Non-alcoholic fatty liver disease may be a risk factor for liver metastasis after radical surgery for colorectal cancer: a retrospective study

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Hepatectomy for colorectal liver metastasis (CRLM) is the only potentially curative treatment for these patients. However, few metastatic CRC patients meet the criteria for this radical resection, and they have a low 5-year survival rate. Among those who undergo hepatectomy for CRLM, the recurrence rate is 60%. Thus, identifying risk factors for patients with CRLM is critical. One risk factor is non-alcoholic fatty liver disease (NAFLD), the incidence of which is increasing worldwide. NAFLD has become a main cause of chronic liver disease, and it is also an independent risk factor for CRC development. However, the effect of NAFLD on CRC liver metastasis after radical surgery remains unclear. The aim of this study was to retrospectively investigate the impact of NAFLD-associated hepatic fibrosis on liver metastasis after radical surgery for CRC. Methods We retrospectively analyzed data from 388 CRC patients with hepatic metastasis who underwent curative hepatectomy for CLRM at our hospital between April 2008 and March 2015. Data on each patient’s clinical results, surgical procedure, and postoperative course and their pathological and survival data were collected from our hospital records. The NAFLD fibrosis score (NFS) was also calculated, and patients were divided into two groups (NAFLD and non-NAFLD) on the basis of the NFS. Results Recurrence was observed in 83 (21.4%) of 388 patients after a mean follow-up 65.6 ± 15.1 months. Twenty-five patients had liver metastasis, and eight of them had NAFLD (8/45; 17.8%), while 17 of them (17/343; 5.0%) did not have NAFLD ( p = 0.004). Additionally, liver metastasis-free survival in NAFLD patients was significantly worse than that in non-NAFLD patients ( p < 0.001). We also showed that NAFLD and stage were independent risk factors for liver metastasis recurrence. Conclusions These results suggest that NAFLD may be a risk factor for liver metastasis in CRC patients who undergo curative surgery. non-alcoholic fatty liver disease colorectal cancer liver metastasis non-alcoholic fatty liver disease fibrosis score Figures Figure 1 Background Colorectal cancer (CRC) is the third most common cancer and has the second highest cancer-related mortality rate worldwide [ 1 ]. Although radical surgery and postoperative adjuvant therapy have evolved, approximately 30% of patients with CRC develop metachronous liver metastases, and the liver is the most common site for distant CRC metastasis [ 2 ]. Hepatectomy for colorectal liver metastasis (CRLM) is the only potentially curative treatment, but few patients meet the requirements for surgery, and people who unable to undergo radical resection have a low 5-year survival rate [ 3 , 4 ]. Additionally, if surgical treatment is possible, 60% of patients undergoing hepatectomy for CRLM will experience recurrence [ 5 ]. Therefore, studying the risk factors for CRLM is important and an effective strategy to improve the prognosis for CRC patients. Due to changes in lifestyle and dietary structure, the incidence of adult non-alcoholic fatty liver disease (NAFLD) is moderately increasing. The worldwide prevalence of NAFLD is 32.4% [ 6 ], and NAFLD has become a main cause of chronic liver disease [ 7 ]. Additionally, molecular and pathophysiological changes caused by NAFLD may change the epidemiology of primary and metastatic liver cancer [ 8 – 10 ]. While NAFLD has been reported to be an independent risk factor for CRC development [ 11 , 12 ], the effect of NAFLD on CRC liver metastasis after radical surgery is poorly documented. Given the expected increase in CRC and NAFLD patients and the medical costs associated with the number of patients who have both diseases, identifying the clinical link between CRLM and NAFLD is a critical requirement. Therefore, we retrospectively investigated the impact of NAFLD-associated hepatic fibrosis on liver metastasis after radical surgery for CRC. Methods Patients Newly diagnosed CRC patients with histologically confirmed stage I, II or III cancer who underwent curative surgical resection for CRC at our hospital between April 2008 and March 2015 were considered for inclusion in this study. Three hundred eighty-eight patients met the inclusion criteria and comprised the study population. We excluded patients who received preoperative treatment such as surgery; interventional treatment, chemotherapy, or radiotherapy for CRC; patients who underwent emergency surgery; patients with malignant tumors in other parts of the body; patients who were not followed-up for 5 years after surgery; those with appendix carcinoma; patients with insufficient data to allow preoperative calculation of the NAFLD fibrosis score (NFS); patients with known cirrhosis or chronic viral hepatitis; or those who underwent previous liver surgery, including patients with recurrence within 6 months after surgery, who are also called “simultaneous metastasis” patients. We also investigated 87 CRC patients other than these 388 with synchronous metastasis to only one organ at the initial diagnosis, 66 CRC patients with only synchronous liver metastases, and 21 CRC patients with synchronous metastasis only other than the liver. The study protocol was approved by the Institutional Review Committee from the Department of General and Digestive Surgery, Kanazawa Medical University Hospital, Ishikawa, Japan (No. I457), which followed the ethical criteria outlined in the Declaration of Helsinki. Informed written consent to participate was obtained from all participants. Clinical data We retrospectively collected patient data including clinical, surgical procedure, postoperative course, pathological data, and survival data from our hospital records. Clinical and laboratory data were collected before surgery. Clinical data included age, sex, overweight (body mass index [BMI] was calculated using the patient’s height and weight), and the presence of diabetes mellitus (DM; a fasting glucose level of 126 mg/dL or taking antidiabetic drugs). Laboratory evaluation included the following: NAFLD, hepatitis B surface antigen (HBsAg), neutrophil-to-lymphocyte ratio, and carcinoembryonic antigen (CEA) and carbohydrate antigen 19 − 9 (CA19-9) levels, which are tumor markers. The tumor site was classified as the right-sided colon (from the cecum to the transverse colon), left-sided colon (from the descending to rectosigmoid colon), or rectum. The CRC classification was in accordance with the guidelines from the American Joint Committee on Cancer Stage, 7th edition [ 13 ] using the detailed description from each patient’s pathology report. All metastasis diagnoses were independently confirmed using computed tomography (CT), magnetic resonance imaging, and positron emission tomography–CT by at least two radiologists. NAFLD fibrosis score The NFS was used to confirm the presence of a fibrotic liver. The score was calculated as follows: NFS = − 1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m 2 ) + 1.13 × IFG or DM (yes = 1, no = 0) + 0.99 × AST/ALT − 0.013 × platelet count (10 9 /L) − 0.66 × albumin level (g/dL). where BMI is body mass index, IFG is impaired fasting glucose, DM is diabetes mellitus, AST is aspartate aminotransferase, and ALT is alanine aminotransferase. NAFLD patients were grouped on the basis of a high NFS (> 0.676) and non-NAFLD patients were defined as having a low NFS (< 0.676), as reported previously [ 14 ]. Statistical analysis Continuous values were expressed as the mean ± standard deviation. Categorical variables are presented as the number of cases and percentages. Statistical analyses were performed using the two-sided Student’s t -test and the Mann–Whitney U -test for continuous data or Fisher’s exact test. A log-rank test was used to identify significant differences between curves. Patterns of recurrence consist of several distinct recurrence events attributed exclusively to one event, which is defined as a “competing risks situation.” Recurrences were therefore grouped as either liver-specific or extrahepatic. The cumulative incidence was estimated using each type of recurrence as a competing risk (liver-specific vs. extrahepatic). We included age, sex, BMI, and DM as an interaction analysis for all multivariate analyses. All statistical tests were two-sided. In all analyses, death before an event of interest was treated as a censoring event. All statistical analyses were performed using SPSS 28 (IBM Corp., Released 2021. IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY: IBM Corp.). Significance was defined as p < 0.05. Results Patients’ characteristics and intraoperative findings after curative surgical resection Three hundred eighty-eight CRC patients undergoing curative surgical resection during the study period were included in the analysis. The mean NFS was − 1.52 ± 1.72. Among the patients, 45 were diagnosed with NAFLD, and 343 patients did not have NAFLD (non-NAFLD group). Data from the two groups are summarized in Table 1 . Age, BMI, and the presence of DM were significantly higher in the NAFLD group compared with those in the non-NAFLD group, while the white blood cell level, CA19-9 level, and adjuvant chemotherapy use also showed a significant difference between two groups. Table 1 CRC patients’ perioperative clinical variables NAFLD (n = 45) non-NAFLD (n = 343) p -value Age (years) 76.1 ± 12.1 70.5 ± 11.0 < 0.001 Sex (male) 24 (53%) 189 (55%) 1.0 BMI (kg/m 2 ) 24.1 ± 4.0 22.5 ± 3.1 0.011 ASA-PS 1 or 2 3 or 4 43 (95%) 2 (5%) 333 (97%) 10 (3%) 0.491 Diabetes mellitus present 29 (64%) 61 (18%) < 0.001 Hepatitis B surface antigen present 5 (11%) 38 (11%) 1.0 Location right left rectum 15 (33%) 22 (49%) 8 (18%) 141 (41%) 141 (41%) 61 (18%) 0.785 CRP 0.57 ± 1.0 0.90 ± 2.8 0.692 WBC 5568 ± 1973 6264 ± 2802 0.022 NLR 3.69 ± 3.88 3.30 ± 4.31 0.953 LMR 4.70 ± 2.27 4.89 ± 2.32 0.588 CEA > 5.0 ng/mL 20 (44%) 109 (32%) 0.095 CA19-9 > 37 U/mL 15 (33%) 43 (13%) 0.001 Surgery time (mins) 219 ± 80.4 213 ± 86 0.297 Approach (laparotomy) 37 (82%) 274 (80%) 0.843 Complication ≤CD-II >CD-III 8 (18%) 5 (11%) 48 (14%) 19 (6%) 0.558 0.180 Pathological stage Stage I Stage II Stage III 7 (16%) 20 (44%) 18 (40%) 62 (18%) 122 (36%) 159 (46%) 0.634 Differentiation well or moderate poor or other 45 (100%) 0 (0%) 320 (93%) 23 (7%) 0.092 Vascular invasion present 24 (53%) 211 (62%) 0.331 Nerve invasion present 30 (67%) 238 (69%) 0.733 Adjuvant chemotherapy yes 18 (40%) 199 (58%) 0.005 CRC, colorectal cancer; NAFLD, non-alcoholic fatty liver disease; BMI, body mass index; ASA-PS, American Society of Anesthesiologists Physical Status; CRP, C-reactive protein; WBC, white blood cell; NLR, neutrophil-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19 − 9; CD, Clavien–Dindo Patient outcomes and their association with NAFLD The mean follow-up period was 65.6 ± 15.1 months. Recurrence was observed in 83 (21.4%) of 388 patients, among whom three were classified as stage I, 16 were stage II, and 64 were stage III. Twenty-five patients had liver metastasis, 18 patients had recurrence of liver metastasis alone, and seven patients had multiple organ recurrences including liver metastasis. Among the 25 patients with liver metastasis, eight of them were NAFLD patients (8/45; 17.8%), while 17 of 343 patients (5.0%) in the non-NAFLD group had liver metastasis recurrence, which was a significant difference ( p = 0.004). Among the 58 patients with recurrence in organs other than the liver, only three of 45 patients (6.7%) were in the NAFLD group and 55 of 343 (16.0%) were in the non-NAFLD group, which was not a significant difference in extrahepatic recurrence between the two groups ( p = 0.120) (Table 2 ). Table 2 CRC patients’ postoperative recurrence NAFLD (n = 45) non-NAFLD (n = 343) p -value Overall recurrence 11 (24%) 72 (21%) 0.567 All liver metastasis 8 (18%) 17 (5%) 0.004 All metastasis other than liver 3 (7%) 55 (16%) 0.120 CRC, colorectal cancer; NAFLD, non-alcoholic fatty liver disease Liver metastasis recurrence was investigated in the NAFLD and non-NAFLD groups. A Kaplan–Meier curve of hepatic metastasis-free survival showed the 5-year cumulative incidence of liver metastasis recurrence. Metastasis-free survival in the NAFLD group was significantly worse than that in the non-NAFLD group (NAFLD, 79.4%, 95% confidence interval [CI] 62.4–89.4 vs. non-NAFLD, 95.2%, 95% CI 92.2–97.1, p < 0.001). However, there was no significant difference in the 5-year cumulative incidence of recurrence-free survival (NAFLD, 72.6%, 95% CI 55.3–84.1 vs. non-NAFLD, 79.7%, 95% CI 74.9–83.8, p = 0.427) and extrahepatic metastasis-free survival (NAFLD, 93.0%, 95% CI 79.8–97.7 vs. non-NAFLD 84.5%, 95% CI 79.9–88.0, p = 0.160) between the two groups (Fig. 1 a–c). Univariate and multivariate analyses We performed univariate and multivariate analyses to evaluate the significance of NAFLD as an independent prognostic marker of liver metastasis ( Table 3 ) . Logistic regression analysis showed that NAFLD ( p = 0.013, hazard ratio [HR]: 3.239, 95% CI 1.282–8.187) and stage ( p = 0.009, HR: 3.059, 95% CI 1.330–7.035) were independent risk factors for liver metastasis recurrence. Table 3 Analysis of risk factors for liver metastasis Univariate analysis Multivariate analysis p -value HR 95% CI p -value CRP 0.492 WBC 0.718 NLR 0.093 LMR 0.016 0.796 0.613–1.034 0.088 T-cho 0.079 CHE 0.021 0.998 0.992–1.004 0.453 CEA > 5.0 0.125 CA19-9 > 37.0 0.081 NAFLD 0.004 3.239 1.282–8.187 0.013 Location 0.734 Stage 0.002 3.059 1.330–7.035 0.009 Complication 0.440 Differentiation 1.000 Vascular invasion 0.202 Nerve invasion 0.106 Adjuvant chemotherapy 0.659 CRP, C-reactive protein; WBC, white blood cell; NLR, neutrophil-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio; T-cho, total cholesterol; CHE, cholinesterase; CEA, carcinoembryonic antigen carbohydrate antigen; CA19-9, carbohydrate antigen 19 − 9; NAFLD, non-alcoholic fatty liver disease; HR, hazard ratio; CI, confidence interval Patient outcomes including synchronous distant metastasis at initial diagnosis In 66 patients with only synchronous liver metastasis, the mean NFS value was − 1.68 ± 2.04, and among them, 15 patients were diagnosed with NAFLD, while 51 of them did not have NAFLD. In 21 CRC patients with synchronous metastasis other than the liver, the mean NFS value was − 2.03 ± 1.75, and all 21 patients did not have NAFLD. When the 87 patients with synchronous metastasis were evaluated, the prevalence of synchronous liver metastases was 100% in the NAFLD group, which was also significantly higher than that in the non-NAFLD group (70.8%; p = 0.017) (Table 4 ). Additionally, considering all 475 cases examined this study, the prevalence of synchronous liver metastases was 25.0% in the NAFLD group, which was significantly higher than that in the non-NAFLD group (12.3%; p = 0.015) (Table 4 a). Table 4 Prevalence of NAFLD in patients with only synchronous liver metastasis of CRC at the initial diagnosis a NAFLD (n = 15) non-NAFLD (n = 72) p -value synchronous liver metastases 15 (100%) 51 (70.8%) 0.017 b NAFLD (n = 60) non-NAFLD (n = 415) synchronous liver metastases 15 (25%) 51 (12.3%) 0.01 CRC, colorectal cancer; NAFLD, non-alcoholic fatty liver disease Discussion In this retrospective analysis, our novel findings revealed that NAFLD significantly increased the risk of liver metastasis after curative CRC resection, while NAFLD had no influence on the development of extrahepatic recurrence. NAFLD was also associated with more synchronous liver metastases. These results suggest that changes in the liver microenvironment that are caused by a host-side factor such as NAFLD may affect the development of liver metastases. We considered this to be a significant finding in the increasing number of patients with CRC and NAFLD. Autopsy studies in the United States in the 1940s reported that cancer patients with cirrhosis were less likely to develop liver metastases than those without cirrhosis [ 15 ], suggesting the “seed-soil” hypothesis that metastatic tumor cells will migrate to an area where the local microenvironment is favorable [ 16 ]. Since then, however, most previous CRC research has focused on revealing how cancer cells promote metastasis, not the status of metastatic target organs. Additionally, a mouse CRC model involving injected colon cancer cells showed that reducing hepatic fibrosis also reduced hepatic metastasis development, suggesting that the microenvironment in a fatty liver may increase invasion and metastasis proliferation [ 17 ]. Since then, there have been some reports on the relationship between NAFLD and CRC liver metastasis [ 18 , 19 ]. Several studies showed a connection between NAFLD and CRC [ 20 , 21 ]. Patients with inflammatory bowel disease (IBD) are thought to have a higher risk of developing CRC than those without IBD, suggesting that inflammation also facilitates CRC initiation [ 22 , 23 ]. Similarly, NAFLD is often associated with a high degree of inflammation. A significant positive correlation was recently shown between high C-reactive protein (CRP) levels and increased mortality in CRC patients, and high CRP levels may be an indicator of metastasis [ 24 , 25 ]. This result is interesting because it suggests that NAFLD may promote CRC cell migration and colonization of livers in highly inflammatory NAFLD patients. A meta-analysis estimated that the overall global prevalence of NAFLD was 32.4% and that its prevalence has increased significantly over time, from 25.5% in or before 2005. NAFLD is a main cause of liver-related morbidity and mortality and represents a major current medical problem [ 6 ]. Additionally, NFS is easily calculated using age, BMI, hyperglycemia, the platelet count, albumin levels, and the AST/ALT ratio, and the NFS classifications are as follows: liver fibrosis low-risk group ( < − 1.455), intermediate risk group (− 1.455 to 0.674), and high-risk group (≥ 0.675) [ 26 ]. In this study, the prevalence of NAFLD was 12.6%, which slightly low, but we consider it to be within the acceptable range because the NFS selected in our study was 0.675 or higher, which is in the liver fibrosis high-risk group, as shown above. Easily obtainable NFS results are important because the incidence of CRC and NAFLD is increasing. In contrast to the results of our study, some reports indicated that CRC-derived liver metastases occur less frequently in patients with, compared with those without, NAFLD or chronic hepatitis virus infection [ 27 , 28 ]. However, the relationship between NAFLD and CRC liver metastasis requires further investigation. Our study has some limitations. First, the study sample size was small, there were inaccuracies in the serology-based scoring systems, and this was a retrospective study performed at a single institution. Second, the correlation between pathological examination of the liver environment when liver metastasis occurs and NAFLD remains to be fully clarified. This is because NFS is a surrogate parameter for preoperative examination of CRC and not the results of a more definitive histopathological tissue test such as liver biopsy. A larger cohort study is required to confirm our findings using a different dataset that does not contain the original population involved in our study. Conclusions Our results suggest that NAFLD may be a risk factor for liver metastasis in patients treated surgically for CRC. Further research will identify new therapeutic strategies for CRC and should also address NAFLD treatment. List of abbreviations CRC, colorectal cancer; CRLM, colorectal liver metastasis; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score; BMI, body mass index; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9 Declarations Ethics approval and consent to participate Written informed consent was obtained from all participants for publication of this study, and this study was approved by the institutional review committee from the department of General and Digestive Surgery, Kanazawa Medical University Hospital, Ishikawa, Japan (No. I457), which followed the ethical criteria outlined in the Declaration of Helsinki, and all patients gave their informed consent. Consent for publication Not applicable. Availability of data and material All data are available without restriction. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding No authors have direct or indirect commercial and financial incentives associated with publishing the article. Authors’ contributions Takashi M contributed to the study. Takashi M and Hiroyuki T designed this study. Takashi M, Yuki S, SM, Yuta S, Hozumi T, TN, RK, HN, AH, DK, YT, NN, Tomoharu M, HF, and NU collected and analyzed the data. Takashi M wrote the paper. Hiroyuki T revised the paper critically. All authors read and approved the final manuscript. Acknowledgements We thank Jodi Smith, PhD ELS, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript and helping to draft the abstract. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006;244:254–9. Eichler K, Dufas T, Hammerstingl R, Gruber-Rouh T, Vogl TJ, Zangos S. Hepatic arterial infusion with irinotecan in patients with liver metastases of colorectal cancer: results of an extended phase I study. Chemotherapy. 2013;59:66–73. Waisberg J, Ivankovics IG. Liver-first approach of colorectal cancer with synchronous hepatic metastases: a reverse strategy. World J Hepatol. 2015;7:1444–9. Wanebo HJ, Chu QD, Avradopoulos KA, Vezeridis MP. Current perspectives on repeat hepatic resection for colorectal carcinoma: a review. Surgery. 1996;119:361–71. Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7:851–61. Marchesini G, Babini M. Nonalcoholic fatty liver disease and the metabolic syndrome. Minerva Cardioangiol. 2006;54:229–39. van der Bilt JD, Kranenburg O, Borren A, van Hillegersberg R, Borel Rinkes IH. Ageing and hepatic steatosis exacerbate ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases. Ann Surg Oncol. 2008;15:1392–8. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76. Lv Y, Zhang HJ. Effect of non-alcoholic fatty liver disease on the risk of synchronous liver metastasis: analysis of 451 consecutive patients of newly diagnosed colorectal cancer. Front Oncol. 2020;10:251. Mantovani A, Dauriz M, Byrne CD, Lonardo A, Zoppini G, Bonora E, et al. Association between nonalcoholic fatty liver disease and colorectal tumours in asymptomatic adults undergoing screening colonoscopy: a systematic review and meta-analysis. Metabolism. 2018;87:1–12. Chen J, Bian DX, Zang SF, Yang ZX, Tian GY, Luo Y, et al. The association between nonalcoholic fatty liver disease and risk of colorectal adenoma and cancer incident and recurrence: a meta-analysis of observational studies. Expert Rev Gastroenterol Hepatol. 2019;13:385–95. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. France: Springer; 2010. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54. Lieber MM. The rare occurrence of metastatic carcinoma in the cirrhotic liver. Am J Med Sci. 1957;233:145–52. Langley RR, Fidler IJ. The seed and soil hypothesis revisited—the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer. 2011;128:2527–35. VanSaun MN, Lee IK, Washington MK, Matrisian L, Gorden DL. High fat diet induced hepatic steatosis establishes a permissive microenvironment for colorectal metastases and promotes primary dysplasia in a murine model. Am J Pathol. 2009;175:355–64. Wu K, Zhai MZ, Weltzien EK, Cespedes Feliciano EM, Meyerhardt JA, Giovannucci E, et al. Non-alcoholic fatty liver disease and colorectal cancer survival. Cancer Causes Control. 2019;30:165–8. Kondo T, Okabayashi K, Hasegawa H, Tsuruta M, Shigeta K, Kitagawa Y. The impact of hepatic fibrosis on the incidence of liver metastasis from colorectal cancer. Br J Cancer. 2016;115:34–9. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases Gut. 2017;66:1138–1153. Chakraborty D, Wang J. Nonalcoholic fatty liver disease and colorectal cancer: Correlation and missing links. Life Sci. 2020;262:118507. Rector RS, Thyfault JP, Wei Y, Ibdah JA. Non-alcoholic fatty liver disease and the metabolic syndrome: an update. World J Gastroenterol. 2008;14:185–92. Han YD, Al Bandar MH, Dulskas A, Cho MS, Hur H, Min BS, et al. Prognosis of ulcerative colitis colorectal cancer vs. sporadic colorectal cancer: propensity score matching analysis. BMC Surg. 2017;17:28. Hamilton TD, Leugner D, Kopciuk K, Dixon E, Sutherland FR, Bathe OF. Identification of prognostic inflammatory factors in colorectal liver metastases. BMC Cancer. 2014;14:542. Goyal A, Terry MB, Jin Z, Siegel AB. C-reactive protein and colorectal cancer mortality in U.S. adults. Cancer Epidemiol Biomarkers Prev. 2014;23:1609–18. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328–57. Murono K, Kitayama J, Tsuno NH, Nozawa H, Kawai K, Sunami E, et al. Hepatic steatosis is associated with lower incidence of liver metastasis from colorectal cancer. Int J Colorectal Dis. 2013;28:1065–72. Wang FS, Shao ZG, Zhang JL, Liu YF. Colorectal liver metastases rarely occur in patients with chronic hepatitis virus infection. Hepatogastroenterology. 2012;59:1390–2. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 19 Mar, 2024 Read the published version in Journal of Gastrointestinal Cancer → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2145570","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":144792330,"identity":"2b82d2d6-4f16-45fb-ab9b-3fe34579e782","order_by":0,"name":"Takashi Miyata","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIiWNgGAWjYPACiXp59vaDDxL/2QA5jI0HCChnbABqSTDsOZNs8IAtDSxAjBaGBIYbCWaSD9gOg4XwajGfkWP+4GeORR5jz4E0iQSe83Zr2w8DbamxicalReZGjmFj7zaJYnb2xsMWCRK3k7edSQRqOZaW24BDi4REjmED7zYJxsaeA4k3EgxuJ5sdAGphbDiMV0vjX6CWBqB6iYSEc8lm5x8S1tIMtCURqMVIIuHAATuzG4Rs4XlWOFt2m4QxOJATG5ITzG4AbUnA5xf25A0f326rkwNF5cOfDXb2ZufTHz74UGODUwuDQAIqPxGsMgFDHRLgP4DKt8eneBSMglEwCkYmAAAsEGn0U1KgYQAAAABJRU5ErkJggg==","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Miyata","suffix":""},{"id":144792331,"identity":"ea30897d-30c9-4960-b5b7-fbd7c67602d6","order_by":1,"name":"Yuki Shinden","email":"","orcid":"","institution":"Kanazawa Medical University 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hozumi","middleName":"","lastName":"Tamezawa","suffix":""},{"id":144792335,"identity":"ebaefd80-24b1-463b-9c52-0e0f25b5a54b","order_by":5,"name":"Taigo Nagayama","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Taigo","middleName":"","lastName":"Nagayama","suffix":""},{"id":144792336,"identity":"78acde8e-bb12-4a4d-854a-339eb9a698a0","order_by":6,"name":"Ryosuke Kin","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ryosuke","middleName":"","lastName":"Kin","suffix":""},{"id":144792337,"identity":"0a4c1630-107f-4dc3-8258-5232064d7b68","order_by":7,"name":"Hisashi Nishiki","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hisashi","middleName":"","lastName":"Nishiki","suffix":""},{"id":144792338,"identity":"bf77fcfb-f37b-418b-ae83-d467ba442bc4","order_by":8,"name":"Akifumi Hashimoto","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Akifumi","middleName":"","lastName":"Hashimoto","suffix":""},{"id":144792339,"identity":"c9860210-9d2e-4d84-b962-422ecd3c01e8","order_by":9,"name":"Daisuke Kaida","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Daisuke","middleName":"","lastName":"Kaida","suffix":""},{"id":144792340,"identity":"bc5eb637-0c04-482c-8107-a000c87ad693","order_by":10,"name":"Yasuto Tomita","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yasuto","middleName":"","lastName":"Tomita","suffix":""},{"id":144792341,"identity":"872e3edf-ef80-441a-9ff5-6160ce2e0cc8","order_by":11,"name":"Naohiko Nakamura","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Naohiko","middleName":"","lastName":"Nakamura","suffix":""},{"id":144792342,"identity":"68693ef9-4d6a-47b9-aeb9-9b027b353b27","order_by":12,"name":"Tomoharu Miyashita","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tomoharu","middleName":"","lastName":"Miyashita","suffix":""},{"id":144792343,"identity":"0cabadf3-d2a4-47da-9893-22efe42e99ba","order_by":13,"name":"Hideto Fujita","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hideto","middleName":"","lastName":"Fujita","suffix":""},{"id":144792344,"identity":"90d613d5-89e2-4c70-907e-0ecac0f42630","order_by":14,"name":"Nobuhiko Ueda","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nobuhiko","middleName":"","lastName":"Ueda","suffix":""},{"id":144792346,"identity":"6054ccb2-8755-48ff-859b-8fec12543370","order_by":15,"name":"Hiroyuki Takamura","email":"","orcid":"","institution":"Kanazawa Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Takamura","suffix":""}],"badges":[],"createdAt":"2022-10-08 14:59:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2145570/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2145570/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12029-024-01042-6","type":"published","date":"2024-03-19T15:21:10+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":27994838,"identity":"0c902bfa-1c85-4fbc-abf5-141ebdd04fe1","added_by":"auto","created_at":"2022-10-19 14:38:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":650012,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curve of RFS between the NAFLD and non-NAFLD groups by recurrence site.\u003c/p\u003e\n\u003cp\u003e(a) Hepatic metastasis-free survival curve. Patients in the NAFLD group had a significantly worse hepatic metastasis survival rate compared with that in the non-NAFLD group (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.001). (b) RFS curve. (c) Extrahepatic metastasis-free survival curve. The 5-year RFS rate and extrahepatic RFS rate in the NAFLD group were not significantly worse than those in the non-NAFLD group.\u003c/p\u003e\n\u003cp\u003eNAFLD, non-alcoholic fatty liver disease; RFS, recurrence-free survival\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2145570/v1/5134b97e37180361bb6955ec.jpg"},{"id":58673810,"identity":"d746d811-6185-4a18-85fc-203e476ca74e","added_by":"auto","created_at":"2024-06-19 15:21:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1299691,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2145570/v1/8c1c1915-c02d-4e31-925e-8a411a360311.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Non-alcoholic fatty liver disease may be a risk factor for liver metastasis after radical surgery for colorectal cancer: a retrospective study","fulltext":[{"header":"Background","content":"\u003cp\u003eColorectal cancer (CRC) is the third most common cancer and has the second highest cancer-related mortality rate worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although radical surgery and postoperative adjuvant therapy have evolved, approximately 30% of patients with CRC develop metachronous liver metastases, and the liver is the most common site for distant CRC metastasis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Hepatectomy for colorectal liver metastasis (CRLM) is the only potentially curative treatment, but few patients meet the requirements for surgery, and people who unable to undergo radical resection have a low 5-year survival rate [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Additionally, if surgical treatment is possible, 60% of patients undergoing hepatectomy for CRLM will experience recurrence [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Therefore, studying the risk factors for CRLM is important and an effective strategy to improve the prognosis for CRC patients.\u003c/p\u003e \u003cp\u003eDue to changes in lifestyle and dietary structure, the incidence of adult non-alcoholic fatty liver disease (NAFLD) is moderately increasing. The worldwide prevalence of NAFLD is 32.4% [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and NAFLD has become a main cause of chronic liver disease [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Additionally, molecular and pathophysiological changes caused by NAFLD may change the epidemiology of primary and metastatic liver cancer [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile NAFLD has been reported to be an independent risk factor for CRC development [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], the effect of NAFLD on CRC liver metastasis after radical surgery is poorly documented. Given the expected increase in CRC and NAFLD patients and the medical costs associated with the number of patients who have both diseases, identifying the clinical link between CRLM and NAFLD is a critical requirement. Therefore, we retrospectively investigated the impact of NAFLD-associated hepatic fibrosis on liver metastasis after radical surgery for CRC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eNewly diagnosed CRC patients with histologically confirmed stage I, II or III cancer who underwent curative surgical resection for CRC at our hospital between April 2008 and March 2015 were considered for inclusion in this study. Three hundred eighty-eight patients met the inclusion criteria and comprised the study population. We excluded patients who received preoperative treatment such as surgery; interventional treatment, chemotherapy, or radiotherapy for CRC; patients who underwent emergency surgery; patients with malignant tumors in other parts of the body; patients who were not followed-up for 5 years after surgery; those with appendix carcinoma; patients with insufficient data to allow preoperative calculation of the NAFLD fibrosis score (NFS); patients with known cirrhosis or chronic viral hepatitis; or those who underwent previous liver surgery, including patients with recurrence within 6 months after surgery, who are also called \u0026ldquo;simultaneous metastasis\u0026rdquo; patients. We also investigated 87 CRC patients other than these 388 with synchronous metastasis to only one organ at the initial diagnosis, 66 CRC patients with only synchronous liver metastases, and 21 CRC patients with synchronous metastasis only other than the liver. The study protocol was approved by the Institutional Review Committee from the Department of General and Digestive Surgery, Kanazawa Medical University Hospital, Ishikawa, Japan (No. I457), which followed the ethical criteria outlined in the Declaration of Helsinki. Informed written consent to participate was obtained from all participants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eClinical data\u003c/h2\u003e \u003cp\u003eWe retrospectively collected patient data including clinical, surgical procedure, postoperative course, pathological data, and survival data from our hospital records. Clinical and laboratory data were collected before surgery. Clinical data included age, sex, overweight (body mass index [BMI] was calculated using the patient\u0026rsquo;s height and weight), and the presence of diabetes mellitus (DM; a fasting glucose level of 126 mg/dL or taking antidiabetic drugs). Laboratory evaluation included the following: NAFLD, hepatitis B surface antigen (HBsAg), neutrophil-to-lymphocyte ratio, and carcinoembryonic antigen (CEA) and carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (CA19-9) levels, which are tumor markers. The tumor site was classified as the right-sided colon (from the cecum to the transverse colon), left-sided colon (from the descending to rectosigmoid colon), or rectum. The CRC classification was in accordance with the guidelines from the American Joint Committee on Cancer Stage, 7th edition [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] using the detailed description from each patient\u0026rsquo;s pathology report. All metastasis diagnoses were independently confirmed using computed tomography (CT), magnetic resonance imaging, and positron emission tomography\u0026ndash;CT by at least two radiologists.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eNAFLD fibrosis score\u003c/h2\u003e \u003cp\u003eThe NFS was used to confirm the presence of a fibrotic liver. The score was calculated as follows:\u003c/p\u003e \u003cp\u003e \u003cem\u003eNFS\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;1.675\u0026thinsp;+\u0026thinsp;0.037 \u0026times; age (years)\u0026thinsp;+\u0026thinsp;0.094 \u0026times; BMI (kg/m\u003c/em\u003e \u003csup\u003e \u003cem\u003e2\u003c/em\u003e \u003c/sup\u003e \u003cem\u003e)\u0026thinsp;+\u0026thinsp;1.13 \u0026times; IFG or DM (yes\u0026thinsp;=\u0026thinsp;1, no\u0026thinsp;=\u0026thinsp;0)\u0026thinsp;+\u0026thinsp;0.99 \u0026times; AST/ALT\u0026thinsp;\u0026minus;\u0026thinsp;0.013 \u0026times; platelet count (10\u003c/em\u003e \u003csup\u003e \u003cem\u003e9\u003c/em\u003e \u003c/sup\u003e \u003cem\u003e/L)\u0026thinsp;\u0026minus;\u0026thinsp;0.66 \u0026times; albumin level (g/dL).\u003c/em\u003e \u003c/p\u003e \u003cp\u003ewhere BMI is body mass index, IFG is impaired fasting glucose, DM is diabetes mellitus, AST is aspartate aminotransferase, and ALT is alanine aminotransferase.\u003c/p\u003e \u003cp\u003eNAFLD patients were grouped on the basis of a high NFS (\u0026gt;\u0026thinsp;0.676) and non-NAFLD patients were defined as having a low NFS (\u0026lt;\u0026thinsp;0.676), as reported previously [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous values were expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Categorical variables are presented as the number of cases and percentages. Statistical analyses were performed using the two-sided Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test and the Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e-test for continuous data or Fisher\u0026rsquo;s exact test. A log-rank test was used to identify significant differences between curves. Patterns of recurrence consist of several distinct recurrence events attributed exclusively to one event, which is defined as a \u0026ldquo;competing risks situation.\u0026rdquo; Recurrences were therefore grouped as either liver-specific or extrahepatic. The cumulative incidence was estimated using each type of recurrence as a competing risk (liver-specific vs. extrahepatic). We included age, sex, BMI, and DM as an interaction analysis for all multivariate analyses. All statistical tests were two-sided. In all analyses, death before an event of interest was treated as a censoring event. All statistical analyses were performed using SPSS 28 (IBM Corp., Released 2021. IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY: IBM Corp.). Significance was defined as \u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003ePatients\u0026rsquo; characteristics and intraoperative findings after curative surgical resection\u003c/h2\u003e\n\u003cp\u003eThree hundred eighty-eight CRC patients undergoing curative surgical resection during the study period were included in the analysis. The mean NFS was \u0026minus;\u0026thinsp;1.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.72. Among the patients, 45 were diagnosed with NAFLD, and 343 patients did not have NAFLD (non-NAFLD group). Data from the two groups are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Age, BMI, and the presence of DM were significantly higher in the NAFLD group compared with those in the non-NAFLD group, while the white blood cell level, CA19-9 level, and adjuvant chemotherapy use also showed a significant difference between two groups.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCRC patients\u0026rsquo; perioperative clinical variables\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNAFLD (n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003enon-NAFLD (n\u0026thinsp;=\u0026thinsp;343)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e76.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex (male)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (53%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e189 (55%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.011\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eASA-PS\u003c/p\u003e\n\u003cp\u003e1 or 2\u003c/p\u003e\n\u003cp\u003e3 or 4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43 (95%)\u003c/p\u003e\n\u003cp\u003e2 (5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e333 (97%)\u003c/p\u003e\n\u003cp\u003e10 (3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.491\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes mellitus present\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29 (64%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (18%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHepatitis B surface antigen present\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (11%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38 (11%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLocation\u003c/p\u003e\n\u003cp\u003eright\u003c/p\u003e\n\u003cp\u003eleft\u003c/p\u003e\n\u003cp\u003erectum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (33%)\u003c/p\u003e\n\u003cp\u003e22 (49%)\u003c/p\u003e\n\u003cp\u003e8 (18%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e141 (41%)\u003c/p\u003e\n\u003cp\u003e141 (41%)\u003c/p\u003e\n\u003cp\u003e61 (18%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.785\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCRP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.57\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.90\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.692\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWBC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5568\u0026thinsp;\u0026plusmn;\u0026thinsp;1973\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6264\u0026thinsp;\u0026plusmn;\u0026thinsp;2802\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.022\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNLR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.69\u0026thinsp;\u0026plusmn;\u0026thinsp;3.88\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.30\u0026thinsp;\u0026plusmn;\u0026thinsp;4.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.953\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLMR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.70\u0026thinsp;\u0026plusmn;\u0026thinsp;2.27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.89\u0026thinsp;\u0026plusmn;\u0026thinsp;2.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.588\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCEA\u0026thinsp;\u0026gt;\u0026thinsp;5.0 ng/mL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (44%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e109 (32%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.095\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCA19-9\u0026thinsp;\u0026gt;\u0026thinsp;37 U/mL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (33%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43 (13%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSurgery time (mins)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e219\u0026thinsp;\u0026plusmn;\u0026thinsp;80.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e213\u0026thinsp;\u0026plusmn;\u0026thinsp;86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.297\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApproach (laparotomy)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37 (82%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e274 (80%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.843\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eComplication\u003c/p\u003e\n\u003cp\u003e\u0026le;CD-II\u003c/p\u003e\n\u003cp\u003e\u0026gt;CD-III\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (18%)\u003c/p\u003e\n\u003cp\u003e5 (11%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48 (14%)\u003c/p\u003e\n\u003cp\u003e19 (6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.558\u003c/p\u003e\n\u003cp\u003e0.180\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePathological stage\u003c/p\u003e\n\u003cp\u003eStage I\u003c/p\u003e\n\u003cp\u003eStage II\u003c/p\u003e\n\u003cp\u003eStage III\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (16%)\u003c/p\u003e\n\u003cp\u003e20 (44%)\u003c/p\u003e\n\u003cp\u003e18 (40%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62 (18%)\u003c/p\u003e\n\u003cp\u003e122 (36%)\u003c/p\u003e\n\u003cp\u003e159 (46%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.634\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDifferentiation\u003c/p\u003e\n\u003cp\u003ewell or moderate\u003c/p\u003e\n\u003cp\u003epoor or other\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (100%)\u003c/p\u003e\n\u003cp\u003e0 (0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e320 (93%)\u003c/p\u003e\n\u003cp\u003e23 (7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.092\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVascular invasion present\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (53%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e211 (62%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.331\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNerve invasion present\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (67%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e238 (69%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.733\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdjuvant chemotherapy yes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (40%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e199 (58%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eCRC, colorectal cancer; NAFLD, non-alcoholic fatty liver disease; BMI, body mass index; ASA-PS, American Society of Anesthesiologists Physical Status; CRP, C-reactive protein; WBC, white blood cell; NLR, neutrophil-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9; CD, Clavien\u0026ndash;Dindo\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003ePatient outcomes and their association with NAFLD\u003c/h2\u003e\n\u003cp\u003eThe mean follow-up period was 65.6\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1 months. Recurrence was observed in 83 (21.4%) of 388 patients, among whom three were classified as stage I, 16 were stage II, and 64 were stage III. Twenty-five patients had liver metastasis, 18 patients had recurrence of liver metastasis alone, and seven patients had multiple organ recurrences including liver metastasis. Among the 25 patients with liver metastasis, eight of them were NAFLD patients (8/45; 17.8%), while 17 of 343 patients (5.0%) in the non-NAFLD group had liver metastasis recurrence, which was a significant difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). Among the 58 patients with recurrence in organs other than the liver, only three of 45 patients (6.7%) were in the NAFLD group and 55 of 343 (16.0%) were in the non-NAFLD group, which was not a significant difference in extrahepatic recurrence between the two groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.120) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCRC patients\u0026rsquo; postoperative recurrence\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNAFLD (n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003enon-NAFLD (n\u0026thinsp;=\u0026thinsp;343)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOverall recurrence\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (24%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72 (21%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.567\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAll liver metastasis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (18%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAll metastasis other than liver\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55 (16%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.120\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eCRC, colorectal cancer; NAFLD, non-alcoholic fatty liver disease\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLiver metastasis recurrence was investigated in the NAFLD and non-NAFLD groups. A Kaplan\u0026ndash;Meier curve of hepatic metastasis-free survival showed the 5-year cumulative incidence of liver metastasis recurrence. Metastasis-free survival in the NAFLD group was significantly worse than that in the non-NAFLD group (NAFLD, 79.4%, 95% confidence interval [CI] 62.4\u0026ndash;89.4 vs. non-NAFLD, 95.2%, 95% CI 92.2\u0026ndash;97.1,\u0026nbsp;\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, there was no significant difference in the 5-year cumulative incidence of recurrence-free survival (NAFLD, 72.6%, 95% CI 55.3\u0026ndash;84.1 vs. non-NAFLD, 79.7%, 95% CI 74.9\u0026ndash;83.8,\u0026nbsp;\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.427) and extrahepatic metastasis-free survival (NAFLD, 93.0%, 95% CI 79.8\u0026ndash;97.7 vs. non-NAFLD 84.5%, 95% CI 79.9\u0026ndash;88.0,\u0026nbsp;\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.160) between the two groups (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea\u0026ndash;c).\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eUnivariate and multivariate analyses\u003c/h2\u003e\n\u003cp\u003eWe performed univariate and multivariate analyses to evaluate the significance of NAFLD as an independent prognostic marker of liver metastasis \u003cstrong\u003e(\u003c/strong\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e. Logistic regression analysis showed that NAFLD (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013, hazard ratio [HR]: 3.239, 95% CI 1.282\u0026ndash;8.187) and stage (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, HR: 3.059, 95% CI 1.330\u0026ndash;7.035) were independent risk factors for liver metastasis recurrence.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAnalysis of risk factors for liver metastasis\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eUnivariate analysis\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eMultivariate analysis\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCRP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.492\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWBC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.718\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNLR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.093\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLMR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.016\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.796\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.613\u0026ndash;1.034\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.088\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT-cho\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.079\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCHE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.021\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.998\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.992\u0026ndash;1.004\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.453\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCEA\u0026thinsp;\u0026gt;\u0026thinsp;5.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.125\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCA19-9\u0026thinsp;\u0026gt;\u0026thinsp;37.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.081\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNAFLD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.239\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.282\u0026ndash;8.187\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.013\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLocation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.734\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStage\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.002\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.059\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.330\u0026ndash;7.035\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eComplication\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.440\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDifferentiation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVascular invasion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.202\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNerve invasion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.106\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdjuvant chemotherapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.659\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eCRP, C-reactive protein; WBC, white blood cell; NLR, neutrophil-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio; T-cho, total cholesterol; CHE, cholinesterase; CEA, carcinoembryonic antigen carbohydrate antigen; CA19-9, carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9; NAFLD, non-alcoholic fatty liver disease; HR, hazard ratio; CI, confidence interval\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003ePatient outcomes including synchronous distant metastasis at initial diagnosis\u003c/h2\u003e\n\u003cp\u003eIn 66 patients with only synchronous liver metastasis, the mean NFS value was \u0026minus;\u0026thinsp;1.68\u0026thinsp;\u0026plusmn;\u0026thinsp;2.04, and among them, 15 patients were diagnosed with NAFLD, while 51 of them did not have NAFLD. In 21 CRC patients with synchronous metastasis other than the liver, the mean NFS value was \u0026minus;\u0026thinsp;2.03\u0026thinsp;\u0026plusmn;\u0026thinsp;1.75, and all 21 patients did not have NAFLD. When the 87 patients with synchronous metastasis were evaluated, the prevalence of synchronous liver metastases was 100% in the NAFLD group, which was also significantly higher than that in the non-NAFLD group (70.8%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Additionally, considering all 475 cases examined this study, the prevalence of synchronous liver metastases was 25.0% in the NAFLD group, which was significantly higher than that in the non-NAFLD group (12.3%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePrevalence of NAFLD in patients with only synchronous liver metastasis of CRC at the initial diagnosis\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ea\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNAFLD (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003enon-NAFLD (n\u0026thinsp;=\u0026thinsp;72)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esynchronous liver metastases\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (100%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51 (70.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.017\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eb\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNAFLD (n\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003enon-NAFLD (n\u0026thinsp;=\u0026thinsp;415)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003esynchronous liver metastases\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (25%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51 (12.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eCRC, colorectal cancer; NAFLD, non-alcoholic fatty liver disease\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective analysis, our novel findings revealed that NAFLD significantly increased the risk of liver metastasis after curative CRC resection, while NAFLD had no influence on the development of extrahepatic recurrence. NAFLD was also associated with more synchronous liver metastases. These results suggest that changes in the liver microenvironment that are caused by a host-side factor such as NAFLD may affect the development of liver metastases. We considered this to be a significant finding in the increasing number of patients with CRC and NAFLD.\u003c/p\u003e \u003cp\u003eAutopsy studies in the United States in the 1940s reported that cancer patients with cirrhosis were less likely to develop liver metastases than those without cirrhosis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], suggesting the \u0026ldquo;seed-soil\u0026rdquo; hypothesis that metastatic tumor cells will migrate to an area where the local microenvironment is favorable [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Since then, however, most previous CRC research has focused on revealing how cancer cells promote metastasis, not the status of metastatic target organs. Additionally, a mouse CRC model involving injected colon cancer cells showed that reducing hepatic fibrosis also reduced hepatic metastasis development, suggesting that the microenvironment in a fatty liver may increase invasion and metastasis proliferation [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Since then, there have been some reports on the relationship between NAFLD and CRC liver metastasis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral studies showed a connection between NAFLD and CRC [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Patients with inflammatory bowel disease (IBD) are thought to have a higher risk of developing CRC than those without IBD, suggesting that inflammation also facilitates CRC initiation [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Similarly, NAFLD is often associated with a high degree of inflammation. A significant positive correlation was recently shown between high C-reactive protein (CRP) levels and increased mortality in CRC patients, and high CRP levels may be an indicator of metastasis [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This result is interesting because it suggests that NAFLD may promote CRC cell migration and colonization of livers in highly inflammatory NAFLD patients.\u003c/p\u003e \u003cp\u003eA meta-analysis estimated that the overall global prevalence of NAFLD was 32.4% and that its prevalence has increased significantly over time, from 25.5% in or before 2005. NAFLD is a main cause of liver-related morbidity and mortality and represents a major current medical problem [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Additionally, NFS is easily calculated using age, BMI, hyperglycemia, the platelet count, albumin levels, and the AST/ALT ratio, and the NFS classifications are as follows: liver fibrosis low-risk group (\u0026thinsp;\u0026lt;\u0026thinsp;\u0026minus;\u0026thinsp;1.455), intermediate risk group (\u0026minus;\u0026thinsp;1.455 to 0.674), and high-risk group (\u0026ge;\u0026thinsp;0.675) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In this study, the prevalence of NAFLD was 12.6%, which slightly low, but we consider it to be within the acceptable range because the NFS selected in our study was 0.675 or higher, which is in the liver fibrosis high-risk group, as shown above. Easily obtainable NFS results are important because the incidence of CRC and NAFLD is increasing. In contrast to the results of our study, some reports indicated that CRC-derived liver metastases occur less frequently in patients with, compared with those without, NAFLD or chronic hepatitis virus infection [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, the relationship between NAFLD and CRC liver metastasis requires further investigation.\u003c/p\u003e \u003cp\u003eOur study has some limitations. First, the study sample size was small, there were inaccuracies in the serology-based scoring systems, and this was a retrospective study performed at a single institution. Second, the correlation between pathological examination of the liver environment when liver metastasis occurs and NAFLD remains to be fully clarified. This is because NFS is a surrogate parameter for preoperative examination of CRC and not the results of a more definitive histopathological tissue test such as liver biopsy. A larger cohort study is required to confirm our findings using a different dataset that does not contain the original population involved in our study.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur results suggest that NAFLD may be a risk factor for liver metastasis in patients treated surgically for CRC. Further research will identify new therapeutic strategies for CRC and should also address NAFLD treatment.\u003c/p\u003e"},{"header":"List of abbreviations","content":"\u003cp\u003eCRC, colorectal cancer; CRLM, colorectal liver metastasis; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score; BMI, body mass index; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all participants for publication of this study, and this study was approved by the institutional review committee from the department of General and Digestive Surgery, Kanazawa Medical University Hospital, Ishikawa, Japan (No. I457), which followed the ethical criteria outlined in the Declaration of Helsinki, and all patients gave their informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and material\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are available without restriction. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo authors have direct or indirect commercial and financial incentives associated with publishing the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026rsquo; contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTakashi M contributed to the study. Takashi M and Hiroyuki T designed this study. Takashi M, Yuki S, SM, Yuta S, Hozumi T, TN, RK, HN, AH, DK, YT, NN, Tomoharu M, HF, and NU collected and analyzed the data. Takashi M wrote the paper. Hiroyuki T revised the paper critically. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Jodi Smith, PhD ELS, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript and helping to draft the abstract.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eManfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006;244:254\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEichler K, Dufas T, Hammerstingl R, Gruber-Rouh T, Vogl TJ, Zangos S. Hepatic arterial infusion with irinotecan in patients with liver metastases of colorectal cancer: results of an extended phase I study. Chemotherapy. 2013;59:66\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWaisberg J, Ivankovics IG. Liver-first approach of colorectal cancer with synchronous hepatic metastases: a reverse strategy. World J Hepatol. 2015;7:1444\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWanebo HJ, Chu QD, Avradopoulos KA, Vezeridis MP. Current perspectives on repeat hepatic resection for colorectal carcinoma: a review. Surgery. 1996;119:361\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7:851\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarchesini G, Babini M. Nonalcoholic fatty liver disease and the metabolic syndrome. Minerva Cardioangiol. 2006;54:229\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan der Bilt JD, Kranenburg O, Borren A, van Hillegersberg R, Borel Rinkes IH. Ageing and hepatic steatosis exacerbate ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases. Ann Surg Oncol. 2008;15:1392\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLv Y, Zhang HJ. Effect of non-alcoholic fatty liver disease on the risk of synchronous liver metastasis: analysis of 451 consecutive patients of newly diagnosed colorectal cancer. Front Oncol. 2020;10:251.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMantovani A, Dauriz M, Byrne CD, Lonardo A, Zoppini G, Bonora E, et al. Association between nonalcoholic fatty liver disease and colorectal tumours in asymptomatic adults undergoing screening colonoscopy: a systematic review and meta-analysis. Metabolism. 2018;87:1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen J, Bian DX, Zang SF, Yang ZX, Tian GY, Luo Y, et al. The association between nonalcoholic fatty liver disease and risk of colorectal adenoma and cancer incident and recurrence: a meta-analysis of observational studies. Expert Rev Gastroenterol Hepatol. 2019;13:385\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEdge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. France: Springer; 2010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAngulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLieber MM. The rare occurrence of metastatic carcinoma in the cirrhotic liver. Am J Med Sci. 1957;233:145\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLangley RR, Fidler IJ. The seed and soil hypothesis revisited\u0026mdash;the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer. 2011;128:2527\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVanSaun MN, Lee IK, Washington MK, Matrisian L, Gorden DL. High fat diet induced hepatic steatosis establishes a permissive microenvironment for colorectal metastases and promotes primary dysplasia in a murine model. Am J Pathol. 2009;175:355\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu K, Zhai MZ, Weltzien EK, Cespedes Feliciano EM, Meyerhardt JA, Giovannucci E, et al. Non-alcoholic fatty liver disease and colorectal cancer survival. Cancer Causes Control. 2019;30:165\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKondo T, Okabayashi K, Hasegawa H, Tsuruta M, Shigeta K, Kitagawa Y. The impact of hepatic fibrosis on the incidence of liver metastasis from colorectal cancer. Br J Cancer. 2016;115:34\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases Gut. 2017;66:1138\u0026ndash;1153.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChakraborty D, Wang J. Nonalcoholic fatty liver disease and colorectal cancer: Correlation and missing links. Life Sci. 2020;262:118507.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRector RS, Thyfault JP, Wei Y, Ibdah JA. Non-alcoholic fatty liver disease and the metabolic syndrome: an update. World J Gastroenterol. 2008;14:185\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan YD, Al Bandar MH, Dulskas A, Cho MS, Hur H, Min BS, et al. Prognosis of ulcerative colitis colorectal cancer vs. sporadic colorectal cancer: propensity score matching analysis. BMC Surg. 2017;17:28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHamilton TD, Leugner D, Kopciuk K, Dixon E, Sutherland FR, Bathe OF. Identification of prognostic inflammatory factors in colorectal liver metastases. BMC Cancer. 2014;14:542.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoyal A, Terry MB, Jin Z, Siegel AB. C-reactive protein and colorectal cancer mortality in U.S. adults. Cancer Epidemiol Biomarkers Prev. 2014;23:1609\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurono K, Kitayama J, Tsuno NH, Nozawa H, Kawai K, Sunami E, et al. Hepatic steatosis is associated with lower incidence of liver metastasis from colorectal cancer. Int J Colorectal Dis. 2013;28:1065\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang FS, Shao ZG, Zhang JL, Liu YF. Colorectal liver metastases rarely occur in patients with chronic hepatitis virus infection. Hepatogastroenterology. 2012;59:1390\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"non-alcoholic fatty liver disease, colorectal cancer, liver metastasis, non-alcoholic fatty liver disease fibrosis score","lastPublishedDoi":"10.21203/rs.3.rs-2145570/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2145570/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe liver is the most common site for distant colorectal cancer (CRC) metastasis, which develops in approximately one-third of CRC patients who undergo radical surgery. Hepatectomy for colorectal liver metastasis (CRLM) is the only potentially curative treatment for these patients. However, few metastatic CRC patients meet the criteria for this radical resection, and they have a low 5-year survival rate. Among those who undergo hepatectomy for CRLM, the recurrence rate is 60%. Thus, identifying risk factors for patients with CRLM is critical. One risk factor is non-alcoholic fatty liver disease (NAFLD), the incidence of which is increasing worldwide. NAFLD has become a main cause of chronic liver disease, and it is also an independent risk factor for CRC development. However, the effect of NAFLD on CRC liver metastasis after radical surgery remains unclear. The aim of this study was to retrospectively investigate the impact of NAFLD-associated hepatic fibrosis on liver metastasis after radical surgery for CRC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed data from 388 CRC patients with hepatic metastasis who underwent curative hepatectomy for CLRM at our hospital between April 2008 and March 2015. Data on each patient\u0026rsquo;s clinical results, surgical procedure, and postoperative course and their pathological and survival data were collected from our hospital records. The NAFLD fibrosis score (NFS) was also calculated, and patients were divided into two groups (NAFLD and non-NAFLD) on the basis of the NFS.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eRecurrence was observed in 83 (21.4%) of 388 patients after a mean follow-up 65.6\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1 months. Twenty-five patients had liver metastasis, and eight of them had NAFLD (8/45; 17.8%), while 17 of them (17/343; 5.0%) did not have NAFLD (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). Additionally, liver metastasis-free survival in NAFLD patients was significantly worse than that in non-NAFLD patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). We also showed that NAFLD and stage were independent risk factors for liver metastasis recurrence.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThese results suggest that NAFLD may be a risk factor for liver metastasis in CRC patients who undergo curative surgery.\u003c/p\u003e","manuscriptTitle":"Non-alcoholic fatty liver disease may be a risk factor for liver metastasis after radical surgery for colorectal cancer: a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-10-19 14:38:31","doi":"10.21203/rs.3.rs-2145570/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a90d8fe6-b0e0-4200-8986-5dacb2b9f5a1","owner":[],"postedDate":"October 19th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-06-19T15:21:10+00:00","versionOfRecord":{"articleIdentity":"rs-2145570","link":"https://doi.org/10.1007/s12029-024-01042-6","journal":{"identity":"journal-of-gastrointestinal-cancer","isVorOnly":false,"title":"Journal of Gastrointestinal Cancer"},"publishedOn":"2024-03-19 15:21:10","publishedOnDateReadable":"March 19th, 2024"},"versionCreatedAt":"2022-10-19 14:38:31","video":"","vorDoi":"10.1007/s12029-024-01042-6","vorDoiUrl":"https://doi.org/10.1007/s12029-024-01042-6","workflowStages":[]},"version":"v1","identity":"rs-2145570","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2145570","identity":"rs-2145570","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}