Review for 10.1186/s12876-025-03769-3 (2025)

Title: Eradication of Helicobacter pylori that contributes to hepatogenic ulcer is beneficial to
the healing of hepatogenic ulcer
Version: 2 Date: 22 Jan 2025
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
Yes - experiments and analyses were performed appropriately
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
Yes - the author's interpretation is reasonable
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: A beautiful and valuable article. Well designed. Study protocols,
patient selection, study duration are very good. However, the number of patients is not
sufficient. Despite the length of the study period, the number of patients is very small.
Nevertheless, valuable findings were obtained, but these results were presented with very
ambitious conclusions. The small number of patients limits the generalization of the obtained
data. Therefore, it would be more appropriate to give the conclusions with more moderate
expressions. Reviewer's comments and authors' answers were reviewed step by step. There are
insufficient answers and things that were not done. Corrections are necessary and will make the
article richer.
ADDITIONAL REQUESTS/SUGGESTIONS:
REV#EWER 1:
“The research on hepatic ulcer has not been extensively studied in recent years, and there is
inconsistency in the conclusions regarding its correlation with Hp infection. This study aims to
further explore the relationship between hepatic ulcer and Hp infection through two parts, which
has a certain extentclinical implications.”
The above evaluations seem to be unanswered. Studies and publications on the association of
hepatogenic ulcers and helicobacter pylori infection should be reviewed comprehensively. The
results and comparisons of the publications in the reference section should be examined in more
detail in the discussion section. There are ambitious clinical implications in the results of the
study. Instead of these ambitious implications, more moderate expressions should be preferred.
1. It is unclear if both parts of the study were prospective studies, and if the patients of the second
part come from the first.
Response: Thank you for your suggestion. This study was divided into two parts, the first part
was a retrospective study and the second part was a prospective study. The combination of
retrospective study and prospective study can bring multiple benefits, making the study more
comprehensive and in-depth. Combining the two methods enables research to validate past
findings while also exploring future possibilities, improving the overall value and application
prospects of the research. The patients in second part were not come from the first.
Although it is stated in the abstract that the first part is retrospective, it is not stated in the material
and methods section of the article that it is retrospective and it is described as a prospective study.
These statements should be corrected. Again, it should be stated in the material and methods
section of the article that the second part of the study is prospective.
2. The pre-registration time for the second part of the study (ChiCTR2200061355) was in
June 2022, while the patient enrollment time indicated in the study was from January 2010 to
December 2019. If the subjects in the second part of the study were derived from the patients
in the first part, there is a discrepancy in the timeline. Additionally, why did the study use
the standard triple therapy instead of the preferred bismuth-based quadruple therapy for Hp
eradication in 2022.
Response: Thank you for your suggestion. The two parts of the study were separate, the subjects
in the second part of the study were not from the first part. We would like to clarify the
choice of treatment modality as follows. The advantages and disadvantages of bismuth in
clinical application are controversial, and the understanding and application of bismuth are
also constantly changing. Bismuth is mainly distributed in kidney, brain, liver, spleen and
bone after being absorbed by human body, and has certain toxic effects on these organs. More
importantly, the damage of bismuth to the brain and kidney has not attracted the attention of
related specialties, and the corresponding examination is also blank, so there is a potential
risk of medication. Therefore, we still choose triple therapy to eradicate Hp. Rabeprazole, as a
second-generation proton pump inhibitor, has little effect on liver function and is suitable for
patients with liver disease. Levofloxacin is a common anti-Hp drug. Amoxicillin has a strong
anti-Hp effect, is not easy to produce drug resistance, and the incidence of adverse reactions in
nonallergic patients is low, so it’s the preferred antibacterial drug.
It is stated that the patients in the second part were not selected from the patients in the first part
and were included in the study later, together with the dates. In other words, the inconsistency
in the timeline has been resolved. The above explanation of why the standard triple therapy was
used instead of the bismuth-based quadruple therapy preferred for Hp eradication is sufficient,
but should be added appropriately to the materials and methods section.
3. It is recommended to clearly list the inclusion and exclusion criteria.
Response: Thank you for your suggestion. The inclusion and exclusion criteria for the first part
of the study are described in the General Information section 2.2.1. The inclusion and exclusion
criteria for the second part of the study are supplemented in section 2.3.1 of the manuscript. The
inclusion criteria were patients diagnosed with HU and Hp infection. Exclusion criteria: 1. Non-
HU and Hp infection; 2. Patients with gastrointestinal cancer; 3. Taking antibiotics and non-
steroidal anti-inflammatory drugs within the last month, and acid inhibitors and gastric mucosal
protectants within two weeks.
Sufficient explanation has been added to the article.
4. If the C-UBT cessation period one month for bismuth rather than NSAIDs.
Response: All subjects did not take antibiotics or nonsteroidal anti-inflammatory drugs within
the last month (as nonsteroidal anti-inflammatory drugs affect ulcers), and did not take acid
inhibitors or gastric mucosal protectors (including bismuth) within two weeks.
Sufficient explanation has been added to the article.
5. The study indicates that there should be 64 cases according to an 80% Hp positive rate, but
the final inclusion was only 60 cases. It is suggested to provide additional explanations for this
discrepancy.
Response: Thank you for your suggestion. The two parts of the study were separate. The 60
patients with Hp-positive HU in the second part were not from the first part.
Sufficient explanation has been added to the article. There is no inconsistency in numbers and
proportions. However, as I mentioned above, there is a need to specify in detail the type of study
(retrospective or prospective), the number or proportion of patients in the first and second part,
and the dates of inclusion in the study. Confusion needs to be resolved.
6. The study results suggest a higher proportion of Hp infection in patients with mild esophageal
varices compared to moderate and severe cases. It is recommended to provide the clinical
significance and possible explanations for this finding.
Response: Thank you for your suggestion. Esophageal varices are caused by hypertension (portal
hypertension) of the blood vessels in and around the liver. Gastric mucosal atrophy caused by
HP is accompanied by decreased gastric acid secretion, and its infection also appears to prevent
bleeding, as is the clinical practice of acid suppression in patients with upper gastrointestinal
bleeding to maintain platelet aggregation and coagulation. The results of a Japanese study have
also shown this [1], that Hp infection has a certain protective effect on esophagogastric variceal
bleeding by inducing atrophic gastritis and accompanying low acidity in patients with cirrhosis
and portal hypertension. However, this effect has not been consistent in other studies, so further
clinical research and exploration are needed.
1. Sakamoto Y, Oho K, Toyonaga A, Kumamoto M, Haruta T, Inoue H, et al. Effect of
Helicobacter pylori infection on esophagogastric variceal bleeding in patients with liver cirrhosis
and portal hypertension. J Gastroenterol Hepatol. 2013;28(9):1444-9
The above explanation is appropriate and sufficient. However, this explanation and the related
article should be placed in the appropriate place within the working text.
REV#EWER 2:
“The study titled “Eradication of Helicobacter pylori that contributes to hepatogenic ulcer
is beneficial the healing of hepatogenic ulcer” was reviewed according to the publication
guidelines of journal BMC Gastroenterology. First of all when I read the manuscript; I heard
first time the term “Hepatogenic ulcer”. Thus I made a search from Pubmed. The concept of
“Hepatogenic gastroduodenal ulcer” was described firstly in 1964. There is almost no studies
regarding this issue in last decade. But I raised a question about the relationship between
Hepatogenic ulcer and Helicobacter pylori. When a liver cirrhosis patient have an ulcer and
colonized by Helicobacter pylori, how can we define this ulcer is not due to Helicobacter pylori.
I think this issue is the most important part of this manuscript. Authors must consider this
and write the discussion carefully about and they must refer to the studies that were published
in 1970s and 1960s even if most of them are not written in English. For example the first
study also asked the same question “Is there a hepatogenic ulcer” (Strobach G, Wildhirt E.
Is There a Hepatogenic Ulcer?. Deutsche medizinische Wochenschrift. 1964;89:2241-4) I did
not find this study furthermore it is written in German. Other wise; the questions whether HP
contributes to the ulcer pathogenesis in liver cirrhosis patient and we can diagnose these patients
as “hepatogenic ulcer” are worth to research. The manuscript can be published after revisions.
Revisions that must be corrected can be found below 1. Authors mentioned about the results of
the study in introduction section (Page 2 line 52-53) these sentences must be deleted.
Response: Thank you for your suggestion. We have deleted the results mentioned in the
introduction.
No correction was found regarding the addition of the mentioned publications to the article. The
addition of the mentioned publications would enrich the article. In addition, the results in the
introduction section were deleted.
2) Authors explained how rapid urease test is done ( page 3 line 83- 90) I think this is unnecessary
because rapid urease test is a routine laboratory test and authors may give areferance intead of
explaining how it works detailly I suggest to delete this part but it is up to authors.
Response: Thank you for your suggestion. We give a brief description of the experimental
procedure, which we think can be retained.
The explanation on the subject is sufficient.
3) Authors must explain why do perform two test for HP diagnose. Both of the test have a
sensitivity above 80% and they are routinely used by clinicians for their daily practice.
Response: Thank you for your suggestion. 14C urea breath test has been recognized as the best
method for the detection and diagnosis of Hp. Gastroscopy can diagnose PU as active ulcer, and
it is helpful to evaluate the change of gastric mucosal ulcer area and ulcer healing after different
treatment methods.
The explanation on the subject is sufficient.
4) Authors did not give treatment to 30 patients with HP and hepatogenic ulcer. I think itmat
raise an ethical problem because if one patient is diagnosed with HP, individual must receive a
treatment whether or not HP can be eradicated because HP is accepted as most significant risk
factor for gastric cancer.
Response: Thank you for your suggestion. Both groups received therapeutic intervention, and
the cure rate was compared 1 month after the end of the treatment. The treatment group was
given rabeprazole (20 mg), amoxicillin (1.0 g) and levofloxacin (0.2 g) twice a day for 2 weeks.
The control group was treated with rabeprazole (20 mg), twice a day, orally for 2 weeks. All
cases were given appropriate liver protection and nutritional support according to the clinical
situation. Patients who are not completely cured will also be continued with further treatment.
Timely monitoring and adjustment during the whole process of the study ensured the health of
the patients.
The explanation on the subject is sufficient.
5) Table 1 should be prepared again with p values appropriately
Response: Thank you for your suggestion. We have supplemented the p values in Table 1.
The explanation on the subject is not sufficient. P values in the tables should be given as full
numbers. (For example; p=0.047 instead of p<0.05)
6) Why authors prefer” rabeprazole plus amoxicillin and levofloxacin” for eradication of HP.
They may refer to the studies that shows the effectivity of this regimen
Response: Thank you for your suggestion. We have supplemented relevant literature reports.
Li et al. [1] found that rabeprazole, levofloxacin and amoxicillin combined with Hp infection
in gastric ulcer could effectively eradicate Hp, regulate the levels of inflammatory factors and
improve clinical symptoms. Another study also showed that triple therapy had high clinical
application value [2].
1. Na L, Jie C, Kun C, Jianling Z. To observe the efficacy of rabeprazole, levofloxacin combined
with amoxicillin in the treatment of gastric ulcer Helicobacter pylori infection. Pharmacy in
northern China. 2020;17(02):22-23.^(in Chinese with English abstract)
2. Jinhong L. Transport and distribution characteristics of amoxicillin and levofloxacin in the
stomach of patients with Helicobacter pylori infection treated with triple therapy. Journal of
Clinical Military Medicine. 2020;48(11):1370-1371.^(in Chinese with English abstract)
The explanation is sufficient and is included in the article.
7) What is “FU group”. Authors did not give a abbreviation for “FU”. Did they mean “Functional
Dyspepsia and the abbreviation is “FD” ?
Response: Thank you for your suggestion. Yes, we wrote it wrong and it has been changed to FD.
The explanation is sufficient and is included in the article."