Review for 10.1186/s12876-025-03974-0 (2025)

Title: The HbA1c/HDL-C Ratio as a Screening indicator of NAFLD in U.S. Adults:A Cross-
sectional NHANES Analysis (2017–2020)
Version: 1 Date: 29 Mar 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-The study is cross-sectional, which limits the ability to infer causality. While the association
between HbA1c/HDL-C ratio and liver fibrosis/NAFLD is demonstrated, it is impossible to
conclude whether an elevated ratio causes NAFLD or liver fibrosis or is merely a marker of these
conditions. A prospective cohort study or randomized trial would be needed to better understand
causality.
-The exclusion of participants with hepatitis B or C infections is appropriate for isolating
NAFLD as the cause of liver disease. However, it could be argued that these exclusions limit
the external validity of the results. Specifically, in real-world clinical settings, people with both
NAFLD and viral hepatitis are common, and excluding them could affect the generalizability
of the findings.
-Although the HbA1c/HDL-C ratio is presented as a potential biomarker for liver disease, the
complexity of liver disease suggests that relying on a single biomarker may be overly simplistic.
There may be other important biomarkers or factors influencing the progression of NAFLD and
liver fibrosis that were not included in the analysis.
-The study relies on plasma HbA1c and HDL-C levels measured in a single instance. This might
not fully capture the dynamic nature of glucose and lipid metabolism over time. Given that
fluctuations in these markers can occur, repeated measurements or longitudinal data would likely
yield more accurate and reliable information.
-While the authors appropriately mention using multiple imputation techniques to handle
missing data, the handling of missing data could still be a limitation. There is a potential for bias
if the missing data is not missing at random, and the imputation process may not fully account
for all complexities.
-Although the study uses a nationally representative sample from the U.S., the findings may
not necessarily be generalizable to other populations with different risk profiles, such as those
from lower- or middle-income countries, or non-Caucasian ethnic groups with different disease
patterns and metabolic responses.
-Given that liver fibrosis and NAFLD progress over time, the study could be strengthened
by examining the long-term outcomes of those with varying HbA1c/HDL-C ratios. A
longitudinal study could better assess how early HbA1c/HDL-C ratio predicts future liver
disease progression.
-A key limitation of the study is the lack of a significant association between the HbA1c/HDL-C
ratio and liver fibrosis. While this is acknowledged in the discussion, it is somewhat downplayed.
The study’s primary aim was to assess the association with liver fibrosis, and the failure to find
a significant relationship here reduces the clinical applicability of the HbA1c/HDL-C ratio as
a marker for liver fibrosis severity. The authors could have explored this further by suggesting
potential reasons for the absence of a correlation and proposing future research directions to
address this gap.
-While the authors mention the use of Vibration-Controlled Transient Elastography (VCTE)
for liver assessment, they acknowledge that VCTE is not the gold standard for diagnosing
liver fibrosis, with liver biopsy remaining the definitive method. This could be a limitation of
the study, as VCTE might underestimate or overestimate the severity of liver fibrosis. More
discussion could be provided regarding the potential limitations of VCTE in assessing fibrosis
compared to liver biopsy, especially in the context of a cross-sectional study design.
-While the authors mention the roles of insulin resistance, lipid metabolism, and inflammation
in the development of NAFLD, they could have provided a more in-depth discussion of the
mechanisms behind the relationship between the HbA1c/HDL-C ratio and liver disease. For
example, a more detailed explanation of how changes in lipid metabolism influence liver fibrosis
or how oxidative stress might contribute to disease progression could add further context to the
study’s findings.