Review for 10.1186/s12876-025-04000-z (2025)

Title: Association between C-reactive protein to lymphocyte ratio and gallstones: A cross-
sectional study
Version: 0 Date: 19 Feb 2025
Reviewer's report:
Authors studied the relationship between inflammation (CLR) and gallstone prevalence, a topic
of clinical significance given the role of chronic inflammation in gallstone formation.
Given the increasing prevalence of gallstones worldwide, identifying novel inflammatory
markers could improve early risk assessment. uses data from 9,585 participants derived from the
National Health and Nutrition Examination Survey (NHANES), ensuring broad generalizability
to the U.S. population.
The use of NHANES data enhances reliability and external validity due to its standardized data
collection methods. However several issues noted that require revisions.
- Objectives are clear but the problem is not fully elucidated in the introduction. Gallstone
is associated with inflammatory burden (Journal of gastroenterology and hepatology, 2018,
33.11: 1920-1924.). CRP and CRP based marker CLR is associated with inflammation,
too. Inflammatory role of CRP has been confirmed in type 2 diabetes (Current Trends
in Endocrinology 2023;14: 11-23.), diabetic nephropathy (Primary Care Diabetes 2021;
15(6): 1071-1074. DOI: 10.1016/j.pcd.2021.08.015), thyroiditis (Precision Medical Sciences
2022;11:31-34. DOI: 10.1002/prm2.12065.), diabetic neuropathy (Biomol Biomed. 2024;24(5):
1380-1386. DOI: 10.17305/bb.2024.10426.) and hepatitis (Rev Assoc Med Bras 2022;68(6):
838-841. DOI: 10.1590/1806-9282.20220236.). Moreover, a recent work found association
between Covid-19 mortality and CRP based inflammatory markers (Cirugia y Cirujanos
2022;90(5):696-701. DOI: 10.24875/CIRU.22000124). In addition, low levels of lymphocyte
has been linked to various inflammatory conditions including diabetes mellitus (AIMS Medical
Science, 2024;11(1): 47–57. DOI: 10.3934/medsci.2024004), thyroiditis (Rev Assoc Med
Bras 2017; 63(12):1065-1068. DOI: 10.1590/1806-9282.63.12.1065), other thyroid conditions
(Ethiop J Health Dev.2021; 35(3):149-153), irritable bowel disease (Fam Med Prim Care Rev
2020; 22(2): 107–110. DOI: 10.5114/fmpcr.2020.95311. ), mortality in ICU (Hitit Medical
Journal. October 2024;6(3):367-378. doi:10.52827/hititmedj.1443663), and Covid-19 infection
(Rev Assoc Med Bras 2021;67(Suppl 1):1-2.   DOI: 10.1590/1806-9282.67.Suppl1.20200678.).
Since gallstone is associated with inflammation, too, it is rational to study CLR in this condition.
Improve the background data please.
- The study is cross-sectional, meaning it can only establish associations, not causality. Reverse
causation is possible, could gallstones themselves contribute to systemic inflammation, raising
CLR levels? Future prospective cohort studies are needed to clarify the temporal relationship
between CLR and gallstone formation. Discuss please.
- Authors attempted to adjust for multiple covariates, but they didn’t specify whether key
gallstone risk factors, such as dietary intake, hormonal status (estrogen exposure), or genetic
predisposition, were included in the models. Without adjusting for these, the CLR-gallstone
relationship may be confounded by other metabolic or inflammatory conditions.
- CLR showed promise as an inflammatory marker, however its diagnostic or predictive utility
for gallstones is unclear. Future research should compare CLR’s performance with traditional
inflammatory markers (e.g., CRP alone, neutrophil-to-lymphocyte ratio [NLR]) in predicting
gallstone risk.