Overview

Information about the prevention of cancer and the science of screening appropriate individuals at high risk of developing cancer is gaining interest. Physicians and individuals alike recognize that the best ”treatment“ of cancer is preventing its occurrence in the first place or detecting it early when it may be most treatable.

The chance of an individual developing cancer depends on both genetic and non-genetic factors. A genetic factor is an inherited, unchangeable trait, while a non-genetic factor is a variable in a person’s environment, which can often be changed. Non-genetic factors may include diet, exercise, or exposure to other substances present in our surroundings. These non-genetic factors are often referred to as environmental factors. Some non-genetic factors play a role in facilitating the process of healthy cells turning cancerous (for example, the correlation between smoking and lung cancer) while other cancers have no known environmental correlation but are known to have a genetic predisposition. A genetic predisposition means that a person may be at higher risk for a certain cancer if a family member has that type of cancer.

Heredity or Genetic Factors

A majority of cases of hepatocellular carcinoma can be attributed to environmental factors such as chronic viral infections and heavy alcohol use (discussed in greater detail below). Nevertheless, family history of liver cancer does appear to influence risk of the disease. Certain inherited conditions, such as hereditary hemochromatosis, also increase risk.

Family history of liver cancer: In a study conducted in the United States, individuals with a first-degree family history of liver cancer (liver cancer in a parent, sibling, or child) were roughly four times more likely to develop liver cancer than individuals without such a family history. This increased risk was observed even in the subset of people without viral hepatitis.1 This study suggests that either genetic factors or shared environmental factors influence the risk of liver cancer.

Hereditary hemochromatosis: Hemochromatosis is a disease in which the body absorbs and stores too much iron. Some of this excess iron is stored in the liver. Hereditary hemochromatosis is one of the most common genetic disorders in the United States, and occurs when an individual inherits a specific genetic mutation from both parents.2 People with hereditary hemochromatosis have an increased risk of developing liver cancer3 as well as other health problems.

Environmental or Non-genetic Factors

Hepatocellular carcinoma is often (but not always) preceded by cirrhosis of the liver. In cirrhotic livers healthy liver tissue is replaced by scar tissue. Factors that contribute to liver cirrhosis and liver cancer are chronic infection with hepatitis C or hepatitis B viruses and chronic heavy alcohol use. 

Chronic infection with hepatitis B virus (HBV): Chronic infection with HBV is thought to account for more than half the cases of liver cancer that occur worldwide.4 HBV can be transmitted through contact with infected blood or needles or sexual intercourse with an infected partner, or from an infected mother to her newborn. The likelihood that an HBV infection will become chronic varies by the age at infection. Chronic infection develops in roughly 90% people who are infected as infants and 2-6% of people who are infected as adults. Among those who develop chronic infections, an estimated 15-25% will die prematurely as a result of liver cirrhosis or liver cancer.5

Chronic infection with hepatitis C virus (HCV): Chronic infection with HCV is another important risk factor for liver cancer, and is thought to account for some of the increase in liver cancer that has occurred in the United States in recent decades.6 In North America HCV causes more cases of liver cancer than HBV.7 HCV is transmitted through contact with infected blood or needles. Sexual transmission and transmission from mother to child during birth are less common routes of infection. Chronic infection develops in a majority of people (70-85%) who are infected with HCV.8

Heavy alcohol use: Long-term, heavy alcohol use increases the risk of liver cancer. According to one estimate, consumption of 6-7 drinks per day for more than 10 years increases the risk of liver cancer more than fivefold.9 The combination of heavy alcohol use with chronic HCV infection results in a particularly high risk. In the United States, heavy alcohol use is thought to account for roughly one-third of all cases of hepatocellular carcinoma.10

Diabetes: A combined analysis of previously published studies (most of which focused on type II diabetes) suggests that diabetes is linked with a more than twofold increased risk of hepatocellular carcinoma.11 It remains possible, however, that diabetes was the result (rather than the cause) of the chronic underlying liver disease.12 Additional studies are needed to better understand the link between diabetes and hepatocellular carcinoma.

Obesity: Obesity increases the risk of several types of cancer, including endometrial cancer, postmenopausal breast cancer, and colon cancer. More recently, studies have suggested that obesity may also increase the risk of liver cancer.13 14 The development of nonalcoholic fatty liver disease may explain some of the link between obesity and hepatocellular carcinoma.

Smoking: Tobacco smoking has been linked with a moderate increase in risk of liver cancer. In a large combined analysis of previously published studies, current smokers were 56% more likely than nonsmokers to develop liver cancer.15

Coffee: Several studies have suggested that coffee consumption decreases the risk of liver cancer.16 17 It’s uncertain whether this effect is causal or simply the result of a reduction in coffee intake among those with liver disease.

Other exposures: Occupational exposure to vinyl chloride increases the risk of angiosarcoma of the liver (a rare type of liver cancer). Aflatoxin—a toxin produced by fungi that can contaminate food—is an important risk factor for liver cancer in less developed countries.18

Prevention 

Because many cases of hepatocellular carcinoma are linked with heavy alcohol use or chronic infection with HCV or HBV, control of these exposures is an important part of liver cancer prevention.

Hepatitis B vaccination: Routine vaccination of infants against HBV is recommended in the U.S. and several other countries to prevent infection with HBV. Older children and adolescents who were not vaccinated previously, and adults at risk for HBV infection, may also be vaccinated.19

Avoidance of HCV: The U.S. blood supply has been screened for HCV since 1992, greatly reducing the risk of infection through blood transfusion. Injection drug use remains an important route of transmission, and injection drug users are advised to avoid sharing needles.20 Currently, there is no vaccine against HCV.

Limited alcohol consumption: For those who drink, general dietary guidelines recommend no more than two drinks per day for men and no more than one drink per day for women.21 People with hepatitis or other liver disease may need to avoid alcohol completely. Talk with your doctor about what’s best for you.

Screening and Early Diagnosis

For many types of cancer, progress in cancer screening has offered promise for earlier detection and higher cure rates. The term screening refers to the regular use of certain examinations or tests in persons who do not have symptoms of cancer.

Thus far, there is no conclusive evidence that screening for liver cancer reduces the risk of death from the disease.22 Nevertheless, some physicians recommend that individuals at high risk of liver cancer—such as those with cirrhosis of the liver—undergo regular screening with tests such as ultrasound of the liver and/or alpha-fetoprotein testing.

Ultrasound: An ultrasound of the liver every 6-12 months may be recommended in order to detect liver cancer at the earliest possible stage in high-risk individuals.23 If a liver nodule (growth) is detected on ultrasound, the patient may undergo additional testing or more frequent surveillance to establish the diagnosis.24

Alpha-fetoprotein testing: Liver cancer can result in elevated blood levels of a protein known as alpha-fetoprotein (AFP), and AFP testing may be used as a screening tool for liver cancer. AFP is not a perfect marker for liver cancer, however, and some researchers have suggested that it should not be the only screening test used.

Strategies to Improve Prevention and Screening

The potential for earlier detection and higher cure rates increases with the advent of more refined screening techniques. In an effort to provide more screening options and perhaps more effective prevention strategies, researchers continue to explore new techniques for the screening and early detection of cancer. Researchers also continue to search for new ways to prevent liver cancer from developing in the first place.

Predicting risk of liver cancer: Although important risk factors for liver cancer have been identified (such as chronic infection with HBV or HCV), many people with these risk factors will never develop liver cancer. Researchers are therefore trying to understand why some groups of patients with chronic liver disease develop liver cancer and others don’t. Answers to this question would improve our understanding of how liver cancer develops (and how it might be prevented), and could also help target screening efforts. As an example of this work, researchers in China developed a risk score to predict risk of liver cancer among individuals with chronic HBV infection.25 The score incorporated information about age, gender, HBV DNA levels, HBV gene mutations, and cirrhosis. Although it’s unclear whether this score will be applicable outside of this particular population, it represents the progress that is being made.

References:


1 Hassan MM, Spitz MR, Thomas MB et al. The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States. Journal of Hepatology. Early online publication October 16, 2008.

2 National Institute of Diabetes and Digestive and Kidney Diseases. Hemochromatosis. Available at: National Digestive Diseases Information Clearinghouse (Accessed January 12, 2008).

3 Elmberg M, Hultcrantz R, Ekbom A et al. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology. 2003;125:1733-41.

4 Parkin DM. The global burden of infection-associated cancers in the year 2002. International Journal of Cancer. 2006;118:3030-3044.

5 Centers for Disease Control and Prevention, Division of Viral Hepatitis. Hepatitis B. Available at: http://www.cdc.gov/hepatitis/HBV.htm (Accessed January 9, 2009).

6 El-Serg HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States. Annals of Internal Medicine. 2003;139:817-823.

7 Raza SA, Clifford GM, Franceschi S. Worldwide variation in the relative importance of hepatitis B and hepatitis C viruses in hepatocellular carcinoma: a systematic review. British Journal of Cancer. 2007;96:1127-34.

8 Centers for Disease Control and Prevention, Division of Viral Hepatitis. Hepatitis C. Available at: http://www.cdc.gov/hepatitis/HCV.htm (Accessed January 9, 2009).

9 Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004;127:S87-S96.

10 Hassan MM, Hwang L-Y, Hatten CJ et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology. 2002;36:1206-1213.

11 El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clinical Gastroenterology and Hepatology. 2006;4:369-380.

12 Chuang S-C, La Vecchia C, Boffetta P. Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Letters. Early online publication 2008. doi:10.1016/j.canlet.2008.10.040.

13 Polesel J, Zucchetto A, Montella M et al. The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma. Annals of Oncology. Early online publication August 22, 2008.

14 Ohki T, Tateishi R, Sato T et al. Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients. Clinical Gastroenterology and Hepatology. 2008;6:459-464.

15 Gandini S, Botteri E, Iodice S et al. Tobacco smoking and cancer: a meta-analysis. International Journal of Cancer. 2007;122:155-164.

16 Hu G, Tuomilehto J, Pukkala E et al. Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer. Hepatology. 2008;48:129-136.

17 Inoue M, Yoshimi I, Sobue T, Tsugane S. Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan. Journal of the National Cancer Institute. 2005;97:293-300.

18 Chuang S-C, La Vecchia C, Boffetta P. Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Letters. Early online publication 2008. doi:10.1016/j.canlet.2008.10.040.

19 Centers for Disease Control and Prevention. Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/index.htm (Accessed January 14, 2008).

20 Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Disease. MMWR. 1998;47(RR-19):1-39.

21 U.S. Department of Health and Human Services and U.S. Department of Agriculture. Dietary Guidelines for Americans, 2005. 6th Edition, Washington, DC: U.S. Government Printing Office, January 2005. Available at: www.healthierus.gov/dietaryguidelines. (Accessed January 8, 2008).

22 National Cancer Institute. Liver (Hepatocellular) Cancer Screening (PDQ®). Available at Liver (Hepatocellular) Cancer Screening (PDQ®) Accessed January 13, 2008.

23 Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236.

24 Parikh S, Hyman D. Hepatocellular cancer: a guide for the internist. The American Journal of Medicine. 2007;120:194-202.

25 Yuen M-F, Tanaka Y, Fong D Y-T et al. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. Journal of Hepatology. 2009;50:80-88.

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