INTRODUCTION

In 2024, an estimated 865,000 new cases of primary liver cancer were diagnosed, and 758,000 deaths were attributed to the disease, making it the sixth most common cancer and the third leading cause of cancer-related mortality worldwide.¹ Hepatocellular carcinoma (HCC) is the predominant histological type, accounting for approximately 80-85% of all primary liver cancers, followed by intrahepatic cholangiocarcinoma as the second most common subtype.²

HCC incidence peaks between the ages of 60 and 70 and disproportionately affects men.³ Its global distribution varies significantly by region, largely reflecting differences in the prevalence of underlying risk factors. Historically, chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections were the primary drivers of cirrhosis and HCC. However, major public health initiatives, including universal hepatitis B vaccination and the introduction of highly effective direct-acting antivirals (DAA) for hepatitis C, have led to substantial reductions in the burden of viral hepatitis.⁴ As a result, the etiological landscape of HCC is evolving, with non-viral causes -particularly metabolic dysfunction-associated steatotic liver disease (MASLD)- gaining increasing prominence.⁵

Despite recent progress, HCC remains a pressing global public health concern due to its frequent late-stage presentation, limited curative treatment options, and persistently high mortality.⁶ The increasing prevalence of metabolic risk factors, aging populations, and disparities in access to surveillance and care continue to drive HCC-related inequities. These trends underscore the need to revisit the current prevention and control strategies from a population health perspective. In this review, we synthesize the current evidence on the burden and epidemiology of HCC, highlight established and emerging risk factors, and evaluate strategies for prevention and control, including vaccination, antiviral therapies, and surveillance. We also discuss persistent challenges and future directions to inform more effective and equitable HCC control worldwide.

EPIDEMIOLOGY

Several well-established risk factors contribute to the global incidence of HCC. Table 1 summarizes the underlying mechanisms, global disease burdens, estimated population attributable fractions (PAFs), and relevant public health implications for each major risk factor. Although the proportion of HCC cases attributable to specific risk factors varies by geographic region, chronic HBV and HCV infections remain the predominant contributors worldwide.⁷ Notably, PAFs show substantial regional heterogeneity, for example, HBV accounts for 6% to 79% and HCV for 3% to 56% of HCC cases, depending on the setting.^7,8 Alcohol consumption contributes an estimated 13% to 37% of HCC cases globally,⁷ while obesity accounts for 4% to 24%,⁷ with estimates reaching up to 37% in the United States.^9,10 Although global estimates for aflatoxin exposure are lacking, regional studies suggest that 5% to 28% of HCC cases in high-exposure areas may be attributable to this carcinogen.^11-13 In contrast, robust PAF estimates are not yet available for family history or genetic susceptibility, though both are recognized as important contributors to individual HCC risk.

Chronic viral hepatitis

Chronic HBV and HCV infections remain major risk factors for HCC, particularly in East Asia.¹⁴ As of 2015, over 250 million people were living with chronic HBV infection. The highest prevalence of hepatitis B surface antigen (HBsAg) is observed in the Sub-Saharan African and Western Pacific regions, where the infection is considered to be high-intermediate to high endemicity (5% to ≥8%). In several countries with these regions, prevalence estimates exceed 15%. Regions with low-intermediate endemicity (2.0-5.0%) include parts of the Eastern Mediterranean and Europe,^15,16 while prevalence in most Western countries remains below 2%. Globally, chronic HBV accounts for approximately one-third of liver cirrhosis cases and contributes substantially to HCC development.^17,18 HBV seromarkers reflect different phases of the natural course of infection and play a central role in clinical management.¹⁹ Notably, serum levels of HBV DNA and hepatitis B e-antigen (HBeAg) seropositivity are strong predictors of HCC risk.^20,21 Quantitative HBsAg levels are also associated with the risk of cirrhosis and HCC,²² with their predictive value varying across immune phases of infection.²³ These markers reflect the natural history of HBV infection and are instrumental in risk stratification and management decisions.

In parallel, HCV infection also represents a major global health burden, with more than 70 million individuals infected worldwide. Prevalence is highest in Central Asia and the Mediterranean (>3.5%), compared to about 1.5% in North America.²⁴ Although the prevalence is lower in Western regions, HCV-related liver cancer is more frequently reported in Western Europe and North America. By early 2020, 56.8 million people were estimated to have active (viremic) HCV infection.²⁵ A community-based study has shown wide variation in anti-HCV prevalence (0.5-24.3%), highlighting marked geographic heterogeneity.²⁶ Notably, individuals residing in townships with high HCV viremia rates are more likely to be anti-HCV seropositive, suggesting that those with chronic HCV infection serve as reservoirs for ongoing transmission.²⁷ Effective management of HCV-infected individuals is therefore critical for population-level control. HCV infection is well established as a major risk factor for both HCC and liver-related mortality. Long-term cohort data indicate that approximately 1.3% to 51.0% of individuals with chronic HCV develop cirrhosis, and 0.1% to 5.3% progress to HCC over 3.9 to 25.0 years.^28,29 Notably, HCV RNA positivity is a strong predictor of future HCC risk, underscoring the importance of identifying and treating viremic cases.³⁰

Metabolic dysfunction-associated steatotic liver disease

The global prevalence of steatotic liver disease has increased substantially, currently affecting approximately 29.6% of the population, with projections indicating further growth by 2030.³¹ This alarming trend parallels the global obesity epidemic, driven by rising body mass index (BMI) worldwide. Clinically, steatosis is now categorized into three major forms: MASLD, MASLD with excessive alcohol consumption (MetALD), and alcohol-related liver disease (ALD).³² The adoption of the MASLD terminology reflects a paradigm shift toward improved diagnostic clarity, risk stratification, and management strategies. From a public health standpoint, the rise of MASLD reflects increasing global prevalence of obesity, insulin resistance, and type 2 diabetes. These metabolic conditions drive liver disease progression and elevate risks for cardiovascular and oncologic outcomes, underscoring MASLD as a multisystem disorder.³³ Addressing MASLD requires upstream interventions such as obesity prevention, lifestyle modification, and early metabolic screening. Integrating MASLD risk assessment into primary care and chronic disease management may help identify high-risk individuals earlier, especially in underserved populations. While earlier terms such as non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) were used interchangeably, these conditions share significant clinical overlap with MASLD.³⁴

MASLD is increasingly recognized as a major contributor to liver-related morbidity and mortality, including cirrhosis and HCC.⁵ Critically, MASLD may progress from simple steatosis to fibrosis and HCC, even in the absence of cirrhosis, over 35% of MASLD-related HCC cases occurring in non-cirrhotic individuals.³⁵ Longitudinal cohort studies have confirmed that MASLD significantly elevates the risk of cirrhosis and HCC.^36-38 Notably, MASLD also confers elevated HCC risk among patients with viral hepatitis who have achieved virological suppression, underscoring its growing importance in the post-antiviral era.³⁸ In a large European cohort of 18 million individuals, hazard ratios (HRs) for cirrhosis and HCC in NAFLD patients were 5.83 and 3.15, respectively, for non-alcoholic steatohepatitis (NASH), the risks escalated to 22.67 and 8.02, respectively.³⁶ A prospective cohort study of 332,175 participants further stratified risk by steatosis subtype, revealing HRs for cirrhosis of 1.30 for MASLD, 1.72 for MetALD, and 2.82 for ALD; corresponding HRs for HCC were 1.31, 1.83, and 1.52, respectively.³⁷ These data underscore the heterogeneous natural history and differential malignant potential across steatosis subtypes. Non-invasive indicators such as ultrasound-detected steatosis and elevated alanine aminotransferase (ALT) levels offer valuable tools for risk stratification. Persistently elevated ALT has been associated with increased risks of cirrhosis, HCC, and liver-related mortality, highlighting its role as a surrogate marker for steatohepatitis and a pragmatic approach to identifying high-risk individuals in population health management.^39,40 Unlike viral hepatitis-related HCC, where surveillance is recommended for patients with cirrhosis or specific risk profiles, current clinical guidelines generally do not recommend routine HCC surveillance in MASLD patients without cirrhosis.^41,42 However, accumulating evidence suggests that a substantial proportion of MASLD-related HCC cases arise in non-cirrhotic livers.⁴³ This discrepancy underscores a key challenge in MASLD management: the lack of clear risk stratification tools to identify high-risk individuals prior to cirrhosis development. Future efforts to develop and validate non-invasive biomarkers and risk prediction models tailored to MASLD populations are crucial to enabling earlier detection and informing targeted surveillance strategies.

Alcohol consumption

Excessive alcohol consumption remains a well-established and substantial risk factor for HCC.^44,45 Although global alcohol consumption per capita declined slightly from 5.7 L in 2010 to 5.5 L in 2019 (4.5% relative reduction), it remains high in many regions, particularly the World Health Organization (WHO) European Region (9.2 L) and the Region of the Americas (7.5 L).⁴⁶ In 2019 alone, alcohol contributed to an estimated 2 million deaths and accounted for 6.9% of all disability-adjusted life years (DALYs) among men, and 0.6 million deaths and 2.0% of DALYs among women.⁴⁶ Globally, the pooled proportion of HCC attributable to alcohol is approximately 30.4%, with regional variation, from 37.6% in Europe and 32.7% in the Western Pacific to 23.2% in South-East Asia and 15.8% in the Americas.⁴⁷

The hepatocarcinogenic effects of alcohol are mediated through several biological pathways, including acetaldehyde-induced DNA and protein adduct formation, enhanced oxidative stress, disruptions in lipid metabolism, chronic hepatic inflammation, impaired immune responses, and epigenetic modifications such as DNA methylation changes. In large European cohorts, patients with alcoholic cirrhosis exhibited an annual HCC incidence as high as 2.9%, with host factors such as age, sex, liver function, and genetic polymorphisms modulating individual risk profiles.⁴⁸ Alcohol also interacts synergistically with other HCC risk factors. In individuals consuming more than 80 g of alcohol per day, the relative risk of HCC rose dramatically among those with comorbid conditions, escalating from 2.4 to 9.9 in individuals with diabetes, and from 19.1 to 53.9 in those co-infected with HCV.⁴⁹ A pooled US cohort study further highlighted the complex interplay between alcohol and metabolic factors: light-to-moderate alcohol consumption was associated with a 35% reduced HCC risk among non-diabetics but conferred no such benefit in those with diabetes.⁵⁰ Furthermore, genetic polymorphisms that affect alcohol metabolism -particularly in alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2)- modulate both drinking behavior and HCC susceptibility, reinforcing the role of host genetics in shaping individual and population-level risks.⁵¹

Aflatoxin exposures

Aflatoxins, toxic secondary metabolites produced by Aspergillus species, commonly contaminate dietary staples such as maize, groundnuts, and tree nuts, particularly in warm and humid climates.⁵² Among these, aflatoxin B1 (AFB1) is the most potent and widely studied, classified as a group 1 human carcinogen due to its strong association with HCC.⁵³ Human exposure primarily occurs through the ingestion of contaminated food products, with the liver as the principal target organ. Once ingested, AFB1 is metabolically activated by hepatic cytochrome P450 enzymes into reactive intermediates that bind covalently to DNA, leading to mutagenic changes and genomic instability.

Epidemiologic studies from high-exposure regions in Asia and Africa have underscored the public health relevance of AFB1, with substantial proportions of liver cancer cases in these regions may be attributable to AFB1.^12,13 A striking example of effective primary prevention was observed in China in the mid- 1980s: economic reforms enabled the substitution of maize with rice in high-risk communities, resulting in a significant reduction in AFB1 exposure and a corresponding decline in liver cancer incidence.^54,55 This experience highlights the feasibility and impact of food policy interventions in reducing environmental carcinogen exposures.

Importantly, the carcinogenic potential of AFB1 is markedly amplified in the presence of chronic HBV infection. There is compelling evidence for a synergistic interaction between AFB1 exposure and HBV in elevating HCC risk.^56,57 In a nested case-control study among HBV-infected individuals, higher serum levels of AFB1-albumin adducts were associated with a significantly increased and earlier onset of cirrhosis and HCC, demonstrating a clear dose-response relationship.⁵⁸ Furthermore, a 20-year prospective study reported that elevated serum AFB1-albumin adducts predicted shorter time to HCC development among individuals with HCV infection and those without viral hepatitis but with habitual alcohol use.⁵⁹ These findings underscore the multifactorial nature of HCC pathogenesis and the need for integrated strategies targeting both infectious and environmental risk factors in high-burden settings.

Family history and genetic susceptibility

Familial clustering of HCC has been consistently observed across different populations, suggesting a heritable component to disease susceptibility.⁶⁰ Such aggregation may result from shared environmental exposures, lifestyle factors, and inherited genetic predispositions, or from complex interactions between these elements.⁶¹ As the understanding of cancer genomics evolves, genetic susceptibility has become increasingly recognized as a key contributor to HCC risk.⁶²

Recent advances in genomic research, particularly genomewide association studies (GWAS), have facilitated the systematic identification of single nucleotide polymorphisms (SNPs) associated with HCC risk.^63-70 These studies typically employ multistage analyses involving discovery and validation cohorts to ensure the robustness of identified associations. Early GWAS focused predominantly on individuals with chronic HBV or HCV infection, uncovering host genetic variants that modulate susceptibility to viral persistence, liver inflammation, fibrosis, and tumorigenesis.^63,70 Additionally, GWAS have identified variants associated with serologic markers -such as HbsAg positivity, HCV RNA clearance, and elevated liver enzymes- that may provide mechanistic insights into virus-related hepatocarcinogenesis.^65,66,71

Crucially, some genetic variants retain predictive value for HCC even after viral suppression or cure, emphasizing their potential utility in risk stratification and long-term surveillance planning.⁶⁷ More recently, attention has turned to uncovering genetic variants relevant in non-viral contexts.^64,68,69 Variants linked to MASLD and alcohol-related liver disease have been identified, expanding the spectrum of inherited risk factors beyond traditional viral etiologies.^64,68,69 This emerging body of evidence supports the integration of genetic profiling into risk prediction models, enabling more personalized approaches to HCC prevention and surveillance.⁷² From a public health perspective, incorporating genetic information into clinical decision-making could enhance risk-based screening strategies and inform the development of precision prevention programs.

PREVENTIVE STRATEGIES

From a public health perspective, HCC prevention must be addressed across multiple levels of intervention, as illustrated in Fig. 1. Primordial prevention aims to reduce the populationwide burden by addressing upstream social and environmental determinants of liver disease. Health education initiatives that promote liver health awareness and improve public understanding of liver disease risks are critical at this level. In addition, government policies that target risk reduction and foster healthier environments are essential. These strategies help raise population-level awareness and knowledge about liver diseases. Primary prevention focus on reducing risk factors before disease onset. Core strategies include universal hepatitis B vaccination, broader implementation and accessibility of antiviral therapies for viral hepatitis, and lifestyle interventions such as weight management, alcohol cessation, and health promotion to prevent metabolic dysfunction and toxin exposure. These efforts help reduce individual exposure to key risk factors for HCC. Secondary prevention centers on early disease detection to improve outcomes. This includes large-scale screening for HBV and HCV to identify infected individuals, along with routine HCC surveillance using ultrasonography and serum biomarkers in high-risk populations to enable early, curative intervention. Early identification and prompt linkage to clinical care are essential for these patients. Finally, tertiary prevention centers on the clinical management of diagnosed HCC to prevent progression, minimize complications, and enhance survival outcomes. Coordinated efforts across all levels of prevention are essential to reduce HCC incidence and mortality globally.

Coordinated efforts across all levels of prevention are essential to reduce the global burden of HCC. To strengthen this framework, we expanded the review to highlight key public health interventions. This includes a dedicated section on alcohol control strategies, presenting evidence that links policy measures to reductions in liver disease and HCC burden. We also emphasized the pivotal roles of HBV vaccination programs, antiviral therapy, and HCC surveillance in lowering population-level risk. Together, these strategies underscore the importance of multilevel, equity-oriented approaches in achieving comprehensive HCC prevention.

Alcohol control strategies

Alcohol consumption is a key contributor to global illness, disability, and mortality.⁷³ While numerous studies demonstrate that public health policies can reduce alcohol intake and associated harms, such as road traffic injuries,⁷⁴ fewer have evaluated their long-term effects on liver-related outcomes such as ALD and HCC. A recent study in Latin America showed that alcohol-related public health policies were strongly associated with reduced prevalence of alcohol use disorders and ALD mortality.⁷³ However, the impact of such policies may vary depending on global social, cultural, and economic contexts.⁷⁵ Another study developed an alcohol preparedness index (API) to assess policy strength and found that higher API scores were inversely associated with ALD mortality, alcohol-attributable HCC, and cancer-related mortality.⁷⁶ These findings support the long-term value of policy-based interventions. In the US, restrictive alcohol regulations were similarly linked to reduced ALD mortality, with alcohol taxes alone showing limited impact without price controls.⁷⁷ Furthermore, taxation and price regulation remain the most effective strategies for reducing alcohol-related mortality, though policy interactions and national contexts influence effectiveness.⁷⁸ Global Burden of Disease estimates suggest that stronger, age-targeted interventions are necessary, especially for individuals aged 15-39 years, who represent the majority of harmful drinkers worldwide.⁷⁹

HBV vaccination programs

Hepatitis B vaccination remains a cornerstone of public health strategies to prevent chronic HBV infection and its long-term complications, including cirrhosis and HCC. Since its incorporation into the WHO’s expanded program on immunization (EPI), HBV vaccination has led to marked reductions in HBV prevalence among children under 5 years of age, as well as declines in chronic HBV infection and HBV-related HCC incidence.⁸⁰ Recognizing its pivotal role, WHO has set a global target of achieving 90% vaccine coverage by 2030. Despite this, timely birth dose coverage remains inadequate, with substantial regional disparities and an overall global rate of just 46%.⁸¹ While early strategies focused on vaccinating high-risk groups, accumulating evidence underscores the superiority and sustainability of universal infant immunization.⁸²

Taiwan was the first country to implement a nationwide HBV immunization program in 1984. The program provided HBV vaccination to all newborns, and administered hepatitis B immunoglobulin (HBIG) within 24 hours to those born to HBeAg-positive mothers or those with high HBsAg titers. The immunization coverage quickly exceeded 90%, leading to substantial public health benefits. The HBsAg seropositive rate among children at age six declined dramatically, from over 10% in unvaccinated cohorts to less than 1% in those vaccinated.⁸³ After 35 years, the overall HBsAg and anti-hepatitis B core antibody (anti-HBc) seropositivity rates in the population declined to 4.05% and 21.3%, respectively, with significantly lower rates in vaccinated versus unvaccinated cohorts (HBsAg, 0.64% vs. 9.78%; anti-HBc, 2.1% vs. 53.55%; P<0.0001).⁸⁴ These findings underscore the long-term efficacy of universal HBV vaccination in infancy in preventing persistent infection and reducing HBV transmission.

Despite these successes, perinatal transmission remains a concern. Among vaccinated individuals who developed chronic infection, 89% had HBsAg-positive mothers,⁸⁵ underscoring the importance of HBIG administration at birth, particularly in hyperendemic regions.⁸⁶ The public health impact of this vaccination program has been extensively documented. Long-term cohort studies demonstrate significant reductions in fulminant hepatitis, chronic liver disease, and HCC incidence among vaccinated birth cohorts.⁸⁷ Importantly, incomplete immunization emerged as the strongest predictor of HCC, fulminant hepatitis, and chronic liver disease, with adjusted hazard ratios significantly elevated among those with partial vaccine coverage.⁸⁸ These findings reinforce the urgent need for universal, complete, and timely HBV immunization and support continued investment in vaccination programs as a foundational strategy in global HCC prevention.

Antiviral therapy for HBV and HCV

The WHO has set ambitious targets for the global control and eventual elimination of HBV and HCV infections. Without scaling up existing prevention and treatment interventions, modeling estimates predict that between 2015 and 2030, there could be 63 million new chronic infections and 17 million HBV-related deaths, particularly in low-resource settings where transmission persists and access to care remains limited.⁸⁹ Clinical guidelines strongly recommend that patients with chronic HBV or HCV infections receive antivirals to reduce their risk of end-stage liver disease.^41,42

Antiviral therapy serves as a key of HCC prevention among individuals chronically infected with HBV. The principal goals are to prevent liver failure, cirrhosis, and HCC by achieving sustained viral suppression, mitigating hepatic inflammation, and halting fibrosis progression. Antiviral treatment is recommended during the immunoactive phase of infection, typically characterized by elevated ALT levels and high HBV DNA concentrations (defined as >2,000 IU/mL in HBeAg-negative and >20,000 IU/mL in HBeAg-positive individuals) or when histological examination reveals at least moderate inflammation or fibrosis. All patients with cirrhosis should receive treatment regardless of ALT or HBV DNA levels.¹⁸ Suppression of HBV DNA to undetectable levels improves liver biochemistry and histological liver parameters and substantially reduces the risk of cirrhosis and HCC.⁹⁰ Moreover, even in patients with indeterminate clinical profiles, antiviral therapy has shown promising benefits in lowering HCC risk.⁹¹ A recent randomized controlled trial (RCT) further supports early initiation of tenofovir alafenamide, showing reduced rates of liver-related serious adverse events in non-cirrhotic individuals with moderate or high viremia, even those with normal ALT levels.⁹² Among patients with HBV-related HCC, antiviral therapy has been associated with improved survival outcomes; however, real-world treatment uptake remains suboptimal, highlighting persistent inequities and gaps in the implementation of care.⁹³

For HCV infection, the therapeutic landscape has been revolutionized by the introduction of DAA. Before DAA, interferon- based therapies -limited by modest efficacy and frequent adverse effects- restricted both uptake and adherence. DAAs, introduced in 2013, provide highly effective, well-tolerated, and orally administered therapy across all HCV genotypes, making them ideal for widespread population-based implementation. Achieving sustained virological response (SVR) through DAA therapy significantly reduces the risk of HCC, especially in patients without advanced fibrosis or cirrhosis. Nevertheless, in patients with established cirrhosis, risidual risk of HCC persists even after SVR, necessitating continued surveillance.⁹⁴ In addition to HCC prevention, SVR achieved with DAA therapy is associated with a reduced incidence of liver decompensation, improved management of extrahepatic conditions such as diabetes, cardiovascular disease, and chronic kidney disease, and overall reductions in mortality.⁹⁵ Notably, no significant differences have been observed in early HCC recurrence rates between patients treated with interferon-based versus DAA therapies following HCC treatment, alleviating prior concerns about DAA-associated recurrence.⁹⁶

At the population level, the impact of large-scale antiviral programs is clear. In Taiwan, a national antiviral treatment program targeting high-risk patients with chronic HBV and HCV infections was launched in October 2003. A population-based evaluation revealed substantial reductions in liver disease burden following its implementation: a 22% reduction in mortality from chronic liver disease and cirrhosis, a 24% reduction in HCC mortality, and a 14% reduction in HCC incidence between 2008 and 2011, compared to the period before the program (2000-2003).⁹⁷ These findings highlight that antiviral therapies not only yield individual-level clinical benefits but also translate into measurable public health gains by reducing the population burden of liver cancer and its complications.

Real-world progress toward hepatitis elimination

Several countries have made notable advances in viral hepatitis elimination, particularly targeting hepatitis C, through ambitious and well-coordinated national strategies. Egypt, which once had the world’s highest HCV prevalence due to past medical practices, launched a government-led campaign that combined price negotiations, bulk procurement, and domestic production of direct-acting antivirals DAAs.⁹⁸ This approach enabled free, large-scale screening and treatment, dramatically reducing the national HCV burden.⁹⁹ In Rwanda, a low-income country, a national HCV elimination program began in 2018. By 2022, over 7 million people had been screened and more than 60,000 treated.¹⁰⁰ Strategic drug pricing and efficient implementation are expected to help Rwanda eliminate HCV by 2027, 3 years ahead of the WHO target, while saving an estimated 25.3 million dollars in health system costs. Mongolia, which has the world’s highest liver cancer incidence,¹⁰¹ launched the Healthy Liver program to eliminate HCV and reduce mortality from cirrhosis and liver cancer through national screening, prevention, and treatment campaigns. These efforts show that hepatitis C elimination is feasible when supported by strong political commitment, strategic planning, and equitable access to care.

Several Asian countries have also demonstrated strong public health commitment.¹⁰² Taiwan provides universal DAA coverage,¹⁰³ has expanded community-based screening, and adopted micro-elimination strategies to reach the WHO’s 2030 goal by 2025. In Japan, HCV prevalence continues to decline, and high treatment uptake suggests the country is on track for elimination.¹⁰⁴ Continued efforts to address residual transmission risks and enhance coordination remain essential to sustain progress in hepatitis C control.

Early detection and HCC surveillance

Despite significant advances in therapeutic options, the overall prognosis for HCC remains poor, with 5-year survival rates below 20%.¹⁰⁵ The stage at diagnosis is the most critical determinant of prognosis. Curative treatments can yield 5-year survival rates exceeding 60% in early-stage HCC, whereas median survival drops to just 1-2 years for those diagnosed at advanced stages.^41,42,106 While RCTs are considered the gold standard for evaluating cancer screening efficacy, practical and ethical barriers have limited their application to HCC surveillance. Many patients are unwilling to accept randomization due to concerns about being assigned to a non-surveillance arm, and routine HCC screening is already widely practiced and accepted among both clinicians and patients. These factors render traditional RCTs ethically challenging and logistically difficult to implement in this context.¹⁰⁷

To date, RCTs evaluating the effectiveness of HCC surveillance remain limited. Table 2 summarizes findings from three such trials conducted in different settings and populations.^108-110 The landmark study by Zhang et al.¹¹⁰ was a community-based RCT of 18,816 HBsAg-positive individuals in China. Participants who received ultrasound and alpha-fetoprotein (AFP) testing every 6 months had significantly higher HCC detection rates, more early-stage diagnoses, and improved overall survival compared to those receiving no surveillance (HR for mortality, 0.63; 95% confidence interval [CI], 0.41-0.98). Notably, the compliance rate was only 58.2%, suggesting that the benefits observed may have underestimated the true efficacy of regular surveillance. In contrast, a multicenter, hospital-based RCT¹⁰⁸ involving 1,200 cirrhotic patients found no significant difference in HCC incidence or survival between ultrasound every 3 months and every 6 months, although detection of smaller tumors (<10 mm) was more frequent with shorter surveillance intervals. Similarly, a community-based trial of 744 HBV- or HCV-infected individuals comparing ultrasound every 4 months to every 12 months.¹⁰⁹ While differences in HCC incidence and survival were not statistically significant, early-stage tumors were more commonly detected with more frequent surveillance. Collectively, these studies suggest that HCC surveillance may improve early detection and potentially enhance survival in high-risk populations, but the magnitude of benefit varies depending on study design, patient characteristics, and surveillance adherence.

The optimal interval for HCC surveillance remains under investigation. However, most clinical guidelines currently recommend semiannual (every 6 months) surveillance for individuals at elevated risk, particularly those with hepatitis B, hepatitis C, or cirrhosis.^41,42,111 Evidence indicates that 6-month surveillance interval increases the likelihood of detecting HCC at an earlier, more treatable stage and reduces the number of advanced tumors compared to annual screening programs.¹¹² Moreover, shorter surveillance intervals have been associated with reduced overall mortality in a dose-dependent manner. In a large population-based study.¹¹³ when compared to 6-month surveillance, the adjusted HRs for mortality rose significantly among individuals receiving surveillance every 12 months (HR, 1.11; 95% CI, 1.07-1.15), 24 months (HR, 1.23; 95% CI, 1.19-1.28), 36 months (HR, 1.31; 95% CI, 1.26-1.37), and those who never underwent screening (HR, 1.47; 95% CI, 1.43-1.51), all with P<0.001. Another study indicated that patients with underlying hepatitis B or cirrhosis were found to have the greatest improvement in life expectancy with shorter screening intervals.¹¹⁴

In terms of surveillance modality, combining ultrasound with AFP measurement improves sensitivity for detecting early-stage HCC compared to ultrasound alone. A meta-analysis reported a pooled relative risk of 0.81 (95% CI, 0.71-0.93) for early HCC detection when comparing ultrasound alone to the combined approach, with respective sensitivities of 45% (95% CI, 30-62) and 63% (95% CI, 48-75).¹¹⁵ Despite strong evidence supporting the benefits of surveillance, its implementation remains suboptimal. For instance, an analysis of Taiwan’s National Health Insurance Research Database from 2000 to 2015 revealed that only 14% of individuals with HCV-related cirrhosis adhered to annual HCC surveillance.¹¹⁶ Multiple patient- and provider-related barriers contribute to this underutilization. Enhancing surveillance adherence among high-risk populations is therefore a critical public health priority in efforts to reduce HCC-related morbidity and mortality.

CHALLENGES IN HCC CONTROL: GAPS IN DIAGNOSIS, TREATMENT, AND SURVEILLANCE

Chronic HBV and HCV infections remain the primary etiological factors driving HCC worldwide. Expanding large-scale screening programs to improve the identification of individuals with chronic hepatitis is critical to initiating timely care. A global modeling study estimated that in the Asia-Pacific region, only 13% of individuals with chronic HBV infection were diagnosed, and just 25% of those diagnosed received antiviral treatment as of 2019.¹¹⁷ Several factors contribute to this considerable treatment gap, including financial barriers, limited access to quality-assured diagnostics and affordable medications, social stigma, and deficiencies in tracking individuals along the care continuum.¹¹⁸ Additionally, strict treatment eligibility criteria and inconsistencies across clinical guidelines introduce confusion among healthcare providers, further limiting the utilization of antiviral therapies.¹¹⁹

For HCV, although DAAs offer highly effective, well-tolerated, and curative treatment, access remains inadequate in many regions. The WHO estimated that in 2022, only 14% of individuals with HCV infection in Southeast Asia and 16% in the Western Pacific received treatment, with a global treatment rate of just 20%.¹¹⁹ These figures highlight critical implementation gaps that persist even in the face of highly efficacious treatments.

HCC surveillance has been shown to enable earlier detection of tumors and increase the probability of receiving curative treatments, regardless of whether the underlying etiology is HBV, HCV, or cirrhosis.¹²⁰ However, its implementation remains far from optimal. A systematic review and meta-analysis reported that fewer than 25% of at-risk individuals underwent surveillance in accordance with clinical guidelines.¹²¹ Both patient- and provider-level barriers contribute to this underutilization. On the patient side, challenges include financial burden, lack of awareness or understanding of HCC risk, logistical difficulties such as transportation, and limited health literacy. On the provider side, inconsistent recommendations, time constraints, and insufficient familiarity with current surveillance protocols hinder routine implementation.¹²²

Emerging evidence further underscores the critical impact of social determinants of health (SDoH) on HCC outcomes. A large US cohort study showed that prior surveillance was associated with higher rates of curative treatment, while disparities in care and healthcare costs were linked to race, education level, and language proficiency.¹²³ In Europe, persistent inequities in liver cancer prevention and care are observed among socioeconomically disadvantaged populations.¹²⁴ Additionally, social deprivation has been independently associated with increased HCC mortality.¹²⁵ These findings highlight the urgent need for equity-oriented public health strategies to improve early diagnosis and treatment access.

These multifaceted obstacles result in delayed diagnoses and missed opportunities for curative treatment. Improving HCC surveillance uptake -particularly among high-risk groups- is therefore a public health priority. Addressing these challenges demands coordinated efforts to scale up viral hepatitis screening and treatment, invest in provider education and clinical guideline harmonization, and implement patient-centered strategies to enhance surveillance adherence and accessibility.

CONCLUSIONS

HCC remains a major, yet preventable, global health challenge. Its development is driven by a complex interplay of risk factors, including chronic HBV and HCV infections, MASLD, excessive alcohol consumption, aflatoxin exposure, and genetic susceptibility. These diverse and often overlapping etiologies underscore the importance of a broad, population-based approach that integrates biological, behavioral, and social determinants of liver cancer risk.

From a public health perspective, effective tools for HCC prevention and control already exist. Universal HBV vaccination has dramatically reduced infection rates and HCC incidence in high-burden countries. The widespread availability of potent antiviral therapies for HBV and HCV offers the opportunity to reduce disease progression and HCC risk, provided that challenges related to access, affordability, and clinical implementation are effectively addressed. Furthermore, regular surveillance among high-risk individuals enables the early detection of HCC, improving eligibility for curative therapies and enhancing long-term survival outcomes.

Despite these significant achievements, substantial gaps remain. Inadequate viral screening, limited treatment coverage, underutilization of surveillance, and persistent inequities in healthcare systems undermine the impact of proven interventions. A comprehensive response is required, one that encompasses public health education, policy reform, health system strengthening, and equitable delivery of care. A renewed public health commitment -integrating prevention, early diagnosis, and continuity of care- is essential to reduce the global burden of HCC and close the gap between scientific knowledge and its implementation.

Article information

Data Availability

Not applicable.

Authors Contributions

Conceptualization: MHL

Funding acquisition: MHL

Writing - original draft: MHL

Writing - review & editing: MHL

Figure 1.

Prevention levels from a public health perspective in hepatocellular carcinoma. HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus.

References

• 1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229−263.ArticlePubMed
• 2. Gigante E, Paradis V, Ronot M, Cauchy F, Soubrane O, Ganne-Carrié N, et al. New insights into the pathophysiology and clinical care of rare primary liver cancers. JHEP Rep 2020;3:100174. ArticlePubMedPMC
• 3. Petrick JL, Florio AA, Znaor A, Ruggieri D, Laversanne M, Alvarez CS, et al. International trends in hepatocellular carcinoma incidence, 1978-2012. Int J Cancer 2020;147:317−330.ArticlePubMedPMCPDF
• 4. Tan EY, Danpanichkul P, Yong JN, Yu Z, Tan DJH, Lim WH, et al. Liver cancer in 2021: global burden of disease study. J Hepatol 2025;82:851−860.ArticlePubMed
• 5. Liu XR, Yin SC, Chen YT, Lee MH. Metabolic dysfunction-associated steatotic liver disease and its associated health risks. J Chin Med Assoc 2025;88:343−351.ArticlePubMed
• 6. Goutté N, Sogni P, Bendersky N, Barbare JC, Falissard B, Farges O. Geographical variations in incidence, management and survival of hepatocellular carcinoma in a Western country. J Hepatol 2017;66:537−544.ArticlePubMed
• 7. Baecker A, Liu X, La Vecchia C, Zhang ZF. Worldwide incidence of hepatocellular carcinoma cases attributable to major risk factors. Eur J Cancer Prev 2018;27:205−212.ArticlePubMedPMC
• 8. Zhou K, Lim T, Dodge JL, Terrault NA, Wilkens LR, Setiawan VW. Population-attributable risk of modifiable lifestyle factors to hepatocellular carcinoma: the multi-ethnic cohort. Aliment Pharmacol Ther 2023;58:89−98.ArticlePubMedPMC
• 9. Welzel TM, Graubard BI, Quraishi S, Zeuzem S, Davila JA, El-Serag HB, et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am J Gastroenterol 2013;108:1314−1321.ArticlePubMedPMCPDF
• 10. Makarova-Rusher OV, Altekruse SF, McNeel TS, Ulahannan S, Duffy AG, Graubard BI, et al. Population attributable fractions of risk factors for hepatocellular carcinoma in the United States. Cancer 2016;122:1757−1765.ArticlePubMedPMC
• 11. Fan JH, Wang JB, Jiang Y, Xiang W, Liang H, Wei WQ, et al. Attributable causes of liver cancer mortality and incidence in china. Asian Pac J Cancer Prev 2013;14:7251−7256.ArticlePubMed
• 12. Liu Y, Chang CC, Marsh GM, Wu F. Population attributable risk of aflatoxin-related liver cancer: systematic review and meta-analysis. Eur J Cancer 2012;48:2125−2136.ArticlePubMedPMC
• 13. Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect 2010;118:818−824.ArticlePubMedPMC
• 14. de Martel C, Maucort-Boulch D, Plummer M, Franceschi S. World-wide relative contribution of hepatitis B and C viruses in hepatocellular carcinoma. Hepatology 2015;62:1190−1200.ArticlePubMedPMCPDF
• 15. Nelson NP, Easterbrook PJ, McMahon BJ. Epidemiology of hepatitis B virus infection and impact of vaccination on disease. Clin Liver Dis 2016;20:607−628.ArticlePubMedPMC
• 16. 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.PubMedPMC
• 17. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006;45:529−538.ArticlePubMed
• 18. Tang LSY, Covert E, Wilson E, Kottilil S. Chronic hepatitis B infection: a review. JAMA 2018;319:1802−1813.ArticlePubMed
• 19. Chen CJ, Yang HI. Natural history of chronic hepatitis B REVEALed. J Gastroenterol Hepatol 2011;26:628−638.ArticlePubMed
• 20. 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.ArticlePubMed
• 21. Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168−174.ArticlePubMed
• 22. Lee MH, Yang HI, Liu J, Batrla-Utermann R, Jen CL, Iloeje UH, et al. Prediction models of long-term cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B patients: risk scores integrating host and virus profiles. Hepatology 2013;58:546−554.ArticlePubMed
• 23. Tseng TC, Hosaka T, Pan MH, Liu CJ, Suzuki F, Chen CJ, et al. Higher level of HBsAg associated with delayed development of HCC in immune-tolerant patients. Hepatology 2025;Mar 25 doi: 10.1097/HEP.0000000000001313. [Epub ahead of print].Article
• 24. Petruzziello A, Marigliano S, Loquercio G, Cozzolino A, Cacciapuoti C. Global epidemiology of hepatitis C virus infection: an up-date of the distribution and circulation of hepatitis C virus genotypes. World J Gastroenterol 2016;22:7824−7840.ArticlePubMedPMC
• 25. Polaris Observatory HCV Collaborators. Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study. Lancet Gastroenterol Hepatol 2022;7:396−415.PubMed
• 26. Lee MH, Yang HI, Yuan Y, L'Italien G, Chen CJ. Epidemiology and natural history of hepatitis C virus infection. World J Gastroenterol 2014;20:9270−9280.PubMedPMC
• 27. Lee MH, Yang HI, Jen CL, Lu SN, Yeh SH, Liu CJ, et al. Community and personal risk factors for hepatitis C virus infection: a survey of 23,820 residents in Taiwan in 1991-2. Gut 2011;60:688−694.ArticlePubMed
• 28. Wiese M, Grüngreiff K, Güthoff W, Lafrenz M, Oesen U, Porst H, et al. Outcome in a hepatitis C (genotype 1b) single source outbreak in Germany--a 25-year multicenter study. J Hepatol 2005;43:590−598.ArticlePubMed
• 29. Tong MJ, el-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995;332:1463−1466.ArticlePubMed
• 30. Lee MH, Yang HI, Lu SN, Jen CL, Yeh SH, Liu CJ, et al. Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: longterm predictors from a community-based cohort study. J Clin Oncol 2010;28:4587−4593.ArticlePubMed
• 31. Estes C, Chan HLY, Chien RN, Chuang WL, Fung J, Goh GB, et al. Modelling NAFLD disease burden in four Asian regions-2019-2030. Aliment Pharmacol Ther 2020;51:801−811.ArticlePubMedPMCPDF
• 32. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 2023;79:1542−1556.PubMed
• 33. Yin SC, Chen YT, Chang WT, Chen TI, Yang TH, Liu XR, et al. Attributable burden of steatotic liver disease on cardiovascular outcomes in Asia. JHEP Rep 2025;7:101479. ArticlePubMedPMC
• 34. Hagström H, Vessby J, Ekstedt M, Shang Y. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J Hepatol 2024;80:e76−e77.ArticlePubMed
• 35. Mittal S, El-Serag HB, Sada YH, Kanwal F, Duan Z, Temple S, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2016;14:124−131.e1.ArticlePubMedPMC
• 36. Alexander M, Loomis AK, van der Lei J, Duarte-Salles T, Prieto-Alhambra D, Ansell D, et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: realworld study of 18 million patients in four European cohorts. BMC Med 2019;17:95. ArticlePubMedPMCPDF
• 37. Chen YT, Chen TI, Yang TH, Yin SC, Lu SN, Liu XR, et al. Long-term risks of cirrhosis and hepatocellular carcinoma across steatotic liver disease subtypes. Am J Gastroenterol 2024;119:2241−2250.ArticlePubMedPMC
• 38. Lee MH, Chen YT, Huang YH, Lu SN, Yang TH, Huang JF, et al. Chronic viral hepatitis B and C outweigh MASLD in the associated risk of cirrhosis and HCC. Clin Gastroenterol Hepatol 2024;22:1275−1285.e2.ArticlePubMed
• 39. Huang YH, Chan C, Lee HW, Huang C, Chen YJ, Liu PC, et al. Influence of nonalcoholic fatty liver disease with increased liver enzyme levels on the risk of cirrhosis and hepatocellular carcinoma. Clin Gastroenterol Hepatol 2023;21:960−969.e1.ArticlePubMedPMC
• 40. Chen YT, Chen TI, Yin SC, Huang CW, Huang JF, Lu SN, et al. Prevalence, proportions of elevated liver enzyme levels, and long-term cardiometabolic mortality of patients with metabolic dysfunction-associated steatotic liver disease. J Gastroenterol Hepatol 2024;39:1939−1949.ArticlePubMed
• 41. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of hepatocellular carcinoma. J Hepatol 2025;82:315−374.ArticlePubMed
• 42. 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.ArticlePubMedPDF
• 43. Stine JG, Wentworth BJ, Zimmet A, Rinella ME, Loomba R, Caldwell SH, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharmacol Ther 2018;48:696−703.ArticlePubMedPMCPDF
• 44. Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V, et al. Alcohol consumption and site-specific cancer risk: a comprehensive doseresponse meta-analysis. Br J Cancer 2015;112:580−593.ArticlePubMedPMCPDF
• 45. Turati F, Galeone C, Rota M, Pelucchi C, Negri E, Bagnardi V, et al. Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies. Ann Oncol 2014;25:1526−1535.ArticlePubMed
• 46. World Health Organization. Global status report on alcohol and health and treatment of substance use disorders [Internet]. Geneva (CH): World Health Organization; [cited 2024 Jun 25]. Available from: https://www.who.int/publications/i/item/9789240096745
• 47. Zeng RW, Ong CEY, Ong EYH, Chung CH, Lim WH, Xiao J, et al. Global prevalence, clinical characteristics, surveillance, treatment allocation, and outcomes of alcohol-associated hepatocellular carcinoma. Clin Gastroenterol Hepatol 2024;22:2394−2402. e15.ArticlePubMed
• 48. Ganne-Carrié N, Nahon P. Hepatocellular carcinoma in the setting of alcohol-related liver disease. J Hepatol 2019;70:284−293.ArticlePubMed
• 49. Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 2002;36:1206−1213.ArticlePubMedPDF
• 50. Petrick JL, Campbell PT, Koshiol J, Thistle JE, Andreotti G, Beane-Freeman LE, et al. Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the liver cancer pooling project. Br J Cancer 2018;118:1005−1012.ArticlePubMedPMCPDF
• 51. Liu J, Yang HI, Lee MH, Jen CL, Hu HH, Lu SN, et al. Alcohol drinking mediates the association between polymorphisms of ADH1B and ALDH2 and hepatitis B-related hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev 2016;25:693−699.ArticlePubMedPDF
• 52. International Agency for Research on Cancer. Overall evaluations of carcinogenicity: an updating of IARC monographs volumes 1 to 42. IARC Monogr Eval Carcinog Risks Hum Suppl 1987;7:1−440.PubMed
• 53. Wild CP, Turner PC. The toxicology of aflatoxins as a basis for public health decisions. Mutagenesis 2002;17:471−481.ArticlePubMed
• 54. Chen JG, Egner PA, Ng D, Jacobson LP, Muñoz A, Zhu YR, et al. Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 2013;6:1038−1045.ArticlePubMedPMCPDF
• 55. Sun Z, Chen T, Thorgeirsson SS, Zhan Q, Chen J, Park JH, et al. Dramatic reduction of liver cancer incidence in young adults: 28 year follow-up of etiological interventions in an endemic area of China. Carcinogenesis 2013;34:1800−1805.ArticlePubMedPMC
• 56. Wu HC, Santella R. The role of aflatoxins in hepatocellular carcinoma. Hepat Mon 2012;12:e7238.ArticlePubMedPMC
• 57. Wu HC, Wang Q, Yang HI, Ahsan H, Tsai WY, Wang LY, et al. Aflatoxin B1 exposure, hepatitis B virus infection, and hepatocellular carcinoma in Taiwan. Cancer Epidemiol Biomarkers Prev 2009;18:846−853.ArticlePubMedPMCPDF
• 58. Chu YJ, Yang HI, Wu HC, Liu J, Wang LY, Lu SN, et al. Aflatoxin B1 exposure increases the risk of cirrhosis and hepatocellular carcinoma in chronic hepatitis B virus carriers. Int J Cancer 2017;141:711−720.ArticlePubMedPMCPDF
• 59. Chu YJ, Yang HI, Wu HC, Lee MH, Liu J, Wang LY, et al. Aflatoxin B1 exposure increases the risk of hepatocellular carcinoma associated with hepatitis C virus infection or alcohol consumption. Eur J Cancer 2018;94:37−46.ArticlePubMedPMC
• 60. Turati F, Edefonti V, Talamini R, Ferraroni M, Malvezzi M, Bravi F, et al. Family history of liver cancer and hepatocellular carcinoma. Hepatology 2012;55:1416−1425.ArticlePubMed
• 61. 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.e1-3.ArticlePubMedPMC
• 62. Yang TH, Chan C, Yang PJ, Huang YH, Lee MH. Genetic susceptibility to hepatocellular carcinoma in patients with chronic hepatitis virus infection. Viruses 2023;15:559. ArticlePubMedPMC
• 63. Lee MH, Huang YH, Chen HY, Khor SS, Chang YH, Lin YJ, et al. Human leukocyte antigen variants and risk of hepatocellular carcinoma modified by hepatitis C virus genotypes: a genome-wide association study. Hepatology 2018;67:651−661.ArticlePubMedPDF
• 64. Hassan MM, Li D, Han Y, Byun J, Hatia RI, Long E, et al. Genome-wide association study identifies high-impact susceptibility loci for HCC in North America. Hepatology 2024;80:87−101.PubMed
• 65. Huang YH, Liao SF, Khor SS, Lin YJ, Chen HY, Chang YH, et al. Large-scale genome-wide association study identifies HLA class II variants associated with chronic HBV infection: a study from Taiwan Biobank. Aliment Pharmacol Ther 2020;52:682−691.ArticlePubMedPDF
• 66. Liu PC, Chan C, Huang YH, Chen YJ, Liao SF, Lin YJ, et al. Genetic variants associated with serum alanine aminotransferase levels among patients with hepatitis C virus infection: a genome-wide association study. J Viral Hepat 2021;28:1265−1273.ArticlePubMedPDF
• 67. Matsuura K, Sawai H, Ikeo K, Ogawa S, Iio E, Isogawa M, et al. Genomewide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection. Gastroenterology 2017;152:1383−1394.ArticlePubMed
• 68. Trépo E, Caruso S, Yang J, Imbeaud S, Couchy G, Bayard Q, et al. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study. Lancet Oncol 2022;23:161−171.ArticlePubMed
• 69. Wang Z, Budhu AS, Shen Y, Wong LL, Hernandez BY, Tiirikainen M, et al. Genetic susceptibility to hepatocellular carcinoma in chromosome 22q13.31, findings of a genome-wide association study. JGH Open 2021;5:1363−1372.ArticlePubMedPMCPDF
• 70. 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.ArticlePubMedPDF
• 71. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798−801.ArticlePubMedPMCPDF
• 72. Nahon P, Bamba-Funck J, Layese R, Trépo E, Zucman-Rossi J, Cagnot C, et al. Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosis. J Hepatol 2023;78:584−595.PubMed
• 73. Díaz LA, Idalsoaga F, Fuentes-López E, Márquez-Lomas A, Ramírez CA, Roblero JP, et al. Impact of public health policies on alcohol-associated liver disease in Latin America: an ecological multinational study. Hepatology 2021;74:2478−2490.ArticlePubMedPDF
• 74. Ayares G, Idalsoaga F, Arnold J, Fuentes-López E, Arab JP, Díaz LA. Public health measures and prevention of alcohol-associated liver disease. J Clin Exp Hepatol 2022;12:1480−1491.ArticlePubMedPMC
• 75. Díaz LA, Roblero JP, Bataller R, Arab JP. Alcohol-related liver disease in Latin America: local solutions for a global problem. Clin Liver Dis (Hoboken) 2020;16:187−190.ArticlePubMedPMCPDF
• 76. Díaz LA, Fuentes-López E, Idalsoaga F, Ayares G, Corsi O, Arnold J, et al. Association between public health policies on alcohol and worldwide cancer, liver disease and cardiovascular disease outcomes. J Hepatol 2024;80:409−418.ArticlePubMed
• 77. Parikh ND, Chung GS, Mellinger J, Blanchette JG, Naimi TS, Tapper EB. Alcohol policies and alcohol-related liver disease mortality. Gastroenterology 2021;161:350−352.ArticlePubMedPMC
• 78. Ventura-Cots M, Ballester-Ferré MP, Ravi S, Bataller R. Public health policies and alcohol-related liver disease. JHEP Rep 2019;1:403−413.ArticlePubMedPMC
• 79. GBD 2020 Alcohol Collaborators. Population-level risks of alcohol consumption by amount, geography, age, sex, and year: a systematic analysis for the Global Burden of Disease Study 2020. Lancet 2022;400:185−235.PubMedPMC
• 80. Wong GL, Hui VW, Yip TC, Liang LY, Zhang X, Tse YK, et al. Universal HBV vaccination dramatically reduces the prevalence of HBV infection and incidence of hepatocellular carcinoma. Aliment Pharmacol Ther 2022;56:869−877.ArticlePubMedPDF
• 81. Al-Busafi SA, Alwassief A. Global perspectives on the hepatitis B vaccination: challenges, achievements, and the road to elimination by 2030. Vaccines (Basel) 2024;12:288. ArticlePubMedPMC
• 82. Pattyn J, Hendrickx G, Vorsters A, Van Damme P. Hepatitis B vaccines. J Infect Dis 2021;224 Suppl 2:S343−S351.ArticlePubMedPMCPDF
• 83. Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336:1855−1859.ArticlePubMed
• 84. Chang KC, Chang MH, Chen HL, Cheng FW, Wu JF, Su WJ, et al. Survey of hepatitis B virus infection status after 35 years of universal vaccination implementation in Taiwan. Liver Int 2024;44:2054−2062.ArticlePubMed
• 85. Ni YH, Huang LM, Chang MH, Yen CJ, Lu CY, You SL, et al. Two decades of universal hepatitis B vaccination in taiwan: impact and implication for future strategies. Gastroenterology 2007;132:1287−1293.ArticlePubMed
• 86. Chien YC, Jan CF, Kuo HS, Chen CJ. Nationwide hepatitis B vaccination program in Taiwan: effectiveness in the 20 years after it was launched. Epidemiol Rev 2006;28:126−135.ArticlePubMed
• 87. Chiang CJ, Yang YW, You SL, Lai MS, Chen CJ. Thirty-year outcomes of the national hepatitis B immunization program in Taiwan. JAMA 2013;310:974−976.ArticlePubMed
• 88. Chien YC, Jan CF, Chiang CJ, Kuo HS, You SL, Chen CJ. Incomplete hepatitis B immunization, maternal carrier status, and increased risk of liver diseases: a 20-year cohort study of 3.8 million vaccinees. Hepatology 2014;60:125−132.ArticlePubMed
• 89. Nayagam S, Thursz M, Sicuri E, Conteh L, Wiktor S, Low-Beer D, et al. Requirements for global elimination of hepatitis B: a modelling study. Lancet Infect Dis 2016;16:1399−1408.ArticlePubMed
• 90. Dusheiko G, Agarwal K, Maini MK. New approaches to chronic hepatitis B. N Engl J Med 2023;388:55−69.ArticlePubMed
• 91. Lai JC, Wong GL, Tse YK, Hui VW, Lai MS, Chan HL, et al. Histological severity, clinical outcomes and impact of antiviral treatment in indeterminate phase of chronic hepatitis B: a systematic review and metaanalysis. J Hepatol 2025;82:992−1003.ArticlePubMed
• 92. Lim YS, Yu ML, Choi J, Chen CY, Choi WM, Kang W, et al. Early antiviral treatment with tenofovir alafenamide to prevent serious clinical adverse events in adults with chronic hepatitis B and moderate or high viraemia (ATTENTION): interim results from a randomised controlled trial. Lancet Gastroenterol Hepatol 2025;10:295−305.ArticlePubMed
• 93. Kudaravalli S, Kam LY, Huang DQ, Cheung R, Nguyen MH. Utilization of antiviral therapy for patients with hepatitis B-related hepatocellular carcinoma: a nationwide real-world US study. Clin Gastroenterol Hepatol 2023;21:3305−3313.e4.ArticlePubMed
• 94. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 2017;153:996−1005.e1.ArticlePubMed
• 95. Ogawa E, Chien N, Kam L, Yeo YH, Ji F, Huang DQ, et al. Association of direct-acting antiviral therapy with liver and nonliver complications and long-term mortality in patients with chronic hepatitis C. JAMA Intern Med 2023;183:97−105.ArticlePubMedPMC
• 96. Kinoshita MN, Minami T, Tateishi R, Wake T, Nakagomi R, Fujiwara N, et al. Impact of direct-acting antivirals on early recurrence of HCV-related HCC: comparison with interferon-based therapy. J Hepatol 2019;70:78−86.ArticlePubMed
• 97. Chiang CJ, Yang YW, Chen JD, You SL, Yang HI, Lee MH, et al. Significant reduction in end-stage liver diseases burden through the national viral hepatitis therapy program in Taiwan. Hepatology 2015;61:1154−1162.ArticlePubMed
• 98. Waked I, Esmat G, Elsharkawy A, El-Serafy M, Abdel-Razek W, Ghalab R, et al. Screening and treatment program to eliminate hepatitis C in Egypt. N Engl J Med 2020;382:1166−1174.ArticlePubMed
• 99. Gomaa A, Gomaa M, Allam N, Waked I. Hepatitis C elimination in Egypt: story of success. Pathogens 2024;13:681. ArticlePubMedPMC
• 100. Zhong H, Aaron A, Hiebert L, Serumondo J, Zhuo Y, Adee M, et al. Hepatitis C elimination in Rwanda: progress, feasibility, and economic evaluation. Value Health 2024;27:918−925.ArticlePubMed
• 101. Znaor A, Chimed T, Laversanne M, Tudev U, Sanjaajamts E, Sandagdorj T, et al. The public health challenge of liver cancer in Mongolia. Lancet Gastroenterol Hepatol 2018;3:660−662.ArticlePubMed
• 102. Liu CH, Lin HC, Kao JH. Toward the hepatitis C virus elimination in Asia: the policy forum from the 2023 Asian Pacific Association of the Study of the Liver (APASL). J Formos Med Assoc 2023;122:1234−1237.ArticlePubMed
• 103. Chen DS. Taiwan commits to eliminating hepatitis C in 2025. Lancet Infect Dis 2019;19:466−467.ArticlePubMed
• 104. Ko K, Akita T, Satake M, Tanaka J. Epidemiology of viral hepatitis C: road to elimination in Japan. Glob Health Med 2021;3:262−269.ArticlePubMedPMC
• 105. Moon AM, Singal AG, Tapper EB. Contemporary epidemiology of chronic liver disease and cirrhosis. Clin Gastroenterol Hepatol 2020;18:2650−2666.ArticlePubMedPMC
• 106. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021;7:6. ArticlePubMedPDF
• 107. Poustchi H, Farrell GC, Strasser SI, Lee AU, McCaughan GW, George J. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed? Hepatology 2011;54:1998−2004.ArticlePubMed
• 108. Trinchet JC, 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. Hepatology 2011;54:1987−1997.ArticlePubMed
• 109. Wang JH, Chang KC, Kee KM, Chen PF, Yen YH, Tseng PL, et al. Hepatocellular carcinoma surveillance at 4- vs. 12-month intervals for patients with chronic viral hepatitis: a randomized study in community. Am J Gastroenterol 2013;108:416−424.ArticlePubMedPDF
• 110. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417−422.ArticlePubMedPMCPDF
• 111. Cho Y, Kim BH, Park JW. Overview of Asian clinical practice guidelines for the management of hepatocellular carcinoma: an Asian perspective comparison. Clin Mol Hepatol 2023;29:252−262.ArticlePubMedPMCPDF
• 112. Santi V, Trevisani F, Gramenzi A, Grignaschi A, Mirici-Cappa F, Del Poggio P, et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J Hepatol 2010;53:291−297.ArticlePubMed
• 113. Wu CY, Hsu YC, Ho HJ, Chen YJ, Lee TY, Lin JT. Association between ultrasonography screening and mortality in patients with hepatocellular carcinoma: a nationwide cohort study. Gut 2016;65:693−701.ArticlePubMed
• 114. Kuo SC, Lin CN, Lin YJ, Chen WY, Hwang JS, Wang JD. Optimal intervals of ultrasonography screening for early diagnosis of hepatocellular carcinoma in Taiwan. JAMA Netw Open 2021;4:e2114680.ArticlePubMedPMC
• 115. Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology 2018;154:1706−1718.e1.ArticlePubMedPMC
• 116. Chang SS, Hu HY, Cheng FS, Chen YC, Yen YF, Huang N. Factors associated with nonadherence to surveillance for hepatocellular carcinoma among patients with hepatic C virus cirrhosis, 2000-2015. Medicine (Baltimore) 2022;101:e31907.ArticlePubMedPMC
• 117. Le LV, Blach S, Rewari B, Chan P, Fuqiang C, Ishikawa N, et al. Progress towards achieving viral hepatitis B and C elimination in the Asia and Pacific region: results from modelling and global reporting. Liver Int 2022;42:1930−1934.ArticlePubMedPDF
• 118. Mak LY, Liu K, Chirapongsathorn S, Yew KC, Tamaki N, Rajaram RB, et al. Liver diseases and hepatocellular carcinoma in the Asia-Pacific region: burden, trends, challenges and future directions. Nat Rev Gastroenterol Hepatol 2024;21:834−851.ArticlePubMedPDF
• 119. World Health Organization. Global hepatitis report 2024: action for access in low- and middle-income countries [Internet]. Geneva (CH): World Health Organization; [cited 2024 Apr 9]. Available from: https://www.who.int/publications/i/item/9789240091672
• 120. Sohn W, Kang D, Kang M, Guallar E, Cho J, Paik YH. Impact of nationwide hepatocellular carcinoma surveillance on the prognosis in patients with chronic liver disease. Clin Mol Hepatol 2022;28:851−863.ArticlePubMedPMCPDF
• 121. Wolf E, Rich NE, Marrero JA, Parikh ND, Singal AG. Use of hepatocellular carcinoma surveillance in patients with cirrhosis: a systematic review and meta-analysis. Hepatology 2021;73:713−725.ArticlePubMedPMCPDF
• 122. Huang DQ, Singal AG, Kanwal F, Lampertico P, Buti M, Sirlin CB, et al. Hepatocellular carcinoma surveillance - utilization, barriers and the impact of changing aetiology. Nat Rev Gastroenterol Hepatol 2023;20:797−809.ArticlePubMedPDF
• 123. Singal AG, Kilgore KM, Shvets E, Parikh ND, Mehta N, Ozbay AB, et al. Impact of social determinants of health on hepatocellular carcinoma surveillance, treatment, and health care costs. Hepatol Commun 2024;8:e0517.ArticlePubMedPMC
• 124. Kondili LA, Lazarus JV, Jepsen P, Murray F, Schattenberg JM, Korenjak M, et al. Inequities in primary liver cancer in Europe: the state of play. J Hepatol 2024;80:645−660.ArticlePubMed
• 125. Nephew LD, Gupta D, Carter A, Desai AP, Ghabril M, Patidar KR, et al. Social determinants of health impact mortality from HCC and cholangiocarcinoma: a population-based cohort study. Hepatol Commun 2023;7:e0058.ArticlePubMedPMC

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