High levels of triglycerides, apolipoprotein B, and the number of colorectal polyps are risk factors for colorectal polyp recurrence after endoscopic resection: a retrospective study
Introduction
Colorectal cancer (CRC) is a common cancer, it is currently ranked third for incidence and first for mortality (1). Nearly 900,000 people die of CRC every year (2). Early diagnosis and treatment of CRC can substantially improve 5-year survival rates (3). The National Polyp Study demonstrated the incidence of CRC was reduced by 76–90% after the colon was cleared via colonoscopy (4). Prevention and screening remain priorities for countries with high CRC incidence and mortality (5). Ideally, colorectal polyps are detected and removed early, which can reduce the risk of CRC (6). However, polyps can recur after endoscopic removal in 22–69% of patients (7-10). The risk of polyp recurrence has been associated with several factors, including gender, age, obesity index, use of tobacco and alcohol, polyp characteristics, and diet (11). For example, recurrence risk is higher among patients who are obese (12), who have been smoking for longer than 35 years [odds ratio (OR): 2.88, 95% confidence interval (CI): 2.06 to 4.01, P=0.001] (13), or who drink alcohol (14).
Identifying non-invasive markers of polyp recurrence risk could help identify at-risk patients. Elevated triglyceride (TG) levels in serum are an independent risk factor for polyp recurrence in patients with advanced adenomas (15). Long-term lipid stimulation suppresses anti-tumor immune responses, facilitating colorectal tumorigenesis and distant metastasis, and suppresses immune infiltrating cell function in the tumor microenvironment, thereby accelerating tumor progression (16). On the other hand, several studies have suggested no association or a negative correlation between lipid levels in blood and risk of colorectal polyps or CRC (17-22). This may be a secondary outcome of changes in patient metabolism or nutrition, or there is detection bias and confounding bias. Therefore, more high-quality studies are needed to determine the association of blood lipids with colorectal polyp recurrence. This study had strict inclusion and exclusion criteria, the diagnosis was clear, all blood samples were tested by the same automatic analyzer in the Department of Laboratory Medicine of our hospital.
To help clarify these discrepancies, we retrospectively analyzed data from 357 patients at our hospital who underwent endoscopic resection of colorectal polyps in order to identify independent risk factors for colorectal polyp recurrence, including lipid levels in the blood. We present the following article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-491/rc).
Methods
Study design
We used a cohort study to elaborate on risk factors for postoperative recurrence of colorectal polyposis, in which we screened all 2,738 patients who underwent intestinal polypectomy for the first time between 1 January 2019 and 1 June 2020 in the Gastroenterology Department of Sichuan Provincial People’s Hospital. To be enrolled, patients had to be 65 years or younger, and had to undergo at least one colonoscopic follow-up after polypectomy. Patients were then divided into recurrence versus nonrelapse groups, and clinical imaging and laboratory data were collected. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Sichuan Provincial People’s Hospital (No. 237 of 2022). The ethics committee of Sichuan Provincial People’s Hospital waived the requirement for written informed consent since this was a retrospective study, it could not cause any adverse effects on included patients.
Patients
Patients were excluded if they were diagnosed with high-grade intraepithelial neoplasia or carcinoma based on histopathology; if they had hypertension, diabetes, thyroid disease, or severe cardiac or pulmonary dysfunction; or if they had a history of familial adenomatous polyposis, inflammatory bowel disease, or a malignant tumor at any site. They were also excluded if they took hypolipidemic drugs before or during follow-up.
Surgical procedure
All patients were placed on a liquid diet 24 hours before surgery, and bowel washing medication was taken to clean the bowel. The patients underwent general anesthesia enteroscopy surgery after fasting for 4 hours. The procedures were performed by physicians with experience in digestive endoscopy centers. Surgical modalities collectively included high-frequency electrocoagulation, argon plasma coagulation (APC), endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD). Finally, biopsy specimens were analyzed under the microscope by experienced pathologists.
Polyp classification and definition of polyp recurrence
Pathology type reports were obtained from the hospital pathology department. According to the World Health Organization (WHO) classification, polyps can be classified into 4 types: adenomatous polyps, inflammatory polyps, hyperplastic polyps, and hamartomatous polyps (23). High-grade intraepithelial neoplasia and carcinoma were excluded. Polyp recurrence was defined as the detection of 1 or more polyps at any time after polypectomy, irrespective of site (24).
Blood lipid analysis
Fasting peripheral venous blood was analyzed within 24 hours after admission for TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apolipoprotein B (apoB). Patients were diagnosed with dyslipidemia if their TC level was ≥5.2 mmol/L; TG ≥1.7 mmol/L; HDL-C <1.03 mmol/L; LDL-C ≥3.3 mmol/L; apoA1 <1.05 g/L; and apoB ≥1.4 g/L.
Follow-up and data collection
Patients had at least one follow-up colonoscopy postoperatively. The following baseline data were collected for all patients: gender, age, body mass index (BMI), history of smoking and alcohol consumption, as well as polyp size, number, and histopathological type. Continuous or cumulative smoking for 6 months or more in a lifetime was defined as a smoker. Drinkers were defined as greater than 20 g/day for men and 10 g/day for women. The data were collected through an electronic medical record system.
Bias
Patients with other underlying conditions were excluded according to the patient exclusion criteria, and other factors affecting the recurrence of intestinal polyps were avoided. In addition, to avoid selection bias, the researcher in charge of collecting the data was not aware of the grouping.
Study size
The minimum sample size was established based on previous reports that hypertriglyceridemia predicts polyp recurrence (15), and we defined 0.3 mmol/L as the minimum clinical value for polyp recurrence caused by hypertriglyceridemia. These considerations, combined with a medium effect size of 0.5, power of 0.8, and alpha error of 0.2, meant that at least 76 patients had to be enrolled in the study.
Statistical analysis
All analyses were performed using SPSS 26.0 (IBM Corp., Armonk, NY, USA). Normally distributed data were expressed as mean (standard deviation), otherwise, as median (interquartile range). Inter-group differences in continuous data (such as age, follow-up time, BMI, and blood lipid levels) were assessed for significance using the Student’s t-test, analysis of variance (ANOVA), or the Kruskal-Wallis test, as appropriate. Differences in categorical data were assessed using the chi-squared test. The risk of polyp recurrence is associated with several factors, including gender, age, obesity index, tobacco and alcohol use, polyp characteristics, and diet. Binary logistic regression was used to identify independent risk factors for polyp recurrence. Differences of P<0.05 were considered statistically significant and P<0.05 was two-sided. For random missing data were handled by direct deletion.
Results
Of the 2,738 patients screened, 1,212 were excluded because no follow-up enteroscopy data were available, 437 were lost to follow-up, and 732 met the exclusion criteria. Finally, 357 patients were included in the study, of whom 225 (63%) were men and 161 (45%) experienced recurrence during follow-up, which lasted a mean of 12 months (Figure 1). Relatively small percentages of patients reported smoking (22%) or drinking (21%) (Table 1).
Table 1
| Reason | N |
|---|---|
| No follow-up enteroscopy data | 1,212 |
| Lost to follow-up | 437 |
| Met exclusion criteria | 732 |
N, number.
Among the 357 included cases, the follow-up time was 12.0±3.0 months in the recurrence group and 12.0±0.75 months in the non-recurrence group. Patients who experienced recurrence or not were similar in gender distribution, mean age, mean BMI, and smoking or alcohol consumption (Table 2). Similarly, the 2 groups of patients did not differ significantly in the size or histopathological type of polyps (Table 3). In contrast, the number of polyps was statistically significantly different between the two groups.
Table 2
| Characteristic | Recurrence (n=161) | No recurrence (n=196) | P value* |
|---|---|---|---|
| Gender | 0.097 | ||
| Male | 109 | 116 | |
| Female | 52 | 80 | |
| Age, years | 50.2 (12.0) | 48.8 (12.0) | 0.121 |
| Follow-up, months | 12.0 (3.0) | 12.0 (0.75) | 0.411 |
| History of smoking | 42 | 37 | 0.103 |
| History of drinking | 37 | 39 | 0.479 |
| BMI, kg/m2 | 23.1 (4.0) | 23.0 (3.9) | 0.946 |
Values are n or mean (standard deviation). *, based on Student’s t-test or the Mann-Whitney test (continuous variables) or Fisher’s exact test (categorical variables). n, number; BMI, body mass index.
Table 3
| Characteristics | Recurrence (n=161) | No recurrence (n=196) | P value* |
|---|---|---|---|
| Polyp type, n | 0.081 | ||
| Hyperplastic | 85 | 96 | |
| Inflammatory | 10 | 10 | |
| Tubular adenoma | 20 | 12 | |
| Hamartomatous | 1 | 4 | |
| N/A | 45 | 74 | |
| Polyp size, n | 0.793 | ||
| <10 mm | 126 | 157 | |
| 10–19 mm | 24 | 24 | |
| ≥20 mm | 8 | 9 | |
| N/A | 3 | 6 | |
| Polyp number, n | <0.001 | ||
| 1 | 33 | 75 | |
| 2 | 30 | 45 | |
| ≥3 | 96 | 72 | |
| N/A | 2 | 4 |
*, based on Student’s t-test or the Mann-Whitney test (continuous variables) or Fisher’s exact test (categorical variables). n, number; N/A, unclear.
In addition, TGs (1.54±0.95 vs. 1.25±1.01 mmol/L, P=0.036) and apoB (0.87±0.26 vs. 0.79±0.16 g/L, P=0.001) were significantly different in both the recurrence and non-recurrence groups. (Table 4). The 2 groups of patients did not differ significantly in levels of TC (4.97±0.96 vs. 4.60±1.00 mmol/L, P=0.895), HDL-C (1.27±0.42 vs. 1.29±0.44 mmol/L, P=0.762) or LDL-C (2.30±0.97 vs. 2.17±0.78 mmol/L, P=0.146), or apoA1 (1.33±0.35 vs. 1.32±0.32 g/L, P=0.741).
Table 4
| Lipid species | Recurrence (n=161) | No recurrence (n=196) | P value* |
|---|---|---|---|
| TG, mmol/L | 1.54 (0.95) | 1.25 (1.01) | 0.036 |
| TC, mmol/L | 4.97 (0.96) | 4.60 (1.00) | 0.895 |
| HDL-C, mmol/L | 1.27 (0.42) | 1.29 (0.44) | 0.762 |
| LDL-C, mmol/L | 2.30 (0.97) | 2.17 (0.78) | 0.146 |
| Apolipoprotein A1, g/L | 1.33 (0.35) | 1.32 (0.32) | 0.741 |
| Apolipoprotein B, g/L | 0.87 (0.26) | 0.79 (0.16) | 0.001 |
Values are mean (standard deviation). *, based on Student’s t-test or the Mann-Whitney test (continuous variables) or Fisher’s exact test (categorical variables). n, number; TG, triglycerides; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
Binary logistic regression identified the following independent risk factors for polyp recurrence (Table 5): high TG (OR: 1.763, 95% CI: 1.003 to 3.098, P=0.049), high apoB (OR: 5.438, 95% CI: 1.411 to 20.961, P=0.014), and the presence of at least 3 polyps (OR: 2.540, 95% CI: 1.649 to 3.911, P<0.001).
Table 5
| Parameters | OR (95% CI) | P value |
|---|---|---|
| Gender | 0.724 (0.446–1.175) | 0.191 |
| Age | 1.017 (0.994–1.042) | 0.152 |
| Follow-up time | 0.978 (0.925–1.033) | 0.420 |
| Smoking | 0.669 (0.329–1.363) | 0.268 |
| Drinking | 1.308 (0.642–2.664) | 0.459 |
| BMI ≥25 kg/m² | 1.002 (0.631–1.59) | 0.995 |
| Polyp size ≥20 mm | 1.073 (0.404–2.848) | 0.888 |
| Polyp number ≥3 | 2.540 (1.649–3.911) | <0.001 |
| TG (≥1.7 mmol/L) | 1.763 (1.003–3.098) | 0.049 |
| TC (≥5.2 mmol/L) | 1.639 (0.923–2.908) | 0.092 |
| HDL-C | 1.309 (0.577–2.971) | 0.519 |
| LDL-C | 0.980 (0.926–1.037) | 0.485 |
| Apolipoprotein A1 | 1.300 (0.382–4.432) | 0.675 |
| Apolipoprotein B | 5.438 (1.411–20.961) | 0.014 |
*, based on binary regression analysis. OR, odds ratio; CI, confidence interval; BMI, body mass index; TG, triglyceride; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
Discussion
Here, we provide evidence that hypertriglyceridemia, high apoB, and the number of polyps are independent risk factors for polyp recurrence. To our knowledge, this is the first report linking high apoB to polyp recurrence. A recent meta-analysis confirmed that elevated TG is associated with the development of colorectal polyps, which is consistent with our study (25). Our findings are consistent with studies suggesting that hypertriglyceridemia promotes the formation of reactive oxygen species that damage DNA and thereby initiate CRC (26), and that this and other abnormalities of lipid metabolism suppress anti-tumor immune responses (16).
Early polyp detection and removal are effective for preventing CRC. Adenomatous polyps can progress to malignancy via the adenoma-carcinoma pathway (27,28), while hyperplastic polyps can progress to malignancy via the serrated or microsatellite instability pathway (29). A hamartoma adenoma-carcinoma sequence has also been suggested (30). Therefore, identifying patient characteristics associated with the risk of polyp recurrence may help reduce the risk of CRC.
Studies have explored potential correlations between blood lipid indices and the risk of CRC, but they have been unable to separate potential associations from other dietary or metabolic confounders (17,18,31). Similarly, studies have failed to unambiguously identify associations between dyslipidemia and the risk of colorectal polyps (32,33). Our study provides strong evidence linking hypertriglyceridemia to polyp recurrence. At least 3 mechanisms may underlie this association. One is that hypertriglyceridemia causes hyperinsulinemia and insulin resistance, which drives the proliferation of normal and cancer cells in the large intestine (34). Another mechanism is that dyslipidemia creates a tumorigenic environment by increasing levels of interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α) and other inflammatory cytokines (35). Finally, Liu et al. suggested that TG may affect polyp recurrence by increasing the proliferative capacity of cancer stem cells or stimulating signaling pathways that promote cell invasion (15).
Our data also link high levels of apoB to polyp recurrence. ApoB is a structural component of chylomicrons as well as lipoproteins of various densities (36), so it plays an important role in atherogenesis (36,37). Given one study linking elevated LDL-C to the formation of colorectal polyps (38), we suggest that apoB may influence polyp recurrence by affecting the metabolism of LDL-C. Elevated levels of LDL-C have been linked to oxidative stress and inflammatory responses in the intestine (35,39). By reducing levels of LDL-C in serum, statins may inhibit polyp formation (40-42), which may help explain their ability to slow the growth of several types of colorectal tumors (43-46). Future studies should explore whether other hypolipidemic agents such as fibrates can inhibit polyp formation and CRC.
Our findings should be interpreted with caution given that our patient sample was relatively small and came from a single center. The numbers of polyps differed between cases that experienced recurrence or not, which may have confounded our analyses. Despite these limitations, our data suggest that administering hypolipidemic drugs to individuals with hyperlipidemia may help reduce the risk of polyp recurrence and thereby CRC.
Conclusions
High levels of TGs, apoB, and the number of colorectal polyps are risk factors for colorectal polyp recurrence after endoscopic resection. Therefore, for patients at high risk of polyp recurrence, we recommend aggressive control of TG and apoB levels.
Acknowledgments
Funding: This work was supported by Key Research and Development Projects of Sichuan Science and Technology Department (grant Nos. 22ZDYF1691 and 2018FZ0062).
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-491/rc
Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-491/dss
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-491/coif). All authors report that this work was supported by Key Research and Development Projects of Sichuan Science and Technology Department (grant Nos. 22ZDYF1691 and 2018FZ0062). The authors have no other conflicts of interest to declare.
Ethical Statement:
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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(English Language Editor: J. Jones)
