Liver (Hepatocellular) Cancer Prevention (PDQ®)–Health Professional Version

Overview

Note: Separate PDQ summaries on Liver (Hepatocellular) Cancer Screening; Adult Primary Liver Cancer Treatment; Childhood Liver Cancer Treatment; and Levels of Evidence for Cancer Screening and Prevention Studies are also available.

Who Is at Risk?

The critical etiologic agent in at least 80% of hepatocellular cancer (HCC) cases worldwide is chronic hepatitis B virus (HBV) infection or chronic hepatitis C virus (HCV) infection.[1] Both viruses, either alone or when present with other risk factors, are responsible for staggering increases in the risk of HCC, relative to the absence of these hepatitis viruses. Men with chronic HBV or HCV infection are more likely to develop HCC than are women with the same chronic infection, with some, but not the entire difference explained by varying prevalence of other risk factors.[2] Cirrhosis, regardless of its etiology, predisposes patients to HCC [3] and is present in 70% to 90% of HCC patients at the time of diagnosis.[4] Heavy alcohol use is a strong etiologic agent for HCC because it can cause cirrhosis and the presence of HBV or HCV increases risk even more.[5] Exposure to aflatoxin B1 strongly increases HCC risk in individuals with chronic HBV infection and may do so, but to a much lesser extent, in individuals without chronic HBV infection.[1] Nonalcoholic steatohepatitis (NASH) increases risk of HCC among patients who have accompanying cirrhosis [6] and may modestly increase risk in patients without cirrhosis.[7,8] Cigarette smoking modestly increases the risk.[9] Untreated hereditary hemochromatosis and certain other rare medical and genetic conditions are responsible for large increases in HCC risk but are responsible for only a small percentage of cases.[1] The future HCC incidence among patients newly diagnosed with nonalcoholic fatty liver (NAFL) is not known, and because NAFL can progress to NASH, and NAFL patients can develop cirrhosis, there is reason to believe that NAFL patients are at elevated risk.[10] A diagnosis of metabolic syndrome (MetS) is associated with an increased risk of HCC,[11] as are obesity and type 2 diabetes, which are common component conditions of MetS.[11] Those three conditions also can occur concurrently with NAFL.[12] The frequent coexistence of these four conditions makes the interpretation of condition-specific risk measures difficult. Decreases in HCC incidence rates have occurred after implementation of HBV vaccination programs,[13] and treatment with nucleos(t)ide analog therapy reduces but does not eliminate the risk of HCC in patients with chronic HBV infection.[14] Replacement of a food supply that was heavily contaminated with aflatoxin B1 with one that contained much lower levels resulted in a more than 50% reduction in primary liver cancer.[15] HCV treatment with direct-acting antivirals that results in sustained virologic response may reduce HCC risk.[16]

Factors With Adequate Evidence of Increased Risk of Hepatocellular Cancer (HCC)

Chronic hepatitis B virus (HBV) infection

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 of HBV are at least fivefold.[2]

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

Chronic hepatitis C virus (HCV) infection

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.

Cirrhosis

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.

Heavy alcohol use

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

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 persons without HBV, although the available limited data suggest that the increase in risk may be fourfold.[20]

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

Nonalcoholic steatohepatitis (NASH)

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.

Cigarette smoking

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.

Certain rare genetic and medical conditions (untreated hereditary hemochromatosis [HH], alpha-1-antitrypsin deficiency, glycogen storage disease, porphyria cutanea tarda, and Wilson disease)

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).

Factors With Inadequate Evidence of Increased Risk of HCC

Nonalcoholic fatty liver

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.

Metabolic syndrome (MetS)

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.

Obesity

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

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

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

Type 2 diabetes

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

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

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

Interventions With Adequate Evidence of Decreased Risk of HCC

HBV vaccination

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, historical trends, mathematical modeling.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Treatment for chronic HBV infection

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.

Availability of food not contaminated with aflatoxin B1

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.

Interventions With Inadequate Evidence of Decreased Risk of HCC

HCV treatment with direct acting antivirals (DAAs)

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). Nevertheless, among patients who achieved a sustained response, 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).

  • Study Design: Retrospective cohort, case series.
  • Internal Validity: Fair.
  • Consistency: Fair.
  • External Validity: Fair.
References
  1. London WT, McGlynn K: Liver cancer. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 3rd ed. New York, NY: 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]

Description of the Evidence

Incidence, Mortality, and Survival

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 fifth-leading cause of cancer deaths in the United States.[1] About 42,220 new cases of liver cancer are expected to occur in the United States in 2018; the expected number of deaths is 30,200 individuals.[2] Hepatocellular cancer (HCC) accounts for about three-fourths of all liver cancers in the United States.[3] In 1975, liver cancer incidence in the United States was 2.64 per 100,000. In 2014, the rate had risen more than threefold to 8.9 per 100,000.[3] Five-year survival varies by stage, from a high of 31% for localized disease to a low of 3% for distant disease.[1] In the United States, rates of liver cancer incidence and death are lowest in whites and highest in Asian/Pacific Islanders and American Indian/Alaska Natives. Rates are also higher in Hispanics, as compared with non-Hispanics.[1]

Worldwide, liver cancer is the fifth most frequently diagnosed cancer in adult men and the ninth most commonly diagnosed cancer in women.[4] It is the second leading cause of cancer-related death in the world.[4] HCC results in about 750,000 deaths worldwide each year;[4] in most countries, the HCC annual incidence and mortality rates are nearly identical.[4] The incidence of HCC varies widely according to geographic location.[4] High-incidence regions include sub-Saharan Africa, China, Hong Kong, and Taiwan. HCC incidence is low in North and South America, most of Europe, Australia, and parts of the Middle East.[5] In all parts of the world, HCC is more common in men than in women.[5]

Factors With Adequate Evidence of Increased Risk of HCC

Chronic HBV infection

Chronic hepatitis B virus (HBV) infection is the leading cause of HCC in Asia and Africa.[6] 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.[7] In addition to maternal-to-child transmission, HBV can be spread through sexual contact and contact with infected blood.[8] In the United States, the most common route of transmission is sharing drug-injecting needles.[9] It is estimated that 850,000 to 2.2 million people in the United States have chronic HBV infection [8] and that the infection is responsible for 10% to 15% of HCC cases.[10] The World Health Organization (WHO) estimates that 240 million people are infected worldwide.[9]

Evidence for a causal relationship between chronic HBV infection and HCC comes from etiologic studies, case series, case-control studies, and prospective epidemiologic studies.[7] Ecologic 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,[7] and HBV DNA has been found in 10% to 20% of HCC tumors in patients who are seronegative but are positive for HBV antibodies.[7] Case-control studies and prospective studies have observed odds ratios or relative risks (RRs) of at least 5 for chronic HBV infection.[7] Some prospective studies have observed RRs exceeding 50.[7] The lifetime risk of HCC in persons chronically infected with HBV is estimated to be between 10% and 25%.[7] 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.[11] The presence of cirrhosis increases risk, although HBV can cause HCC in the absence of cirrhosis.[4]

Co-infection with HCV appears to have an additive effect on risk.[12] 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

Chronic HCV infection is the leading cause of HCC in North America, Europe, and Japan.[6] Chronic HCV infection accounts for about one-third of HCC cases in the United States.[9] 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.[13] In the United States, more cases are attributable to chronic HCV infection than to any other risk factor.[14]

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.[11] 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;[15] other prospective studies, including cases series of individuals accidently infected with HCV through blood transfusion, have produced a wide range of incidence estimates.[7] 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.[11] Once HCV-related cirrhosis develops, HCC develops annually in 1% to 8% of patients.[11] 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.[11]

Co-infection with HBV appears to have an additive effect on risk.[12] 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.

Cirrhosis

The prevalence of cirrhosis in the United States is estimated to be 0.3%, which corresponds to more than 600,000 adults.[16] Because cirrhosis is present in 70% to 90% of HCC patients at the time of diagnosis,[17] cirrhosis is considered a predisposing factor for HCC.[18] In autopsy studies, 80% to 90% of individuals who die of HCC have cirrhotic livers.[18] 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).[7] 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.[11]

With perhaps the exception of aflatoxin B1, all HCC risk factors are also risk factors for cirrhosis.[6] In patients with established cirrhosis, HCC risk may be modifiable with elimination of the factor responsible for cirrhosis.[19] 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.[19]

Patients with HCV-related cirrhosis are at greater risk of developing HCC than are those with cirrhosis related to HBV and alcohol-related cirrhosis.[18] 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%.[18]

Heavy alcohol use

Heavy alcohol use causes cirrhosis; between 8% and 20% of chronic alcoholics develop the condition.[6] 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.[20]

Many epidemiologic 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.[6] 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.[20] 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.[18,20] 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.[18] 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.[20] 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.[21]

Aflatoxin B1

Aflatoxin B1 is a mycotoxin that can contaminate corn and peanuts stored in warm, humid environments.[7] The highest levels of aflatoxin B1 exposure are found in sub-Saharan Africa, Southeast Asia, and China.[22]

Aflatoxin B1 was deemed a carcinogen by the International Agency for Research on Cancer (IARC) in 1987.[7] The population-attributable risk of aflatoxin B1 to HCC is estimated to be 20% in the Western Pacific (includes China), 27% in southeast Asia, and 40% in Africa.[23] Exposure may be responsible for up to 155,000 HCC cases worldwide.[23]

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.[24] 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.[24]

NASH

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.[25]

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.[26] 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.[27] 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.[26]

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%.[28]

Cigarette smoking

The relationship between tobacco use and liver cancer has been studied extensively for many years.[29] Early epidemiologic 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, 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.[29] In 2014, the U.S. Surgeon General concluded a causal relationship on the basis of study results published after 2004.[30]

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.[29] 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.[31]

A meta-analysis that examined the relationship of cigarette smoking in the presence and absence of chronic HBV or HCV infection observed the following:[32] 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 persons 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.[32]

Certain rare medical and genetic conditions (untreated HH, alpha-1-antitrypsin deficiency, glycogen storage disease, porphyria cutanea tarda, and Wilson disease)

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.[7] 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.[33] Patients with untreated hemochromatosis may develop cirrhosis. The annual incidence of HCC in patients with hemochromatosis is 4% once cirrhosis has been established.[34] In cohorts of patients with untreated hemochromatosis and cirrhosis, the observed number of HCC cases is at least 20-fold higher than expected.[33] HCC is seen, albeit rarely, in hemochromatosis patients who do not have cirrhosis.[33] Between 25% and 45% of premature deaths in hemochromatosis patients are caused by HCC.[33] Hemochromatosis can be treated successfully through phlebotomy, repeated at necessary intervals.[34] Treatment before the development of cirrhosis appears to greatly reduce the risk of HCC.[34] 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,[33] 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.[35] Liver disease results from the accumulation within hepatocytes of unsecreted variant AAT proteins.[36] Individuals with certain AAT deficiency genotypes are at high risk of developing HCC.[37]

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.[38] 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.[39] PCT and AIP are associated with increases in HCC risk.[7] A prospective study in Sweden of individuals with porphyria observed a standardized incidence ratio of 21 for PCT and 70 for AIP.[40]

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.[41] 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, include HCC, are observed in Wilson patients.[42]

Factors With Inadequate Evidence of Increased Risk of HCC

NAFL

Nonalcoholic fatty liver (NAFL) is diagnosed when hepatic steatosis cannot be explained by alcohol use or viral infection.[43] It generally is an asymptomatic, benign condition and is often detected incidentally.[44] NAFL can progress to cirrhosis or NASH. Up to 4% of NAFL patients may develop cirrhosis,[45] and a small clinical study suggested that between 20% and 50% of NAFL patients may develop NASH.[46] 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 NAFL and NASH have different clinical relevance, they often are combined into one clinical entity known as NAFLD. While prevalence estimates and measures of 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%.[28] NAFLD prevalence has more than doubled in the last 30 years [43] and is now the most common liver disorder in the United States.[43] NAFLD is sometimes referred to as the hepatic presentation of MetS;[28] increases in NAFLD rates parallel those of MetS, including obesity and type 2 diabetes.[43] MetS, obesity, and type 2 diabetes are frequent NAFLD comorbidities. Estimates of global prevalence of MetS, obesity, and type 2 diabetes in individuals with NALFD are as follows: MetS, 43%; obesity, 51%; and type 2 diabetes, 23%.[43] 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% CI, 1.28–2.92).[43] HCC has been diagnosed in patients with both cirrhotic and noncirrhotic NAFLD.[47] 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 (histologic) of no cirrhosis, and 31 patients had level 2 evidence (imaging or biospecimen) of no cirrhosis.[48] Furthermore, the percentage of noncirrhotic HCC patients among those with NAFLD was greater than was observed for other known HCC risk factors.[48]

MetS

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.[49] 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.[50]

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.[51] 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.[43] 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 epidemiologic 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.[52] These factors will not be discussed further.

Obesity

Obesity has been considered extensively as a risk factor for HCC, and in most instances, a positive association has been observed. An 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.[53] 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.[54,55]

NAFLD is estimated to be present in up to 90% of obese individuals.[56] 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 epidemiologic data is not warranted. Observed associations should not be interpreted as causal relationships.

Type 2 diabetes

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.[57] 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.[58]

NAFLD is estimated to be present in up to 70% of type 2 diabetics.[56] 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.[4] With the exception of cirrhosis, attempts to disentangle the independent impact on HCC risk of type 2 diabetes using epidemiologic data is not warranted. Observed associations should not be interpreted as causal relationships.

Interventions With Adequate Evidence of Decreased Risk of HCC

HBV vaccination

HBV vaccines became available for the prevention of HBV infection in the early 1980s.[59] WHO recommends that all infants receive the hepatitis B vaccine as soon as possible after birth, preferably within 24 hours.[60] 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%.[59] 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.[60]

Epidemiologic evidence regarding the ability of hepatitis B vaccination to reduce 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 an 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% CI, 0.03–0.77).[61] 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.[62]

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.[22] Booster immunizations currently are not recommended for those who are not immunocompromised.[63]

Treatment for chronic HBV infection

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,[64] 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.[65] A reduction in HCC risk consistently has been observed for patients treated with NA therapy, regardless of cirrhosis status.[65]

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.[65,66] 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.[67] A U.S. cohort of more than 2,000 patients with chronic HBV infection observed a hazard ratio (HR) of 0.39 (95% CI, 0.27–0.56) with treatment, although the cohort included patients treated with interferon.[68]

Use of lamivudine and adefovir can lead to resistance, with resistance leading to re-elevation of HCC risk.[65] Newer NA therapies are more potent and resistance is less likely.[65] 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.

Availability of food not contaminated with aflatoxin B1

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 for 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.[24]

Interventions with Inadequate Evidence of Decreased Risk of HCC

HCV treatment with DAAs

Treatment with direct acting antivirals (DAAs) leads to elimination of HCV infection in almost all patients.[69] 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 can therefore be considered cured of the HCV infection.[69]

Results from studies of HCC risk after attaining SVR have produced conflicting results; some have observed increases in risk after treatment.[70] Most studies have included small numbers of patients, and some had insufficient follow-up time.[70] Some studies did not consider that the presence or absence of cirrhosis could affect the impact of DAAs on HCC risk.[71]

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.[70] 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 in RR with SVR was similar in patients with cirrhosis (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).

References
  1. National Cancer Institute: SEER Stat Fact Sheets: Liver and Intrahepatic Bile Duct Cancer. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 2, 2018.
  2. American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available online. Last accessed August 3, 2018.
  3. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review (CSR) 1975-2014. Bethesda, Md: National Cancer Institute. Also available online. Last accessed August 2, 2018.
  4. 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]
  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]
  6. Lafaro KJ, Demirjian AN, Pawlik TM: Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am 24 (1): 1-17, 2015. [PUBMED Abstract]
  7. London WT, McGlynn K: Liver cancer. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 3rd ed. New York, NY: Oxford University Press, 2006, pp 763-86.
  8. 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 August 2, 2018.
  9. 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 August 2, 2018.
  10. Mittal S, El-Serag HB: Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 47 (Suppl): S2-6, 2013. [PUBMED Abstract]
  11. El-Serag HB: Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142 (6): 1264-1273.e1, 2012. [PUBMED Abstract]
  12. 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]
  13. 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 August 2, 2018.
  14. Ghouri YA, Mian I, Rowe JH: Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis. J Carcinog 16: 1, 2017. [PUBMED Abstract]
  15. 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]
  16. 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]
  17. Hartke J, Johnson M, Ghabril M: The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol 34 (2): 153-159, 2017. [PUBMED Abstract]
  18. 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]
  19. Saffioti F, Pinzani M: Development and Regression of Cirrhosis. Dig Dis 34 (4): 374-81, 2016. [PUBMED Abstract]
  20. Grewal P, Viswanathen VA: Liver cancer and alcohol. Clin Liver Dis 16 (4): 839-50, 2012. [PUBMED Abstract]
  21. 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]
  22. 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]
  23. Liu Y, Wu F: Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect 118 (6): 818-24, 2010. [PUBMED Abstract]
  24. 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]
  25. Diehl AM, Day C: Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med 377 (21): 2063-2072, 2017. [PUBMED Abstract]
  26. 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]
  27. 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]
  28. 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]
  29. 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]
  30. 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. Atlanta, Ga: 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 August 2, 2018.
  31. 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]
  32. 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]
  33. 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]
  34. Villanueva A, Newell P, Hoshida Y: Inherited hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 24 (5): 725-34, 2010. [PUBMED Abstract]
  35. 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]
  36. 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]
  37. 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]
  38. 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]
  39. Harber LC, Bickers DR: Photosensitivity Diseases: Principles of Diagnosis and Treatment. Philadelphia, Pa: Saunders, 1981.
  40. 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]
  41. Huster D: Wilson disease. Best Pract Res Clin Gastroenterol 24 (5): 531-9, 2010. [PUBMED Abstract]
  42. Pfeiffenberger J, Mogler C, Gotthardt DN, et al.: Hepatobiliary malignancies in Wilson disease. Liver Int 35 (5): 1615-22, 2015. [PUBMED Abstract]
  43. 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]
  44. 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]
  45. Rinella ME: Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (22): 2263-73, 2015. [PUBMED Abstract]
  46. Calzadilla Bertot L, Adams LA: The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 17 (5): , 2016. [PUBMED Abstract]
  47. 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]
  48. 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]
  49. Kim D, Touros A, Kim WR: Nonalcoholic Fatty Liver Disease and Metabolic Syndrome. Clin Liver Dis 22 (1): 133-140, 2018. [PUBMED Abstract]
  50. 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]
  51. 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]
  52. 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]
  53. 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]
  54. 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]
  55. 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]
  56. 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]
  57. 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]
  58. 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]
  59. Kao JH: Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 29 (6): 907-17, 2015. [PUBMED Abstract]
  60. World Health Organization: Hepatitis B Fact Sheet. Geneva, Switzerland: World Health Organization, 2017. Available online. Last accessed August 2, 2018.
  61. 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]
  62. 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]
  63. Leuridan E, Van Damme P: Hepatitis B and the need for a booster dose. Clin Infect Dis 53 (1): 68-75, 2011. [PUBMED Abstract]
  64. Perrillo R: Benefits and risks of interferon therapy for hepatitis B. Hepatology 49 (5 Suppl): S103-11, 2009. [PUBMED Abstract]
  65. Lai CL, Yuen MF: Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatology 57 (1): 399-408, 2013. [PUBMED Abstract]
  66. 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]
  67. 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]
  68. 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]
  69. 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]
  70. 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]
  71. 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]

Changes to This Summary (08/02/2018)

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.

This summary was comprehensively reviewed, extensively revised, and reformatted.

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® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about liver (hepatocellular) cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Liver (Hepatocellular) Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/liver/hp/liver-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389403]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

  • Updated: August 2, 2018

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