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

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Summary of Evidence

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.

Hepatitis B Vaccine to Prevent Hepatocellular Cancer

Based on solid evidence, immunizing individuals against hepatitis B would lead to a decrease in the incidence of hepatocellular cancer (HCC).

Description of the Evidence

  • Internal Validity: Fair (ecologic control; no direct comparison group).
  • Consistency: Limited number of studies.
  • Magnitude of Effects on Health Outcomes: Reduction of risk occurs with prevention of hepatitis B infection in one intervention study. A study in Taiwan shows that vaccination of newborns (the vaccination program includes administration of hepatitis B immunoglobulin at birth, followed by a course of hepatitis B vaccine) of mothers infected with hepatitis B virus was associated with a reduction in the average annual incidence of HCC from 0.70 per 100,000 children between 1981 and 1986 to 0.57 and 0.36 for the time periods of 1986 to 1990 and 1990 to 1994, respectively (P < .01).[1] Although there was no direct control group, the decline in incidence of HCC over time would unlikely be explained by other causes. Failures in a vaccination program may be related to either failure to receive hepatitis B immunoglobulin or failure of the hepatitis B vaccine itself.[2]
  • External Validity: Good.
  1. Chang MH, Chen CJ, Lai MS, et al.: Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 336 (26): 1855-9, 1997. [PUBMED Abstract]
  2. Chang MH, Chen TH, Hsu HM, et al.: Prevention of hepatocellular carcinoma by universal vaccination against hepatitis B virus: the effect and problems. Clin Cancer Res 11 (21): 7953-7, 2005. [PUBMED Abstract]


Incidence and Mortality

Hepatocellular cancer (HCC) is the fifth most common cancer in the world in men and the second leading cause of cancer mortality worldwide. In women, hepatocellular cancer is the seventh most common cancer and the sixth leading cause of cancer mortality worldwide.[1] Age-standardized incidence rates are 2.1 per 100,000 population in North America.[2] In the United States, HCC incidence and mortality rates continue to increase, particularly among middle-aged black, Hispanic, and white men.[3]

It is estimated that there will be 39,230 new cases diagnosed and 27,170 deaths due to this disease in the United States in 2016.[4] There is a distinct male preponderance among all ethnic groups in the United States, although this trend is most marked among Chinese Americans, in whom the annualized rate of HCC is 19.9 per 100,000 population among men and 8.4 per 100,000 population among women.[5] Table 1 summarizes the incidence of HCC by geographic region.[6]

In the United States, chronic hepatitis B is the underlying cause of an estimated 2,000 to 4,000 deaths each year from cirrhosis and liver cancer; it is estimated that more than one million Americans have a chronic hepatitis B infection, many of whom do not know they are infected. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are among the most frequent viral infections in humans and represent a major global public health problem. HBV- and HCV-related chronic hepatitis are the main causes of cirrhosis and HCC, which are responsible for a high rate of morbidity and mortality. In the last few years, knowledge of the epidemiology and the natural history of HBV and HCV infections has markedly improved, and considerable progress has been made in the efficacy of therapy.

Table 1. Incidence of Hepatocellular Carcinoma by Geographic Regiona
Region Incidence (per 100,000 population)
aAdapted from Russo et al.[6]
China 27–36
Mediterranean 5–20
South America 0.2–5.0
Northern Europe 5
Western Africa 30–48
United States 4

HCC is very rare in persons younger than 40 years in the United States, and a much higher risk of HCC is associated with a long duration of infection with hepatitis C (e.g., greater risk after 30 years of infection). About 80% of persons with HCC have cirrhosis.[7]

Viruses Associated With Hepatitis and/or Hepatocellular Cancer

There are several types of viruses associated with hepatitis and/or HCC. Hepatitis is also the name of a family of viral infections that affect the liver; the most common types are hepatitis A, hepatitis B, and hepatitis C.[8]

Table 2. Viruses Associated With Hepatitis
Hepatic Virus Types Mode of Transmission Clinical Consequences
Hepatitis A Food, drinking water. Little or no association with cancer. Full recovery (usually)
Hepatitis B Body fluids, e.g., blood, semen Can cause liver damage; can result in acute or chronic HCC
Hepatitis C Body fluids, e.g., blood, semen Acute hepatitis and chronic liver disease, including cirrhosis and liver cancer
Hepatitis D Body fluids, e.g., blood, semen Acute hepatitis
Hepatitis E Infected drinking water  
Hepatitis F No virus confirmed  
Hepatitis G To be determined  

Hepatitis A, hepatitis B, and hepatitis C are diseases caused by three different viruses. Although each disease can cause similar symptoms, the diseases have different modes of transmission and can affect the liver differently.


Hepatitis B and hepatitis C can also begin as acute infections, but in some people, the virus remains in the body, resulting in chronic disease and long-term liver problems. There are vaccines to prevent hepatitis A and B; however, there is not a vaccine for hepatitis C. If a person has had one type of viral hepatitis in the past, it is still possible to get the other types.[8]

After the hepatitis A and hepatitis B viruses were discovered, neither agent was found responsible for many cases of transfusion-related hepatitis—hence the designation non-A, non-B (NANB) hepatitis. Initial follow-up of these cases showed that approximately 50% of patients developed chronic hepatitis, based on persistence of serum enzymes for at least 6 months. Approximately 15 years later, after HCV had been identified as the cause of NANB hepatitis, chronic hepatitis was found to develop more frequently as indicated by persistent viral infection in more than 80% of infected adults but in only about 50% of infected children or young women.[10]

Hepatitis A

Hepatitis A is caused by eating food and drinking water infected with a virus called HAV. It does not lead to chronic or lifelong disease. Almost everyone who develops hepatitis A has a full recovery.

Hepatitis B

Hepatitis B is caused by the virus HBV, which is spread by contact with an infected person's blood, semen, or other body fluid. It is a sexually transmitted disease. Hepatitis B can be a serious infection that can cause liver damage, which may result in cancer.[11,12]

Hepatitis C

Hepatitis C is of concern to both industrialized and developing countries.[13]

Hepatitis C liver disease ranges in severity from a mild illness lasting a few weeks to a serious, lifelong illness that attacks the liver. Hepatitis C results from infection with HCV, which is spread primarily through contact with the blood of an infected person. Hepatitis C can be either acute or chronic.[10] Most people who have hepatitis C develop a chronic infection; this may lead to a scarring of the liver, called cirrhosis. Blood banks test all donated blood for both hepatitis B and hepatitis C, which greatly reduces the risk of getting the virus from blood transfusions or blood products.[10,12,14,15]

Hepatitis D

Hepatitis D is caused by the virus HDV. A person can only get hepatitis D if they are already infected with hepatitis B. It is spread through contact with infected blood, dirty needles, and unprotected sex with a person infected with HDV. Hepatitis D causes swelling of the liver.[16,17]

Hepatitis E

Hepatitis E is caused by the hepatitis E virus. Hepatitis E can be spread through oral-anal contact or by drinking infected water.[18] This type of hepatitis does not occur often in the United States.

Hepatitis G

Chronic hepatitis G infection is not associated with HCC in either hepatitis B surface antigen-positive carriers or noncarriers.[19,20]

Risk Factors

Hepatitis B and C

Chronic hepatitis B and chronic hepatitis C (CHC) are recognized as the major factors worldwide that increase the risk of HCC, with risk being greater in the presence of coinfection.[21-26] The incidence of HCC in individuals with chronic hepatitis is as high as 0.46% per year. In the United States, chronic hepatitis B and CHC account for about 30% to 40% of HCC. Long-term iron depletion in CHC patients has been studied as a modality for lowering the risk of progression to HCC.[27] Iron depletion improves serum alanine aminotransferase levels and hepatic oxidative DNA damage. In a cohort study of biopsy-proven CHC patients with moderate or severe liver fibrosis, patients were divided into two groups. Patients in group A (n = 35) underwent weekly phlebotomy (200 g) until they reached a state of mild iron deficiency, followed by monthly maintenance phlebotomy for 44 to 144 months (median, 107 months), and were advised to consume a low-iron diet (5–7 mg iron/day).[27] Group B (n = 40) comprised CHC patients who declined to receive iron depletion therapy. Both groups included patients who failed to respond to previous interferon (IFN) therapy or had conditions for which IFN was contraindicated. Hepatocarcinogenesis rates in groups A and B were 5.7% and 17.5% at the end of the fifth year and 8.6% and 39% in the tenth year, respectively.[27]

Cirrhosis and other factors

Cirrhosis is a risk factor for HCC, irrespective of the etiology of the cirrhosis.[21,22] The annual risk of developing HCC among persons with cirrhosis is between 1% and 6%.[23] Other risk factors include hemochromatosis, alpha-1-antitrypsin deficiency, glycogen storage disease, porphyria cutanea tarda, tyrosinemia, and Wilson disease,[2] but rarely biliary cirrhosis.[28] Aflatoxins, which are mycotoxins formed by certain Aspergillus species, are a frequent contaminant of improperly stored grains and nuts. In parts of Africa, the high incidence of HCC in humans may be related to ingestion of foods contaminated with aflatoxins. This association, however, is blurred by the frequent coexistence of hepatitis B infection in those population groups. Heavy aflatoxin exposure is associated with inactivation of the p53 tumor suppressor gene, but epidemiological evidence of a causal association is limited.[29] The likely etiology of HCC is summarized in Table 3.[30]

Table 3. Likely Etiology of Hepatocellular Carcinoma
Causative Agents Dominant Geographical Areas
Hepatitis B virus Asia and Africa
Hepatitis C virus Europe, United States, and Japan
Alcohol Europe and United States
Aflatoxins East Asia and Africa
  1. American Cancer Society: Global Cancer Facts and Figures. 2nd ed. Atlanta, Ga: American Cancer Society, 2011. Available online. Last accessed February 8, 2016.
  2. Di Bisceglie AM, Carithers RL Jr, Gores GJ: Hepatocellular carcinoma. Hepatology 28 (4): 1161-5, 1998. [PUBMED Abstract]
  3. Altekruse SF, McGlynn KA, Reichman ME: Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 27 (9): 1485-91, 2009. [PUBMED Abstract]
  4. American Cancer Society: Cancer Facts and Figures 2016. Atlanta, Ga: American Cancer Society, 2016. Available online. Last accessed July 11, 2016.
  5. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2012. Bethesda, Md: National Cancer Institute, 2015. Also available online. Last accessed June 29, 2016.
  6. Russo MW, Jacobson IM: Hepatocellular cancer: screening, surveillance, and prevention. In: Kelsen DP, Daly JM, Kern SE, et al., eds.: Gastrointestinal Oncology: Principles and Practices. Philadelphia, Pa: Lippincott, Williams and Wilkins, 2002, pp 559-568.
  7. Okuda K, Nakashima T, Kojiro M, et al.: Hepatocellular carcinoma without cirrhosis in Japanese patients. Gastroenterology 97 (1): 140-6, 1989. [PUBMED Abstract]
  8. Centers for Disease Control and Prevention: Viral Hepatitis FAQs for the Public. Atlanta, Ga: Centers for Disease Control and Prevention, Division of Viral Hepatitis, 2008. Available Online. Last accessed May 26, 2016.
  9. Fiore AE, Wasley A, Bell BP, et al.: Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 55 (RR-7): 1-23, 2006. [PUBMED Abstract]
  10. Seeff LB: The history of the "natural history" of hepatitis C (1968-2009). Liver Int 29 (Suppl 1): 89-99, 2009. [PUBMED Abstract]
  11. Liu CJ, Jeng YM, Chen CL, et al.: Hepatitis B virus basal core promoter mutation and DNA load correlate with expression of hepatitis B core antigen in patients with chronic hepatitis B. J Infect Dis 199 (5): 742-9, 2009. [PUBMED Abstract]
  12. Marcellin P: Hepatitis B and hepatitis C in 2009. Liver Int 29 (Suppl 1): 1-8, 2009. [PUBMED Abstract]
  13. Lavanchy D: The global burden of hepatitis C. Liver Int 29 (Suppl 1): 74-81, 2009. [PUBMED Abstract]
  14. Bruno S, Crosignani A, Maisonneuve P, et al.: Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: a seventeen-year prospective cohort study. Hepatology 46 (5): 1350-6, 2007. [PUBMED Abstract]
  15. Persico M, Persico E, Suozzo R, et al.: Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels. Gastroenterology 118 (4): 760-4, 2000. [PUBMED Abstract]
  16. Rizzetto M: Hepatitis D: thirty years after. J Hepatol 50 (5): 1043-50, 2009. [PUBMED Abstract]
  17. Rizzetto M: Hepatitis D: the comeback? Liver Int 29 (Suppl 1): 140-2, 2009. [PUBMED Abstract]
  18. Abro AH, Abdou AM, Saleh AA, et al.: Hepatitis E: a common cause of acute viral hepatitis. J Pak Med Assoc 59 (2): 92-4, 2009. [PUBMED Abstract]
  20. Schröter M, Polywka S, Zöllner B, et al.: Detection of TT virus DNA and GB virus type C/Hepatitis G virus RNA in serum and breast milk: determination of mother-to-child transmission. J Clin Microbiol 38 (2): 745-7, 2000. [PUBMED Abstract]
  24. Beasley RP: Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 61 (10): 1942-56, 1988. [PUBMED Abstract]
  25. Bruix J, Barrera JM, Calvet X, et al.: Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 2 (8670): 1004-6, 1989. [PUBMED Abstract]
  26. Tsukuma H, Hiyama T, Tanaka S, et al.: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328 (25): 1797-801, 1993. [PUBMED Abstract]
  27. Kato J, Miyanishi K, Kobune M, et al.: Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J Gastroenterol 42 (10): 830-6, 2007. [PUBMED Abstract]
  29. Ross RK, Yuan JM, Yu MC, et al.: Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 339 (8799): 943-6, 1992. [PUBMED Abstract]

Evidence of Benefit

Prevention of Hepatitis B

Strong evidence that hepatocellular cancer (HCC) can be prevented is provided by a cluster randomized controlled trial of the immunization of 75,000 newborns. After a median of about 25 years of follow-up, the incidence ratio of primary liver cancer in the vaccination-at-birth group to the control group (68% of whom received catch-up vaccinations at ages 10–14 years) was 0.16 (95% confidence interval, 0.03–0.77).[1] These findings suggest that if hepatitis can be prevented, then much HCC can be prevented. Immunization programs are already known to prevent important short-term consequences of hepatitis B infection, such as acute hepatitis, chronic hepatitis, and cirrhosis.

  1. 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]

Changes to This Summary (05/26/2016)


Evidence of Benefit

Revised text to state that strong evidence that hepatocellular cancer can be prevented is provided by a cluster randomized controlled trial of the immunization of 75,000 newborns. Also added text to state that after a median of about 25 years of follow-up, the incidence ratio of primary liver cancer in the vaccination-at-birth group to the control group was 0.16 (cited Qu et al. as reference 1).


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



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



Levels of Evidence


Permission to Use This 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: Accessed <MM/DD/YYYY>. [PMID: 26389403]




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  • Updated: May 26, 2016

