Review for 10.1186/s12876-025-03778-2 (2025)

Title: High sensitivity C-reactive protein Implicates Heterogeneous Metabolic Phenotypes and
Severity in Metabolic Dysfunction Associated-Steatotic Liver Disease
Version: 2 Date: 05 Feb 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-While the transition from MAFLD to MASLD is clearly stated, a more thorough explanation
of how these terms are operationalized could be beneficial, especially for readers who may
not be familiar with the exact diagnostic criteria for MASLD. Including clear definitions and
distinctions between MAFLD, MASLD, and the newly introduced metabolic dysfunction could
provide further clarity.
-The introduction mentions two separate cross-sectional studies, but this could be clarified
further. How does the cohort from the First Affiliated Hospital of Sun Yat-sen University
compare to the group from other hospitals? Are these two studies integrated, or are they
independent? More explanation regarding the use of these multiple hospitals could prevent any
confusion about the scope of the data.
-The introduction mentions that the study aims to assess the association between hs-CRP and
various inflammatory markers, but more detail on the specific statistical methods planned would
be useful. For example, how will the study control for potential confounders, such as age, sex,
or comorbid conditions, in these analyses? Providing a brief outline of the statistical analyses
(e.g., regression models, correlation tests) would make the methodology more transparent.
-While the introduction explains that hs-CRP is a known marker of inflammation, it could
benefit from a more detailed discussion about its limitations and the controversies mentioned.
For instance, why is hs-CRP a point of contention in MASLD diagnostics? A deeper dive into
the conflicting findings in the literature could strengthen the rationale for this study and its
importance.
-While the study mentions the inclusion of diverse hospitals and patients, there is no mention
of baseline characteristics (e.g., age, gender, BMI, comorbidities). Including this information
would enhance the understanding of the sample and allow for better contextualization of the
results.
-While the authors acknowledge the cross-sectional nature of the study and the inability to infer
causality, the discussion could more thoroughly emphasize the limitations this imposes on the
interpretation of their findings. It may be useful to further elaborate on how a longitudinal or
interventional study could help clarify the directionality of the observed associations between
hs-CRP and liver outcomes.
-Although the discussion touches on some potential mechanisms (e.g., the role of visceral
adipose tissue and IL-6), these could be expanded upon. More detailed exploration of
the pathophysiological processes linking hs-CRP with liver steatosis and fibrosis would be
beneficial. For example, discussing potential molecular or cellular mechanisms (e.g., how
elevated hs-CRP may interact with specific liver cell types or pathways) could provide additional
insights into why hs-CRP is associated with liver damage.
-The authors mention that the AUCs for hs-CRP had limited diagnostic significance. It would
be helpful to expand on why this is the case. Are there specific characteristics of MASLD or
subtypes that limit hs-CRP's predictive power? Is the diagnostic value of hs-CRP less reliable
in certain populations (e.g., those with comorbid conditions like diabetes or obesity)? Further
discussion on this point would help readers understand the practical implications of the study.
-While the authors acknowledge that further validation in larger cohorts is needed, it would
strengthen the discussion to provide more specific suggestions on how future studies might
address this gap. Would larger prospective studies with longitudinal data be ideal? Would
multi-center studies, or studies in different populations (e.g., non-Asian populations), provide
additional insights?