Title: An updated systematic review and meta-analysis: Correlation between circulating
Plasminogen Activator Inhibitor-1 levels and Metabolic Dysfunction-Associated Steatotic Liver
Disease
Version: 1 Date: 01 Mar 2025
Reviewer's report:
1. Experts renamed NAFLD as ‘metabolic-associated fatty liver disease’ (MAFLD) because
it with obesity, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are closely
related.
If you are using the updated terminology, please also mention MASLD along with MAFLD,
which is actually, the globally accepted name and not MAFLD.
2. The authors have included patients with MAFLD. The authors must clarify what exact
proportion of these patients have history of alcohol intake. According to the MASLD definition,
there is a term called ‘MetALD’. This is important because there is a fundamental difference
between NAFLD and MAFLD/MASLD. MAFLD/MASLD include patients who consume
alcohol. There is a strong relationship between alcohol intake and PAI-1 levels (Liu, S., Xie,
X., Zhao, D. et al. Alcohol use disorder disrupts BDNF maturation via the PAI-1 pathway
which could be reversible with abstinence. Sci Rep 14, 22150 (2024). https://doi.org/10.1038/
s41598-024-73347-2). This issue must be addressed because whether PAI-1 levels are affected
by mere steatosis/steatohepatitis or by concurrent alcohol intake needs to be better investigated.
3. The authors would do well to find out any association between different categories of NAFLD
(steatosis/steatohepatitis/fibrosis/advanced CLD) and their association with PAI-1 levels. This
would provide more clarity.
4. The studies included are observational studies.  Based on this, it would be erroneous to
conclude that “PAI-1 levels were strongly related to MAFLD development.” This is because
no causal association can be established. Increased PAI-1 may be an antecedent or may be a
subsequent development of NAFLD development. There can be many confounders itself like
diabetes, metabolic syndrome, dyslipidemia which can influence the circulating PAI-1 levels.
5. The authors should mention if there were any lean subjects with NAFLD. If so, what was the
level of expression of PAI-1 in them? This would help us understand the dynamics of PAI-1
expression in NAFLD better.
Title: An updated systematic review and meta-analysis: Correlation between circulating
Plasminogen Activator Inhibitor-1 levels and Metabolic Dysfunction-Associated Steatotic Liver
Disease
Version: 1 Date: 01 Mar 2025
Reviewer's report:
1. Experts renamed NAFLD as ‘metabolic-associated fatty liver disease’ (MAFLD) because
it with obesity, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are closely
related.
If you are using the updated terminology, please also mention MASLD along with MAFLD,
which is actually, the globally accepted name and not MAFLD.
2. The authors have included patients with MAFLD. The authors must clarify what exact
proportion of these patients have history of alcohol intake. According to the MASLD definition,
there is a term called ‘MetALD’. This is important because there is a fundamental difference
between NAFLD and MAFLD/MASLD. MAFLD/MASLD include patients who consume
alcohol. There is a strong relationship between alcohol intake and PAI-1 levels (Liu, S., Xie,
X., Zhao, D. et al. Alcohol use disorder disrupts BDNF maturation via the PAI-1 pathway
which could be reversible with abstinence. Sci Rep 14, 22150 (2024). https://doi.org/10.1038/
s41598-024-73347-2). This issue must be addressed because whether PAI-1 levels are affected
by mere steatosis/steatohepatitis or by concurrent alcohol intake needs to be better investigated.
3. The authors would do well to find out any association between different categories of NAFLD
(steatosis/steatohepatitis/fibrosis/advanced CLD) and their association with PAI-1 levels. This
would provide more clarity.
4. The studies included are observational studies.  Based on this, it would be erroneous to
conclude that “PAI-1 levels were strongly related to MAFLD development.” This is because
no causal association can be established. Increased PAI-1 may be an antecedent or may be a
subsequent development of NAFLD development. There can be many confounders itself like
diabetes, metabolic syndrome, dyslipidemia which can influence the circulating PAI-1 levels.
5. The authors should mention if there were any lean subjects with NAFLD. If so, what was the
level of expression of PAI-1 in them? This would help us understand the dynamics of PAI-1
expression in NAFLD better.
Please review this paper.
user
Title: An updated systematic review and meta-analysis: Correlation between circulating
Plasminogen Activator Inhibitor-1 levels and Metabolic Dysfunction-Associated Steatotic Liver
Disease
Version: 1 Date: 01 Mar 2025
Reviewer's report:
1. Experts renamed NAFLD as ‘metabolic-associated fatty liver disease’ (MAFLD) because
it with obesity, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are closely
related.
If you are using the updated terminology, please also mention MASLD along with MAFLD,
which is actually, the globally accepted name and not MAFLD.
2. The authors have included patients with MAFLD. The authors must clarify what exact
proportion of these patients have history of alcohol intake. According to the MASLD definition,
there is a term called ‘MetALD’. This is important because there is a fundamental difference
between NAFLD and MAFLD/MASLD. MAFLD/MASLD include patients who consume
alcohol. There is a strong relationship between alcohol intake and PAI-1 levels (Liu, S., Xie,
X., Zhao, D. et al. Alcohol use disorder disrupts BDNF maturation via the PAI-1 pathway
which could be reversible with abstinence. Sci Rep 14, 22150 (2024). https://doi.org/10.1038/
s41598-024-73347-2). This issue must be addressed because whether PAI-1 levels are affected
by mere steatosis/steatohepatitis or by concurrent alcohol intake needs to be better investigated.
3. The authors would do well to find out any association between different categories of NAFLD
(steatosis/steatohepatitis/fibrosis/advanced CLD) and their association with PAI-1 levels. This
would provide more clarity.
4. The studies included are observational studies.  Based on this, it would be erroneous to
conclude that “PAI-1 levels were strongly related to MAFLD development.” This is because
no causal association can be established. Increased PAI-1 may be an antecedent or may be a
subsequent development of NAFLD development. There can be many confounders itself like
diabetes, metabolic syndrome, dyslipidemia which can influence the circulating PAI-1 levels.
5. The authors should mention if there were any lean subjects with NAFLD. If so, what was the
level of expression of PAI-1 in them? This would help us understand the dynamics of PAI-1
expression in NAFLD better.
assistant