To the Editor: Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer death worldwide.[1] Colorectal adenoma (CRA) is a precursor lesion of CRC. Timely diagnosis and treatment of CRA are important for preventing the occurrence of CRC and improving prognosis. Considering the risks associated with invasive procedures and the high cost of colonoscopy, there is an urgent need to identify reliable non-invasive markers of colorectal neoplasms (CRNs).
The atherogenic index of plasma (AIP) is defined as the logarithmically transformed ratio of triglyceride (TG) to high-density lipoprotein-cholesterol (HDL-C) that is reported as a molar concentration (mmol/L).[2] The AIP is a simple and cost-effective marker for the prediction of various vascular diseases. However, research on AIP and CRNs has not focused specifically on the population with chronic hypertension. Therefore, we launched a case-control study aiming to investigate the role of AIP in predicting CRNs among patients with hypertension.
A total of 1196 hypertensive patients who underwent colonoscopy in the Department of Gastroenterology, Beijing Friendship Hospital Affiliated to Capital Medical University, from January 1, 2016 to December 31, 2019 were enrolled. The exclusion criteria were as follows: (1) insufficient clinical data; (2) malignant tumors of the digestive system (except for CRC), respiratory system, urogenital system, and nervous system; and (3) chylomicronemia or familial hypertriglyceridemia. Finally, 1064 patients were included in this study [Supplementary Figure 1, https://links.lww.com/CM9/B357]. The study was approved by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University (No. 2021-P3–138-01). The informed consent of patients has been obtained and the informed consent notice has been signed.
We collected clinical information of patients, including gender, age, body mass index (BMI), history of smoking and drinking, and family history of CRC. The lipid profile and fasting plasma glucose (FPG) levels in the morning on the day of colonoscopy were recorded. Stool samples were obtained for fecal occult blood testing (FOBT) within the day before colonoscopy. Colonoscopy and polypectomy were performed by experienced endoscopists. The histopathology of all colorectal polyps removed was evaluated by gastrointestinal pathologists. According to the endoscopic and postoperative pathological results, all participants were divided into the neoplasm group and the non-neoplastic group. The neoplasm group consisted of patients with CRA or CRC. The non-neoplastic group consisted of patients without any elevated lesions under endoscopy and patients with non-adenomatous colorectal polyps.
Normally distributed continuous variables were reported as mean ± standard deviation, and categorical variables were represented as frequencies and percentages. Student's t-test or one-way analysis of variance (ANOVA) for continuous variables and chi-squared or Fisher's exact test for categorical variables were used to compare the differences between groups. Univariate and multivariate logistic regression models were used to evaluate the associations between AIP and CRN in hypertensive patients. The restricted cubic splines with four knots fit the non-linear relationship between the AIP index and the risk of CRN in hypertensive patients. Multivariate binary logistic regression was used to construct diagnostic models for CRN in hypertensive patients. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to assess the diagnostic performance of the models. We randomly selected two-thirds of the total population as the training set and the remaining one-third as the test set. A nomogram was developed based on the AIP index and potential risk factors for CRN. Data analysis was performed using SPSS 25.0 (SPSS, Inc., Chicago, IL, USA) and R software (version 4.1.2, https://www.r-project.org/). A P value < 0.05 was considered statistically significant.
A total of 1064 participants (mean age: 62.2 ± 10.2 years; 60.15% men) were divided into a non-neoplastic group and a neoplastic group. Clinical and laboratory characteristics at baseline are presented in Supplementary Table 1, https://links.lww.com/CM9/B357. Compared with individuals in the non-neoplasm group, individuals in the neoplasm group tended to have lower HDL-C and higher AIP levels and were more likely to be elderly, male, smokers, FOBT positive, and with a family history of CRC (P < 0.05). Simultaneously, the total population were also divided into four groups based on the quartile of the AIP [Supplementary Table 2, https://links.lww.com/CM9/B357]. Compared with individuals in the lowest quartile group, individuals with a higher AIP tended to be younger, more obese with a higher BMI, current smokers, and male (P < 0.001). Individuals with a higher AIP had higher FPG, total cholesterol, TG, and low-density lipoprotein cholesterol (LDL-C) levels and lower HDL-C levels (P < 0.001).
Univariate logistic regression analysis showed that seven variables, namely gender, age, smoking, HDL-C, AIP, family history, and fecal occult blood, were significantly associated with CRNs (P < 0.05) [Supplementary Table 3, https://links.lww.com/CM9/B357]. In multivariate logistic regression analysis using these seven variables, male {odds ratio (OR) (95% confidence interval [CI]): 1.78 [1.24–2.49], P = 0.001}, age (OR [95% CI]: 1.07 [1.06–1.09], P < 0.001), AIP (OR [95% CI]: 3.09 [1.50–6.35], P = 0.002), family history of CRC (OR [95% CI]: 2.29 [1.15–4.57], P = 0.019), and positive fecal occult blood (OR [95% CI]: 2.20 [1.20–4.02], P = 0.010) were independent predictors of CRNs in the entire cohort.
As a continuous variable, a higher AIP was related to an increased risk of CRN (OR [95% CI]: 1.90 [1.17–3.10], P < 0.05) [Supplementary Table 4, https://links.lww.com/CM9/B357]. We also found that with the increase of other risk factors (age, gender, smoking status, family history, and FOBT), the association between AIP and CRN was still strong (P < 0.05). When using the lowest quartile of AIP as a reference, individuals in the third (OR [95% CI]: 1.57 [1.04–2.38]) and fourth (OR [95% CI]: 1.89 [1.24–2.89]) quartiles had a higher risk of CRN (P < 0.05) in the fully adjusted model. The restricted cubic spline plot revealed a clear linear relationship between the AIP and neoplasm in men, but the relationship was non-linear in women [Supplementary Figure 2, https://links.lww.com/CM9/B357].
According to the logistic regression results, the CRN prediction models were constructed based on the training set consisting of two-thirds of the entire population and validated in the test set consisting of the remaining one-third of the population. The diagnostic accuracies of these AIP-based models are shown in Supplementary Table 5, https://links.lww.com/CM9/B357. ROC curves were plotted to show the ability of the three models to identify CRNs [Supplementary Figure 3, https://links.lww.com/CM9/B357]. The AIP + age + gender + smoking status + family history + FOBT model had an overall sensitivity of 67.6% and a specificity of 64.7% with an AUC of 0.706 (95% CI: 0.663–0.749). Given that the fully adjusted model (Model 3) contained the most comprehensive risk factors and had the largest AUC, we chose Model 3 as the final risk-predicting CRN model and further constructed the corresponding nomogram [Figure 1].
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Figure 1: Nomogram for calculation of individual neoplasm probability. AIP: Atherogenic index of plasma; FOBT: fecal occult blood testing.
We demonstrated that the incidence of CRNs was higher among hypertensive patients with increasing AIP levels. As a parameter related to abnormal lipid and glucose metabolism, the AIP represents a good marker for cardiovascular events as well as the best predictor of hypertension and diabetes.[3] Compared with traditional single blood lipid indicators easily affected by various factors, the AIP can better reflect the comprehensive level of blood lipid metabolism in the body. Chronic inflammation caused by dyslipidemia may underlie the association between AIP and CRNs. Previous studies have shown that hypertriglyceridemia is an independent risk factor for colon adenomas. High serum TG levels can lead to intestinal endothelial cell damage, which causes an imbalance in local anti-inflammatory cytokines and proinflammatory cytokines. The AIP has also been suggested to be a surrogate of small, dense low-density lipoprotein cholesterol, which is an important signaling molecule involved in the induction of proinflammatory mediators and the reduction-inducing antioxidants.[4] Alterations in the state of equilibrium of inflammation-regulating cytokines further influence neoplasm development through various cytokine-mediated functions, such as cell proliferation, angiogenesis, and apoptosis.
Numerous studies have demonstrated that men have higher rates of colorectal polyps and carcinoma than women. Our findings are similar to those of previous studies. The reason for the higher proportion of CRNs in men may be related to estrogen. Estrogen may play a protective role in the prevention of neoplasm formation by activating estrogen receptors with anti-inflammatory and antitumor properties. Interestingly, a significant positive linear relationship was noted between the OR value of CRNs and AIP in men. However, the OR value of CRNs in women first increased and then decreased with increasing AIP.
The model we developed exhibited good sensitivity and accuracy, and the nomogram was further constructed based on the fully adjusted model. Our research results can guide the targeted screening of colonoscopy in hypertensive patients. This nomogram can increase the detection rate of neoplasms in this specific population, thereby ameliorating long-term prognosis.
In summary, we demonstrated that the AIP represents a biomarker that could be used to predict the risk of CRNs in patients with hypertension. However, due to the limited number of cases included in this study, the conclusion must be further confirmed in large-scale multicentre studies.
Funding
This work was funded by the National Natural Science Foundation of China (82070575), Beijing Municipal Administration of Hospitals’ Youth Program (QML20190104, QML20180102), Beijing Nova Program (Z201100006820147), and Beijing Municipal Science & Technology Commission (Z181100001718221).
Conflicts of interest
None.
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