Liver Cancer Prevention

In This Section

• Who Is at Risk?
• Factors With Adequate Evidence of Increased Risk of Hepatocellular Cancer (HCC)
  • Chronic hepatitis B virus (HBV) infection
  • Chronic hepatitis C virus (HCV) infection
  • Cirrhosis
  • Heavy alcohol use
  • Aflatoxin B1
  • Nonalcoholic steatohepatitis (NASH)
  • Cigarette smoking
  • Certain rare genetic and medical conditions (untreated hereditary hemochromatosis [HH], alpha-1-antitrypsin deficiency, glycogen storage disease, porphyria cutanea tarda, and Wilson disease)
• Factors With Inadequate Evidence of Increased Risk of HCC
  • Nonalcoholic fatty liver
  • Metabolic syndrome (MetS)
  • Obesity
  • Type 2 diabetes
• Interventions With Adequate Evidence of Decreased Risk of HCC
  • HBV vaccination
  • Treatment for chronic HBV infection
  • Availability of food not contaminated with aflatoxin B1
• Interventions With Inadequate Evidence of Decreased Risk of HCC
  • HCV treatment with direct-acting antivirals (DAAs)
  • Statin use among adults with HBV or HCV

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries containing information related to liver (hepatocellular) cancer prevention include the following:

• Liver (Hepatocellular) Cancer Screening
• Primary Liver Cancer Treatment
• Childhood Liver Cancer Treatment
• Levels of Evidence for Cancer Screening and Prevention Studies

Based on solid evidence, chronic HBV infection causes HCC.

Magnitude of Effect: Chronic HBV infection is the leading cause of HCC in Asia and Africa.[17] HBV, either alone or in the presence of other risk factors, is responsible for large increases in the risk of developing HCC. Although degree of increase in risk varies by the presence of other factors or characteristics of infection, it is reasonable to assume that, on average, relative risks (RRs) of HBV are at least fivefold.[2]

• Study Design: Prospective cohort studies; case-control studies.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Based on solid evidence, chronic HCV infection causes HCC.

Magnitude of Effect: HCV infection is the leading cause of HCC in North America, Europe, and Japan.[17] HCV, either alone or in the presence of other risk factors, is responsible for staggering increases in the risk of developing HCC. Although degree of increase in risk varies by the presence of other factors or characteristics of infection, it is reasonable to assume that, on average, relative risks of HCV are at least 15-fold.[18]

• Study Design: Prospective cohort studies; case-control studies.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Based on solid evidence, cirrhosis, regardless of its etiology, predisposes patients to HCC.[3] HCC develops in the presence of a cirrhotic liver in most instances.[3]

Magnitude of Effect: In autopsy studies, 80% to 90% of individuals who die of HCC have cirrhotic livers.[3] The risk of HCC varies by cause of cirrhosis; patients with HCV-related cirrhosis are at greater risk than those with HBV-related cirrhosis, and those with HBV-related cirrhosis are at greater risk than those with alcohol-related cirrhosis.[17,18] The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%.[18]

• Study Design: Autopsy studies, prospective cohort studies, case-control studies.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Based on solid evidence, heavy alcohol use increases HCC risk.[2] Heavy alcohol use causes cirrhosis, and the development of most alcohol-related HCC is thought to occur via that pathway.[3] However, heavy alcohol users who do not develop cirrhosis are also at elevated risk of developing HCC.[3]

Magnitude of Effect: Heavy alcohol consumption increases HCC risk at least twofold; some studies suggest at least a fivefold increase.[17] Among individuals with HBV or HCV infection, the magnitude of the association is about the same.[19] However, heavy alcohol consumption and chronic HCV infection appear to act synergistically on HCC risk, resulting in perhaps a 100-fold increase in risk relative to individuals who are not infected and not heavy consumers of alcohol. The existence of a synergistic effect with HBV is less consistent, although one study observed a 50-fold increase in risk.[19]

• Study Design: Case-control study, case series, cohort studies.
• Internal Validity: Fair.
• Consistency: Good.
• External Validity: Good.

Aflatoxin B1 is a mycotoxin that can contaminate corn and peanuts stored in warm, humid environments.[1] Based on solid evidence, aflatoxin B1 exposure increases HCC risk.[18]

Magnitude of Effect: In individuals with chronic HBV infection, aflatoxin B1 exposure is estimated to increase risk 60-fold.[18] Because chronic HBV infection is highly prevalent in areas where exposure to aflatoxin B1 is an environmental concern, it is difficult to assess the magnitude of effect in individuals without HBV, although the available limited data suggest that the increase in risk may be fourfold.[20]

• Study Design: Ecological studies, prospective cohort studies.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Based on fair evidence, NASH increases risk of HCC.

Magnitude of Effect: In a study of 195 patients with NASH and cirrhosis, 13% were diagnosed with HCC after a median follow-up of 3.2 years.[6] In patients with NASH without cirrhosis, HCC occurs infrequently; however, these patients are thought to have a modestly elevated risk of HCC.[7,8]

• Study Design: Prospective cohort studies, medical record abstraction, case series.
• Internal Validity: Fair.
• Consistency: Good.
• External Validity: Fair.

Based on fair evidence, cigarette smoking increases HCC risk.

Magnitude of Effect: Cigarette smoking in the absence of viral infection is associated with a modest (up to twofold) increase in HCC risk. Cigarette smoking and presence of chronic HBV or HCV infection results in at least an additive effect on HCC risk.[9]

• Study Design: Case-control and cohort studies.
• Internal Validity: Fair.
• Consistency: Fair.
• External Validity: Fair.

Based on solid evidence, untreated HH, alpha-1-antitrypsin deficiency (AAT), glycogen storage disease, porphyria cutanea tarda, and Wilson disease increase the risk of HCC, but account for few cases.[1] In the absence of treatment, HH leads to cirrhosis, although there are reports of HCC developing in patients with noncirrhotic livers.[1]

Magnitude of Effect: Untreated HH confers at least a 20-fold increase in risk,[17] although risk varies according to other factors (including HBV and HCV infection). Treatment to reduce iron stores can greatly reduce risk. AAT deficiency, glycogen storage disease, porphyria cutanea tarda, and Wilson disease confer large but varied increases in risk of HCC.[1]

• Study Design: Prospective cohort studies (HH), case series (other conditions).
• Internal Validity: Fair (HCC), not applicable (N/A; other conditions).
• Consistency: Fair (HCC), good (other conditions).
• External Validity: Fair (HCC), N/A (other conditions).

Based on limited evidence, some patients with NAFL will develop NASH or cirrhosis.[10] Therefore, NAFL is assumed to increase HCC risk.

Magnitude of Effect: A small clinical study suggested that between 20% and 50% of NAFL patients may develop NASH.[10] Up to 4% of NAFL patients may develop cirrhosis.[21] The observation that NAFL patients have developed these conditions, which are known to increase HCC risk, leads to the conclusion that NAFL increases HCC risk, even though the future incidence of HCC among patients newly diagnosed with NAFL is not known.

• Study Design: Biopsy studies, case series.
• Internal Validity: Poor.
• Consistency: N/A.
• External Validity: N/A.

Based on fair evidence, a diagnosis of MetS is associated with an increased risk of HCC.[22]

Magnitude of Effect: A meta-analysis of more than 7,000 HCC cases from four studies produced a risk ratio of 1.8 (95% confidence interval [CI], 1.37–2.40) for a diagnosis of MetS. The combined risk ratios were varied (range, 1.2 [95% CI, 0.55–2.53] to 3.7 [95% CI, 1.78–7.58]).[23]

• Study Design: Case-control studies and cohort studies.
• Internal Validity: Fair.
• Consistency: Good.
• External Validity: Good.

Based on fair evidence, obesity is associated with an increase in HCC risk.

Magnitude of Effect: Numerous large epidemiological studies suggest about a twofold increase in HCC risk for individuals who are obese.[11]

• Study Design: Case-control studies, retrospective and prospective cohort studies.
• Internal Validity: Fair.
• Consistency: Good.
• External Validity: Good.

Based on fair evidence, type 2 diabetes is associated with an increase in HCC risk.

Magnitude of Effect: Numerous large epidemiological studies suggest a twofold to fourfold increase in HCC risk for individuals with type 2 diabetes.[11]

• Study Design: Case-control studies, retrospective and prospective cohort studies.
• Internal Validity: Fair.
• Consistency: Good.
• External Validity: Good.

Based on solid evidence, neonatal HBV vaccination or catch-up vaccination at young ages reduces HCC incidence in young adults.[24]

Magnitude of Effect: Reductions in pediatric and young adult HCC risk of at least 50% have been observed in cohorts immunized at birth or during early childhood. It is predicted that universal neonate immunization will ultimately eliminate 70% to 85% of global HCC cases.[24,25]

• Study Design: Cluster randomized controlled trial (RCT), historical trends, mathematical modeling.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Based on solid evidence, chronic HBV treatment with nucleos(t)ide analog therapy reduces the risk of HCC.[14]

Magnitude of Effect: About a 50% reduction in incidence.

• Study Design: Meta-analysis of clinical trials (some randomized, some blinded), retrospective cohort studies.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Based on solid evidence, replacement of food highly contaminated with aflatoxin B1 with food that harbors much lower levels of aflatoxin B1 leads to a reduction in liver cancer mortality.[15]

Magnitude of Effect: A more-than-50% reduction in liver cancer mortality.

• Study Design: Historical trends.
• Internal Validity: Good.
• Consistency: N/A.
• External Validity: N/A.

Based on fair evidence, HCV treatment with DAAs that results in sustained virologic response (SVR) may reduce HCC risk.

Magnitude of Effect: Patients treated with DAAs who attained SVR had an approximately 75% reduction in HCC risk relative to those who did not attain SVR.[16] Reduction in relative risk with SVR was similar in patients with cirrhosis (hazard ratio [HR], 0.31; 95% CI, 0.23–0.44) and patients without cirrhosis (HR, 0.18; 95% CI, 0.11–0.30). There does not appear to be an increased risk of HCC among individuals, with or without cirrhosis, who received DAAs as opposed to those who received interferon.[26,27]

• Study Design: Retrospective cohort, case series.
• Internal Validity: Fair.
• Consistency: Fair.
• External Validity: Fair.

Based on fair evidence, statin use may be associated with a reduced risk of developing HCC in patients with HBV or HCV infection.[28] Statin use may be associated with a reduced risk of developing HCC in all adults.

Magnitude of Effect: Relative reductions in HCC risk in adults with HBV or HCV infection of approximately 50% was found in a systematic review of observational studies (kappa statistic, 13). A statistically significant effect was observed with lipophilic statin use (HR, 0.52; P < .001; kappa statistic, 2) but not with hydrophilic statin use (RR, 0.89; P = .21; kappa statistic, 2) (P for subgroup difference < .001).[28] However, there was moderate heterogeneity in the two studies that reported on hydrophilic statin use, with one study [29,30] showing a 49% statistically significant relative reduction and the other study [31,32] showing a nonsignificant 5% relative reduction.

• Study Design: Systematic review and meta-analysis of observational study.
• Internal Validity: Good.
• Consistency: Good across patient characteristics, including possibly HBV/HCV status but possibly inconsistent for the type of statin use (lipophilic vs. hydrophilic).
• External Validity: Unclear. A systematic review and meta-analysis of observational and randomized studies in adults with and without HBV/HCV infection (kappa statistic, 10) reported that statin use was associated with a 37% relative reduction in developing HCC (odds ratio [OR], 0.63; 95% CI, 0.52–0.76). Five studies did not report the baseline prevalence of HBV/HCV in individuals; one study noted that 100% of individuals had HBV infection, another study noted that HBV/HCV was present in 23.9%/25.1% at baseline while another study noted 1.9%/14.7%, respectively. Two other studies reported that HBV/HCV was present in less than 10% of the population. In sensitivity analyses, the association between statin use and HCC was observed in observational studies (kappa statistic, 7; adjusted OR, 0.60; 95% CI, 0.49–0.73) but not in RCTs (kappa statistic, 3; OR, 0.95; 95% CI, 0.62–1.45 [although CIs were wide]).[33]

References

1. London WT, McGlynn K: Liver cancer. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 3rd ed. Oxford University Press, 2006, pp 763-86.
2. El-Serag HB, Kanwal F: Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology 60 (5): 1767-75, 2014. [PUBMED Abstract]
3. Fattovich G, Stroffolini T, Zagni I, et al.: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1): S35-50, 2004. [PUBMED Abstract]
4. Hartke J, Johnson M, Ghabril M: The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol 34 (2): 153-159, 2017. [PUBMED Abstract]
5. Donato F, Tagger A, Gelatti U, et al.: Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 155 (4): 323-31, 2002. [PUBMED Abstract]
6. Ascha MS, Hanouneh IA, Lopez R, et al.: The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51 (6): 1972-8, 2010. [PUBMED Abstract]
7. White DL, Kanwal F, El-Serag HB: Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 10 (12): 1342-1359.e2, 2012. [PUBMED Abstract]
8. Perumpail RB, Wong RJ, Ahmed A, et al.: Hepatocellular Carcinoma in the Setting of Non-cirrhotic Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome: US Experience. Dig Dis Sci 60 (10): 3142-8, 2015. [PUBMED Abstract]
9. Chuang SC, Lee YC, Hashibe M, et al.: Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 19 (5): 1261-8, 2010. [PUBMED Abstract]
10. Calzadilla Bertot L, Adams LA: The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 17 (5): , 2016. [PUBMED Abstract]
11. Streba LA, Vere CC, Rogoveanu I, et al.: Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: an open question. World J Gastroenterol 21 (14): 4103-10, 2015. [PUBMED Abstract]
12. Kim D, Touros A, Kim WR: Nonalcoholic Fatty Liver Disease and Metabolic Syndrome. Clin Liver Dis 22 (1): 133-140, 2018. [PUBMED Abstract]
13. Kao JH: Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 29 (6): 907-17, 2015. [PUBMED Abstract]
14. Singal AK, Salameh H, Kuo YF, et al.: Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther 38 (2): 98-106, 2013. [PUBMED Abstract]
15. Chen JG, Egner PA, Ng D, et al.: Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 6 (10): 1038-45, 2013. [PUBMED Abstract]
16. Kanwal F, Kramer J, Asch SM, et al.: Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology 153 (4): 996-1005.e1, 2017. [PUBMED Abstract]
17. Lafaro KJ, Demirjian AN, Pawlik TM: Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am 24 (1): 1-17, 2015. [PUBMED Abstract]
18. El-Serag HB: Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142 (6): 1264-1273.e1, 2012. [PUBMED Abstract]
19. Grewal P, Viswanathen VA: Liver cancer and alcohol. Clin Liver Dis 16 (4): 839-50, 2012. [PUBMED Abstract]
20. Bosetti C, Turati F, La Vecchia C: Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol 28 (5): 753-70, 2014. [PUBMED Abstract]
21. Rinella ME: Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (22): 2263-73, 2015. [PUBMED Abstract]
22. Mittal S, El-Serag HB, Sada YH, et al.: Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 14 (1): 124-31.e1, 2016. [PUBMED Abstract]
23. Jinjuvadia R, Patel S, Liangpunsakul S: The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis. J Clin Gastroenterol 48 (2): 172-7, 2014. [PUBMED Abstract]
24. Qu C, Chen T, Fan C, et al.: Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial. PLoS Med 11 (12): e1001774, 2014. [PUBMED Abstract]
25. McGlynn KA, Petrick JL, London WT: Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19 (2): 223-38, 2015. [PUBMED Abstract]
26. Li DK, Ren Y, Fierer DS, et al.: The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: An ERCHIVES study. Hepatology 67 (6): 2244-2253, 2018. [PUBMED Abstract]
27. Carrat F, Fontaine H, Dorival C, et al.: Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet 393 (10179): 1453-1464, 2019. [PUBMED Abstract]
28. Li X, Sheng L, Liu L, et al.: Statin and the risk of hepatocellular carcinoma in patients with hepatitis B virus or hepatitis C virus infection: a meta-analysis. BMC Gastroenterol 20 (1): 98, 2020. [PUBMED Abstract]
29. Tsan YT, Lee CH, Wang JD, et al.: Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol 30 (6): 623-30, 2012. [PUBMED Abstract]
30. Tsan YT, Lee CH, Ho WC, et al.: Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J Clin Oncol 31 (12): 1514-21, 2013. [PUBMED Abstract]
31. Simon TG, Duberg AS, Aleman S, et al.: Lipophilic Statins and Risk for Hepatocellular Carcinoma and Death in Patients With Chronic Viral Hepatitis: Results From a Nationwide Swedish Population. Ann Intern Med 171 (5): 318-327, 2019. [PUBMED Abstract]
32. Simon TG, Bonilla H, Yan P, et al.: Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES. Hepatology 64 (1): 47-57, 2016. [PUBMED Abstract]
33. Singh S, Singh PP, Singh AG, et al.: Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144 (2): 323-32, 2013. [PUBMED Abstract]

Liver cancer, regardless of histology, accounts for about 2% of cancer diagnoses and 5% of cancer deaths in the United States, and is not among the top ten diagnosed cancers in the United States.[1] It is, however, the sixth-leading cause of cancer deaths in the United States.[1] About 41,630 new cases of liver cancer are expected to occur in the United States in 2024; the expected number of deaths is 29,840 individuals.[2] Hepatocellular cancer (HCC) accounts for about 71% of all liver cancers in the United States.[2] In 1975, liver cancer incidence in the United States was 2.64 per 100,000. In 2019, the rate had risen more than threefold to 8.66 per 100,000.[3] Five-year survival rates varies by stage, from a high of 37.3% for localized disease to a low of 3.5% for distant disease.[1] In the United States, rates of liver cancer incidence are lowest in White individuals and highest in American Indian or Alaska Native individuals. Rates of liver cancer death are lowest in White individuals and highest in American Indian or Alaska Native individuals. Rates are also higher in Hispanic individuals, as compared with non-Hispanic individuals.[1]

Worldwide, liver cancer is the sixth most common cancer and the third leading cause of cancer-related death.[4] HCC results in about 905,677 new cases and 830,180 deaths worldwide each year;[4] in most countries, the HCC annual incidence and mortality rates are nearly identical.[4] It is the fifth most frequently diagnosed cancer in adult men and the ninth most commonly diagnosed cancer in women.[4] The incidence of HCC varies widely according to geographic location.[4] High-incidence regions include Northern and Western Africa (Egypt, the Gambia, Guinea) and Eastern and South-Eastern Asia (Mongolia, Cambodia, and Vietnam). HCC incidence is low in North and South America, most of Europe, Australia, and parts of the Middle East.[4,5] In all parts of the world, HCC is more common in men than in women.[4,5]

References

1. National Cancer Institute: SEER Stat Fact Sheets: Liver and Intrahepatic Bile Duct Cancer. Bethesda, Md: National Cancer Institute. Available online. Last accessed April 12, 2024.
2. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. Available onlineExit Disclaimer. Last accessed June 21, 2024.
3. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed March 6, 2024.
4. Sung H, Ferlay J, Siegel RL, et al.: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71 (3): 209-249, 2021. [PUBMED Abstract]
5. Jemal A, Bray F, Center MM, et al.: Global cancer statistics. CA Cancer J Clin 61 (2): 69-90, 2011 Mar-Apr. [PUBMED Abstract]

In This Section

• Chronic HBV Infection
• Chronic HCV Infection
• Cirrhosis
• Heavy Alcohol Use
• Aflatoxin B1
• NASH
• Cigarette Smoking
• Certain Rare Medical and Genetic Conditions (Untreated HH, Alpha-1-Antitrypsin Deficiency, Glycogen Storage Disease, Porphyria Cutanea Tarda, and Wilson Disease)

Chronic hepatitis B virus (HBV) infection is the leading cause of hepatocellular cancer (HCC) in Asia and Africa.[1] Hepatitis B is transmitted through contact with infected blood, semen, or other body fluids. In areas with high incidence of chronic HBV infection and HCC, about 70% of infections are acquired in the perinatal period or in early childhood.[2] In addition to maternal-to-child transmission, HBV can be spread through sexual contact and contact with infected blood.[3] In the United States, the most common route of transmission is sharing drug-injecting needles.[4] It is estimated that 850,000 to 2.2 million people in the United States have chronic HBV infection [3] and that the infection is responsible for 10% to 15% of HCC cases.[5] The World Health Organization (WHO) estimates that 240 million people are infected worldwide.[4]

Evidence for a causal relationship between chronic HBV infection and HCC comes from etiologic studies, case series, case-control studies, and prospective epidemiological studies.[2] Ecological studies demonstrate a strong positive correlation between the prevalence of chronic HBV and HCC incidence and mortality. HBV is present in liver tissue in nearly all patients who are seropositive for the virus and have HCC,[2] and HBV DNA has been found in 10% to 20% of HCC tumors in patients who are seronegative but are positive for HBV antibodies.[2] Case-control studies and prospective studies have observed odds ratios or relative risks (RRs) of at least 5 for chronic HBV infection.[2] Some prospective studies have observed RRs exceeding 50.[2] The lifetime risk of HCC in individuals chronically infected with HBV is estimated to be between 10% and 25%.[2] Clinical factors that have been reported to increase risk in individuals with chronic HBV infection include higher levels of HBV replication; certain HBV genotypes; longer duration of infection; and co-infection with hepatitis C virus (HCV), HIV, or hepatitis D virus.[6] The presence of cirrhosis increases risk, although HBV can cause HCC in the absence of cirrhosis.[7]

Co-infection with HCV appears to have an additive effect on risk.[8] In addition, degree of increased risk of chronic HBV varies with the presence of other factors and is discussed in sections of this summary that cover those specific factors.

Chronic HCV infection is the leading cause of HCC in North America, Europe, and Japan.[1] Chronic HCV infection accounts for about one-third of HCC cases in the United States.[4] HCV is a blood-borne pathogen; before screening of the blood supply or donated human organs (1992), HCV infection often was acquired during blood transfusions or organ transplants. Today, most new infections are caused by the sharing of drug-injecting needles. HCV can be transmitted during sexual contact, although this occurs infrequently. An estimated 2.7 to 3.9 million people in the United States have chronic hepatitis C.[9] In the United States, more cases are attributable to chronic HCV infection than to any other risk factor.[10]

Even though the mechanisms through which HCV increases HCC risk are unclear, chronic HCV infection is accepted as playing a causal role in the development of HCC. Evidence of a strong association comes primarily from cross-sectional and case-control studies, which suggest that individuals with HCV infection have at least a 15-fold increase in HCC risk, relative to individuals without HCV infection.[6] A prospective study of more than 23,000 residents of Taiwan observed a cumulative lifetime HCC incidence of 24% in men and 17% in women;[11] other prospective studies, including cases series of individuals accidently infected with HCV through blood transfusion, have produced a wide range of incidence estimates.[2] The reason for such variability is likely the variation in prevalence of advanced fibrosis and cirrhosis in the groups being studied. Chronic HCV infection typically leads to liver fibrosis, but HCC is rare in HCV-positive individuals with minimal or no fibrosis.[6] Once HCV-related cirrhosis develops, HCC develops annually in 1% to 8% of patients.[6] Other clinical factors that have been reported to increase risk in individuals with chronic HCV infection include co-infection with HBV or HIV, HCV genotype 1b, and steatosis.[6]

Co-infection with HBV appears to have an additive effect on risk.[8] In addition, degree of increased risk of chronic HCV varies with the presence of other factors and is discussed in sections of this summary that cover those specific factors.

The prevalence of cirrhosis in the United States is estimated to be 0.3%, which corresponds to more than 600,000 adults.[12] Because cirrhosis is present in 70% to 90% of HCC patients at the time of diagnosis,[13] cirrhosis is considered a predisposing factor for HCC.[14] In autopsy studies, 80% to 90% of individuals who die of HCC have cirrhotic livers.[14] A standardized incidence ratio of 60 was observed in a prospective 16-year study of 11,065 Danish individuals with cirrhosis (more than one-half of cases caused by alcohol consumption).[2] The 5-year cumulative risk of developing HCC for patients with cirrhosis is 5% to 30%, with risk dependent on cause of cirrhosis and stage of cirrhosis.[6]

With perhaps the exception of aflatoxin B1, all HCC risk factors are also risk factors for cirrhosis.[1] In patients with established cirrhosis, HCC risk may be modifiable with elimination of the factor responsible for cirrhosis.[15] However, evidence to support that possibility is limited, and reduction in risk is likely to occur only in patients with precirrhotic changes or very early-stage cirrhosis.[15]

Patients with HCV-related cirrhosis are at greater risk of developing HCC than are those with cirrhosis related to HBV and alcohol-related cirrhosis.[14] Using data from several prospective studies, 5-year cumulative HCC incidence rates for individuals with cirrhosis and specific risk factors were estimated as follows: HCV, 30% in Japan and 17% in Western countries; HBV, 15% in endemic areas and 10% in Western countries; and alcohol, 8%.[14]

Heavy alcohol use causes cirrhosis; between 8% and 20% of chronic alcoholics develop the condition.[1] HCC also occurs in heavy alcohol users who do not have cirrhosis. Some data exist to suggest a synergistic effect on HCC risk by heavy alcohol use and tobacco use, fatty liver disease, and metabolic syndrome (MetS) components.[16]

Many epidemiological studies have examined the association of alcohol use and HCC; those that could examine the impact of increasing exposure typically have seen a positive correlation between consumption and risk. The following RRs (95% confidence intervals [CIs]) were generated by using models derived from a meta-analysis: 1.19 (1.12–1.27) for 25 g of alcohol per day; 1.40 (1.25–1.56) for 50 g/d; and 1.81 (1.50–2.19) for 100 g/d.[1] While there is agreement that alcohol consumption, especially heavy consumption, is an important HCC risk factor, the magnitude of the increase in risk varies across studies.[16] Some studies report a twofold increase in risk with heavy consumption, while others observe a greater increase, at least fivefold. Variability is likely caused by many factors, including choice of control subjects, choice of referent categories, definition of heavy alcohol use, and presence of cofactors.

Alcoholics with cirrhosis appear to have a roughly tenfold risk of developing HCC, relative to alcoholics without cirrhosis.[14,16] In a cohort study of alcoholics, the summary incidence rate was 0.2 per 100 person-years in people with cirrhosis, and 0.01 per 100 person-years in those without cirrhosis.[14] The evidence for a twofold to threefold increase in risk with heavy alcohol use is more consistent for individuals with chronic HCV infection than for individuals with chronic HBV infection.[16] An Italian case-control study observed synergistic effects of heavy alcohol use and HBV or HCV infection: heavy alcohol use and HBV infection led to a 50-fold increase in risk, and heavy alcohol use and HCV infection led to a 100-fold increase in risk, relative to absence of heavy alcohol use and HBV or HCV infection.[17]

Aflatoxin B1 is a mycotoxin that can contaminate corn and peanuts stored in warm, humid environments.[2] The highest levels of aflatoxin B1 exposure are found in sub-Saharan Africa, Southeast Asia, and China.[18]

Aflatoxin B1 was deemed a carcinogen by the International Agency for Research on Cancer (IARC) in 1987.[2] The population-attributable risk of aflatoxin B1 to HCC is estimated to be 20% in the Western Pacific (including China), 27% in southeast Asia, and 40% in Africa.[19] Exposure may be responsible for up to 155,000 HCC cases worldwide.[19]

Prospective cohort studies established aflatoxin B1 as an etiologic agent for HCC, and demonstrated that magnitude of risk varies by presence or absence of chronic HBV infection. A nested case-control study comprising about 18,000 men who resided in Shanghai in the 1980s indicated that aflatoxin exposure increases risk 4-fold among individuals without chronic HBV infection, but exposure increases risk 60-fold among individuals with chronic HBV infection.[20] A subsequent cohort study in Taiwan observed a similar multiplicative or more-than-multiplicative increase in risk with the presence of both factors, relative to the presence of neither factor.[20]

Nonalcoholic steatohepatitis (NASH) is an aggressive yet dynamic condition; it can regress, persist at a relatively constant level of activity, or cause progressive fibrosis that leads to cirrhosis. It is estimated that 6% of the U.S. adult population has NASH and that 2% of U.S. adults will develop NASH-related cirrhosis at some time in their lives.[21]

At least 17 prospective cohort studies have examined HCC risk in patients with either NASH or nonalcoholic fatty liver disease (NAFLD), but few have examined NASH patients alone.[22] The most frequently referenced study of NASH patients is a prospective study conducted in the United States that examined HCC experience in 195 patients with NASH-related cirrhosis. After a median follow-up of 3.2 years, 13% of the patients had been diagnosed with HCC.[23] Yearly cumulative incidence in this case series was 2.6%. A case series of HCV patients was conducted concurrently; that group experienced higher rates (20% had an HCC diagnosis, and yearly cumulative incidence was 4%).

HCC has been observed in patients with NASH who do not have cirrhosis. Reliable risk estimates are not available, but most researchers believe that these individuals are at elevated risk, albeit lower than in those with cirrhosis.[22]

MetS, obesity, type 2 diabetes, insulin resistance, hypertension, and hyperlipidemia or dyslipidemia, are suspected risk factors for HCC and are associated with NASH. A study of 8.5 million people from 22 countries reported prevalence estimates for NASH patients with the following diagnoses: overweight or obesity, 80%; hyperlipidemia or dyslipidemia, 72%; type 2 diabetes, 44%; and MetS, 71%.[24]

The relationship between tobacco use and liver cancer has been studied extensively for many years.[25] Early epidemiological studies produced positive associations, but doubt regarding the legitimacy of tobacco use as an independent risk factor existed because of the possibility of residual confounding by HBV status, HCV status, and alcohol consumption. In addition, some studies also suggested that the increase in risk might exist only in subgroups, particularly in patients with chronic HBV infection. In 2004, the IARC reported that tobacco use was causally associated with HCC; that conclusion was on the basis of studies that had consistently shown increased risk with increased duration or intensity of tobacco use after careful consideration of potential confounders.[25] In 2014, the U.S. Surgeon General concluded a causal relationship on the basis of study results published after 2004.[26]

An extensive meta-analysis published in 2009 examined 38 cohort and 58 case-control studies that evaluated the relationship between cigarette smoking and liver cancer.[25] Studies varied in their degree of adjustment for possible confounders, though most adjusted for age and about one-third adjusted for alcohol consumption. Relative to never-smokers, the summary RR (SRR) for current smokers was 1.51 (95% CI, 1.37–1.67) and for former smokers, 1.12 (95% CI, 0.78–1.60). The point estimate was similar when restricted to five high-quality studies that adjusted for alcohol use (RR, 1.45; 95% CI, 1.14–1.80); the point estimates were similar but not significant when restricted to three studies that adjusted for chronic HBV infection and three studies that adjusted for chronic HCV infection. A dose-response relationship for the number of cigarettes smoked per day was observed, even though there was substantial statistical heterogeneity in the eight studies that were analyzed together for that analysis. A prospective cohort study published after the meta-analysis observed significant linear increases in risk with increasing number of cigarettes smoked per day, years smoked, and pack-years; analyses were adjusted for grams of alcohol consumed per day, and significant linear increases also were observed when daily drinkers were excluded.[27]

A meta-analysis that examined the relationship of cigarette smoking in the presence and absence of chronic HBV or HCV infection observed the following:[28] in the absence of viral infection, cigarette smoking was associated with an RR of about 1.5 to 2; in the presence of HBV, the increase in risk appeared additive; and in the presence of HCV, the increase in risk appeared to be more than multiplicative. Relative to persons who were negative for HBV and did not smoke cigarettes, the adjusted random effects estimate was 21.7 (11.8–40) for those with HBV who smoked cigarettes. Relative to individuals who were negative for HCV and did not smoke cigarettes, the adjusted random effects estimate was 19.6 (1.55–247) for those with HCV who smoked cigarettes.[28]

Untreated hereditary hemochromatosis (HH), alpha-1-antitrypsin (AAT) deficiency, glycogen storage disease, porphyria cutanea tarda (PCT), and Wilson disease are known to increase the risk of developing HCC. While increases in risk are known or believed to be large, these conditions contribute little to the burden of HCC.

Hemochromatosis is an autosomal recessive disorder that leads to excessive absorption of dietary iron and subsequent iron loading in certain organs, including the liver.[2] Between 1 in 200 and 1 in 400 individuals of northern European descent carry the most common genetic mutation, although many of these individuals do not develop progressive iron overload.[29] Patients with untreated hemochromatosis may develop cirrhosis. The annual incidence of HCC in patients with hemochromatosis is 4% once cirrhosis has been established.[30] In cohorts of patients with untreated hemochromatosis and cirrhosis, the observed number of HCC cases is at least 20-fold higher than expected.[29] HCC is seen, albeit rarely, in hemochromatosis patients who do not have cirrhosis.[29] Between 25% and 45% of premature deaths in hemochromatosis patients are caused by HCC.[29] Hemochromatosis can be treated successfully through phlebotomy, repeated at necessary intervals.[30] Treatment before the development of cirrhosis appears to greatly reduce the risk of HCC.[30] It is hypothesized that the presence of other HCC risk factors, particularly chronic HBV infection, chronic HCV infection, and heavy alcohol use, could increase risk among patients with untreated hemochromatosis in a more-than-additive manner,[29] but appropriate data in which to explore this possibility are not available.

AAT deficiency is an inherited disorder affecting the lungs, liver, and rarely, the skin. It is estimated that about 100,000 individuals in the United States have AAT deficiency.[31] Liver disease results from the accumulation within hepatocytes of unsecreted variant AAT proteins.[32] Individuals with certain AAT deficiency genotypes are at high risk of developing HCC.[33]

Glucose-6-phosphatase deficiency (G6PD) is an autosomal-recessive disorder. It also is known as von Gierke disease and is more commonly known as glycogen storage disease, or GSD1. The defective enzymes involved are mainly active in the liver and kidneys. The incidence of GSD1 is 1 per 100,000 live births. HCC is recognized as a late complication of GSD1.[34] No estimates of increase in HCC risk are available.

PCT is the result of deficient activity of hepatic uroporphyrinogen; acute intermittent porphyria (AIP, also known as Swedish porphyria) is characterized by deficient activity of porphobilinogen. The prevalence of PCT in the United States is 1 in 25,000.[35] PCT and AIP are associated with increases in HCC risk.[2] A prospective study in Sweden of individuals with porphyria observed a standardized incidence ratio of 21 for PCT and 70 for AIP.[36]

Wilson disease (hepatolenticular degeneration) is caused by a genetic abnormality inherited in an autosomal recessive manner that leads to impairment of cellular copper transport. Worldwide prevalence is approximately 1 in 30,000 live births.[37] Wilson disease causes progressive liver damage, including cirrhosis. The association between Wilson disease and HCC is uncertain but suspected given that tumors of the liver, including HCC, are observed in Wilson disease patients.[38]

References

1. Lafaro KJ, Demirjian AN, Pawlik TM: Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am 24 (1): 1-17, 2015. [PUBMED Abstract]
2. London WT, McGlynn K: Liver cancer. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 3rd ed. Oxford University Press, 2006, pp 763-86.
3. Centers for Disease Control and Prevention: Hepatitis B FAQs for the Public. Atlanta, GA: Centers for Disease Control and Prevention, Division of Viral Hepatitis, 2016. Available online. Last accessed April 12, 2024.
4. U.S. Department of Health and Human Services: Hepatitis B Basic Information. Washington, DC: U.S. Department of Health and Human Services, 2017. Available online. Last accessed April 12, 2024.
5. Mittal S, El-Serag HB: Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 47 (Suppl): S2-6, 2013. [PUBMED Abstract]
6. El-Serag HB: Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142 (6): 1264-1273.e1, 2012. [PUBMED Abstract]
7. Ferlay J, Soerjomataram I, Dikshit R, et al.: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136 (5): E359-86, 2015. [PUBMED Abstract]
8. El-Serag HB, Kanwal F: Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology 60 (5): 1767-75, 2014. [PUBMED Abstract]
9. Centers for Disease Control and Prevention: Hepatitis C FAQs for Health Professionals. Atlanta, GA: Centers for Disease Control and Prevention, Division of Viral Hepatitis, 2017. Available online. Last accessed April 12, 2024.
10. Ghouri YA, Mian I, Rowe JH: Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis. J Carcinog 16: 1, 2017. [PUBMED Abstract]
11. Huang YT, Jen CL, Yang HI, et al.: Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C. J Clin Oncol 29 (27): 3643-50, 2011. [PUBMED Abstract]
12. Scaglione S, Kliethermes S, Cao G, et al.: The Epidemiology of Cirrhosis in the United States: A Population-based Study. J Clin Gastroenterol 49 (8): 690-6, 2015. [PUBMED Abstract]
13. Hartke J, Johnson M, Ghabril M: The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol 34 (2): 153-159, 2017. [PUBMED Abstract]
14. Fattovich G, Stroffolini T, Zagni I, et al.: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1): S35-50, 2004. [PUBMED Abstract]
15. Saffioti F, Pinzani M: Development and Regression of Cirrhosis. Dig Dis 34 (4): 374-81, 2016. [PUBMED Abstract]
16. Grewal P, Viswanathen VA: Liver cancer and alcohol. Clin Liver Dis 16 (4): 839-50, 2012. [PUBMED Abstract]
17. Donato F, Tagger A, Gelatti U, et al.: Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 155 (4): 323-31, 2002. [PUBMED Abstract]
18. McGlynn KA, Petrick JL, London WT: Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19 (2): 223-38, 2015. [PUBMED Abstract]
19. Liu Y, Wu F: Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect 118 (6): 818-24, 2010. [PUBMED Abstract]
20. Chen JG, Egner PA, Ng D, et al.: Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 6 (10): 1038-45, 2013. [PUBMED Abstract]
21. Diehl AM, Day C: Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med 377 (21): 2063-2072, 2017. [PUBMED Abstract]
22. White DL, Kanwal F, El-Serag HB: Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 10 (12): 1342-1359.e2, 2012. [PUBMED Abstract]
23. Ascha MS, Hanouneh IA, Lopez R, et al.: The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51 (6): 1972-8, 2010. [PUBMED Abstract]
24. Younossi ZM, Koenig AB, Abdelatif D, et al.: Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64 (1): 73-84, 2016. [PUBMED Abstract]
25. Lee YC, Cohet C, Yang YC, et al.: Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer. Int J Epidemiol 38 (6): 1497-511, 2009. [PUBMED Abstract]
26. Cancer. In: U.S. Department of Health and Human Services: The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. U.S. Department of Health and Human Services, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014, pp 139-351. Also available online. Last accessed April 12, 2024.
27. Koh WP, Robien K, Wang R, et al.: Smoking as an independent risk factor for hepatocellular carcinoma: the Singapore Chinese Health Study. Br J Cancer 105 (9): 1430-5, 2011. [PUBMED Abstract]
28. Chuang SC, Lee YC, Hashibe M, et al.: Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 19 (5): 1261-8, 2010. [PUBMED Abstract]
29. Harrison SA, Bacon BR: Relation of hemochromatosis with hepatocellular carcinoma: epidemiology, natural history, pathophysiology, screening, treatment, and prevention. Med Clin North Am 89 (2): 391-409, 2005. [PUBMED Abstract]
30. Villanueva A, Newell P, Hoshida Y: Inherited hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 24 (5): 725-34, 2010. [PUBMED Abstract]
31. Campos MA, Wanner A, Zhang G, et al.: Trends in the diagnosis of symptomatic patients with alpha1-antitrypsin deficiency between 1968 and 2003. Chest 128 (3): 1179-86, 2005. [PUBMED Abstract]
32. Lomas DA, Evans DL, Finch JT, et al.: The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 357 (6379): 605-7, 1992. [PUBMED Abstract]
33. Nelson DR, Teckman J, Di Bisceglie AM, et al.: Diagnosis and management of patients with α1-antitrypsin (A1AT) deficiency. Clin Gastroenterol Hepatol 10 (6): 575-80, 2012. [PUBMED Abstract]
34. Limmer J, Fleig WE, Leupold D, et al.: Hepatocellular carcinoma in type I glycogen storage disease. Hepatology 8 (3): 531-7, 1988 May-Jun. [PUBMED Abstract]
35. Harber LC, Bickers DR: Photosensitivity Diseases: Principles of Diagnosis and Treatment. Saunders, 1981.
36. Linet MS, Gridley G, Nyrén O, et al.: Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden. Am J Epidemiol 149 (11): 1010-5, 1999. [PUBMED Abstract]
37. Huster D: Wilson disease. Best Pract Res Clin Gastroenterol 24 (5): 531-9, 2010. [PUBMED Abstract]
38. Pfeiffenberger J, Mogler C, Gotthardt DN, et al.: Hepatobiliary malignancies in Wilson disease. Liver Int 35 (5): 1615-22, 2015. [PUBMED Abstract]

In This Section

• NAFL
• MetS
• Obesity
• Type 2 Diabetes

Nonalcoholic fatty liver (NAFL) is diagnosed when hepatic steatosis cannot be explained by alcohol use or viral infection.[1] It generally is an asymptomatic, benign condition and is often detected incidentally.[2] NAFL can progress to cirrhosis or nonalcoholic steatohepatitis (NASH). Up to 4% of NAFL patients may develop cirrhosis,[3] and a small clinical study suggested that between 20% and 50% of NAFL patients may develop NASH.[4] The observation that NAFL patients have developed these conditions, which are known to increase hepatocellular cancer (HCC) risk, leads to the conclusion that NAFL increases HCC risk.

Even though NAFL and NASH have different clinical relevance, they often are combined into one clinical entity known as NAFLD (nonalcoholic fatty liver disease). While prevalence estimates and measures of relative risk (RR) are available for NAFLD and NASH, they are unavailable for NAFL. NAFLD estimates can provide an upper bound for NAFL, however.

In the United States, NAFLD prevalence is estimated at 25%.[5] NAFLD prevalence has more than doubled in the last 30 years [1] and is now the most common liver disorder in the United States.[1] NAFLD is sometimes referred to as the hepatic presentation of metabolic syndrome (MetS);[5] increases in NAFLD rates parallel those of MetS, including obesity and type 2 diabetes.[1] MetS, obesity, and type 2 diabetes are frequent NAFLD comorbidities. Estimates of global prevalence of MetS, obesity, and type 2 diabetes in individuals with NAFLD are as follows: MetS, 43%; obesity, 51%; and type 2 diabetes, 23%.[1] A meta-analysis that considered data from countries around the world reported that the HCC incidence rate ratio for NAFLD versus non-NAFLD patients was 1.94 (95% confidence interval [CI], 1.28–2.92).[1] HCC has been diagnosed in patients with both cirrhotic and noncirrhotic NAFLD.[6] A study of 1,500 U.S. Veterans' Administration patients with NAFLD, 107 patients developed HCC. Of the 107 patients, 6 patients had level 1 evidence (histological) of no cirrhosis, and 31 patients had level 2 evidence (imaging or biospecimen) of no cirrhosis.[7] Furthermore, the percentage of noncirrhotic HCC patients among those with NAFLD was greater than was observed for other known HCC risk factors.[7]

MetS is diagnosed when at least three of five metabolic risk factors (central adiposity, high triglyceride levels, low levels of high-density lipoprotein, high fasting glucose levels, and hypertension) are present.[8] The prevalence of MetS has been rising for at least the last 30 years, and by 2012, more than one-third of U.S. adults met the criteria for MetS.[9]

A meta-analysis of more than 7,000 HCC cases from five studies produced a risk ratio of 1.8 (95% CI, 1.37–2.40) for a diagnosis of MetS.[10] The combined risk ratios were varied (range, 1.2 [95% CI, 0.55–2.53] to 3.7 [96% CI, 1.78–7.58]).

MetS and NAFLD are frequently comorbid conditions. The prevalence of MetS among patients with NAFLD was estimated to be 42.5% in a meta-analysis that included studies from around the world.[1] Given that obesity and type 2 diabetes, two suspected HCC risk factors, are component causes of MetS and also prevalent in patients with NAFLD, attempts to disentangle the independent impact on HCC risk of MetS using epidemiological data is not warranted. Observed associations should not be interpreted as causal relationships.

Only a few studies have examined insulin resistance, hypertension, and dyslipidemia, yet there is a suggestion that the first two are associated with an increase in HCC risk.[11] These factors will not be discussed further.

Obesity has been considered extensively as a risk factor for HCC, and in most instances, a positive association has been observed. A European multicenter prospective cohort study with 177 HCC cases examined central obesity, as measured by waste-to-hip ratio, and observed a more-than-threefold increase in HCC risk for the highest tertile (males, ≥ 27.81; females, ≥ 26.65), relative to the lowest (RR, 3.51; 95% CI, 2.09–5.87), after adjustment for several potential confounders, including alcohol consumption.[12] A meta-analysis of 26 prospective studies (25,337 HCC cases) reported that obesity (BMI ≥ 30 kg/m2) was associated with an increased risk of primary liver cancer (SRR, 1.83; 95% CI, 1.59–2.11). Of note is that the included studies varied in their control for confounding, with 11 not controlling for alcohol consumption and 15 not controlling for history of diabetes; furthermore, not all studies were population based. Nevertheless, point estimates were somewhat consistently suggestive of a modest increase in risk, and associations of a similar magnitude have been seen in Japanese and U.S. populations.[13,14]

NAFLD is estimated to be present in up to 90% of individuals with obesity.[15] Obesity is a component cause of MetS, another suspected HCC risk factor; obesity also is a frequent comorbidity to type 2 diabetes, yet another suspected HCC risk factor. Attempts to disentangle the independent impact on HCC risk of obesity using epidemiological data is not warranted. Observed associations should not be interpreted as causal relationships.

Type 2 diabetes has been considered extensively as a risk factor for HCC, and in most instances, positive associations have been observed. The most recent meta-analysis of diabetes and HCC was published in 2012.[16] Seventeen case-control studies and 32 cohort studies were included, and a summary RR of 2.31 (95% CI, 1.87–2.84) for either type 1 or type 2 diabetes was observed. Of the 49 studies used to produce the summary RR, only 19 adjusted for alcohol use and 13 for obesity, and not all were population based. The summary risk estimate for type 2 diabetes alone, based on data from 13 studies, was 2.18 (95% CI, 1.58–3.01). Studies published since the meta-analysis produced estimates similar to those of the summary measure.[17]

NAFLD is estimated to be present in up to 70% of type 2 diabetics.[15] Type 2 diabetes is a component cause of MetS, another suspected HCC risk factor; type 2 diabetes is a frequent comorbidity to obesity, yet another suspected HCC risk factor. An additional complexity is that diabetes can be caused by cirrhosis.[18] With the exception of cirrhosis, attempts to disentangle the independent impact on HCC risk of type 2 diabetes using epidemiological data is not warranted. Observed associations should not be interpreted as causal relationships.

References

1. Younossi ZM, Stepanova M, Afendy M, et al.: Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 9 (6): 524-530.e1; quiz e60, 2011. [PUBMED Abstract]
2. Dyson JK, Anstee QM, McPherson S: Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging. Frontline Gastroenterol 5 (3): 211-218, 2014. [PUBMED Abstract]
3. Rinella ME: Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (22): 2263-73, 2015. [PUBMED Abstract]
4. Calzadilla Bertot L, Adams LA: The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 17 (5): , 2016. [PUBMED Abstract]
5. Younossi ZM, Koenig AB, Abdelatif D, et al.: Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64 (1): 73-84, 2016. [PUBMED Abstract]
6. Baffy G, Brunt EM, Caldwell SH: Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 56 (6): 1384-91, 2012. [PUBMED Abstract]
7. Mittal S, El-Serag HB, Sada YH, et al.: Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 14 (1): 124-31.e1, 2016. [PUBMED Abstract]
8. Kim D, Touros A, Kim WR: Nonalcoholic Fatty Liver Disease and Metabolic Syndrome. Clin Liver Dis 22 (1): 133-140, 2018. [PUBMED Abstract]
9. Aguilar M, Bhuket T, Torres S, et al.: Prevalence of the metabolic syndrome in the United States, 2003-2012. JAMA 313 (19): 1973-4, 2015. [PUBMED Abstract]
10. Jinjuvadia R, Patel S, Liangpunsakul S: The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis. J Clin Gastroenterol 48 (2): 172-7, 2014. [PUBMED Abstract]
11. Rahman R, Hammoud GM, Almashhrawi AA, et al.: Primary hepatocellular carcinoma and metabolic syndrome: An update. World J Gastrointest Oncol 5 (9): 186-94, 2013. [PUBMED Abstract]
12. Schlesinger S, Aleksandrova K, Pischon T, et al.: Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort. Int J Cancer 132 (3): 645-57, 2013. [PUBMED Abstract]
13. Welzel TM, Graubard BI, Zeuzem S, et al.: Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology 54 (2): 463-71, 2011. [PUBMED Abstract]
14. Chen Y, Wang X, Wang J, et al.: Excess body weight and the risk of primary liver cancer: an updated meta-analysis of prospective studies. Eur J Cancer 48 (14): 2137-45, 2012. [PUBMED Abstract]
15. Streba LA, Vere CC, Rogoveanu I, et al.: Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: an open question. World J Gastroenterol 21 (14): 4103-10, 2015. [PUBMED Abstract]
16. Wang P, Kang D, Cao W, et al.: Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev 28 (2): 109-22, 2012. [PUBMED Abstract]
17. Wainwright P, Scorletti E, Byrne CD: Type 2 Diabetes and Hepatocellular Carcinoma: Risk Factors and Pathogenesis. Curr Diab Rep 17 (4): 20, 2017. [PUBMED Abstract]
18. Ferlay J, Soerjomataram I, Dikshit R, et al.: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136 (5): E359-86, 2015. [PUBMED Abstract]

In This Section

• HBV Vaccination
• Treatment for Chronic HBV Infection
• Availability of Food Not Contaminated With Aflatoxin B1

Hepatitis B virus (HBV) vaccines became available for the prevention of HBV infection in the early 1980s.[1] The World Health Organization recommends that all infants receive the hepatitis B vaccine as soon as possible after birth, preferably within 24 hours.[2] By 2011, 180 countries had introduced infant HBV vaccination, and the global HBV vaccination coverage rate for the final dose was estimated to be about 78%.[1] It is estimated that in 2015, the worldwide prevalence of HBV infection in children younger than 5 years was about 1.3%, compared with about 4.7% in the prevaccination era.[2]

Epidemiological evidence regarding the ability of hepatitis B vaccination to reduce hepatocellular cancer (HCC) comes from follow-up studies of children and risk of childhood liver cancer. In a cluster randomized controlled trial of HBV immunization of 75,000 newborns in Qidong, China (an area where HBV is endemic), the incidence ratio of primary liver cancer in the vaccination-at-birth group compared with the control group (68% of whom received catch-up vaccinations at ages 10–14 years) was 0.16 (95% confidence interval [CI], 0.03–0.77).[3] A registry study conducted in Taiwan identified 1,509 patients aged 6 to 26 years with HCC, and observed that HCC incidence per 100,000 person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts.[4]

It is too soon to know if neonate vaccination also will reduce HCC risk in later adulthood, and no data have been published on the impact of vaccination in adulthood. Nevertheless, vaccination at any age before infection should reduce HCC risk. Mathematical modeling suggests that neonatal HBV vaccination ultimately will lead to the elimination of 70% to 85% of HBV-related HCC cases worldwide.[5] Booster immunizations currently are not recommended for those who are not immunocompromised.[6]

Expanded and sustained HBV vaccination ultimately will shrink the pool of individuals with chronic HBV infection, but for the foreseeable future the need exists to minimize downstream consequences of chronic infection, including the risk of HCC. Treatment options for chronic HBV carriers are interferon and nucleos(t)ide analog (NA) therapy. Interferon is used in young patients who want a short course of therapy and have well-compensated liver disease,[7] although it is not consistently associated with a reduction in HCC incidence. Reductions in risk, when observed, have typically been among treatment responders with preexisting cirrhosis of the liver.[8] A reduction in HCC risk consistently has been observed for patients treated with NA therapy, regardless of cirrhosis status.[8]

The degree of HCC risk reduction with NA therapy has been nearly consistent across studies, with treated patients experiencing about half the risk of those who are not treated with NA therapy.[8,9] Most studies have been conducted in countries outside North America, yet the two studies conducted in North America observed similarly-sized, statistically significant reductions. A Canadian cohort of 322 patients with chronic HBV infection experienced lower than expected rates of HCC: the standardized incidence ratio was 0.46 (95% CI, 0.23–0.82) for patients who were treated with NA therapy, relative to those who were not treated with NA therapy.[10] A U.S. cohort of more than 2,000 patients with chronic HBV infection observed a hazard ratio of 0.39 (95% CI, 0.27–0.56) with treatment, although the cohort included patients treated with interferon.[11]

Use of lamivudine and adefovir can lead to resistance, with resistance leading to re-elevation of HCC risk.[8] Newer NA therapies are more potent and resistance is less likely.[8] Sufficient data are not yet available to examine whether these therapies will lead to the same or greater reduction in HCC risk and whether their impact on risk will differ by liver function and degree of fibrosis.

Qidong, China, historically has had exceptionally high rates of primary liver cancer, due to endemic chronic HBV infection and a food supply (predominately corn) with high levels of aflatoxin B1 contamination. Agricultural reforms in the 1980s led to greater availability of rice, which typically harbors much lower levels of aflatoxin B1. A population-based cancer registry was used to examine primary liver cancer mortality in Qidong in residents born before 2002, the year that universal HBV vaccination of newborns was achieved. For that group, a higher-than-50% reduction in mortality from primary liver cancer was observed following the availability of rice. About 80% of the benefit was estimated to be among those infected with HBV.[12]

References

1. Kao JH: Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 29 (6): 907-17, 2015. [PUBMED Abstract]
2. World Health Organization: Hepatitis B Fact Sheet. Geneva, Switzerland: World Health Organization, 2017. Available onlineExit Disclaimer. Last accessed April 12, 2024.
3. Qu C, Chen T, Fan C, et al.: Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial. PLoS Med 11 (12): e1001774, 2014. [PUBMED Abstract]
4. Chang MH, You SL, Chen CJ, et al.: Long-term Effects of Hepatitis B Immunization of Infants in Preventing Liver Cancer. Gastroenterology 151 (3): 472-480.e1, 2016. [PUBMED Abstract]
5. McGlynn KA, Petrick JL, London WT: Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19 (2): 223-38, 2015. [PUBMED Abstract]
6. Leuridan E, Van Damme P: Hepatitis B and the need for a booster dose. Clin Infect Dis 53 (1): 68-75, 2011. [PUBMED Abstract]
7. Perrillo R: Benefits and risks of interferon therapy for hepatitis B. Hepatology 49 (5 Suppl): S103-11, 2009. [PUBMED Abstract]
8. Lai CL, Yuen MF: Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology 57 (1): 399-408, 2013. [PUBMED Abstract]
9. Singal AK, Salameh H, Kuo YF, et al.: Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther 38 (2): 98-106, 2013. [PUBMED Abstract]
10. Coffin CS, Rezaeeaval M, Pang JX, et al.: The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy. Aliment Pharmacol Ther 40 (11-12): 1262-9, 2014. [PUBMED Abstract]
11. Gordon SC, Lamerato LE, Rupp LB, et al.: Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population. Clin Gastroenterol Hepatol 12 (5): 885-93, 2014. [PUBMED Abstract]
12. Chen JG, Egner PA, Ng D, et al.: Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 6 (10): 1038-45, 2013. [PUBMED Abstract]

In This Section

• HCV Treatment With DAAs
• Statin Use Among Adults With HBV or HCV

Treatment with direct-acting antivirals (DAAs) leads to elimination of hepatitis C virus (HCV) infection in almost all patients.[1] The goal of therapy is to eradicate HCV RNA and attain a sustained virologic response (SVR), which is defined as an undetectable RNA level 12 weeks after the completion of therapy. Attainment of an SVR is associated with a 97% to 100% chance of being HCV RNA negative during 5-year follow-up, and patients can therefore be considered cured of the HCV infection.[1]

Results from studies of hepatocellular cancer (HCC) risk after attaining SVR have produced conflicting results; some have observed increases in risk after treatment.[2] Most studies have included small numbers of patients, and some had insufficient follow-up time.[2] Some studies did not consider that the presence or absence of cirrhosis could affect the impact of DAAs on HCC risk.[3]

The strongest evidence to date regarding DAA treatment and HCC risk comes from a cohort study of more than 22,000 U.S. veterans receiving DAA treatment for HCV infection.[2] In that cohort, 271 HCC diagnoses occurred. Patients treated with DAAs who attained an SVR had an approximately 75% reduction in the HCC risk, relative to those who did not attain an SVR. Reduction relative risk with SVR was similar in patients with cirrhosis (hazard ratio [HR], 0.31; 95% CI, 0.23–0.44) and patients without cirrhosis (HR, 0.18; 95% CI, 0.11–0.30). Nevertheless, among patients who achieved an SVR, those with cirrhosis had an almost fivefold increase in HCC risk, relative to those without cirrhosis (HR, 4.73; 95% CI, 3.34–6.68).

Statins, also known as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, are cholesterol-lowering medications. Statins have been implicated in the regulation of cell proliferation, apoptosis, and tumor progression in cancer patients, and statin use at the time of cancer diagnosis has been reported to be associated with reduced cancer risk and improved survival. A previous systematic review and meta-analysis noted that statin use was associated with lower cancer mortality and progression overall and in patients who initiated statin use after cancer diagnosis.[4] A previous meta-analysis indicated that statin use may be related to lower HCC incidence, with a 37% reduced risk.[5] However, this meta-analysis included a patient population with and without HBV/HCV infection, making the results difficult to interpret for individuals at increased risk of developing HCC caused by HBV or HCV infection.[6] While many previous studies have suggested an association between statin use and lowered HCC risk, results have been mixed.

References

1. Simmons B, Saleem J, Hill A, et al.: Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis. Clin Infect Dis 62 (6): 683-694, 2016. [PUBMED Abstract]
2. Kanwal F, Kramer J, Asch SM, et al.: Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology 153 (4): 996-1005.e1, 2017. [PUBMED Abstract]
3. Buonomo AR, Gentile I, Borgia G: Direct acting antiviral agents and hepatocellular carcinoma development: don't take it for granted. Transl Gastroenterol Hepatol 2: 101, 2017. [PUBMED Abstract]
4. Mei Z, Liang M, Li L, et al.: Effects of statins on cancer mortality and progression: A systematic review and meta-analysis of 95 cohorts including 1,111,407 individuals. Int J Cancer 140 (5): 1068-1081, 2017. [PUBMED Abstract]
5. Singh S, Singh PP, Singh AG, et al.: Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144 (2): 323-32, 2013. [PUBMED Abstract]
6. Li X, Sheng L, Liu L, et al.: Statin and the risk of hepatocellular carcinoma in patients with hepatitis B virus or hepatitis C virus infection: a meta-analysis. BMC Gastroenterol 20 (1): 98, 2020. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Incidence, Mortality, and Survival

Updated statistics with estimated new cases and deaths for 2024 (cited American Cancer Society as reference 2).

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.