Primary liver and biliary tract tumors encompass a range of benign and malignant neoplasms. They consist of histologically distinct types of tumors that arise from and are influenced by hepatocytes, biliary epithelial cells, and mesenchymal cells. Improvements in imaging have allowed the detection and diagnosis of these neoplasms to be refined. Investigation at the histologic, molecular, and genetic levels has allowed neoplasms to be categorized and treated. Epidemiology has improved understanding of geographic, ethnic, gender, and cultural differences that link exposures with cancer risk. This article focuses on the epidemiology of major primary adult liver and biliary tract tumors.
Key points
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Primary liver and biliary tumors are a significant health threat globally.
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These tumors have wide geographic, ethnic, and gender variation.
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Research investigating the epidemiology and risk factors associated with these tumors has resulted in significant global public health measures to reduce incidence rates.
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Recently identified risk factors, such as metabolic disorders, show the important role that epidemiology will continue to have in the understanding and treatment of these tumors.
Hepatocellular cancer
Hepatocellular cancer (HCC) is the most common form of primary liver cancer, accounting for 85% to 90% of all primary liver cancers, with the burden of disease expected to increase in coming years, especially in the developing world. It is the fifth most common cancer worldwide and the third most common cause of cancer mortality, accounting for more than 600,000 deaths annually. HCC was one of the first cancers to be linked epidemiologically to a defined risk factor (hepatitis B virus [HBV] in Taiwan). Approximately 80% of HCC worldwide is caused by chronic infection with HBV or hepatitis C virus (HCV). Chronic hepatitis B infection remains the most common risk factor for HCC worldwide. There are an estimated 450 million carriers of HBV worldwide. However, chronic hepatitis C has become an important cause of chronic liver disease around the world, with an estimated 200 million people infected with HCV. HCC has several interesting epidemiologic features, including dynamic temporal trends; marked variations among geographic regions and racial, ethnic, and gender groups; and the presence of several well-documented, preventable environmental risk factors.
Global Incidence of HCC
The incidence of HCC is not evenly distributed throughout the world. It is broadly divided into 3 major geographic subgroups: (1) sub-Saharan Africa; (2) eastern Asia; and (3) North and South America, northern Europe, and Oceania. Most cases occur in sub-Saharan Africa or in eastern Asia. Recent estimates published in the GLOBOCAN analysis indicate that 82% of liver cancer cases occur in developing countries, with more than 50% of cases in China (male, 35.2 per 100,000; female, 13.3 per 100,000). Other areas of high incidence include South Korea (male, 48.8 per 100,000; female, 11.6 per 100,000), Gambia (male, 39.7 per 100,000; female, 14.6 per 100,000), and Senegal (male, 28.5 per 100,000; female, 12.2 per 100,000). The rates of HCC in North America, South America, and northern Europe are lower compared with the geographic regions mentioned earlier, typically with incidence rates of less than 5 per 100,000. Southern European countries tend to have incidence levels between these 2 geographic extremes.
Although the incidence of HCC remains high, several regions are experiencing a decrease in overall rate, accounted for by public health measures including vaccination and environmental exposure restriction. The world’s first nationwide hepatitis B vaccination program was implemented in Taiwan in 1984 and resulted in a decrease in the average annual incidence of hepatocellular carcinoma from 0.7 per 100,000 children between 1981 and 1986 to 0.36 per 100,000 children between 1990 and 1994. The mortality from HCC also decreased during this period. Aflatoxin contaminants in corn and peanuts infected with Aspergillus flavus correlated with HCC mortality and the presence of aflatoxin-albumin adducts is higher in hyperendemic HCC areas. A Chinese government program started in the late 1980s to shift the diet of the Jiangsu Province from corn to rice may have limited exposure to known hepatocarcinogen aflatoxin B1 in this area. However, registries in several low-rate areas, including the United States, United Kingdom, and Australia, have shown an increase in HCC incidence. It is thought that the increased incidence in low-rate areas has resulted from the later introduction of HCV infection through intravenous drug abuse within these areas.
HCC is the fastest growing cause of cancer-related mortality in the United States. Between 1985 and 2002, age-adjusted HCC incidence doubled. The increase in HCC started in the mid-1980s, with the greatest proportional increase occurring in Hispanic and non-Hispanic white people. In the United States, the mean age of diagnosis is approximately 65 years, with 75% of cases in men. The racial distribution is 48% white, 15% Hispanic, 13% African American, and 24% other (predominantly Asian). The greatest proportional increase occurred in HCV-related HCC, whereas HBV-related HCC had the lowest rate.
Gender
Liver cancer is the fifth most common cancer in men worldwide and the seventh most common cancer in women. In almost all populations, the rate of HCC is higher among men than among women, with the male/female ratio usually averaging between 2:1 and 4:1. According to GLOBOCAN estimates for 2002, the overall male/female incidence ratio was 2.4. The most discrepant ratios are found in Europe where registries have reported male/female ratios of greater than 5:1. Some of the lowest differences are found in Central and South America. In Colombia and Costa Rica, male/female ratios have been as low as 1.2:1. It is thought that the discrepancy in the ratio of HCC rates between men and women is related to differences in environmental risk factor exposure. Men are more likely to be exposed to HBV and HCV, to consume alcohol, and to smoke cigarettes. However, environmental exposure may be only part of the explanation. Gender difference in hormone levels may also alter the virulence of these risk factors. A positive association between increased circulating testosterone levels and HCC in men infected with HBV has been found even when accounting for the effects of other hepatocellular carcinoma risk factors.
Age
HCC is rarely seen during the first 4 decades of life, except in populations in which HBV infection is hyperendemic. The mean age of diagnosis of HCC is 55 to 59 years in China and 63 to 65 years in Europe and North America, reflecting high-risk and low-risk populations. In Qidong, China, where the HBV and HCC burden is among the world’s highest, the age-specific incidence rate of HCC in men peaks at around 45 years of age. HBV tends to be acquired at a younger age with a longer incubation period than HCV, with mother-to-child transmission being the main route of transfer. The differences in age of onset of HCC vary based on gender, with male rates peaking earlier by 5 to 10 years. These differences in age-specific incidence are related to the type of virus that is dominant within a population as well as age at infection.
Distribution of Risk Factors
The distribution of risk factors varies by geographic location. In most developing countries, which tend to be the high-risk areas, HBV infection is the dominant risk factor. In Asia, excluding Japan, HBV infection is usually acquired through mother-to-child transmission. However, in Africa, sibling-to-sibling transmission is also common. Exposure to AFB1-contaminated foodstuffs is the other major HCC risk factor in high-risk areas. In Japan, HCV is the predominant virus causing HCC and it has been documented that the older the age in Japan, the higher the prevalence. Shortly after World War II, HCV began to circulate in Japan. It is thought that this occurred because of illicit intravenous amphetamine abuse. As a result, HCC rates began to increase in the mid-1970s, and the incidence is expected to peak around 2015.
In low-rate HCC regions, cirrhosis from chronic alcohol consumption and the increasing metabolic syndrome epidemic are the leading causes of HCC development. The predominant causal factors include HCV and, to a lesser extent, HBV infection. Infection by HCV and HBV began in the 1960s and 1970s and spread as a result of intravenous drug abuse. The presence of the virus in the national blood supply further enhanced its spread. With the advent of a screening test in the 1990s, the rates of new infection decreased greatly. It is thought that, in low-rate areas, peak incidence of HCV-related HCC occurred around 2010.
Risk Factors for HCC
HBV
Worldwide, HBV is the most frequent underlying cause of HCC. HBV is a member of the Hepadnaviridae family, which are small, partially double-stranded DNA viruses containing 4 overlapping genes that encode for the nucleocapsid, envelope, polymerase with reverse transcriptase activity, and X proteins. It is thought that HBV can contribute to the development of HCC through at least 4 mechanisms. HBV DNA can integrate into the host chromosome resulting in nonselective, insertional mutagenic events. The hepatitis Bx gene product can function as a transcriptional transactivator of various cellular genes associated with growth control. Chronic HBV infection causes hepatocyte injury, inflammation, and cell turnover, increasing the risk for malignant transformation. In addition, a high HBV replication phenotype and mutations in the core promoter region have been identified as viral risk factors for the development of HCC.
Approximately 350 million to 400 million people are infected with this HBV. Carriers of HBV have a 5-foldto 15-fold increased risk of HCC compared with the general population. Approximately 8% of the population of Asia and sub-Saharan Africa are carriers of HBV surface antigen, whereas only 2% carry it in North America and northern and western Europe. Although 70% to 90% of carriers of HBV who develop HCC do so in the context of cirrhosis, HCC develops in the absence of cirrhosis. HBV infection is most commonly passed from mother to child (vertical transmission). Up to 90% of these transmissions result in chronic infection. However, HBV infection is also passed on through sexual and parenteral routes (horizontal transmission). In these instances, more than 90% of acute infections resolve spontaneously. The annual rate of HCC incidence in chronic HBV carriers ranges between 0.4% and 0.6%. Risk factors associated with increased rate of HCC in HBV carriers include male sex; older age, because of the longer time course of infection; exposure to alcohol, tobacco, or aflatoxin B1; Asian or African race; or coinfection with HCV or hepatitis D viral infection. Higher levels of HBV replication, as shown by increased presence of hepatitis B e antigen and high HBV DNA levels, also increase the HCC rate.
Hepatitis B vaccination is the most effective measure of prevention from HBV infection and HCC formation. The results from the Taiwanese vaccination program show that, 10 years after the initiation of immunization, the incidence of HCC among children 6 to 14 years old had declined from 0.7 per 100,000 to 0.36 per 100,000.
HCV
HCV is a single-stranded RNA virus. Unlike HBV, it does not integrate into the host genome so insertional mutagenesis does not play a role in malignant transformation. It is thought that HCV infection results in HCC by one of 2 mechanisms. The first involves inflammation from chronic HCV infection leading to subsequent regeneration, fibrosis, and cirrhosis. It is within these cirrhotic foci that HCC develops, possibly from adenomatous hyperplastic or dysplastic nodules. The other mechanism may involve HCV proteins that influence cellular genes, resulting in the malignant phenotype.
Chronic HCV infection that promotes inflammation, fibrosis, and cirrhosis is a significant risk factor for the development of HCC. HCC risk is increased approximately 17-fold in patients infected with HCV compared with HCV-negative controls. The annual rate of HCC development is about 1% to 5% once HCV-related cirrhosis has developed, which is 10 times that in HBV. Various risk factors are associated with the progression to cirrhosis. These factors include older age, older age at the time of acquisition of infection, male sex, heavy alcohol intake (>50 g/d), diabetes, obesity, and coinfection with human immunodeficiency virus or HBV.
Alcohol
Heavy alcohol intake, defined as greater than 50 to 70 g/d for prolonged periods, is a well-established risk factor for hepatocellular cancer. Despite the association between heavy alcohol intake and HCC, there is little evidence of a direct carcinogenic effect of alcohol. There is evidence of a synergistic effect of heavy alcohol ingestion with HCV or HBV. It is thought that the combination of these factors increases HCC risk by promoting cirrhosis. One report indicated that, with the concomitant presence of HCV infection among alcohol drinkers, there was an additional 2-fold increase in HCC risk compared with that observed with alcohol alone.
Aflatoxin
AFB1 is a mycotoxin produced by the Aspergillus fungus ( A flavus and Aspergillus parasiticus ). This fungus grows on foodstuffs such as corn and peanuts stored in warm, damp conditions. Animal experiments have shown that AFB1 is a hepatocarcinogen. Once ingested, AFB1 is metabolized to an active epoxide intermediate that can bind to DNA and cause damage. It can produce a mutation in the p53 tumor-suppressor gene. This mutation has been observed in 30% to 60% of HCC tumors in aflatoxin-endemic areas. Regions that have AFB1 exposure also have high rates of HBV infection. Prospective studies in Shanghai, China, showed that urinary excretion of aflatoxin metabolites increased the risk of HCC 4-fold. HBV infection increased the risk 7-fold. However, individuals who excreted AFB1 metabolites and had HBV infection had as much as a 60-fold increased risk in HCC.
Nonalcoholic fatty liver disease
Studies in the United States evaluating risk factors for chronic liver disease or HCC failed to identify HCV, HBV, or heavy alcohol intake in approximately 30% to 40% of patients. Several clinic-based, case-control studies have indicated that patients with HCC with cryptogenic cirrhosis tend to have clinical and demographic features that suggest non-alcoholic steatohepatitis (NASH) compared with age-matched and sex-matched patients with HCC of well-defined viral or alcoholic cause. In one study of 210 patients who underwent resection for HCC, patients with no identifiable cause for chronic liver disease had higher rates of obesity and diabetes compared with patients with alcohol and viral hepatitis. A systematic review and meta-analysis found a significant association between HCC and diabetes that was independent of alcohol and viral hepatitis. Longer duration of diabetes has been reported to increase the risk of HCC. A prospective cohort study of more than 900,000 individuals that spanned a 16-year period showed that liver cancer mortality was 5 times greater among men with the highest body mass index (range, 35–40) compared with those with a normal body mass index. Two other population-based cohort studies from Sweden and Denmark found 2-fold to 3-fold increased risk of HCC in obese men and women compared with those with a normal body mass index. Insulin resistance is associated with obesity and is known to contribute to hepatic steatosis. There is a growing metabolic syndrome epidemic in the United States. The contribution of this disorder to future trends in cirrhosis and liver cancer will be watched closely.
Hepatocellular cancer
Hepatocellular cancer (HCC) is the most common form of primary liver cancer, accounting for 85% to 90% of all primary liver cancers, with the burden of disease expected to increase in coming years, especially in the developing world. It is the fifth most common cancer worldwide and the third most common cause of cancer mortality, accounting for more than 600,000 deaths annually. HCC was one of the first cancers to be linked epidemiologically to a defined risk factor (hepatitis B virus [HBV] in Taiwan). Approximately 80% of HCC worldwide is caused by chronic infection with HBV or hepatitis C virus (HCV). Chronic hepatitis B infection remains the most common risk factor for HCC worldwide. There are an estimated 450 million carriers of HBV worldwide. However, chronic hepatitis C has become an important cause of chronic liver disease around the world, with an estimated 200 million people infected with HCV. HCC has several interesting epidemiologic features, including dynamic temporal trends; marked variations among geographic regions and racial, ethnic, and gender groups; and the presence of several well-documented, preventable environmental risk factors.
Global Incidence of HCC
The incidence of HCC is not evenly distributed throughout the world. It is broadly divided into 3 major geographic subgroups: (1) sub-Saharan Africa; (2) eastern Asia; and (3) North and South America, northern Europe, and Oceania. Most cases occur in sub-Saharan Africa or in eastern Asia. Recent estimates published in the GLOBOCAN analysis indicate that 82% of liver cancer cases occur in developing countries, with more than 50% of cases in China (male, 35.2 per 100,000; female, 13.3 per 100,000). Other areas of high incidence include South Korea (male, 48.8 per 100,000; female, 11.6 per 100,000), Gambia (male, 39.7 per 100,000; female, 14.6 per 100,000), and Senegal (male, 28.5 per 100,000; female, 12.2 per 100,000). The rates of HCC in North America, South America, and northern Europe are lower compared with the geographic regions mentioned earlier, typically with incidence rates of less than 5 per 100,000. Southern European countries tend to have incidence levels between these 2 geographic extremes.
Although the incidence of HCC remains high, several regions are experiencing a decrease in overall rate, accounted for by public health measures including vaccination and environmental exposure restriction. The world’s first nationwide hepatitis B vaccination program was implemented in Taiwan in 1984 and resulted in a decrease in the average annual incidence of hepatocellular carcinoma from 0.7 per 100,000 children between 1981 and 1986 to 0.36 per 100,000 children between 1990 and 1994. The mortality from HCC also decreased during this period. Aflatoxin contaminants in corn and peanuts infected with Aspergillus flavus correlated with HCC mortality and the presence of aflatoxin-albumin adducts is higher in hyperendemic HCC areas. A Chinese government program started in the late 1980s to shift the diet of the Jiangsu Province from corn to rice may have limited exposure to known hepatocarcinogen aflatoxin B1 in this area. However, registries in several low-rate areas, including the United States, United Kingdom, and Australia, have shown an increase in HCC incidence. It is thought that the increased incidence in low-rate areas has resulted from the later introduction of HCV infection through intravenous drug abuse within these areas.
HCC is the fastest growing cause of cancer-related mortality in the United States. Between 1985 and 2002, age-adjusted HCC incidence doubled. The increase in HCC started in the mid-1980s, with the greatest proportional increase occurring in Hispanic and non-Hispanic white people. In the United States, the mean age of diagnosis is approximately 65 years, with 75% of cases in men. The racial distribution is 48% white, 15% Hispanic, 13% African American, and 24% other (predominantly Asian). The greatest proportional increase occurred in HCV-related HCC, whereas HBV-related HCC had the lowest rate.
Gender
Liver cancer is the fifth most common cancer in men worldwide and the seventh most common cancer in women. In almost all populations, the rate of HCC is higher among men than among women, with the male/female ratio usually averaging between 2:1 and 4:1. According to GLOBOCAN estimates for 2002, the overall male/female incidence ratio was 2.4. The most discrepant ratios are found in Europe where registries have reported male/female ratios of greater than 5:1. Some of the lowest differences are found in Central and South America. In Colombia and Costa Rica, male/female ratios have been as low as 1.2:1. It is thought that the discrepancy in the ratio of HCC rates between men and women is related to differences in environmental risk factor exposure. Men are more likely to be exposed to HBV and HCV, to consume alcohol, and to smoke cigarettes. However, environmental exposure may be only part of the explanation. Gender difference in hormone levels may also alter the virulence of these risk factors. A positive association between increased circulating testosterone levels and HCC in men infected with HBV has been found even when accounting for the effects of other hepatocellular carcinoma risk factors.
Age
HCC is rarely seen during the first 4 decades of life, except in populations in which HBV infection is hyperendemic. The mean age of diagnosis of HCC is 55 to 59 years in China and 63 to 65 years in Europe and North America, reflecting high-risk and low-risk populations. In Qidong, China, where the HBV and HCC burden is among the world’s highest, the age-specific incidence rate of HCC in men peaks at around 45 years of age. HBV tends to be acquired at a younger age with a longer incubation period than HCV, with mother-to-child transmission being the main route of transfer. The differences in age of onset of HCC vary based on gender, with male rates peaking earlier by 5 to 10 years. These differences in age-specific incidence are related to the type of virus that is dominant within a population as well as age at infection.
Distribution of Risk Factors
The distribution of risk factors varies by geographic location. In most developing countries, which tend to be the high-risk areas, HBV infection is the dominant risk factor. In Asia, excluding Japan, HBV infection is usually acquired through mother-to-child transmission. However, in Africa, sibling-to-sibling transmission is also common. Exposure to AFB1-contaminated foodstuffs is the other major HCC risk factor in high-risk areas. In Japan, HCV is the predominant virus causing HCC and it has been documented that the older the age in Japan, the higher the prevalence. Shortly after World War II, HCV began to circulate in Japan. It is thought that this occurred because of illicit intravenous amphetamine abuse. As a result, HCC rates began to increase in the mid-1970s, and the incidence is expected to peak around 2015.
In low-rate HCC regions, cirrhosis from chronic alcohol consumption and the increasing metabolic syndrome epidemic are the leading causes of HCC development. The predominant causal factors include HCV and, to a lesser extent, HBV infection. Infection by HCV and HBV began in the 1960s and 1970s and spread as a result of intravenous drug abuse. The presence of the virus in the national blood supply further enhanced its spread. With the advent of a screening test in the 1990s, the rates of new infection decreased greatly. It is thought that, in low-rate areas, peak incidence of HCV-related HCC occurred around 2010.
Risk Factors for HCC
HBV
Worldwide, HBV is the most frequent underlying cause of HCC. HBV is a member of the Hepadnaviridae family, which are small, partially double-stranded DNA viruses containing 4 overlapping genes that encode for the nucleocapsid, envelope, polymerase with reverse transcriptase activity, and X proteins. It is thought that HBV can contribute to the development of HCC through at least 4 mechanisms. HBV DNA can integrate into the host chromosome resulting in nonselective, insertional mutagenic events. The hepatitis Bx gene product can function as a transcriptional transactivator of various cellular genes associated with growth control. Chronic HBV infection causes hepatocyte injury, inflammation, and cell turnover, increasing the risk for malignant transformation. In addition, a high HBV replication phenotype and mutations in the core promoter region have been identified as viral risk factors for the development of HCC.
Approximately 350 million to 400 million people are infected with this HBV. Carriers of HBV have a 5-foldto 15-fold increased risk of HCC compared with the general population. Approximately 8% of the population of Asia and sub-Saharan Africa are carriers of HBV surface antigen, whereas only 2% carry it in North America and northern and western Europe. Although 70% to 90% of carriers of HBV who develop HCC do so in the context of cirrhosis, HCC develops in the absence of cirrhosis. HBV infection is most commonly passed from mother to child (vertical transmission). Up to 90% of these transmissions result in chronic infection. However, HBV infection is also passed on through sexual and parenteral routes (horizontal transmission). In these instances, more than 90% of acute infections resolve spontaneously. The annual rate of HCC incidence in chronic HBV carriers ranges between 0.4% and 0.6%. Risk factors associated with increased rate of HCC in HBV carriers include male sex; older age, because of the longer time course of infection; exposure to alcohol, tobacco, or aflatoxin B1; Asian or African race; or coinfection with HCV or hepatitis D viral infection. Higher levels of HBV replication, as shown by increased presence of hepatitis B e antigen and high HBV DNA levels, also increase the HCC rate.
Hepatitis B vaccination is the most effective measure of prevention from HBV infection and HCC formation. The results from the Taiwanese vaccination program show that, 10 years after the initiation of immunization, the incidence of HCC among children 6 to 14 years old had declined from 0.7 per 100,000 to 0.36 per 100,000.
HCV
HCV is a single-stranded RNA virus. Unlike HBV, it does not integrate into the host genome so insertional mutagenesis does not play a role in malignant transformation. It is thought that HCV infection results in HCC by one of 2 mechanisms. The first involves inflammation from chronic HCV infection leading to subsequent regeneration, fibrosis, and cirrhosis. It is within these cirrhotic foci that HCC develops, possibly from adenomatous hyperplastic or dysplastic nodules. The other mechanism may involve HCV proteins that influence cellular genes, resulting in the malignant phenotype.
Chronic HCV infection that promotes inflammation, fibrosis, and cirrhosis is a significant risk factor for the development of HCC. HCC risk is increased approximately 17-fold in patients infected with HCV compared with HCV-negative controls. The annual rate of HCC development is about 1% to 5% once HCV-related cirrhosis has developed, which is 10 times that in HBV. Various risk factors are associated with the progression to cirrhosis. These factors include older age, older age at the time of acquisition of infection, male sex, heavy alcohol intake (>50 g/d), diabetes, obesity, and coinfection with human immunodeficiency virus or HBV.
Alcohol
Heavy alcohol intake, defined as greater than 50 to 70 g/d for prolonged periods, is a well-established risk factor for hepatocellular cancer. Despite the association between heavy alcohol intake and HCC, there is little evidence of a direct carcinogenic effect of alcohol. There is evidence of a synergistic effect of heavy alcohol ingestion with HCV or HBV. It is thought that the combination of these factors increases HCC risk by promoting cirrhosis. One report indicated that, with the concomitant presence of HCV infection among alcohol drinkers, there was an additional 2-fold increase in HCC risk compared with that observed with alcohol alone.
Aflatoxin
AFB1 is a mycotoxin produced by the Aspergillus fungus ( A flavus and Aspergillus parasiticus ). This fungus grows on foodstuffs such as corn and peanuts stored in warm, damp conditions. Animal experiments have shown that AFB1 is a hepatocarcinogen. Once ingested, AFB1 is metabolized to an active epoxide intermediate that can bind to DNA and cause damage. It can produce a mutation in the p53 tumor-suppressor gene. This mutation has been observed in 30% to 60% of HCC tumors in aflatoxin-endemic areas. Regions that have AFB1 exposure also have high rates of HBV infection. Prospective studies in Shanghai, China, showed that urinary excretion of aflatoxin metabolites increased the risk of HCC 4-fold. HBV infection increased the risk 7-fold. However, individuals who excreted AFB1 metabolites and had HBV infection had as much as a 60-fold increased risk in HCC.
Nonalcoholic fatty liver disease
Studies in the United States evaluating risk factors for chronic liver disease or HCC failed to identify HCV, HBV, or heavy alcohol intake in approximately 30% to 40% of patients. Several clinic-based, case-control studies have indicated that patients with HCC with cryptogenic cirrhosis tend to have clinical and demographic features that suggest non-alcoholic steatohepatitis (NASH) compared with age-matched and sex-matched patients with HCC of well-defined viral or alcoholic cause. In one study of 210 patients who underwent resection for HCC, patients with no identifiable cause for chronic liver disease had higher rates of obesity and diabetes compared with patients with alcohol and viral hepatitis. A systematic review and meta-analysis found a significant association between HCC and diabetes that was independent of alcohol and viral hepatitis. Longer duration of diabetes has been reported to increase the risk of HCC. A prospective cohort study of more than 900,000 individuals that spanned a 16-year period showed that liver cancer mortality was 5 times greater among men with the highest body mass index (range, 35–40) compared with those with a normal body mass index. Two other population-based cohort studies from Sweden and Denmark found 2-fold to 3-fold increased risk of HCC in obese men and women compared with those with a normal body mass index. Insulin resistance is associated with obesity and is known to contribute to hepatic steatosis. There is a growing metabolic syndrome epidemic in the United States. The contribution of this disorder to future trends in cirrhosis and liver cancer will be watched closely.
Hemangioma
Hepatic hemangioma is the most common benign lesion of the liver, with an estimated prevalence of 5% to 20% in the general population. Hepatic hemangiomas are vascular abnormalities characterized by blood-filled, sinusoidal spaces lined with endothelium. It is thought that dilatation of these spaces, and not angiogenesis, causes enlargement over time. These lesions are incidentally found on abdominal exploration and on imaging studies. Most hepatic hemangiomas are identified in patients between the ages of 30 and 50 years. They are seen more commonly in women than in men, with a female/male ratio of 6:1. They are typically seen as solitary lesions but in more than 10% of cases they are found as multiple hemangiomas. These lesions are benign with no malignant potential, but can cause symptoms. Symptomatic lesions are more frequently found in women and can cause abdominal discomfort, pain from capsular stretch, spontaneous rupture, or thrombocytopenia and hypofibrinogenemia from consumption (Kasabach-Merritt syndrome).
Focal nodular hyperplasia
Focal nodular hyperplasia (FNH) is a benign, indolent tumor of the liver with no known malignant potential. It is the second most common benign liver tumor after hepatic hemangiomas. FNH is reported to occur with a frequency between 0.31% and 3%. It is more commonly identified incidentally in young women between the ages of 30 and 50 years. The female/male ratio has been reported to be between 8:1 and 12:1. FNH is rarely found in the pediatric population and the elderly. The higher risk of FNH in women raises the possibility that these benign tumors are under hormonal influence (pregnancy or oral contraceptive pills). In most cases, FNH is asymptomatic and is commonly seen as an incidental finding on imaging studies. It is thought to arise as a hyperplastic lesion from a preexisting arterial malformation. There are reports in the literature of rupture as well as bleeding caused by FNH.
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