Update in Molecular Aspects and Diagnosis of Autoimmune Gastritis

Round 1

Reviewer 1 Report

This is a well-described review article on autoimmune gastritis. Followings are my suggestions to improve the draft.

1. Abstract – Please add more contents. Important summaries and advisable messages would be helpful to the readers. At least, main molecular aspects and updates on the diagnosis of autoimmune gastritis should be summarized.

2. Introduction – This review summarizes only the articles published within the last three years (Line 47-49); however, some of the references are published before 2020. For better review, do not confine the period. Remind that this is not a meta-analysis study based on PRISMA guidelines.

3. In the last paragraph of the Introduction, add purpose of this review. For example, to discuss about recent developments in the pathophysiology and diagnosis of autoimmune gastritis.

4. Multiple molecular mechanisms described under the subheadings 4.1~4.7 are not well organized. Consider adding a table showing the link between the items (subtitles 4.2~4.7) and progress of autoimmune gastritis (onset, perpetuation, and exacerbation of inflammation, gastric mucosal atrophy, metaplasia, and neoplasm development, etc).

5. In the "5.2. Autoantibodies" - Mention about the different diagnostic role of anti-parietal cell antibody and anti-intrinsic factor antibody according to the phase of autoimmune gastritis.

6. In the "5.3. Serum pepsinogen" – Even in the same autoimmune gastritis patients, low PG I/II ratios and PG I levels differ significantly according to the presence of H. pylori infection.Consider adding comments on the serum PG titers of “sole type A gastritis patients” versus “type A + B gastritis (autoimmune gastritis patient with H. pylori infection) patients”.

7. Add a subtitle “5.4. Gastrin” is needed before describing on endoscopy finding.

8. In the "5.4. Esophagogastroduodenoscopy" –  It would be better to describe “5.6. Microscopic findings” and “5.7. Risk of gastric neoplasm” using different subtitles.

9. In the "6. Conclusion" à 7. Conclusion

10. Overall, the contents are too much descriptive on small-sized studies which cannot be generalized. So please consider adding tables and schemas after summarizing the main messages on diagnosis and pathophysiological processes of autoimmune gastritis.

Author Response

COMMENTS FOR THE AUTHOR

Reviewer #1

This is a well-described review article on autoimmune gastritis. Followings are my suggestions to improve the draft.

1. Abstract – Please add more contents. Important summaries and advisable messages would be helpful to the readers. At least, main molecular aspects and updates on the diagnosis of autoimmune gastritis should be summarized.

Response: Thank you for dedicating your time to review our manuscript. I have duly revised the Abstract in accordance with your insightful comments.

2. Introduction – This review summarizes only the articles published within the last three years (Line 47-49); however, some of the references are published before 2020. For better review, do not confine the period. Remind that this is not a meta-analysis study based on PRISMA guidelines.

Response: I appreciate your insightful suggestion. In accordance with your advice, I have removed the specified search timeframe ("three years") from the Introduction section.

3. In the last paragraph of the Introduction, add purpose of this review. For example, to discuss about recent developments in the pathophysiology and diagnosis of autoimmune gastritis.

Response: I have revised the sentence accordingly.

4. Multiple molecular mechanisms described under the subheadings 4.1~4.7 are not well organized. Consider adding a table showing the link between the items (subtitles 4.2~4.7) and progress of autoimmune gastritis (onset, perpetuation, and exacerbation of inflammation, gastric mucosal atrophy, metaplasia, and neoplasm development, etc).

Response: In Figure 2, we have elucidated plausible correlations between the pathophysiological mechanisms underlying autoimmune gastritis and the factors expounded upon in this review. The visual depiction showcases the associations of each factor through a spectrum of color intensities, signifying their respective degrees of relevance. It is our aspiration that this figure facilitates enhanced comprehension of the article's contents for readers.

5. In the "5.2. Autoantibodies" - Mention about the different diagnostic role of anti-parietal cell antibody and anti-intrinsic factor antibody according to the phase of autoimmune gastritis.

Response: I have included an additional sentence to elucidate the diverse diagnostic roles of anti-parietal cell antibody and anti-intrinsic factor antibody based on the specific phases of autoimmune gastritis.

6. In the "5.3. Serum pepsinogen" – Even in the same autoimmune gastritis patients, low PG I/II ratios and PG I levels differ significantly according to the presence of H. pylori infection. Consider adding comments on the serum PG titers of “sole type A gastritis patients” versus “type A + B gastritis (autoimmune gastritis patient with H. pylori infection) patients”.

Response: I have incorporated elucidations regarding the disparity in serum pepsinogen levels between autoimmune gastritis patients with and without H. pylori infection.

7. Add a subtitle “5.4. Gastrin” is needed before describing on endoscopy finding.

Response: I have appended a subsection delineating the pivotal role of gastrin in the pathophysiology of autoimmune gastritis.

8. In the "5.4. Esophagogastroduodenoscopy" – It would be better to describe “5.6. Microscopic findings” and “5.7. Risk of gastric neoplasm” using different subtitles.

Response: Thank you for your suggestion. I have included additional subsections elucidating the intricate microscopic characteristics of autoimmune gastritis and the associated risk of gastric neoplasms.

9. In the "6. Conclusion" à 7. Conclusion

Response: I apologize for the oversight in my previous error. I have rectified the numbering of the subheading accordingly.

10. Overall, the contents are too much descriptive on small-sized studies which cannot be generalized. So please consider adding tables and schemas after summarizing the main messages on diagnosis and pathophysiological processes of autoimmune gastritis.

Response: We have included Figure 2, depicting the conceivable correlations between the pathophysiological mechanisms underlying autoimmune gastritis and the factors deliberated in this review. The visual representation showcases the interconnections of each factor employing diverse color intensities, symbolizing their individual levels of significance. Our objective is to augment readers' comprehension of the article's content through the utilization of this figure.

Reviewer 2 Report

I read with interest the review entitled "Update in the Diagnosis and Molecular Aspects of Autoimmune Gastritis" and I appreciated the effort of the authors to provide a detailed overview of pathogenetic mechanisms and diagnosis of this so often unrecognized or lately diagnosed condition. The literature research was accurated and supported by the methodology of systematic review. 

Please find here below my comments:

Title: I would suggest to mention first the molecular aspects and then diagnosis to be consistent with the order of the paragraphs of the review: "Updated in Molecular Aspects and Diagnosis of Autoimmune Gastritis"

Introduction: I would suggest to use intrinsic factor instead of intrinsic factors (lines 22 and 25 and also later on, for example line 257, in the manuscript)

1. Introduction: line 39: I would suggest to mention acid reflux as the last one of the reported symptoms and to modifiy it in reflux disease as this symtpom is very rare due to hypochlorhydria. Reflux disease may be present, but it is often non acid.

3. Search strategy: The search strategy as well as the flow-chart are reported according to PRISMA guidelines, the reference should be reported (lines 50-61).

Figure 1: the sum of the excluded studies does not give 100, but 89. So, there must be some mistake in the calculations of included and excluded studies.

4. Molecular aspects of the pathophysiology of autoimmune gastritis: lines94-95. Please check reference 6, does it refer to a single case? If yes, this should be stated or the statement deleted.

5. Diagnosis of autoimmune gastritis: line 253, the reference 39 in this context is not the most appropriate on, I would suggest reference 28 or Lenti M, et al Autoimmune Gastritis, Nature Dis Primers 2019

5.3 Serum pepsinogen: lines 276-277: pepsinogens are produced by chief cells of the oxyntic mucosa, not by parietal cells.

Line 291: The gastropanel is mainly proposed for screening of preneoplastic gastric condition as atrophic gastritis, I would not mention in this context the Zollinger-Ellison syndrome

5.4 Esophagogastroduodenoscopy: line 315: Why the potential marker for autoimmune gastritis (by definition with a spared antral mucosa) was investigated in the antrum instead of the corpus mucosa? I think this should be briefly discussed or explained. 

6. Autoimmune gastritis without typical features: line 353: the reference 59 is not appropriated. It might be eventually used in the Conclusion para.  

Author Response

Point-by-point Responses to Reviewers’ Comments

Reviewer #2

I read with interest the review entitled "Update in the Diagnosis and Molecular Aspects of Autoimmune Gastritis" and I appreciated the effort of the authors to provide a detailed overview of pathogenetic mechanisms and diagnosis of this so often unrecognized or lately diagnosed condition. The literature research was accurated and supported by the methodology of systematic review.

Please find here below my comments:

Title: I would suggest to mention first the molecular aspects and then diagnosis to be consistent with the order of the paragraphs of the review: "Updated in Molecular Aspects and Diagnosis of Autoimmune Gastritis"

Response: We express our gratitude for your valuable suggestion, and in accordance with it, we have amended the title.

Introduction: I would suggest to use intrinsic factor instead of intrinsic factors (lines 22 and 25 and also later on, for example line 257, in the manuscript)

Response: I have rectified the term in accordance with the provided comments.

1. Introduction: line 39: I would suggest to mention acid reflux as the last one of the reported symptoms and to modifiy it in reflux disease as this symtpom is very rare due to hypochlorhydria. Reflux disease may be present, but it is often non acid.

Response: I have revised the sentence accordingly.

3. Search strategy: The search strategy as well as the flow-chart are reported according to PRISMA guidelines, the reference should be reported (lines 50-61).

Response: Thank you for your valuable suggestion. I have integrated the appropriate reference (PMID: 33782057) into the designated "Search strategy" section.

Figure 1: the sum of the excluded studies does not give 100, but 89. So, there must be some mistake in the calculations of included and excluded studies.

Response: Thank you for your correction. We have excluded a total of 69 articles, as opposed to the originally mentioned 58 articles, due to the fact that their primary focus did not pertain to autoimmune gastritis. I have thoroughly revised the numerical value and can confirm its accuracy. I sincerely apologize for the oversight.

4. Molecular aspects of the pathophysiology of autoimmune gastritis: lines94-95. Please check reference 6, does it refer to a single case? If yes, this should be stated or the statement deleted.

Response: Thank you for your confirmation. The article (reference number 6) solely focused on the investigation of a solitary family, and the validation of PTH1R gene mutation was not established in the subsequent publication by the identical research group (reference number 10). As a result, I have chosen to remove those sentences.

5. Diagnosis of autoimmune gastritis: line 253, the reference 39 in this context is not the most appropriate on, I would suggest reference 28 or Lenti M, et al Autoimmune Gastritis, Nature Dis Primers 2019

Response: We greatly appreciate your valuable suggestions regarding the citation of the article. In accordance with your comments, I have proceeded to replace the references accordingly.

5.3 Serum pepsinogen: lines 276-277: pepsinogens are produced by chief cells of the oxyntic mucosa, not by parietal cells.

Response: Thank you for your correction. I have amended the sentence.

Line 291: The gastropanel is mainly proposed for screening of preneoplastic gastric condition as atrophic gastritis, I would not mention in this context the Zollinger-Ellison syndrome

Response: I have expunged the term in alignment with your comments.

5.4 Esophagogastroduodenoscopy: line 315: Why the potential marker for autoimmune gastritis (by definition with a spared antral mucosa) was investigated in the antrum instead of the corpus mucosa? I think this should be briefly discussed or explained.

Response: Thank you for posing this inquiry. We appreciate the opportunity to provide further elucidation on our research study. In order to enhance the comprehensiveness of the study findings, we have expanded the description. Gastric mucosal lymphocytes were isolated from both the gastric body and antrum regions. Subsequently, a meticulous investigation was undertaken to evaluate the proportions of CD8+ and CD4+ cells within the T cell population (CD3+ cells). Upon division of the CD4+/CD3+ ratio in the gastric body by the CD4+/CD3+ ratio in the gastric antrum (body CD4+/antrum CD4+ ratio), a significantly elevated value emerged in instances of autoimmune gastritis when juxtaposed against H. pylori-associated gastritis. Likewise, the division of the CD8+/CD3+ ratio by the CD4+/CD3+ ratio in the gastric antrum (antrum CD8+/CD4+ ratio) yielded a higher value for autoimmune gastritis in contrast to H. pylori-associated gastritis. The application of receiver-operating characteristic analysis unveiled the superior discriminatory capability of antrum CD8+/CD4+ in distinguishing autoimmune gastritis from its H. pylori-associated counterpart, when juxtaposed against body CD4+/antrum CD4+. Notably, an antrum CD8+/CD4+ ratio surpassing 4.0 demonstrated a sensitivity of 71.4% and a specificity of 93.3% in the diagnostic assessment of autoimmune gastritis.

6. Autoimmune gastritis without typical features: line 353: the reference 59 is not appropriated. It might be eventually used in the Conclusion para.

Response: I have eliminated reference 59 from the manuscript.

Round 2

Reviewer 1 Report

Thanks a lot for answering to my comments.

I have nothing to mention further.