Review for 10.1186/s12876-024-03542-y (2025)

Title: Platelet Derived Growth Factor Receptor-# as a Non-Invasive Biomarker for Liver
Fibrosis Prediction in Diabetic Non-alcoholic Fatty Liver Disease
Version: 1 Date: 15 Oct 2024
Reviewer's report:
The study evaluated the utility of platelet-derived growth factor receptor # (PDGFR#) as a non-
invasive biomarker for predicting significant liver fibrosis in NAFLD patients, particularly those
with type 2 diabetes mellitus (T2DM), in comparison to the widely used FIB-4 score.
Comments
1. Comparison to FIB-4: One major limitation is the lack of extensive validation for PDGFR#
compared to FIB-4, which has been validated in numerous studies and populations. The findings
on PDGFR# are based on a relatively small cohort (90 NAFLD patients), and there is limited
external validation in different ethnicities, settings, or non-diabetic populations. The paper relied
heavily on magnetic resonance elastography (MRE) for liver stiffness measurements, which is
accurate but costly and not widely accessible. In contrast, FIB-4 is a widely available, low-
cost tool that can be used in primary care settings without the need for advanced technology.
One of the strengths of FIB-4 is its cost-effectiveness due to the use of common laboratory
parameters (AST, ALT, platelet count, and age). The present paper did not provide a cost-
effectiveness analysis comparing PDGFR# to FIB-4, especially since PDGFR# is measured
through enzyme-linked immunosorbent assays (ELISA), which may be more expensive and
less available in routine clinical practice. The submitted paper acknowledged that FIB-4 has
limitations, particularly when it falls into "indeterminate" ranges in about 30% of cases.
However, the manuscript did not offer a clear strategy for how PDGFR# could address this issue
in practice. Furthermore, the submitted paper did not address how PDGFR# correlated with long-
term clinical outcomes such as liver-related morbidity, mortality, or progression to cirrhosis or
hepatocellular carcinoma (HCC). In contrast, FIB-4 has been studied extensively in relation to
patient outcomes, providing clinicians with more actionable information regarding prognosis.
2. A previous recent study explored the use of PDGFR# as a positron emission tomography
(PET) imaging biomarker for assessing hepatic stellate cells (HSCs) activation, which is a key
process in liver fibrosis (Li Z, et al. Eur J Nucl Med Mol Imaging 2024;51:1530-1543). This
molecular imaging approach is highly effective for monitoring disease progression and treatment
response in liver fibrosis, providing real-time, high-contrast images of fibrosis. In contrast, the
submitted manuscript relied on traditional serum biomarkers measured via ELISA, which are
less dynamic and do not offer the spatial resolution or precision of imaging modalities like PET.
The study by Li Z, et al. also investigated PDGFR# in multiple liver fibrosis etiologies, including
viral hepatitis (HBV, HCV), which broadens the clinical settings.
3. The present study did not address the temporal variability of PDGFR# expression. The reliance
on single-timepoint serum measurements of PDGFR# may not accurately reflect the dynamic
nature of fibrosis and its response to treatment. This limits the biomarker’s clinical utility, as
PDGFR# levels might vary throughout disease progression or treatment.
4. The paper primarily focused on PDGFR# in isolation, without adequately comparing it to
other established biomarkers of liver fibrosis, such as #-SMA (smooth muscle actin), collagen,
and integrins. This creates a narrow view of PDGFR#’s role in fibrosis and does not offer
clinicians a comprehensive diagnostic panel to assess liver damage.
5. The authors should discuss how serum PDGFR# could complement or improve current non-
invasive diagnostic strategies, including liver stiffness measured by elastography or MRE, and
other non-invasive scores.
6. The paper did not address PDGFR#’s potential in therapeutic monitoring, even though
NAFLD patients are often treated with lifestyle modifications or medications aimed at reducing
fibrosis. The lack of discussion on how PDGFR# levels change with treatment limits its value
in longitudinal disease monitoring.