**2. Epidemiology**

Hepatocellular carcinoma (HCC) accounts for 85% to 90% of the primary liver cancers (El-Serag & Rudolph, 2007). The alarming results of epidemiologic studies performed over the last 2 decades have raised awareness, and shed light on its magnitude as a public health problem. Hepatoma is the fifth most common cancer worldwide, accounting for roughly 4% of all the new cancers diagnosed. It is currently the third most common cause of cancerrelated death in the world (Altekruse, 2009; Parkin, 2005). Recent data presented by the Center for Disease Control and Prevention has liver cancer listed as the ninth leading cause of cancer-related deaths in the United States. In addition, hepatocellular carcinoma has become one of the fastest growing causes of malignancy-related death in this North American country, and its overall age-adjusted incidence has also significantly increased over the last 20 years (El-Serag & Rudolph, 2007).

The incidence of hepatocellular carcinoma differs depending on aspects such as geographic location, sex, age, race and ethnicity, environmental exposure to certain agents, as well as presence of other risk factors. In general, it has been clearly established that the vast majority of the cases of hepatocellular carcinoma occur in the setting of cirrhosis arising from chronic liver disease with approximately 80% of the cases due to chronic hepatitis B and hepatitis C infection (Perz, 2006). Sub-Saharan Africa and Eastern Asia, which are endemic areas for hepatitis B, are considered among the regions with highest rate of hepatoma. The incidence for men is as high as 35.5/100,000 in China, where more than 50% of all hepatocellular carcinomas occur (El Serag & Rudolph, 2007, as cited in Parkin, 2002). Interestingly, a downtrend in the rate of hepatocellular carcinoma has been seen in several high risk Asian countries. The success of vaccination programs against hepatitis B may be one of the main factors contributing to this decrease (Chang et al., 2009). In contrast to most other Asian countries, Japan's incidence of primary liver cancer is associated to chronic hepatitis C infection which came about after the rampant spread of this virus during the post-World War II years (Yoshizawa, 2002). Recent studies suggest that this incidence is also now decreasing (Tanaka et al., 2008).

The rates of primary hepatic cancer in areas that are considered low risk are well below 10 per 100,000. These include most of Europe, North and South America, Australia and New Zealand (Bosch, 2005). The risk factors for hepatoma in these geographic locations are somewhat different to Sub-Saharan and Asian countries with hepatitis C, alcohol and nonalcoholic fatty liver disease playing a pivotal role. In the United States, for example, the aging large population of chronic hepatitis C infected patients that progress to cirrhosis has caused a disturbing increase in the incidence of hepatocellular carcinoma over the last two decades (Davila, 2004, Kanwal, 2011). This trend has also been seen in other developed nations. In addition to the effect of chronic hepatitis C-related cirrhosis, these countries are experiencing growing problems with heavy alcohol consumption, as well as diabetes and obesity which are associated to nonalcoholic fatty liver disease, and could all lead to cirrhosis and liver cancer (Nordenstedt, 2010).

#### **2.1 Age and sex**

The rate of hepatocellular carcinoma is higher across the board in males than females. This has been well documented in multiple registries that looked at different populations affected by this cancer (Bosch et al., 2005). In general, the male to female ratios range between 2:1 and 4:1, with the larger variation seen in regions with higher and intermediate incidence of hepatoma. Interestingly, the discrepancy in rates is up to 5:1 in France (El-Serag & Rudolph, 2007). The grounds for this global disparity between men and women are not well understood, but several theories exist linking this phenomenon to differences in sexspecific exposure to risk factors such as viral hepatitis, alcohol, and tobacco (Donato, 2002). The trophic effects of androgens have also been implicated (Yu et al., 2001).

Hepatocellular carcinoma most commonly occurs in the presence of cirrhosis as a result of long standing chronic liver disease. In general, the process of inflammation and fibrosis that leads to cirrhosis usually takes many years, although it could be accelerated when more than one risk factor is affecting an individual. As a result, most cases of hepatoma are seen in older patients. The age at which the incidence of primary liver cancer peaks in high risk areas is typically lower than in areas of lesser risk, 50 to 60 years old and 70 to 75 years old, respectively. However, it is not uncommon to see hepatocellular carcinoma affecting people ages 20 to 35 in geographic locations of high incidence, and where factors such as chronic hepatitis B and aflatoxins, an environmental toxin and carcinogen, are endemic. Vertical transmission of hepatitis B with over 90% chronicity of infected persons, and early constant exposure to aflatoxins in these areas contribute to the earlier incidence of hepatoma (Bosch, 2005).

#### **2.2 Race and ethnicity**

278 Liver Transplantation – Basic Issues

endemic areas for hepatitis B, are considered among the regions with highest rate of hepatoma. The incidence for men is as high as 35.5/100,000 in China, where more than 50% of all hepatocellular carcinomas occur (El Serag & Rudolph, 2007, as cited in Parkin, 2002). Interestingly, a downtrend in the rate of hepatocellular carcinoma has been seen in several high risk Asian countries. The success of vaccination programs against hepatitis B may be one of the main factors contributing to this decrease (Chang et al., 2009). In contrast to most other Asian countries, Japan's incidence of primary liver cancer is associated to chronic hepatitis C infection which came about after the rampant spread of this virus during the post-World War II years (Yoshizawa, 2002). Recent studies suggest that this incidence is also

The rates of primary hepatic cancer in areas that are considered low risk are well below 10 per 100,000. These include most of Europe, North and South America, Australia and New Zealand (Bosch, 2005). The risk factors for hepatoma in these geographic locations are somewhat different to Sub-Saharan and Asian countries with hepatitis C, alcohol and nonalcoholic fatty liver disease playing a pivotal role. In the United States, for example, the aging large population of chronic hepatitis C infected patients that progress to cirrhosis has caused a disturbing increase in the incidence of hepatocellular carcinoma over the last two decades (Davila, 2004, Kanwal, 2011). This trend has also been seen in other developed nations. In addition to the effect of chronic hepatitis C-related cirrhosis, these countries are experiencing growing problems with heavy alcohol consumption, as well as diabetes and obesity which are associated to nonalcoholic fatty liver disease, and could all lead to

The rate of hepatocellular carcinoma is higher across the board in males than females. This has been well documented in multiple registries that looked at different populations affected by this cancer (Bosch et al., 2005). In general, the male to female ratios range between 2:1 and 4:1, with the larger variation seen in regions with higher and intermediate incidence of hepatoma. Interestingly, the discrepancy in rates is up to 5:1 in France (El-Serag & Rudolph, 2007). The grounds for this global disparity between men and women are not well understood, but several theories exist linking this phenomenon to differences in sexspecific exposure to risk factors such as viral hepatitis, alcohol, and tobacco (Donato, 2002).

Hepatocellular carcinoma most commonly occurs in the presence of cirrhosis as a result of long standing chronic liver disease. In general, the process of inflammation and fibrosis that leads to cirrhosis usually takes many years, although it could be accelerated when more than one risk factor is affecting an individual. As a result, most cases of hepatoma are seen in older patients. The age at which the incidence of primary liver cancer peaks in high risk areas is typically lower than in areas of lesser risk, 50 to 60 years old and 70 to 75 years old, respectively. However, it is not uncommon to see hepatocellular carcinoma affecting people ages 20 to 35 in geographic locations of high incidence, and where factors such as chronic hepatitis B and aflatoxins, an environmental toxin and carcinogen, are endemic. Vertical transmission of hepatitis B with over 90% chronicity of infected persons, and early constant exposure to aflatoxins in these areas contribute to the earlier incidence of hepatoma (Bosch,

The trophic effects of androgens have also been implicated (Yu et al., 2001).

now decreasing (Tanaka et al., 2008).

cirrhosis and liver cancer (Nordenstedt, 2010).

**2.1 Age and sex** 

2005).

The racial and ethnic variations seen in the incidence of hepatocellular carcinoma are influenced by the geographic distribution of this malignancy. Accordingly, the higher incidence is seen in individuals from Africa and Asia. The migratory patterns of populations moving from intermediate and high risk areas into developed countries, has contributed to change the frequency of primary liver cancer not only globally, but within people living in the same region. In the United States, for example, the highest age-adjusted rates of hepatocellular carcinoma are seen in Asians for both sexes (El-Serag & Rudolph, 2007). This group is followed in occurrence by Hispanics, African Americans and Caucasians. The marked growth in the Hispanic population over the last decade, making it the largest minority in the United States has also had an impact in the liver cancer demographics in this North American nation (El-Serag, 2007).
