C-Reactive Protein to High-Density Lipoprotein Cholesterol Ratio as an Inflammatory-Lipid Composite Marker: Predictive Value for Advanced Colorectal Adenoma

1. Introduction

Colorectal cancer (CRC) is the third most common malignant tumor globally and ranks second in cancer-related mortality, posing a serious challenge to public health systems worldwide. As a malignancy with high incidence and mortality rates globally, data from the Global Burden of Disease (GBD) study show that between 1990 and 2021, the number of new CRC cases worldwide increased to 2.1941 million, and the number of deaths rose to 1.0441 million [1]. Colorectal adenoma is the most important precancerous lesion of CRC, with approximately 85% of sporadic CRCs arising through the classical "adenoma–carcinoma" sequence [2]. Among these, advanced colorectal adenoma (ACA) carries a significantly elevated risk of malignant transformation; according to estimates cited by the MSD Manual, the annual cancerization rate of advanced adenomas is approximately 1%–5% [3]. Most colorectal adenomas have no typical clinical symptoms, and only a few present with occult blood in the stool; they are therefore easily overlooked, leading to delayed intervention such as endoscopic resection and missing the optimal window for cure before malignant transformation [4]. Consequently, identifying simple and efficient predictors of risk is of great practical significance for reducing the disease burden of colorectal cancer.

Previous studies have confirmed that the development of colorectal adenoma (CRA) results from the combined effects of genetic and environmental factors, with chronic inflammation and lipid metabolism disorders playing key roles [5,6]. Dyslipidemia, particularly decreased high-density lipoprotein cholesterol (HDL-C), may promote colorectal mucosal lesions by affecting reverse cholesterol transport and exacerbating oxidative stress [7,8]. C-reactive protein (CRP), a classic marker of systemic inflammation, has been shown to be associated with an increased risk of colorectal adenoma [9]; however, a single indicator is susceptible to confounding factors such as age, obesity, and smoking, leading to insufficient predictive specificity [10]. Inflammation-lipid composite indicators integrate key parameters of both pathological processes. The C-reactive protein (CRP)/high-density lipoprotein cholesterol (HDL-C) ratio (CRP/HDL-C), as a representative composite indicator, has demonstrated excellent risk prediction capability in metabolic syndrome, cardiovascular disease, and other fields [11,12]. Nevertheless, studies on its association with ACA remain scarce.

Based on this, the present study retrospectively analyzed the clinical data of subjects who underwent colonoscopy to investigate the strength of the association between CRP/HDL-C and ACA, evaluate its predictive value, and provide experimental evidence for early risk stratification and precise screening of ACA.

2. Materials and Methods

2.1. Study Population

Subjects with CRA who underwent colonoscopy for health checkups or gastrointestinal symptoms at the First Hospital of Lanzhou University from April 2024 to August 2025 were enrolled. Inclusion criteria included complete colonoscopy and histopathological data, as well as complete baseline and clinical indicator data. Exclusion criteria included confirmed colorectal cancer or other malignancies; concomitant inflammatory bowel disease, familial adenomatous polyposis, or other colonic adenomatosis syndromes; a Boston Bowel Preparation Scale score ≤6; acute infection, severe liver or kidney dysfunction, or other serious illnesses; use of medications that may affect the measured indicators (e.g., anti-inflammatory drugs, lipid-lowering agents) within the preceding three months; and incomplete clinical data.

2.2. Data Collection

The hospital’s electronic medical record system provided demographic information and biochemical variables of the subjects, including age, sex, smoking history, drinking history, history of hypertension, history of diabetes, height, and weight. All subjects provided peripheral venous blood samples after an overnight fast of at least 8 hours, and the samples were sent for testing within 4 hours of collection. After centrifugation to separate serum, the following measurements were performed: total cholesterol (TC), triglycerides (TG), HDL-C, low density lipoprotein cholesterol (LDL-C), blood urea nitrogen (BUN), creatinine (Cr), and uric acid (UA) were measured using an automated biochemical analyzer (Hitachi 7600, Tokyo, Japan); and CRP levels were measured using a Roche cobas 8000 automated analyzer (Roche Diagnostics GmbH, Mannheim, Germany) by immunoturbidimetry. The CRP/HDL-C ratio was calculated as CRP (mg/L) / HDL-C (mmol/L). Colonoscopy was performed by experienced gastroenterologists; any lesions detected during the examination were observed and, depending on the specific situation, removed by endoscopic resection, and the obtained tissue specimens were subjected to pathological diagnosis.

2.3. Diagnostic Criteria

The diagnosis of hypertension was based on the Chinese Guideline for the Management of Hypertension in the Elderly (2023) [13]; the diagnosis of diabetes was based on the American Diabetes Association (ADA) 2023 Standards of Care [14]. ACA was defined as an adenoma meeting one or more of the following criteria: (i) diameter >10 mm; (ii) villous or tubulovillous adenoma; or (iii) presence of high-grade dysplasia. For the characterization of multiple adenomas, the adenoma with the largest diameter or the highest pathological grade was used; if the adenoma with the largest diameter and that with the highest pathological grade were not the same lesion, the one with the higher pathological grade was selected [15].

2.4. Statistical Analysis

Data processing was performed using SPSS 29.0 (IBM SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± standard deviation or median (interquartile range). Differences in means and proportions between two independent groups were determined using the independent samples t-test (for normally distributed data), the Mann-Whitney U test (for skewed data), and the chi-square test (for categorical variables). Univariate logistic regression analysis was used to screen for potential risk factors for ACA. When CRP/HDL-C was treated as a continuous variable, binary logistic regression was used to analyze the overall prevalence risk of ACA across quartiles of CRP/HDL-C. Multivariate logistic regression models were used to analyze the independent association between CRP/HDL-C and CRA. The predictive performance of CRP/HDL-C and combined indicators was evaluated using receiver operating characteristic (ROC) curves, and the area under the curve (AUC), sensitivity, specificity, and optimal cutoff value were calculated. A two-sided P value < 0.05 was considered statistically significant.

3. Results

A total of 712 subjects were enrolled in this study, including 311 in the ACA group (63.44% male) and 401 in the non-ACA group (50.43% male). The clinical characteristics of the two groups are shown in Table 1. Compared with the non-ACA group, subjects in the ACA group were older, had higher BMI values, and a higher proportion of drinking history. In addition, the CRP/HDL-C level was significantly higher in the ACA group than in the control group (2.91±1.38 vs. 1.93±0.82; P<0.001); the ACA group had lower HDL-C levels (1.16±0.29 vs. 1.27±0.30; P<0.001) and higher CRP levels (3.23±1.35 vs. 2.33±0.84; P<0.001). No statistically significant differences were observed in the remaining indicators (P>0.05) (Table 1).

According to the quartiles of the baseline CRP/HDL-C ratio, patients were divided into four groups: quartile Q1: CRP/HDL-C < 1.599, n=178; Q2: 1.600–2.095, n=178; Q3: 2.096–2.710, n=178; Q4: >2.710, n=178. The incidence rates in the four groups were Q1: 14.6%; Q2: 33.7%; Q3: 59.5%; Q4: 70.2%. As the CRP/HDL-C quartile increased, the prevalence of ACA showed a significant upward trend (P<0.001). Then, using Q1 as the reference group, Q2, Q3, and Q4 were all significantly associated with ACA prevalence: Q2 group (OR=2.967, 95% CI: 1.501–5.862, P=0.002); Q3 group (OR=8.555, 95% CI: 4.372–16.739, P<0.001); Q4 group (OR=14.636, 95% CI: 7.324–29.245, P<0.001) (Table 2). After adjusting for age, sex, drinking history, BMI and other factors, compared with the CRP/HDL-C Q1 group, Q2 (OR=3.089, 95% CI: 1.474–6.473, P=0.003); Q3 (OR=7.204, 95% CI: 3.487–14.882, P<0.001); and Q4 (OR=13.773, 95% CI: 6.476–29.289, P<0.001) still significantly increased the risk of ACA prevalence.

Univariate logistic regression analysis showed that age, sex, drinking history, BMI, CRP, HDL-C, and CRP/HDL-C were associated with the occurrence of ACA. These variables were included in a multivariate logistic regression model. After adjusting for confounding factors, age (OR=1.062, 95% CI: 1.036–1.090, P<0.001), drinking history (OR=1.787, 95% CI: 1.075–2.972, P=0.025), BMI (OR=1.316, 95% CI: 1.196–1.449, P<0.001), and CRP/HDL-C (OR=2.464, 95% CI: 1.870–3.246, P<0.001) were identified as risk factors for ACA (Table 3). ROC curve analysis and AUC were performed for the above factors to evaluate the predictive value of each parameter for the risk of developing ACA. ROC curve analysis showed that the diagnostic value of the CRP/HDL-C ratio had an AUC of 0.799 (95% CI: 0.756–0.841), with an optimal cutoff value of 1.581, corresponding to a sensitivity of 82.8% and a specificity of 68.5%. The AUCs for other factors were: age: 0.628 (95% CI: 0.575–0.681); drinking history: 0.567 (95% CI: 0.512–0.623); BMI: 0.686 (95% CI: 0.636–0.737). Then, we combined the four AUC indicators for comprehensive assessment, and the AUC increased to 0.859 (95% CI: 0.824–0.895), indicating that the predictive performance was significantly better than that of any single indicator (Figure 1).

4. Discussion

After fully adjusting for the effects of various covariates, this study revealed a significant dose-response relationship between CRP/HDL-C and the risk of ACA. Specifically, the odds ratios for the second, third, and fourth quartiles of CRP/HDL-C were 3.089 (95% CI: 1.474–6.473), 7.204 (95% CI: 3.487–14.882), and 13.773 (95% CI: 6.476–29.289), respectively, suggesting that elevated CRP/HDL-C levels may have a threshold effect on the risk warning for CRA. Furthermore, when CRP/HDL-C was included as a continuous variable in the multivariate logistic regression model, it remained an independent risk factor for the occurrence of ACA (OR=2.464, 95% CI: 1.870–3.246, P<0.001). This study further confirmed that advancing age, history of alcohol consumption, and increased body mass index are independent influencing factors for the risk of advanced colorectal adenoma, a finding that is highly consistent with previous epidemiological studies [16,17,18].

Colorectal adenoma, as the most important precancerous lesion of CRC, typically requires 5 to 10 years to progress through the "adenoma–carcinoma" sequence to invasive carcinoma [19]. This relatively long progression period provides a critical window for early screening of the disease. However, the global screening coverage for colorectal adenoma remains low. A systematic review encompassing 45 countries showed that screening coverage varied widely across countries [20], ranging from 1.0% (China, 2020) to 79.4% (Finland, 2021). With the accelerating aging of the population, westernization of dietary patterns, increased intake of ultra-processed foods, and the continued rise in obesity rates, the disease burden of CRA is expected to further increase, posing a major challenge to public health [21,22,23,24]. Therefore, identifying simple and efficient risk prediction indicators has important clinical value for reducing the incidence and mortality of CRC.

CRP/HDL-C, as a composite biomarker integrating inflammatory response and lipid metabolism status, has the advantage of overcoming the limitations of a single indicator, reflecting both the chronic low-grade inflammation level represented by CRP and the lipid metabolism disorder status associated with HDL-C [11]. Xue et al. defined high-sensitivity C-reactive protein (hs-CRP)/HDL-C as a novel inflammation-lipid composite marker and indicated its potential for assessing metabolic risk. These evidences suggest that CRP/HDL-C can serve as an effective predictor of metabolic syndrome in clinical practice [25]. There is a complex interaction between lipid metabolism disorders and inflammatory pathways, which synergistically promote the malignant transformation of colorectal mucosa from normal tissue to adenoma and even adenocarcinoma [26]. Therefore, the CRP/HDL-C ratio more comprehensively reflects the metabolic-inflammatory balance than a single indicator and has potential clinical value in assessing the risk of ACA. Epidemiological evidence has established the role of dyslipidemia in the development of CRA [9]. The study by Coppola JA et al. showed that HDL-C levels are negatively correlated with the risk of CRA [27]. Recent experimental studies have confirmed that elevating HDL-C can induce anti-inflammatory reprogramming of macrophages through an ATF3-dependent pathway while enhancing intestinal barrier function, thereby reducing the severity of intestinal inflammation [28]. Therefore, lipid metabolism disorders, particularly decreased HDL-C, may promote the occurrence and development of colorectal mucosal lesions by amplifying oxidative stress and inflammatory responses [29]. Lee et al. reported that elevated serum CRP levels are independently associated with high-risk adenomas, suggesting that CRP plays an important role in the pathogenesis of ACA [30]. At the molecular mechanism level, CRP not only reflects inflammatory status but also has pro-inflammatory effects. CRP is converted into a highly pro-inflammatory monomeric subtype, mCRP, which is selectively enriched in the CRC tumor microenvironment [31,32], suggesting that CRP may act as an active local pro-inflammatory mediator rather than merely a systemic inflammatory marker. Consequently, elevated CRP levels may participate in the occurrence and development of ACA.

The innovations and advantages of this study are mainly reflected in two aspects. First, it is the first to focus on the association between CRP/HDL-C and ACA, clarifying the independent predictive value of this composite indicator and providing a new biomarker for risk stratification of CRA. Second, using large sample clinical data, multiple confounding factors were systematically adjusted, and various statistical methods such as dose-response analysis and ROC curve validation were employed; the correlation between the CRP/HDL-C ratio and ACA risk remained stable, ensuring the robustness and persuasiveness of the results. However, some limitations of this study should be objectively considered. First, the study design was a single-center cross-sectional study, which may have introduced selection bias, and caution is needed when extrapolating the results to other populations. Second, the CRP/HDL-C ratio was not compared with traditional tumor markers such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) or with screening methods such as fecal immunochemical testing (FIT), making it impossible to determine its incremental value in clinical screening. Third, the retrospective design cannot establish a causal relationship between the CRP/HDL-C ratio and ACA; future prospective cohort studies are needed to verify the temporal association between the two. Fourth, although common confounding factors were adjusted for, unmeasured factors such as dietary habits, physical activity, and gut microbiota may still contribute to residual confounding, which should be further controlled in subsequent studies.

5. Conclusions

This study confirmed through multidimensional analysis that the level of CRP/HDL-C is significantly positively correlated with the risk of ACA, with a clear dose-response relationship. The composite indicator CRP/HDL-C has good predictive efficacy for ACA and can be used as an auxiliary tool in clinical screening to predict the risk of ACA.