOGY TODAY - SPRING 2022
Case presentation
We report a 54-year-old man who was diagnosed with delayed but
high-risk massive upper GI bleeding that was the result of a fish bone
piercing the esophagus, causing a mediastinal abscess that corroded
the left subclavian artery. He was saved effectively by early and timely
multidisciplinary collaboration.
Conclusion
A fish bone-caused mediastinal abscess that corrodes the left
subclavian artery and induces delayed but high-risk massive upper GI
bleeding is very rare. In addition to routine consideration of upper GI
bleeding, medical history, endoscopy and CT are helpful for achieving
a diagnosis. Importantly, early and timely multidisciplinary collaboration
can effectively save critically ill patients.
Keywords
Delayed but high-risk massive upper gastrointestinal bleeding, Fish
bone, Mediastinal abscess, Left subclavian artery (LSA), Early and timely
multidisciplinary collaboration
Background
Upper gastrointestinal (GI) bleeding is a severe acute disease
associated with four main causes, namely, esophageal variceal
bleeding, peptic ulcer (PU) bleeding, gastric cancer bleeding
and acute erosive hemorrhagic gastritis, and prompt diagnosis
and treatment are mandatory [1, 2]. In adults, a fish bone is the
most common food-related foreign body [3, 4]. A fish bone can
unfortunately pierce the left subclavian artery (LSA) and cause a
pseudoaneurysm in rare cases, resulting in an LSA esophageal
fistula [3, 5]. Arterioesophageal fistula are rare, but they can cause
massive life-threatening bleeding [6, 7]. Here, we report an adult
case of a mediastinal abscess corroding the LSA, resulting in
delayed but high-risk massive upper GI bleeding.
On admission, the patient’s vital signs included a temperature of 36.4 °C,
blood pressure of 80/50 mmHg, and heart rate of 135 bpm. Laboratory
data showed routine blood tests: hemoglobin 72 g/L (normal, 130–175
g/L), white blood cells 13.41×10 9 /l (normal, 4–10*10 9 /L), total platelets
60×10 9 (normal, 100–300*10 9 /L); C-reactive protein 159.90 mg/l
(normal 0–8 mg/L); blood gas analysis: oxygen partial pressure 79.3
mmHg, CO 2
partial pressure 30.8 mmHg, pH value 7.281; and normal
liver and renal function and coagulation tests. Therefore, GI hemorrhage
was first considered, and esomeprazole was administered. Computed
tomography (CT) on admission showed a visible breach on the left side
of the esophageal wall, a low-density lesion was found between the
esophageal wall and the LSA, and the demarcation from the esophageal
wall and subclavian artery was unclear (Fig. 1). Because the patient had
no history of foreign body ingestion, we initially considered esophageal
diverticula with bleeding potential. However, the patient still presented
with repeated hematemesis with a large volume of bright red blood;
his vital signs could not be maintained, and he developed progressive
unconsciousness 30 min after admission to the hospital. We applied
a multidisciplinary approach; critical care doctors were included in the
treatment, and a member of the Department of Anesthesiology performed
an urgent consultation. Tracheal intubation-assisted respiration, aspiration
prevention, and anti-shock therapy were applied, and 6 units of red blood
cells were transfused. Additionally, urgent esophagogastroduodenoscopy
was performed in the operating room, which indicated active and massive
bleeding from the esophageal wall (Fig. 2). However, due to massive
bleeding, this patient suffered from two cardiac arrests, so a detailed
endoscopic examination could not be performed.
Urgent thoracotomy through the median sternal incision was performed
immediately, and an abscess cavity 4 cm in size was detected between
the LSA and the left common carotid artery. A stench of putrefaction
accompanied by a large gush of blood was present when the abscess
cavity was opened. The active bleeding point was found in the posterior
lateral wall of the LSA with a 3 mm rupture. During the repair of the LSA
and clean-up of the abscess cavity, an esophageal fistula was detected
and repaired on the other side of the abscess cavity. However, no foreign
22
*Correspondence: onlyoneliuxuemei@163.com
†
Zhiqiang Yi and Cheng Chen contributed equally and shared first authorship
1
Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
©The Author(s) 2022

FEATURE
Fig. 1 Image from CT scan. CT showed that the local soft tissue
was Fig. thickened 1 Image in the from esophagus CT scan. CT at the showed cervicothoracic that the local junction, soft tissue
and was a gaseous thickened cavity in was the esophagus present on at the the left cervicothoracic posterior wall of junction, the
esophagus and a gaseous (red arrow), cavity approaching was present the on left the subclavian left posterior artery wall (white of the
arrow). esophagus Esophageal (red breach arrow), was approaching detected (black the left arrow) subclavian artery (white
arrow). Esophageal breach was detected (black arrow)
body was observed (Fig. 3a, b). With prompt and effective treatment, the
patient recovered. Revisiting family history indicated that chest pain and
discomfort occurred in this patient after eating fish 4 days prior.
Discussion and conclusions
Fig. 2 Image from the emergent endoscopy. Active and massive
bleeding Fig. 2was Image detected from from the emergent the esophageal endoscopy. wall by Active emergent and massive
endoscopy bleeding was detected from the esophageal wall by emergent
endoscopy
There are generally four main causes of upper GI bleeding, namely,
esophageal variceal bleeding, PU-caused bleeding, gastric cancercaused
bleeding and acute erosive hemorrhagic gastritis [1, 2].
In addition, there are also reports of NSAIDs causing esophageal
mucosal damage. These drugs may cause mucosal damage by
reducing the cytoprotective effect of prostaglandins on the mucosa
or aggravating reflux esophagitis [8, 9]. The clinical manifestations of
these patients are usually retrosternal pain, sore throat and dysphagia
[9]. Esophageal bleeding caused by NSAIDs is a rare nonfatal bleeding,
mostly secondary to superficial esophageal ulcer oozing, and some
bleeding can even be discovered during endoscopy [10, 11]. However,
Fig. 3 Image from the surgical operation. a The abscess cavity (white arrow) was located between the left subclavian artery (black arrow) and the
left common carotid artery (blue arrow). b Schematic diagram of surgical anatomy
GASTROENTEROLOGY TODAY - SPRING 2022
23

FEATURE
GASTROENTEROLOGY TODAY - SPRING 2022
in the present case, the patient’s condition progressed so rapidly and
dangerously that the challenge was to determine the cause of the
bleeding and how to treat it. Based on medical history, physiological
signs, examination and treatment, this case of delayed but high-risk
massive upper GI bleeding was the result of a fish bone piercing
the esophagus, causing the mediastinal abscess that corroded the
LSA. Fistulas between the subclavian artery and esophagus are rare
but can rapidly become life-threatening [12, 13]. Clinically, among
arterial-esophageal fistulas caused by esophageal foreign bodies,
the proportion of LSA esophageal fistulas is only 2% [3]. Most
mediastinal abscesses are related to infections of deep sternal wounds,
esophageal perforations, or descending necrotizing mediastinitis [14,
15]. Mediastinal abscess directly caused by taking glucocorticoids
has not been reported. It may be a contributing factor to the formation
of abscesses after mediastinal infection. Glucocorticoids have many
complex quantitative and qualitative immunosuppressive effects,
which can induce cellular immune deficiency and may increase the
susceptibility of the host to various viruses, bacteria, fungi and parasites
[16]. The patient’s risk of infection increases with increasing treatment
dose and treatment time. In patients exposed to low doses, even if the
cumulative dose is high, the risk of infection is often low. In addition, the
host’s underlying disease status also determines the changes in the risk
of infection in clinical practice [17]. Therefore, in this case, we believe
that the patient’s long-term use of glucocorticoids is not an independent
risk factor for mediastinal abscess.
Generally, fish bones or sharp foreign bodies can directly pierce the large
arteries in the mediastinum, causing fatal upper GI bleeding. For example,
some case reports have reported sharp foreign bodies such as fish
bones or chicken bones piercing the esophagus and mediastinal artery
[3, 18, 19]. Because the symptoms are initially not serious, they are often
ignored by patients and their families. Once the foreign body leaves the
artery, the patient will die suddenly due to acute upper GI bleeding [3, 18].
If the patient seeks medical attention in time and the foreign body does
not break away from the artery, the patient can be successfully cured by
surgery [19]. In contrast, in this rare case, the mediastinal abscess that
resulted from puncture of the esophagus by the fishbone corroded the
LSA, causing delayed but high-risk arterial hemorrhage.
This case suggests that in addition to routine consideration of upper GI
bleeding, medical history, endoscopy and CT are helpful for achieving
a diagnosis. Importantly, early and timely multidisciplinary collaboration
can effectively save critically ill patients. Emergency thoracotomy
remains a life-saving treatment.
Abbreviations
GI: Gastrointestinal; NSAIDs: Nonsteroidal anti-inflammatory drugs; LSA:
Left subclavian artery; CT: Computed tomography; PU: Peptic ulcer.
Acknowledgements
The authors are grateful to Prof. Hua Zhang and Jiaxing Zhu
(Department of Gastroenterology, Affiliated Hospital of Zunyi Medical
University, Zunyi, Guizhou Province, China) for study support.
Authors’ contributions
ZQY collected and interpreted the data; ZQY and XML drafted the
manuscript; CC established the surgical plan; BGT analyzed the
radiological images; TLL and XML designed the study and revised
the draft; and XML supervised the study. All the authors listed have
approved the enclosed manuscript.
Funding
This research was supported by the National Natural Science
Foundation of China (81860103 and 82070536 to X.M.L., 81660098
and 82160505 to T.L.L., 81960532 to C.C., and 82073087 to B.G.T.),
the Guizhou Province International Science and Technology Cooperation
(Gastroenterology) Base (Qian Ke He Platform Talents-HZJD [2021] 001
to X.M.L.), the Guizhou Province Science Plan Program (Qian Ke He
Foundation-ZK [2021] General 461 to T.L.L.), the Cultivation of high-level
innovative talents in Guizhou Province [“Thousand” level] (fzc120200615
to T.L.L.), the 15851 Talent Projects of Zunyi City (2018 to T.L.L.), and
the Guizhou Province Science and Technology Plan (No. Qiankehe
Support [2021] General 073 to C.C.).
Availability of data and materials
All information about the patient came from the Affiliated Hospital of
Zunyi Medical University. The data used and analyzed during the current
study are included in this article.
Declarations
Ethics approval and consent to participate
The study was reviewed and approved by the Ethics Committee of the
Affiliated Hospital of Zunyi Medical University.
Consent for publication
Written informed consent was obtained from the patient for publication
of this report and any accompanying images. A copy of the written
consent is available upon request.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Department of Gastroenterology, Affiliated Hospital of Zunyi Medical
University, Zunyi 563003, Guizhou Province, China. 2 Department of
Thoracis Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi,
Guizhou Province, China. 3 Department of Thyroid and Breast Surgery,
Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province,
China.
Received: 27 August 2021 Accepted: 3 February 2022
Published online: 15 February 2022
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24

FEATURE
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Publisher’s Note
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published maps and institutional affiliations.
Find out more at www.calprotectin.co.uk
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GASTROENTEROLOGY TODAY - SPRING 2022
Healthcare survey highlights
the impact of the pandemic
on IBD patient care
Over 7,000 people responded to the
Crohn’s & Colitis UK Healthcare Survey,
providing an insight into how IBD patients
experienced healthcare during 2021.
The responses showed that health services
have continued to be disrupted by the
coronavirus pandemic and there’s been a big
impact on patient care. Difficulties accessing
GPs, specialists, medicines, tests, and
procedures have led to delays in diagnosis,
flares, and complications for people with
Crohn’s and Colitis. Mental wellbeing,
relationships, and ability to work have also
been affected.
Ruth Wakeman, Director of Services,
Advocacy & Evidence at Crohn’s & Colitis
UK says: ‘The results of the Healthcare
Survey highlight that the pandemic has
exacerbated existing issues with resourcing
of IBD services, which need to be addressed,
but also some opportunities as services
have adapted to the pandemic. We are
very grateful for the care and support that
healthcare professionals continue to give
to people with Crohn’s and Colitis in such
difficult circumstances.’
The results showed that whilst huge efforts
had been made to deliver excellent care for
people with Crohn’s and Colitis, prioritisation
and investment are vital to tackle increasingly
long waits for care. The recent Getting it Right
First Time (GIRFT) gastroenterology report
called for more proactive management of IBD,
with the aim of reducing admissions. It also
highlighted improvements that could be made
to triage to speed up diagnosis and early
treatment.
This survey, which was conducted between
August and October 2021, asked questions
about experiences of healthcare during the
previous 6-12 months. It builds on previous
surveys by Crohn’s & Colitis UK, including
the Life in Lockdown Survey in 2020 and IBD
Patient Survey in 2019, all contributing to
build a comprehensive view of healthcare over
the last 3 years.
What people with living with Crohn’s and
Colitis said
Diagnosis
Many said that getting a diagnosis during
the pandemic has been difficult, with 29% of
respondents diagnosed during the previous
12 months reporting that this had taken
over a year. This is an increase from 26% in
2019. Respondents also reported that it had
taken longer for treatment to start following
diagnosis. 41% said it took more than two
weeks for treatment to start, compared to
2019 when only 24% reported waiting more
than two weeks for treatment.
Access to healthcare professionals
The results also showed that people found
it harder to get through to IBD teams for
specialist advice, with 27% of those who tried
to contact their advice line saying they did not
get a response by the end of the next working
day.
This was in addition to 41% of those who had
needed care from their GP during the previous
6 months saying they had been unable to get
the care they needed. Furthermore, 29% had
not been able to get the help they needed from
urgent care services.
Access to medicines, tests and procedures
The results indicate a particularly big disruption
to surgery and colonoscopy. 29% reported
cancelled surgery and 24% cancelled
colonoscopies, with many still waiting for a
new date.
Additionally, 18% had experienced disruption
to getting medication.
Impact of difficulties accessing health
services or treatment
22% of those who have needed health
services or treatment during the previous 6
months said that difficulties accessing this had
resulted in a flare of their condition. In addition
to this, 24% reported that their mental health
had been affected. Respondents relayed
how this has led to time off work, affected
relationships and ability to do everyday tasks.
Changes to how patients access care
The survey found that 72% of those who had
needed outpatient appointments during the
previous 6 months had mostly had these by
telephone, with only 3% having mostly video
appointments. Only 13% were offered a
choice. Comments highlighted the benefits of
remote appointments, but also preferences for
some face-to-face appointments. Whichever
method was used, quality of care and a
personalised approach were considered
important.
Quality of care
Despite the challenges during this period, 56%
felt that their quality of care was the same as
before the pandemic, with a small proportion
(4%) considering it was better.
More information about the survey can be
found on the Crohn’s & Colitis UK website. If
you’re an IBD Nurse Specialist or Healthcare
Professional working in IBD, you may want
to use these results alongside your service’s
IBD UK Benchmarking reports as your service
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involve your IBD patients in service redesign,
the charity also has a Patient Engagement
Toolkit, also available on their website which
may be helpful.
Cause of inflammatory
bowel disease discovered
Interaction between gut bacteria and
mucus layer cells
Chronic inflammatory bowel disease (IBD)
is becoming increasingly widespread. Until
now, however, the underlying causes of
the inflammation responses were unclear.
Scientists at the Technical University
of Munich (TUM) have now identified a
mechanism that triggers a problematic
interaction between intestinal bacteria and
cells in the intestinal mucus layer in XLP2,
a condition associated with IBD. The team
believes that the results can be applied to
other intestinal diseases and could offer
approaches to the development of new
drugs.
The billions of bacteria living in the human
gut – known collectively as the microbiome
– are of enormous importance. They help
with digestion, among other functions.
Consequently, the immune system in the gut
must be extremely well regulated: It should
fight only harmful pathogens without attacking
useful microorganisms. However, this fine
balance can be disrupted by various factors.
A defect in the gene XIAP, which causes
the rare disease XLP2, results in chronic
inflammation of the bowels in 30 percent of all
26

NEWS
Dr Monica Yabal
cases, among other symptoms. Babies with this
genetic defect often display serious symptoms
such as diarrhea, abdominal pain, weakness
and weight loss soon after birth. Until now,
scientists have been unable to understand the
underlying mechanism or discover effective
treatments – apart from stem cell transplants,
which involve a high risk of mortality.
Overreaction of the innate immune system
Working with organoids – intestinal cells in a
Petri dish – and animal experiments, a team
headed by Dr. Monica Yabal, Adam Wahida and
Madeleine Müller of the Institute for Molecular
Immunology and the Clinic of Hematology
and Oncology of TUM’s university hospital,
Klinikum rechts der Isar, has now identified the
mechanism behind the inflammation response
and learned how it becomes chronic. “The
innate immune system overreacts to microbes
in the gut,” says Yabal. The immune system in
healthy people eliminates bacteria that cause
illness and then returns to its resting state. But
in some XLP2 patients, a fatal chain reaction
begins:
Every person has toll-like receptors (TLRs) that
use unique structures such as molecules in the
cell wall to identify harmful microbes. When a
TLR binds a molecule, the signaling substance
TNF and its TNFR1 and TNFR2 receptors
activate the immune system to eliminate the
pathogen. However, this does not work properly
in XLP2 patients. Instead, the binding of TNF to
the TNFR1 receptor on cells known as Paneth
cells causes these cells to die, resulting in a
vicious circle. That is because the Paneth cells
in the gut mucus layer produce antimicrobial
substances and thus ensure a bacterial balance
in the intestines. The loss of those cells changes
the composition of the microbiome. Beneficial
bacteria such as clostridia are attacked and can
no longer perform their Publication:
regulatory role. This Adam Wahida, Madeleine Müller, Andreas
again activates the Hiergeist, Bastian Popper, Katja Steiger,
immune system. Caterina Branca, Markus Tschurtschenthaler,
Thomas Engleitner, Sainitin Donakonda,
New drugs
Jordy De Coninck, Rupert Öllinger, Marie K.
could stop the Pfautsch, Nicole Müller, Miguel Silva, Sinem
inflammation
Usluer, Erik Thiele Oberg, Jan P. Böttcher,
response
Nicole Pfarr, Martina Anton, Julia B. Slotta-
“We believe that this Huspenina, Andreas G. Nerlich, Tobias Madl,
principle might also Marijana Basic, André Bleich, Geert Berx,
be applicable to other Jürgen Ruland, Percy A. Knolle, Roland
inflammatory bowel Rad, Timon E. Adolph, Peter Vandenabeele,
diseases and not only Hirokazu Kanegane, André Gessner, Philipp
in XLP2 patients,” says J. Jost, Monica Yabal. XIAP restrains TNFdriven
intestinal inflammation and dysbiosis by
Prof. Percy Knolle,
the Director of the promoting innate immune responses of Paneth
Institute for Molecular Immunology at TUM. and dendritic cells (2021) Science Immunology,
Malfunctioning Paneth cells have also been Vol 6, Issue 65. DOI: 10.1126/sciimmunol.
observed in many patients with inflammatory abf7235.
bowel diseases with various causes.
More information:
These insights might open up important The study was funded by the European
avenues for the development of new drugs. Research Council (ERC), the German Research
Patients with chronic bowel inflammation Foundation (DFG), the Austrian Research
have been treated for many years with drugs Promotion Agency (FFG) and the German
that inhibit the TNF ScheBo_GastroToday_Aug_2020 Center for Multi-Ad_Address_Change
Infection Research (FFG).
receptors. However,
these molecules are
not very specific
and deactivate both
TNFR1 and TNFR2.
“Our experiments
show that it would
be better if we had a
selective inhibitor for
the TNFR1 receptor,”
says Yabal. It also
remains unclear
why some people
respond very well
to this treatment
while others show
no response at
all. Consequently,
the team would
now like to turn
its attention to the
adaptive immune
system, which
learns throughout an
individual’s lifetime
through contact
with pathogens
and forms special
antigens, and also
study its special role
in the gut.
GASTROENTEROLOGY TODAY - SPRING 2022
27

NEWS
GASTROENTEROLOGY TODAY - SPRING 2022
Go with the Flow!
How the Rare Disease Collaborative
Network can support you in diagnosis and
management of refractory coeliac disease
Woodward JM 1 , Soilleux E 1 , Passmore R 2 ,
Sanders D 3
Coeliac disease that is refractory to the
withdrawal of gluten from the diet is rare,
and as a result prone to both over and under
diagnosis. Two types are described: ‘Type 1’ is
indistinguishable from non-responsive coeliac
disease (1) and may be due to the individual
being highly sensitized to trace amounts of
gluten remaining in the diet that would not
affect most people with the condition. ‘Type 2’
refractory coeliac disease (RCD2) progresses
to an aggressive T-cell lymphoma in as many
as 67% of cases over 5 years (2). RCD2 is
distinguished from non-responsive coeliac
disease or RCD1 by the abnormal clonal
increase of an unusual population of intestinal
intra-epithelial lymphocytes (IELs) characterized
by the presence of the T-cell marker CD3
within the cytoplasm but not on the surface of
the cell (3). These cells also usually lack the
normal expression of another surface marker,
CD8. However, immunohistochemistry for T-cell
markers or polymerase chain reaction (PCR) for
T-cell receptor clonality are unreliable diagnostic
tests for RCD2 (3,4), whereas flow cytometry
to identify individual IELs isolated from fresh
intestinal biopsies is definitive (figure 1a).
It is important to distinguish RCD1 from other
causes of non-responsive coeliac disease
and from RCD2 as specific treatments exist
– for instance, the use of topical steroids or
azathioprine for RCD1 and cladribine and
autologous stem cell transplantation for
RCD2. In 2018, NHS England designated
Sheffield and Cambridge as the two national
centres in the first ever UK Rare Disease
Collaborative network in order to refine
diagnostic and therapeutic techniques, and
to develop a national database in order to
further the understanding of the conditions
and facilitate trials of treatment (5,6). The
ongoing development of flow cytometry of
intra-epithelial lymphocytes in the network
has unexpectedly also demonstrated the
utility of this technique in the diagnosis of
coeliac disease itself (7). A characteristic
change in the IEL composition occurs
following the development of coeliac disease
(8) and remains regardless of normalization
of duodenal histology and serological tests
on institution of a gluten free diet. Hence IEL
flow cytometry is the only existing accessible
test capable of confirming or refuting the
diagnosis of coeliac disease in a patient
following a strict gluten free diet. Referrals
to the national centres remain lower than the
expected prevalence of RCD (6) and indicates
ongoing failure to recognize the condition. The
following case studies demonstrate the utility
of referral to the specialist national centres.
Coeliac UK
have developed
resources on
refractory and
non-responsive
coeliac disease
to support
you and your
patients, scan
the QR code to
find out more.
Case 1. Misdiagnosis of coeliac disease.
A 20-year old woman contacted Coeliac UK
for advice. Following a period of chronic
fatigue she presented to her GP who found a
very high anti-TTG antibody titre in her serum.
Indirect immunofluorescence was negative for
anti-endomysial antibodies. Following referral
to her local gastroenterologist she underwent
a gastroscopy and duodenal biopsies which
were reported as showing equivocal features
but consistent with coeliac disease. She
was commenced on a gluten free diet which
marginally improved her symptoms, however
on follow up her anti-TTG titres remained
high and she was repeatedly told by her
hospital team that this meant that she was
continuing to ingest gluten, which was a cause
of significant anxiety for her and contributed
to her fatigue. The patient was advised to
request a second opinion from a tertiary
centre. Further blood tests at the national
centre revealed a negative anti-TTG titre
and non-compatible HLA (human leucocyte
antigen) haplotype for coeliac disease (9).
Duodenal biopsies were reported as showing
mild peptic duodenitis and flow cytometry
revealed no evidence of coeliac disease (fig
1a). Following reassurance that she did not
have coeliac disease she was able to tolerate
a normal diet without symptoms. This case
demonstrates the variability of anti-TTG assays
between laboratories, and the potential flaws
of current diagnostic techniques.
Case 2. Delayed diagnosis of RCD2.
A previously fit and well 56-year old man
presented via his GP to the local hospital
following a business trip to the tropics with
diarrhoea. A strong family history of coeliac
disease was elicited, and duodenal biopsies
at gastroscopy demonstrated sub-total villous
atrophy, however anti-TTG antibodies were
negative. He was therefore considered not
to have coeliac disease and was treated
empirically for tropical parasitic infections.
However, his symptoms progressed and 12
months later he was reinvestigated and found
to have ongoing severe villous atrophy in the
duodenum with thickening of the distal jejunum
on magnetic resonance enterography. He was
referred to one of the national tertiary centres
for enteroscopy and biopsy of the thickened
jejunum in order to make a diagnosis. An
experienced clinician considered the possibility
of RCD2 and lymphoma and instead carried
out a gastroscopy and duodenal biopsy with
flow cytometry the day after receiving the
referral. The flow cytometry demonstrated
a large population of atypical IELs lacking
surface CD3 (fig 1b) in keeping with RCD2
and a presumptive diagnosis of enteropathy
associated lymphoma was made. Within
3 weeks of referral he was admitted for
establishment of home parenteral nutrition
and underwent laparotomy and resection
of the tumour, which was confirmed as a T
cell lymphoma. He subsequently underwent
CHOP chemotherapy and autologous
haematopoeitic stem cell transplant. In his
case earlier consideration of the diagnosis of
RCD and referral to a national centre could
have led to preventative treatment prior to
developing lymphoma.
Case 3. Overdiagnosis and overtreatment.
A 37-year old woman presented to her GP
in 2013 with diarrhoea and weight loss. A
positive anti-tissue transglutaminase (TTG)
antibody titre led to referral to the local
gastroenterologist and a diagnosis was
confirmed by the presence of sub-total
villous atrophy on duodenal biopsy. She
was commenced on a gluten free diet.
However, in 2016 the presence of ongoing
symptoms led to a repeat endoscopy which
demonstrated persistent villous atrophy in
the duodenal biopsies. She was told by her
local gastroenterologist that she had refractory
coeliac disease and that she needed to start
on steroids and azathioprine as she was
otherwise at risk of developing lymphoma. At
this stage she sought a referral for a second
28

NEWS
Figure 1a Figure 1b Figure 1c
opinion through one of the national tertiary
centres. An experienced clinician elicited a
history of a shared kitchen with potential for
gluten contamination during food preparation,
and that the patient was consuming foods
that were labelled as ‘may contain traces of
gluten’. It was recommended that she did
not start steroids or azathioprine but made
the necessary changes to her lifestyle and
attend for a repeat duodenal biopsy after a
further 9 months. At endoscopy the patient
reported complete resolution of her symptoms,
biopsies were reported as entirely normal
while flow cytometry confirmed the underlying
diagnosis of coeliac disease (figure 1c). She
therefore avoided potentially harmful treatment,
considerable health anxiety and achieved rapid
resolution of her condition following referral.
Notably the referral came from herself via her
GP, not the local gastroenterologist.
Figure 1. Typical duodenal IEL flow cytometry
plots for a non-coeliac individual (a), a
patient with RCD2 (b), and a patient with
coeliac disease (c). Each dot on the plot
represents a separate cell, immunostained
for surface CD3 (y-axis) and cytoplasmic CD3
(x-axis). In addition, CD3+ T cells bearing the
gamma-delta type of TCR are in dark blue,
those with the alpha-beta TCR are in light
blue. Clearly defined population of IELs are
apparent based on the lack of expression of
CD3 (green), the expression of surface and
cytoplasmic CD3 (light and dark blue), or just
cytoplasmic CD3 (orange). Note that RCD1 is
not distinguishable from coeliac disease using
any available diagnostic tests (including flow
cytometry) (reference 2), whereas populations
of CD3+ and gamma delta TCR positive
cells are clearly increased in coeliac disease
compared to normal.
References
1. Rubio-Tapia A, Murray JA. Classification
and management of refractory coeliac
disease. Gut 2010 Apr;59(4):547-57.
2. Nijeboer P, van Wanrooij, van Gils T, et
al. Lymphoma development and survival
in refractory coeliac disease type II:
histological response as a prognostic
factor. United European Gastroenterol J
2017; 5(2): 208-217
3. Woodward JM. Improving outcomes of
refractory Celiac Disease: current and
emerging treatment strategies. Clinical
and Experimental Gastroenterology 2016;
9: 225-236
4. Liu H, Brais R, Lavergne-Slove A, et al.
Continual monitoring of intraepithelial
lymphocyte immunophenotype and clonality
is more important than snapshot analysis
in the surveillance of refractory coeliac
disease. Gut. 2010 Apr;59(4):452-60.
5. https://www.coeliac.org.uk/about-us/
media-centre/news/first-rare-diseasecollaborative-network-on-refractorycoeliac/
6. Baggus E, Urwin H, Watson S, Woodward
JM, Sanders DS. How to manage
adult coeliac disease: The perspective
from the NHS England Rare Diseases
Collaborative Network for Non-Responsive
and Refractory Coeliac Disease. Frontline
Gastroenterol. 2019 Aug 8;11(3):235-242
7. Basu K, Creasey H, Bruggemann N,
Stevens J, Bloxham DM, Woodward
JM. The diagnosis of coeliac disease
by flow cytometry of intraepithelial
lymphocytes – a new ‘gold standard’?
Frontline Gastroenterology 2021 epub
ahead of print http://dx.doi.org/10.1136/
flgastro-2021-101838
8. Mayassi T, Ladell K, Gudjonson H, et
al. Chronic inflammation permanently
reshapes tissue-resident immunity in celiac
disease. Cell 2019;176:967–81.
9. Abadie V, Sollid LM, Barreiro LB, et al.
Integration of genetic and immunological
insights into a model of celiac disease
pathogenesis. Annu Rev Immunol.
2011;29:493-525
1
NHS Refractory Coeliac Disease Rare
Disease Collaborative Network
Box 133
Addenbrooke’s Hospital
Hills Road
Cambridge CB2 0QQ
01223-596231
(jeremy.woodward@nhs.net)
*Corresponding author
2
Coeliac UK
Apollo Centre,
Desborough Road
High Wycombe
HP11 2QW
3
NHS Refractory Coeliac Disease Rare
Disease Collaborative Network
Academic unit of gastroenterology,
Royal Hallamshire Hospital,
Sheffield S10 2JF
(david.sanders1@nhs.net)
GASTROENTEROLOGY TODAY - SPRING 2022
29

NEWS
Mother thanks doctors for
saving her and unborn baby
A Herefordshire mother has thanked
clinicians at University Hospitals of North
Midlands NHS Trust (UHNM) for life-saving
treatment she received.
Pregnant Lucy Rossiter was initially thought
to have irritable bowel syndrome (IBS) after
suffering for months with stomach pain, but
doctors in Hereford later found she had a bile
duct infection which posed a serious risk to her
and her baby.
“My doctors contacted Royal Stoke University
Hospital in Stoke-on-Trent and the entire
endoscopy team got together and agreed
that the necessary procedure could be carried
out at Stoke and would be scheduled for the
following morning.
“When I arrived at Stoke I was in terrible pain
and almost unable to stand, let alone walk.
I would have given anything to stop the pain
and make me feel better.
“I found the endoscopy team ready and
waiting for me at Royal Stoke. Everybody I
came into contact with was aware of who I
was and exactly why I was there.
The team were able to remove the bile duct
stone which was causing Lucy’s infection and
affecting her liver function.
Dr Hebbar said: “Lucy’s was an extremely
complicated case, made more challenging
by the fact that she was pregnant. The
endoscopic procedure to remove the stone
in the bile duct involves using X-ray to assess
the location of the stone and understand
the anatomy. In a pregnant lady in her first
trimester, the radiation is a significant risk to
the baby. An additional risk of this particular
procedure is pancreatitis - especially so
in young women - because the bile duct
and pancreas are close to each other. This
complication can be serious and even fatal.
34-year-old Lucy, a primary school teacher
from Kingsland in Herefordshire, was seven
weeks’ pregnant when her condition began to
rapidly deteriorate.
“When I left after having my procedure,
everybody was amazed that I could not only
stand but also walk out of hospital, the pain was
gone instantly. The change was just incredible
“Unfortunately other trusts were unable to
accept Lucy’s case because of the complexity
involved, so we were contacted.
Doctors at Hereford County Hospital scoured
the country to find clinicians with the expert
knowledge needed to treat the mother-of-two.
UHNM’s endoscopy team were contacted
and made such a difference to my condition, it
was as if someone had turned a tap off. William
commented that it was like a different person
who walked out of Royal Stoke.
“When I was ill I was having flare-ups a good
“If we had not done the procedure, there was
clearly a significant risk to Lucy because of
the infection but at the same time, we did not
want to put the baby at any risk because of the
procedure.”
and Lucy was taken to Royal Stoke University
Hospital for care.
Lucy said: “I started to experience abdominal
pains in early May 2020. My GP suspected I
had IBS but over time various remedies proved
to be ineffective and the flare-ups increased
few times a week, so trying to look after my
daughter Poppy was really hard. Now I have a
controlled diet but I can live more normally.
“I need to have my gall bladder removed and
might have to always be a bit more restricted in
what I eat, but I feel I will be able to manage it.
The team performed an endoscopic
ultrasound, which helps to identify internal
structures and can assess the pancreas and
bile duct in detail. Using this, they were able
to identify the location and size of the bile duct
stone and successfully remove it.
in intensity and frequency and on a number of
occasions I had to go to hospital.
“I had been living with these symptoms for about
12 months and during this time I discovered I
“Dr Hebbar and his team at Royal Stoke
were incredible. The care that I had, their
professionalism, just everything. I cannot thank
them enough.
Dr Hebbar continued: “As it turned out, we
did not need to use any x-ray in the end, so
the procedure was completed and the stone
removed with no risk to the baby.
GASTROENTEROLOGY TODAY - SPRING 2022
was pregnant with my second child, Thomas.
“In April 2021 me and my partner William
became very worried. Not only did my
symptoms continue to get worse but I now
also had our unborn baby to worry about.
“Events finally came to a head one night when
I was in severe pain, vomiting and unable to
stand. William called 111 and I was bluelighted
to Hereford County Hospital. I then
spent the next few days as an inpatient waiting
for a diagnosis. It was horrible, I was desperate
to get home so that I could see my daughter.
“Eventually I was able to get home but my liver
function continued to get worse and I was
back in hospital in May, where my condition
deteriorated rapidly.
“Now I can get back to a more normal life.
We’re quite an active family and we like the
outdoors, we like spending time at the coast,
we spend quite a lot of time with our extended
family. We’ve got holidays booked as well.
When I was ill I couldn’t really enjoy them, so
it’s nice to have something to look forward to.
“I am very grateful to all the NHS for working
together to help me.”
Lucy lives with her partner William Wood, 37,
and is mum to two-year-old daughter Poppy
and new baby Thomas.
Consultant gastroenterologist Dr Srisha
Hebbar and his team cared for Lucy at Royal
Stoke University Hospital.
“Lucy was able to travel back to Hereford the
same day and was discharged the next day.”
30

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