Review Reports - Hepatoprotective Effects of Liv.52 in Chronic Liver Disease Preclinical, Clinical, and Safety Evidence: A Review

Round 1

Reviewer 1 Report

The manuscript is aimed to report the current knowledge about Liv.52, a herbal medication for primary and acquired liver diseases.

However, the authors report a limited number of updated references (only 6/48 from the last 5 years).

The first part of the manuscript is interesting and well organized.

Special attention must be paid to taxonomic names, using italics for plants.

The paragraphs 2.3.3 and 2.3.4 are critical. In fact, the authors discuss in general the viral hepatitis, but any of them has specific features and requires a particular assesment. So, a more extensive discussion should be done at least for the most common viral liver diseases, including dose related to non-primary (i.e., CMV, Adenovirus, EBV, yellow fever virus, etc.). In addition, great attention must be reserved to viral hepatitis in pregnancy, in particular those related to HEV. And an extensive discussion must be dedicated to possible interactions with other medications and natural products in pregnancy.

At last, the authors provided an excessively short discussion and no conclusion.

Some typos must be amended. English language requires a minor revision.

Author Response

Point 1: The manuscript is aimed to report the current knowledge about Liv.52, a herbal medication for primary and acquired liver diseases.

Point 2: However, the authors report a limited number of updated references (only 6/48 from the last 5 years).

Response for Point 2:

A trial conducted by Choijamts G in 2018 has been added to section 2.3.1.
Three clinical trials, one conducted in 2015 by Maity S G et al, the other conducted in Indonesia in 2021 by Siregar G et al and Ghosh S et al in 2014 have been added in section 2.4.7.
Two review articles on hepatoprotective effects of Liv.52 and Liv.52 HB published in 2022 have been added.
Clinical trials conducted by Siregar et al in 2021, Choijamts et al in 2018, and Jha et al in 2018 have been added.
Preclinical trials conducted by Cimen et al in 2020 and Pavan K.B. et al in 2021 have also been added.

Point 3: The first part of the manuscript is interesting and well organized.

Point 4: Special attention must be paid to taxonomic names, using italics for plants.

Response for Point 4: The changes have been made in the manuscript.

Point 5: The paragraphs 2.3.3 and 2.3.4 are critical. In fact, the authors discuss in general the viral hepatitis, but any of them has specific features and requires a particular assesment. So, a more extensive discussion should be done at least for the most common viral liver diseases, including dose related to non-primary (i.e., CMV, Adenovirus, EBV, yellow fever virus, etc.). In addition, great attention must be reserved to viral hepatitis in pregnancy, in particular those related to HEV. And an extensive discussion must be dedicated to possible interactions with other medications and natural products in pregnancy.

Response to Point 5: The available clinical studies suggest the effectiveness of Liv.52 in acute viral Hepatitis caused by Hepatitis virus. The efficacy of Liv.52 in the treatment of hepatitis caused due to CMV, Adenovirus, EBV, yellow fever virus is yet to be explored. A study on the effectiveness of Liv.52 in 84 pregnant women with jaundice due to various liver disorders (conducted by Mitra A K in 1978 has been discussed in 2.4.5 section. There are no other clinical studies on Liv.52 in pregnancy.

Point 6: At last, the authors provided an excessively short discussion and no conclusion.

Response to Point 6: The discussion has been elaborated with a separate conclusion.

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Paper submitted to MDPI, Gastroenterology Insights by Chetan Kantharia and others titled: “Hepatoprotective effects of Liv.52 in chronic liver disease-preclinical, clinical and safety evidence: A Review”, summarized known published data on Liv.52 activity tested in animals and in humans. The paper attempts to concisely bring together several studies and separate known Liv.52 therapeutic effects observed into the following subchapters: Hepatoprotective effect, Antioxidant effect and Radiation Hazard, Alcoholic liver disease, Viral hepatitis, Liver function in pregnancy, Liver cirrhosis, Hepatomegaly syndrome.

Overall the paper requires revisions in order to organize and provide with additional details on Liv.52 components that make it a remedy for liver disease and cirrhosis. Therefore the paper is not recommended for publication, unless after major revisions will be introduced.

In general review prior publication requires edits in text, in data presentation (Figure 1 and Table 1), reference citation and general re-organization of text in specific chapters.

There are following critiques/recommendations to improve this article:

1. In the Introduction section authors should prepare the reader for content of this paper: please list known demographics in details for liver disease(s) susceptibility in Western world, and in developing countries, with details on people affected with specific liver disease.

2. In addition, introduction should cover major biomarkers used for different liver diseases as measured in clinical trials.

3. In the introduction, please describe history of Liv.52, used as a diet supplement and tested in clinical trials to prevent/treat liver disease.

4. Liv.52 is a natural herbal based product used as dietary supplement that showed previously in clinical trials efficacy protecting and slowing down progression of liver disease, and/or cirrhosis. Such statements require proper use of references. It is recommended to correct text throughout for the proper use of citations, and introduce correct references, not at the end of paragraph, but at the place when first referring to the specific paper.

5. Sub-chapter titled: “Liv.52 formulation” does not describe what herbs and known active ingredients are in Liv.52. Instead part of the Introduction is listing plants species and some reactive compounds. This chapter needs to include necessary information on Liv.52 and what plants/herbs Liv.52 is derived from, such as list of herbs, at least the known active herbal elements that were studied previously.

6. Mechanism of action (MOF) is divided to hepatoprotective effect and benefits in liver cirrhosis, presented in Figure 1. This figure needs to show in larger font biological Liv.52 activities. The mechanism of action should be proposed and organized in a single paragraph. Please, correct any inconsistencies when discussing Liv.52 MOF throughout the paper, and refer to Figure 1.

7. The markers regarding liver disease progression whether those are molecular markers or overall survival need to be introduced and separated in the text, explained the measurements criteria for assessment of Liv.52 activity in patients. Consistently, molecular markers of liver disease and specific liver condition, such as cirrhosis, or alcoholic liver disease and/or radiation induced liver fibrosis, etc., have distinct markers for disease progression and need to be clearly outlined. If necessary use separate Table that would introduce the biomarkers of the disease with Liv.52 treatment response. It is recommended to split Table 1 into two different Tables that would supplement necessary information on clinical trials.

8. When discussing specific clinical trials of Liv.52 please include what was the control group and how control group of individuals responded to any given treatment. Focus on human clinical trials, since it is a review of Liv.52 activity as measured in humans.

9. It is recommended to use Table to outline the specific features of disease and what clinical trial was used with Liv.52.

10. Sometimes the details from particular study don't illustrate the most important conclusion(s) and provide the evidence for Liv.52 activity. Please be consistent with specific markers for specific type of disease.

11. Clinical trials mentioned in Table 1 are referred once in the text of this paper what is unacceptable. Table 1 is not referred throughout the text, but loosely described. Please refer to Table 1 when mentioning specific clinical trials.

Overall, the text in English should be corrected preferably by a native speaker; there is a need for a paper re-organization and careful edits with the specific chapter title representing correct content and properly used supporting references.

Author Response

In general review prior publication requires edits in text, in data presentation (Figure 1 and Table 1), reference citation and general re-organization of text in specific chapters.

There are following critiques/recommendations to improve this article:

Point 1: In the Introduction section authors should prepare the reader for content of this paper: please list known demographics in details for liver disease(s) susceptibility in Western world, and in developing countries, with details on people affected with specific liver disease.

Response to Point 1: The comment has been addressed in the introduction section.

Point 2: In addition, introduction should cover major biomarkers used for different liver diseases as measured in clinical trials.

Response to Point 2: The comment has been addressed in the introduction section.

Point 3: In the introduction, please describe history of Liv.52, used as a diet supplement and tested in clinical trials to prevent/treat liver disease.

Response to Point 3: The comment has been addressed in the introduction section.

Point 4: Liv.52 is a natural herbal based product used as dietary supplement that showed previously in clinical trials efficacy protecting and slowing down progression of liver disease, and/or cirrhosis. Such statements require proper use of references. It is recommended to correct text throughout for the proper use of citations, and introduce correct references, not at the end of paragraph, but at the place when first referring to the specific paper.

Response to Point 4: The efficacy of Liv.52 in liver disorders has been discussed in clinical studies. Use of Liv.52 in malnutrition in paediatric cases has been added.

Point 5: Sub-chapter titled: “Liv.52 formulation” does not describe what herbs and known active ingredients are in Liv.52. Instead part of the Introduction is listing plants species and some reactive compounds. This chapter needs to include necessary information on Liv.52 and what plants/herbs Liv.52 is derived from, such as list of herbs, at least the known active herbal elements that were studied previously.

Response to Point 5: The information on all herbs used in the formulation has been added.

Point 6: Mechanism of action (MOF) is divided to hepatoprotective effect and benefits in liver cirrhosis, presented in Figure 1. This figure needs to show in larger font biological Liv.52 activities. The mechanism of action should be proposed and organized in a single paragraph. Please, correct any inconsistencies when discussing Liv.52 MOF throughout the paper, and refer to Figure 1.

Response to Point 6:

The fonts in the figure are already adjusted to accommodate the content in small space after checking various sizes of content to fit into the space. Hence, we have not changed the font size.
A sentence on the probable multifactorial mechanism of Liv. 52 has been added.
The Liv.52 mechanism of action has been discussed only at one place hence there are no inconsistencies.

Point 7: The markers regarding liver disease progression whether those are molecular markers or overall survival need to be introduced and separated in the text, explained the measurements criteria for assessment of Liv.52 activity in patients. Consistently, molecular markers of liver disease and specific liver condition, such as cirrhosis, or alcoholic liver disease and/or radiation induced liver fibrosis, etc., have distinct markers for disease progression and need to be clearly outlined. If necessary use separate Table that would introduce the biomarkers of the disease with Liv.52 treatment response. It is recommended to split Table 1 into two different Tables that would supplement necessary information on clinical trials.

Response to Point 7:

The necessary biomarkers have been added. The biomarkers of liver diseases such as bilirubin, AST, ALT, ALP, albumin, total protein are added in the description of the clinical trials.
Since focus of the paper is hepatoprotective effects of Liv.52 in chronic liver disease we have segregated clinical trials of Liv.52 according to diseases.
A separate table on preclinical studies of Liv.52 has been added. Another table summarizing review articles on hepatoprotective role of Liv.52 has been added.
Point 8: When discussing specific clinical trials of Liv.52 please include what was the control group and how control group of individuals responded to any given treatment. Focus on human clinical trials, since it is a review of Liv.52 activity as measured in humans.

Response to Point 8 : The comment has been addressed for trials where control group was mentioned.

Point 9: It is recommended to use Table to outline the specific features of disease and what clinical trial was used with Liv.52.

Response to Point 9: Disease feature with respect to its type and the evaluation parameters necessary

to evaluate the effect of Liv. 52 have already been added to table 2.

Point 10: Sometimes the details from particular study don't illustrate the most important conclusion(s) and provide the evidence for Liv.52 activity. Please be consistent with specific markers for specific type of disease.

Response to Point 10: The comment has been addressed in Table 2.

Point 11: Clinical trials mentioned in Table 1 are referred once in the text of this paper what is unacceptable. Table 1 is not referred throughout the text, but loosely described. Please refer to Table 1 when mentioning specific clinical trials.

Response to Point 11: The comment has been addressed.

Point 12: Comments on the Quality of English Language- Overall, the text in English should be corrected preferably by a native speaker; there is a need for a paper re-organization and careful edits with the specific chapter title representing correct content and properly used supporting references.

Response to Point 12: The document has been checked for English language errors.

Please see attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

The manuscript presents a literature review on hepatoprotective effects of Liv.52 in Chronic Liver Disease.

The research concludes that Liv.52 is very effective on liver protection by using both syrup and tablet formulations and well tolerated and does not present any side effects reported in any of the studied patient groups.

I find the topic interesting and being worth of investigation and the document is well structured.

Although I propose the following comments/suggestions:

- Abstract should be better organized: problem, motivation, aim, methodology, main results, further impact of those results.

- Keywords should be in alphabetical order

- In the methodology a repeatable approach such as PRISMA method should had been used instead of a narrative review

- In this narrative review it is not clear how the cited studies were selected and others non cited were excluded

- Discussion and conclusion should be different sections

The English language used should be reviewed by a native speaker.

Author Response

The manuscript presents a literature review on hepatoprotective effects of Liv.52 in Chronic Liver Disease.

I find the topic interesting and being worth of investigation and the document is well structured.

Although I propose the following comments/suggestions:

Point 1: Abstract should be better organized: problem, motivation, aim, methodology, main results, further impact of those results.

Response to Point 1: The abstract has been edited as per the requirement. Motivation to write the review is clubbed with the aim. Since it is a narrative review, specific methodology of writing is not described. The results are presented as favorable efficacy and safety of Liv.52. Option of Liv.52 as a favorable herbal choice for management of CLD has been suggested in the end.

Point 2: Keywords should be in alphabetical order.

Response to Point 2: Keywords rearranged in the alphabetical order in the manuscript.

Point 3: In the methodology a repeatable approach such as PRISMA method should had been used instead of a narrative review.

Response to Point 3: Since the focus of the current paper is to provide a summary/overview of preclinical, clinical, and safety evidence of Liv.52 in hepatic dysfunction and chronic liver disease we decided to write a narrative review instead of a systematic review.

Point 4: In this narrative review it is not clear how the cited studies were selected and others non cited were excluded.

Response to Point 4: The preclinical and clinical studies pertaining to Liv.52 were searched using databases like Pubmed and Google Scholar. Some of the old studies not available in these databases were retrieved from the website of Himalaya wellness company. https://researchpapers.himalayawellness.in/liv52.html

Point 5: Discussion and conclusion should be different sections.

Response to Point 5: The discussion and conclusion have been separated in the manuscript.

Please see attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The authors addressed all the reviewers' comments and the manuscript has been improved

acceptable

Author Response

The reviewer has replied that the authors addressed all the reviewers' comments and the manuscript has been improved.

Reviewer 2 Report

Revised version of the review paper submitted to Gastroenterology by Chetan Kantharia and others titled: “Hepatoprotective effects of Liv.52 in chronic liver disease-preclinical, clinical and safety evidence: A Review”, was corrected and includes modified Tables. In general, authors corrected the paper and it is acceptable for publication, however after additional revisions, such as English grammar and Tables content and how Tables are referred to in the text. Tables are important for illustration and clarification of the paper message, potentially decreasing the details included in plain text of this article.

English language and grammar require additional careful corrections.

Author Response

We have made corrections as suggested by the reviewer.

Reviewer 3 Report

I would like to mention that I do not agree with authors in their view of a narrative review since it add a bias to it and is not repeatable as using a PRISMA systematic review.

Although the document has improved since last version.

It has been improved.

Author Response

Due to our intention to offer a concise summary of the preclinical, clinical, and safety data concerning Liv.52's effectiveness in hepatic dysfunction and chronic liver disease, we have opted to compose a narrative review rather than a PRISMA systematic review. The primary aim of this paper is to provide an overview of the available evidence in these areas.