Isotretinoin and Hepatotoxicity in Patients with Acne: A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an interesting article about hepatotoxicity caused by oral isotretinoin in patients with acne.
Acne vulgaris are very common especially in younger populations and even moderate forms can cause psychological problems.
Therapeutic possibilities are numerous but not all of them are universally effective. Oral isotretinoin is indicated in patients with severe, recalcitrant, nodular acne. It is teratogenic and associated with a number of other adverse effects (mucocutaneous and extracutaneous) that can limit its use.

Hepatotoxicity is a rare but possible severe side effect that can require ending treatment.
Acne vulgaris is very common, that’s why an article that discusses one treatment option with its potential side effects may be interesting for readers that are into this field of medicine.
This article is well written and well organized with citations that are relevant to this topic.
It provides all of the necessary information about isotretinoin from dosage to mechanism of producing liver drug injury.
In my opinion the authors have to add one piece of information about dosing- should dosing of isotretinoin be calculated based on total body weight (TBW) or ideal body weight (IBW)?

 

 

 

Author Response

Responses to reviewers

We sincerely appreciate your helpful comments and constructive suggestions, which have significantly improved the quality of this manuscript. We kindly request that the manuscript be considered for publication in theCosmetics, a high-quality journal. We believe the manuscript is now greatly enhanced. Revisions have been made in response to all reviewers' suggestions, and the changes for each reviewer are highlighted in green. Our response follows (comments are in italics).

Reviewer 1

Comment 1. This is an interesting article about hepatotoxicity caused by oral isotretinoin in patients with acne. Acne vulgaris are very common especially in younger populations and even moderate forms can cause psychological problems. Therapeutic possibilities are numerous but not all of them are universally effective. Oral isotretinoin is indicated in patients with severe, recalcitrant, nodular acne. It is teratogenic and associated with a number of other adverse effects (mucocutaneous and extracutaneous) that can limit its use. Hepatotoxicity is a rare but possible severe side effect that can require ending treatment. Acne vulgaris is very common, that’s why an article that discusses one treatment option with its potential side effects may be interesting for readers that are into this field of medicine. This article is well written and well organized with citations that are relevant to this topic. It provides all of the necessary information about isotretinoin from dosage to mechanism of producing liver drug injury. In my opinion the authors have to add one piece of information about dosing- should dosing of isotretinoin be calculated based on total body weight (TBW) or ideal body weight (IBW)?

Reply

Thank you for your valuable comment. We have revised the manuscript as follows:

"As a lipophilic drug, isotretinoin accumulates in fatty tissues, resulting in a high volume of distribution. Dosing isotretinoin based on total body weight (TBW) ensures an accurate reflection of the increased volume of distribution in obese patients, facilitates proper drug redistribution, and maintains therapeutic efficacy. This approach aligns with the recommendations in the U.S. Food and Drug Administration (FDA)-approved patient medication guides.”

We look forward to hearing from you regarding our submission. We would be glad to respond to any further questions and comments that you may have.

Authors

Reviewer 2 Report

Comments and Suggestions for Authors

This narrative review highlights the importance of evidence-based guidelines to balance effective acne treatment with the risk of isotretinoin-induced hepatotoxicity.

Suggestion for the authors:

In the Introduction the sentence: For mild to moderate acne, lower doses of 0.1 to 0.4 mg/kg/d over a treatment period of 6 to 8 months have been shown to be effective for mild-to-moderate acne [16, 17]. needs to be corrected.

In Methods: what about expert opinions, editorials, and non-systematic reviews?

Table 1 lacks bibliography.

The paragraph describing the study of Daye at al. is about an animal study on rats, excluded by the authors in the exclusion criteria. 

The last sentence form 3.2 also lacks reference.

I would recommend to add in a flow chart or in text the number of identified studied, excluded ones after the title and abstract screening, and remained for full text review. 

 

Author Response

Responses to reviewers

We sincerely appreciate your helpful comments and constructive suggestions, which have significantly improved the quality of this manuscript. We kindly request that the manuscript be considered for publication in theCosmetics, a high-quality journal. We believe the manuscript is now greatly enhanced. Revisions have been made in response to all reviewers' suggestions, and the changes for each reviewer are highlighted in green. Our response follows (comments are in italics).

Reviewer 2

Comment 1. This narrative review highlights the importance of evidence-based guidelines to balance effective acne treatment with the risk of isotretinoin-induced hepatotoxicity.

Reply

Thank you for your comment. We appreciate your recognition of our focus on balancing effective acne treatment with the risk of isotretinoin-induced hepatotoxicity.

 

Comment 2. In the Introduction the sentence: For mild to moderate acne, lower doses of 0.1 to 0.4 mg/kg/d over a treatment period of 6 to 8 months have been shown to be effective for mild-to-moderate acne [16, 17]. needs to be corrected.

Reply

Thank you for pointing this out. We have corrected the sentence as follows:

"For mild to moderate acne, lower doses of 0.1 to 0.4 mg/kg/day over a treatment period of 6 to 8 months have been shown to be effective [16, 17]."

 

Comment 3. In Methods: what about expert opinions, editorials, and non-systematic reviews?

Reply

Thank you for your thoughtful comment. Expert opinions, editorials, and non-systematic reviews were not in the inclusion criteria to maintain a focus on robust, evidence-based data from original research or comprehensive reviews. While these sources may be valuable for context or background information, they do not typically provide the same level of empirical and high-quality evidence required to support the conclusions of this narrative review. We have also acknowledged this point in the limitations section of the manuscript.

 

Comment 4. Table 1 lacks bibliography.

Reply

Thank you for your comment. We have addressed your concern by adding a note below the table to clarify the sources of the data.

 

Comment 5. The paragraph describing the study of Daye at al. is about an animal study on rats, excluded by the authors in the exclusion criteria.

Reply

Thank you for your insightful comment. Our study primarily aims to identify the incidence of isotretinoin-related hepatotoxicity to provide evidence-based guidance on the appropriate frequency of liver function monitoring during isotretinoin therapy. The study by Daye et al. is discussed in the section on the mechanism of isotretinoin and hepatotoxicity. Although it is an animal study, we referred it due to the limited availability of human-specific evidence, as it offers a broader understanding of isotretinoin's effects and hypothesized pathways.

Our main findings, as detailed in section 3.3 (Incidence of Hepatitis and Elevated Liver Enzymes), are exclusively based on human data. Similarly, section 3.4 (How to Monitor and Prevent Liver Function Abnormalities?) primarily references human studies to provide evidence-based recommendations. However, we also incorporated insights from animal studies to highlight potential trends and mechanisms that could inform future research. This distinction ensures that the review remains focused on human studies while providing additional context where necessary. We appreciate the opportunity to clarify this point.

 

Comment 6. The last sentence form 3.2 also lacks reference.

Reply

Thank you for your valuable comment. We have added the appropriate reference to the last sentence in section 3.2 as suggested.

 

Comment 7. I would recommend to add in a flow chart or in text the number of identified studied, excluded ones after the title and abstract screening, and remained for full text review.

Reply

Thank you for your insightful suggestion to include details regarding the number of studies identified, excluded, and included in the review process. In response, we have revised the Methods section to provide this information in the text. Specifically, our search identified 24 articles from PubMed, 11 articles from the Directory of Open Access Journals (DOAJ), and 203 articles from Scopus. After removing duplicates, 218 articles remained for screening. Following the title and abstract screening, 78 articles were selected for full-text review. Ultimately, 44 articles met the inclusion and exclusion criteria and were included in this narrative review. We appreciate your recommendation and believe this addition enhances the transparency of our methodology.

We look forward to hearing from you regarding our submission. We would be glad to respond to any further questions and comments that you may have.

Authors