Association of Periodontitis and Hepatocellular Carcinoma: a Systematic Exploratory Review
Abstract
Introduction: Periodontitis is a highly prevalent oral disease characterized by chronic inflammation and microbial dysbiosis. Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide. Emerging evidence suggests a potential association between these diseases; however, current evidence remains scarce and fragmented. Objective: To systematically map and synthesize the available human evidence regarding the association between periodontitis and HCC.
Materials and Methods: A scoping review was conducted following the Joanna Briggs Institute guidelines. Electronic searches were performed across PubMed, Scopus, Web of Science, Cochrane library, and OVID databases. Eligibility was restricted to primary human studies.
Results: six studies met the inclusion criteria. Epidemiological findings regarding initiation risk were inconsistent. Conversely, clinical and microbiological studies converged on a plausible association of periodontitis with HCC progression and severity. Overall, HCC patients exhibited reduced oral immunity and microbial diversity, with enrichment of specific pathogens such as Fusobacterium nucleatum, Porphyromonas gingivalis and Cyanobacteria. Furthermore, periodontitis was clinically associated with advanced HCC staging, and increased serum reactive oxygen metabolites, indicating synergistic oxidative burden.
Conclusions: While epidemiological evidence on periodontitis as a risk factor for HCC remains conflicting, growing clinical research supports periodontitis may contribute to HCC progression and severity. Further longitudinal and mechanistic research are needed to clarify this relationship, explore its underlying mechanisms, and determine its implications for cancer prevention and multidisciplinary care.
Downloads
References
Meisel P, Heins G, Carlsson LE, Giebel J, John U, Schwahn C, Kocher T. Impact of genetic polymorphisms on the smoking-related risk of periodontal disease: the population-based study SHIP. Tob Induc Dis. 2003 Sep 15;1(3):197. https://doi.org/10.1186/1617-9625-1-3-197. PMID: 19570260; PMCID: PMC2671548.
Bascones Martínez A, Figuero Ruiz E. Las enfermedades periodontales como infec-ciones bacterianas. Avances en Periodoncia e Implantología Oral. 2005;17:147-56.
Carvajal P. Enfermedades periodontales como un problema de salud pública: el desafío del nivel primario de atención en salud. Rev Clin Periodoncia Implantol Rehabil Oral (PIRO). 2016;9:177-83.
Chapple ILC, Mealey BL, Van Dyke TE, Bartold PM, Dommisch H, Eickholz P, Geisinger ML, Genco RJ, Glogauer M, Goldstein M, Griffin TJ, Holmstrup P, Johnson GK, Kapila Y, Lang NP, Meyle J, Murakami S, Plemons J, Romito GA, Shapira L, Tatakis DN, Teughels W, Trombelli L, Walter C, Wimmer G, Xenoudi P, Yoshie H. Periodontal health and gingival diseases and conditions on an intact and a reduced periodontium: Consensus report of workgroup 1 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. J Periodontol. 2018;89 Suppl 1: S74-S84. https://doi.org/10.1002/JPER.17-0719. PMID: 29926944.
Papapanou PN, Sanz M, Buduneli N, Dietrich T, Feres M, Fine DH, Flemmig TF, Garcia R, Giannobile WV, Graziani F, Greenwell H, Herrera D, Kao RT, Kebschull M, Kinane DF, Kirkwood KL, Kocher T, Kornman KS, Kumar PS, Loos BG, Machtei E, Meng H, Mombelli A, Needleman I, Offenbacher S, Seymour GJ, Teles R, Tonetti MS. Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. J Periodontol. 2018;89 Suppl 1:S173-S182. https://doi.org/10.1002/JPER.17-0721. PMID: 29926951.
Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol. 2021;21(7):426-440. https://doi.org/10.1038/s41577-020-00488-6. Epub 2021 Jan 28. PMID: 33510490; PMCID: PMC7841384.
Michaud DS, Fu Z, Shi J, Chung M. Periodontal Disease, Tooth Loss, and Cancer Risk. Epidemiol Rev. 2017;39(1):49-58. https://doi.org/10.1093/epirev/mxx006. PMID: 28449041; PMCID: PMC5868279.
Tuominen H, Rautava J. Oral Microbita and Cancer Development. Pathobiology. 2021;8 (2):116-126. https://doi.org/10.1159/00510979. Epub 2020 Nov 11. PMID: 33176328.
Olsen I, Yilmaz Ö. Possible role of Porphyromonas gingivalis in orodigestive cancers. J Oral Microbiol. 2019;11(1):1563410. https://doi.org/10.1080/20002297.2018.1563410
Nagaraju GP, Dariya B, Kasa P, Peela S, El-Rayes BF. Epigenetics in hepatocellular carcinoma. Semin Cancer Biol. 2022;86(Pt 3): 622-632. https://doi.org/10.1016/j.semcancer.2021.07.017. Epub 2021 Jul 26. PMID: 343-24953.
Prieto Ortíz JE, Restrepo Gutiérrez JC. Epidemiología y factores de riesgo. Revista colom-biana de Gastroenterología. 2013;28:7-11.
Kirstein MM, Vogel A. The pathogenesis of hepatocellular carcinoma. Dig Dis. 2014; 32(5): 545-53. https://doi.org/10.1159/000360499. Epub 2014 Jul 14. PMID: 25034287.
Tabrizian P, Jibara G, Shrager B, Schwartz M, Roayaie S. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg. 2015;261(5):947-55. https://doi.org/10.1097/SLA.0000000000000710. PMID: 25010665.
Luan X, Zhou X, Fallah P, Pandya M, Lyu H, Foyle D, Burch D, Diekwisch TGH. MicroRNAs: Harbingers and shapers of periodontal inflammation. Semin Cell Dev Biol. 2022;124:85-98. https://doi.org/10.1016/j.semcdb.2021.05.030. Epub 2021 Jun 10. PMID: 34120836; PMCID: PMC9071582.
Luan X, Zhou X, Naqvi A, Francis M, Foyle D, Nares S, Diekwisch TGH. MicroRNAs and immunity in periodontal health and disease. Int J Oral Sci. 2018 Aug 6;10(3):24. https://doi.org/10.1038/s41368-018-0025-y. PMID: 300788 42; PMCID: PMC6080405.
Polizzi A, Alibrandi A, Lo Giudice A, Distefano A, Orlando L, Analazi AM, Pizzo G, Volti GL, Isola G. Impact of periodontal microRNAs associated with alveolar bone remodeling during orthodontic tooth movement: a randomized clinical trial. J Transl Med. 2024;22(1):1155. https://doi.org/10.1186/s12967-024-05933-x. PMID: 39736760; PMCID: PMC11684316.
Polizzi A, Nibali L, Tartaglia GM, Isola G. Impact of nonsurgical periodontal treatment on arterial stiffness outcomes related to endothelial dysfunction: A systematic review and meta-analysis. J Periodontol. 2025;96(4): 330-345. https://doi.org/10.1002/JPER.24-0422. Epub 2024 Nov 16. PMID: 39549247; PMCID: PMC 12062727.
Singh V, Sen A, Saini S, Dwivedi S, Agrawal R, Bansal A, Shekhar S. MicroRNA Significance in Cancer: An Updated Review on Diagnostic, Prognostic, and Therapeutic Perspectives. EJIFCC. 2024;35(4):265-284. PMID: 39810890; PMCID: PMC11726331.
Fan X, Song Z, Qin W, Yu T, Peng B, Shen Y. Potential Common Molecular Mechanisms Between Periodontitis and Hepatocellular Carcinoma: A Bioinformatic Analysis and Validation. Cancer Genomics Proteomics. 2023;20(6):602-616. https://doi.org/10.21873/cgp.20409. PMID: 37889061; PMCID: PMC10614 068.
Aromataris E, Lockwood C, Porritt K, Pilla B, Jordan Z, editors. JBI Manual for Evidence Synthesis. JBI; 2024. https://doi.org/10.46658/JBIMES-24-01
Tamaki N, Takaki A, Tomofuji T, Endo Y, Kasuyama K, Ekuni D, Yasunaka T, Yamamoto K, Morita M. Stage of hepatocellular carcinoma is associated with periodontitis. J Clin Periodontol. 2011;38(11):1015-20. https://doi.org/10.1111/j.1600-051X.2011.01777.x. Epub 2011 Sep 15. PMID: 22092473.
Jordao HW, McKenna G, McMenamin UC, Kunzmann AT, Murray LJ, Coleman HG. The association between self-reported poor oral health and gastrointestinal cancer risk in the UK Biobank: A large prospective cohort study. United European Gastroenterol J. 2019;7(9):1241-9.
Takuma R, Morozumi T, Yamamoto Y, Kobayashi T, Matsui T, Yoneda M, Kessoku T, Nogami A, Tamura M, Kamata Y, Sugihara S, Nomura Y, To M, Minabe M, Mitsudo K, Nakajima A, Komaki M. Association between Non-Alcoholic Steatohepatitis-Related Hepatocellular Carcinoma and Periodontopathic Bacteria: A Cross-Sectional Pilot Study. Applied Sciences. 2023;13(6):3839. https://doi.org/10.3390/app13063893
Matsui T, Morozumi T, Yamamoto Y, Kobayashi T, Takuma R, Yoneda M, Nogami A, Kessoku T, Tamura M, Nomura Y, Takahashi T, Kamata Y, Sugihara S, Arai K, Minabe M, Aoyama N, Mitsudo K, Nakajima A, Komaki M. Relationship of Metabolic Dysfunction-Associated Steato-hepatitis-Related Hepatocellular Carcinoma with Oral and Intestinal Microbiota: A Cross-Sectional Pilot Study. Medicina (Kaunas). 2024; 60(7):1150. https://doi.org/10.3390/medicina60071150. PM- ID: 39064580; PMCID: PMC 11279156.
Nwizu NN, Marshall JR, Moysich K, Genco RJ, Hovey KM, Mai X, LaMonte MJ, Freudenheim JL, Wactawski-Wende J. Periodontal Disease and Incident Cancer Risk among Postmenopausal Women: Results from the Women's Health Initiative Observational Cohort. Cancer Epidemiol Biomarkers Prev. 2017;26(8):1255-1265. https://doi.org/10.1158/1055-9965.EPI-17-0212. PMID: 28 765338; PMCID: PMC5551444.
Hernandez BY, Zhu X, Risch HA, Lu L, Ma X, Irwin ML, Lim JK, Taddei TH, Pawlish KS, Stroup AM, Brown R, Wang Z, Wong LL, Yu H. Oral Cyanobacteria and Hepatocellular Carcinoma. Cancer Epidemiol Biomarkers Prev. 2022 Jan;31(1):221-229. https://doi.org/10.1158/1055-9965.EPI-21-0804. Epub 2021 Oct 25. PMID: 34697061; PMCID: PMC8755591.
Holmstrup P, Damgaard C, Olsen I, Klinge B, Flyvbjerg A, Nielsen CH, Hansen PR. Comorbidity of periodontal disease: two sides of the same coin? An introduction for the clinician. J Oral Microbiol. 2017;9(1):1332710. https://doi.org/10.1080/20002297.2017.1332710. PMID: 287480 36; PMCID: PMC5508374.
Hajishengallis G. Interconnection of perio-dontal disease and comorbidities: Evidence, mechanisms, and implications. Periodontol 2000. 2022;89(1):9-18. https://doi.org/10.1111/prd.12430. Epub 2022 Mar 4. PMID: 35244969; PMCID: PMC9018559.
Sergeeva I, Meng Z, Ma Y. Periodontitis and Hepatocellular Carcinoma: A Two-Sample Men-delian Randomisation Study. Int Dent J. 2025 Apr;75(2):605-612. https://doi.org/10.1016/j.identj.2024.09.015. Epub 2024 Oct 2. PMID: 39358171; PMCID: PMC11976544.
Sakamoto S, Nagasaki A, Shrestha M, Shintani T, Watanabe A, Furusho H, Chayama K, Takata T, Miyauchi M. Porphyromonas gingivalis-odontogenic infection is the potential risk for progression of nonalcoholic steatohepatitis-related neoplastic nodule formation. Sci Rep. 2023 Jun 8;13(1):9350. https://doi.org/10.1038/s41598-023-36553-y. PMID: 37291206; PMCID: PMC10250332.
Ohno T, Kikuchi T, Suzuki Y, Goto R, Takeuchi D, Hayashi JI, Nishida E, Yamamoto G, Kondo S, Ono K, Nomoto S, Mitani A. Periodontitis promotes hepatocellular carcinoma in Stelic Animal model (STAM) mice. Sci Rep. 2024;14(1):17560. https://doi.org/10.1038/s41598-024-68422-7. PMID: 39080409; PMCID: PMC11289391.
Kang Y, Cai Y, Yang Y. The Gut Microbiome and Hepatocellular Carcinoma: Implications for Early Diagnostic Biomarkers and Novel Therapies. Liver Cancer. 2021 Dec 21;11(2):113-125. https://doi.org/10.1159/000521358. PMID: 35634424; PMCID: PMC9109080.
Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015;15(1):30-44. https://doi.org/10.1038/nri3785. PMID: 25534621; PMCID: PMC4276050.
Bao J, Li L, Zhang Y, Wang M, Chen F, Ge S, Chen B, Yan F. Periodontitis may induce gut microbiota dysbiosis via salivary microbiota. Int J Oral Sci. 2022;14(1):32. https://doi.org/10.1038/s41368-022-00183-3. PMID: 35732628; PMCID: PMC9217941.
Nishiwaki-Matsushima R, Ohta T, Nishiwaki S, Suganuma M, Kohyama K, Ishikawa T, Carmichael WW, Fujiki H. Liver tumor promo-tion by the cyanobacterial cyclic peptide toxin microcystin-LR. J Cancer Res Clin Oncol. 1992;118(6):420-4. https://doi.org/10.1007/BF01629424. PMID: 1618889; PMCID: PMC12200900.
Luo M, Li Q, Gu Q, Zhang C. Fusobacterium nucleatum: a novel regulator of antitumor immune checkpoint blockade therapy in colorectal cancer. Am J Cancer Res. 2024;14(8): 3962-3975. https://doi.org/10.62347/MYZA2640. PMID: 39267665; PMCID: PMC11387864.
Chen S, Zhang L, Li M, Zhang Y, Sun M, Wang L, Lin J, Cui Y, Chen Q, Jin C, Li X, Wang B, Chen H, Zhou T, Wang L, Hsu CH, Zhuo W. Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis. Nat Commun. 2022;13(1):1248. https://doi.org/10.1038/s41467-022-28913-5. PMID: 35273176; PMCID: PMC8913623.
Li J, Li L, Wang X, Xiao L. Porphyromonas gingivalis Inhibition of MicroRNA-205-5p Expression Modulates Proinflammatory Cytokines in Gingival Epithelial Cells. Biochem Genet. 2020;58(4):566-579. https://doi.org/10.1007/s10528-020-09957-y. Epub 2020 Apr 17. PMID: 3230 3947.
Ding LY, Liang LZ, Zhao YX, Yang YN, Liu F, Ding QR, Luo LJ. Porphyromonas gingivalis-derived lipopolysaccharide causes excessive hepatic lipid accumulation via activating NF-κB and JNK signaling pathways. Oral Dis. 2019;25(7):1789-1797. https://doi.org/10.1111/odi.13153. Epub 20 19 Jul 28. PMID: 31283861.
Liu G, Tang J, Zhou J, Dong M. Short-chain fatty acids play a positive role in colorectal cancer. Discov Oncol. 2024 Sep 10;15(1):425. https://doi.org/10.1007/s12672-024-01313-5. PMID: 392 56239; PMCID: PMC11387572.
Hou M, Yu QQ, Yang L, Zhao H, Jiang P, Qin L, Zhang Q. The role of short-chain fatty acid metabolism in the pathogenesis, diagnosis and treatment of cancer. Front Oncol. 2024;14:1451045. https://doi.org/10.3389/fonc.2024.1451045. PMID: 39435279; PMCID: PMC11 491288.
Fu Y, Chung FL. Oxidative stress and hepatocar-cinogenesis. Hepatoma Res. 2018;4:39. https://doi.org/10.20517/2394-5079.2018.29. Epub 2018 Aug 1. PMID: 30761356; PMCID: PMC6370311.
Tomofuji T, Irie K, Sanbe T, Azuma T, Ekuni D, Tamaki N, Yamamoto T, Morita M. Periodontitis and increase in circulating oxidative stress. Japanese Dental Science Review. 2009;45(1):46-51. https://doi.org/10.1016/j.jdsr.2008.12.002
Ahmadi-Motamayel F, Goodarzi MT, Jamshidi Z, Kebriaei R. Evaluation of Salivary and Serum Antioxidant and Oxidative Stress Statuses in Patients with Chronic Periodontitis: A Case-Control Study. Front Physiol. 2017 Mar 31;8:189. https://doi.org/10.3389/fphys.2017.00189. PMID: 28408887; PMCID: PMC5374205.
Sobaniec H, Sobaniec-Lotowska ME. MorphOlogical examinations of hard tissues of periodontium and evaluation of selected processes of lipid peroxidation in blood serum of rats in the course of experimental periodontitis. Med Sci Monit. 2000;6(5):875-81. PMID: 11208425.
Bains VK, Bains R. The antioxidant master glutathione and periodontal health. Dent Res J (Isfahan). 2015 Sep-Oct;12(5):389-405. https://doi.org/10.4103/1735-3327.166169. PMID: 26604952; PMCID: PMC4630702.
Pessoa LS, Pereira-da Silva FR, Alves EH, França LF, di Lenardo D, Carvalho JS, Martins VB, Sousa FB, Drumond KO, Medeiros JV, de Oliveira JS, Vasconcelos DF. One or two ligatures inducing periodontitis are sufficient to cause fatty liver. Med Oral Patol Oral Cir Bucal. 2018 May 1;23(3):e269-e276. https://doi.org/10.4317/medoral.22204. PMID: 29680842; PMCID: PMC5945241.
Tomofuji T, Ekuni D, Yamanaka R, Kusano H, Azuma T, Sanbe T, Tamaki N, Yamamoto T, Watanabe T, Miyauchi M, Takata T. Chronic administration of lipopolysaccharide and proteases induces periodontal inflammation and hepatic steatosis in rats. J Periodontol. 2007;78(10):1999-2006. https://doi.org/10.1902./jop.2007.070056. PMID: 17916001.
Publishing rights
The authors grant Journal of Oral Research rights to publish and disseminate the works selected and reviewed for the journal, both in their paper versions, electronic or any other medium, as well as their inclusion in catalogs, libraries, servers or virtual sites. The authors retain full author and publication rights to their articles.
