Title: Associations of C-reactive protein to lymphocyte ratio and  metabolic-dysfunction-
associated steatotic liver disease: evidence from NHANES 2017-2018
Version: 4 Date: 26 Aug 2024
Reviewer:  Dimitrios S. Karagiannakis
Reviewer's report:
1. Changing the term NAFLD to the newer and more accurate term MASLD is better.
2. Substitute reference No1 with the latest one referring to the most recent clinical practice
guidelines for MASLD.
3. On page 2: "Inflammation plays an important role in the pathogenesis of NAFLD, which
is not only a direct causative agent of liver parenchymal cell injury, but also an important
pathologic basis for driving disease progression [16]. However, there is a gap in studies on the
association between CLR and NAFLD." Please add the reference confirming the gap regarding
the association between CLR and NAFLD.
4. Please add the reference regarding the NHANES survey in the last paragraph of page 2 ("Data
for this study came from NHANES (https://www.cdc.gov/nchs/nhanes/). NHANES collects
comprehensive data on diet, nutritional status, and chronic diseases in the United States and is
valuable for medical research").
5. In the exclusion criteria, please give information about patients' alcohol consumption.
6. In the statistical analysis section, please define saturation levels.
7. In section 3.3 (Non-Linearity and Saturation Effect Analysis Between CLR and NAFLD),
you mention that "the results confirmed that the inflection point value of CLR was ln(CLR ) of
1.08 (log-likelihood test: P < 0.05). " Please correct.
8. The authors should explain how and why they decided to use the covariates of age, race, and
sex in the adjusted model 1.
9. Similarly, they must explain how they decided to investigate further whether CLR and the
risk of developing NAFLD were merely affected by sex, diabetes, race, and smoking status and
not by other factors.
10. On page 8, the authors describe that "one study found that hs-CRP levels were associated
with elevated levels in patients with NAFLD, and after adjustment for waist-to-hip ratio and
glycosylated hemoglobin (HbA1C), hs-CRP remained significantly correlated with NAFLD".
With elevated levels of what? Please clarify.
11. In the fifth line on the same page, the authors state, "The inflammation-immunity balance is
increasingly recognized as a key factor in the development and progression of NAFLD.". Please
add the appropriate reference.
12. In the same paragraph, the authors declare that "inflammation and immune dysregulation are
associated with the pathogenesis of NAFLD and emphasize that CLR is a potential biomarker for
early detection and risk stratification of individuals at risk for NAFLD." This is an overstatement.
How does the association between the CLR and NAFLD confirm that immune dysregulation is
associated with the pathogenesis of NAFLD?
13. In the discussion, some sentences and statements are a little bit arbitrary, such as "For
example, a moderate increase in CLR may predict the early stages of NAFLD, whereas a
significant increase may be associated with disease progression, providing a theoretical basis
for CLR-based NAFLD management strategies" or "the convenience of the CLR assay (which
can be performed in routine clinical laboratories) makes it an attractive tool for early screening
for NAFLD" and "strategies aimed at reducing systemic inflammation, such as weight loss,
exercise, and anti-inflammatory drugs, have the potential to reduce CLR as a novel approach to
the treatment of NAFLD.". The study's results cannot confirm these statements; thus, the authors
must change them. Generally, the authors must be more precise in their conclusions, avoiding
overstatement.
Title: Associations of C-reactive protein to lymphocyte ratio and  metabolic-dysfunction-
associated steatotic liver disease: evidence from NHANES 2017-2018
Version: 4 Date: 26 Aug 2024
Reviewer:  Dimitrios S. Karagiannakis
Reviewer's report:
1. Changing the term NAFLD to the newer and more accurate term MASLD is better.
2. Substitute reference No1 with the latest one referring to the most recent clinical practice
guidelines for MASLD.
3. On page 2: "Inflammation plays an important role in the pathogenesis of NAFLD, which
is not only a direct causative agent of liver parenchymal cell injury, but also an important
pathologic basis for driving disease progression [16]. However, there is a gap in studies on the
association between CLR and NAFLD." Please add the reference confirming the gap regarding
the association between CLR and NAFLD.
4. Please add the reference regarding the NHANES survey in the last paragraph of page 2 ("Data
for this study came from NHANES (https://www.cdc.gov/nchs/nhanes/). NHANES collects
comprehensive data on diet, nutritional status, and chronic diseases in the United States and is
valuable for medical research").
5. In the exclusion criteria, please give information about patients' alcohol consumption.
6. In the statistical analysis section, please define saturation levels.
7. In section 3.3 (Non-Linearity and Saturation Effect Analysis Between CLR and NAFLD),
you mention that "the results confirmed that the inflection point value of CLR was ln(CLR ) of
1.08 (log-likelihood test: P < 0.05). " Please correct.
8. The authors should explain how and why they decided to use the covariates of age, race, and
sex in the adjusted model 1.
9. Similarly, they must explain how they decided to investigate further whether CLR and the
risk of developing NAFLD were merely affected by sex, diabetes, race, and smoking status and
not by other factors.
10. On page 8, the authors describe that "one study found that hs-CRP levels were associated
with elevated levels in patients with NAFLD, and after adjustment for waist-to-hip ratio and
glycosylated hemoglobin (HbA1C), hs-CRP remained significantly correlated with NAFLD".
With elevated levels of what? Please clarify.
11. In the fifth line on the same page, the authors state, "The inflammation-immunity balance is
increasingly recognized as a key factor in the development and progression of NAFLD.". Please
add the appropriate reference.
12. In the same paragraph, the authors declare that "inflammation and immune dysregulation are
associated with the pathogenesis of NAFLD and emphasize that CLR is a potential biomarker for
early detection and risk stratification of individuals at risk for NAFLD." This is an overstatement.
How does the association between the CLR and NAFLD confirm that immune dysregulation is
associated with the pathogenesis of NAFLD?
13. In the discussion, some sentences and statements are a little bit arbitrary, such as "For
example, a moderate increase in CLR may predict the early stages of NAFLD, whereas a
significant increase may be associated with disease progression, providing a theoretical basis
for CLR-based NAFLD management strategies" or "the convenience of the CLR assay (which
can be performed in routine clinical laboratories) makes it an attractive tool for early screening
for NAFLD" and "strategies aimed at reducing systemic inflammation, such as weight loss,
exercise, and anti-inflammatory drugs, have the potential to reduce CLR as a novel approach to
the treatment of NAFLD.". The study's results cannot confirm these statements; thus, the authors
must change them. Generally, the authors must be more precise in their conclusions, avoiding
overstatement.
Please review this paper.
user
Title: Associations of C-reactive protein to lymphocyte ratio and  metabolic-dysfunction-
associated steatotic liver disease: evidence from NHANES 2017-2018
Version: 4 Date: 26 Aug 2024
Reviewer:  Dimitrios S. Karagiannakis
Reviewer's report:
1. Changing the term NAFLD to the newer and more accurate term MASLD is better.
2. Substitute reference No1 with the latest one referring to the most recent clinical practice
guidelines for MASLD.
3. On page 2: "Inflammation plays an important role in the pathogenesis of NAFLD, which
is not only a direct causative agent of liver parenchymal cell injury, but also an important
pathologic basis for driving disease progression [16]. However, there is a gap in studies on the
association between CLR and NAFLD." Please add the reference confirming the gap regarding
the association between CLR and NAFLD.
4. Please add the reference regarding the NHANES survey in the last paragraph of page 2 ("Data
for this study came from NHANES (https://www.cdc.gov/nchs/nhanes/). NHANES collects
comprehensive data on diet, nutritional status, and chronic diseases in the United States and is
valuable for medical research").
5. In the exclusion criteria, please give information about patients' alcohol consumption.
6. In the statistical analysis section, please define saturation levels.
7. In section 3.3 (Non-Linearity and Saturation Effect Analysis Between CLR and NAFLD),
you mention that "the results confirmed that the inflection point value of CLR was ln(CLR ) of
1.08 (log-likelihood test: P < 0.05). " Please correct.
8. The authors should explain how and why they decided to use the covariates of age, race, and
sex in the adjusted model 1.
9. Similarly, they must explain how they decided to investigate further whether CLR and the
risk of developing NAFLD were merely affected by sex, diabetes, race, and smoking status and
not by other factors.
10. On page 8, the authors describe that "one study found that hs-CRP levels were associated
with elevated levels in patients with NAFLD, and after adjustment for waist-to-hip ratio and
glycosylated hemoglobin (HbA1C), hs-CRP remained significantly correlated with NAFLD".
With elevated levels of what? Please clarify.
11. In the fifth line on the same page, the authors state, "The inflammation-immunity balance is
increasingly recognized as a key factor in the development and progression of NAFLD.". Please
add the appropriate reference.
12. In the same paragraph, the authors declare that "inflammation and immune dysregulation are
associated with the pathogenesis of NAFLD and emphasize that CLR is a potential biomarker for
early detection and risk stratification of individuals at risk for NAFLD." This is an overstatement.
How does the association between the CLR and NAFLD confirm that immune dysregulation is
associated with the pathogenesis of NAFLD?
13. In the discussion, some sentences and statements are a little bit arbitrary, such as "For
example, a moderate increase in CLR may predict the early stages of NAFLD, whereas a
significant increase may be associated with disease progression, providing a theoretical basis
for CLR-based NAFLD management strategies" or "the convenience of the CLR assay (which
can be performed in routine clinical laboratories) makes it an attractive tool for early screening
for NAFLD" and "strategies aimed at reducing systemic inflammation, such as weight loss,
exercise, and anti-inflammatory drugs, have the potential to reduce CLR as a novel approach to
the treatment of NAFLD.". The study's results cannot confirm these statements; thus, the authors
must change them. Generally, the authors must be more precise in their conclusions, avoiding
overstatement.
assistant