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Can we use HCC risk scores to individualize surveillance in chronic hepatitis B infection?

  • Vincent Wai-Sun Wong
    Affiliations
    Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong

    State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
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  • Harry L.A. Janssen
    Correspondence
    Corresponding author. Address: Division of Gastroenterology, University Health Network, 399 Bathurst Street, 6B FP, Room 164, Toronto, ON M5T 2S8, Canada. Tel.: +1 416 603 5800x2776; fax: +1 416 603 6281.
    Affiliations
    Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada

    Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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Open AccessPublished:May 27, 2015DOI:https://doi.org/10.1016/j.jhep.2015.05.019

      Summary

      Chronic hepatitis B is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. Accurate prediction of HCC risk is important for decisions on antiviral therapy and HCC surveillance. In the last few years, a number of Asian groups have derived and validated several HCC risk scores based on well-known risk factors such as cirrhosis, age, male sex and high viral load. Overall, these scores have high negative predictive values of over 95% in excluding HCC development in 3 to 10 years. The REACH-B score was derived from a community cohort of non-cirrhotic patients and is better applied in the primary care setting. In contrast, the GAG-HCC and CU-HCC scores were derived from hospital cohorts and include cirrhosis as a major integral component. While the latter scores may be more applicable to patients at specialist clinics, the diagnosis of cirrhosis based on routine imaging and clinical parameters can be inaccurate. To this end, recent developments in non-invasive tests of liver fibrosis may further refine the risk prediction. The application of HCC risk scores in patients on antiviral therapy and in other ethnic groups should be evaluated in future studies.

      Abbreviations:

      AFP (alpha-fetoprotein), AASLD (American Association for the Study of Liver Diseases), ALT (alanine aminotransferase), APASL (Asian Pacific Association for the Study of the Liver), AST (aspartate aminotransferase), AUROC (area under the receiver-operating characteristics curve), EASL (European Association for the Study of the Liver), HBeAg (hepatitis B e antigen), HBsAg (hepatitis B surface antigen), HBV (hepatitis B virus), HCC (hepatocellular carcinoma), LSM (liver stiffness measurement)

      Keywords

      Introduction

      Chronic hepatitis B virus (HBV) infection affects over 350 million people worldwide and remains one of the leading causes of cirrhosis, liver failure and hepatocellular carcinoma (HCC) [
      • Trepo C.
      • Chan H.L.
      • Lok A.
      Hepatitis B virus infection.
      ]. In the past three decades, we have witnessed major improvements in the prevention and management of HBV-related HCC. Universal immunization against HBV, now reaching 30 years in some countries, effectively prevents new HBV infection and HBV-related HCC [
      • Chiang C.J.
      • Yang Y.W.
      • You S.L.
      • Lai M.S.
      • Chen C.J.
      Thirty-year outcomes of the national hepatitis B immunization program in Taiwan.
      ]. A landmark randomized controlled trial and multiple observational studies confirmed that antiviral therapy can profoundly reduce HCC risk in cirrhotic patients [
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      • Chow W.C.
      • Farrell G.
      • Lee C.Z.
      • Yuen H.
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      Lamivudine for patients with chronic hepatitis B and advanced liver disease.
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      Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection.
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      • Lam A.T.
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      Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis.
      ]. In patients who have developed HCC, improvements in surgical, locoregional and systemic therapies further contribute to better survival [
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      • Gores G.J.
      • Mazzaferro V.
      Hepatocellular carcinoma: clinical frontiers and perspectives.
      ]. In addition, antiviral therapy after liver resection may reduce HCC recurrence and mortality [
      • Wong J.S.
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      • Chong C.N.
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      Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection.
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      Antiviral therapy improves post-hepatectomy survival in patients with hepatitis B virus-related hepatocellular carcinoma: a prospective-retrospective study.
      ].
      At present, immunization has not covered people aged above 30 years, while the majority of HCC occur in middle-aged patients. The full impact of universal immunization will take 2 to 3 more decades to manifest. Besides, antiviral therapy reduces but cannot eliminate the risk of HCC. Therefore, HCC surveillance is still indicated in at risk individuals.
      Figure thumbnail fx6

      Risk factors of HCC in HBV infection

      Patient factors

      Similar to other chronic liver diseases, cirrhosis is the single most important risk factor for HCC in patients with chronic hepatitis B (Table 1). In East Asian countries, the incidence of HCC ranges from 0.2 per 100 person-years among inactive carriers, 0.6 in patients with non-cirrhotic chronic hepatitis B and 3.7 in those with compensated cirrhosis [
      • Fattovich G.
      • Bortolotti F.
      • Donato F.
      Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
      ,
      • Liaw Y.F.
      • Tai D.I.
      • Chu C.M.
      • Lin D.Y.
      • Sheen I.S.
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      Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. A prospective study.
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      • Yuen J.C.
      • Wong W.M.
      • Chan A.O.
      • et al.
      Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications.
      ]. The corresponding figures in Europe and the United States are 0.02, 0.3, and 2.2 per 100 person-years, respectively [
      • Fattovich G.
      • Bortolotti F.
      • Donato F.
      Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
      ]. However, since HBV is directly carcinogenic, HCC may arise in a non-cirrhotic liver. This highlights the importance of considering other HCC risk factors in the management of chronic hepatitis B.
      Table 1Risk factors of HCC in patients with chronic hepatitis B.
      HBV, hepatitis B virus; HCC, hepatocellular carcinoma.
      As HCC usually develops in the background of liver injury and cirrhosis which takes decades to develop, the incidence of HCC increases with age. Moreover, studies have consistently shown that men have higher rates of HCC than women, with male:female ratios ranging from 2:1 to 4:1 [
      • El-Serag H.B.
      • Rudolph K.L.
      Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.
      ]. This may be because men are more likely to smoke, drink alcohol, and have more active hepatitis and higher iron stores. Besides, both estrogen and androgen receptors have been implicated in hepatocarcinogenesis through the upregulation of interleukin-6 and cell cycle-related kinase [
      • Naugler W.E.
      • Sakurai T.
      • Kim S.
      • Maeda S.
      • Kim K.
      • Elsharkawy A.M.
      • et al.
      Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.
      ,
      • Feng H.
      • Cheng A.S.
      • Tsang D.P.
      • Li M.S.
      • Go M.Y.
      • Cheung Y.S.
      • et al.
      Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives beta-catenin/T cell factor-dependent hepatocarcinogenesis.
      ].
      It has long been observed that HCC runs in families. On average, first-degree relatives of patients with HCC have a 2-fold increase in HCC incidence [
      • Fernandez E.
      • La Vecchia C.
      • D’Avanzo B.
      • Negri E.
      • Franceschi S.
      Family history and the risk of liver, gallbladder, and pancreatic cancer.
      ,
      • Yu M.W.
      • Chang H.C.
      • Liaw Y.F.
      • Lin S.M.
      • Lee S.D.
      • Liu C.J.
      • et al.
      Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives.
      ]. The effect of family history appears to be synergistic to HBV carriage [
      • Loomba R.
      • Liu J.
      • Yang H.I.
      • Lee M.H.
      • Lu S.N.
      • Wang L.Y.
      • et al.
      Synergistic effects of family history of hepatocellular carcinoma and hepatitis B virus infection on risk for incident hepatocellular carcinoma.
      ]. Although the observation can be partly explained by HBV infection and similar lifestyles among family members, recent genomic studies have begun to unravel genetic and epigenetic changes conducive to HCC development [
      • Nahon P.
      • Zucman-Rossi J.
      Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis.
      ,
      • Sung W.K.
      • Zheng H.
      • Li S.
      • Chen R.
      • Liu X.
      • Li Y.
      • et al.
      Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma.
      ,
      • Chan K.C.
      • Jiang P.
      • Chan C.W.
      • Sun K.
      • Wong J.
      • Hui E.P.
      • et al.
      Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing.
      ].
      On another note, chronic hepatitis B patients with obesity and diabetes also have higher risk of HCC [
      • Chen C.L.
      • Yang H.I.
      • Yang W.S.
      • Liu C.J.
      • Chen P.J.
      • You S.L.
      • et al.
      Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan.
      ,
      • Yu M.W.
      • Shih W.L.
      • Lin C.L.
      • Liu C.J.
      • Jian J.W.
      • Tsai K.S.
      • et al.
      Body-mass index and progression of hepatitis B: a population-based cohort study in men.
      ]. This is partly explained by the increased fibrosis progression in patients with metabolic syndrome [
      • Wong G.L.
      • Wong V.W.
      • Choi P.C.
      • Chan A.W.
      • Chim A.M.
      • Yiu K.K.
      • et al.
      Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B.
      ]. In fact, among cirrhotic patients who used tenofovir for 5 years, regression of cirrhosis was less likely in those with diabetes or high body mass index [
      • Marcellin P.
      • Gane E.
      • Buti M.
      • Afdhal N.
      • Sievert W.
      • Jacobson I.M.
      • et al.
      Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.
      ]. It remains unclear whether the effect of metabolic syndrome on fibrosis progression and hepatocarcinogenesis is mediated through concomitant non-alcoholic steatohepatitis. In population studies, fatty liver is less common in patients with chronic hepatitis B [
      • Wong V.W.
      • Wong G.L.
      • Chu W.C.
      • Chim A.M.
      • Ong A.
      • Yeung D.K.
      • et al.
      Hepatitis B virus infection and fatty liver in the general population.
      ].

      Viral factors

      Patients with positive hepatitis B e antigen (HBeAg) and high HBV DNA levels have increased risk of HCC. In a population study of 11,893 men in Taiwan, the relative risk of HCC was 60.2 for those with positive hepatitis B surface antigen (HBsAg) and HBeAg and 9.6 for those with positive HBsAg alone, as compared with those with negative HBsAg and HBeAg [
      • Yang H.I.
      • Lu S.N.
      • Liaw Y.F.
      • You S.L.
      • Sun C.A.
      • Wang L.Y.
      • et al.
      Hepatitis B e antigen and the risk of hepatocellular carcinoma.
      ]. Furthermore, baseline HBV DNA is associated with future HCC risk. In the REVEAL-HBV Study, 3653 community non-cirrhotic patients with positive HBsAg were followed up for a mean of 11.4 years [
      • Chen C.J.
      • Yang H.I.
      • Su J.
      • Jen C.L.
      • You S.L.
      • Lu S.N.
      • et al.
      Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.
      ]. The incidence of HCC was 108 per 100,000 person-years for patients with HBV DNA below 300 copies/ml, 962 for those with HBV DNA 100,000–999,999 copies/ml, and 1152 for those with HBV DNA ⩾1 million copies/ml. It should be noted that the study included only Asian patients aged 30 to 65 years at baseline. The findings cannot be extrapolated to younger patients, in whom positive HBeAg and high HBV DNA are the hallmark of the immune tolerance phase and are not associated with histological activity and HCC development [
      • Andreani T.
      • Serfaty L.
      • Mohand D.
      • Dernaika S.
      • Wendum D.
      • Chazouilleres O.
      • et al.
      Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome.
      ].
      HBV is divided into different genotypes (A–H) based on a ⩾8% nucleotide sequence difference in the viral genome. Genotypes A and D are originally prevalent in Europe, while genotypes B and C are prevalent in Asia [
      • Wong V.W.
      • Sung J.J.
      Diagnosis and personalized management of hepatitis B including significance of genotypes.
      ]. Due to the large influx of immigrants in North America and Europe, HBV genotypes vary widely within these continents. Among different genotypes, genotype C is associated with delayed HBeAg seroconversion [
      • Chu C.J.
      • Hussain M.
      • Lok A.S.
      Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C.
      ]. Because of longer immune clearance phase and prolonged liver injury, patients with HBV genotype C infection are more likely to develop cirrhosis [
      • Chan H.L.
      • Wong G.L.
      • Tse C.H.
      • Chim A.M.
      • Yiu K.K.
      • Chan H.Y.
      • et al.
      Hepatitis B virus genotype C is associated with more severe liver fibrosis than genotype B.
      ] and have a 2- to 5-fold increase in the risk of HCC [
      • Chan H.L.
      • Hui A.Y.
      • Wong M.L.
      • Tse A.M.
      • Hung L.C.
      • Wong V.W.
      • et al.
      Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma.
      ,
      • Yu M.W.
      • Yeh S.H.
      • Chen P.J.
      • Liaw Y.F.
      • Lin C.L.
      • Liu C.J.
      • et al.
      Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men.
      ,
      • Yang H.I.
      • Yeh S.H.
      • Chen P.J.
      • Iloeje U.H.
      • Jen C.L.
      • Su J.
      • et al.
      Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma.
      ,
      • Wong G.L.
      • Chan H.L.
      • Yiu K.K.
      • Lai J.W.
      • Chan V.K.
      • Cheung K.K.
      • et al.
      Meta-analysis: the association of hepatitis B virus genotypes and hepatocellular carcinoma.
      ]. Furthermore, the T1762/A1764 basal core promoter mutant is more common in genotype C [
      • Kao J.H.
      • Chen P.J.
      • Lai M.Y.
      • Chen D.S.
      Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers.
      ]. The mutations are again associated with cirrhosis and HCC [
      • Yang H.I.
      • Yeh S.H.
      • Chen P.J.
      • Iloeje U.H.
      • Jen C.L.
      • Su J.
      • et al.
      Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma.
      ,
      • Kao J.H.
      • Chen P.J.
      • Lai M.Y.
      • Chen D.S.
      Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers.
      ,
      • Baptista M.
      • Kramvis A.
      • Kew M.C.
      High prevalence of 1762(T) 1764(A) mutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers.
      ,
      • Tseng T.C.
      • Liu C.J.
      • Yang H.C.
      • Chen C.L.
      • Yang W.T.
      • Tsai C.S.
      • et al.
      Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers.
      ].
      In recent years, there has been resurgence of interest in HBsAg quantification because the level probably reflects the level and activity of intrahepatic covalently closed circular DNA [
      • Chan H.L.
      • Thompson A.
      • Martinot-Peignoux M.
      • Piratvisuth T.
      • Cornberg M.
      • Brunetto M.R.
      • et al.
      Hepatitis B surface antigen quantification: why and how to use it in 2011 – A core group report.
      ]. A study from Taiwan showed that on the whole HBV DNA is a better predictor of HCC than HBsAg level [
      • Tseng T.C.
      • Liu C.J.
      • Yang H.C.
      • Su T.H.
      • Wang C.C.
      • Chen C.L.
      • et al.
      High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load.
      ]. However, among patients with HBeAg-negative disease and low HBV DNA <2000 IU/ml, an HBsAg level of ⩾1000 IU/ml had a hazard ratio of 13.7 for HCC as compared with lower HBsAg levels.
      Finally, co-infection with hepatitis D virus and HIV clearly increases the risk of disease progression, liver failure and HCC [
      • Fattovich G.
      • Giustina G.
      • Christensen E.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • et al.
      Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep).
      ,
      • Thio C.L.
      • Seaberg E.C.
      • Skolasky Jr., R.
      • Phair J.
      • Visscher B.
      • Munoz A.
      • et al.
      HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS).
      ,
      • Bonacini M.
      • Louie S.
      • Bzowej N.
      • Wohl A.R.
      Survival in patients with HIV infection and viral hepatitis B or C: a cohort study.
      ]. On the other hand, data on the natural history of HBV-hepatitis C virus co-infection are less consistent [
      • Zarski J.P.
      • Bohn B.
      • Bastie A.
      • Pawlotsky J.M.
      • Baud M.
      • Bost-Bezeaux F.
      • et al.
      Characteristics of patients with dual infection by hepatitis B and C viruses.
      ,
      • Liu C.J.
      • Chu Y.T.
      • Shau W.Y.
      • Kuo R.N.
      • Chen P.J.
      • Lai M.S.
      Treatment of patients with dual hepatitis C and B by peginterferon alpha and ribavirin reduced risk of hepatocellular carcinoma and mortality.
      ].

      Current recommendations on HCC surveillance

      Guidelines on HCC management have been issued by the American Association for the Study of Liver Diseases (AASLD), Asian Pacific Association for the Study of the Liver (APASL) and European Association for the Study of the Liver (EASL) (Table 2) [
      • Bruix J.
      • Sherman M.
      American Association for the Study of Liver Diseases
      Management of hepatocellular carcinoma: an update.
      ,
      • Omata M.
      • Lesmana L.A.
      • Tateishi R.
      • Chen P.J.
      • Lin S.M.
      • Yoshida H.
      • et al.
      Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma.
      ,
      European Association for the Study of the LiverEuropean Organisation for Research and Treatment of Cancer
      EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.
      ]. All three guidelines recommend HCC surveillance in patients with compensated and decompensated cirrhosis. Although the APASL guidelines acknowledge the occurrence of HCC in the non-cirrhotic liver, it calls for further studies to define the at risk group [
      • Omata M.
      • Lesmana L.A.
      • Tateishi R.
      • Chen P.J.
      • Lin S.M.
      • Yoshida H.
      • et al.
      Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma.
      ]. The EASL guidelines also recommend surveillance in HBV carriers with active hepatitis and patients with family history of HCC, but it is unclear what constitutes active hepatitis [
      European Association for the Study of the LiverEuropean Organisation for Research and Treatment of Cancer
      EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.
      ]. In addition to cirrhosis and family history, the AASLD guidelines specifically consider age, gender and ethnic origin in selecting patients for surveillance [
      • Bruix J.
      • Sherman M.
      American Association for the Study of Liver Diseases
      Management of hepatocellular carcinoma: an update.
      ]. In particular, Africans and North American blacks have high risk of HCC and are recommended for surveillance early regardless of their age and disease status.
      Table 2Recommendations on HCC surveillance by regional guidelines.
      The recommendations have been modified to focus on patients with chronic hepatitis B.
      AASLD, American Association for the Study of Liver Diseases; APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; EORTC, European Organisation for Research and Treatment of Cancer.
      All three guidelines support 6-monthly HCC surveillance. APASL recommends using abdominal ultrasonography and serum alpha-fetoprotein (AFP) for surveillance [
      • Omata M.
      • Lesmana L.A.
      • Tateishi R.
      • Chen P.J.
      • Lin S.M.
      • Yoshida H.
      • et al.
      Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma.
      ]. In contrast, AASLD and EASL recommend abdominal ultrasonography only because of the limited sensitivity and specificity of serum HCC biomarkers [
      • Bruix J.
      • Sherman M.
      American Association for the Study of Liver Diseases
      Management of hepatocellular carcinoma: an update.
      ,
      European Association for the Study of the LiverEuropean Organisation for Research and Treatment of Cancer
      EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.
      ].

      HCC prediction in untreated patients

      The recommendation by current guidelines is incomplete. If HCC surveillance is restricted to cirrhotic patients, high risk non-cirrhotic patients would be missed. On the other hand, indiscriminate surveillance in low risk patients would impose heavy burden on manpower and resources, particularly in developing countries where HBV infection tends to be endemic. Although the guidelines mention the consideration of disease severity and risk factors, they remain undefined. With this background, several Asian groups derived and validated HCC risk scores to predict HCC development in patients with chronic hepatitis B.
      The methodology to develop HCC risk scores in the different studies is similar (Fig. 1). First, risk factors associated with HCC are identified in a cohort of patients with chronic hepatitis B (training cohort or derivation cohort). The Cox proportional hazard model is used if a survival analysis is performed. Alternatively, binary logistic regression model may be used if HCC is considered as a binary variable at a defined time point (e.g. 5 or 10 years). Based on the multivariable analysis, independent HCC risk factors and their corresponding weights are determined. This can be used to construct a risk score. The most important final step is to validate the accuracy of the risk score in an independent cohort of patients (validation cohort). This is because the risk score is modelled against the training cohort and is bound to perform well in the same cohort.

      GAG-HCC score

      The GAG (Guide with age, gender, HBV DNA, core promoter mutations and cirrhosis)-HCC score was derived from 820 hospital patients with chronic hepatitis B in Hong Kong (Table 3) [
      • Yuen M.F.
      • Tanaka Y.
      • Fong D.Y.
      • Fung J.
      • Wong D.K.
      • Yuen J.C.
      • et al.
      Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B.
      ]. During a mean follow-up of 77 months, 40 patients developed HCC. In the original form, much importance was given to core promoter mutations. Nevertheless, because core promoter mutations would unlikely be tested in routine clinical practice, the score was simplified to include the four remaining factors only. Cirrhosis received the heaviest weighting, followed by male sex, age and HBV DNA. Because of the relatively small sample size and the small number of events, the cohort was not divided into training and validation sets. Instead, the statistical method of bootstrapping was performed. Overall, the area under the receiver-operating characteristics curve (AUROC) for predicting HCC in 5 and 10 years was 0.87 and 0.88, respectively. In the cross-validation analysis, the negative predictive value at a cut-off of 82 points to exclude HCC in 10 years approached 100%, while the positive predictive value was 26%.
      Table 3HCC risk scores in untreated patients.
      ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.

      CU-HCC score

      The CU (Chinese University)-HCC score was derived in 1005 hospital patients who participated in a prospective HCC surveillance study led by oncologists [
      • Mok T.S.
      • Yeo W.
      • Yu S.
      • Lai P.
      • Chan H.L.
      • Chan A.T.
      • et al.
      An intensive surveillance program detected a high incidence of hepatocellular carcinoma among hepatitis B virus carriers with abnormal alpha-fetoprotein levels or abdominal ultrasonography results.
      ] and validated in 424 patients at a hospital clinic in Hong Kong [
      • Chan H.L.
      • Hui A.Y.
      • Wong M.L.
      • Tse A.M.
      • Hung L.C.
      • Wong V.W.
      • et al.
      Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma.
      ]. The median follow-up of both cohorts was 10 years [
      • Wong V.W.
      • Chan S.L.
      • Mo F.
      • Chan T.C.
      • Loong H.H.
      • Wong G.L.
      • et al.
      Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers.
      ]. HCC developed in 105 patients in the training cohort and 45 patients in the validation cohort. Hypoalbuminaemia and cirrhosis were the most important factors, followed by HBV DNA, age and bilirubin. The AUROC for predicting HCC in 5 and 10 years in the validation cohort was 0.76 and 0.78, respectively. At a cut-off of 5 points, the negative predictive value to exclude HCC in 10 years was 97%, while the positive predictive value was 27%.
      Other than the low risk group, the study further defined an intermediate-risk group with a CU-HCC score of 5–19.5 and a high risk group with a score of ⩾20. In the validation cohort, the 5- and 10-year HCC-free survival rates were 91% and 71% in the intermediate-risk group, and 79% and 68% in the high risk group, respectively.

      REACH-B score

      In 2010, the REVEAL-HBV investigators first developed nomograms for HCC prediction using data from 3653 patients [
      • Yang H.I.
      • Sherman M.
      • Su J.
      • Chen P.J.
      • Liaw Y.F.
      • Iloeje U.H.
      • et al.
      Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection.
      ]. The same investigators later refined the analysis and developed the REACH-B (risk estimation for hepatocellular carcinoma in chronic hepatitis B) score, which was derived in 3584 community patients in Taiwan and validated in 1505 hospital patients from Hong Kong and Korea [
      • Yang H.I.
      • Yuen M.F.
      • Chan H.L.
      • Han K.H.
      • Chen P.J.
      • Kim D.Y.
      • et al.
      Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score.
      ]. HCC developed in 131 patients in the training cohort and 111 patients in the validation cohort. Factors in the score include male sex, age, alanine aminotransferase (ALT), positive HBeAg and HBV DNA. The AUROC for predicting HCC in 5 and 10 years in the validation cohort was 0.80 and 0.77, respectively. Instead of using one or two cut-off values, the REACH-B score offers granularity in risk prediction with a score ranging from 0 to 17 points (Table 3). It is noteworthy that the REACH-B score was derived in a community non-cirrhotic cohort and therefore did not include cirrhosis as a predicting factor. When the score was applied to cirrhotic patients in the validation cohort, the AUROC was lower at 0.70 at 5 years and 0.65 at 10 years.

      Additional molecular markers

      The three scores above include mainly routine clinical parameters because they are more likely to be used in real-life clinical practice and were already available in the study cohorts. Nonetheless, there are additional HCC risk factors not considered in the scores above (see section on risk factors of HCC). These potential markers may include HBsAg level, HBV genotype, HBV mutations (e.g. core promoter mutation) and host mutations. In a post-hoc analysis of the REVEAL-HBV cohort, the inclusion of clinical and virological parameters of age, sex, ALT, family history of HCC, HBeAg status, HBV DNA level, HBsAg level and HBV genotype allows the derivation of a composite score with an AUROC of 0.89, 0.85, and 0.86 in predicting HCC in 5, 10, and 15 years, respectively (Table 3) [
      • Lee M.H.
      • Yang H.I.
      • Liu J.
      • Batrla-Utermann R.
      • Jen C.L.
      • Iloeje U.H.
      • et al.
      Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles.
      ]. On the other hand, HCC is genetically a heterogeneous cancer. Few host gene polymorphisms confer more than a 2-fold increase in HCC risk [
      • Clifford R.J.
      • Zhang J.
      • Meerzaman D.M.
      • Lyu M.S.
      • Hu Y.
      • Cultraro C.M.
      • et al.
      Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma.
      ,
      • 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.
      ,
      • Jiang D.K.
      • Sun J.
      • Cao G.
      • Liu Y.
      • Lin D.
      • Gao Y.Z.
      • et al.
      Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma.
      ]. It is unlikely that a single host mutation will have sufficient impact on HCC prediction. These markers may only be useful in clinical practice when they have become more widely available and are better evaluated in combination with traditional HCC risk factors.

      Summary of natural history studies

      The risk scores derived and validated in natural history cohorts share similar predicting factors. Although the weighting and selection of risk factors are slightly different, these scores have similarly high negative predictive values to exclude HCC in 5–10 years. Notably, the studies did not exclude inactive HBV carriers who would have low risk of HCC. Nonetheless, the scores include components reflecting the features of inactive HBV carriers and may be simpler for non-specialists and primary care physicians to stratify the risk of their patients without the need to understand in details the different stages of chronic hepatitis B.
      The CU-HCC score identifies not only the low risk group but also the intermediate and high risk groups, while the REACH-B score offers gradated risk prediction based on the individual scores. It is however unclear if further categorization would impact on clinical practice beyond prognostication. Arguably, patients outside the low risk category should undergo regular HCC surveillance anyway, and there is no evidence that patients with even higher scores have faster growing tumors that warrant more frequent surveillance. In fact, more frequent surveillance has not been shown to increase uptake of curative treatment and improve survival [
      • Trinchet J.C.
      • Chaffaut C.
      • Bourcier V.
      • Degos F.
      • Henrion J.
      • Fontaine H.
      • et al.
      Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities.
      ].

      HCC prediction in patients on nucleos(t)ide analogues

      Asian data

      The three HCC risk scores described above were derived and validated in patient cohorts recruited in the 1990s and early 2000s, when antiviral therapy was not widely available. Nowadays, antiviral therapy is the standard treatment in patients at risk of HCC. Predictors of HCC may no longer apply in treated patients. Moreover, antiviral therapy modifies the natural history of chronic hepatitis B [
      • Liaw Y.F.
      • Sung J.J.
      • Chow W.C.
      • Farrell G.
      • Lee C.Z.
      • Yuen H.
      • et al.
      Lamivudine for patients with chronic hepatitis B and advanced liver disease.
      ,
      • Hosaka T.
      • Suzuki F.
      • Kobayashi M.
      • Seko Y.
      • Kawamura Y.
      • Sezaki H.
      • et al.
      Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection.
      ,
      • Wong G.L.
      • Chan H.L.
      • Mak C.W.
      • Lee S.K.
      • Ip Z.M.
      • Lam A.T.
      • et al.
      Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis.
      ]. Risk factors of HCC such as HBeAg status, HBV DNA, ALT and cirrhosis may alter after treatment [
      • Wong V.W.
      • Wong G.L.
      • Chim A.M.
      • Choi P.C.
      • Chan A.W.
      • Tsang S.W.
      • et al.
      Surrogate end points and long-term outcome in patients with chronic hepatitis B.
      ]. It is unclear how one should interpret changes in risk scores after antiviral therapy.
      The performance of HCC risk scores in treated patients has been tested in a cohort of 1531 patients from Hong Kong (Table 4) [
      • Wong G.L.
      • Chan H.L.
      • Chan H.Y.
      • Tse P.C.
      • Tse Y.K.
      • Mak C.W.
      • et al.
      Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment.
      ]. The patients were treated with entecavir 0.5 mg daily for a mean of 42 months. Apart from using a treatment cohort, this study evaluated not only baseline predictors but also serial on-treatment data. Overall, the time-dependent AUROC for predicting HCC development was 0.76–0.95 for the GAG-HCC score, 0.77–0.95 for the CU-HCC score, and 0.71–0.97 for the REACH-B score. The negative predictive values, according to the published cut-offs, of both the baseline and on-treatment scores to exclude HCC were 98–100% for all three scores. On the other hand, the positive predictive values of the scores were only 0.2–10.3%. In other words, because antiviral therapy further reduces the risk of HCC, treated patients with low risk scores have very low risk of HCC. Although HCC surveillance is still required in patients with high risk scores, the risk is also considerably lower than that of untreated patients.
      Table 4HCC risk scores in patients on oral nucleos(t)ide analogues.
      The PAGE-B score is calculated as age (<30 years = −4; 30–39 = −2; 40–49 = 0; 50–59 = 2; 60–69 = 4; ⩾70 = 6) + sex (male = 5; female = 0) + platelet count (× 1000/mm3; ⩾200 = 0; 100–199 = 6; <100 = 11). The optimal cut-off in the original study was 6 points or above. Please refer to Table 3 regarding the proposed cut-offs of the other scores.
      AUROC, area under the receiver-operating characteristics curve; NPV, negative predictive value; PPV, positive predictive value.
      The second aim of the study was to determine the clinical meaning of an improvement in risk scores during antiviral therapy. For both the GAG-HCC and CU-HCC scores, patients who had high risk scores at baseline and low risk scores 2 years after entecavir treatment had their HCC incidence reduced by more than half compared with those whose risk scores remained high. Nonetheless, their HCC incidence remained higher than that of patients with low risk scores at baseline. In the latter group, the incidence of HCC was <1% in 5 years.
      Although the study suggests that the HCC risk scores can also be applied to treated patients to exclude future HCC development, it should be noted that not all components of the risk scores were important HCC risk factors. In particular, a baseline or on-treatment HBV DNA level of ⩾2000 IU/ml was no longer associated with HCC. Instead, complete HBV DNA suppression and the duration of complete HBV DNA suppression were associated with HCC-free survival in cirrhotic patients [
      • Wong G.L.
      • Chan H.L.
      • Chan H.Y.
      • Tse P.C.
      • Tse Y.K.
      • Mak C.W.
      • et al.
      Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment.
      ]. The increased risk of disease progression and HCC development in treated patients with incomplete viral suppression has been independently confirmed in European and Korean cohorts [
      • Zoutendijk R.
      • Reijnders J.G.
      • Zoulim F.
      • Brown A.
      • Mutimer D.J.
      • Deterding K.
      • et al.
      Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis.
      ,
      • Cho J.Y.
      • Paik Y.H.
      • Sohn W.
      • Cho H.C.
      • Gwak G.Y.
      • Choi M.S.
      • et al.
      Patients with chronic hepatitis B treated with oral antiviral therapy retain a higher risk for HCC compared with patients with inactive stage disease.
      ]. This observation has two clinical implications. First, combination therapy or new treatment modalities may be needed in patients with incomplete HBV DNA suppression [
      • Chan H.L.
      • Chan C.K.
      • Hui A.J.
      • Chan S.
      • Poordad F.
      • Chang T.T.
      • et al.
      Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA.
      ]. Second, HCC risk scores may need to be refined for patients on antiviral therapy. In particular, since the majority of patients on entecavir and tenofovir treatment would have undetectable or very low level of HBV DNA, it may be necessary to use a lower HBV DNA cut-off in the risk scores. Alternatively, if HBV DNA is already insufficiently discriminatory in treated patients, it may have to be supplemented by other biomarkers such as HBsAg levels. Quantitative HBsAg has been tested as a biomarker of peginterferon response in chronic hepatitis B patients and can be used to predict spontaneous and treatment-induced HBsAg seroclearance [
      • Chan H.L.
      • Thompson A.
      • Martinot-Peignoux M.
      • Piratvisuth T.
      • Cornberg M.
      • Brunetto M.R.
      • et al.
      Hepatitis B surface antigen quantification: why and how to use it in 2011 – A core group report.
      ]. HBsAg levels correlate with HCC in patients with low-to-moderate but not high HBV DNA [
      • Tseng T.C.
      • Liu C.J.
      • Chen C.L.
      • Yang H.C.
      • Su T.H.
      • Wang C.C.
      • et al.
      Risk stratification of hepatocellular carcinoma in hepatitis B virus e antigen-negative carriers by combining viral biomarkers.
      ]. Hence, this marker may be most relevant in patients on antiviral therapy.

      Do HCC risk scores work in other populations?

      Since the above risk scores were all developed in Asian populations, the obvious question is whether they can be applied to other ethnic groups. There are reasons to suspect they may not. First, perinatal transmission accounts for over 90% of HBV infection in Asia. As a result, Asian patients typically have a long period of immune tolerance phase (20–40 years) before entering into the immune clearance phase [
      • Trepo C.
      • Chan H.L.
      • Lok A.
      Hepatitis B virus infection.
      ]. In contrast, horizontal transmission through unsafe sex practice and parenteral exposure is more common in Western countries. Patients acquiring HBV infection during adulthood do not go through the immune tolerance phase, and the interpretation and prognostic significance of the virological markers can be starkly different. Besides, because patients acquiring HBV through perinatal and horizontal transmission have different duration of infection, the incidence of cirrhosis and HCC is also different for patients at the same age. Finally, genetic differences of different ethnic groups may also contribute to a difference in the natural history of disease. Based on a systematic review of observational studies, the 5-year cumulative risk of HCC in cirrhotic patients is 17% in East Asia and 10% in Western Europe [
      • Fattovich G.
      • Bortolotti F.
      • Donato F.
      Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
      ].
      To date, HCC risk scores have been tested in two Western cohorts. In the Vigilance against Viral Resistance (VIRGIL) Surveillance Study, 744 patients with HBV monoinfection were treated with entecavir at 11 European centres [
      • Arends P.
      • Sonneveld M.J.
      • Zoutendijk R.
      • Carey I.
      • Brown A.
      • Fasano M.
      • et al.
      Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians.
      ]. 42% were Caucasians and 29% were Asians. During a median follow-up of 167 weeks, 14 patients developed HCC, of whom nine had cirrhosis at baseline and seven were Caucasians. The AUROC for HCC prediction of the GAG-HCC, CU-HCC and REACH-B scores in the entire cohort was 0.85, 0.78, and 0.71, respectively. The corresponding AUROC in Caucasian patients was 0.74, 0.66, and 0.54, respectively. The negative predictive values at the proposed cut-offs to exclude HCC at 4 years were 95%, 98%, and 95%, respectively (Table 4).
      Although the VIRGIL results suggest the risk scores may not perform as well in Caucasians, the short duration of follow-up and the small number of Caucasian patients with HCC preclude firm conclusions. Therefore, another multi-centre retrospective study was conducted to address this issue. 1666 patients from seven centres in Europe and Canada were treated with entecavir or tenofovir disoproxil fumarate [
      • Papatheodoridis G.V.
      • Dalekos G.N.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • Arends P.
      • et al.
      Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir.
      ]. The diagnosis of cirrhosis was based on histology, ultrasonographic findings or clinical portal hypertension. 28.6% of the patients had compensated cirrhosis and 3.3% had decompensated cirrhosis. During a median follow-up of 39 months, 71 developed HCC. In the entire population, the AUROC for HCC prediction of the GAG-HCC, CU-HCC, and REACH-B scores was 0.76, 0.62, and 0.61, respectively. In the PAGE-B score derived from this cohort, older age, male gender and low platelet count were the independent factors associated with HCC development (Table 4) [
      • Papatheodoridis G.V.
      • Dalekos G.N.
      • Sypsa V.
      • Yurdaydin C.
      • Buti M.
      • Goulis J.
      • et al.
      PAGE-B: risk score for hepatocellular carcinoma (HCC) development in Caucasian chronic hepatitis B (CHB) patients receiving entecavir (ETV) or tenofovir (TDF).
      ]. It is however difficult to distinguish whether the difference in score performance is due to ethnic influence or the disease-modifying effect of antiviral therapy. Suggestions on future research direction are listed in Table 5.
      Table 5Future research directions in HCC prediction.

      Diagnosis of cirrhosis as the Achilles heel

      Cirrhosis is the single most important risk factor of HCC and is an integral component of the GAG-HCC and CU-HCC scores. Current HBV treatment guidelines recommend liver biopsy in patients with borderline treatment indications [
      • Lok A.S.
      • McMahon B.J.
      Chronic hepatitis B: update 2009.
      ,
      European Association for the Study of the Liver
      EASL clinical practice guidelines: management of chronic hepatitis B virus infection.
      ,
      • Liaw Y.F.
      • Kao J.H.
      • Piratvisuth T.
      • Chan H.L.
      • Chien R.N.
      • Liu C.J.
      • et al.
      Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update.
      ], but the procedure is limited by its invasiveness and poor patient acceptance. In routine clinical practice, the diagnosis of cirrhosis is not uncommonly based on abdominal ultrasonography or clinical features of portal hypertension such as varices, ascites and splenomegaly. Early cirrhosis is often undiagnosed and the risk of HCC would be underestimated. The CU-HCC score partially compensates by including surrogates of cirrhosis such as albumin and bilirubin levels, but those are again insensitive markers of early cirrhosis [
      • Wong V.W.
      • Chan S.L.
      • Mo F.
      • Chan T.C.
      • Loong H.H.
      • Wong G.L.
      • et al.
      Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers.
      ].
      In recent years, liver stiffness measurement (LSM) by transient elastography (FibroScan®, Echosens, Paris, France) has become a popular non-invasive test of liver fibrosis in Europe and Asia [
      • Wong V.W.
      • Chan H.L.
      Transient elastography.
      ]. It is highly reproducible and has been validated against liver histology in patients with chronic hepatitis B [
      • Wong G.L.
      • Wong V.W.
      • Choi P.C.
      • Chan A.W.
      • Chum R.H.
      • Chan H.K.
      • et al.
      Assessment of fibrosis by transient elastography compared with liver biopsy and morphometry in chronic liver diseases.
      ,
      • Chan H.L.
      • Wong G.L.
      • Choi P.C.
      • Chan A.W.
      • Chim A.M.
      • Yiu K.K.
      • et al.
      Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B.
      ,
      • Marcellin P.
      • Ziol M.
      • Bedossa P.
      • Douvin C.
      • Poupon R.
      • de Ledinghen V.
      • et al.
      Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B.
      ]. The accuracy of LSM in diagnosing cirrhosis is good, with an AUROC of 0.80–0.95.
      Because LSM can accurately diagnose cirrhosis, it comes as no surprise that chronic hepatitis B patients with high LSM have increased risk of HCC. In a Korean cohort of 1130 patients with chronic hepatitis B followed for a median of 31 months, baseline LSM correlated with HCC risk in a dose-dependent manner [
      • Jung K.S.
      • Kim S.U.
      • Ahn S.H.
      • Park Y.N.
      • Kim do Y.
      • Park J.Y.
      • et al.
      Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement (FibroScan).
      ]. Compared with patients with LSM ⩽8.0 kPa, the hazard ratios of HCC for patients with LSM 8.1–13.0 kPa, 13.1–18.0 kPa, 13.1–23.0 kPa, and >23.0 kPa were 3.1, 4.7, 5.6, and 6.6, respectively.
      Since liver fibrosis and cirrhosis is just one of the risk factors of HCC in patients with chronic hepatitis B, it would be incomplete to rely on LSM alone to guide HCC surveillance. In a prospective cohort of 1555 patients in Hong Kong, LSM was combined with other clinical parameters to optimize the CU-HCC score [
      • Wong G.L.
      • Chan H.L.
      • Wong C.K.
      • Leung C.
      • Chan C.Y.
      • Ho P.P.
      • et al.
      Liver stiffness-based optimization of hepatocellular carcinoma risk score in patients with chronic hepatitis B.
      ]. During a mean follow-up of 69 months, 55 patients developed HCC. Independent predictors of HCC included age >50 years, albumin ⩽35 g/L, high HBV DNA and increased LSM (Table 3). After adjusting for other predictors, the hazard ratios for HCC were 3.9 for an LSM of 8.1–12.0 kPa and 6.0 for an LSM of >12.0 kPa. The AUROC of the LSM-HCC score was 0.89 at 3 years and 0.83 at 5 years; the corresponding AUROC of the CU-HCC score was 0.81 and 0.75, respectively. In another Korean cohort of 1250 patients with chronic hepatitis B followed for a median of 31 months, 56 patients developed HCC and the risk factors of HCC included age, male gender, LSM and HBV DNA [
      • Kim do Y.
      • Song K.J.
      • Kim S.U.
      • Yoo E.J.
      • Park J.Y.
      • Ahn S.H.
      • et al.
      Transient elastography-based risk estimation of hepatitis B virus-related occurrence of hepatocellular carcinoma: development and validation of a predictive model.
      ]. A regression formula including the four factors achieved an AUROC of 0.81 in predicting HCC. Similarly, in a smaller cohort of 192 patients with complete virological response with entecavir treatment from the same group, 25 patients developed liver-related events, including 15 having HCCs [
      • Lee M.H.
      • Yang H.I.
      • Liu J.
      • Batrla-Utermann R.
      • Jen C.L.
      • Iloeje U.H.
      • et al.
      Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles.
      ]. The addition of LSM to the REACH-B score had a higher AUROC to predict liver-related events than REACH-B score alone (0.81 vs. 0.63).
      Though the initial results are promising, it should be noted that transient elastography measures liver stiffness as a surrogate for fibrosis. Liver stiffness may also increase during active hepatic necroinflammation [
      • Wong G.L.
      • Wong V.W.
      • Choi P.C.
      • Chan A.W.
      • Chim A.M.
      • Yiu K.K.
      • et al.
      Increased liver stiffness measurement by transient elastography in severe acute exacerbation of chronic hepatitis B.
      ,
      • Wong V.W.
      • Lampertico P.
      • deLedinghen V.
      • Chang P.E.
      • Kim S.U.
      • Chen Y.
      • et al.
      Probability-based interpretation of liver stiffness measurement in untreated chronic hepatitis B patients.
      ], heart failure [
      • Millonig G.
      • Friedrich S.
      • Adolf S.
      • Fonouni H.
      • Golriz M.
      • Mehrabi A.
      • et al.
      Liver stiffness is directly influenced by central venous pressure.
      ], biliary obstruction [
      • Millonig G.
      • Reimann F.M.
      • Friedrich S.
      • Fonouni H.
      • Mehrabi A.
      • Buchler M.W.
      • et al.
      Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis.
      ] and food intake [
      • Mederacke I.
      • Wursthorn K.
      • Kirschner J.
      • Rifai K.
      • Manns M.P.
      • Wedemeyer H.
      • et al.
      Food intake increases liver stiffness in patients with chronic or resolved hepatitis C virus infection.
      ]. In particular, high ALT level contributes to increased liver stiffness. After ALT normalization with antiviral therapy, the liver stiffness typically declines even without regression of fibrosis [
      • Wong G.L.
      • Wong V.W.
      • Choi P.C.
      • Chan A.W.
      • Chim A.M.
      • Yiu K.K.
      • et al.
      On-treatment monitoring of liver fibrosis with transient elastography in chronic hepatitis B patients.
      ]. Whether the on-treatment liver stiffness remains robust in prognostication is currently unclear.
      Other than transient elastography, acoustic radiation force impulse, shear-wave elsatography and magnetic resonance elastography also provides physical measurements of liver elasticity or stiffness and have been used to diagnose cirrhosis in chronic hepatitis B [
      • Zhang D.
      • Chen M.
      • Wang R.
      • Liu Y.
      • Zhang D.
      • Liu L.
      • et al.
      Comparison of acoustic radiation force impulse imaging and transient elastography for non-invasive assessment of liver fibrosis in patients with chronic hepatitis B.
      ,
      • Leung V.Y.
      • Shen J.
      • Wong V.W.
      • Abrigo J.
      • Wong G.L.
      • Chim A.M.
      • et al.
      Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B carriers: comparison of shear-wave elastography and transient elastography with liver biopsy correlation.
      ,
      • Shi Y.
      • Guo Q.
      • Xia F.
      • Dzyubak B.
      • Glaser K.J.
      • Li Q.
      • et al.
      MR elastography for the assessment of hepatic fibrosis in patients with chronic hepatitis B infection: does histologic necroinflammation influence the measurement of hepatic stiffness?.
      ]. However, these techniques have not been extensively evaluated. The optimal cut-offs and their roles in HCC prediction are yet to be defined.
      In addition, a number of serum tests have been developed to aid the diagnosis of cirrhosis. Some serum tests make use of routine clinical parameters such as aspartate aminotransferase (AST)-to-ALT ratio, AST-to-platelet ratio index and the Hui’s index (body mass index, platelet count, albumin and bilirubin) [
      • Hui A.Y.
      • Chan H.L.
      • Wong V.W.
      • Liew C.T.
      • Chim A.M.
      • Chan F.K.
      • et al.
      Identification of chronic hepatitis B patients without significant liver fibrosis by a simple noninvasive predictive model.
      ,
      • Wong G.L.
      • Wong V.W.
      • Choi P.C.
      • Chan A.W.
      • Chan H.L.
      Development of a non-invasive algorithm with transient elastography (Fibroscan) and serum test formula for advanced liver fibrosis in chronic hepatitis B.
      ]. Other tests adopt specific biomarkers of fibrosis and have been commercialized as combined panels (e.g. FibroTest, enhanced liver fibrosis panel) [
      • Poynard T.
      • Zoulim F.
      • Ratziu V.
      • Degos F.
      • Imbert-Bismut F.
      • Deny P.
      • et al.
      Longitudinal assessment of histology surrogate markers (FibroTest-ActiTest) during lamivudine therapy in patients with chronic hepatitis B infection.
      ,
      • Wong G.L.
      • Chan H.L.
      • Choi P.C.
      • Chan A.W.
      • Yu Z.
      • Lai J.W.
      • et al.
      Non-invasive algorithm of enhanced liver fibrosis and liver stiffness measurement with transient elastography for advanced liver fibrosis in chronic hepatitis B.
      ]. Abnormal fibrosis biomarkers are associated with HCC development [
      • Kim B.K.
      • Kim H.S.
      • Yoo E.J.
      • Oh E.J.
      • Park J.Y.
      • Kim do Y.
      • et al.
      Risk assessment of clinical outcomes in Asian patients with chronic hepatitis B using enhanced liver fibrosis test.
      ]. Further studies are required to evaluate the possibility of combining these serum tests with other clinical parameters to improve HCC prediction.

      How may the knowledge of HCC risk be translated into clinical practice?

      Since all studies consistently showed that patients in the low risk group comprise over half of the population and have minimal risk of HCC in the next 3–5 years, it is reasonable and probably cost-effective to repeat abdominal ultrasonography in 3 years unless the clinical condition changes in between. We still recommend 6-monthly surveillance by abdominal ultrasonography for all patients outside the low risk group. Although some risk scores allow further differentiation of patients into different levels of risk, there is yet evidence to show a survival benefit in high risk patients receiving more frequent surveillance.
      If more frequent ultrasonography does not help, is it possible to use better tumor markers and imaging for surveillance in high risk patients? Other than AFP, the Lens culinaris agglutinin-reactive glycoform of AFP (AFP-L3), des-γ-carboxyprothrombin, Golgi protein 73 and osteopontin have been evaluated in the screening population [
      • Chaiteerakij R.
      • Addissie B.D.
      • Roberts L.R.
      Update on biomarkers of hepatocellular carcinoma.
      ,
      • Johnson P.J.
      • Pirrie S.J.
      • Cox T.F.
      • Berhane S.
      • Teng M.
      • Palmer D.
      • et al.
      The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers.
      ]. On the whole, these tumor markers have modest performance but may pick up a proportion of AFP-negative HCCs. Furthermore, the use of computed tomography and magnetic resonance imaging improves the detection of HCC particularly in cirrhotic patients [
      • Yu N.C.
      • Chaudhari V.
      • Raman S.S.
      • Lassman C.
      • Tong M.J.
      • Busuttil R.W.
      • et al.
      CT and MRI improve detection of hepatocellular carcinoma, compared with ultrasound alone, in patients with cirrhosis.
      ]. While it is unrealistic to use expensive cross-sectional imaging for surveillance in every patient with chronic hepatitis B, their use in high risk patients should be further evaluated.

      Conclusions

      Despite variable performance of the HCC risk scores in different populations, they consistently demonstrate high negative predictive values to exclude HCC development in the next 3 to 10 years in Asian and Caucasian chronic hepatitis B patients with and without antiviral therapy. While the performance of the risk scores appears to differ in cirrhotic and non-cirrhotic patients, it may be impractical to apply different scores for different populations in real-life practice, especially as the diagnosis of cirrhosis may be inaccurate. Instead, the inclusion of non-invasive tests of fibrosis in risk prediction should be more clinically meaningful. The apparent inferior performance of HCC risk scores in Caucasians may be explained by ethnic difference in the natural history of chronic hepatitis B, different proportion of patients with cirrhosis, short duration of follow-up and the influence of antiviral therapy. In any case, antiviral therapy is clearly an important disease modifier in both Asian and Caucasian patients. An updated HCC risk score for treated patients is likely needed.

      Conflict of interest

      Vincent Wong has served as an advisory board member for AbbVie and Gilead Sciences, a consultant for Merck and NovaMedica, and a speaker for Echosens and Gilead Sciences. Harry Janssen received grants from and is a consultant for Abbott, Anadys, Bristol-Myers Squibb, Gilead Sciences, Innogenetics, Medtronic, Merck, Novartis, Roche, Santaris and Tibotec.

      Authors’ contributions

      Vincent Wong and Harry Janssen shared writing of the manuscript.

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