Brief overview of the paper and its main findings

The authors have conducted a systematic review and meta-analysis on the efficacy of vitamin E in NAFLD. The study is interesting as it points out the emerging problem of NAFLD and its potential treatment which is currently often not effective. This manuscript included nine randomized controlled trials (RCTs). Eventually, they concluded that adjuvant vitamin E presents significant biochemical and histological improvements in adult patients, while an insignificant efficacy in pediatric patients. They also highlight that data on the impact of vitamin E on hepatic histology are still lacking. Moreover, they advocate for further long-duration RCTs with a deeper focus on both safety and efficacy.

Major and minor points

The study has well-defined methods, and the results were presented clearly.

However, I would like to point out some critical issues.

• The authors use a strong tone in their conclusion while the meta-analysis included only five RCTs of relatively small sample size and showed no statistically significant difference at any outcome. I suggest re-writing this section with a less certain statement.

• The analysis did not separate studies with short-term follow-ups from those with long-term follow-up, hence, it combined inequivalent designs and did not address different milestone of efficacy. I suggest subgrouping of the studies in the forest plots based on the different follow-ups.

• It appears that the literature search was not comprehensive as it did not reach the work of Balmer et al. 2009 and Dufour et al. 2006.
  Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, Zala JF, Helbling B, Steuerwald M, Zimmermann A; Swiss Association for the Study of the Liver. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2006 Dec;4(12):1537-43. doi: 10.1016/j.cgh.2006.09.025. PMID: 17162245. Balmer ML, Siegrist K, Zimmermann A, Dufour JF. Effects of ursodeoxycholic acid in combination with vitamin E on adipokines and apoptosis in patients with nonalcoholic steatohepatitis. Liver International : Official Journal of the International Association for the Study of the Liver. 2009 Sep;29(8):1184-1188. DOI: 10.1111/j.1478-3231.2009.02037.x. I suggest re-conducting the database search and inclusion of these two articles and further possible citations.

• Among the studies included as an RCT is the work of Hoofnagle et al., yet the study is a post hoc analysis of the PIVENS trial, and the authors made no further clarification. I suggest the exclusion of this citation.

• The unreliable statistical combination of mean change with final endpoint means throws into significant doubt the findings and conclusions. I suggest that the authors should adhere to the recommendation of the Cochrane Handbook 16.1.3.2.

• There should be more debate regarding the safety of vitamin E in the discussion since it represents an important concern in vitamin E treatment. I suggest the authors include more relevant references regarding this issue and expand their comments, especially for long-term safety.

• The authors should state whether the included studies report any data on vitamin E effect on CAP of LSM measured by Fibroscan or non-invasive markers such as FIB-4, FLI. If so, these data should be included in the analysis and discussion.

• In the inclusion criteria, the RCTs use vitamin E alone or combined with other co-interventions. To gain precise findings, authors should have only included the RCTs that use vitamin E alone. I suggest that they either point to this issue in the discussion or they have to exclude these RCTs and re-run the analysis or they should conduct further meta-regression models to examine the effect of these co-interventions.

Overall, these critical issues in the methodology and the analysis, if not addressed, can not guarantee the validity and reliability of the findings and conclusions.

Conflicts of interest

None to declare.