EASL Clinical Practice Guidelines

Epidemiology, risk factors, and prevention

Epidemiology

The burden of cancer is increasing worldwide. Each year there are 10.9 million new cases of cancer and 6.7 million cancer-related deaths. The most commonly diagnosed cancers are lung, breast, and colorectal while the most common causes of cancer death are lung, stomach, and liver [[3], [4]]. Liver cancer is the sixth most common cancer (749,000 new cases), the third cause of cancer-related death (692,000 cases), and accounts for 7% of all cancers [4]. HCC represents more than 90% of primary liver cancers and is a major global health problem.

The incidence of HCC increases progressively with advancing age in all populations, reaching a peak at 70 years [5]. In Chinese and in black African populations, the mean age of patients with the tumor is appreciably younger. This is in sharp contrast to Japan, where the incidence of HCC is highest in the cohort of men aged 70–79 years [6]. HCC has a strong male preponderance with a male to female ratio estimated to be 2.4 [4].

The pattern of HCC occurrence has a clear geographical distribution, with the highest incidence rates in East Asia, sub-Saharan Africa, and Melanesia, where around 85% of cases occur [[3], [4]]. In developed regions, the incidence is low with the exception of Southern Europe where the incidence in men (10.5 age-standardized incidence rates per 100,000) is significantly higher than in other developed regions [7] (Fig. 1).



Fig. 1 Incidence rates of primary liver cancer according to geographical distribution in Europe. Age-adjusted incidence rates per 100,000 of liver cancer in Europe in 2008. The color intensity is proportional to the magnitude of incidence. M, males; F, females. (Data from: Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.)

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There is a growing incidence of HCC worldwide. Overall, the incidence and mortality rates were of 65,000 and 60,240 cases in Europe and 21,000 and 18,400 cases in the United States in 2008, respectively. It is estimated that by 2020 the number of cases will reach 78,000 and 27,000, respectively [4]. People infected with HCV in Europe during the period 1940–60 and in the United States of America (USA) one decade later led to the current increase of HCC incidence. In Europe, the incidence and mortality rates reported are heterogeneous. HCC mortality during the last decades increased in males in most of the countries (i.e. Austria, Denmark, Germany, Greece, Ireland, Portugal, Norway, Spain, Switzerland, and United Kingdom), but decreased in others (Finland, France, Italy, Netherlands, and Sweden) [7]. In the United States, the rate of HCC deaths appears to have increased by about 40% over the period 1990–2004, whereas the overall rate of cancer deaths has declined by about 18% during this same period [8]. Besides the emergence of liver disease due to hepatitis C, this growth in incidence may be also due to an increase in HBV-related HCC, particularly among immigrants from endemic countries. Conversely, in Japan, a country where the impact of HCV-related HCC was first noticed after World War II, there has been an apparent decline in the incidence of this neoplasm for the first time since 1990 [6]. Finally, the impact of universal infant vaccination against HBV has decreased the rate of HBV-related HCC in endemic countries. So far, this has been observed among children in Taiwan, but it is expected to become more apparent as these vaccinated children grow into adults [9].

Etiology and risk factors

Approximately 90% of HCCs are associated with a known underlying risk factor (Table 2). The most frequent factors include chronic viral hepatitis (types B and C), alcohol intake and aflatoxin exposure. In Africa and East Asia, the largest attributable fraction is due to hepatitis B (60%) whereas in the developed Western world, only 20% of cases can be attributed to HBV infection, while chronic hepatitis C appears to be the major risk factor [3]. Worldwide, approximately 54% of cases can be attributed to HBV infection (which affects 400 million people globally) while 31% can be attributed to HCV infection (which affects 170 million people), leaving approximately 15% associated with other causes.


Table 2
Geographical distribution of main risk factors for HCC worldwide.∗



∗Updated from Llovet et al. [99], according to IARC data [4]. AAIR, age-adjusted incidence rate.

Cirrhosis is an important risk factor for HCC, and may be caused by chronic viral hepatitis, alcohol, inherited metabolic diseases such as hemochromatosis or alpha-1-antitrypsin deficiency, and non-alcoholic fatty liver disease. All etiologic forms of cirrhosis may be complicated by tumor formation, but the risk is higher in patients with hepatitis infection. Overall, one-third of cirrhotic patients will develop HCC during their lifetime [10]. Long-term follow-up studies have demonstrated that approximately 1–8% per year of patients with cirrhosis develop HCC (e.g. 2% in HBV-infected cirrhotic patients and 3–8% in HCV-infected cirrhotic patients) [11]. In general, features of liver disease severity (low platelet count of less than 100 × 103, presence of esophageal varices), in addition to older age and male gender, correlate with HCC development among patients with cirrhosis [12]. Recent studies have shown that liver cancer incidence increases in parallel to portal pressure as directly measured [13] or in parallel to the degree of liver stiffness as measured by transient elastography [[14], [15]].

Several studies have identified HBV-related factors as key predictors of HCC development in patients with chronic hepatitis B infection [16]. Hepatitis B virus e antigen (HBeAg) seropositivity [17], high viral load [18], and genotype C [19] are independent predictors of HCC development. In addition, hepatitis B viral load correlates with the risk of progression to cirrhosis [20]. Similarly, in a recent meta-analysis, HCV genotype 1b is claimed to increase the risk of HCC development [21].

Dietary exposure to aflatoxin B1, derived from the fungi Aspergillus flavus and A. parasiticus, is an important co-factor for HCC development in some parts of Africa and Asia. These molds are ubiquitous in nature and contaminate a number of staple foodstuffs in tropical and subtropical regions. Epidemiologic studies have shown a strong correlation between the dietary intake of aflatoxin B1, TP53 mutations and incidence of HCC, specifically in HBV-infected individuals [22]. Regarding other risk factors, patients with hemochromatosis develop HCC in up to 45% of cases [23], most often with a background of cirrhosis, and HCC is well documented as a complication of cirrhosis associated with alpha-1-antitrypsin deficiency [24]. HCC develops occasionally in patients with Wilson's disease, but only in the presence of cirrhosis [25].

Obesity, diabetes and fatty liver disease have come to be recognized as a cause of HCC [[26], [27]], although the mechanisms by which these overlapping conditions contribute to cancer development remain elusive. Cirrhosis due to non-alcoholic steatohepatitis may give rise to HCC but it appears that these factors may also be additive to chronic viral hepatitis [27]. Epidemiologic evidence of a link between cigarette smoking and the occurrence of HCC was traditionally conflicting [26], but recent evidence support that smoking is a clear co-factor [28]. Heavy smokers have a higher risk than non-smokers. In the general population, the incidence of HCC is increased among patients with HIV infection compared to controls, and HIV appears to be an additive co-factor, exacerbating the risk of HCC in patients with chronic viral hepatitis [29].

Identification of mutations in germline DNA that define patients at high risk of developing cancer has become a challenge for surveillance programs and chemopreventive strategies. This is the case of mutations in BRCA1 or BRCA2 and increased risk of breast or ovarian cancer [30] or in genes involved in DNA mismatch repair and hereditary colon cancer [31]. In HCC, a recent case–control study found a significant association between an epidermal growth factor (EGF) gene polymorphism and the risk of HCC [32], while another study suggests genetic predisposition of SNPs at loci involved in immune response [33]. These findings require validation by independent investigators.

Prevention

Primary prevention of HCC can be achieved with universal vaccination against HBV infection [9]. Vaccination against hepatitis B is recommended to all newborns and high risk groups, following the recommendations of the World Health Organization [34]. Since perinatal or early postnatal transmission is an important cause of chronic HBV infections globally, the first dose of hepatitis B vaccine should be given as soon as possible after birth, even in low-endemicity countries (those with prevalence of HBsAg carriers <2%). Vaccination is also recommended in age-specific cohorts (young adolescents) and people with risk factors for acquiring HBV infection (i.e. health workers, travellers to areas where HBV-infection is prevalent, injecting drug users, and people with multiple sex partners).

Antiviral treatment for patients with chronic hepatitis B and C infection should follow the recommendations from existing EASL guidelines [[35], [36]]. Interferon, lamivudine, adefovir, entecavir, telbivudine and tenofovir are now available for HBV treatment, but long-term follow-up data assessing their effect in secondary prevention are only available with interferon and lamivudine. Observational studies assessing the effect of interferon showed a potential effect in reduction of HCC incidence [37], but this was not confirmed by Asian case-controlled studies [38]. Similarly, a randomized controlled trial (RCT) assessing the effect of lamivudine showed a significant reduction in HCC incidence. Nonetheless, there are some concerns regarding the effects obtained in this study as prevention of HCC occurrence was not the primary end-point of the study, and because the marginal effect obtained disappeared once adjusted for co-variables [39]. As a result, it appears prudent to conclude that surveillance for HCC should be maintained in those patients who already qualified before starting the treatment.

In hepatitis C viral infection, the results of a meta-analysis of retrospective studies suggest that the risk of HCC is reduced among patients with HCV who achieve a sustained virological response (SVR) with antiviral therapy with interferon–ribavirin [40]. Once cirrhosis is established, there is no conclusive evidence that anti-viral therapy can prevent or delay the occurrence of HCC [[41], [42]]. Maintenance therapy with PEG–interferon in cirrhotic patients has not significantly decreased the incidence of HCC according to the HALT-C [[43], [44]] and EPIC studies [45]. Additional studies are required to test the potential preventive effect of combination with new protease inhibitors (boceprevir, telaprevir) in cirrhotic patients.


Table 3
Recommendations for HCC surveillance: categories of adult patients in whom surveillance is recommended.



∗Evidence 3A; strength B1;
∗∗evidence 3D; strength B1;
∗∗∗evidence 1B; strength A1 for Asian patients; evidence 3D; strength C1 for Western patients;
∗∗∗∗evidence 3D; strength B1 for Asian patients; evidence 3D; strength B2 for Western patients.