Published May 26, 2024

Arnd Scholten  


Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver condition characterized by excess fat accumulation in the liver in the absence of significant alcohol consumption. While NAFLD itself is generally considered benign, it can progress to more severe forms such as non-alcoholic steatohepatitis, which can ultimately lead to liver cirrhosis and hepatocarcinoma, a type of liver cancer. The risk of developing hepatocarcinoma in individuals with NAFLD is considerably higher than in the general population. Factors such as obesity, diabetes, insulin resistance, and inflammation contribute to the development and progression of NAFLD and its subsequent transformation into hepatocarcinoma. Regular monitoring, lifestyle modifications, and timely treatment of co-existing conditions are crucial in mitigating the risk of hepatocarcinoma among patients with NAFLD. Further research into the underlying mechanisms linking NAFLD to hepatocarcinoma is essential for developing effective preventive strategies and treatments for this increasingly prevalent condition.



Non-Alcoholic Fatty Liver Disease, Hepatocarcinoma, Liver Cirrhosis, Risk Factors, Preventive Strategies

1. Pouwels S, Sakran N, Graham Y, Leal A, Pintar T, Yang W, Kassir R, Singhal R, Mahawar K, Ramnarain D. Non-alcoholic fatty liver disease (NAFLD): A review of pathophysiology, clinical management and effects of weight loss. BMC Endocr Disord 2022; 22(1):63. DOI: https://doi.org/10.1186/s12902-022-00980-1

2. Chrysavgis L, Giannakodimos I, Diamantopoulou P, Cholongitas E. Non-alcoholic fatty liver disease and hepatocellular carcinoma: Clinical challenges of an intriguing link. World J Gastroenterol 2022; 28(3):310-331. DOI: https://doi.org/10.3748/wjg.v28.i3.310

3. Shengir M, Krishnamurthy S, Ghali P, Deschenes M, Wong P, Chen T, Sebastiani G. Prevalence and predictors of nonalcoholic fatty liver disease in South Asian women with polycystic ovary syndrome. World J Gastroenterol 2020; 26(44):7046-7060. DOI: https://doi.org/10.3748/wjg.v26.i44.7046

4. Carter JK, Friedman SL. Hepatic stellate cell-immune interactions in NASH. Front Endocrinol (Lausanne) 2022; 13:867940. DOI: https://doi.org/10.3389/fendo.2022.867940

5. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: Incidence and risk factors. Gastroenterology 2004; 127(5 Suppl 1):S35-S50. DOI: https://doi.org/10.1053/j.gastro.2004.09.014

6. Huh Y, Cho YJ, Nam GE. Recent epidemiology and risk factors of nonalcoholic fatty liver disease. J Obes Metab Syndr 2022; 31(1):17-27. DOI: https://doi.org/10.7570/jomes22021

7. Lazarus JV, Mark HE, Anstee QM, Arab JP, Batterham RL, Castera L, Cortez-Pinto H, Crespo J, Cusi K, Dirac MA, Francque S, George J, Hagström H, Huang TT, Ismail MH, Kautz A, Sarin SK, Loomba R, Miller V, Newsome PN, Ninburg M, Ocama P, Ratziu V, Rinella M, Romero D, Romero-Gómez M, Schattenberg JM, Tsochatzis EA, Valenti L, Wong VW, Yilmaz Y, Younossi ZM, Zelber-Sagi S; NAFLD Consensus Consortium. Advancing the global public health agenda for NAFLD: A consensus statement. Nat Rev Gastroenterol Hepatol 2022; 19(1):60-78. DOI: https://doi.org/10.1038/s41575-021-00523-4

8. Riazi K, Swain MG, Congly SE, Kaplan GG, Shaheen AA. Race and ethnicity in non-alcoholic fatty liver disease (NAFLD): A narrative review. Nutrients 2022; 14(21):4556. DOI: https://doi.org/10.3390/nu14214556

9. Fitzpatrick E, Dhawan A. Childhood and adolescent nonalcoholic fatty liver disease: Is it different from adults? J Clin Exp Hepatol 2019; 9(6):716-722. DOI: https://doi.org/10.1016/j.jceh.2019.05.005

10. Chung GE, Han K, Lee KN, Cho EJ, Bae JH, Yang SY, Yu SJ, Choi SH, Yim JY, Heo NJ. Combined effects of chronic kidney disease and nonalcoholic fatty liver disease on the risk of cardiovascular disease in patients with diabetes. Biomedicines 2022; 10(6):1245. DOI: https://doi.org/10.3390/biomedicines10061245

11. Riazi K, Swain MG, Congly SE, Kaplan GG, Shaheen AA. Race and ethnicity in non-alcoholic fatty liver disease (NAFLD): A narrative review. Nutrients 2022; 14(21):4556. DOI: https://doi.org/10.3390/nu14214556

12. Iqbal U, Perumpail BJ, Akhtar D, Kim D, Ahmed A. The epidemiology, risk profiling and diagnostic challenges of nonalcoholic fatty liver disease. Medicines (Basel) 2019; 6(1):41. DOI: https://doi.org/10.3390/medicines6010041

13. Michelotti A, de Scordilli M, Palmero L, Guardascione M, Masala M, Roncato R, Foltran L, Ongaro E, Puglisi F. NAFLD-related hepatocarcinoma: The malignant side of metabolic syndrome. Cells 2021; 10(8):2034. DOI: https://doi.org/10.3390/cells10082034

14. Allameh A, Niayesh-Mehr R, Aliarab A, Sebastiani G, Pantopoulos K. Oxidative stress in liver pathophysiology and disease. Antioxidants (Basel) 2023; 12(9):1653. DOI: https://doi.org/10.3390/antiox12091653

15. Chatrath H, Vuppalanchi R, Chalasani N. Dyslipidemia in patients with nonalcoholic fatty liver disease. Semin Liver Dis 2012; 32(1):22-29. DOI: https://doi.org/10.1055/s-0032-1306423

16. Petrelli F, Manara M, Colombo S, De Santi G, Ghidini M, Mariani M, Iaculli A, Rausa E, Rampulla V, Arru M, Viti M, Lonati V, Ghidini A, Luciani A, Facciorusso A. Hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis: HCC and Steatosis or Steatohepatitis. Neoplasia 2022; 30:100809. DOI: https://doi.org/10.1016/j.neo.2022.100809

17. Ahmad MI, Khan MU, Kodali S, Shetty A, Bell SM, Victor D. Hepatocellular carcinoma due to nonalcoholic fatty liver disease: Current concepts and future challenges. J Hepatocell Carcinoma 2022; 9:477-496. DOI: https://doi.org/10.2147/JHC.S344559

18. Seko Y, Yamaguchi K, Itoh Y. The genetic backgrounds in nonalcoholic fatty liver disease. Clin J Gastroenterol 2018; 11(2):97-102. DOI: https://doi.org/10.1007/s12328-018-0841-9

19. Chen Y, Wang W, Morgan MP, Robson T, Annett S. Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: Current status and therapeutic targets. Front Endocrinol (Lausanne) 2023; 14:1148934. DOI: https://doi.org/10.3389/fendo.2023.1148934

20. Teng YX, Xie S, Guo PP, Deng ZJ, Zhang ZY, Gao W, Zhang WG, Zhong JH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: Current progresses and challenges. J Clin Transl Hepatol 2022; 10(5):955-964. DOI: https://doi.org/10.14218/JCTH.2021.00586

21. Yıldırım HÇ, Kavgaci G, Chalabiyev E, Dizdar O. Advances in the early detection of hepatobiliary cancers. Cancers (Basel) 2023; 15(15):3880. DOI: https://doi.org/10.3390/cancers15153880

22. Kaya E, Daniel Mazzolini G, Yilmaz Y, Canbay A. Prevention of hepatocellular carcinoma and monitoring of high-risk patients. Hepatol Forum 2022; 3(1):33-38. DOI: https://doi.org/10.14744/hf.2021.2021.0033

23. Ericson E, Bergenholm L, Andréasson AC, Dix CI, Knöchel J, Hansson SF, Lee R, Schumi J, Antonsson M, Fjellström O, Nasr P, Liljeblad M, Carlsson B, Kechagias S, Lindén D, Ekstedt M. Hepatic patatin-like phospholipase domain-containing 3 levels are increased in I148M risk allele carriers and correlate with NAFLD in humans. Hepatol Commun 2022; 6(10):2689-2701. DOI: https://doi.org/10.1002/hep4.2032

24. Mondul A, Mancina RM, Merlo A, Dongiovanni P, Rametta R, Montalcini T, Valenti L, Albanes D, Romeo S. PNPLA3 I148M variant influences circulating retinol in adults with nonalcoholic fatty liver disease or obesity. J Nutr 2015; 145(8):1687-1691. DOI: https://doi.org/10.3945/jn.115.210633

25. Raia GYS, Abdelsameea E, Taie DHT, Elshaarawy O, Bayomy NR, Mostafa RG, Alsharnoby AAA, Diab KA. The TM6SF2 variant as a risk factor for hepatocellular carcinoma development in chronic liver disease patients. Clin Exp Hepatol 2022; 8(3):211-218. DOI: https://doi.org/10.5114/ceh.2022.119265

26. Shi F, Zhao M, Zheng S, Zheng L, Wang H. Advances in genetic variation in metabolism-related fatty liver disease. Front Genet 2023; 14:1213916. DOI: https://doi.org/10.3389/fgene.2023.1213916

27. Mattos ÂZ, Debes JD, Dhanasekaran R, Benhammou JN, Arrese M, Patrício ALV, Zilio AC, Mattos AA. Hepatocellular carcinoma in nonalcoholic fatty liver disease: A growing challenge. World J Hepatol 2021; 13(9):1107-1121. DOI: https://doi.org/10.4254/wjh.v13.i9.1107

28. Daher D, Dahan KSE, Singal AG. Non-alcoholic fatty liver disease-related hepatocellular carcinoma. J Liver Cancer 2023; 23(1):127-142. DOI: https://doi.org/10.17998/jlc.2022.12.30

29. Chavez-Tapia NC, Murúa-Beltrán Gall S, Ordoñez-Vázquez AL, Nuño-Lambarri N, Vidal-Cevallos P, Uribe M. Understanding the role of metabolic syndrome as a risk factor for hepatocellular carcinoma. J Hepatocell Carcinoma 2022; 9:583-593. DOI: https://doi.org/10.2147/JHC.S283840

30. Singh S, Hoque S, Zekry A, Sowmya A. Radiological diagnosis of chronic liver disease and hepatocellular carcinoma: A review. J Med Syst 2023; 47(1):73. DOI: https://doi.org/10.1007/s10916-023-01968-7

31. Zunica ERM, Heintz EC, Axelrod CL, Kirwan JP. Obesity management in the primary prevention of hepatocellular carcinoma. Cancers (Basel) 2022; 14(16):4051. DOI: https://doi.org/10.3390/cancers1416405 1

32. Jarvis H, O’Keefe H, Craig D, Stow D, Hanratty B, Anstee QM. Does moderate alcohol consumption accelerate the progression of liver disease in NAFLD? A systematic review and narrative synthesis. BMJ Open 2022; 12(1):e049767. DOI: https://doi.org/10.1136/bmjopen-2021-049767

33. van der Windt DJ, Sud V, Zhang H, Tsung A, Huang H. The effects of physical exercise on fatty liver disease. Gene Expr 2018; 18(2):89-101. DOI: https://doi.org/10.3727/105221617X15124844266408

34. Romero-Gómez M, Zelber-Sagi S, Martín F, Bugianesi E, Soria B. Nutrition could prevent or promote non-alcoholic fatty liver disease: An opportunity for intervention. BMJ 2023; 383:e075179. DOI: https://doi.org/10.1136/bmj-2023-075179

35. Rasha F, Paul S, Simon TG, Hoshida Y. Hepatocellular carcinoma chemoprevention with generic agents. Semin Liver Dis 2022; 42(4):501-513. DOI: https://doi.org/10.1055/a-1942-6693

36. Piekuś-Słomka N, Mocan LP, Shkreli R, Grapă C, Denkiewicz K, Wesolowska O, Kornek M, Spârchez Z, Słomka A, Crăciun R, Mocan T. Don’t judge a book by its cover: The role of statins in liver cancer. Cancers (Basel) 2023; 15(20):5100. DOI: https://doi.org/10.3390/cancers15205100

37. Vell MS, Loomba R, Krishnan A, Wangensteen KJ, Trebicka J, Creasy KT, Trautwein C, Scorletti E, Seeling KS, Hehl L, Rendel MD, Zandvakili I, Li T, Chen J, Vujkovic M, Alqahtani S, Rader DJ, Schneider KM, Schneider CV. Association of statin use with risk of liver disease, hepatocellular carcinoma, and liver-related mortality. JAMA Netw Open 2023; 6(6):e2320222. DOI: https://doi.org/10.1001/jamanetworkopen.2023.20222

38. Pinyopornpanish K, Leerapun A, Pinyopornpanish K, Chattipakorn N. Effects of metformin on hepatic steatosis in adults with nonalcoholic fatty liver disease and diabetes: Insights from the cellular to patient levels. Gut Liver 2021; 15(6):827-840. DOI: https://doi.org/10.5009/gnl20367

39. Perumpail BJ, Li AA, John N, Sallam S, Shah ND, Kwong W, Cholankeril G, Kim D, Ahmed A. The role of vitamin E in the treatment of NAFLD. Diseases 2018; 6(4):86. DOI: https://doi.org/10.3390/diseases6040086

40. Rinaldi L, Vetrano E, Rinaldi B, Galiero R, Caturano A, Salvatore T, Sasso FC. HCC and molecular targeting therapies: Back to the future. Biomedicines 2021; 9(10):1345. DOI: https://doi.org/10.3390/biomedicines9101345

41. Mattos ÂZ, Debes JD, Vogel A, Arrese M, Revelo X, Pase THS, Manica M, Mattos AA. Non-alcoholic fatty liver disease-related hepatocellular carcinoma: Is there a role for immunotherapy? World J Gastroenterol 2022; 28(28):3595-3607. DOI: https://doi.org/10.3748/wjg.v28.i28.3595

42. Howell J, Samani A, Mannan B, Hajiev S, Motedayen Aval L, Abdelmalak R, Tam VC, Bettinger D, Thimme R, Taddei TH, Kaplan DE, Seidensticker M, Sharma R. Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: An international cohort study. Therap Adv Gastroenterol 2022; 15:17562848221100106. DOI: https://doi.org/10.1177/17562848221100106

43. Chan LL, Chan SL. Novel perspectives in immune checkpoint inhibitors and the management of non-alcoholic steatohepatitis-related hepatocellular carcinoma. Cancers (Basel) 2022; 14(6):1526. DOI: https://doi.org/10.3390/cancers14061526

44. Tanaka N, Aoyama T, Kimura S, Gonzalez FJ. Targeting nuclear receptors for the treatment of fatty liver disease. Pharmacol Ther 2017; 179:142-157. DOI: https://doi.org/10.1016/j.pharmthera.2017.05.011

45. Monroy-Ramirez HC, Galicia-Moreno M, Sandoval-Rodriguez A, Meza-Rios A, Santos A, Armendariz-Borunda J. PPARs as metabolic sensors and therapeutic targets in liver diseases. Int J Mol Sci 2021; 22(15):8298. DOI: https://doi.org/10.3390/ijms22158298

46. Lee HJ, Yeon JE, Ko EJ, Yoon EL, Suh SJ, Kang K, Kim HR, Kang SH, Yoo YJ, Je J, Lee BJ, Kim JH, Seo YS, Yim HJ, Byun KS. Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease. World J Gastroenterol 2015; 21(45):12787-12799. DOI: https://doi.org/10.3748/wjg.v21.i45.12787

47. Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, Knight R. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 2018; 15(7):397-411. DOI: https://doi.org/10.1038/s41575-018-0011-z. Erratum in: Nat Rev Gastroenterol Hepatol. 2018 May 21.

48. Li S, Eguchi N, Lau H, Ichii H. The role of the Nrf2 signaling in obesity and insulin resistance. Int J Mol Sci 2020; 21(18):6973. DOI: https://doi.org/10.3390/ijms21186973

49. Sayaf K, Battistella S, Russo FP. NLRP3 inflammasome in acute and chronic liver diseases. Int J Mol Sci 2024; 25(8):4537. DOI: https://doi.org/10.3390/ijms25084537

50. Fang C, Pan J, Qu N, Lei Y, Han J, Zhang J, Han D. The AMPK pathway in fatty liver disease. Front Physiol 2022; 13:970292. DOI: https://doi.org/10.3389/fphys.2022.970292

51. Gluais-Dagorn P, Foretz M, Steinberg GR, Batchuluun B, Zawistowska-Deniziak A, Lambooij JM, Guigas B, Carling D, Monternier PA, Moller DE, Bolze S, Hallakou-Bozec S. Direct AMPK activation corrects NASH in rodents through metabolic effects and direct action on inflammation and fibrogenesis. Hepatol Commun 2022; 6(1):101-119. DOI: https://doi.org/10.1002/hep4.1799

52. Feng J, Qiu S, Zhou S, Tan Y, Bai Y, Cao H, Guo J, Su Z. mTOR: A potential new target in nonalcoholic fatty liver disease. Int J Mol Sci 2022; 23(16):9196. DOI: https://doi.org/10.3390/ijms23169196

53. Ferrín G, Guerrero M, Amado V, Rodríguez-Perálvarez M, De la Mata M. Activation of mTOR signaling pathway in hepatocellular carcinoma. Int J Mol Sci 2020; 21(4):1266. DOI: https://doi.org/10.3390/ijms21041266

54. Rodríguez-Sanabria JS, Escutia-Gutiérrez R, Rosas-Campos R, Armendáriz-Borunda JS, Sandoval-Rodríguez A. An update in epigenetics in metabolic-associated fatty liver disease. Front Med (Lausanne) 2022; 8:770504. DOI: https://doi.org/10.3389/fmed.2021.770504

55. Shi Y, Qi W. Histone modifications in NAFLD: Mechanisms and potential therapy. Int J Mol Sci 2023; 24(19):14653. DOI: https://doi.org/10.3390/ijms241914653
How to Cite
Scholten, A. (2024). Non-Alcoholic Fatty Liver Disease and the Risk of Future Hepatocarcinoma. Science Insights, 44(5), 1357–1364. https://doi.org/10.15354/si.24.re1000