Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

Contents lists available at ScienceDirect

Best Practice & Research Clinical Gastroenterology

1

Hepatocellular carcinoma epidemiology Cristina Bosetti, ScD, Unit Head a, 2, Federica Turati, ScD, Post Doc a, 1, Carlo La Vecchia, MD, Professor b, * a

Department of Epidemiology, IRCCS e Istituto di Ricerche Farmacologiche “Mario Negri”, Via G. La Masa 19, 20156 Milan, Italy  degli Studi di Milano, Via A. Vanzetti 5, Department of Clinical Sciences and Community Health, Universita 20133 Milan, Italy b

a b s t r a c t Keywords: Hepatocellular cancer Hepatitis virus Epidemiology Liver cancer Risk factors

Primary liver cancer (namely hepatocellular carcinoma, HCC) is worldwide the fifth most common cancer in men and the seventh one in women, and it represents the third most frequent cause of cancer death. HCC rates are particularly high in eastern/southeastern Asia and in Africa, intermediate in Southern Europe, and low in most high-income countries. Persistent infections by HBV or HCV are the main recognized risk factors for HCC. Aflatoxin exposure is also an important risk factor for HCC development in Africa and eastern Asia. In high-income countries heavy alcohol drinking, tobacco smoking, overweight, diabetes, familial/genetic factors, and selected dietary aspects, have a relevant role. Updated geographic patterns and time trends in mortality from HCC in Europe, USA, Japan, and Australia are provided in the present review, together with an overview of relevant etiologic factors for HCC and main measures for the prevention of this neoplasm. © 2014 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ39 0250320871; fax: þ39 0250320866. E-mail addresses: [email protected] (C. Bosetti), [email protected] (F. Turati), [email protected] (C. La Vecchia). 1 Tel.: þ39 0239014665; fax: þ39 0233200231. 2 Tel.: þ39 0239014526; fax: þ39 0233200231.

http://dx.doi.org/10.1016/j.bpg.2014.08.007 1521-6918/© 2014 Elsevier Ltd. All rights reserved.

754

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

Introduction The epidemiology of liver cancer is made complex by the difficulty to separate the large number of secondary tumours from primary liver cancers [1]. In most populations, the major histological type of primary liver neoplasm is hepatocellular carcinoma (HCC), other forms including adult cholangiocarcinoma originating from the intrahepatic biliary ducts, angiosarcoma from the intrahepatic blood vessels, and childhood hepatoblastoma [2e4]. Primary liver cancer (namely HCC) is one of the most frequent malignancies in the world: it ranks as the fifth most common cause of cancer in men and the seventh one in women, with an estimated number of new cases of 520,000 and 230,000 respectively for men and women in 2008 [5]. Agestandardized rates (world population) are particularly high in eastern and south-eastern Asia (over 20/100,000 men and over 10/100,000 women) and middle and western Africa (15e20/100,000 men and about 8e19/100,000 women); in most high-income countries, including the Americas, Australia, and western and northern Europe, rates are below 7.5/100,000 men and below 2.5/100,000 women, while intermediate rates (around 10/100,000 men and 3/100,000 women) are observed in Southern Europe. Rates are 2e3 folds higher in men than women, the difference being generally larger in high-incidence than in low-incidence areas. Liver cancer incidence has substantially increased in North America and Northern Europe, while it has been decreasing in some high-risk countries from Asia [6e8]. Although almost half liver cancers worldwide are from China, there are scanty incidence data on liver cancer from this country; aflatoxin is its second cause after persistent infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in China, and its control is responsible for some likely recent falls in rates [9]. Five-year survival from liver cancer was about 15% in the USA in 2002e2008 [8], about 12% in Europe in 2000e2007 [10], and even lower (about 5% in 2002) in low-income countries [11]. Given its poor prognosis, the estimated number of deaths from liver cancer is not appreciably different from that of new cases (about 500,000 in men and 220,000 in women in 2008) and liver cancer represents the third most frequent cause of cancer death worldwide (the second one in low-income countries) [5]. Although liver cancer is a rapidly evolving and fatal disease for which treatment is still unsatisfactory, there is sufficient knowledge for effective primary prevention [2e4]. Indeed, causal factors have been identified for three major histological types of primary liver cancer, i.e., HCC, cholangiocarcinoma, and angiosarcoma. Persistent infections by HBV or HCV e which account for over three-quarters of all liver cancer cases in the world e result in chronic liver damage, which can play an important role in liver cancer development. In the minority of liver cancers in which viral infection is not involved, exposures that also damage the liver, as heavy alcohol consumption, or may be directly genotoxic, as tobacco smoke or aflatoxin, are of relevant importance. In the present review, we provide some descriptive information on the geographic patterns and time trends in mortality from primary liver cancer (namely HCC) in major European countries, the European Union (EU) as a whole, and, for comparison purpose, in the USA, Japan, and Australia. Moreover, we give an overview of major environmental risk factors for this neoplasm, including established ones, as HBV and HCV infections, heavy alcohol drinking, tobacco smoking, aflatoxin, as well as selected dietary factors, overweight/obesity, diabetes, and use of oral contraceptives (OC) [2e4,12]. Familial and genetic factors are also considered. Mortality from hepatocellular carcinoma Over the last few decades, mortality from HCC has been considerably variable across Europe [13,14]. Mortality from primary liver cancer (namely HCC) in the EU overall, after an increase in the early 1990's, started to decline since 1994, with a decline by 1.9% per year in men and by 3.4% in women [15]. Between 2002 and 2007, overall EU mortality rates (age-standardized on the world population) from HCC decreased from 3.9 to 3.6/100,000 men and from 0.93 to 0.77/100,000 women. Male mortality substantially decreased in Italy (by 4% per year in men and by 5% in women); appreciable declines were also observed in the Czech Republic, France (after the mid 1990's), and Spain (after 2000) (Fig. 1). In contrast, recent trends were upwards in Germany, the UK, a few other northern European countries, and Portugal, particularly in men. Mortality rates remained approximately stable in Austria for both sexes, and in Finland, Germany, and Portugal for women. Mortality rates in middle-age population

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

755

Fig. 1. Trends in age-standardized (world population) mortality rates from liver cancer (including primary liver cancer, intrahepatic bile duct carcinoma, and unspecified liver cancers) in 23 selected European countries and the European Union (EU) overall, 1980e2009. men, all ages; men, 35e64 years; women, all ages; women, 35e64 years.

756

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

(45e64 years) decreased from 7.4 to 7.0/100,000 men between 2002 and 2007, and from 1.4 to 1.1/ 100,000 women in the EU. Around 2007, the highest overall mortality rates from primary liver cancer in men were in France (6.2/100,000), Spain (4.9), Austria (4.3), and Italy (4.0), while the lowest ones were in Sweden (1.1), the Netherlands (1.2), the UK (1.8), and Denmark (1.9). In women, there was much less variation across Europe; the highest mortality rates were around 1/100,000 in Spain and Italy, while the lowest ones were in Denmark (0.32), Sweden, and in the UK (0.41). HCC mortality rates were upwards in US men (but not in women) over the last decades; between 2002 and 2007, rates increased from 2.3 to 2.5/100,000 men, while they were stable around 0.6/100,000 in women [15]. In Japan, rates were appreciably higher, but downwards trends, by approximately 4% per year, were observed in both sexes after 1996e97; between 2002 and 2007 they declined from 17.6 to 13.7/100,000 men and from 5.1 to 4.1/100,000 women; in Australia rates were almost stable over the last decades around 2.3/100,000 men and 0.5/100,000 women. Among adults aged 45e64, some rises in HCC mortality were observed in the USA and Australia, with rates respectively of 7.3 and 5.2/100,000 men and 1.1e1.2/100,000 women in 2007, whereas substantial declines were registered in Japan, although rates remained exceedingly high (25.1/100,000 men and 4.1/100,000 women in 2007). Thus, over the last decades HCC mortality has decreased in traditionally high mortality areas from southern European countries, such as Italy and France, and recently in Spain, but has increased in former low mortality areas of central and northern Europe, and in Portugal. Consequently, mortality rates of HCC have become more uniform across Europe over recent years. In most European countries, mortality trends from HCC in women were more favourable than in men. Trends of HCC mortality in the USA and Australia were similar to those observed in central and northern European countries, showing upwards trends particularly in people aged 45e64 years and more favourable trends in women. Rates in Japan remain extremely high, even if marked falls were observed since the mid 1990's. The observed trends mortality from HCC should be interpreted with caution, given the substantial problems of validity of death certification data, mainly due to the difficulty in distinguishing primary from secondary liver neoplasms [1]. Some of the observed trends may therefore be due to changes in classification of the diseases; in any case, the consistency of mortality trends at all ages and in middleage and the differences observed between sexes weighs against the possibility that problems in diagnosis and classification largely explain the observed trends. Trends in HCC across Europe, as in most other areas of the world, can be largely related to changes in prevalence of HBV and HCV chronic infections in subsequent generations [14]. In southern Europe, the decreased prevalence of HBV and HCV in younger generations, after the adoption of HBV vaccination programs [16], and the reduction in alcohol drinking over the last few decades likely explains the favourable HCC trends [17], whereas the increasing prevalence of HCV infection and of alcohol consumption in central and northern Europe accounts for the unfavourable trends in those areas of the continent. Similarly, the increases in HCC mortality in the USA have been attributed to HCV exposure during the 1960's and 1970's, due to contact with contaminated blood and injection drug use in generations born between 1945 and 1965 [18]. The decline in the prevalence of tobacco smoking e another recognized risk factor for HCCe in men from Western European countries may have also favourably influenced HCC mortality trends. Diabetes is also related to an excess risk of HCC [19] and the increased prevalence of overweight and obesity, and consequently of diabetes, in several populations may have had some role in recent unfavourable trends of HCC, particularly in North America. Environmental risk factors for hepatocellular carcinoma Hepatitis infections Chronic infections with HBV and HCV are the major recognized risk factors for HCC worldwide [2e4,20], HBV being most common in eastern Asia and HCV in Mediterranean countries [16]. Several epidemiological studies conducted over the last few decades in more than 25 countries provided definite evidence for a causal role of chronic HBV infection in HCC [20]. Most studies estimated excess risks of HCC between 10 and 30 for serologic Hepatitis B surface antigen (HBsAg) positivity, the relative risks (RRs) being higher in cohort studies [20e24]. The risk of HCC has been inversely related to age at first infection with HBV [25,26]. This is also supported by the higher risk of HCC

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

757

observed in the younger age groups in high-risk populations e where most HBV infections occur perinatally or in early childhood e as compared to low- and intermediate-risk areas e where liver cancer below age 40 years is rare [27]. Chronic HBV infection may promote liver cancerogenesis through the continual turnover of hepatocytes resulting from constant inflammation and damage to the liver [20]. In fact, most cases of HCC arise within cirrhotic livers. Low prevalences of HBV (i.e., prevalence of HBsAg detection 8%) is in China, Southeast Asia, and sub-Saharan Africa [16,20]. A strong geographic correlation has been demonstrated between the prevalence of chronic HBV infection and incidence of HCC. Globally, it has been estimated that 54% of all liver cancers can be attributed to HBV infection [28]. Most of the HBV-associated liver cancers occur in low- and middle-income countries (attributable fraction, 59%), the areas with the greatest burden being Melanesia (77%), western and central Africa (70%), and China (69.5%). In high-income countries, with generally much lower HCC incidence, less than a quarter of liver cancers are attributed to HBV and less than 10% in North America and western/northern Europe. The availability of a safe and effective vaccine against HBV has provided the opportunity to prevent a substantial proportion of HCC in generations born since the 1980's [16]. Childhood vaccination programs initiated in HBV-endemic areas have led to a substantial reduction in the prevalence of HBV carriers in those populations. Subsequently, programs aimed at the universal immunization of infants have been established in several high-risk countries worldwide. The estimated risk of developing HCC among subjects infected by HCV compared to uninfected ones ranges between 20 and 30 in most epidemiological studies [20]. There is evidence of a strong interaction between heavy alcohol consumption and HCV infection on HCC risk [21,29,30]. An interaction between HBV and HCV infections in the development of HCC has also been reported, combined infection leading to a RR of HCC over 50 [24,31]. The mechanisms by which HCV causes liver cancer are not well understood. As a non-integrating virus, HCV is unlikely to have a direct role in HCC initiation. Since most HCV-associated HCC occurs in the presence of cirrhosis [32], HCV infection may lead to cancer through the indirect mechanism of immune-mediated damage and subsequent liver cell turnover [20]. Thus, a prolonged period of hepatocellular damage progressing from chronic hepatitis to cirrhosis to HCC is required for the development of HCV-related malignancy. Heavy alcohol consumption enhances HCC risk among those with HCV-associated cirrhosis. In most populations, the prevalence of antibody to HCV (anti-HCV) is below 2%; however, the prevalence of infection is very high (>10%) in Egypt, due to mass schistosomiasis treatment campaigns with non sterile equipment in the 1950's [20]; relatively high HCV seroprevalence have also been reported in selected areas of Japan and (southern) Italy. About one-third of all liver cancers occurring in the world are attributed to HCV [28]; the proportion of liver cancers due to HCV is higher in low and middle-income (33%) than in high-income (20%) countries; in particular, it is 30%e40% in Southeastern Asia, and 50%e60% in northern and central Africa, but is over 60% in Italy [24]. Although there is no vaccine to prevent HCV infection, significant reduction in new infections through the interruption of parenteral transmission e the major route of transmission e of the virus is possible [16]. The screening of blood donations for anti-HCV has led to substantial decreases in the number of post-transfusion hepatitis C cases; further, the use of disposable needles and syringes and other changes in medical procedures have substantially reduced HCV infection. In addition, some studies have shown a possible protective effect of interferon treatments as well as of newer biological direct-acting antiviral agents on the development of HCC among HCV carriers [33]. Alcohol drinking Heavy alcohol drinking is associated with increased risk of primary liver cancer [34,35], although less strongly than with cancers of the upper aerodigestive tract [34]. Most of the evidence linking heavy alcohol consumption to increased HCC risk comes from case-control studies [32]. The results from cohort studies, if anything, show less strong associations.

758

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

The largest cohorts providing results on alcohol and HCC were conducted in Asian countries. In particular, the Korean Cancer Prevention Study estimated a RR for HCC of 1.5 (95% confidence interval, CI, 1.2e2.0) for 100 grams of alcohol per day compared to non drinking, after adjustment for HBV infection [36]. For the same level of intake, another Korean cohort of civil servants, based on almost 1000 male liver cancer deaths, estimated a RR of 1.09 (95% CI 0.77e1.54), taking into account HBV infection [37]. Results from the Korea national health insurance corporation's health examinee cohort in 2000 indicated a significant increased risk of liver cancer mortality (by 23% for 90 grams of alcohol per day compared to non drinking) [38]. In a pooled analysis of four Japanese cohorts, compared to occasional drinkers, the RRs were 1.66 (95% CI 0.98e2.84) for males drinking 92 grams of alcohol per day, but 3.60 (95% CI 1.22e10.66) for females drinking 23 grams per day [39]. A prospective study from China including 1115 male deaths for liver cancer found a hazard ratio (HR) of 1.21 (95% CI 0.92e1.09) for drinkers of 700 grams per week, compared to non drinkers [40]. Among the cohorts from non Asian countries, in the National Institutes of Health (NIH)-AARP Diet and Health Study, compared to drinkers of less than one drink per day, non-drinkers as well as drinkers of >3 drinks per day were at increased liver cancer risk, with HRs of 1.71 (95% CI 1.37e2.14) and 1.92 (95% CI, 1.42e2.60), respectively [41]. Further, the Million Women Study from UK estimated a HR of 1.41 (95% CI 1.16e1.72) for women who did not drink and of 1.70 (95% CI 1.12e2.56) for women drinking 15 drinks per week, compared to those drinking two drinks per week or less [42]. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort showed that 33% (95% CI 7e13%) and 18% (3e38%) of the incidence of liver cancer was attributable to former and current alcohol drinking, respectively, in eight selected European countries [43]. A recent meta-analysis of 19 prospective studies, for a total of 4445 incident cases and 5550 deaths from liver cancer, estimated pooled RRs of 1.16 (95% CI 1.01e1.34) among alcohol drinkers of 3 drinks per day, and 1.22 (95% CI 1.10e1.35) among drinkers of 6 drinks per day, compared with non drinkers, and suggested a linear but modest relationship with increasing alcohol intake in drinkers [44]. A metaanalysis assessing the risk of cancer at various sites related to light alcohol drinking (up to one drink per day), gave a pooled RR of 1.03 (95% CI 0.90e1.17) for liver cancer, based on seven cohort and 13 caseecontrol studies [45]. Moreover, summary RR estimates for >50 grams of ethanol per day (approximately >4 drinks per day) derived by Bagnardi et al (submitted) were 1.12 (95% CI 1.02e1.23) for cohort and 2.79 (95% CI 2.00e3.87) for case-control studies (Fig. 2). Light (drinkers of 12.5 grams per day, about 1 drink per day) and moderate drinkers (drinkers of 50 grams per day) were not at increased risk of liver cancer. Tobacco smoking Following a number of investigations with consistent positive results, IARC has included HCC among the cancer types causally associated to tobacco smoking [46,47]. A meta-analysis of 38 cohort and 58 case-control studies published up to 2009 estimated a pooled RR of 1.51 (95% CI 1.37e1.67) for current smokers and 1.12 (95% CI 0.78e1.60) for former smokers, compared to never smokers [48]. A positive trend in risk was found for increasing number of cigarettes smoked per day, in the presence, however, of substantial heterogeneity among studies. After that meta-analysis, new evidence became available [49e52]. A US case-control study found that regular cigarette smoking was associated with HCC in men (odds ratio, OR, 1.9, 95% CI 1.1e3.1), but not in women (OR 1.1, 95% CI 0.6e0.9), and that the magnitude of the RR was larger in return to smoking duration than to the intensity of smoking [49]. In the update of the Whitehall study, a cohort of 17,363 male government employees in London, after 38 years of follow-up the HR for death from liver cancer was 1.43 (95% CI 0.69e2.95) in current smokers and 1.03 (95% CI 0.49e2.16) in former smokers [50]. Among smokers, the HR was 1.28 (95% CI 0.88e1.87) for ten cigarettes per day [50]. In a case-control study nested within the EPIC cohort, a significantly increased HCC risk was evident among current (OR 4.55, 95% CI 1.90e10.91) and former (OR ¼ 1.98, 95% CI 0.90e4.39) smokers, and tobacco smoking contributed to almost half of the cases of HCC (31.2% for current and 16.4% for former smokers) [51]. Further, in the Singapore Chinese Health Study, including 394 incident cases of HCC, the HRs for current and former smokers were, respectively, 1.63 (95% CI 1.27e2.10) and 1.13 (95% CI 0.84e1.51), after careful allowance for alcohol [52]. A significant dose- and duration-dependent association between tobacco use and HCC risk was observed, with HRs of 1.53

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

759

Fig. 2. Summary relative risk of hepatocellular carcinoma for light, moderate, and heavy alcohol consumption versus no consumption (modified using data derived from Bagnardi et al submitted). Light consumption: 12.5 grams of ethanol per day (1 drink per day); moderate consumption: 50 grams of ethanol per day (4 drinks per day), high consumption: >50 grams of ethanol per day (>4 drinks per day).

(95% CI 1.10e2.12) for 1e12 and 1.72 (95% CI 1.28e2.30) for >13 cigarettes/day, and HRs of 1.13 (95% CI 0.72e1.78) for 20 years of smoking [52]. The possible interaction between smoking and hepatitis virus infection has been considered, with mixed results. In an Italian study, current smoking was unrelated to HCC risk among individuals negative for both HBV and HCV serum markers but seemed to enhance the adverse effect of hepatitis viruses [24], whereas in a US study there was an absence of synergism between cigarette smoking and HBC and/or HCV infection [53]. With regard to HBV infection, some studies found an association between cigarette smoking and HCC restricted to HBV-negative individuals [54e57], some others observed some associations in HBV carriers [58,59], and other studies reported no interaction between the two factors [21,36,49]. Compared to HBV-negative nonsmokers, a meta-analysis estimated pooled RRs of 1.59 (95% CI 0.94e2.79) for HBV-negative smokers, 18.27 (95% CI 14.5e23.0) for nonsmokers HBV carriers, and 21.7 (95% CI 11.8e40.0) for HBV carriers who did smoke [60]. Considering HCV infection, most studies observed an interaction with cigarette smoking. Compared to HCV-negative nonsmokers, the pooled RRs from a meta-analysis were 1.42 (95% CI 1.05e1.96) for HCV-negative smokers, 6.9 (95% CI 1.12e42.7) for nonsmokers HCV carriers, and 19.6 (95% CI 1.55e247.0) for the joint effect of cigarette smoking and HCV infection, pointing to a more than multiplicative interaction between cigarette smoking and HCV [60]. Aflatoxin The contamination of foodstuffs with aflotoxin is a major risk factor for the development of HCC, particularly in sub-saharian Africa and eastern Asia. Aflatoxin is a mycotoxin produced by fungi of the Aspergillus species, that grows readily on foods such as corn and peanuts when it is stored under warm, damp conditions. Several population from low-income countries are chronically exposed to largely uncontrolled amounts of aflatoxin [61]. In particular, the highest levels of aflatoxin exposure are in subSaharan Africa and southern China. There are four principal aflatoxins (B1, B2, G1 and G2), of which aflatoxin B1 (AFB1) has been shown to be the most potent hepatocarcinogen in animal studies. After ingestion, AFB1 is metabolized to an active intermediate, AFB1-exo-8,9-epoxide, which can bind to DNA and cause damage, such as

760

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

mutation in the p53 suppressor tumour gene. That mutation has been observed in 30e60% of HCC tumours in persons living in aflatoxin-endemic areas [62], whereas it is rarely observed in HCC cases in the USA or Europe, where aflatoxin exposure is low. Many ecological studies of AFB1 contamination of foods conducted in the 1970's and 1980's supported a carcinogen role in human HCC, and IARC classified ‘naturally occurring aflatoxin as a Group 1 human carcinogen [63]. Stronger evidence of an AFB1eHCC relation was provided subsequently by studies based on the detection of AFB1 markers in serum or urine. A recent meta-analysis of studies relating biomarkers of aflatoxin exposure to HCC estimated a pooled RR for aflatoxin exposure of 4.75 (95% CI 2.78e8.11) from studies conducted in populations from aflatoxin-endemic area, after adjustment for HBsAg positivity [64]. The summary ORs were 2.39 (95% CI 1.50e3.82) from studies among HBsAgþ populations and 5.91 (95% CI 3.66e9.55) from studies among HBsAg populations. Evidence from epidemiological studies indicates that aflatoxin exposure interacts with chronic HBV infection in increasing HCC risk. One of the largest study, a case-control nested in a cohort of more than 18,000 middle-aged men in Shanghai and including 55 incident cases of HCC, estimated RRs of 3.4 (95% CI 1.1e10.0) in men with urinary aflatoxin but not HBV biomarkers, 7.3 (95% CI 2.2e24.4) in those unexposed to aflatoxin and chronically infected with HBV, and 59.4 (95% CI 16.6e212.0) in men exhibiting both aflatoxin and HBV biomarkers [65]. A meta-analysis showed that in areas in which the prevalence of aflatoxin contamination and chronic HBV infection was high, these two factors multiplicatively interact in HCC risk, with subjects exposed to both risk factors experiencing a very high risk of HCC (summary RR ¼ 54.1, 95% CI 21.3e137.7) [64]. That meta-analysis also showed that reducing aflatoxin below detectable limits could reduce HCC incidence by 14e19% in the general population, and by 10e29% in HBsAgþ populations. Changes in food policy and economic development have lead to a dramatic decline in the levels of aflatoxin exposure in some endemic regions, such as Taiwan and selected Chinese areas [64,66]. In Quidong, using randomly selected serum samples collected in historical cohorts since the 1980s, the proportion of the population with detectable aflatoxin-albumin adducts (i.e., >0.5 pg adduct per mg albumin) decreased from 100% in 1982 to 23% in 2009 and 7% in 2012. It has been estimated that 65% of the observed reduction in primary liver cancer mortality in that area was due to decreasing aflatoxin exposure from 1982 to 2009 [64]. Dietary factors Beside food contaminated by aflatoxin, no other dietary factors have been consistently related to HCC up to date [63]. High consumption of vegetables has been showed to reduce liver cancer risk in a number of studies [56,67e78]. In particular, in the Shanghai Women's and Men's Health Studies [71], including 267 incident cases of liver cancer, a vegetable-based dietary pattern was inversely associated to liver cancer (HR for the highest compared to the lowest quartile 0.58, 95% CI 0.40e0.84), and high intakes of celery, mushrooms, allium vegetables, composite vegetables (e.g., asparagus, lettuce), and legumes/legume products reduced liver cancer risk. Moreover, a daily intake of green-yellow vegetables was associated with a significant 25% reduction in liver cancer mortality among Japanese atomic bomb survivors [74]. In another Japanese cohort, high intakes of total vegetables, green-yellow vegetables, and green leafy vegetables decreased liver cancer risk [72]. A case-control study from Italy estimated an OR of 0.2 (95% CI 0.2e0.4) for the third tertile of vegetable intake compared to the first one [75]. Another Italian study found a non-significant reduced liver cancer risk for high vegetable intake [77]. However, two studies from Greece, based on 97 and 65 cases respectively [79,80], found no significant association between vegetable intake and liver cancer risk. The association of HCC risk with fruit consumption is less clear, with some studies finding an inverse association [73,75,77], but most reporting no relation [71,72,74,76,80]. Results on meat intake and liver cancer risk are mixed [56,67,68,76,77,79,81e86]. In particular, a meat-based dietary pattern was not related to liver cancer risk in the Shanghai Women's and Men's Health Studies [71]. Similarly, in the EPIC cohort, intakes of total meats as well as of subgroups of red/ processed meats and poultry were not associated to HCC risk [85]. High consumption of red meat significantly increased HCC risk in the NIH-AARP cohort, whereas white meat was inversely associated [81,82,86]. A case-control study from Italy found an OR of 0.44 (95% CI 0.20e0.95) for the highest

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

761

compared to the lowest quartile of white meat intake; high consumption of red meat increased, albeit not significantly, HCC risk, whereas a null association was found for pork/processed meat [77]. Inconsistent results emerged on the role of milk and dairy products on liver cancer risk, with some studies supporting inverse associations [77,78,84], and other not [68,76,80,82,83,87,88]. Inverse associations were observed with fish consumption in some studies [78,88], including the EPIC cohort [85], the NIH-AARP cohort [86], the Japan Public Health Centerebased prospective study [89], and the Japan Collaborative Cohort (JACC) Study [76], but other studies did not confirm those findings [56,67,68,77,84,90e92]. The Mediterranean dietary pattern, characterized by high consumption of plants foods, olive oil, and cereals, moderate consumption of (red) wine and fish, and low consumption of meat and dairy products, has been inversely related to HCC risk in two case-control studies from Italy and Greece, showing a risk reduction by about 50% for individuals with closer adherence to this dietary pattern compared to those with poor adherence [93]. A protective role of the Mediterranean patter was also reported in the NIH-AARP Diet and Health study (HR ¼ 0.62, 95% CI 0.47e0.84 for the highest compared to the lowest quintile of an alternate Mediterranean diet score, adapted from the original Mediterranean diet score for the American population [94]). That study showed also a reduction in HCC risk for adherence to the dietary guidelines for Americans, with a HR of 0.72 (95% CI 0.53e0.97) for the highest compared to the lowest quintile of the Healthy Eating Index. Further, the EPIC cohort showed a lower liver cancer risk among subjects adhering to the World Cancer Research Found/ American Institute for Cancer Research lifestyle guidelines, which, however, include recommendations on maintaining a healthy weight and performing an adequate physical activity in addition to those related to diet [95]. The association between glycaemic load (GL) and liver cancer risk has been assessed in at least three case-control [96e98] and three cohort studies [99e101], with contrasting results. Although two case-control studies from southern Europe suggested a possible detrimental role of high GL diet on liver cancer risk [97,98], results from a Canadian population-based case-control study [100] as well as those from the three cohorts e the NIH-AARP Diet and Health Study [96], the Shanghai Women's and Men's Health Study [101], and the EPIC study [99] e did not find such an association. The pooled RR from these studies for the highest compared to the lowest GL category was 1.14 (95% CI 0.78e1.67). Coffee Coffee contains a variety of chemicals with potential favourable effects on the liver, such as minerals and antioxidants, many phenolic compounds, melanoids, and diterpenes (e.g., cefestol and kahweol). Coffee drinking has been inversely related to liver cancer risk, and specifically HCC, in at least nine casecontrol studies [78,102e109] and eight cohorts [110-117]. Among the cohort studies, a cohort of 27,037 Finnish male smokers, including 194 liver cancer cases, found a RR of 0.53 (95% CI 0.30e0.95) for drinkers of at least four cups/day and a RR of 1.35 (95% CI 0.65e2.82) for never drinkers, compared to drinkers of >0e1 cup/day, compared to non drinkers, was 0.50 (95% CI 0.31e0.79) [116]. Findings from case-control studies were consistent with those from cohorts and supported an inverse association between coffee consumption and liver cancer risk. In particular, the largest study, including 501

762

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

liver cancer cases and 1552 hospital controls, estimated a RR of 0.5 (95% CI 0.4e0.7) for drinkers of three or more cups of coffee/day compared to non drinkers [102]. A recent meta-analysis collecting published data up to September 2012 (16 studies for a total of 3152 liver cancer cases) estimated a pooled RR of 0.60 (95% CI 0.50e0.71) for any coffee drinking, 0.72 (95% CI 0.61e0.84) for low coffee consumption, and 0.44 (95% CI 0.39e0.50) for high coffee consumption, compared to non coffee drinking (Fig. 3) [118].

Other environmental risk factors Obesity and diabetes Epidemiologic data suggested that overweight/obesity is associated with an increased risk of HCC, as of other cancers [119]. A meta-analysis of 11 cohort studies reported a RR for liver cancer of 1.17 (95% CI 1.02e1.34) for overweight and of 1.89 (95% CI 1.51e2.36) for obese versus normo-weight subjects [120]. The effect of obesity on liver cancer risk may be mediated, at least in part, through the strong relationship of overweight with diabetes mellitus [121]. Several epidemiological studies, indeed, have indicated that type 2 diabetes mellitus is associated with an increased risk of HCC [19,122e125]. A meta-analysis of studies published up to February 2011 reported a significant RR of 2.40 (95% CI 1.85e3.11) from 17 case-control studies, 2.23 (95% CI 1.68e2.96) from 25 cohort studies, and 2.43 (95% CI 1.66e3.55) from seven cohort studies on mortality from HCC [19]. It also reported a significant trend with duration of diabetes, with a RR of 3.3 for ten years since diabetes diagnosis. Changes in the hepatic activity related to metabolic alterations or to impaired liver function in diabetics are possible explanations of the association observed [124]. In particular, diabetes increases the risk of non-alcoholic fatty liver disease (NAFLD), a condition characterized by excess fat accumulation in the liver, which ranges from isolated hepatic steatosis to more aggressive non-alcoholic steatohepatitis (NASH) and may progress then to fibrosis, cirrhosis, and eventually HCC [126]. The common mechanism that links HCC to diabetes seems to be hyperinsulinemia and insulin resistance

Fig. 3. Summary relative risk of hepatocellular carcinoma for ever, low, and high coffee consumption versus no consumption (modified using data derived from Bravi et al 2013 [118]).

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

763

and the consequent up-regulation of the insulin-like growth factor-1 (IGF-1) system, which all stimulate cellular proliferation and inhibits apoptosis within the liver [127]. Oral contraceptives Use of combined oestrogeneprogestogen OCs have been associated with an increased risk of liver adenomas and may have an effect on the occurrence of HCC [128,129]. A few case-control studies conducted in high-income countries found 2- to 3-fold increased risks of HCC among OC users. Other reports from high-income countries, however, did not support an effect of OC use on liver cancer in general. In a meta-analysis of 12 caseecontrol studies, including 739 cases and 5223 controls [130], the overall RR liver cancer in relation to OC use was 1.57 (95% CI 0.96e2.54), with some evidence of durationr risk associations in six studies. Exclusion of a multinational European study increased the pooled RR to 1.70 (95% to 1.12e2.59) and decreased heterogeneity. The association was less strong in studies from developing countries, where HBV and HCV infections are more common [128]. It is also possible that the RR is smaller for low hormone OC formulations and there is no evidence of persistent liver cancer excess risk after stopping OC use. Consequently, the long-term public health implications of any modest excess liver cancer risk among current OC users are likely to be small [129]. Familial and genetic susceptibility for hepatocellular carcinoma Familial aggregation of liver cancer has been reported. Transmission of HBV and HCV within family and shared unfavourable lifestyle habits and environmental factors, such as heavy alcohol drinking, tobacco smoking and obesity, may explain part of such clustering. Indeed, familial clustering of HCC has been frequently observed in eastern Asia, particularly in China [131,132], where the prevalence of chronic HBV infection is high. However, family history was associated with the risk of HCC even among subjects without serological markers of HBV or HCV infection [133e136], and among European and American populations [133e135], where HBV/HCV chronic infection is not common, with RRs over two after adjustment for hepatitis and other major risk factors [22,133e135]. A recent meta-analysis including 21 case-control and six cohort studies revealed a more than twofold increased risk for individuals with a family history of liver cancer compared to those without family history (pooled RR ¼ 2.55, 95% CI, 2.05e3.16) [137]. Some inherited disorders have been associated with HCC risk. Hereditary hemochromatosis is an autosomal recessive disorder characterized by excessive dietary iron absorption and subsequent deposition in the parenchymal cells of the liver, pancreas, heart, joints, and pituitary gland. Iron overload may eventually lead to cirrhosis and HCC [138]. Early studies reported that the likelihood of developing HCC among persons with hereditary hemochromatosis was increased more than 200-fold [139,140]. However, recent data suggest that the increased risk is closer to 20-fold, with a risk of liver cancer at ten years of 6% in men and 1.5% in women [141]. Porphyria is the result of enzyme deficiencies in the heme biosynthesis pathway. The two types of porphyria, porphyria cutanea tarda and acute intermittent porphyryia, have been associated with high increased risk of HCC [142,143]. The more common porphyria, porphyria cutanea tarda, has also been associated with HCV infection [144]. A prospective study, including patients hospitalized for porphyria in Denmark and Sweden between 1977 and 1989, reported a 20-fold increase in the risk of liver cancer in patients with porphyria cutanea tarda and a 70-fold increase in risk in patients with acute intermittent porphyria [143]. Alpha-1-antitrypsin is the main proteinase inhibitor in serum and is encoded by the AAT gene on chromosome 14. Homozygous alpha 1-antitrypsin deficiency (PiZZ phenotype) is the most common genetic cause of liver disease in children and, in adults, it increased the risk of cirrhosis and primary liver cancer [145,146]. Heterozygotes of type PiZ may also be at increased risk of primary liver carcinoma [147]. Genetic susceptibility studies have most often focused on genes that encode enzymes involved in the process of AFB1 detoxification in hepatocytes, such as the glutathione-S-transferase (GST) and epoxide hydrolases (EPHX). These studies have yielded conflicting results and suggested that there may be a small excess risk of HCC in individuals with GSTT1 null and GSTM1 null genotypes [148]. A recent meta-analysis found a moderate increased HCC risk for the GSTT1 null genotype among East

764

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

Table 1 Attributable fraction (AF) of primary liver cancer for major risk factors in various countries of the world. Risk factor

Hepatitis B virus Hepatitis C virus Alcohol drinking Tobacco smoking Aflatoxin a b c

Country, AF (%) Italya

Japanb

Chinac

13 61 18 8 e

20 63 20 40 e

64 28 16 14 25

From Franceschi et al 1996 [24]. From Bosch et al 2004 [27]. From Liang & Ghany 2014 [33].

Asian populations (pooled OR 1.40, 95 % CI 1.18e1.66), whereas findings among Caucasian or African or South Asian populations were scanty and inconclusive [149]. Similarly, the GSTM1 null genotype has been associated with a slight-to-moderate increase in HCC risk among East Asians and Indians; as for GSTT1, studies conducted among other populations were few and provided mixed results [150]. Data also suggested a possible interaction between the two GSTs genotypes, with individuals with GSTM1 null and GSTT1 null having a 1.88-fold increased HCC risk compared to those with wild-type genotypes [150]. A possible association between selected GSTP1 gene Ile105Val polymorphism and HCC risk has been suggested by some investigations, but others did not confirm such findings [151]. Some studies reported an association between EPHX1 gene polymorphisms (337 T>C polymorphism and 416A>G polymorphism) and HCC risk, while others found no such association. Overall, data published up to date did not support any consistent role [152]. Given the association of heavy alcohol consumption with the risk of HCC, several studies have examined the role of alcohol metabolizing enzymes e alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) e in the etiology of HCC. The polymorphisms in ALDH2 or ADH2, which are prevalent in approximately half of East Asians but absent in Europeans and Africans [153], are associated with East Asians' alcohol hypersensitivity. Thus far, results from these studies indicate that either ALDH2 or ADH2 polymorphism was not significantly associated with HCC in the East Asian population [154]. Contradictory findings were also observed for polymorphisms in the cytochrome P450 2E1 enzyme [155], which catalyses the oxidation of several compounds in cigarette smoke and is involved in the metabolism of alcohol. Summary During the last 30 years, epidemiologic research has revealed the causes of most HCC cases. Chronic infection with HBV and HCV dominates the etiology of the disease in low and middle income countries. Aflatoxin exposure also contributes to HCC development in Africa and eastern Asia (Table 1). In high-income countries, however, these factors are less prevalent, and heavy alcohol drinking and tobacco smoking have a more relevant role. Diet may also affect the development of liver cancer, but the evidence is not conclusive. Thus, a substantial fraction of liver cancer cases and deaths could actually be prevented given the existing knowledge. The strong role in liver carcinogenesis of persistent infection with HBV, a virus for which effective and cheap vaccines are available, indicates that a large proportion of liver cancers are preventable through vaccination programs in the perinatal period. In the last decades, many countries from Asia, Southern Europe and, to a lesser extent, Africa have expanded the national childhood vaccination programs to include HBV. Vaccination is not available for HCV. Control of transmissions is, however, feasible and medical treatment of HCV carriers with interferon might represent an alternative approach. Control of aflatoxin contamination of foodstuffs represents another important preventive measure. However, its implementation is limited by economic and logistic factors in several high-prevalence regions, particularly in sub-Saharan Africa. Control of excessive alcohol drinking, tobacco smoking, overweight, and diabetes are additional relevant preventive measures.

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

765

Practice points  Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the key risk factors for hepatocellular carcinoma (HCC), accounting for about 70% of HCC worldwide.  Vaccination (for HBV) and control of transmission and disease progression (for both HBV and HCV) would avoid most HCC.  Additional recognized risk factors are aflatoxin in foods, heavy alcohol drinking, tobacco smoking, overweight, and diabetes. These can in principle be controlled, too.

Research agenda  Further advancements in the treatment of HBV and HCV may lead to a reduction in HCC risk, which needs to be quantified in the long-term.  The development of a vaccine against HCV remains an open research issue.  Interaction between various risk factors needs further quantification.

Role of the funding The study sponsors had no role in the collection, analysis, and interpretation of data and in the writing of the manuscript. Conflict of interest None. Acknowledgements This work was partially supported by the Italian Foundation for cancer Research (FIRC) and the Italian Association for Cancer Research (AIRC, Grant number 13203). The authors thank Mrs Ivana Garimoldi for editorial assistance. References [1] Percy C, Ries LG, Van Holten VD. The accuracy of liver cancer as the underlying cause of death on death certificates. Public Health Rep 1990;105:361e7. *[2] London WT, McGlynn KA. Liver cancer. In: Schottenfeld D, Fraumeni Jr JF, editors. Cancer epidemiology and prevention. 3rd ed. New York: Oxford University Press; 2006. p. 763e86. [3] Stuver S, Trichopolous D. Cancer of the liver and biliary tract. In: Adami HO, Hunter D, Trichopolous D, editors. Textbook of cancer epidemiology. 2rd ed. New york: Oxford University Press; 2008. p. 308e32. [4] Boffetta P, Boccia S, La Vecchia C. Cancer of the liver and biliary tract. In: Boffetta P, Boccia S, La Vecchia C, editors. A quick guide to cancer epidemiology. Springer; 2014. *[5] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893e917. [6] 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;27:1485e91. [7] Center MM, Jemal A. International trends in liver cancer incidence rates. Cancer Epidemiol Biomarkers Prev 2011;20: 2362e8. [8] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11e30. [9] Fan JH, Wang JB, Jiang Y, Xiang W, Liang H, Wei WQ, et al. Attributable causes of liver cancer mortality and incidence in China. Asian Pac J Cancer Prev 2013;14:7251e6. [10] De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, et al. Cancer survival in Europe 1999e2007 by country and age: results of EUROCAREe5-a population-based study. Lancet Oncol 2014;15:23e34. [11] Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74e108.

766

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

[12] Chuang SC, La Vecchia C, Boffetta P. Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Lett 2009;286:9e14. [13] La Vecchia C, Lucchini F, Franceschi S, Negri E, Levi F. Trends in mortality from primary liver cancer in Europe. Eur J Cancer 2000;36:909e15. [14] Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C. Trends in mortality from hepatocellular carcinoma in Europe, 1980e2004. Hepatology 2008;48:137e45. *[15] Bertuccio P, Bosetti C, Levi F, Decarli A, Negri E, La Vecchia C. A comparison of trends in mortality from primary liver cancer and intrahepatic cholangiocarcinoma in Europe. Ann Oncol 2013;24:1667e74. [16] Franceschi S, Raza SA. Epidemiology and prevention of hepatocellular carcinoma. Cancer Lett 2009;286:5e8. [17] Dal Maso L, Lise M, Zambon P, Crocetti E, Serraino D, Ricceri F, et al. Incidence of primary liver cancer in Italy between 1988 and 2002: an age-period-cohort analysis. Eur J Cancer 2008;44:285e92. [18] El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 2003;139:817e23. [19] Wang P, Kang D, Cao W, Wang Y, Liu Z. Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev 2012;28:109e22. [20] IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Hepatitis viruses, vol. 59. Lyon: International Agency for Research on Cancer; 1994. [21] Mori M, Hara M, Wada I, Hara T, Yamamoto K, Honda M, et al. Prospective study of hepatitis B and C viral infections, cigarette smoking, alcohol consumption, and other factors associated with hepatocellular carcinoma risk in Japan. Am J Epidemiol 2000;151:131e9. [22] Evans AA, Chen G, Ross EA, Shen FM, Lin WY, London WT. Eight-year follow-up of the 90,000-person Haimen city cohort: I. Hepatocellular carcinoma mortality, risk factors, and gender differences. Cancer Epidemiol Biomarkers Prev 2002;11:369e76. [23] Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168e74. *[24] Franceschi S, Montella M, Polesel J, La Vecchia C, Crispo A, Dal Maso L, et al. Hepatitis viruses, alcohol, and tobacco in the etiology of hepatocellular carcinoma in Italy. Cancer Epidemiol Biomarkers Prev 2006;15:683e9. [25] Munoz N, Lingao A, Lao J, Esteve J, Viterbo G, Domingo EO, et al. Patterns of familial transmission of HBV and the risk of developing liver cancer: a case-control study in the Philippines. Int J Cancer 1989;44:981e4. [26] Kuper H, Hsieh C, Stuver SO, Mucci LA, Tzonou A, Zavitsanos X, et al. Birth order, as a proxy for age at infection, in the etiology of hepatocellular carcinoma. Epidemiology 2000;11:680e3. [27] Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004; 127:S5e16. [28] Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006;118:3030e44. [29] Tagger A, Donato F, Ribero ML, Chiesa R, Portera G, Gelatti U, et al. Case-control study on hepatitis C virus (HCV) as a risk factor for hepatocellular carcinoma: the role of HCV genotypes and the synergism with hepatitis B virus and alcohol. Brescia HCC Study. Int J Cancer 1999;81:695e9. [30] Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 2002;155:323e31. [31] Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer 1998;75:347e54. [32] La Vecchia C, Negri E, Cavalieri d'Oro L, Franceschi S. Liver cirrhosis and the risk of primary liver cancer. Eur J Cancer Prev 1998;7:315e20. [33] Liang TJ, Ghany MG. Therapy of hepatitis Ceback to the future. N Engl J Med 2014;370:2043e7. [34] Bagnardi V, Blangiardo M, La Vecchia C, Corrao G. A meta-analysis of alcohol drinking and cancer risk. Br J Cancer 2001;85:1700e5. [35] IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Alcohol consumption and ethyl carbamate, vol. 96. Lyon: International Agency for Research on Cancer; 2010. [36] Jee SH, Ohrr H, Sull JW, Samet JM. Cigarette smoking, alcohol drinking, hepatitis B, and risk for hepatocellular carcinoma in Korea. J Natl Cancer Inst 2004;96:1851e6. [37] Joshi S, Song YM, Kim TH, Cho SI. Socio-economic status and the risk of liver cancer mortality: a prospective study in Korean men. Public Health 2008;122:1144e51. [38] Kim MK, Ko MJ, Han JT. Alcohol consumption and mortality from all-cause and cancers among 1.34 million Koreans: the results from the Korea national health insurance corporation's health examinee cohort in 2000. Cancer Causes Control 2010;21:2295e302. [39] Shimazu T, Sasazuki S, Wakai K, Tamakoshi A, Tsuji I, Sugawara Y, et al. Alcohol drinking and primary liver cancer: a pooled analysis of four Japanese cohort studies. Int J Cancer 2012;130:2645e53. [40] Yang L, Zhou M, Sherliker P, Cai Y, Peto R, Wang L, et al. Alcohol drinking and overall and cause-specific mortality in China: nationally representative prospective study of 220,000 men with 15 years of follow-up. Int J Epidemiol 2012; 41:1101e13. [41] Persson EC, Schwartz LM, Park Y, Trabert B, Hollenbeck AR, Graubard BI, et al. Alcohol consumption, folate intake, hepatocellular carcinoma, and liver disease mortality. Cancer Epidemiol Biomarkers Prev 2013;22:415e21. [42] Allen NE, Beral V, Casabonne D, Kan SW, Reeves GK, Brown A, et al. Moderate alcohol intake and cancer incidence in women. J Natl Cancer Inst 2009;101:296e305. [43] Schutze M, Boeing H, Pischon T, Rehm J, Kehoe T, Gmel G, et al. Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study. BMJ 2011;342:d1584. *[44] Turati F, Galeone C, Rota M, Pelucchi C, Negri E, Bagnardi V, et al. Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies. Ann Oncol 2014;25:1526e35. [45] Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V, et al. Light alcohol drinking and cancer: a meta-analysis. Ann Oncol 2013;24:301e8.

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

767

[46] IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Tobacco smoke and involuntary smoking, vol. 83. Lyon: International Agency for Research on Cancer; 2004. [47] IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Personal habits and indoor combustions, vol. 100E. Lyon: IARC; 2012. *[48] Lee YC, Cohet C, Yang YC, Stayner L, Hashibe M, Straif K. Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer. Int J Epidemiol 2009;38:1497e511. [49] Hassan MM, Spitz MR, Thomas MB, El-Deeb AS, Glover KY, Nguyen NT, et al. Effect of different types of smoking and synergism with hepatitis C virus on risk of hepatocellular carcinoma in American men and women: case-control study. Int J Cancer 2008;123:1883e91. [50] Batty GD, Kivimaki M, Gray L, Smith GD, Marmot MG, Shipley MJ. Cigarette smoking and site-specific cancer mortality: testing uncertain associations using extended follow-up of the original Whitehall study. Ann Oncol 2008;19:996e1002. [51] Trichopoulos D, Bamia C, Lagiou P, Fedirko V, Trepo E, Jenab M, et al. Hepatocellular carcinoma risk factors and disease burden in a European cohort: a nested caseecontrol study. J Natl Cancer Inst 2011;103:1686e95. [52] Koh WP, Robien K, Wang R, Govindarajan S, Yuan JM, Yu MC. Smoking as an independent risk factor for hepatocellular carcinoma: the Singapore Chinese Health Study. Br J Cancer 2011;105:1430e5. [53] Yuan JM, Govindarajan S, Arakawa K, Yu MC. Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S. Cancer 2004;101:1009e17. [54] Wang LY, You SL, Lu SN, Ho HC, Wu MH, Sun CA, et al. Risk of hepatocellular carcinoma and habits of alcohol drinking, betel quid chewing and cigarette smoking: a cohort of 2416 HBsAg-seropositive and 9421 HBsAg-seronegative male residents in Taiwan. Cancer Causes Control 2003;14:241e50. [55] Trichopoulos D, Day NE, Kaklamani E, Tzonou A, Munoz N, Zavitsanos X, et al. Hepatitis B virus, tobacco smoking and ethanol consumption in the etiology of hepatocellular carcinoma. Int J Cancer 1987;39:45e9. [56] Lam KC, Yu MC, Leung JW, Henderson BE. Hepatitis B virus and cigarette smoking: risk factors for hepatocellular carcinoma in Hong Kong. Cancer Res 1982;42:5246e8. [57] Tanaka K, Hirohata T, Takeshita S. Blood transfusion, alcohol consumption, and cigarette smoking in causation of hepatocellular carcinoma: a caseecontrol study in Fukuoka. Jpn Jpn J Cancer Res 1988;79:1075e82. [58] Tu JT, Gao RN, Zhang DH, Gu BC. Hepatitis B virus and primary liver cancer on Chongming Island, People's Republic of China. Natl Cancer Inst Monogr 1985;69:213e5. [59] Oshima A, Tsukuma H, Hiyama T, Fujimoto I, Yamano H, Tanaka M. Follow-up study of HBs Ag-positive blood donors with special reference to effect of drinking and smoking on development of liver cancer. Int J Cancer 1984;34:775e9. [60] Chuang SC, Lee YC, Hashibe M, Dai M, Zheng T, Boffetta P. Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2010;19:1261e8. [61] Williams JH, Phillips TD, Jolly PE, Stiles JK, Jolly CM, Aggarwal D. Human aflatoxicosis in developing countries: a review of toxicology, exposure, potential health consequences, and interventions. Am J Clin Nutr 2004;80:1106e22. [62] Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 1991;350:429e31. [63] IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Some traditional herbal medicines, some mycotoxins, naphthalene and styrene, vol. 82. Lyon: International Agency for Research on Cancer; 2002. *[64] Liu Y, Chang CC, Marsh GM, Wu F. Population attributable risk of aflatoxin-related liver cancer: systematic review and meta-analysis. Eur J Cancer 2012;48:2125e36. [65] Qian GS, Ross RK, Yu MC, Yuan JM, Gao YT, Henderson BE, et al. A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China. Cancer Epidemiol Biomarkers Prev 1994;3: 3e10. [66] Chen JG, Egner PA, Ng D, Jacobson LP, Munoz A, Zhu YR, et al. Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 2013;6:1038e45. [67] Srivatanakul P, Parkin DM, Khlat M, Chenvidhya D, Chotiwan P, Insiripong S, et al. Liver cancer in Thailand. II. A caseecontrol study of hepatocellular carcinoma. Int J Cancer 1991;48:329e32. [68] Hirayama T. Life-style and mortality: a large-scale census-based cohort study in Japan. In: Wahrendorf J, editor. Contributions to epidemiology and biostatistics. Basel, Switzerland: Karger; 1990. p. 84e5. [69] Yu MW, Chen CJ. Elevated serum testosterone levels and risk of hepatocellular carcinoma. Cancer Res 1993;53:790e4. [70] Yu MW, Hsieh HH, Pan WH, Yang CS, CJ CH. Vegetable consumption, serum retinol level, and risk of hepatocellular carcinoma. Cancer Res 1995;55:1301e5. [71] Zhang W, Xiang YB, Li HL, Yang G, Cai H, Ji BT, et al. Vegetable-based dietary pattern and liver cancer risk: results from the Shanghai women's and men's health studies. Cancer Sci 2013;104:1353e61. [72] Kurahashi N, Inoue M, Iwasaki M, Tanaka Y, Mizokami M, Tsugane S. Vegetable, fruit and antioxidant nutrient consumption and subsequent risk of hepatocellular carcinoma: a prospective cohort study in Japan. Br J Cancer 2009;100: 181e4. [73] Braga C, La Vecchia C, Negri E, Franceschi S. Attributable risks for hepatocellular carcinoma in northern Italy. Eur J Cancer 1997;33:629e34. [74] Sauvaget C, Nagano J, Hayashi M, Spencer E, Shimizu Y, Allen N. Vegetables and fruit intake and cancer mortality in the Hiroshima/Nagasaki Life Span Study. Br J Cancer 2003;88:689e94. [75] Negri E, La Vecchia C, Franceschi S, D'Avanzo B, Parazzini F. Vegetable and fruit consumption and cancer risk. Int J Cancer 1991;48:350e4. [76] Kurozawa Y, Ogimoto I, Shibata A, Nose T, Yoshimura T, Suzuki H, et al. Dietary habits and risk of death due to hepatocellular carcinoma in a large scale cohort study in Japan. Univariate analysis of JACC study data. Kurume Med J 2004;51:141e9. [77] Talamini R, Polesel J, Montella M, Dal Maso L, Crispo A, Tommasi LG, et al. Food groups and risk of hepatocellular carcinoma: a multicenter case-control study in Italy. Int J Cancer 2006;119:2916e21. [78] Kanazir M, Boricic I, Delic D, Tepavcevic DK, Knezevic A, Jovanovic T, et al. Risk factors for hepatocellular carcinoma: a case-control study in Belgrade (Serbia). Tumori 2010;96:911e7.

768

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

[79] Hadziyannis S, Tabor E, Kaklamani E, Tzonou A, Stuver S, Tassopoulos N, et al. A case-control study of hepatitis B and C virus infections in the etiology of hepatocellular carcinoma. Int J Cancer 1995;60:627e31. [80] Kuper H, Tzonou A, Lagiou P, Mucci LA, Trichopoulos D, Stuver SO, et al. Diet and hepatocellular carcinoma: a caseecontrol study in Greece. Nutr Cancer 2000;38:6e12. [81] Freedman ND, Cross AJ, McGlynn KA, Abnet CC, Park Y, Hollenbeck AR, et al. Association of meat and fat intake with liver disease and hepatocellular carcinoma in the NIH-AARP cohort. J Natl Cancer Inst 2010;102:1354e65. [82] Cross AJ, Leitzmann MF, Gail MH, Hollenbeck AR, Schatzkin A, Sinha R. A prospective study of red and processed meat intake in relation to cancer risk. PLoS Med 2007;4:e325. [83] Fukuda K, Shibata A, Hirohata I, Tanikawa K, Yamaguchi G, Ishii M. A hospital-based case-control study on hepatocellular carcinoma in Fukuoka and Saga Prefectures, northern Kyushu. Jpn Jpn J Cancer Res 1993;84:708e14. [84] La Vecchia C, Negri E, Decarli A, D'Avanzo B, Franceschi S. Risk factors for hepatocellular carcinoma in northern Italy. Int J Cancer 1988;42:872e6. [85] Fedirko V, Trichopolou A, Bamia C, Duarte-Salles T, Trepo E, Aleksandrova K, et al. Consumption of fish and meats and risk of hepatocellular carcinoma: the European Prospective Investigation into Cancer and Nutrition (EPIC). Ann Oncol 2013;24:2166e73. [86] Daniel CR, Cross AJ, Graubard BI, Hollenbeck AR, Park Y, Sinha R. Prospective investigation of poultry and fish intake in relation to cancer risk. Cancer Prev Res Phila 2011;4:1903e11. [87] Hsing AW, Guo W, Chen J, Li JY, Stone BJ, Blot WJ, et al. Correlates of liver cancer mortality in China. Int J Epidemiol 1991;20:54e9. [88] Yu SZ, Huang XE, Koide T, Cheng G, Chen GC, Harada K, et al. Hepatitis B and C viruses infection, lifestyle and genetic polymorphisms as risk factors for hepatocellular carcinoma in Haimen, China. Jpn J Cancer Res 2002;93:1287e92. [89] Sawada N, Inoue M, Iwasaki M, Sasazuki S, Shimazu T, Yamaji T, et al. Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma. Gastroenterology 2012;142:1468e75. [90] Fernandez E, Chatenoud L, La Vecchia C, Negri E, Franceschi S. Fish consumption and cancer risk. Am J Clin Nutr 1999; 70:85e90. [91] Lu SN, Lin TM, Chen CJ, Chen JS, Liaw YF, Chang WY, et al. A caseecontrol study of primary hepatocellular carcinoma in Taiwan. Cancer 1988;62:2051e5. [92] Ikeda M, Yoshimoto K, Yoshimura T, Kono S, Kato H, Kuratsune M. A cohort study on the possible association between broiled fish intake and cancer. Gann 1983;74:640e8. [93] Turati F, Trichopoulos D, Polesel J, Bravi F, Rossi M, Talamini R, et al. Mediterranean diet and hepatocellular carcinoma. J Hepatol 2014;60:606e11. [94] Li WQ, Park Y, McGlynn KA, Hollenbeck AR, Taylor PR, Goldstein AM, et al. Index-based dietary patterns and risk of incident hepatocellular carcinoma and mortality from chronic liver disease in a prospective study. Hepatology 2014; 60:588e97. [95] Romaguera D, Vergnaud AC, Peeters PH, van Gils CH, Chan DS, Ferrari P, et al. Is concordance with World Cancer Research Fund/American Institute for Cancer Research guidelines for cancer prevention related to subsequent risk of cancer? Results from the EPIC study. Am J Clin Nutr 2012;96:150e63. [96] George SM, Mayne ST, Leitzmann MF, Park Y, Schatzkin A, Flood A, et al. Dietary glycemic index, glycemic load, and risk of cancer: a prospective cohort study. Am J Epidemiol 2009;169:462e72. [97] Rossi M, Lipworth L, Maso LD, Talamini R, Montella M, Polesel J, et al. Dietary glycemic load and hepatocellular carcinoma with or without chronic hepatitis infection. Ann Oncol 2009;20:1736e40. [98] Lagiou P, Rossi M, Tzonou A, Georgila C, Trichopoulos D, La Vecchia C. Glycemic load in relation to hepatocellular carcinoma among patients with chronic hepatitis infection. Ann Oncol 2009;20:1741e5. [99] Fedirko V, Lukanova A, Bamia C, Trichopolou A, Trepo E, Nothlings U, et al. Glycemic index, glycemic load, dietary carbohydrate, and dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans. Ann Oncol 2013;24:543e53. [100] Hu J, La Vecchia C, Augustin LS, Negri E, de Groh M, Morrison H, et al. Glycemic index, glycemic load and cancer risk. Ann Oncol 2013;24:245e51. [101] Vogtmann E, Li HL, Shu XO, Chow WH, Ji BT, Cai H, et al. Dietary glycemic load, glycemic index, and carbohydrates on the risk of primary liver cancer among Chinese women and men. Ann Oncol 2013;24:238e44. [102] Gallus S, Bertuzzi M, Tavani A, Bosetti C, Negri E, La Vecchia C, et al. Does coffee protect against hepatocellular carcinoma? Br J Cancer 2002;87:956e9. [103] Leung WW, Ho SC, Chan HL, Wong V, Yeo W, Mok TS. Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a caseecontrol study. J Epidemiol Community Health 2011;65: 556e8. [104] Gelatti U, Covolo L, Franceschini M, Pirali F, Tagger A, Ribero ML, et al. Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a caseecontrol study. J Hepatol 2005;42:528e34. [105] Montella M, Polesel J, La Vecchia C, Dal Maso L, Crispo A, Crovatto M, et al. Coffee and tea consumption and risk of hepatocellular carcinoma in Italy. Int J Cancer 2007;120:1555e9. [106] Ohfuji S, Fukushima W, Tanaka T, Habu D, Tamori A, Sakaguchi H, et al. Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: a caseecontrol study. Hepatol Res 2006; 36:201e8. [107] Tanaka K, Hara M, Sakamoto T, Higaki Y, Mizuta T, Eguchi Y, et al. Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a caseecontrol study in Japan. Cancer Sci 2007;98:214e8. [108] Kuper H, Tzonou A, Kaklamani E, Hsieh CC, Lagiou P, Adami HO, et al. Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma. Int J Cancer 2000;85:498e502. [109] Wakai K, Kurozawa Y, Shibata A, Fujita Y, Kotani K, Ogimoto I, et al. Liver cancer risk, coffee, and hepatitis C virus infection: a nested caseecontrol study in Japan. Br J Cancer 2007;97:426e8. [110] Lai GY, Weinstein SJ, Albanes D, Taylor PR, McGlynn KA, Virtamo J, et al. The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers. Br J Cancer 2013;109:1344e51.

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

769

[111] Johnson S, Koh WP, Wang R, Govindarajan S, Yu MC, Yuan JM. Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study. Cancer Causes Control 2011;22:503e10. [112] Inoue M, Kurahashi N, Iwasaki M, Shimazu T, Tanaka Y, Mizokami M, et al. Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status. Cancer Epidemiol Biomarkers Prev 2009; 18:1746e53. [113] Ohishi W, Fujiwara S, Cologne JB, Suzuki G, Akahoshi M, Nishi N, et al. Risk factors for hepatocellular carcinoma in a Japanese population: a nested caseecontrol study. Cancer Epidemiol Biomarkers Prev 2008;17:846e54. [114] Hu G, Tuomilehto J, Pukkala E, Hakulinen T, Antikainen R, Vartiainen E, et al. Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer. Hepatology 2008;48:129e36. [115] Shimazu T, Tsubono Y, Kuriyama S, Ohmori K, Koizumi Y, Nishino Y, et al. Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan. Int J Cancer 2005;116:150e4. [116] Kurozawa Y, Ogimoto I, Shibata A, Nose T, Yoshimura T, Suzuki H, et al. Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan. Br J Cancer 2005;93:607e10. [117] Inoue M, Yoshimi I, Sobue T, Tsugane S. Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan. J Natl Cancer Inst 2005;97:293e300. *[118] Bravi F, Bosetti C, Tavani A, Gallus S, La Vecchia C. Coffee reduces risk for hepatocellular carcinoma: an updated metaanalysis. Clin Gastroenterol Hepatol 2013;11:1413e21. e1411. [119] Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625e38. [120] Larsson SC, Wolk A. Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 2007; 97:1005e8. [121] Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004;4:579e91. [122] La Vecchia C, Negri E, Decarli A, Franceschi S. Diabetes mellitus and the risk of primary liver cancer. Int J Cancer 1997; 73:204e7. [123] Lagiou P, Kuper H, Stuver SO, Tzonou A, Trichopoulos D, Adami HO. Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst 2000;92:1096e9. *[124] El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006;4:369e80. [125] Bosetti C, Rosato V, Polesel J, Levi F, Talamini R, Montella M, et al. Diabetes mellitus and cancer risk in a network of caseecontrol studies. Nutr Cancer 2012;64:643e51. [126] Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 2012;56:1384e91. [127] Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. Diabetes Care 2010;33:1674e85. [128] IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Combined estrogeneprogestogen contraceptives and combined estrogeneprogestogen menopausal therapy, vol. 91. Lyon: International Agency for Research on Cancer; 2007. [129] Cibula D, Gompel A, Mueck AO, La Vecchia C, Hannaford PC, Skouby SO, et al. Hormonal contraception and risk of cancer. Hum Reprod Update 2010;16:631e50. [130] Maheshwari S, Sarraj A, Kramer J, El-Serag HB. Oral contraception and the risk of hepatocellular carcinoma. J Hepatol 2007;47:506e13. [131] Yu MW, Chang HC, Liaw YF, Lin SM, Lee SD, Liu CJ, et al. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. J Natl Cancer Inst 2000;92:1159e64. [132] Cai RL, Meng W, Lu HY, Lin WY, Jiang F, Shen FM. Segregation analysis of hepatocellular carcinoma in a moderately high-incidence area of East China. World J Gastroenterol 2003;9:2428e32. [133] Turati F, Edefonti V, Talamini R, Ferraroni M, Malvezzi M, Bravi F, et al. Family history of liver cancer and hepatocellular carcinoma. Hepatology 2012;55:1416e25. [134] Donato F, Gelatti U, Chiesa R, Albertini A, Bucella E, Boffetta P, et al. A case-control study on family history of liver cancer as a risk factor for hepatocellular carcinoma in North Italy. Brescia HCC Study. Cancer Causes Control 1999;10: 417e21. [135] Hassan MM, Spitz MR, Thomas MB, Curley SA, Patt YZ, Vauthey JN, et al. The association of family history of liver cancer with hepatocellular carcinoma: a caseecontrol study in the United States. J Hepatol 2009;50:334e41. [136] Tanaka K, Hirohata T, Takeshita S, Hirohata I, Koga S, Sugimachi K, et al. Hepatitis B virus, cigarette smoking and alcohol consumption in the development of hepatocellular carcinoma: a caseecontrol study in Fukuoka, Japan. Int J Cancer 1992;51:509e14. *[137] Yang Y, Wu QJ, Xie L, Chow WH, Rothman N, Li HL, et al. Prospective cohort studies of association between family history of liver cancer and risk of liver cancer. Int J Cancer 2014;135:1605e14. [138] Harrison SA, Bacon BR. Relation of hemochromatosis with hepatocellular carcinoma: epidemiology, natural history, pathophysiology, screening, treatment, and prevention. Med Clin North Am 2005;89:391e409. [139] Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985;313:1256e62. [140] Bradbear RA, Bain C, Siskind V, Schofield FD, Webb S, Axelsen EM, et al. Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases. J Natl Cancer Inst 1985;75:81e4. [141] Elmberg M, Hultcrantz R, Ekbom A, Brandt L, Olsson S, Olsson R, et al. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 2003;125:1733e41. [142] Stewart MF. Review of hepatocellular cancer, hypertension and renal impairment as late complications of acute porphyria and recommendations for patient follow-up. J Clin Pathol 2012;65:976e80. [143] Linet MS, Gridley G, Nyren O, Mellemkjaer L, Olsen JH, Keehn S, et al. Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden. Am J Epidemiol 1999;149:1010e5.

770

C. Bosetti et al. / Best Practice & Research Clinical Gastroenterology 28 (2014) 753e770

[144] Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis. J Hepatol 2003;39:620e7. [145] Needham M, Stockley RA. Alpha 1-antitrypsin deficiency. 3: clinical manifestations and natural history. Thorax 2004; 59:441e5. [146] Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. N Engl J Med 1986;314:736e9. [147] Zhou H, Ortiz-Pallardo ME, Ko Y, Fischer HP. Is heterozygous alpha-1-antitrypsin deficiency type PIZ a risk factor for primary liver carcinoma? Cancer 2000;88:2668e76. [148] White DL, Li D, Nurgalieva Z, El-Serag HB. Genetic variants of glutathione S-transferase as possible risk factors for hepatocellular carcinoma: a HuGE systematic review and meta-analysis. Am J Epidemiol 2008;167:377e89. [149] Chen KJ, Fan F, Wang Y, Wei GT, Hu L, Xu F. GSTT1 null genotype contributes to hepatocellular carcinoma risk: a metaanalysis. Tumour Biol 2014;35:213e8. [150] Song K, Yi J, Shen X, Cai Y. Genetic polymorphisms of glutathione S-transferase genes GSTM1, GSTT1 and risk of hepatocellular carcinoma. PLoS One 2012;7:e48924. [151] Zhao Y, Wang Q, Deng X, Shi P, Wang Z. Quantitative assessment of the association between GSTP1 gene Ile105Val polymorphism and susceptibility to hepatocellular carcinoma. Tumour Biol 2013;34:2121e6. [152] Duan CY, Liu MY, Li SB, Ma KS, Bie P. Lack of association of EPHX1 gene polymorphisms with risk of hepatocellular carcinoma: a meta-analysis. Tumour Biol 2014;35:659e66. [153] Goedde HW, Agarwal DP, Fritze G, Meier-Tackmann D, Singh S, Beckmann G, et al. Distribution of ADH2 and ALDH2 genotypes in different populations. Hum Genet 1992;88:344e6. [154] Zhou D, Xiao L, Zhang Y, Xian J, Jiang J, Zong W, et al. Genetic polymorphisms of ALDH2 and ADH2 are not associated with risk of hepatocellular carcinoma among East Asians. Tumour Biol 2012;33:841e6. [155] Tian Z, Li YL, Zhao L, Zhang CL. CYP2E1 RsaI/PstI polymorphism and liver cancer risk among east Asians: a HuGE review and meta-analysis. Asian Pac J Cancer Prev 2012;13:4915e21.