Evaluation and Management of Nutritional Consequences of Chronic Liver Diseases

Round 1

Reviewer 1 Report

Espina et al. presented a narrative review on the mechanism of malnutrition, nutrient and vitamin changes in liver diseases, and also discussed the diagnosis and management of malnutrition in these patients.

General comments:

There are lots of repetitions throughout the manuscript which can be eliminated to make it more succinct. Some examples are listed below but there are more. This review is not cohesive and should be more focused on nutrition rather than explaining the diseases. In some sections a deeper review and discussion is required. English language and punctuations need improvement. Overall, needs a major revision and updated search in the literature.

Specific comments:   

1. Abstract: page 1, line 23, metabolic dysfunction-associated fatty liver disease (MAFLD) has been mainly used in prior literature (J Hepatol. 2020 Jul;73(1):202-209; World J Gastroenterol. 2023 Jan 21;29(3):549-560) and recommend using this term instead of the metabolic associated fatty liver disease throughout the manuscript.

 

2 2. Key words: Please spell out MAFLD.

 

3  3. Introduction: page 1, line 40, please spell out CLD for the first time in the text.

 

44. Page2, line 57-58: mayor should be changed to major. Also, Jaundice is not a sign of decompensated cirrhosis and should be removed.

 

55. Page2, line 57-58: portal hypertensive bleeding is general and esophageal variceal bleeding should be used instead.

 

66.  Page 3 last paragraph: as one of the complications of vitamin D deficiency in liver disease decreased bone density especially in the hip should be emphasized.

 

77. Table 2: vitamin b12 increases in liver disease but the side effects that are mentioned in the table are from vitamin b12 deficiency and should not be included. The third column, “imbalance association” seems presenting the liver diseases that vitamin imbalances can be detected as well describing the side effects in some instances; these two (i.e., liver diseases that these imbalances are reported and clinical manifestations) can be separately described in two different columns for clarity.

 

88.   Page 3, line 89: Please elaborate on “toxic effects”.  What are the toxic effects and how can they cause beta cell dysfunction?

 

99.   Page 5, lines 170-171: “Pancreatic insufficiency, secondary to alcoholic abuse and common in liver cirrhotic patients, may also contribute to fat malabsorption” is not clear and needs to be written again more clearly.

 

110. Page 5, line 181-182: “In addition, all patients with decompensated cirrhosis who are candidates for liver transplantation have some degree of malnutrition” is redundant and needs to be removed.

 

111. Page 5, lines 186-189: “As liver dysfunction progresses in cirrhosis, proteolysis is more activated and protein synthesis more inhibited. As previously mentioned, liver cirrhosis is a hypercatabolic state in which the decreased hepatic glycogen store increases gluconeogenesis, primarily through proteolysis of skeletal muscle amino acids” is redundant and should be removed.

 

112. Page 6, first paragraph: Please elaborate on endotoxemia and the mechanisms it can cause sarcopenia. Is it through lipopolysaccharides or any other mechanism?

113.  Page 6, lines 206-207: Please specify the prevalence of osteopenia and osteoporosis in different liver diseases and if they vary between different disease such as compensated vs. decompensated cirrhosis.

 

114. Page 7, first paragraph: Please explain more about the pathogenesis of bone disease in MAFLD, alcoholic liver disease, and viral hepatitis. Which cytokines are involved and what is the mechanism?

 

115. Table 3: Sensibility should be changed to sensitivity.

 

116. Table 4: Please add the salt/sodium intake limitations for patients with cirrhosis and also fluid restriction for patients with Na<125.

 

117. Page 14, section 4.1.3: Please separate the salt intake portion and move it to a separate section.

 

118. Page 14, section 4.1.3: Please discuss the studies about using vitamin D or A supplements in patients with liver disease.

 

119. Page 15, line 512: “and this fact is related to the presence of sarcopenia in this group of patients” please change this sentence to make it clear.

 

220. Page 15, line 552: BMI has been used multiple times before this line and only the first time needs to be spelled out and not after that. Please spell it out the first time used in manuscript and after that only use BMI.

 

221. Page 20, section 4.5.1, lines 749-50: Hereditary hemochromatosis is diagnosed on patients with homozygous for C282Y gene not heterozygous. This needs to be corrected and also please only focus on the liver cirrhosis secondary to HH.

222.  Page 20, line 761: “Moreover, patients with hereditary hemochromatosis must alcohol consumption” This sentence is not clear and needs to be revised.

 

223. Page 21, first paragraph: Focus should be on nutrition restriction or vitamins that patients with Wilson’s disease need. Discussing disease features is out of the scope of your review. Same for other related sections.

 

224. Page 21, first paragraph: Clarify why patients on penicillamine need to be on vitamin B6.

 

225. Page 21, line 799: Spell out MCT

English language and punctuations need improvement. 

Author Response

We have read with interest the comments and suggestions from the reviewer. We would like to thank the reviewer for this comments and efforts towards improving our manuscript. We have revised our manuscript accordingly, and we hope you will find it suitable for publication in Nutrients.

 

There are lots of repetitions throughout the manuscript which can be eliminated to make it more succinct. Some examples are listed below but there are more. This review is not cohesive and should be more focused on nutrition rather than explaining the diseases. In some sections a deeper review and discussion is required. English language and punctuations need improvement. Overall, needs a major revision and updated search in the literature.

We have tried to suppress unnecessary repetitions and explanations of certain aspects of liver diseases. In addition, we have expanded the review of the recommended sections and have improved the quality of writing and English language.

Specific comments:

1. Abstract: page 1, line 23, metabolic dysfunction-associated fatty liver disease (MAFLD) has been mainly used in prior literature (J Hepatol. 2020 Jul;73(1):202-209; World J Gastroenterol. 2023 Jan 21;29(3):549-560) and recommend using this term instead of the metabolic associated fatty liver disease throughout the manuscript.

Thank you for the clarification, we have used the term “metabolic dysfunction-associated fatty liver disease” instead of “metabolic associated fatty liver disease” throughout all the manuscript.

2. Key words: Please spell out MAFLD.

We have included the spelled term “metabolic dysfunction-associated fatty liver disease” into the key words.

3. Introduction: page 1, line 40, please spell out CLD for the first time in the text.

We have added the term “CLD” spelled out the first time it has been used in the manuscript.

4. Page 2, line 57-58: mayor should be changed to major. Also, Jaundice is not a sign of decompensated cirrhosis and should be removed.

We have modified the text according to the recommendations.

5. Page 2, line 57-58: portal hypertensive bleeding is general and esophageal variceal bleeding should be used instead.

We have modified the text according to the recommendations.

6. Page 3 last paragraph: as one of the complications of vitamin D deficiency in liver disease decreased bone density especially in the hip should be emphasized.

We have added the following sentence to emphasize the importance of vitamin D deficiency: “Patients with vitamin D deficiency can also develop alterations in bone metabolism such as a significant decrease in bone mineral density (BMD) at the total hip and femoral neck and increased risk of fractures [28,29]”. (line 124-126)

7. Table 2: vitamin b12 increases in liver disease but the side effects that are mentioned in the table are from vitamin b12 deficiency and should not be included. The third column, “imbalance association” seems presenting the liver diseases that vitamin imbalances can be detected as well describing the side effects in some instances; these two (i.e., liver diseases that these imbalances are reported and clinical manifestations) can be separately described in two different columns for clarity.

We have added a column to Table 2 titled “imbalance associated-liver disease” that explains the liver disease in which the vitamin imbalance occurs, and we have changed the title of the third column to “liver and muscle-related consequences”. We have tried to improve the review of the consequences of micronutrient imbalances, also modifying those of the vitamin B12 according to recommendations. Modifications are highlighted.

8. Page 3, line 89: Please elaborate on “toxic effects”.  What are the toxic effects and how can they cause beta cell dysfunction?

We have tried to explain the main toxic mechanisms of liver cirrhosis and how they act on pancreatic β-cells: “Chronic hyperglycemia causes toxic injury to the pancreatic cells. The accumulation of advanced glycation end-products that are normally cleared by the liver accelerates this process by producing oxidative stress in β-cells. In addition, low-grade systemic hypoxia generated by advanced CLD contributes to the further impairment of β-cell function. Pancreatic β-cell dysfunction in patients with liver cirrhosis marks the transition from impaired glucose tolerance to HD [18]”. (line 94-99)

9.  Page 5, lines 170-171: “Pancreatic insufficiency, secondary to alcoholic abuse and common in liver cirrhotic patients, may also contribute to fat malabsorption” is not clear and needs to be written again more clearly.

We have rewritten the text for better understanding: “Pancreatic insufficiency may also contribute to fat malabsorption, and is common in patients with alcoholic cirrhosis”. (line 184-185)

10. Page 5, line 181-182: “In addition, all patients with decompensated cirrhosis who are candidates for liver transplantation have some degree of malnutrition” is redundant and needs to be removed.

We have removed the text in the manuscript.

11. Page 5, lines 186-189: “As liver dysfunction progresses in cirrhosis, proteolysis is more activated and protein synthesis more inhibited. As previously mentioned, liver cirrhosis is a hypercatabolic state in which the decreased hepatic glycogen store increases gluconeogenesis, primarily through proteolysis of skeletal muscle amino acids” is redundant and should be removed.

We have removed the text in the manuscript.

12. Page 6, first paragraph: Please elaborate on endotoxemia and the mechanisms it can cause sarcopenia. Is it through lipopolysaccharides or any other mechanism?

We have added the following sentence: “In addition, endotoxemia resulting from hepatocellular and immune dysfunction and portosystemic shunt may contribute to impaired protein synthesis and potentially active autophagy via TNFα-dependent and potentially TNF-independent pathways [19] such as reducing micronutrients derived from gut-microbiota (butyrate, acetate) [48]”. (line 208-212)

13. Page 6, lines 206-207: Please specify the prevalence of osteopenia and osteoporosis in different liver diseases and if they vary between different disease such as compensated vs. decompensated cirrhosis.

We have added the following explanation: “Osteoporosis is more prevalent in cholestatic chronic liver disease, in up to a quarter of patients, than in other CLD [52]. Alcoholic liver disease, haemochromatosis and MAFLD are associated with reduced BMD, and patients with chronic hepatitis C virus are at risk of osteoporosis [49]. In the end-stage of CLD, the prevalence of osteoporosis is higher and is detected in up to 38% of patients [53]”. (line 230-235)

14. Page 7, first paragraph: Please explain more about the pathogenesis of bone disease in MAFLD, alcoholic liver disease, and viral hepatitis. Which cytokines are involved and what is the mechanism?

We have added the following sentence: “In MAFLD, viral hepatitis and alcoholic liver disease, the increase in proinflammatory cytokine production such as TNFα represents the pathophysiological mechanism through stimulation of osteoclastogenesis” [49]. (line 241-243)

15. Table 3: Sensibility should be changed to sensitivity

We have changed the term in the manuscript.

16. Table 4: Please add the salt/sodium intake limitations for patients with cirrhosis and also fluid restriction for patients with Na<125.

We have changed the table according to the Reviewer suggestion.

16. Page 14, section 4.1.3: Please separate the salt intake portion and move it to a separate section.

We have created a separate section according to Reviewer suggestion.

16. Page 14, section 4.1.3: Please discuss the studies about using vitamin D or A supplements in patients with liver disease.

We have modified the section according to the Reviewer suggestion.

16. Page 15, line 512: “and this fact is related to the presence of sarcopenia in this group of patients” please change this sentence to make it clear.

All the manuscript has undergo an English edition in order to make theses senteces clear.

16. Page 15, line 552: BMI has been used multiple times before this line and only the first time needs to be spelled out and not after that. Please spell it out the first time used in manuscript and after that only use BMI.

We have changed the term in the manuscript.

16. Page 20, section 4.5.1, lines 749-50: Hereditary hemochromatosis is diagnosed on patients with homozygous for C282Y gene not heterozygous. This needs to be corrected and also please only focus on the liver cirrhosis secondary to HH.

We have changed the term in the manuscript. The aim of these special sections in to give specific reccomendations for both cirrhotics and non-cirrhotics patients.

16. Page 20, line 761: “Moreover, patients with hereditary hemochromatosis must alcohol consumption” This sentence is not clear and needs to be revised.

We have revised and changed the sentence in the manuscript.

16. Page 21, first paragraph: Focus should be on nutrition restriction or vitamins that patients with Wilson’s disease need. Discussing disease features is out of the scope of your review. Same for other related sections.

Thank you for the comment, however we consider that theses shorts introductions are needed.

16. Page 21, first paragraph: Clarify why patients on penicillamine need to be on vitamin B6.

We have modified the text according to the recommendations.

16. Page 21, line 799: Spell out MCT

We have modified the text according to the recommendations.

 

Reviewer 2 Report

The present review summarized the physiopathology and factors that impact on nutritional status in the liver diseases and the assessment and prevention of malnutrition and sarcopenia. The review is overall comprehensive and well written. A suggestion is that the Figure 4 should be re-organized as the pyramid plot is not suitable to demonstrate some factors that should be avoided for patients with MAFLD such as alcohol consumption and refined sugars.

Minor editing of English language required

Author Response

We have read with interest the comments and suggestions from the reviewer. We would like to thank the reviewer for this comments and efforts towards improving our manuscript. We have revised our manuscript accordingly, and we hope you will find it suitable for publication in Nutrients.

1. The present review summarized the physiopathology and factors that impact on nutritional status in the liver diseases and the assessment and prevention of malnutrition and sarcopenia. The review is overall comprehensive and well written. A suggestion is that the Figure 4 should be re-organized as the pyramid plot is not suitable to demonstrate some factors that should be avoided for patients with MAFLD such as alcohol consumption and refined sugars.

We thank the Reviewer for the comment and we agree. We have changed the Figure 4 to a plot we consider is suitable to demostrate factors that should be avoided or recommended.

Reviewer 3 Report

The authors have undertaken a huge task and consequently some areas are covered superficially

This manuscript is too long; I lost interest halfway through the manuscript; it looks and feels more like an introductory chapter to a thesis

The authors have attempted to address all aspects of nutritional deficiencies and nutrition support in one paper and as such the manuscript suffers from this

Some sections are dealt with very superficially and these would be better addressed as a separate manuscript

The section on steatotic liver disease should probably be condensed as there are many articles on this topic and there are some guidelines on nutrition in steatotic liver disease in an EASL publication

In some sections the language and writing style needs to be amended; I think the authors tried to rush through the last few sections and there are some inaccuracies in the information as well as some fairly careless language

P 4:

Authors make no mention of the role of branched chain amino acids in protein synthesis

P4, line 154: incorrect reference

P7, 8: the authors need to differentiate between nutritional screening tools and nutritional assessment tools – they are very different

P12,13: the table does not contain any references for the very specific recommendations

P 14: ref no 111does not really support the authors statement theat BCAAs may increase the risk of cancer; the summary of that reference states:

In summary, loss of BCAA catabolism in tumors confers functional advantages, which could be exploited by therapeutic interventions in certain cancers

There is also published evidence to indicate that supplementation with BCAAs in patients with cirrhosis results in prolonged event free survival;  also, supplementation with branched-chain amino acids is also recommended as it improves response to treatment (A Ruiz-Margáin et al: Nutritional therapy for hepatocellular carcinoma)

P 14: Zinc is carried on albumin so improving albumin is critical to zinc homeostasis

P19; line 696: the statement: malnutrition, sarcopenia and frailty should not be an absolute contraindication to LT should acknowledge that some centres now delay listing or place patients on pending lists until frailty scores have improved

P19; line 710: this sentence doesn’t make sense – needs rewording

P20; line 717: I would suggest that malnutrition and sarcopenia are frequently present rather than “could be”

 

P 20; lines 727-729: these recommendations must be referenced

P20;  line 761: there seems to be a word missing between must and alcohol

P21; line 778: medications for the management of Wilsons disease are much more effective in managing copper levels than any dietary restrictions; there is controversy around restricting the foods listed by the authors

P21; line 788: this statement is inaccurate; the first hydroxylation occurs in the liver and the second hydroxylation occurs in the kidneys

 

P 21; line795: I would suggest rewording; perhaps say oral supplementation should be considered rather than necessary

 

In parts the English expression is poor - it almost seems as though some sections were written by different people

Author Response

We have read with interest the comments and suggestions from the reviewer. We would like to thank the reviewer for this comments and efforts towards improving our manuscript. We have revised our manuscript accordingly, and we hope you will find it suitable for publication in Nutrients.

 

The authors have undertaken a huge task and consequently some areas are covered superficially. This manuscript is too long; I lost interest halfway through the manuscript; it looks and feels more like an introductory chapter to a thesis. The authors have attempted to address all aspects of nutritional deficiencies and nutrition support in one paper and as such the manuscript suffers from this. Some sections are dealt with very superficially and these would be better addressed as a separate manuscript. 

We thank the reviewer for the comment. The topic of our manuscript is very broad. We prepared the review according to the aim of the Special Issue described in the “Special Issue Information” section. The aim was to update knowledge on the pathogenesis of nutritional alterations commonly observed in liver disease and on nutritional management in most frequent etiologies and scenarios. Due to theme global vision, our manuscript and the Special Issue aspire to be useful both to registered dietitian nutritionists and to family doctors, gastroenterologist, internists, and surgeons. As the reviewer suggests, some topics would need a specific review to be fully addressed.

The section on steatotic liver disease should probably be condensed as there are many articles on this topic and there are some guidelines on nutrition in steatotic liver disease in an EASL publication

We have reviewed and modified this section.

In some sections the language and writing style needs to be amended; I think the authors tried to rush through the last few sections and there are some inaccuracies in the information as well as some fairly careless language.

We have send the manuscript to an English editing service before resubmit it.

1. P 4: Authors make no mention of the role of branched chain amino acids in protein synthesis

We have modified the sentence to include the branched chain amino acids in the “energy metabolism disturbances” and to explain their role in protein synthesis: “BCAA, physical exercise, testosterone and growth hormone [38]. BCAAs activates protein synthesis via mTOR (mammalian target of rapamycin) [38]”. (line 155-157)

• P4, line 154: incorrect reference

We have changed the reference according your recommendation [42]

• P7, 8: the authors need to differentiate between nutritional screening tools and nutritional assessment tools – they are very different

Thank you for your recommendation. We have changed the title of section 3. “Nutritional Screening & Assessment of Patients with Chronic Liver Disease” and the title of the subsection 3.2. “Nutritional Assessment of Malnutrition”. In addition, we have adapted the terms that could be confusing to “nutritional screening tools” and “nutritional assessment tools”. The changes are highlighted

• P12,13: the table does not contain any references for the very specific recommendations

We have added references as suggested.

• P 14: ref no 111does not really support the authors statement theat BCAAs may increase the risk of cancer; the summary of that reference states: In summary, loss of BCAA catabolism in tumors confers functional advantages, which could be exploited by therapeutic interventions in certain cancers There is also published evidence to indicate that supplementation with BCAAs in patients with cirrhosis results in prolonged event free survival;  also, supplementation with branched-chain amino acids is also recommended as it improves response to treatment (A Ruiz-Margáin et al: Nutritional therapy for hepatocellular carcinoma)

We have modified the main text and references according to the reviewer suggestions.

• P 14: Zinc is carried on albumin so improving albumin is critical to zinc homeostasis

We have modified this section.

• P19; line 696: the statement: malnutrition, sarcopenia and frailty should not be an absolute contraindication to LT should acknowledge that some centres now delay listing or place patients on pending lists until frailty scores have improved

The manuscript has undergo an English edition before resubmission in odrder to make theses sentences more clear.

• P19; line 710: this sentence doesn’t make sense – needs rewording

The manuscript has undergo an English edition before resubmission in odrder to make theses sentences more clear. 

• P20; line 717: I would suggest that malnutrition and sarcopenia are frequently present rather than “could be”

We have changed the sentence as suggested.

• P 20; lines 727-729: these recommendations must be referenced

We have addedd references.

• P20;  line 761: there seems to be a word missing between must and alcohol

We have changed the text.

• P21; line 778: medications for the management of Wilsons disease are much more effective in managing copper levels than any dietary restrictions; there is controversy around restricting the foods listed by the authors

We have added the Reviewer's recommendation to the manuscript.

• P21; line 788: this statement is inaccurate; the first hydroxylation occurs in the liver and the second hydroxylation occurs in the kidneys

We thank the reviewer for the suggestion. We have corrected the statement.

• P 21; line795: I would suggest rewording; perhaps say oral supplementation should be considered rather than necessary

We have change the sentence.

• In parts the English expression is poor - it almost seems as though some sections were written by different people

The manuscript have been revised by an English edition service before resubmission.

Reviewer 4 Report

In this review, the Authors summarize the physiopathology and factors that impact on nutritional status in liver disease patients.  In particular, the assessment of malnutrition and sarcopenia and its complications in this setting are discussed. I found the following points to be improved:

1. Introduction section: sevarl reports indicate the pivotal role of the intestinal permeability to onset and influence the pathogenesis of liver diasease as alcohlolic and non-alcoholic fatty liver disease (PMID: 36595801). Please consider it in your article. 

2. The Author have been discussed the role of Mediterranean diet in MAFLD patients. However, MAFLD is a very recent definition. Literature report several items of the application of the MD regimen in liver disease patients with NAFLD. Please include it.

3. the role of the gut microbiota and the supplementation of probiotics, are partially discussed. I suggest to improve this part with regards to dysbiosis state in cirrhotic patients (PMID: 3736792)

Author Response

We have read with interest the comments and suggestions from the reviewer. We would like to thank the reviewer for this comments and efforts towards improving our manuscript. We have revised our manuscript accordingly, and we hope you will find it suitable for publication in Nutrients.

 

1. Introduction section: several reports indicate the pivotal role of the intestinal permeability to onset and influence the pathogenesis of liver disease as alcoholic and non-alcoholic fatty liver disease (PMID: 36595801). Please consider it in your article.

We have added the following sentence in the introduction section: “Furthermore, the dysregulation of the gut microbiome that develops in liver cirrhosis may accelerate liver fibrogenesis and complications of cirrhosis” [7]. (line 40-42). In section 2.5. called “Nutrient Malabsorption”, we have explained: “SIBO causes excessive production of ammonia and increases the translocation of bacteria and the absorption of bacterial antigens into the bloodstream and this may promote the development of hepatic inflammation, steatosis and fibrosis [7,44]. Moreover, several complications and decompensations of advanced chronic liver disease, like overt hepatic encephalopathy or spontaneous bacterial peritonitis are directly or indirectly associated with gut microbiota dysregulation [7,44]”. (line 177-182)

2. The Author have been discussed the role of Mediterranean diet in MAFLD patients. However, MAFLD is a very recent definition. Literature report several items of the application of the MD regimen in liver disease patients with NAFLD. Please include it.

 We have changed the definition of MAFLD to NAFLD when it is referred to the MD regimens as suggested.

3. The role of the gut microbiota and the supplementation of probiotics, are partially discussed. I suggest to improve this part with regards to dysbiosis state in cirrhotic patients (PMID: 3736792)

We agree with the Reviewer that is an interesting topic and that should be discussed in our manuscript. We have added a special section regarding the supplementation of probiotics in cirrhosis as an emerging treatment. Unfortunately, we were not able to find the reference that the Reviewer has suggested. The PMID: 3736792 go to the article:

"In vitro production and release of opioid peptides in the tooth pulp induced by bradykinin. T Kudo, M Kuroi, R Inoki. Neuropeptides. 1986 May-Jun;7(4):391-7. doi: 10.1016/0143-4179(86)90032-6."

Reviewer 5 Report

The manuscript is an interesting and extensive review on nutritional support in liver diseases. However it is too long and repetitive reducing its impact in clinical practice. My major concerns regards:

1. Section 2: Consequences of Liver Disease on Nutritional Status. The described metabolic alterations need  a more in-depth and clear analysis of their pathogenesis. Such an effort could endorse the nutritional intervention proposed by the authors in the last part of the manuscript.

2. Section 4. Nutritional intervention. This section is too long and confused. Since the authors stated that "regardless the etiology of underlying disease, physiopatholgy and clinical consequences are common...", it would be better to summarize the common general aspects of nutritional intervention and afterwards specify the peculiarities intrinsic to specific disease.

Minor comments:

- lines 443-447: the sentence needs to be checked and re-written

 

Extensive editing of English language required

Author Response

We have read with interest the comments and suggestions from the reviewer. We would like to thank the reviewer for this comments and efforts towards improving our manuscript. We have revised our manuscript accordingly, and we hope you will find it suitable for publication in Nutrients.

The manuscript is an interesting and extensive review on nutritional support in liver diseases. However it is too long and repetitive reducing its impact in clinical practice. My major concerns regards:

Section 2: Consequences of Liver Disease on Nutritional Status. The described metabolic alterations need  a more in-depth and clear analysis of their pathogenesis. Such an effort could endorse the nutritional intervention proposed by the authors in the last part of the manuscript.

Thank you for your recommendation. We have made an effort trying to improve the explanation of the pathogenesis without lengthening the manuscript excessively. We have modified the following subsections: 2.2. Altered macro and micronutrients metabolism, 2.3. Energy metabolism disturbances, 2.4. nutrient malabsorption -adding the role of gut microbiota dysregulation-, 2.6. sarcopenia and muscle function, and 2.7. metabolic osteopathy. Changes and new bibliography are highlighted.

2. Section 4. Nutritional intervention. This section is too long and confused. Since the authors stated that "regardless the etiology of underlying disease, physiopatholgy and clinical consequences are common...", it would be better to summarize the common general aspects of nutritional intervention and afterwards specify the peculiarities intrinsic to specific disease.

Thank you for your recommendation. Also in this section, we have made an effort in order to improving our manuscript. Changes and new bibliography are highlighted.

Minor comments:

• lines 443-447: the sentence needs to be checked and re-written

We have cheked and revwritten the sentence. Moreover, the manuscript has undergone an extensive editing of English language before resubmission.

 

Round 2

Reviewer 1 Report

Thank you for your revisions. overall manuscript has improved a lot, but I still think it is long and can be more focused on nutrition. 

1. Table 1. BCAA needs to be spelled out in the table or add a footnote under table.

2. Authors have used "Advanced chronic liver disease" throughout the manuscript, which is not very specific. Please explain what do you mean by that? If you mean cirrhosis, then specify as cirrhosis and when indicated compensated vs. uncompensated. 

3. Page 14, section 4.1.3: please add the data on use of vit D supplements in patients with cirrhosis or CLD. 

 

English has improved but still needs some minor improvement. 

Author Response

Thank you for your revisions. overall manuscript has improved a lot, but I still think it is long and can be more focused on nutrition. 

1. Table 1. BCAA needs to be spelled out in the table or add a footnote under table.

We have spelled out the word BCAA inside the Table 1.

2. Authors have used "Advanced chronic liver disease" throughout the manuscript, which is not very specific. Please explain what do you mean by that? If you mean cirrhosis, then specify as cirrhosis and when indicated compensated vs. uncompensated. 

Thanks for the comment. We have removed the term “advanced chronic liver disease” from the manuscript to avoid confusion. We have left the term “cirrhosis” and “chronic liver disease” (CLD) trying to be as precise as possible. The changes are highlighted in the text.

3. Page 14, section 4.1.3: please add the data on use of vit D supplements in patients with cirrhosis or CLD.

We have added the data on vitamin D supplementation in patients with CLD and cirrhosis.

Reviewer 3 Report

In the section on dietary patterns the authors should take care to use the correct nomenclature: fatty liver disease is now steatotic liver disease and NAFLD and NASH are no longer the preferred terminology

I suggest the authors look at this recent article to tidy up the nomenclature:  A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. June 24, 2023. DOI:10.1097/HEP.0000000000000520

L 787: It should read 25-hydroxy vitamin D, NOT 25-dihydroxy vitamin D; the 2^nd hydroxylation occurs in the kidney

Some minor alterations to clarify some statement

Author Response

In the section on dietary patterns the authors should take care to use the correct nomenclature: fatty liver disease is now steatotic liver disease and NAFLD and NASH are no longer the preferred terminology

I suggest the authors look at this recent article to tidy up the nomenclature:  A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. June 24, 2023. DOI:10.1097/HEP.0000000000000520

We thank the reviewer for the suggestion. We changed NAFLD and NASH for the suggested term.

L 787: It should read 25-hydroxy vitamin D, NOT 25-dihydroxy vitamin D; the 2^nd hydroxylation occurs in the kidney

We corrected the sentence.

Reviewer 5 Report

The manuscript quality is improved after revision. Only 2 minor comments are suggested:

- line 503 Paragraph title 4.1.3: "sodium intake" needs to be removed from the title since a new paragraph has been inserted on this topic

- lines 589-591: the term  "NAFLD" appears in the text,  instead of the acronym MAFLD previously used. An explanation is required to avoid confusion

Author Response

The manuscript quality is improved after revision. Only 2 minor comments are suggested:

• line 503 Paragraph title 4.1.3: "sodium intake" needs to be removed from the title since a new paragraph has been inserted on this topic

We corrected the paraghraph title.

• lines 589-591: the term  "NAFLD" appears in the text,  instead of the acronym MAFLD previously used. An explanation is required to avoid confusion

We thank the Reviewer for the suggestion. In order to avoid confusion we have modified the term according to the new fatty liver disease nomenclature (A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. June 24, 2023. DOI:10.1097/HEP.0000000000000520)