Lysosomal Acid Lipase Deficiency in the Etiological Investigation of Cryptogenic Liver Disease in Adults: A Multicenter Brazilian Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

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Dear Authors,

I had the opportunity to read your manuscript with great pleasure.

I do believe that your work has some remarkable aspects, as dealing with a rare medical condition, being multicentric, and relying on a rigorous selection of patients performed also through invasive methods such as liver biopsy.  Nevertheless I think that unfortunately the paper cannot be published in its current form. Below you will find some major and minor revisions that needs to be addressed in order to improve its quality.

 

Major revisions:

My main worry about your work is the complete absence of any statistical test. If on the one hand it is explained by the very low number of patients with LAL-D, on the other it makes the reliability of your conclusion very questionable. Moreover, I think that performing instead a descriptive comparative analysis of the 37 patients with MALD compared to the remaining group of patients with cryptogenic liver cirrhosis not MALD-related, could be useful.

The second limit of the work is related to the first point, and regards the way you present your results. The results section contains too may tables. Tables are too wordy and not pleasant to be read throughout.  Most of the table content could be shifted in the text body.

Finally, all the paper really needs a careful revision for English grammar and fluency as it does not sound scientific in most of its parts and contains relevant grammar mistakes.

 

Minor revisions:

 

lines 35-38: “Cryptogenic chronic hepatitis is a condition characterized by a lack of explanation through conventional clinical, laboratory, and histological findings that would define the etiology of liver disease”. Please rewrite the sentence as it difficult to understand, e.g. you could say “Chriptogenetic Chronic Hepatits is a form of progressive liver disease characterized by a lack of explanation of its etiology”

 

lines 88-89: “Current and previous alcohol intake as well as use of potentially hepatotoxic medications, teas, herbs, and supplements was assessed to exclude alcoholic liver disease and drug/herbal induced liver injury, respectively”. How did you assess that patients did not use these substances? Did you set a cut-off beyond which you considered that the patient “abused” of alcohol and/or other potentially hepatotoxic substances? If yes, which were the cut-offs? Please specify.

 

lines 192-195: “On the other hand, patients with cryptogenic liver disease (n =132) were older (mean age 192 51.5±14.6 years), with higher weight (mean BMI 27.6±5.9), with higher serum glucose lev- 193 els (110±354.7 mg/dL) and HDL levels (48.1±17 mg/dL) and lower triglycerides levels 194 (114±376.7 mg/dL).” As you have stated in methods, given the extremely low number of patients with LAL-D, you were not able to perform any comparative analysis. Therefore, please be consistent in the results and do not compare them with other patients with cryptogenic cirrhosis.

 

Tables 2 and 4. I would avoid to report hematochemical parameters of patients with MASLD and with chriptogenic cirrhosis in Tables, but I would rather include these values in the main text. Moreover I think that reporting median and SD for continous parametric variables would be enough, without reporting the minumum and maximum values. I would use Tables only to describe data of the three clinical cases with LAL-D (Table 3 is interesting in this sense).  

Comments on the Quality of English Language

Extensive english revision required

Author Response

Thank you for your comments. Please check the attached reply.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Great value of the study! The clinicians should he instructed how and which patients to be screened for LLAL-D. On page 5, figure contain dose of ceruloplasmin...Could you rethink to change "dose" to abnormal 

Author Response

Thank you for your comments. Please check the attached reply.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Authors Candolo et al. have submitted a manuscript for publication describing an investigation into the etiology of cryptogenic liver disease to determine an association with lysosomal acid lipase deficiency (LAL-D).  In general, the aim is to provide a basis for accurate diagnosis and potential treatment of patients diagnosed with cryptogenic liver disease, given the recent success with Sebelipase Alfa in LAL-D.  The study provides a rare basis of understanding for progression of disease in patients that often leads to cirrhosis and hepatocellular carcinoma, and requires liver transplantation.  Therefore, this study is timely and of interest to a subset of patients with grim prognoses.  

The manuscript is generally well-written and easy to understand, but I think the largest deficit in its construction is the presentation of data.  Of course, clinical studies are often filled with charts and tables of several data points, as is true with this one.  I think that some additional visualizations and comparisons would be warranted in this case.  As in to compare the LAL-D patients with the 132 others via Venn diagrams to show commonalities and distinctions between the populations in the biochemical and clinical analyses and even in the MASLD criteria.  

In addition, I think if any regression-type analyses could be performed to see how various parameters or groups of parameters correspond to the populations would be a nice addition. 

Lastly, I think the highlighted limitations are always useful in these studies, but are there any thoughts by the authors concerning the ethnicities of the patients as the centers were solely in Brazil?  A little discussion to this end would be a great addition.

Comments on the Quality of English Language

English language is appropriate.  A few instances of typos are noted, which can be fixed with a thorough proofread/spellcheck.  For instance, lines 215-218 are a repeated sentence.  Save that, should be fine.

Author Response

Thank you for your comments. Please check the attached reply.

Author Response File: Author Response.pdf