The evolving epidemiology of hepatocellular carcinoma: a global perspective.

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The evolving epidemiology of hepatocellular carcinoma: a global perspective Expert Rev. Gastroenterol. Hepatol. Early online, 1–15 (2015)

Michael C Wallace1–3, David Preen2, Gary P Jeffrey1,3 and Leon A Adams*1,3 1 University of Western Australia, School of Medicine and Pharmacology, 35 Stirling Highway, Crawley, Perth, Western Australia, Australia 2 University of Western Australia, School of Population Health, Perth, Australia 3 Liver Transplant Unit, Sir Charles Gairdner Hospital, Perth, Australia *Author for correspondence: [email protected]

Primary liver cancer, the majority of which are hepatocellular carcinomas, is now the second leading cause of cancer death worldwide. Hepatocellular carcinoma is a unique cancer that typically arises in the setting of chronic liver disease at a rate dependent upon the complex interplay between the host, disease and environmental factors. Infection with chronic hepatitis B or C virus is currently the dominant risk factor worldwide. However, changing lifestyle and environmental factors in western countries plus rising neonatal hepatitis B vaccination rates and decreasing exposure to dietary aflatoxins in developing countries are driving an evolution of the epidemiology of this cancer. An understanding of this change is crucial in combating the rising incidence currently being seen in western regions and will underpin the efforts to reduce the mortality rates associated with this cancer. KEYWORDS: chronic viral hepatitis . cirrhosis . epidemiology . hepatocellular carcinoma . nonalcoholic fatty liver disease

Incidence, geographical distribution & the global burden of hepatocellular carcinoma Global burden of hepatocellular carcinoma

Primary liver cancers, the vast majority of which are hepatocellular carcinomas (HCCs), are now the fifth and ninth most frequently occurring cancer in men and women, respectively, with over 782,000 cases estimated to have occurred in 2012 according to the International Agency for Research on Cancer (IARC) [1]. Prevalence closely mirrors incidence, which reflects its typically late-stage presentation, limited treatment options, aggressive nature and very poor overall survival. Primary liver cancer is now the second largest cause of cancer deaths worldwide (746,000 cases or 9.1% of all cancer deaths). [1,2]. The global cost of cancer is considered to be the single largest health-related economic burden worldwide with direct and indirect costs estimated to have been in excess of US$895 billion in 2010 [3]. The cost of treating chronic hepatitis C-related HCC in the USA is estimated to be up to US$45,000 per patient; although as more patients are being offered liver transplantation, this cost is likely to rise [4].

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Geographical distribution & changing incidence

HCC is no longer a disease considered to be virtually exclusive to East Asia and sub-Saharan Africa. Trends across the last three decades show decreases in HCC cases in traditionally high incident areas [5,6] and increases in traditionally low incident areas [7,8]. Between 1975 and 2005, the age-standardized incidence rate of HCC tripled in the USA [7]. In contrast, the incidences of other major causes of cancer in the western world, such as lung, prostate and colorectal, have decreased across a similar period [9]. Despite this, the vast majority of HCC cases (83%) still arise in non-western countries, with China accounting for slightly >50% of all new cases in 2012 [1]. According to International Agency for Research on Cancer (IARC) (summarized in FIGURES 1 & 2), regions with high estimated incidence in 2012 include East Asia and sub-Saharan Africa. Medium incidence regions include West Africa, parts of Southeast Asia and Melanesia. Regions of low incidence include Australasia, North America and Western Europe [1]. Possible explanations for the falling incidence in areas of high hepatitis B virus (HBV) prevalence include the impact of newborn HBV vaccination (see Prevention and

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Wallace, Preen, Jeffrey & Adams

Female

Male Eastern Asia South-Eastern Asia Northern Africa Western Africa Less developed regions

Incidence Mortality


Melanesia World Middle Africa Micronesia Central America Southern Europe Northern America More developed regions Caribbean Western Europe Southern Africa South America Australia/New Zealand Eastern Africa Polynesia Western Asia

developed countries in which the incidence continues to increase [1,12]. This is most likely due to the epidemic of HCV infections occurring earlier in Japan (beginning in the 1930s [13]) than in other developed countries, such as the USA and Australia, where infections rates were highest in the decades after World War II among the so-called ‘babyboomers’. This differential pattern of HCV infection may explain slightly different patterns of HCC incidence amongst populations with similar risk factor profiles. The contribution of obesity and its associated metabolic consequences to HCC risk is increasingly being recognized. While the absolute risk of HCC in those with the metabolic syndrome is low, given the already high and increasing prevalence in western countries, the population attributable fraction (PAF) of metabolic disease is significant and is likely to become a dominant risk factor in the future [14,15].

Central and Eastern Europe

Projections of future burden of disease

Northern Europe South-Central Asia

It is not possible to provide projections for the future global burden of HCC using one standardized approach. This is, Figure 1. Estimated age-standardised incidence and mortality rates for primary liver cancer in 2012 by region and gender per 100,000 persons. in part, owing to each region having a Reproduced with permission from reference [1]. unique mixture of demographics, risk factors (see Risk Factors section), anti-viral Protective Factors section) and reductions in aflatoxin exposure. treatment availability and uptake, and population growth proTaiwan implemented a national HBV immunization program jections. Examination of regional estimates may provide insight in 1984, at which point, up to 20% of people under the age into future burden of disease, particularly in western countries of 40 were chronically infected with HBV [10]. A 20-year data where epidemiological data collection is more rigorous. Data linkage analysis of >3.8 million HBV vaccinees in Taiwan from the US National Cancer Institute’s Surveillance, Epidemidemonstrated a significant difference between the incidence of ology and End Results (SEER) cancer registry database demonHCC in unvaccinated and vaccinated newborns (0.293 vs strated a non-significant increase in the overall HCC incidence 0.117 per 100,000 person-years) [10]. The full effect of HBV from 2007 to 2010 [16], defying a decades long trend of steeply vaccination programs in traditionally high HBV regions is rising incidence [7]. This may suggest that climbing HCC inciunlikely to be fully appreciated until the aging, chronically dence rates in the USA may in fact be plateauing and that the infected HBV cohort is replaced by a highly vaccinated, low peak may come sooner than the previously suggested crest of HBV infected cohort. Aflatoxin exposure is also decreasing in 2020 [17]. Furthermore, the most recent SEER data analysis some East Asian populations, particularly in Taiwan, which in (which assessed up to the end of 2011), predicted a decrease in turn is translating into lower HCC rates. It has been estimated HCC incidence by 2017 [18]. In western countries where that reducing aflatoxin exposure to undetectable levels could chronic hepatitis C is an important risk factor for HCC, the reduce HCC rates in these high-risk areas by up to 23% [11]. uptake of treatment with newly developed direct-acting antiThe incidence of HCC in developed countries is under the viral drugs is likely to significantly influence the future burden influence of changing epidemiology of HCV infection, immi- of HCC. Modeling performed in the UK, which examined sevgration patterns and the rising epidemic of metabolic risk fac- eral chronic HCV treatment scenarios, predicted that the numtors. In Japan, where chronic HCV is a dominant risk factor ber of patients developing decompensated liver disease and for HCC, incidence rates are, in fact, now decreasing after HCC can be drastically reduced with increased treatment peaking in the early 2000s, which is in contrast to many other uptake [19]. The impact of chronic HCV treatment will be 40

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Morbidity & mortality

HCC arises almost exclusively within the setting of chronic liver disease, and in up to 90% of cases, the patient has underlying cirrhosis [22,23]. HCC development depends upon a multitude of factors, including etiology and severity of underlying liver disease, host, lifestyle, behavioral and environmental risk factors (see Risk Factors section). Thus, the contribution of HCC to morbidity and mortality of chronic liver disease is heavily etiology dependent. There is a paucity of long-term data in large cohorts for many of the common underlying liver diseases. Many cohorts include a composite endpoint that combines HCC with overall deaths from the complications of liver disease. According to the CDC, in the USA in 2011, there were 33,642 deaths due to chronic liver disease or cirrhosis and 21,608 deaths due to primary liver cancer (which includes HCC and intrahepatic cholangiocarcinoma) [24]. Given that the majority of primary liver cancers are HCCs, and that most people with HCC have cirrhosis, a rough estimate of 40% of all deaths in cirrhosis can be attributed to HCC in western population. HCC is generally considered to be the single largest cause of death in those with cirrhosis [2]. In a large cohort of patients from Australia with chronic viral hepatitis, HCC was the cause of death in more than half of liver-related deaths in chronic HBV (199/358; 55.6%) and approximately a quarter in chronic HCV (238/943; 25.2%) [25]. Mortality is heavily dependent on disease stage at diagnosis and treatment selection, and thus, any in-depth discussion should be accompanied by an analysis of treatment-specific survival, a rapidly developing area that is beyond the scope of this review. The number of new cases of HCC per year is very similar to the number of deaths. The 5-year survival rate in the USA from 2003 to 2009 for primary liver cancer (which includes intrahepatic cholangiocarcinoma) was 16% [9]. Survival was similar from 1999 to 2007 in Europe (12%) [26], but was significantly worse in less developed regions where it may be 50% of cases [1,43]. In high HCC incidence areas, such as East Asia and sub-Saharan Africa, it accounts for almost all cases (with the exception of Japan); infection typically occurs at childbirth or in early childhood, which explains the earlier median age at diagnosis in these areas [35,43]. HBsAg positivity conferred a 10-fold risk of developing HCC in a large Taiwanese cohort compared with being HBsAg negative; having additional HBeAg positivity increased that risk to 60-fold [44]. Anecdotally, chronic HBV is Expert Rev. Gastroenterol. Hepatol.


The evolving epidemiology of hepatocellular carcinoma

a well-known cause of non-cirrhotic HCC as infection alone is hepatocarcinogenic [42]. Despite this, the vast majority of cases of HCC in a single western series (88–94%) arose in the setting of cirrhosis [45], although this observation may not hold true in Asian populations where the pattern of infection and genotype mix is different. In HBV-associated cirrhosis, the estimated 5-year cumulative risk of HCC is 15% in high HBV endemic areas, such as Asia, and 10% in western regions [46]. The risk of HCC in chronic HBV depends upon host, environmental and viral factors [47]. Host factors include advanced age, male gender, ethnicity, family history and presence of cirrhosis, and environmental or lifestyle factors, which include alcohol and tobacco use, exposure to aflatoxin and metabolic diseases. Viral factors, such as serological status, HBV viral load, HBV genotype, HBV variants and co-infection with HCV, hepatitis D virus (HDV) and HIV all may affect the risk of HCC development in chronic HBV. Care should be taken when attempting to extrapolate the results from Asian cohorts chronically infected with HBV to western populations given the different ages of acquisition and natural history. A meta-analysis of 42 cohort studies attempted to calculate the risk of HCC development in those with chronic HBV [47]. The analysis demonstrated that the risk of HCC development varied by geographical region (Asian countries > western countries), underlying the stage of liver disease (cirrhosis > no cirrhosis) and by disease activity (chronic active hepatitis > chronic inactive carrier). In studies from North America and Europe, the estimated incidence of HCC development was 2 per 100,000 person-years in chronic inactive carriers, 30 in chronic hepatitis without cirrhosis and 220 in patients with compensated cirrhosis. In studies from Asian countries, the rates were 20 in inactive carriers, 60 in chronic hepatitis without cirrhosis and 370 in compensated cirrhosis. While rates are lowest amongst chronic inactive carriers, the relative risk for developing HCC in 1932 Taiwanese patients with chronic inactive HBV compared with HBsAg-negative controls was 4.6, highlighting the ongoing risk of HCC and requirement for surveillance in this population [48]. In general, cohorts from western populations tend to be of smaller sample size and have shorter follow-up time; however, a large Australian cohort of 44,323 patients with chronic HBV followed for a median of 4.2 years reported a crude HCC incidence rate of 94 per 100,000 person-years [49]. Unfortunately, no virusassociated information was available. A landmark trial published in 2006 conclusively established the relationship between HBV viral load and risk of HCC [50]. The REVEAL-HBV Study Group followed 3652 HBsAg-positive, HCV-antibody negative Taiwanese adults aged 30–65 for a median of 11.4 years. The incidence of HCC development increased with higher serum HBV DNA levels at study enrolment in a dosedependent manner. At a serum HBV DNA of 80 g of alcohol per day for 10 years increases the risk of HCC fivefold [66]. The annual incidence of HCC in compensated alcoholic cirrhosis is approximately 2–2.5% [67,68]. Importantly, alcohol synergizes with other causes of liver disease to increase the risk of HCC development. These include chronic infection with HCV or HBV, smoking and metabolic risk factors, such as obesity and diabetes mellitus. A meta-analysis of 16 studies and 13,706 patients with chronic HCV showed that the pooled relative risk of cirrhosis development (including decompensation and HCC in some studies) was 2.33 in heavy drinkers [69]. In an Italian case–control study of the effect of alcohol on HCC development in viral hepatitis, a linear increase in risk of HCC development began after daily consumption of >60 g per day for both HBV and HCV; interestingly, there was no gender differences demonstrated [70]. In a Taiwanese study of chronic HBV, alcohol use and HCC, the annual and 10-year cumulative incidences of HCC were significantly higher in patients with both risk factors (9.9 and 52.8%, respectively) compared with chronic HBV (4.1 and 39.8%) or alcohol abuse (2.1 and 25.6%) alone [68]. A small case–control study of 210 patients with HCC demonstrated that alcohol use and smoking had a multiplicative effect on HCC risk with a synergistic index of 3.3 [71]. Similar results were demonstrated for the combination of alcohol and obesity and the risk of HCC (synergistic index 2.5) [71]. Finally, the combination of diabetes mellitus and heavy alcohol consumption increased the risk of HCC development in a case–control study of 295 HCC cases (OR 4.2) [72].

Hepatitis B/hepatitis D co-infection

The presence of HDV infection is dependent upon co-infection with HBV. HDV/HBV co-infection is anecdotally associated with a more aggressive course of disease that frequently leads to HCC [61]. However, there are little data assessing the actual increase in risk of HCC in co-infection with HDV and HBV. In a Swedish series of 9160 patients with HBV mono-infection and 327 with HDV/HBV co-infection, the risk of HCC increased sixfold in co-infection compared with HBV infection alone [62]. Further work is required in other populations to confirm this increased risk. Human immunodeficiency virus

The implications of co-infection of HIV with either HBV or HCV have been well reviewed recently [63]. Up to 33% of HIV patients are co-infected with HCV and 15% in HBV endemic countries are co-infected with HBV. Rates of HCC and end-stage liver disease in HIV co-infected patients are climbing, most likely due in part to the increasing life expectancy of HIV patients and the addition of metabolic risk factors [64]. Accelerated hepatocarcinogenesis is seen in HIV coinfection with chronic viral hepatitis, owing to a combination of inflammatory and immunosuppressive effects, the direct hepatocarcinogenic effect of HIV viral proteins and the HIVdoi: 10.1586/17474124.2015.1028363

Non alcoholic fatty liver disease/non alcoholic steatohepatitis

A recent meta-analysis of 61 studies concluded that there is an association between non-alcoholic fatty liver disease (NAFLD)/ non-alcoholic steatohepatitis (NASH) and the development of HCC [73]. Although the risk appears to be largely confined to those with cirrhosis, cases from non-cirrhotic NAFLD patients have been reported [74]. The rate of progression to HCC in NASH cirrhosis is low, approximately 2.6% per year [75]. However, given that NAFLD may affect up to one in three people in western populations, the contribution of this disease to overall burden of HCC is likely to become significant [76]. This has been borne out in a recent series from the UK that examined changes in HCC risk factors from 2000 to 2010 in 632 consecutive cases. Across that period, there was a greater than 10-fold increase in cases associated with NAFLD; and by 2010, NAFLD accounted for more than one-third of all new cases [14]. Expert Rev. Gastroenterol. Hepatol.



In the USA, NASH is now the second leading cause of HCC in liver transplant recipients and is the fastest growing indication for liver transplantation [77]. In fact, from 2002 to 2012, there has been an almost fourfold increase in NASH-related HCC liver transplants (accounting for 13.5% of HCC transplants); in the same period, HCV-related HCC liver transplants increased by just twofold (accounting for 49.9% of HCC transplants) [77]. Importantly, the ‘modified’ definition of NASH in this analysis included obese patients transplanted either with a diagnosis of cryptogenic cirrhosis or without a known cause of liver disease and thus caution must be exercised in interpreting these data. Type 2 diabetes, obesity & the metabolic syndrome

The mechanisms by which metabolic risk factors, such as obesity, increased insulin resistance, fatty liver and diabetes mellitus, lead to HCC are complex and interrelated. Importantly, it is not always possible to examine the effect of one condition on HCC development in isolation, since they often occur simultaneously. These alterations subsequently act together with co-existing liver disease (if any) and accelerate the progression of cirrhotic tissue to HCC [78,79]. Caution should be taken when interpreting the effect of Type 2 diabetes mellitus (T2DM) on the risk of HCC. Given that cirrhosis may independently lead to insulin resistance, it is possible that, in fact, the observed diabetes–HCC relationship is purely a consequence of cirrhosis. However, many studies have attempted to control this possibility, for example, by only considering diabetes information in patients prior to the diagnosis of HCC [80]. An analysis of the US SEER-Medicare linked database established that T2DM confers a two- to threefold increased risk of HCC and that this risk is independent of other traditional HCC risk factors [80]. A meta-analysis of 45 studies and 2528 HCC cases among 35,202 participants found similar results. A summary of relative risk for the development of HCC of 1.86 was reported for the presence of T2DM and chronic liver disease compared with chronic liver disease alone [81]. Not only does T2DM predict the development of HCC, it is also a marker of poor outcomes. In a meta-analysis of 21 studies and 9767 HCC patients, the presence of T2DM was independently associated with poorer overall and disease-free, survival [82]. While obesity is a major risk factor for the development of T2DM, it also acts independently of T2DM to increase the risk of HCC. This has been demonstrated by a meta-analysis of 26 prospective studies with 25,337 cases of primary liver cancer (with 90% estimated to be HCC). When the presence of T2DM was controlled, the summary relative risk of primary liver cancer was 1.77 in those with a BMI >30 [83]. Given the high estimated PAF of obesity to HCC, it has been suggested that lifestyle changes could have a significant impact on the future burden of HCC [15]. Finally, the risk of HCC in the setting of the metabolic syndrome as a whole, as defined by at least three of the following: dyslipidemia, hypertension, impaired fasting glucose and central obesity or elevated waist informahealthcare.com

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circumference, has been assessed. A total of 3649 HCC cases from the US SEER-Medicare linked database were identified between 1993 and 2005 and compared against 195,953 controls. The presence of the metabolic syndrome conferred a 2.16-fold increased risk of HCC, independent of other factors [84]. Smoking

Tobacco smoking is a firmly established carcinogen in humans, and the IARC in 2004 declared that it was specifically a cause of liver cancer [85]. Mechanistically, the components of tobacco smoke have been shown to promote hepatocarcinogenesis in animal models [86]. It has proven difficult to disentangle the effect of smoking from other risk factors for HCC (such as chronic viral hepatitis and heavy alcohol consumption) because of their close clustering in many populations. However, a recent analysis from a prospective cohort in the Singapore Chinese Health Study, in which the rates of heavy alcohol consumption were low, identified smoking as a dose and timedependent risk factor for HCC development, even when controlling for alcohol use [87]. Furthermore, a European case– control study of 115 HCC cases matched to 229 controls found that almost half of the cases (47.6%) were contributed by smoking, more than chronic HBV and HCV combined [28]. Aflatoxins

Aflatoxins are carcinogenic fungal metabolites produced by Aspergillus flavus or Aspergillus parasiticus. These fungi may contaminate and colonize a variety of food staples, such as maize, spices and nuts, particularly in the developing world and countries with high HBV rates, such as China, sub-Saharan Africa and southeast Asia [29,88]. Chronic exposure to aflatoxins is an independent risk factor for HCC and also synergizes with chronic HBV infection to drastically increase HCC risk, up to 60-fold [88]. An extensive analysis of worldwide data sets performed recently estimated that exposure to aflatoxins may contribute between 4.6 and 28.2% of all HCC cases [29]. It has been proposed that low technology interventions, such as simple modification of post-harvest techniques among subsistence farmers in developing countries, may lead to significant reductions in aflatoxin exposure, and potentially to reductions in HCC cases by up to 23% [11,89]. Dietary risk factors

Much of the data regarding dietary risk factors for HCC development have focused on meat consumption. In a prospective cohort study of approximately 500,000 people aged 50–71 in the USA with a median of 8.2 years of follow-up, there was 1.6-fold increase in HCC risk for those in the highest quintile of red meat intake compared with those in the lowest quintile; controlled for age, gender, smoking status, alcohol intake and BMI but not for other important possible confounders, such as fatty liver or T2DM [90]. A similar study that in addition controlled for diabetes found a 1.7-fold increase in risk for HCC in those who consumed the highest amount of red meat [91]. doi: 10.1586/17474124.2015.1028363

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Interestingly, a recent study demonstrated that a diet higher in total protein was associated with a reduction in HCC risk, although there was a non-significant increase in HCC risk in those who ate more red meat [92]. Furthermore, a meta-analysis of 17 studies concluded that there was no increased risk of HCC in those who ate more red meat, processed meat or total meat [93]. Non-cirrhotic hepatocellular carcinoma

HCC that arises in a non-cirrhotic liver can be seen in several causes of chronic liver disease, primarily in chronic HBV infection, although also in chronic HCV and fatty liver. Most recent series would suggest that it is a rare entity (particularly in western countries), perhaps as low as 2% of all cases [94]. In general, patients with non-cirrhotic HCC tend to present younger, have more advanced tumors and frequently have a poor outcome despite generally preserved liver function [94,95]. Anecdotally, increasing numbers of noncirrhotic HCC are being discovered in those with metabolic risk factors. A total of 162 consecutively enrolled HCC patients in several European centers reported a remarkable rate of absence of cirrhosis in 41.7% in those with NASH as the underlying etiology [96]. Crucially, the diagnosis of cirrhosis was unable to be made histologically in all patients, which may have skewed the results. In a separate series of 157 cases of non-cirrhotic HCC, an increase in steatosis of the nontumor liver was identified, albeit when compared against the non-tumor tissue of a control group which consisted of patients with cholangiocarcinoma [73]. Despite the obvious limitations, these two studies provide grounds for further investigation into this small, but potentially expanding subset of HCC cases. Autoimmune & cholestatic liver disease

Progression to HCC in autoimmune liver disease is anecdotally thought to be relatively low, although there is a paucity of good quality natural history studies for these diseases. In a retrospective series of 509 patients with primary sclerosing cholangitis, including 119 with cirrhosis and median follow-up of 7 years, no cases of HCC were identified [97]. The incidence of HCC in primary biliary cirrhosis has not been well established, most likely due to its low prevalence; however, it is considered to confer high risk for HCC. This is supported by a metaanalysis of 17 studies, with significant reported heterogeneity, which demonstrated a pooled relative risk of 18.8 for HCC in primary biliary cirrhosis [98]. Furthermore, a large cohort of 402,462 Swedish patients who were admitted to hospital with autoimmune disease (of all types) across a >40-year time period showed that the greatest risk for HCC was in those with primary biliary cirrhosis (standardized incidence ratio 39.5) followed by autoimmune hepatitis (29.0) [99]. The occurrence of HCC in autoimmune hepatitis was reviewed recently [100]. It suggested that HCC occurred in those with autoimmune hepatitis and cirrhosis at a rate of between 1.1 and 1.9% annually; risk factors include cirrhosis for >10 years, the presence of doi: 10.1586/17474124.2015.1028363

portal hypertension and long-term (>3 years) immunosuppressive therapy [100]. Hereditary hemochromatosis & iron overload

Hereditary hemochromatosis confers an increased risk of HCC development of approximately 20-fold as evidenced by a cohort study of 1847 Swedish patients [101]; higher risks have been reported, albeit in smaller studies [102]. The annual incidence of HCC in hereditary hemochromatosis is estimated to be as high as 8–10% and it occurs almost exclusively in those with cirrhosis. As with many other liver diseases, it remains unclear if the accumulation of abnormal levels of hepatic iron is hepatocarcinogenic or if HCC development is simply a consequence of cirrhosis [102]. Evidence for the former can be found by considering the case of dietary iron overload in Africans who consume large volumes of iron-rich home-brewed beer in which the risk of HCC development is estimated to be elevated 10-fold, even when controlling for the presence of chronic viral hepatitis and aflatoxin exposure [103]. Small case series of secondary hemochromatosis and some animal models suggest that HCC may arise in the absence of cirrhosis [102], suggesting that the iron itself has hepatocarcinogenic properties. Finally, excess hepatic iron has been identified in chronic HCV infection, obesity and the metabolic syndrome, and NAFLD/NASH; any contribution to excess HCC risk is yet to be fully elucidated [102,104]. Porphyria

The association between the acute porphyrias and HCC development has been reviewed recently and will be briefly summarized here [104]. HCC appears to arise in acute intermittent porphyria at a greater rate than in the background population potentially independent of the presence of cirrhosis and chronic HCV infection. These data come from relatively small series and case reports but standardized incidence ratios may be as high as 36 [104,105]. HCC in variegate porphyria and in hereditary coproporphyria have been reported, but in such low numbers, meaningful conclusions are unable to be drawn [104]. a1 anti-trypsin deficiency

In a Swedish autopsy series of 31 adults with a1 anti-trypsin deficiency, 5 had HCC [106]. The risk appears to be confined to adults and those with cirrhosis [107]. Numbers are insufficient to calculate the annual incidence with any certainty but surveillance is warranted. Budd–Chiari syndrome

A meta-analysis of 16 studies calculated a pooled prevalence of HCC in Budd–Chiari syndrome of 17.6% [108]. Because of concerns that unidentified concomitant chronic viral hepatitis in those patients with Budd–Chiari syndrome may have been the true cause of the HCC and may have therefore confounded the results, an analysis of the five studies in which chronic viral hepatitis was specifically excluded showed that the pooled Expert Rev. Gastroenterol. Hepatol.


prevalence of HCC in Budd–Chiari syndrome in the absence of chronic viral hepatitis was 15.4%.


Hepatic adenoma

Malignant transformation of hepatic adenoma to HCC has been reported in approximately 6% of cases based upon the analysis of 530 cases in 16 separate case series [109]. Increasing size and number of the lesions may predict malignant transformation [109], as can the presence of specific tissue mutations [110]. Prevention & protective factors Hepatitis B vaccination

The WHO advocates the implementation of universal HBV immunization in an attempt to eradicate the virus by herd immunity. As of 2012, 183 countries vaccinate their newborns against HBV [111]. Taiwan implemented one of the most successful HBV mass vaccination programs in July 1984, and the results serve as a model for the potential benefits of obtaining >90% HBV vaccination coverage [112]. The long-term effects of HBV vaccination rates on HCC incidence are unlikely to be fully appreciated for some time due to the long lag time seen between infection and HCC development. However, as previously mentioned, an analysis of 3.8 million vaccinees in Taiwan has already demonstrated a greater than 50% reduction in HCC incidence in those vaccinated; this difference is likely to increase in the future [10]. Hepatitis B treatment & spontaneous clearance

Several recently published, well-designed studies with appropriately long follow-up times have conclusively demonstrated that viral suppression achieved by newer oral antiviral agents reduces the risk of HCC development in chronic HBV, potentially by up to 70% [113–118]. Several components of this conclusion merit further discussion. First, and perhaps most importantly, the use of oral antiviral therapy does not completely eliminate the occurrence of HCC, and thus surveillance may still be warranted. Second, despite treatment and complete viral suppression, traditional risk factors for HCC development, such as cirrhosis, advancing age and male gender, remain significant and can still be used to calculate the risk. Third, incomplete viral suppression is a strong risk factor for HCC development, and thus complete viral suppression should be a goal for the treatment. And finally, the effectiveness of antiviral therapy appears to be applicable across racial, ethnic and geographical lines as well as being effective in reducing HCC risk in those with and without cirrhosis (although not all studies reached this final conclusion). Spontaneous clearance of HBV protects against HCC risk; whether outcomes from these populations can be extrapolated to patients on treatment is unclear. In a longitudinal study of 2946 HBsAg-positive Taiwanese patients, seroconversion of HBsAg conferred the strongest protection from HCC development (hazard ratio 0.18), followed by seroclearance of HBV DNA (hazard ratio 0.24); however, seroconversion of HBeAg did not reach statistical significance (hazard informahealthcare.com

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ratio 0.63; 95% CI: 0.38–1.05) [119]. The lack of protection from HBeAg seroconversion is in contrast to an older landmark study from 2002 [44]; this may be due to the confounding effect of HBV DNA, which was unable to be incorporated into the earlier study. Hepatitis C treatment

Several meta-analyses have assessed the impact of sustained virological response (SVR) in those with chronic HCV on HCC development. The most recent assessed 30 observational studies and calculated a relative risk of 0.24 for those who achieve an SVR compared with those who did not [120]. Importantly, this conclusion applied to all stages of fibrosis. However, as with chronic HBV, HCC risk remains despite virological cure (or viral suppression in the majority of HBV cases). In a long-term follow-up study of 351 patients with HCV cirrhosis, HCC risk persisted for up to 8 years post-SVR, highlighting the need for on-going surveillance in this group [121]. Finally, long-term suppressive therapy with low dose pegylatedinterferon does not reduce the risk of HCC [122,123]. As discussed, modeling suggests that increased uptake of new direct-acting antiviral therapy is likely to have a significant effect on future burden of HCC in western countries [19]. Drugs Metformin

Two meta-analyses of retrospective studies have concluded that metformin use reduces HCC risk in diabetics, potentially in a dose-dependent manner [124,125]. It is unclear whether this risk attenuation is achieved by improving diabetic control or if metformin itself has some chemopreventative properties. In vitro studies have demonstrated that metformin can reduce the proliferation of hepatoma cell lines by inducing cell-cycle arrest [126]. Prospectively enrolled studies are required to confirm this association. Statins

As with metformin, the majority of evidence of the chemopreventative properties of statins comes from retrospective studies. A meta-analysis of 10 studies with almost 1.5 million people and 4298 cases of HCC concluded that people who used statins had a 37% reduction in risk of HCC compared with those who did not [127]. Protective dietary factors

Adhering to a healthy diet may protect against HCC. This possibility has been assessed in several studies. Higher scores in the Health Eating Index–2010 and the alternative Mediterranean Diet Score, which reflect close adherence to dietary recommendations for western populations, were associated with reduced HCC risk in a cohort of almost half a million Americans by up to 38% [92]. Adherence to the Mediterranean diet in a European cohort also appeared to reduce HCC risk by a similar amount; there was an additional, although non-statistically significant, additive increased risk of HCC development with doi: 10.1586/17474124.2015.1028363


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poor adherence in those with chronic viral hepatitis [128]. Higher fish and fiber consumption, and lower total sugar consumption were protective against HCC development in almost half a million participants in the European Prospective Investigation into Cancer and Nutrition cohort [129,130]. In a metaanalysis of 19 studies and over 1 million participants with 3912 HCC cases, high and daily vegetable consumption protected against HCC development; fruit consumption, however, was not protective [131].

allow for appropriate resource allocation and will provide a firm foundation for advances in diagnostic and surveillance, treatment and prognostic algorithms. The importance of this knowledge cannot be understated, but despite these conceptual advances, they are yet to translate into improved outcomes for patients. Two facets of the increasingly complex epidemiology of HCC deserve mention: .

Coffee

The liver-related benefits of coffee consumption have been analyzed in two separate meta-analyses, each of which reached similar conclusions, namely that the consumption of >2 cups of coffee per day may reduce the risk of HCC by up to 40%, even in the absence of liver disease [132,133]. A recent multiethnic prospective study in the USA with 162,022 participants demonstrated a 38% reduction in the risk of HCC for those who drank two to three cups of coffee per day, independent of known HCC risk factors, such as diabetes, smoking, ethnicity, gender, alcohol use and BMI [134]. A recent update on the management of cirrhosis recommended that all patients with liver disease be encouraged to drink coffee; not only for the HCC risk reduction but also for its potential ability to improve liver function tests, increase the probability of achieving an SVR in chronic HCV and to reduce the degree of steatohepatitis in NAFLD/NASH [135]. Vitamin D

There is emerging evidence that vitamin D has many diverse roles beyond that of calcium and bone metabolism, including in liver physiology. Its association with HCC was recently examined with the European Prospective Investigation into Cancer and Nutrition cohort. Patients with the highest baseline serum 25(OH)D levels had an almost 50% reduction in the risk of HCC development compared with the lowest levels, independent of underlying liver disease or chronic infection with viral hepatitis [136]. While several limitations were identified, this study is suggestive that vitamin D deficiency may contribute to hepatocarcinogenesis. Expert commentary

HCC incidence is increasing significantly in western populations and great progress has been made in defining the underpinnings of the epidemiological evolution of this deadly cancer. Appreciating the unique epidemiology of HCC will

doi: 10.1586/17474124.2015.1028363

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Appreciation of the synergistic nature of many HCC risk factors, and the understanding that they tend to cluster is an important concept, and one that is likely to aid in future HCC risk algorithms. Unfortunately, many of these risk factors tend to be time- and dose-dependent, which are notoriously difficult to accurately quantify in the clinic; Caution must be taken in assigning an HCC patient to one particular etiology of liver disease; this is particularly true for patients with primarily metabolic risk factors as is it often impossible to disentangle several concomitant and mechanistically similar conditions.

Five-year view

The next 5 years is likely to see several significant changes in the epidemiology of HCC. Metabolic risk factors for HCC, particularly in western populations, will continue to increase in prevalence and may become the dominant risk factor in the next 5 years. Rates of HCC will continue to decrease in highprevalence Asian populations. This decrease will be driven by reductions in aflatoxin exposure, increasing hepatitis B vaccination rates and the cumulative effect of hepatitis B viral suppression from new-generation anti-viral agents, such as entecavir and tenofovir. Advances in HCC risk prediction algorithms that incorporate genomic information will likely improve in accuracy and power. This in turn may allow for enrichment of HCC chemotherapy and chemoprevention trials with high-risk patients allowing for smaller sample sizes and shorter follow-up times thereby hastening HCC drug development. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.



Review

Key issues .

Primary liver cancer is now the fifth most common frequently occurring cancer in men, the ninth in women and is the second leading cause of death from cancer worldwide.

.

Hepatocellular carcinoma (HCC) contributes up to 40% of all deaths in cirrhosis, making it the single most common cause of death in this patient population.

.

There is a clear geographical distribution in the epidemiology of hepatocellular carcinoma, with the highest incidence seen in developing


countries with high rates of chronic hepatitis B and aflatoxin exposure and the lowest in some European countries. .

HCC development depends upon a multitude of factors, including etiology and severity of underlying liver disease, host, lifestyle, behavioral and environmental risk factors.

.

A shift in the risk factor profile is driving a clear evolution in the epidemiology of hepatocellular carcinoma; in general, rates are decreasing in high incidence areas and are increasing in low incidence areas.

.

Most cases arise in China (50% of cases) and in the setting of chronic hepatitis B or C.

.

Increasing hepatitis B vaccination and treatment, reducing levels of aflatoxin exposure and more efficacious hepatitis C treatment are likely to change the global epidemiology of HCC in the near future.

.

Metabolic disorders, including fatty liver disease, obesity and insulin resistance are emerging risk factors for hepatocellular carcinoma, and these may become dominant risk factors in western regions in the coming decade.

.

The future burden of HCC, particularly in western populations, is also likely to be dependent upon whether the epidemic of obesity, diabetes mellitus and fatty liver can be stemmed.

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