J Liver Cancer.  2024 Sep;24(2):145-154. 10.17998/jlc.2024.08.03.

Disease modifiers and novel markers in hepatitis B virus-related hepatocellular carcinoma

• Mak LY

• KMID: 2559462
• DOI: http://doi.org/10.17998/jlc.2024.08.03

Abstract

Chronic hepatitis B (CHB) infection is responsible for 40% of the global burden of hepatocellular carcinoma (HCC) with a high case fatality rate. The risk of HCC differs among CHB subjects owing to differences in host and viral factors. Modifiable risk factors include viral load, use of antiviral therapy, co-infection with other hepatotropic viruses, concomitant metabolic dysfunctionassociated steatotic liver disease or diabetes mellitus, environmental exposure, and medication use. Detecting HCC at early stage improves survival, and current practice recommends HCC surveillance among individuals with cirrhosis, family history of HCC, or above an age cut-off. Ultrasonography with or without serum alpha feto-protein (AFP) every 6 months is widely accepted strategy for HCC surveillance. Novel tumor-specific markers, when combined with AFP, improve diagnostic accuracy than AFP alone to detect HCC at an early stage. To predict the risk of HCC, a number of clinical risk scores have been developed but none of them are clinically implemented nor endorsed by clinical practice guidelines. Biomarkers that reflect viral transcriptional activity and degree of liver fibrosis can potentially stratify the risk of HCC, especially among subjects who are already on antiviral therapy. Ongoing exploration of these novel biomarkers is required to confirm their performance characteristics, replicability and practicability.

Keyword

Hepatic steatosis; Risk prediction; Liver cirrhosis; Biomarkers

Figure

• 

  Figure 1. Risk factors associated with development of hepatocellular carcinoma among subjects with chronic hepatitis B infection. They can be broadly classified into modifiable factors and non-modifiable factors, and further stratified into viral factors or host factors. HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HDV, hepatitis delta virus; HIV, human immunodeficiency; HCC, hepatocellular carcinoma; MASLD, metabolic dysfunction-associated steatotic liver disease; T2DM, type 2 diabetes mellitus; SGLT2i, sodium glucose co-transporter 2 inhibitor.

• 

  Figure 2. Parameters to predict risk of HCC (clinical parameters, viral biomarkers or liver fibrosis markers) or diagnose HCC (tumor specific markers). Clinical parameters are commonly incorporated in risk scores. Some of them remain to be research tool only. HBV, hepatitis B virus; HCC, hepatocellular carcinoma; VCTE-LSM, vibration controlled transient elastography-liver stiffness measurement; AFP, alpha feto-protein; qHBsAg, quantitative hepatitis B surface antigen; ELF, enhanced liver fibrosis; PIVKA-II, protein induced by vitamin K absence or antagonist-II; AFP-L3, AFP Lens culinaris agglutinin 3 portion; M2BPGi, Mac-2 binding protein glycosylation isomer; SP70, tumor-specific 70; HBcrAg, hepatitis B core-related antigen; PIgR, polymeric immunoglobin receptor; EVs, extracellular vesicles.

Reference

References

1. GBD 2019 Hepatitis B Collaborators. Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Gastroenterol Hepatol. 2022; 7:796–829.

2. Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat Rev Clin Oncol. 2023; 20:864–884.

3. Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022; 77:1598–1606.

4. Su CC, Chen BS, Chen HH, Sung WW, Wang CC, Tsai MC. Improved trends in the mortality-to-incidence ratios for liver cancer in countries with high development index and health expenditures. Healthcare (Basel). 2023; 11:159.

5. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018; 69:182–236.

6. Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): epidemiology, etiology and molecular classification. Adv Cancer Res. 2021; 149:1–61.

7. World Health Organization (WHO). Global hepatitis report 2024: action for access in low- and middle-income countries. Geneva (CH): WHO;[cited 2024 Jul 25]. Available from: https://www.who.int/publications/i/item/9789240091672.

8. Yuen MF, Tanaka Y, Fong DY, Fung J, Wong DK, Yuen JC, et al. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol. 2009; 50:80–88.

9. Loomba R, Liu J, Yang HI, Lee MH, Lu SN, Wang LY, et al. Synergistic effects of family history of hepatocellular carcinoma and hepatitis B virus infection on risk for incident hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2013; 11:1636–1645.e1-e3.

10. Wong VW, Chan SL, Mo F, Chan TC, Loong HH, Wong GL, et al. Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. J Clin Oncol. 2010; 28:1660–1665.

11. Yang JD, Altekruse SF, Nguyen MH, Gores GJ, Roberts LR. Impact of country of birth on age at the time of diagnosis of hepatocellular carcinoma in the United States. Cancer. 2017; 123:81–89.

12. Zhang H, Zhai Y, Hu Z, Wu C, Qian J, Jia W, et al. Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet. 2010; 42:755–758.

13. Jiang DK, Sun J, Cao G, Liu Y, Lin D, Gao YZ, et al. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet. 2013; 45:72–75.

14. Chan HL, Hui AY, Wong ML, Tse AM, Hung LC, Wong VW, et al. Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut. 2004; 53:1494–1498.

15. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006; 295:65–73.

16. Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology. 2008; 135:1192–1199.

17. Seto WK, Lau EH, Wu JT, Hung IF, Leung WK, Cheung KS, et al. Effects of nucleoside analogue prescription for hepatitis B on the incidence of liver cancer in Hong Kong: a territory-wide ecological study. Aliment Pharmacol Ther. 2017; 45:501–509.

18. Yeo YH, Ho HJ, Yang HI, Tseng TC, Hosaka T, Trinh HN, et al. Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis. Gastroenterology. 2019; 156:635–646.e9.

19. Chow N, Wong D, Lai CL, Mak LY, Fung J, Ma HT, et al. Effect of antiviral treatment on hepatitis B virus integration and hepatocyte clonal expansion. Clin Infect Dis. 2023; 76:e801–e809.

20. Hsu YC, Suri V, Nguyen MH, Huang YT, Chen CY, Chang IW, et al. Inhibition of viral replication reduces transcriptionally active distinct hepatitis B virus integrations with implications on host gene dysregulation. Gastroenterology. 2022; 162:1160–1170. e1.

21. World Health Organization (WHO). Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection. Geneva (CH): WHO;[cited 2024 Jul 25]. Available from: https://www.who.int/publications/i/item/9789240090903.

22. You H, Wang F, Li T, Xu X, Sun Y, Nan Y, et al. Guidelines for the prevention and treatment of chronic hepatitis B (version 2022). J Clin Transl Hepatol. 2023; 11:1425–1442.

23. Thio CL. Hepatitis B and human immunodeficiency virus coinfection. Hepatology. 2009; 49 Suppl 5:S138–S145.

24. Kim HN, Newcomb CW, Carbonari DM, Roy JA, Torgersen J, Althoff KN, et al. Risk of HCC with hepatitis B viremia among HIV/HBV-coinfected persons in North America. Hepatology. 2021; 74:1190–1202.

25. Zampino R, Pisaturo MA, Cirillo G, Marrone A, Macera M, Rinaldi L, et al. Hepatocellular carcinoma in chronic HBV-HCV co-infection is correlated to fibrosis and disease duration. Ann Hepatol. 2015; 14:75–82.

26. Kamal H, Fornes R, Simin J, Stål P, Duberg AS, Brusselaers N, et al. Risk of hepatocellular carcinoma in hepatitis B and D virus co-infected patients: a systematic review and meta-analysis of longitudinal studies. J Viral Hepat. 2021; 28:1431–1442.

27. Zheng Q, Zou B, Wu Y, Yeo Y, Wu H, Stave CD, et al. Systematic review with meta-analysis: prevalence of hepatic steatosis, fibrosis and associated factors in chronic hepatitis B. Aliment Pharmacol Ther. 2021; 54:1100–1109.

28. Choi HSJ, Brouwer WP, Zanjir WMR, de Man RA, Feld JJ, Hansen BE, et al. Nonalcoholic steatohepatitis is associated with liver-related outcomes and all-cause mortality in chronic hepatitis B. Hepatology. 2020; 71:539–548.

29. Mak LY, Hui RW, Fung J, Liu F, Wong DK, Li B, et al. Reduced hepatic steatosis is associated with higher risk of hepatocellular carcinoma in chronic hepatitis B infection. Hepatol Int. 2021; 15:901–911.

30. Li J, Yang HI, Yeh ML, Le MH, Le AK, Yeo YH, et al. Association between fatty liver and cirrhosis, hepatocellular carcinoma, and hepatitis B surface antigen seroclearance in chronic hepatitis B. J Infect Dis. 2021; 224:294–302.

31. Mak LY. Steatotic liver disease: know your enemies. Clin Mol Hepatol. 2024; 30:171–173.

32. Huang SC, Liu CJ. Chronic hepatitis B with concurrent metabolic dysfunction-associated fatty liver disease: challenges and perspectives. Clin Mol Hepatol. 2023; 29:320–331.

33. Wong GL, Wong VW, Yuen BW, Tse YK, Luk HW, Yip TC, et al. An aging population of chronic hepatitis B with increasing comorbidities: a territory-wide study from 2000 to 2017. Hepatology. 2020; 71:444–455.

34. Pang Y, Kartsonaki C, Turnbull I, Guo Y, Clarke R, Chen Y, et al. Diabetes, plasma glucose, and incidence of fatty liver, cirrhosis, and liver cancer: a prospective study of 0.5 million people. Hepatology. 2018; 68:1308–1318.

35. Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology. 2008; 135:111–121.

36. Kim SU, Seo YS, Lee HA, Kim MN, Kim EH, Kim HY, et al. Validation of the CAMD score in patients with chronic hepatitis B virus infection receiving antiviral therapy. Clin Gastroenterol Hepatol. 2020; 18:693–699.e1.

37. Mak LY, Hui RW, Lee CH, Mao X, Cheung KS, Wong DK, et al. Glycemic burden and the risk of adverse hepatic outcomes in patients with chronic hepatitis B with type 2 diabetes. Hepatology. 2023; 77:606–618.

38. Lee CH, Mak LY, Tang EH, Lui DT, Mak JH, Li L, et al. SGLT2i reduces risk of developing HCC in patients with co-existing type 2 diabetes and hepatitis B infection: a territory-wide cohort study in Hong Kong. Hepatology. 2023; 78:1569–1580.

39. Tsan YT, Lee CH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol. 2012; 30:623–630.

40. Marti-Aguado D, Clemente-Sanchez A, Bataller R. Cigarette smoking and liver diseases. J Hepatol. 2022; 77:191–205.

41. Lin CW, Lin CC, Mo LR, Chang CY, Perng DS, Hsu CC, et al. Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis. J Hepatol. 2013; 58:730–735.

42. Leung WW, Ho SC, Chan HL, Wong V, Yeo W, Mok TS. Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study. J Epidemiol Community Health. 2011; 65:556–558.

43. Inoue M, Yoshimi I, Sobue T, Tsugane S; JPHC Study Group. Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan. J Natl Cancer Inst. 2005; 97:293–300.

44. Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023; 78:1922–1965.

45. Murugavel KG, Mathews S, Jayanthi V, Shankar EM, Hari R, Surendran R, et al. Alpha-fetoprotein as a tumor marker in hepatocellular carcinoma: investigations in south Indian subjects with hepatotropic virus and aflatoxin etiologies. Int J Infect Dis. 2008; 12:e71–e76.

46. Liebman HA, Furie BC, Tong MJ, Blanchard RA, Lo KJ, Lee SD, et al. Desgamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med. 1984; 310:1427–1431.

47. Chan HLY, Vogel A, Berg T, De Toni EN, Kudo M, Trojan J, et al. Performance evaluation of the Elecsys PIVKA-II and Elecsys AFP assays for hepatocellular carcinoma diagnosis. JGH Open. 2022; 6:292–300.

48. Chen H, Chen S, Li S, Chen Z, Zhu X, Dai M, et al. Combining desgamma-carboxyprothrombin and alpha-fetoprotein for hepatocellular carcinoma diagnosing: an update meta-analysis and validation study. Oncotarget. 2017; 8:90390–90401.

49. Kim DY, Toan BN, Tan CK, Hasan I, Setiawan L, Yu ML, et al. Utility of combining PIVKA-II and AFP in the surveillance and monitoring of hepatocellular carcinoma in the Asia-Pacific region. Clin Mol Hepatol. 2023; 29:277–292.

50. Lee W, Chung HJ, Kim S, Jang S, Park CJ, Chi HS, et al. PIVKA-II is a candidate marker for monitoring the effects of the oral anticoagulant warfarin. Clin Biochem. 2010; 43:1177–1179.

51. Choi JY, Jung SW, Kim HY, Kim M, Kim Y, Kim DG, et al. Diagnostic value of AFP-L3 and PIVKA-II in hepatocellular carcinoma according to totalAFP. World J Gastroenterol. 2013; 19:339–346.

52. Chan HLY, Vogel A, Berg T, de Toni E, Kudo M, Trojan J, et al. A comparative analysis of Elecsys GALAD and Elecsys GAAD score to detect early-stage hepatocellular carcinoma in an international cohort. J Hepatol. 2022; 77 Suppl 1:S937.

53. Núñez KG, Sandow T, Fort D, Patel J, Hibino M, Carmody I, et al. Baseline alpha-fetoprotein, alpha-fetoprotein-L3, and des-gamma-carboxy prothrombin biomarker status in bridge to liver transplant outcomes for hepatocellular carcinoma. Cancers (Basel). 2021; 13:4765.

54. Liu J, Zhang W, Gu M, Ji Y, Yang L, Cheng X, et al. Serum SP70 is a sensitive predictor of chemotherapy response in patients with advanced nonsmall cell lung cancer. Cancer Med. 2018; 7:2925–2933.

55. Wang L, Shi H, Wei J, Chen WX, Jin YX, Gu CR, et al. SP70 is a novel biomarker of hepatocellular carcinoma. Front Oncol. 2023; 13:1149397.

56. Corcoran RB, Chabner BA. Application of cell-free DNA analysis to cancer treatment. N Engl J Med. 2018; 379:1754–1765.

57. Chalasani NP, Ramasubramanian TS, Bhattacharya A, Olson MC, Edwards DK V, Roberts LR, et al. A novel blood-based panel of methylated DNA and protein markers for detection of early-stage hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2021; 19:2597–2605.e4.

58. Tey SK, Wong SWK, Chan JYT, Mao X, Ng TH, Yeung CLS, et al. Patient pIgR-enriched extracellular vesicles drive cancer stemness, tumorigenesis and metastasis in hepatocellular carcinoma. J Hepatol. 2022; 76:883–895.

59. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018; 68:723–750.

60. Shin J, Lee S, Yoon JK, Roh YH. Diagnostic performance of the 2018 EASL vs. LI-RADS for hepatocellular carcinoma using CT and MRI: a systematic review and meta-analysis of comparative studies. J Magn Reson Imaging. 2023; 58:1942–1950.

61. Yamashita R, Mittendorf A, Zhu Z, Fowler KJ, Santillan CS, Sirlin CB, et al. Deep convolutional neural network applied to the liver imaging reporting and data system (LI-RADS) version 2014 category classification: a pilot study. Abdom Radiol (NY). 2020; 45:24–35.

62. Zhou W, Wang G, Xie G, Zhang L. Grading of hepatocellular carcinoma based on diffusion weighted images with multiple b-values using convolutional neural networks. Med Phys. 2019; 46:3951–3960.

63. Oyama A, Hiraoka Y, Obayashi I, Saikawa Y, Furui S, Shiraishi K, et al. Hepatic tumor classification using texture and topology analysis of noncontrast-enhanced three-dimensional T1-weighted MR images with a radiomics approach. Sci Rep. 2019; 9:8764.

64. Brusset B, Jacquemin M, Teyssier Y, Roth GS, Sturm N, Roustit M, et al. Radiological diagnosis of hepatocellular carcinoma does not preclude biopsy before treatment. JHEP Rep. 2023; 6:100957.

65. Yang HI, Yuen MF, Chan HL, Han KH, Chen PJ, Kim DY, et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACHB): development and validation of a predictive score. Lancet Oncol. 2011; 12:568–574.

66. Wong GL, Chan HL, Wong CK, Leung C, Chan CY, Ho PP, et al. Liver stiffness-based optimization of hepatocellular carcinoma risk score in patients with chronic hepatitis B. J Hepatol. 2014; 60:339–345.

67. Papatheodoridis G, Dalekos G, Sypsa V, Yurdaydin C, Buti M, Goulis J, et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J Hepatol. 2016; 64:800–806.

68. Lee HW, Yoo EJ, Kim BK, Kim SU, Park JY, Kim DY, et al. Prediction of development of liver-related events by transient elastography in hepatitis B patients with complete virological response on antiviral therapy. Am J Gastroenterol. 2014; 109:1241–1249.

69. Wu S, Zeng N, Sun F, Zhou J, Wu X, Sun Y, et al. Hepatocellular carcinoma prediction models in chronic hepatitis B: a systematic review of 14 models and external validation. Clin Gastroenterol Hepatol. 2021; 19:2499–2513.

70. Zhao XL, Yang JR, Lin SZ, Ma H, Guo F, Yang RF, et al. Serum viral duplexlinear DNA proportion increases with the progression of liver disease in patients infected with HBV. Gut. 2016; 65:502–511.

71. Lam YF, Seto WK, Wong D, Cheung KS, Fung J, Mak LY, et al. Seven-year treatment outcome of entecavir in a real-world cohort: effects on clinical parameters, HBsAg and HBcrAg levels. Clin Transl Gastroenterol. 2017; 8:e125.

72. Tseng TC, Liu CJ, Yang HC, Su TH, Wang CC, Chen CL, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology. 2012; 142:1140–1149.e3. quiz e13-e14.

73. Wang J, Shen T, Huang X, Kumar GR, Chen X, Zeng Z, et al. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J Hepatol. 2016; 65:700–710.

74. Mak LY, Cloherty G, Wong DK, Gersch J, Seto WK, Fung J, et al. HBV RNA profiles in patients with chronic hepatitis b under different disease phases and antiviral therapy. Hepatology. 2021; 73:2167–2179.

75. Mak LY, Huang Q, Wong DK, Stamm L, Cheung KS, Ko KL, et al. Residual HBV DNA and pgRNA viraemia is associated with hepatocellular carcinoma in chronic hepatitis B patients on antiviral therapy. J Gastroenterol. 2021; 56:479–488.

76. Mak LY, Ko KL, To WP, Wong DK, Seto WK, Fung J, et al. Entecavir reduced serum hepatitis B core-related antigen in chronic hepatitis B patients with hepatocellular carcinoma. Gut Liver. 2020; 14:665–668.

77. Wu JW, Kao JH, Tseng TC. Three heads are better than two: hepatitis B core-related antigen as a new predictor of hepatitis B virus-related hepatocellular carcinoma. Clin Mol Hepatol. 2021; 27:524–534.

78. Inoue T, Tanaka Y. Novel biomarkers for the management of chronic hepatitis B. Clin Mol Hepatol. 2020; 26:261–279.

79. Cheung KS, Seto WK, Wong DK, Lai CL, Yuen MF. Relationship between HBsAg, HBcrAg and hepatocellular carcinoma in patients with undetectable HBV DNA under nucleos(t)ide therapy. J Viral Hepat. 2017; 24:654–661.

80. Shin SH, Kim SU, Park JY, Kim DY, Ahn SH, Han KH, et al. Liver stiffnessbased model for prediction of hepatocellular carcinoma in chronic hepatitis B virus infection: comparison with histological fibrosis. Liver Int. 2015; 35:1054–1062.

81. Parkes J, Roderick P, Harris S, Day C, Mutimer D, Collier J, et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. Gut. 2010; 59:1245–1251.

82. Pearson M, Nobes J, Macpherson I, Gold L, Miller M, Dow E, et al. Enhanced liver fibrosis (ELF) score predicts hepatic decompensation and mortality. JHEP Rep. 2024; 6:101062.

83. Mak LY, Cheung KS, Hui RW, Wong DK, Fung J, Yuen MF, et al. Enhanced liver fibrosis score stratifies hepatocellular carcinoma risk in patients with hepatitis B surface antigen seroclearance. Clin Infect Dis. 2022; 75:2257–2259.

84. Jun T, Hsu YC, Ogawa S, Huang YT, Yeh ML, Tseng CH, et al. Mac-2 binding protein glycosylation isomer as a hepatocellular carcinoma marker in patients with chronic hepatitis B or C infection. Hepatol Commun. 2019; 3:493–503.

85. Mak LY, To WP, Wong DK, Fung J, Liu F, Seto WK, et al. Serum Mac-2 binding protein glycosylation isomer level predicts hepatocellular carcinoma development in E-negative chronic hepatitis B patients. World J Gastroenterol. 2019; 25:1398–1408.

86. Mak LY, Ko M, To E, Wong DK, Ma JH, Hui TL, et al. Serum Mac-2-binding protein glycosylation isomer and risk of hepatocellular carcinoma in entecavir-treated chronic hepatitis B patients. J Gastroenterol Hepatol. 2019; 34:1817–1823.

87. Yamanaka T, Araki K, Yokobori T, Muranushi R, Hoshino K, Hagiwara K, et al. Potential of Mac-2-binding protein glycan isomer as a new therapeutic target in pancreatic cancer. Cancer Sci. 2024; 115:1241–1249.

88. Kono M, Nakamura Y, Oyama Y, Mori K, Hozumi H, Karayama M, et al. Increased levels of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in idiopathic pulmonary fibrosis. Respir Med. 2016; 115:46–52.

89. Wattacheril JJ, Abdelmalek MF, Lim JK, Sanyal AJ. AGA clinical practice update on the role of noninvasive biomarkers in the evaluation and management of nonalcoholic fatty liver disease: expert review. Gastroenterology. 2023; 165:1080–1088.

90. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023; 77:1797–1835.

91. Poh Z, Shen L, Yang HI, Seto WK, Wong VW, Lin CY, et al. Real-world risk score for hepatocellular carcinoma (RWS-HCC): a clinically practical risk predictor for HCC in chronic hepatitis B. Gut. 2016; 65:887–888.

92. Sinn DH, Lee JH, Kim K, Ahn JH, Lee JH, Kim JH, et al. A novel model for predicting hepatocellular carcinoma development in patients with chronic hepatitis B and normal alanine aminotransferase levels. Gut Liver. 2017; 11:528–534.

93. Fung J, Cheung KS, Wong DK, Mak LY, To WP, Seto WK, et al. Longterm outcomes and predictive scores for hepatocellular carcinoma and hepatitis B surface antigen seroclearance after hepatitis B e-antigen seroclearance. Hepatology. 2018; 68:462–472.

94. Fan C, Li M, Gan Y, Chen T, Sun Y, Lu J, et al. A simple AGED score for risk classification of primary liver cancer: development and validation with long-term prospective HBsAg-positive cohorts in Qidong, China. Gut. 2019; 68:948–949.

95. Kim JH, Kim YD, Lee M, Jun BG, Kim TS, Suk KT, et al. Modified PAGEB score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy. J Hepatol. 2018; 69:1066–1073.

96. Sohn W, Cho JY, Kim JH, Lee JI, Kim HJ, Woo MA, et al. Risk score model for the development of hepatocellular carcinoma in treatment-naïve patients receiving oral antiviral treatment for chronic hepatitis B. Clin Mol Hepatol. 2017; 23:170–178.

97. Chen CH, Lee CM, Lai HC, Hu TH, Su WP, Lu SN, et al. Prediction model of hepatocellular carcinoma risk in Asian patients with chronic hepatitis B treated with entecavir. Oncotarget. 2017; 8:92431–92441.

98. Hsu YC, Yip TC, Ho HJ, Wong VW, Huang YT, El-Serag HB, et al. Development of a scoring system to predict hepatocellular carcinoma in Asians on antivirals for chronic hepatitis B. J Hepatol. 2018; 69:278–285.

99. Yu JH, Suh YJ, Jin YJ, Heo NY, Jang JW, You CR, et al. Prediction model for hepatocellular carcinoma risk in treatment-naive chronic hepatitis B patients receiving entecavir/tenofovir. Eur J Gastroenterol Hepatol. 2019; 31:865–872.