Impact of age at appendectomy on development of HCC: A population-based cohort study

Volume 6, Issue 1, February 2021     |     PP. 32-44      |     PDF (161 K)    |     Pub. Date: January 24, 2021
DOI: 10.54647/cm32404    196 Downloads     3503 Views  


Yang-Ming Lee, Department of Medicine, Kaohsiung Medical University No. 100, Shih-Chuan 1st Road, Kaohsiung 807, Taiwan; Internal Medicine Research Center, Changhua Christian Hospital, Changhua, Taiwan
Chew-Teng Kor, Internal Medicine Research Center, Changhua Christian Hospital, Changhua, Taiwan

Aim: The etiology and epidemiology of hepatocellular carcinoma (HCC) has been linked to the entero-ecosystem, involving microbiome and entero-hepatic endocrine system. The human appendix, a microbial reservoir for repopulating the gastrointestinal tract, has currently been considered a crucial part of the immune system. Thus, appendectomy may change gut microbial structure and immune function, thereby increasing chronic liver diseases, including HCC. The object of this study is to investigate the association between appendectomy and the risk of HCC.
Methods: We analyzed a cohort of 12864 patients who underwent appendectomy between 1998 and 2013 based on the Taiwan National Health Insurance Program database. A comparison cohort of 51456 persons without appendectomy was selected randomly and matched by sex, age, comorbidities, and index year. To ensure reliability of the results, a sensitivity analysis using a propensity score–matched study was performed. We observed the subsequent development of HCC in both cohorts.
Results: Although the overall incidence of HCC in the appendectomy patients was 8.7% higher than that in the non-appendectomy patients, it was not statistically significant (95% confidence interval [CI], 0.833–1.417) after the adjustment of confounding factors. Multivariable regression analysis revealed that the adjusted hazard ratio (HR) of HCC was 1.870 for the appendectomy patients at age< 40 years (95% CI 1.012, 3.454) compared to the non-appendectomy patients. The incidence of HCC was higher within 5 years of post-appendectomy follow-up than for the non-appendectomy patients (HR of 1.771, 95% CI, 1.143–2.674). Age affected the association between appendectomy and HCC risk (Pinteraction = 0.0207); in contrast, sex did not influence the association between appendectomy and HCC risk (Pinteraction = 0.5726).
Conclusions: The results of our study suggest that appendectomy increases HCC risk, particularly when executed before middle age.

Appendectomy, hepatocellular carcinoma (HCC), enteric microbiota

Cite this paper
Yang-Ming Lee, Chew-Teng Kor, Impact of age at appendectomy on development of HCC: A population-based cohort study , SCIREA Journal of Clinical Medicine. Volume 6, Issue 1, February 2021 | PP. 32-44. 10.54647/cm32404


[ 1 ] Haque TR, Barritt ASt. Intestinal microbiota in liver disease. Best Pract Res Clin Gastroenterol. 2016;30(1):133-42.
[ 2 ] Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005;307(5717):1915-20.
[ 3 ] Giannelli V, Di Gregorio V, Iebba V, Giusto M, Schippa S, Merli M, et al. Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol. 2014;20(45):16795-810.
[ 4 ] Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology. 2014;146(6):1513-24.
[ 5 ] Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21(4):504-16.
[ 6 ] Yu LX, Yan HX, Liu Q, Yang W, Wu HP, Dong W, et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology. 2010;52(4):1322-33.
[ 7 ] Xie G, Wang X, Liu P, Wei R, Chen W, Rajani C, et al. Distinctly altered gut microbiota in the progression of liver disease. Oncotarget. 2016;7(15):19355-66.
[ 8 ] Randal Bollinger R, Barbas AS, Bush EL, Lin SS, Parker W. Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. Journal of theoretical biology. 2007;249(4):826-31.
[ 9 ] Berry RJ. The True Caecal Apex, or the Vermiform Appendix: Its Minute and Comparative Anatomy. Journal of anatomy and physiology. 1900;35(Pt 1):83-100.9.
[ 10 ] Spencer J, Finn T, Isaacson PG. Gut associated lymphoid tissue: a morphological and immunocytochemical study of the human appendix. Gut. 1985;26(7):672-9.
[ 11 ] Laurin M, Everett ML, Parker W. The cecal appendix: one more immune component with a function disturbed by post-industrial culture. Anatomical record (Hoboken, NJ : 2007). 2011;294(4):567-79.
[ 12 ] Wu SC, Chen WT, Muo CH, Ke TW, Fang CW, Sung FC. Association between appendectomy and subsequent colorectal cancer development: an Asian population study. PLoS One. 2015;10(2):e0118411.
[ 13 ] Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy is followed by increased risk of Crohn's disease. Gastroenterology. 2003;124(1):40-6.
[ 14 ] Liao KF, Lai SW, Lin CL, Chien SH. Appendectomy correlates with increased risk of pyogenic liver abscess: A population-based cohort study in Taiwan. Medicine (Baltimore). 2016;95(26):e4015.
[ 15 ] Tzeng YM, Kao LT, Kao S, Lin HC, Tsai MC, Lee CZ. An appendectomy increases the risk of rheumatoid arthritis: a five-year follow-up study. PLoS One. 2015;10(5):e0126816.
[ 16 ] Lai SW, Lin CL, Liao KF, Tsai SM. Increased risk of pulmonary tuberculosis among patients with appendectomy in Taiwan. Eur J Clin Microbiol Infect Dis. 2014;33(9):1573-7.
[ 17 ] Sanders NL, Bollinger RR, Lee R, Thomas S, Parker W. Appendectomy and Clostridium difficile colitis: relationships revealed by clinical observations and immunology. World J Gastroenterol. 2013;19(34):5607-14.
[ 18 ] Swidsinski A, Dorffel Y, Loening-Baucke V, Theissig F, Ruckert JC, Ismail M, et al. Acute appendicitis is characterised by local invasion with Fusobacterium nucleatum/necrophorum. Gut. 2011;60(1):34-40.
[ 19 ] Lee YM, Kor CT, Zhou D, Lai HC, Chang CC, Ma WL. Impact of age at appendectomy on development of type 2 diabetes: A population-based cohort study. PLoS One. 2018;13(10):e0205502.
[ 20 ] Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97-101.
[ 21 ] Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360(6391).
[ 22 ] Lee Y-M, Chang W-C, Lei F-J, Kor C-T, Lai H-C, Chen Y-L, et al. Early Exposure to Gut Microbiome Reduces Hepatocellular Carcinoma Risks in Mice. BioMed Research International. 2020;2020:9807379.
[ 23 ] Ren Z, Li A, Jiang J, Zhou L, Yu Z, Lu H, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut. 2019;68(6):1014-23.
[ 24 ] Ivanov, II, Honda K. Intestinal commensal microbes as immune modulators. Cell Host Microbe. 2012;12(4):496-508.
[ 25 ] Margini C, Dufour JF. The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int. 2016;36(3):317-24.