Incidence and Mortality
Viruses Associated With Hepatitis and/or Hepatocellular Cancer
Hepatitis B and C
Cirrhosis and other factors
Incidence and Mortality
Hepatocellular cancer (HCC) is the fourth most common cancer in the world and the third leading cause of cancer mortality worldwide. Age-standardized incidence rates are 2.1 per 100,000 population in North America. In the United States, HCC incidence and mortality rates continue to increase, particularly among middle-aged black, Hispanic, and white men.
It is estimated that there will be 33,190 new cases diagnosed and 23,000 deaths due to this disease in the United States in 2014. 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 22.1 per 100,000 population among men and 8.4 per 100,000 population among women. Table 1 summarizes the incidence of HCC by geographic region.
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.|
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.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.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 A appears only as an acute or newly occurring infection and does not become chronic. People with hepatitis A usually improve without treatment.
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.
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.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.
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. 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. This type of hepatitis does not occur often in the United States.Hepatitis G 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. 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). 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.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%. Other risk factors include hemochromatosis, alpha-1-antitrypsin deficiency, glycogen storage disease, porphyria cutanea tarda, tyrosinemia, and Wilson disease, but rarely biliary cirrhosis. 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. The likely etiology of HCC is summarized in Table 3.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|
- Parkin DM, Whelan SL, Ferlay J, et al., eds.: Cancer Incidence in Five Continents. Volume VII. Lyon, France: International Agency for Research on Cancer, 1997.
- Di Bisceglie AM, Carithers RL Jr, Gores GJ: Hepatocellular carcinoma. Hepatology 28 (4): 1161-5, 1998. [PUBMED Abstract]
- 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]
- American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014.
- Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2008. Bethesda, Md: National Cancer Institute, 2011. Also available online. Last accessed July 2, 2014.
- 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.
- Okuda K, Nakashima T, Kojiro M, et al.: Hepatocellular carcinoma without cirrhosis in Japanese patients. Gastroenterology 97 (1): 140-6, 1989. [PUBMED Abstract]
- 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 February 26, 2014.
- 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]
- Seeff LB: The history of the "natural history" of hepatitis C (1968-2009). Liver Int 29 (Suppl 1): 89-99, 2009. [PUBMED Abstract]
- 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]
- Marcellin P: Hepatitis B and hepatitis C in 2009. Liver Int 29 (Suppl 1): 1-8, 2009. [PUBMED Abstract]
- Lavanchy D: The global burden of hepatitis C. Liver Int 29 (Suppl 1): 74-81, 2009. [PUBMED Abstract]
- 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]
- 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]
- Rizzetto M: Hepatitis D: thirty years after. J Hepatol 50 (5): 1043-50, 2009. [PUBMED Abstract]
- Rizzetto M: Hepatitis D: the comeback? Liver Int 29 (Suppl 1): 140-2, 2009. [PUBMED Abstract]
- 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]
- Yuan JM, Govindarajan S, Gao YT, et al.: Prospective evaluation of infection with hepatitis G virus in relation to hepatocellular carcinoma in Shanghai, China. J Infect Dis 182 (5): 1300-3, 2000. [PUBMED Abstract]
- 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]
- Benvegnù L, Fattovich G, Noventa F, et al.: Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer 74 (9): 2442-8, 1994. [PUBMED Abstract]
- Chiaramonte M, Stroffolini T, Vian A, et al.: Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 85 (10): 2132-7, 1999. [PUBMED Abstract]
- Ikeda K, Saitoh S, Koida I, et al.: A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 18 (1): 47-53, 1993. [PUBMED Abstract]
- Beasley RP: Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 61 (10): 1942-56, 1988. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Farinati F, Floreani A, De Maria N, et al.: Hepatocellular carcinoma in primary biliary cirrhosis. J Hepatol 21 (3): 315-6, 1994. [PUBMED Abstract]
- Ross RK, Yuan JM, Yu MC, et al.: Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 339 (8799): 943-6, 1992. [PUBMED Abstract]
- Shiratori Y, Yoshida H, Omata M: Management of hepatocellular carcinoma: advances in diagnosis, treatment and prevention. Expert Rev Anticancer Ther 1 (2): 277-90, 2001. [PUBMED Abstract]