Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancer, accounting for between 85% and 90% of these malignancies. The overall prognosis of patients with liver cancer is poor, and an understanding of this disease and its risk factors is crucial for screening at-risk individuals, early recognition, and timely diagnosis. Most HCCs arise in the background of chronic liver disease caused by hepatitis B virus, hepatitis C virus, and chronic excessive alcohol intake. These underlying causes are characterized by marked variations in geography, gender, and other well-documented risk factors, some of which are potentially preventable.
Key points
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HCC is a common malignancy worldwide with nearly equal numbers of new cases and cancer-related death each year.
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Most HCCs arise in the background of chronic liver disease caused by hepatitis B virus, hepatitis C virus, and chronic excessive alcohol intake.
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A detailed understanding of these risk factors and how they lead to cancer development is necessary to improve the screaming, prevention, early identification and management of HCC.
Introduction
Primary liver cancer is the fifth most common cancer worldwide and the second leading cause of cancer mortality. In 2008, there were 749,000 new cases and 695,000 deaths from liver cancer, which increased to an estimated 782,000 new cases in 2012. Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancer, and it accounts for between 85% and 90% of these malignancies. HCC arises from hepatocytes that comprise the parenchymal cells of the liver. The overall prognosis of patients with liver cancer is poor (ratio of mortality to incidence 0.95), and thus, a detailed understanding of this disease and its risk factors is crucial for screening at-risk individuals, early recognition, and timely diagnosis, and therefore, it is hoped, more effective and successful intervention. Most HCCs arise in the background of chronic liver disease, and these underlying causes are characterized by marked variations in geography, gender, and other well-documented risk factors, some of which have become potentially preventable in recent years.
Incidence
The incidence of HCC is not evenly distributed throughout the globe. A great preponderance of cases occur in sub-Saharan Africa and Eastern Asia (>80%), and China is believed to account for approximately 50% of all cases of HCC worldwide. Conversely, North and South America, as well as Europe, have a comparatively low incidence of HCC. These marked differences can be attributed to several specific factors.
Asia
More than half of HCCs occur in China alone, where in 2008, the age-standardized incidence rate was 37.4 per 100,000 individuals for males and 13.7 per 100,000 individuals for females. The incidence of HCC in Mongolia and Korea are also high, with 99 and 49 cases per 100,000 persons, respectively. The high incidence of HCC in these areas is related to the high hepatitis B virus (HBV) infection rates in Asia, and especially in China, where HBV has traditionally been acquired via vertical transmission from mother to child. Widespread HBV vaccination programs introduced in the 1980s have brought hope that reduction of the HBV burden might be achieved, thereby decreasing the HCC rates in these endemic areas. In a recent 20-year follow-up study after the introduction of the vaccine in Taiwan, hepatitis B surface antigen (HBsAg) seropositivity rates decreased from 10% to 17% to 0.7% to 1.7%. These studies in Taiwan also showed a decrease in the incidence of HCC among children aged 6 to 19 years (from 0.51 to 0.15/100,000 person-years in children aged 6–9 years, from 0.6 to 0.19/100,000 person-years in children aged 10–14 years, and from 0.52 to 0.16/100,000 person-years in children aged 15–19 years).
Japan also has a high incidence of HCC with a case index of approximately 40 per 100,000 population. Unlike other Asian countries where HBV predominates, hepatitis C virus (HCV) is the dominant hepatitis virus in Japan, accounting for 80% of HCC cases. The prevalence of HCV increased in Japan after World War II secondary to intravenous (IV) drug use, as well as contaminated blood transfusions, which led to quickly increasing rates of infection in the 1970s. It is estimated that the peak in HCV-related HCC rates will occur in approximately 2015. The HCC incidence associated with HCV in Japan is 2-fold higher than that in Europe or the United States, with 5-year cumulative incidences of 30% and 17%, respectively. This incidence may be attributed to the increased incidence of HCV genotype 1b in Japan, which has been shown to have decreased response to antiviral therapy compared with genotype 1 a, which is prevalent in the United States and Europe.
Africa
The first case of HCC in Africa was reported in 1879. Although the true incidence of HCC in Africa is likely underestimated, because of lack of screening and access to medical care in rural areas, it is a major cause of death in the black African population. Within Africa, Mozambique has the highest incidence of recorded HCC, with an age-standardized incidence of 41.2/100,000 persons each year. Most of these cases are found in rural areas. Cirrhosis coexists with HCC in about 60% of patients in this region. Whites living in the subcontinent have a low incidence of HCC. Chronic HBV infection is the major cause of HCC in Africa, where infection occurs early in childhood through horizontal transmission of the virus from sibling to sibling, differing from the vertical transmission commonly seen in Asia ( Fig. 1 ).
United States and Europe
Although the overall incidence of HCC in the United States is lower than in other parts of the world, the age-adjusted incidence rate tripled from 1975 to 2005 from 1.6/100,000 to 4.9/100,000. This increase is likely a result of the increasing prevalence of HCV from unscreened blood transfusions and IV drug use in the 1960s and 1970s, although there are other likely contributing factors. The incidence of HCC in the United States is expected to continue to increase over the next decade, because of peak HCV infection rates in the 1980s and the 20-year to 40-year lag time observed between HCV acquisition and HCC development. HCC is believed to be most associated with HCV, because widespread HBV vaccination programs have been implemented, and HBV accounts for only 10% to 15% of HCC cases in the United States. The mean age of diagnosis of HCC in the United States is 65 years; 74% of cases occur in men. The racial distribution is 48% white, 13% African American, 15% Hispanic, and 24% other/Asian. The highest incidence of HCC is seen in the Asian/Pacific Islander population (11.7/100,000), and the lowest is among whites (3.9/100,000).
Europe has a slightly higher incidence (2–4 times) of HCC than the United States. The Mediterranean countries (Italy, Spain, and Greece) have incidence rates ranging from 10 to 20 per 100,000 individuals. These countries also attribute approximately two-thirds of their cases to chronic HCV infection. The greatest gender disparity has been reported by countries in central Europe, where the male/female ratio is greater than 4:1.
Introduction
Primary liver cancer is the fifth most common cancer worldwide and the second leading cause of cancer mortality. In 2008, there were 749,000 new cases and 695,000 deaths from liver cancer, which increased to an estimated 782,000 new cases in 2012. Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancer, and it accounts for between 85% and 90% of these malignancies. HCC arises from hepatocytes that comprise the parenchymal cells of the liver. The overall prognosis of patients with liver cancer is poor (ratio of mortality to incidence 0.95), and thus, a detailed understanding of this disease and its risk factors is crucial for screening at-risk individuals, early recognition, and timely diagnosis, and therefore, it is hoped, more effective and successful intervention. Most HCCs arise in the background of chronic liver disease, and these underlying causes are characterized by marked variations in geography, gender, and other well-documented risk factors, some of which have become potentially preventable in recent years.
Incidence
The incidence of HCC is not evenly distributed throughout the globe. A great preponderance of cases occur in sub-Saharan Africa and Eastern Asia (>80%), and China is believed to account for approximately 50% of all cases of HCC worldwide. Conversely, North and South America, as well as Europe, have a comparatively low incidence of HCC. These marked differences can be attributed to several specific factors.
Asia
More than half of HCCs occur in China alone, where in 2008, the age-standardized incidence rate was 37.4 per 100,000 individuals for males and 13.7 per 100,000 individuals for females. The incidence of HCC in Mongolia and Korea are also high, with 99 and 49 cases per 100,000 persons, respectively. The high incidence of HCC in these areas is related to the high hepatitis B virus (HBV) infection rates in Asia, and especially in China, where HBV has traditionally been acquired via vertical transmission from mother to child. Widespread HBV vaccination programs introduced in the 1980s have brought hope that reduction of the HBV burden might be achieved, thereby decreasing the HCC rates in these endemic areas. In a recent 20-year follow-up study after the introduction of the vaccine in Taiwan, hepatitis B surface antigen (HBsAg) seropositivity rates decreased from 10% to 17% to 0.7% to 1.7%. These studies in Taiwan also showed a decrease in the incidence of HCC among children aged 6 to 19 years (from 0.51 to 0.15/100,000 person-years in children aged 6–9 years, from 0.6 to 0.19/100,000 person-years in children aged 10–14 years, and from 0.52 to 0.16/100,000 person-years in children aged 15–19 years).
Japan also has a high incidence of HCC with a case index of approximately 40 per 100,000 population. Unlike other Asian countries where HBV predominates, hepatitis C virus (HCV) is the dominant hepatitis virus in Japan, accounting for 80% of HCC cases. The prevalence of HCV increased in Japan after World War II secondary to intravenous (IV) drug use, as well as contaminated blood transfusions, which led to quickly increasing rates of infection in the 1970s. It is estimated that the peak in HCV-related HCC rates will occur in approximately 2015. The HCC incidence associated with HCV in Japan is 2-fold higher than that in Europe or the United States, with 5-year cumulative incidences of 30% and 17%, respectively. This incidence may be attributed to the increased incidence of HCV genotype 1b in Japan, which has been shown to have decreased response to antiviral therapy compared with genotype 1 a, which is prevalent in the United States and Europe.
Africa
The first case of HCC in Africa was reported in 1879. Although the true incidence of HCC in Africa is likely underestimated, because of lack of screening and access to medical care in rural areas, it is a major cause of death in the black African population. Within Africa, Mozambique has the highest incidence of recorded HCC, with an age-standardized incidence of 41.2/100,000 persons each year. Most of these cases are found in rural areas. Cirrhosis coexists with HCC in about 60% of patients in this region. Whites living in the subcontinent have a low incidence of HCC. Chronic HBV infection is the major cause of HCC in Africa, where infection occurs early in childhood through horizontal transmission of the virus from sibling to sibling, differing from the vertical transmission commonly seen in Asia ( Fig. 1 ).
United States and Europe
Although the overall incidence of HCC in the United States is lower than in other parts of the world, the age-adjusted incidence rate tripled from 1975 to 2005 from 1.6/100,000 to 4.9/100,000. This increase is likely a result of the increasing prevalence of HCV from unscreened blood transfusions and IV drug use in the 1960s and 1970s, although there are other likely contributing factors. The incidence of HCC in the United States is expected to continue to increase over the next decade, because of peak HCV infection rates in the 1980s and the 20-year to 40-year lag time observed between HCV acquisition and HCC development. HCC is believed to be most associated with HCV, because widespread HBV vaccination programs have been implemented, and HBV accounts for only 10% to 15% of HCC cases in the United States. The mean age of diagnosis of HCC in the United States is 65 years; 74% of cases occur in men. The racial distribution is 48% white, 13% African American, 15% Hispanic, and 24% other/Asian. The highest incidence of HCC is seen in the Asian/Pacific Islander population (11.7/100,000), and the lowest is among whites (3.9/100,000).
Europe has a slightly higher incidence (2–4 times) of HCC than the United States. The Mediterranean countries (Italy, Spain, and Greece) have incidence rates ranging from 10 to 20 per 100,000 individuals. These countries also attribute approximately two-thirds of their cases to chronic HCV infection. The greatest gender disparity has been reported by countries in central Europe, where the male/female ratio is greater than 4:1.
Risk factors
HCC is a genetically heterogeneous tumor. Hepatocarcinogenesis is complex, requiring multiple genetic and epigenetic alterations and the involvement of several signal transduction pathways, including p53, Ras, MAPK, JAK/STAT, Wnt/β-catenin, and hedgehog. Multiple predisposing causes of HCC have been defined, including HBV, HCV, excessive alcohol consumption, obesity, and aflatoxins, and the prevalence/contribution of these risk factors vary by region ( Fig. 2 ).
Hepatitis B Virus
HBV is a DNA virus with a circular genome that encodes structural and replicative viral proteins. The now widely recognized association of chronic HBV infection and HCC was first elucidated in 1981 by Beasely and colleagues in Taiwanese HBsAg-positive patients. Serum HBsAg, the marker of HBV infection, without the presence of any additional risk factors is found in 70% of patients with HCC in China, 41% of patients with HCC in the United States, and 24% to 27% of patients with HCC in Japan. In Asia, HBV infection is acquired through vertical transmission from mother to child, whereas in Africa, horizontal transmission early in childhood from sibling to sibling, likely via saliva and open wounds, is more common. In low-risk areas, the pattern of transmission is horizontal, through blood from needlesticks with IV drug use, as well as sexual exposure occurring in adulthood ( Fig. 3 ).
There are 8 genotypes of HBV, classified using the letters A to H. The viral genome of each genotype differs by greater than 8%. Genotype A is found in sub-Saharan Africa, Western Africa, and Northern Europe. Genotype B is found primarily in Japan and East Asia. Genotype C is more commonly associated with severe liver disease and an increased risk of HCC than other genotypes and is found in China, Korea, Japan, Southeast Asia, and several South Pacific Island countries. Genotype D is widely distributed throughout Eastern Europe, North Africa, the Mediterranean region, Russia, the Middle East, India, and the Arctic. Genotype E is primarily found in West Africa. Genotypes F and H are found in Central and South America. Genotype C is the most widely studied of these genotypes. Most studies have shown an association between genotype C and an increased risk of liver fibrosis and HCC.
HBV, unlike other risk factors, increases the risk of HCC in cirrhotic as well as noncirrhotic patients. In the setting of cirrhosis, HBV infection causes a chronic necroinflammatory process with fibrosis and hepatocyte proliferation, similar to that seen with other risk factors. Independent from cirrhosis, HBV is capable of hepatocarcinogenesis secondary to virus-specific factors. HBV is a DNA virus with a circular genome that encodes structural and replicative proteins. It also contains DNA regulatory elements. The virus enters hepatocytes, viral messenger RNAs are transcribed and translated into viral proteins, and viral DNA is synthesized. Viral DNA is then able to integrate into the genome of the host in infected hepatocytes. This process may facilitate carcinogenesis in multiple ways, including rapid cell cycling of hepatocytes and integration of viral DNA into the genome, causing instability, and it may insert into, or adjacent to, genes encoding proteins necessary for carcinogenesis. In addition, HBV overexpression alone has been shown to lead to malignant transformation in mice. An increased risk of HCC development correlates with HBV viral load greater than 13 pg/mL.
Vaccination is the most effective intervention to prevent HBV infection and is one of the first examples of a vaccination that significantly reduces the risk of developing cancer. Although the vaccine has been shown to be ineffective in as many as 5% to 10% of people because of hepatitis B surface antibody levels less than 10 U/mL, there have been drastic decreases in the incidence of HBV after vaccination campaigns. In a 20-year follow-up study after the introduction of the vaccine, HBsAg seropositivity rates decreased from 10% to 17% to 0.7% to 1.7% in Taiwan, where transmission of HBV occurs by both horizontal as well as perinatal vertical transmission in approximately equal rates. Twenty-year follow-up studies in Taiwan also showed a decrease in the incidence of HCC among children aged 6 to 19 years (from 0.51 to 0.15/100,000 person-years in children aged 6–9 years, from 0.6 to 0.19/100,000 person-years in children aged 10–14 years, and from 0.52 to 0.16/100,000 person-years in children aged 15–19 years). Despite these findings, although vaccination is routine in the United States and Europe, vaccination is still not routine in all countries, including sub-Saharan Africa.
HBV is unique from other risk factors for HCC, because it does not require the presence of cirrhosis before malignant transformation. Virtually all of the other risk factors for HCC typically are associated with cirrhosis, which is required for HCC development.
Cirrhosis
Cirrhosis, or the histologic development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury, predisposes individuals to the development of HCC. In addition to HCC, complications of cirrhosis include portal hypertension, varices with or without bleeding, and ascites. Autopsy series suggest an 80% to 90% prevalence of cirrhosis in patients with HCC in Italy and Japan. Although the medical management of cirrhotic patients has improved, HCC is still a common cause of death among patients with cirrhosis. Studies from Europe found that HCC was responsible for 54% to 70% of deaths among persons with cirrhosis who died of a liver-related cause. The risk of HCC in cirrhotic patients is increased irrespective of underlying cause; however, different causes lead to different rates of incidence: HCV >HBV >hemochromatosis. The stage of cirrhosis is also significant in determining the risk of HCC development.
Hepatitis C Virus
HCV is an RNA virus belonging to the Flaviviridae family and was first identified in 1989. Greater than 200 million people are estimated to be infected with HCV worldwide, and it is a major risk factor for HCC development. HCV infection rates in patients with HCC are variable, ranging from 44% to 66% in Italy to 80% to 90% in Japan. A meta-analysis of 21 studies showed a 17-fold increased risk of HCC in HCV-infected patients compared with HCV negative controls.
There have been 6 major genotypes identified (genotypes HCV-1–HCV-6), each with multiple subtypes (distinguished by lowercase letters). These genotypes have different geographic as well as virulence patterns. Genotype 1 (a and b) is the most common worldwide. Genotype 1b predominates in Asia, whereas 1a and 1b are most common in Europe and North and South America. Genotype 4 is predominant in Africa.
Mechanism of increased HCC risk
The increased risk of HCC development in HCV-infected patients comes from the development of liver fibrosis and cirrhosis as a result of chronic inflammation. This inflammation leads to the distortion of hepatic architecture and impairment of cellular functions as well as the microcirculation of the liver. Unlike HBV, HCV is unable to integrate into the host genome. Instead, in HCV, viral proteins such as HCV core protein and their evoked host response have been implicated in apoptosis, signal transduction, reactive oxygen species (ROS) formation, transcriptional activation, and immune modulation through upregulation of interleukin 1 (IL-1), IL-6, and tumor necrosis factor α (TNF-α), contributing to malignant transformation.
Twenty-five to 30 years after HCV infection, rates of cirrhosis range between 12% and 35%. Chronic HCV infection is the leading cause of cirrhosis, and the most common indication for liver transplantation in North and South America, Europe, Australia, and Japan. Environmental factors such as age greater than 40 years at time of infection, degree of alcohol intake (greater than 40–50 g daily), male sex, obesity, presence of an increased alanine transaminase level and coinfection with HBV or HIV seem to have a greater impact than genotype or viral load in the progression to cirrhosis.
Effect of treatment on incidence of hepatocellular carcinoma
Unlike other viral infections, antiviral treatment of HCV can eradicate the virus with sustained virologic response (SVR) and the absence of detectable HCV RNA after successful treatment. SVR has been associated with a 54% reduction in all-cause mortality, including HCC-related and liver-related death. A recent meta-analysis showed that HCC developed at a rate of 0.33% per person year (95% confidence interval [CI] 0.22%–0.5%) among individuals who achieved SVR compared with 1.67% per person year (95% CI 1.15%–2.42%) among nonresponders.
Alcohol
Excessive alcohol consumption has been linked with a variety of disorders. Approximately 8% to 20% of chronic alcoholics develop liver cirrhosis. The International Agency for Research on Cancer working group (IARC) suggested a causal relationship between alcohol consumption and liver cancer in 1988 and has since deemed beverages containing alcohol as carcinogenic to humans. The initial causal relationship between alcohol and HCC was subsequently confirmed by multiple studies, with odds ratios (ORs) between 2.4 and 7. Chronic excessive alcohol use (>80 g/d) for greater than 10 years has been shown to increase HCC risk 5-fold. A dose-dependent risk effect was shown by researchers at the University of Michigan, in which 1500 gram-years of alcohol exposure (60 g/d for >25 years) increased the risk of HCC 6-fold (OR 5.7; 95% CI 2.4–13.7). Data from the European Prospective Investigation into Cancer and Nutrition, including 4,409,809 person-years from 1992 to 2006, showed an association between heavy (>40 g/d for men and >20 g/d for women) alcohol intake (OR 1.77; 95% CI 0.73–4.27) and development of HCC. Although there has never been a safety limit set for the hepatotoxic effects of alcohol, a meta-analysis showed a dose-response relationship between alcohol intake and HCC with relative risks (RRs) of 1.19 (95% CI 1.12–1.27), 1.40 (95% CI 1.25–1.56), and 1.81 (95% CI 1.50–2.19) for 25 g/d, 50 g/d and 100 g/d, respectively.
Conversely, a cessation of alcohol consumption has been shown to decrease the risk of liver cancer. A meta-analysis showed that the risk of HCC decreases after abstinence by 6% to 7% per year compared with ongoing drinkers. The same study estimated that a period of 23 years is required after alcohol cessation for the risk of HCC development to return to that of nondrinkers regardless of cirrhotic status.
Mechanism of hepatocellular carcinoma development
Alcohol is metabolized in hepatocytes via oxidation of alcohol to acetaldehyde and subsequently from acetaldehyde to acetate. This reaction is catalyzed by multiple enzymatic pathways, including alcohol dehydrogenase, cytochrome P4502E1, and catalase. The mechanism of alcohol-induced liver damage resulting in HCC is believed to stem from 2 separate processes studied in animal models. First, alcoholic fatty liver that predisposes to cirrhosis with continued chronic alcohol intake results from the oxidative metabolism of alcohol. The oxidative metabolism generates excess of reduced nicotinamide adenine dinucleotide (NADH), resulting in an increased ratio of NADH to NAD+ in hepatocytes, leading to the inhibition of fatty acid oxidation and promotion of lipogenesis. The second mechanism that contributes to hepatocarcinogenesis is the generation of ROS as well as other free radical species in hepatocytes during metabolism of alcohol in the liver. This process results in increased levels of NADH, which provide electrons for the mitochondrial electron transport chain, leading to increased 1-electron reduction of oxygen to superoxide as well as reduction of antioxidants.
Synergism between ethanol and other risk factors
Alcohol has a synergistic effect with preexisting chronic liver disease on HCC risk, including HCV, HBV, fatty liver disease, tobacco use, and obesity. Poynard and colleagues, in their study on the natural history of liver fibrosis progression in patients with HCV, found that daily alcohol consumption greater than 50 g was one of 3 independent factors associated with an increased rate of fibrosis progression. Another retrospective cohort study showed that patients with cirrhosis caused by a combination of HCV and alcohol had a significantly increased risk of HCC compared with those individuals with cirrhosis caused by alcohol alone (hazard ratio [HR] 11.2; 95%, CI 2.3–55.0). It has been suggested that HCC development in patients with HCV and alcohol may differ biologically from patients with HCV alone. When histology was studied after resection of HCC in 80 patients with HCV infection, the proportion of well-differentiated HCC was lower (2/38 [5%]) in those who had consumed greater than 86 g/d of alcohol than those who were nondrinkers (19/42 [45%], P <.0001). Also, patients with HCV and alcohol as risk factors had reduced tumor-free survival compared with those with HCV alone ( P <.05).
A prospective case-control study of 210 patients in the United States showed that the risk of HCC increased 6-fold for patients with lifetime alcohol exposure greater than 1500 gram-years; 5-fold with greater than 20 pack-years of smoking, and 4-fold with body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) greater than 30. There were synergistic indices for the interaction between alcohol and tobacco, tobacco and obesity, and alcohol and obesity of 3.3, 2.9 and 2.5, respectively.
Aflatoxin
Aflatoxin is a mycotoxin produced by molds Aspergillus flavus and Apsergillus parasiticus , which can contaminate grains, legumes, tree nuts, maize, and ground nuts. In addition, when dairy-producing animals consume aflatoxin-contaminated feed, a metabolite, aflatoxin M1, is excreted in the milk. Countries with high risk of dietary aflatoxin intake include Mozambique, Vietnam, China, and India, because of their warm and humid climate, favoring growth of aflatoxin-producing molds. Aflatoxin has been classified as a hepatic carcinogen by the International Agency for Research on Cancer. A risk assessment from 2010 found that aflatoxin is associated with 4.6% to 28.2% of HCC worldwide. There are 4 aflatoxins: B1, B2, G1, and G2. Aflatoxin B1 (AFB1) has been shown to be the most potent hepatic carcinogen of the 4. According to an estimate from 2006, greater than 55 million people worldwide suffer from uncontrolled exposure to aflatoxin. AFB1 is metabolized to the active intermediate AFB1 exo-8,9-epoxide, which can bind to DNA. Detection of a signature aflatoxin mutation was found at codon 249 in the tumor suppressor gene p53, causing a G >T transversion in 30% to 60% of tumors from persons in aflatoxin-rich environments.
AFB1 has a synergistic effect with chronic HBV infection and alcohol on HCC risk. A prospective study in China showed that urinary excretion of AFB1 metabolites was associated with a 4-fold increased risk of HCC, whereas those who excreted AFB1 metabolites and were HBV positive had a 60-fold increase in HCC risk.
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