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The incidence of hepatocellular carcinoma (HCC) has almost tripled since the early 1980s in the United States, where it is the fastest rising cause of cancer-related deaths.1 According to population-based Surveillance Epidemiology and End Results registry data, the overall HCC age-adjusted incidence rates for liver and intrahepatic ducts cancer is as high as 8 per 100,000 underlying population in 2010 (Fig. 1) of which at least 6 per 100,000 are related to HCC. Men are at approximately three times higher risk than women. Asian men (i.e., Chinese, Korean, Filipino, and Japanese) have the highest age-adjusted incidence rates. However, the largest proportional increases have occurred among Hispanics followed by blacks and non-Hispanic whites, whereas the lowest proportional increases have occurred among Asians. In contrast to Asians/Pacific Islanders, HCC incidence rates are reported to be higher among Hispanics born in the United States than among foreign-born Hispanics.2 HCC incidence rates have increased in each successive birth cohort born between 1900 and 19593 (Fig. 2). In addition, the age distribution of HCC patients has shifted to younger ages, with the greatest proportional increases among individuals 45-60 years old (Fig. 2). There is a south to north gradient in the incidence and mortality of HCC; southern states, including Texas, Louisiana, and Mississippi, have some of the highest HCC incidence rates in the nation (Fig. 3). In one study, Texas Latinos and, especially, South Texas Latinos had the highest age-adjusted HCC incidence rates (as high as 10.6 per 100,000).4 Time trends (1975-2010) of population-based age-adjusted incidence and mortality rates for liver and intrahepatic bile ducts cancer in the United States. Both sexes and all races are included. State-specific population-based age-adjusted incidence rates for liver and intrahepatic bile ducts cancer. Both sexes and all races are included. Time-trends of HCC by age groups and birth cohorts in the United States. Source: Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009;27:1485-1491. Most HCC risk factors (chronic infection with hepatitis B [HBV] and/or C virus [HCV] and alcoholic liver disease [ALD]) operate by promoting the development of cirrhosis. Exceptions are rare in HCV-related HCC and mostly represent cases with at least bridging hepatic fibrosis.5 Whereas most cases of HBV-related HCC also occur in the background of cirrhosis (as high as 85% in some studies),6 HBV can cause HCC in the absence of advanced fibrosis or cirrhosis. Although there are several mechanisms for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD-NASH)-related HCC conceivably in the presence of mild or no fibrosis,7 there are no systematic studies to confirm or quantify this contention.8 Indirect measures of severity of hepatic fibrosis, such as degree of liver stiffness using elastography, is associated with risk of HCC.9 The risk of developing HCC in patients with cirrhosis varies with the underlying condition. The highest 5-year cumulative risks are observed in HCV cirrhosis (17% in the West and 30% in Japan), hemochromatosis (21%), HBV cirrhosis (10% in the West and 15% in Asia), alcoholic cirrhosis (8%-12%), and biliary cirrhosis (4%).10, 11 Most large studies and consistent data about the clinical course of HBV infection come from Asian countries, where HBV is endemic and vertical transmission is frequent. This pattern is different in areas that have low incidence of HCC (such as the United States), where HBV infection is mostly acquired in adulthood either through sexual or parenteral routes. There have been only a few adequate studies in Europe and North America that determined the incidence of HCC in hepatitis B surface antigen (HBsAg)-positive individuals—most included only small numbers of HBsAg-positive patients. Nevertheless, the summary HCC incidence rate in these regions is approximately 0.02 per 100 person-years in inactive carriers (HBsAg-positive, but with normal levels of alanine aminotransferase [ALT]), 0.3 in subjects with chronic HBV without cirrhosis, and 2.2 in subjects with HBV-related compensated cirrhosis. On the other hand, cohort studies estimated the incidence rates of HCC among subjects with chronic HBV infection in East Asian countries to be 0.2 per 100 person-years in inactive carriers, 0.6 per 100 person-years for those with chronic HBV infection without cirrhosis, and 3.7 per 100 person-years for those with compensated cirrhosis. Several demographic (male sex, older age, Asian or African ancestry, and family history of HCC), viral (higher levels of HBV replication, HBV genotype, longer duration of infection, coinfection with HCV, human immunodeficiency virus [HIV], or hepatitis D virus), and environmental factors (exposure to aflatoxin and heavy intake of alcohol or tobacco) increase HCC risk among individuals with chronic HBV.2 HBV viral load appears to be an important determinant of HCC risk. The incidence of cirrhosis and HCC increased in proportion to the serum level of HBV DNA12 in Asian countries as well as Alaska.13 HBV genotypes also seem to affect clinical outcomes. In North America and Western Europe, individuals with genotype D had a higher incidence of HCC than those with genotype A. Some data associate genotype B HBV with the development of HCC in young carriers without cirrhosis.14, 15 Mutations in the region of the HBV genome that encode the basal core promoter16 have been associated with increased HCC risk, whereas those in the precore region have been associated with decreased HCC risk.17 Aflatoxin causes a mutation at serine 249 in the tumor suppressor, p53, that was detected in 30%-60% of HCC tumor samples collected from individuals in aflatoxin-endemic areas, most of whom also had HBV infections. Aflatoxin-associated mutation is rarely detected in HCC cases diagnosed in the United States. HCV infection is associated with a 15- to 20-fold increase in risk for HCC, compared with HCV-negative, subjects. The rate of HCC in cohort studies of HCV-infected persons ranges from 1% to 3% over 30 years of chronic infection. Once HCV-related cirrhosis is established, HCC develops at an annual rate of 1%-8% (average, 3.5%). Risk factors for HCC in HCV-infected individuals include male sex, coinfection with HBV or HIV, diabetes, obesity, and high level of alcohol consumption. HCV viremia of any level is a strong risk factor for HCC, compared to no viremia; however, though few studies reported a correlation between HCV viral load levels and risk of progression to cirrhosis18 or HCC, most studies did not find such an association.18 Reports of the association between HCV genotype and HCC risk are inconsistent, but suggest a slightly greater risk of developing HCC in patients with HCV genotype 1b, and possibly genotype 3, than patients with other HCV genotypes.19 Meta-analyses of observational studies from various countries20 report additive effects of HBV and HCV on risk for HCC (35- to 165-fold increase), although a subadditive effect has been suggested based on more recent studies, cohort studies, and studies conducted in areas in which HBV and HCV infection were not common.21 Persons coinfected with HCV (and, to a lesser extent, HBV) and HIV have faster progression to cirrhosis and decompensated liver disease, especially during immunosuppression, than patients with monoinfection. For both HBV and HCV, men have 2-4 times greater risk of HCC across almost all liver disease etiologies than women. Gender-based differences in behavior and environmental exposures, such as alcohol use, might explain some of this difference. However, male and female sex hormones may also play a role. Nested case-control studies in China reported that baseline testosterone levels were higher in HBsAg-positive males, compared to age-matched controls.22 There is a functional polymorphism, a trinucleotide polyglutamine (CAG) short tandem repeat, in exon 1 of the androgen receptor (AR) gene, where increasing number of CAG repeats results in decreased AR signaling. Carriage of the high-risk AR allele (i.e., fewer CAGs) conveyed greater risk of HBV-related HCC in Taiwanese males,22, 23 whereas increased AR CAG repeats were associated with greater HCC risk in females.24 Molecular data indicate that androgens contribute to HCC development by acting as tumor promoters through induction of DNA damage and oxidative stress, whereas estrogens may act as general suppressors of HCC through reduction in the proinflammatory effects of myeloid differentiation primary response 88–mediated secretion of interleukin-6.25 Patients with metabolic syndrome (MetS) or with various components of MetS (e.g., diabetes or obesity) also have higher incidence of HCC than those without MetS. There are also emerging reports of HCC in the setting of MetS arising in the absence of cirrhosis; however, the true extent of this condition or its risk factors are unclear.27, 28 Meta-analyses of observational studies report pooled odds ratios (ORs) of approximately 2.5 for the association between diabetes and HCC independent of viral hepatitis or alcohol use.29, 30 Cirrhosis causes glucose intolerance and type 2 diabetes, and also leads to HCC, making it difficult to interpret the association between HCC and diabetes, especially in case-control and cross-sectional studies. However, this bias is less likely to be present in longitudinal studies; several cohort studies also showed a similar association between diabetes and HCC. This association is less consistent in areas with a high incidence of HBV infection than in other regions. Factors that change HCC risk among patients with diabetes are not clear, but it has been suggested that long diabetes duration and high glycated hemoglobin increase the risk, whereas metformin treatment decreases HCC risk.31 A meta-analysis of 26 prospective cohort studies, including 25,337 primary liver cancer cases, demonstrated that a body mass index (BMI) ≥25 kg/m2 as well as a BMI ≥30 kg/m2 were associated with an increased risk of primary liver cancer. The summary relative risk (RR) for a 5-unit increment in BMI was 1.39 kg/m2 (95% confidence interval [CI]: 1.25-1.55), with the most pronounced increase in risk among persons with a BMI >32 kg/m2. The association between BMI and liver cancer was independent of geographic location, alcohol consumption, or history of diabetes. However, obese males had a higher risk of primary liver cancer than obese females. Furthermore, the association between increasing BMI and HCC was much stronger in individuals with concomitant HCV infection than in persons with HBV infection. NAFLD is the hepatic manifestation of MetS, and it affects approximately one third of the U.S. adult population. Epidemiologic studies support at least a modest association between NAFLD or NASH and HCC, but this association seems to be predominantly limited to those who develop cirrhosis. The few population-based cohort studies of patients with NAFLD are limited by a low number of HCC cases and inability to identify high-risk subgroups (such as cirrhosis, obesity, and diabetes8). Several cross-sectional and case-control studies have evaluated this association indirectly by concomitantly examining the prevalence of diabetes and obesity in NAFLD/NASH-related HCC cases. Diabetes and obesity prevalence was greater in the NAFLD/NASH-related HCC cases, compared to their respective controls with other chronic liver diseases. Prevalence of cirrhosis among HCC cases attributed to NAFLD/NASH ranged between 36% and 90%, with the majority of studies reporting cirrhosis rates ≥70%. These studies are limited because of the difficulty in ascertaining the exposure (histopathological features for confirmed NAFLD/NASH diagnosis) once cirrhosis is established. Furthermore, cirrhosis causes glucose intolerance and type 2 diabetes, and also leads to HCC, rendering it difficult to interpret the association between HCC and diabetes and exclude reverse causality. Recently, a genetic polymorphism of the patatin-like phospholipase domain-containing protein has been shown to be associated with an increase in hepatic fat deposition as well as an increase in the risk of HCC development.32 This and other genetic markers may serve as a part of predictive algorithms to identify high-risk groups for surveillance or chemoprevention. Heavy alcohol intake, defined as ingestion of >50-70 g/day for prolonged periods, is a well-established HCC risk factor. However, even moderate alcohol consumption may increase the risk of HCC in women.33 There is evidence for a synergistic effect between heavy ingestion of alcohol and HCV infection and, to a lesser extent, HBV infection on HCC risk; similar synergism may be present with diabetes. These factors presumably operate together to promote cirrhosis and further increase the risk in individuals with cirrhosis.34, 35 The association between cigarette smoking and HCC has been inconsistent, with few studies finding a positive association and others finding no associations. Among studies reporting positive associations, several found that effects were limited to only those with HBV or HCV infection.36 Estimates of RR, such as risk ratios or ORs, for any of the individual HCC risk factors do not describe their contribution to HCC burden, which is also driven by the prevalence of the risk factor in the general population. Population attributable fraction (PAF) accounts for both an estimate of RR as well as prevalence of a given risk factor in the population, and it describes the proportional reduction in disease that would occur if exposure to a risk factor were to be eliminated. MetS is likely to have the greatest PAF (Table 1). A population-based study of SEER-Medicare-diagnosed HCC cases reported that the highest PAF was for diabetes or obesity (36.6%), followed by alcohol-related disease (23.5%), HCV (22.4%), and HBV (6.3%). Diabetes/obesity had the greatest PAF among whites and Hispanics (38.9% and 38.1%), and HCV had the greatest PAF among Asians and blacks (35.4% and 34.9%). The second greatest PAF were alcohol-related disorders in whites, Hispanics, and blacks (25.6%, 30.1%, and 18.5%) and HBV in Asians (28.5%).37 Therefore, despite having the lowest RR among the risk factors examined, the high prevalence of diabetes/obesity translates into a high attributable fraction. Among patients with HCC currently diagnosed in the United States, 50%-60% are infected with HCV, 10%-15% are infected with HBV, and 20%-25% have ALD. Approximately 20%-30% of HCC cases do not have any of the previously mentioned factors, but have some features of MetS. Several studies examined time trends of risk factors among patients with HCC in the United States; HCV-related HCC had the largest proportional increases during the 1990s and early 2000, whereas the proportion of HCC associated with HBV infection and ALD remained relatively stable. However, based on the PAF arguments, these proportions may change in the next two to three decades with declining HCV-related HCC and increasing cases. of HCC on these risk factors from developing once at an early in to the risk of HCC. On the other hand, surveillance in patients at risk for HCC is to cancer The on primary and HBV have been the most in the incidence of HCC in These have the prevalence of HBV in in and in with a concomitant in the incidence of HCC. the of the for in in to the early the annual incidence of HCC in between 6 and years of age has by In these HBV is the most important risk factor for HCC, and with almost have been in the rate of chronic HBV in the general population. In other regions (e.g., where HBV is by different parenteral a in HBV likely from of and of and However, there are individuals infected with HBV in the that not from and at increased risk for HCC. an estimated to in the United States. There is strong evidence that for HBV or HCV but not the risk of HCC in patients with viral hepatitis who cirrhosis; the annual HCC risk in those patients may the by some for HCC clinical evaluated the of treatment on clinical in patients with In a large Taiwanese study, patients with chronic HBV infection who also had cirrhosis or advanced fibrosis were to 100 of per or for to the incidence of HCC was in the as compared to the this was early a duration of treatment of because of a between treatment groups in the number of data on HCC incidence from studies including patients with HBV who were with was the treatment in in and in one of the studies included HBV patients followed for at least from the only on this as A of patients were diagnosed to have HCC during a of In the three studies with which were all of high and the rate of HCC was in the of than in the patients of most of these data on the effect of HBV treatment on the risk of HCC come from studies that with greater and as and to further the incidence of HCC, though these data have to A cohort study reported clinical in patients with for a of Patients with a response as serum levels had a of developing hepatic HCC, or This effect was among patients with cirrhosis but not in those without cirrhosis the patients in the only HCC. Although this study is limited by a relatively small number of clinical and a short A study patients for a longer duration be to confirm a effect of treatment in patients with In the the data that but not the risk of HCC, in patients with cirrhosis. The of all in patients with cirrhosis is associated with and clinical at 1 with and the most The effect of on HCC incidence in patients with chronic HBV has also been evaluated in several studies and Most of the data suggest that treatment decreases overall HCC incidence in A recent systematic of observational studies examined the risk of HCC among HCV-infected who had been and either a response or did not to was associated with a reduction in RR for HCC for patients at all of liver disease Approximately of patients to treatment develop HCC, compared to of those who did not was associated with a similar reduction in risk for HCC in patients with advanced liver disease or cirrhosis; approximately of patients with HCC, compared to of those without Most studies included in this systematic were from the that rates of HCC are higher in Asian than in or U.S. the of on HCC risk may have been However, these data a moderate effect of on the development of HCC among HCV-infected However, the risk of HCC not to baseline levels among those with cirrhosis, older age, high low high and Furthermore, HCC incidence in to is not by more may further the risk of HCC in HCV-infected There is currently no evidence to that treatment for NAFLD/NASH by any can this risk. Several may have effects in the risk of HCC in patients at high risk for NAFLD Several indicate that the of (such as in diabetes may the risk of HCC. In a of these observational studies, metformin was associated with a reduction in the odds of HCC in patients with diabetes The proportion of patients with NAFLD/NASH was not However, given that all patients had diabetes, one NAFLD to be high in these studies. Therefore, although the extent to which metformin similar may HCC risk in individuals with NAFLD/NASH data also suggest a effect of to HCC. In a large cohort of found that was associated with a reduction in the odds of HCC A recent study from found a strong between and the risk of HCC in individuals with HBV and for of and A meta-analysis of observational studies and evaluated cases of HCC in patients found a overall reduction in HCC risk with the of This finding was driven by observational studies that are to by and There was no observed in the however, of the were to differences in HCC. Several studies suggested an between and risk of HCC. A meta-analysis the results from studies, of which were studies and the other of which were case-control The summary RR of developing HCC with consumption was (95% The summary RR was (95% for low no consumption and (95% for each of of from other than or of is not associated with levels of liver fibrosis, or HCC. such as high aminotransferase and/or and low clinical features such as and type 2 diabetes have been in various algorithms to identify and patients at high HCC risk in HCC surveillance A similar patients at high risk for may the and of in HCC. In the United States, the incidence of HBV-related HCC is likely to HBV HCC, it not cancer in persons with chronic infections. A proportion is infected with of are of their infection persons at high risk for infection, and for HBV and HCV is an important of HCC. A recent based on the prevalence and history of HCV in the U.S. general population of HCV-infected individuals estimated that the number of HCC cases increased from between and to between and with a increase to cases between 2010 and found similar time trends in the prevalence of HCC in a cohort of with Among HCV-infected who the in a given the prevalence of HCC increased from (95% to (95% from to these data that the number of individuals with HCV-related HCC has to and is to in Although the incidence of HCV-related HCC is this may not into a in the number of overall HCC cases. cirrhosis is an important cause of HCC. the high prevalence of MetS in the United States, even small increases in risk related to NASH into a large number of cases of HCC. The recent in the of HCV may change the of HCC in the United States. However, data that the of treatment is limited to patients with of the data that approximately of individuals with HCV in the United States of their infection on the by an rate of treatment cases of cirrhosis by a in However, the treatment of of infected persons would HCC by treatment of all infected individuals would the risk by a reduction in the incidence of HCC may not be an increasing number of patients are diagnosed and The for and to all persons in the United States born between and with the that this identify persons with However, related to and may its overall Furthermore, the degree to which increased in treatment with treatment to be The of the likely be the of and of and individuals in HCV that more in the