Review in basic and clinical GastroenterologyHepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis
Section snippets
Distribution
Liver cancer burden is not distributed evenly throughout the world (Figure 1). Most HCC cases (>80%) occur in either sub-Saharan Africa or in Eastern Asia. China alone accounts for more than 50% of the world’s cases (age-standardized incidence rate: men, 35.2/100,000; women, 13.3/100,000). Other high-rate (>20/100,000) areas include Senegal (men, 28.47/100,000; female, 12.2/100,000), Gambia (male, 39.67/100,000; female, 14.6/100,000), and South Korea (male, 48.8/100,000; female, 11.6/100,000).
HCC in the United States
HCC is the fastest growing cause of cancer-related death in men in the United States (Figure 2). Age-adjusted HCC incidence rates increased more than 2-fold between 1985 and 2002 (Figure 3).13, 14 The average annual, age-adjusted rates of HCC verified by histology or cytology increased from 1.3 per 100,000 during 1978–1980 to 3.3 per 100,000 during 1999–2001.15 The increase in HCC started in the mid-1980s, with the greatest proportional increases occurring during the late 1990s. The largest
Risk Factors of HCC
HCC is unique in that it largely occurs within an established background of chronic liver disease and cirrhosis (∼70%–90% of all detected HCC cases) (Table 1). Major causes of cirrhosis in patients with HCC include hepatitis B, hepatitis C, alcoholic liver disease, and possibly nonalcoholic steatohepatitis. Less common causes include hereditary hemochromatosis, α-1 antitrypsin deficiency, autoimmune hepatitis, and some porphyrias.
Nonalcoholic Fatty Liver Disease
It has been suggested that many cryptogenic cirrhosis and HCC cases represent more severe forms of nonalcoholic fatty liver disease (NAFLD), namely nonalcoholic steatohepatitis (NASH). Studies in the United States evaluating risk factors for chronic liver disease or HCC have failed to identify HCV, HBV, or heavy alcohol intake in a large proportion of patients (30%–40%). Once cirrhosis and HCC are established, it is difficult to identify pathologic features of NASH. Several clinic-based
Obesity
In a large prospective cohort study of more than 900,000 individuals in the United States followed up for a 16-year period, liver cancer mortality rates were 5 times greater among men with the greatest baseline body mass index (range, 35–40) compared with those with a normal body mass index54 (Figure 7). In the same study, the risk of liver cancer was not as increased in women, with a relative risk of 1.68.54 Two other population-based cohort studies from Sweden and Denmark found excess HCC
Diabetes Mellitus
Diabetes has been proposed as a risk factor for both chronic liver disease and HCC through the development of NAFLD and NASH.
Several case-control studies from the United States, Greece, Italy, Taiwan, and Japan examined the association between diabetes, mostly type II, and HCC. At least 8 studies found a significant positive association between diabetes and HCC, 2 studies found a positive association that did not quite reach significance, and 1 study found a significant negative association. A
Genetic Epidemiology of HCC
Epidemiologic research has shown convincingly that the great majority of adult-onset HCC cases are sporadic and that many have at least 1 established nongenetic risk factor such as alcohol abuse or chronic HCV and HBV infection. However, most people with these known environmental risk factors never develop cirrhosis or HCC, whereas a sizable minority of HCC cases develop among individuals without any known risk factors.
Genetic variation has long been suspected to influence the variable risk for
Molecular Mechanisms of Hepatocarcinogenesis
As we can see from the epidemiology, hepatocarcinogenesis is linked tightly to chronic liver damage but rarely develops in healthy liver during normal aging. One possible explanation for this tight correlation is that cancer development in the liver requires cell division, leading to the step-wise acquisition of genetic hits necessary for cellular transformation. In favor of this hypothesis, chemical-induced carcinogenesis in rodents is accelerated when liver cell division is induced by partial
Molecular Mechanisms Inducing Hepatocarcinogenesis at the Cirrhosis Stage
Liver cell proliferation is increased during chronic hepatitis, but cirrhosis is characterized by decreasing hepatocyte proliferation,111 indicating that the regenerative capacity of the liver exhausts at the cirrhosis stage. In the following section we describe 3 basic mechanisms that could accelerate carcinogenesis at the cirrhosis stage (Figure 9).
Molecular Alterations in HCC and Its Possible Role in Promoting Carcinogenesis at the Cirrhosis Stage
In the following section we briefly categorize some of the most common molecular alterations in human HCC and discuss the potential role of these alterations in promoting cancer formation at the cirrhosis stage.
Summary
The pathophysiology of hepatocarcinogenesis is linked tightly to the evolution of cirrhosis. Several mechanisms at the cirrhosis stage appear to accelerate cancer formation including the following: (1) telomere dysfunction inducing chromosomal instability, (2) a growth-inhibitory environment selecting for proliferative cells, (3) alterations of the microenvironment and macroenvironment stimulating cellular proliferation (Figure 10). A detailed understanding of how these alterations select for
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