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PONE-D-20-21370

Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: Lean versus overweight patients

PLOS ONE

Dear Dr. Hirose,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

While the study is of a potential interest, the reviewers identified several important issues such as a large amount of people, who were lost to follow-up. These need to be eliminated or at least properly acknowledged. In addition, multiple large studies have been carried out on this subject. The authors should compare their findings with these studies (a table might be reasonable way to do this) and discuss the discrepancies.   

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Kind regards,

Pavel Strnad

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Overall, this is an interesting and well written paper. Most NALD studies are suffering from short follow ups. In this retrospective monocenter study Hirose et al. examined a long-term cohort of biopsy proven NAFLD in 223 patients over 19 years. They concluded that NASH, older age, and T2DM were significantly associated with all-cause mortality. Factors significantly associated with liver-related events were older age, T2DM, milder hepatic steatosis, and advanced liver fibrosis. As an add on they found that the prognosis was not significantly different between lean and overweight NAFLD patients.

Major issues:

From 223 only 111 (less than 50%) answered and send back the questionnaires. This fact has to be discussed in more detail with regard to medication, drug abuse, sports.

The percentage of lean and overweight patients was 45.7% and 54.3%, respectively. This seems to be special because other studies describe more obese patients. Is it a phenomenon observed in Japan or Asia only?

The authors should discuss, why NASH cirrhosis was not present in their patients.

Minor issues:

The following sentences of the abstract should be better placed in the result section than under methods: “The risk of type 2 diabetes mellitus (T2DM) and hypertension was 11.7 (95% confidence interval [CI] 8.70-15.6) and 7.99 (95% CI 6.09-10.5) times higher, respectively, in NAFLD patients than in the general population. Twenty-three patients died, 22 of whom had NASH.”

Limitations of the study are mentioned. The terminus of “burnt-out” NASH with regard to steatosis with moderate fibrosis should be explained in more detail.

The questionnaire should be added - at least as supplemental material.

Reviewer #2: The submitted manuscript by Hirose et al. describes the 19 year long term prognosis of obese and non-obese patients with NAFLD in a cohort of 223 patients. The worldwide increasing prevalence of NAFLD related mortality implicates the relevance of research in this field. The authors conclude, that T2DM is highly prevalent in NAFLD patients and was correlated to mortality and liver related events. Furthermore they state, that lean patients prognosis appears to be not necessarily better than in obese patients. Several issues flaw the reviewers enthusiam about this manuscript. There are numerous multinational NAFLD cohort studies of significantly larger scale than it is the case in this manuscript, examining the long term effects of NAFLD in different ethnicites. The overall novelty of the authors findings is very limited. The majority of messages in this manuscript have been published previously. Furthermore, as the authors have already stated, there is a relevant selection bias comprising only one quarter of the patients to have NAFLD, while three quarters of patients suffer from NASH, making the cohort not represenative of real life data.

Minor comments:

The authors should have stated what type of questionnaires were utilized for alcohol and health-related issues.

Histological findings appear to be based on HE staining proven fibrosis. Relevant information about NAFLD activity score, ie. extent of steatoisi, lobular inflammation, balloning, etc. is not provided.

Despite the overall small number of patients enrolled in this study the rather high rate of patients lost to FUP of 40% further decreasing the statistical power of this study.

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Reviewer #1: No

Reviewer #2: No

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Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: Lean versus overweight patients

PONE-D-20-21370R1

Dear Dr. Hirose,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Pavel Strnad

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All concers have been removed by the authors response. The mansucript is now ready to publish.

The authors submitted important additonal material in the supplement.

Reviewer #2: The paper significantly improved in direct comparison to the previous version. Therefore it can be accepted for publication in its current form

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No