Review for 10.1186/s12876-025-03870-7 (2025)

Title: Correlation between hs-CRP-Triglyceride Glucose Index and NAFLD and Liver Fibrosis
Version: 1 Date: 11 Mar 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-While the study provides strong correlations, it does not address the potential causality between
CTI and liver fibrosis or NAFLD progression. Given that this is an observational study, it is
important to note the limitations in inferring causal relationships.
-Although the study includes a comprehensive set of variables, the exclusion of certain
characteristics based on low z-values (e.g., alcohol abuse, total bilirubin, and moderate physical
activities) may overlook potentially significant factors. While this is justified by statistical
methods, further exploration of these factors in sensitivity analyses could strengthen the
conclusions.
-Although race is included as a covariate, the study could delve deeper into how race/ethnicity
specifically interacts with CTI and NAFLD progression. Given the known racial disparities in
NAFLD, a more nuanced exploration could add depth to the findings.
-While the study explores the CTI index, it remains unclear whether CTI is more effective than
established markers like liver enzyme levels (e.g., ALT, AST) or other indices (e.g., TyG, hs-
CRP) in predicting NAFLD and liver fibrosis. A more detailed comparison of CTI’s clinical
utility versus existing biomarkers could strengthen its potential adoption in clinical settings.
-The exploration of non-linear relationships with RCS curves is commendable. However, the
results of these analyses are not fully discussed or integrated into the overall findings. It would
be helpful to see a more thorough discussion of how these non-linear relationships impact the
interpretation of CTI in predicting liver fibrosis and NAFLD.
-While the study uses a large sample size, the exclusion criteria (e.g., individuals with severe
infections, hepatitis B or C) narrow the generalizability to certain populations. Additionally,
there is a lack of stratified analysis based on specific disease subtypes (e.g., NASH versus simple
steatosis), which could provide more targeted insights into the relationship between CTI and
liver disease progression.
-While a wide range of covariates has been accounted for, other factors influencing liver health,
such as medication use, dietary patterns, or genetic predispositions, could potentially confound
the results. These factors could be addressed in future research to provide a more comprehensive
understanding.
-While the study identifies a significant correlation between CTI and NAFLD/liver fibrosis, the
authors acknowledge that the cross-sectional design limits the ability to draw causal conclusions.
This is an important limitation, and it would be beneficial to emphasize the necessity of
longitudinal studies to confirm the predictive power of CTI over time and to explore potential
causal pathways.
-The discussion acknowledges that the cross-sectional design hinders the establishment of a
temporal relationship. However, the study could further address how this limitation impacts the
interpretation of their findings. For example, while the association is clear, it remains uncertain
whether elevated CTI is a precursor to NAFLD or if it’s merely a consequence of an established
disease. Greater emphasis on the need for longitudinal or cohort-based studies would strengthen
this aspect.
-Although the study adjusted for a broad range of confounders, including demographic, lifestyle,
and clinical factors, there may be other unmeasured confounders (e.g., genetic factors, detailed
dietary habits, medication use) that could influence the results. The discussion could have placed
more emphasis on the potential for residual confounding and how it might affect the robustness
of the findings.
-While the study briefly mentions the use of Receiver Operating Characteristic (ROC) curves
to assess diagnostic accuracy, the nonlinear relationships between CTI and NAFLD/liver
fibrosis, especially through restricted cubic spline (RCS) analysis, could have been explored
in greater depth. Non-linear patterns might provide a more nuanced understanding of the
relationship between CTI and disease severity, and this aspect could have been discussed more
comprehensively.
-The finding that CTI shows higher diagnostic accuracy than TyG or hs-CRP alone is significant.
However, the discussion could expand on the specific implications of this result. For example,
is the improvement in diagnostic accuracy clinically meaningful? Does the increased AUC
translate into better outcomes for patients (e.g., earlier intervention, reduced risk of progression)?
Discussing the clinical relevance of the improved diagnostic accuracy would strengthen the
interpretation.
-The discussion mentions that transient elastography was used to assess liver fibrosis and
steatosis, but it also acknowledges that liver biopsy remains the gold standard. This is a valid
point, but the authors could expand on the limitations of using elastography as a surrogate for
biopsy-based assessments. It would be helpful to address how these findings might differ if liver
biopsy had been used or to explain how elastography's diagnostic accuracy compares to biopsy
in this context.