Review for 10.1186/s12876-025-04057-w (2025)

Title: Association of serum lactate dehydrogenase levels with non-alcoholic fatty liver disease
and advanced hepatic fibrosis in the United States: a cross-sectional study using NHANES data
from 2007 to 2018
Version: 1 Date: 16 Feb 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-Although the enzymatic rate method used to measure LDH is mentioned, additional details
about the procedure (e.g., equipment used, calibration standards, or sensitivity) would enhance
the transparency and reproducibility of the study.
-The use of tertiles to categorize LDH levels may be appropriate in this case, but it may also
oversimplify the data. The cut-off points for the tertiles are based on specific quartile values
(e.g., Quartile 1 for NAFLD: 3.829–4.796). It would be helpful to explain whether these quartiles
were chosen based on clinical relevance or statistical convenience, as the clinical meaning of
these categories could be debated.
-While the study specifically excludes individuals with excessive alcohol consumption, the
definition of "non-alcoholic fatty liver disease" can sometimes be controversial due to the
complex interplay between diet, lifestyle factors, and alcohol use. It would be useful to further
clarify the criteria used to define "non-alcoholic" in this context, especially as alcohol-related
liver disease can overlap with NAFLD in some cases.
-Despite the comprehensive list of covariates, residual confounding may still affect the findings.
For example, diet quality, medication use, and family history of liver disease are not mentioned
as covariates, even though they could play significant roles in the development and progression
of NAFLD/ AHF. Acknowledging these potential confounders could improve the interpretation
of the results.
-While the study examines the relationship between LDH levels and liver disease, it does not
explore the underlying biological mechanisms that may explain these associations. For instance,
how might increased LDH levels contribute to liver damage, or why does LDH correlate with
advanced fibrosis? A discussion of the potential molecular pathways involved would provide
greater depth to the study’s findings.
-The study notes that while elevated LDH levels increased the odds of having NAFLD in Model
1, the association was not statistically significant in Model 3. This is an interesting finding, but
the authors should further clarify why this might be the case. Specifically, a discussion on the
possible confounders or the limitations of Model 3 in adjusting for other variables that could
explain the attenuation of the association would be useful.
-The authors mention a non-linear relationship between LDH levels and AHF based on the
generalized additive model (GAM). While this is a valuable observation, the discussion on the
specific nature of this non-linearity could be expanded. For example, providing more details on
the thresholds or inflection points at which the risk of AHF significantly increases would make
the finding more actionable.
-While the study includes a wide range of participants, it could benefit from a deeper exploration
of potential confounders that may have influenced the association between LDH and NAFLD/
AHF. Factors such as ethnicity, comorbidities (e.g., diabetes, hypertension), and lifestyle factors
(e.g., physical activity levels, diet) could have a significant impact. A more in-depth analysis of
these factors would strengthen the study's conclusions.
- Although the study provides valuable findings, there could be more emphasis on the potential
clinical applications of these results. For instance, what should clinicians do with elevated LDH
levels in individuals with suspected NAFLD or AHF? Are there specific recommendations for
monitoring LDH levels as part of routine clinical practice, or is further research needed to
validate this approach?