Disease Burden of Hepatocellular Carcinoma: A Global Perspective
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Liver cancer is one of the leading causes of cancer-related mortality around the world. Hepatocellular carcinoma (HCC) is the primary cancer of the liver, accounting for the majority of liver cancers. The risk factors associated with HCC include chronic infections with HBV and HCV, alcoholic liver disease, and nonalcoholic fatty liver disease. Additionally, male patients have higher risk for than females, and the risk increases with older age. Mortality rates for HCC parallel its increasing incidence rates. In this context, incidence rate for HCC shows geographic variations in different parts of the world and is heavily affected by regional differences in risk factor for liver disease. The highest incidence rates for HCC are observed in Asia and Africa, while Europe and North America have lower rates. In fact, HBV is still regarded as the leading cause of HCC globally, while HCV is the most common cause of HCC in the USA. Recently, it has been suggested that HCC cases related to nonalcoholic fatty liver disease is on the rise, while the proportion of HCC attributed to alcoholic liver disease remains stable.
KeywordsHepatocellular carcinoma Epidemiology Hepatitis B Hepatitis C
Liver cancer is a major cause of cancer mortality globally, and hepatocellular carcinoma accounts for at least 75% of all liver cancer cases.
Hepatocellular carcinoma generally arises in the setting of underlying chronic liver disease and is the only solid organ malignancy with an increasing incidence.
Hepatitis B virus remains the leading etiology for hepatocellular carcinoma in most parts of the world, while hepatitis C virus has been the most common etiology in the USA. Nonalcoholic fatty liver disease has recently been recognized as a major and increasing contributor to the global burden of hepatocellular carcinoma.
The prevalence of hepatocellular carcinoma is highest in Asian countries with China experiencing some of the highest rates of hepatocellular carcinoma in the world.
Besides the clinical aspect of hepatocellular carcinoma, its economic impact adds to the total burden of hepatocellular carcinoma in the last decade.
Liver cancer is the second most common cause of cancer-related deaths worldwide, only after lung cancer, with almost 800,000 deaths annually . Hepatocellular carcinoma (HCC) is the primary tumor of the liver and is responsible for almost 75% of all liver cancers . In most cases, HCC arises in the setting of chronic liver diseases and has been a leading cause of death among patients with cirrhosis [3, 4]. The prognosis of HCC mostly depends on its stage and the severity of liver disease at the time of diagnosis . In fact, advanced-stage HCC has a very poor prognosis, with a median survival of less than a year and a 5-year survival rate of only 7%  .
Epidemiology and Risk Factors
Although liver cancer is the second leading cause of cancer-related deaths worldwide, it is the fifth and ninth most common type of cancer seen in men and women, respectively . Previous studies have reported an incidence of hepatocellular carcinoma 16 cases per 100,000 population, which corresponds to 20,000 new cases in the USA. Mortality rates are quite similar to the incidence rates from different parts of the world, both of which have been increasing in the recent years. In the USA, the incidence rate of HCC increased by 3.1% per year between 2008 and 2012 .
Major risk factors for HCC are chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV), alcoholic liver disease, and nonalcoholic fatty liver disease (NAFLD) . HCV is the most common cause of HCC in the USA, while HBV has been implicated as the most common etiological agent worldwide. Given the epidemic of obesity-related NAFLD, many experts anticipate that NAFLD will soon become a leading cause of HCC, especially in the USA and other Western countries . It has been widely believed that any chronic liver disease that causes cirrhosis can also place patients at risk for HCC. In contrast, HCC can rarely occur in the absence of cirrhosis. Although HBV is known to cause HCC without established cirrhosis, there are reports of HCC cases in patients NAFLD without cirrhosis .
The geographic differences in the etiology of liver disease worldwide have led to a geographic variation of the incidence of HCC around the world. In fact, almost 75% of all liver cancers occurs in Asia with China which accounts for more than half of the all the cases worldwide . Furthermore, the incidence of HCC can reach up to 25-35 per 100,000 population in certain parts of Asia and Sub-Saharan Africa . On the other hand, Northern Europe, Middle East and Americas have the lowest incidence rates, whereas Central Europe has intermediate rates . It should be noted that even in the same country, incidence rates can significantly vary according to risk factors for liver disease and other sociodemographic characteristics. For example, in the USA, the immigrant population from areas of the world highly endemic for HBV tend to experience higher rates of HCC [14, 15].
In addition to etiologic agents associated with HCC, there are gender differences in the prevalence of HCC, as men are more likely to develop the disease as compared to women. In the USA, this ratio is about 2.5–3 to 1, while in other parts of the world, this ratio can be as high as 6 to 1 . These differences between males and females is thought to be multifactorial, including environmental exposures as well as hormonal differences, such as the potentially protective effects of estrogens and trophic effects of androgens .
Burden of HCC in Different Regions of the World
As stated above, the highest incidence rates of HCC are observed in the Asian countries with China accounting for a large number of HCC cases. In a recent study, the highest incidence of liver cancer and associated deaths and disability-adjusted years lost were seen in the Eastern Asian countries followed by the Asian-Pacific region . In this context, this region of the world is well known for high prevalence of HBV and HCV. In fact, prevalence of HBV is almost 18% in China, 20% in Taiwan, 5% in India, and about 4% in Japan [19, 20]. On the other hand, prevalence of HCV is 10% in Mongolia, 6.7% in Pakistan, 4.4% in Taiwan, 2.7% in Thailand, 1.3% in China, and 1% in India . These very high prevalence rates of HBV and HCV are responsible for the high rates of HCC experienced in this part of the world.
In addition to chronic viral hepatitis, it is also known that the risk of HCC occurrence significantly increases with chronic aflatoxin exposure, mostly in the setting of viral hepatitis infection [22, 23]. In a study by Fan et al., it was estimated that among Chinese population, HBV was responsible for 66% of HCC in men and 58% in women, whereas HCV was responsible for 27–28% of HCC in both genders, while aflatoxin was responsible for 25% of HCC cases in both sexes . On the other hand, the picture is quite different in Japan. Multiple studies demonstrated that the cause of HCC in Japan differs from other countries in the region; as chronic HCV infection is more common than HBV in Japan, almost 70–80% of HCC burden was due to chronic HCV infection . Although data are not fully available, the increasing rate of obesity in Asia and its associated NAFLD may also contribute to the incidence of HCC. In this context, Vongsuvanh et al. reported that the rate of metabolic diseases and NAFLD has been increasing dramatically in Asia Pacific region and the epidemiology of HCC in this region will undergo significant change in the next decades . Additionally, in some Asian countries (some parts of India), alcohol-related liver disease (ALD) may also contribute to the development of cirrhosis and HCC. In this context, NAFLD or ALD may not only cause primary liver disease but also could accentuate the negative impact of chronic viral hepatitis and accelerate the development of cirrhosis and HCC.
Given these facts, some Asian countries, including China, have developed policies and interventions to reduce their HCC burden. These policies included modification of their national HBV vaccination policies, or policies that will lead to a reduction in aflatoxins exposure . Similarly, periodic hepatitis testing among high-risk populations has been conducted through national programs in Japan, South Korea, and Taiwan . In fact, after applying these changes, China experienced a drop in age-standardized incidence rate and age-standardized mortality rate related to HCC between 1990 and 2015 . Similarly, a decrease in HCC incidence has been reported from Japan, between 1990 and 2003, as well as an increase in survival rate of patients with HCC after the year 2000 . In contrast, in Mongolia, liver cancer deaths increased 171% between 1990 and 2015 with HCC continuing to remain the leading cause of cancer deaths .
Similar to Asia, HCC mortality remains to be the leading cause of cancer-related deaths in Africa. In Africa, HCC is also driven by chronic viral hepatitis, with either HBV or HCV, and exposure to aflatoxins . On the other hand, NAFLD does not seem to be a significant risk factor for liver disease in Africa . It is estimated that almost 20% of African population carries HBV and almost 80% of these individuals acquire the virus before the first decade of their lives . HCV is also highly prevalent in Africa, with prevalence rates as high as 10% is certain parts . In Africa, HBV is responsible for 47% of all HCC cases, while HCV is implicated in 23% and alcohol in 20% of all HCC cases . The age-standardized incidence of HCC is about 41.2 per 100,000 population, but in some specific groups, such as Mozambican men, the incidence rate is as high as 101.7 per 100,000 population .
While many African countries reflect similar sociodemographic characteristics, Egypt is somewhat different. In a recent study, 84% of HCC cases in Egypt was due to HCV, while HBV was responsible for 55% of HCC in other African countries . Additionally, 76% of HCC patients received a specific treatment in Egypt, while this rate was only 3% in other African countries . While vaccination strategies in Africa are ongoing and newer effective treatment modalities for viral hepatitis are available, access and affordability to these treatment regimens remain a major barrier in Africa, especially in the Sub-Saharan Africa . On the other hand, the recent national policy to eliminate HCV from Egypt with highly effective antiviral regimens has led to a large number of patients being identified and treated. The long-term impact of these treatment strategies on the incidence of HCC in Egypt is not known.
According to World Health Organization data, approximately 47,000 patients die of HCC annually in European countries [38, 39]. Although the incidence of HCC in Europe is lower than that of Asia and Africa, this rate is not homogenous across different European countries. In fact, following East Asia and Asia Pacific regions, Western Europe is ranked third for liver cancer incidence rates and fourth for liver cancer mortality . Additionally, studies from England and Wales reported an upward trend in the incidence and mortality of HCC in the last 4 decades [40, 41, 42]. Although the incidence of HCC was increasing in men, these rates were more stable in women . In fact, in the UK, as compared to 1968, age-standardized mortality rate almost doubled in 2008. These rates increased from 2.56 to 5.10 per 100,000 population in men and 1.29 to 2.63 per 100,000 population in women .
Other studies have provided comparative statistics for HCC in Europe. In this context, since early 2000s, highest HCC rates were seen in France, Italy, and Switzerland as compared to lower rates reported from Norway and Sweden [43, 44]. Although more recently the mortality rates from HCC have shown more uniform trends in different parts of Europe, these rates are still higher in Western and Southern Europe as compared to the Scandinavian countries [43, 44].
It important to remember that the driver of HCC in Europe is different than Asia. Although HBV represents the leading risk factor for HCC development globally, its impact has been declining in Europe. In contrast, a study from Italy suggested that HCV infection was an important driver of HCC until 2000 and this trend seems to be diminishing and replaced by alcohol-related liver disease . Furthermore, another study from Austria assessed the changing profile of HCC in the last 20 years . Similar to previous data, this study also reported that compared to females, age-adjusted incidence rate and age-adjusted mortality rate were higher in men and these rates have been increasing . In the same study, the median overall survival for HCC was 4.5 months for males and 3.2 months for females. Interestingly, both studies indicated that since early 2000s, the impact of alcohol may have become more prominent [37, 38].
It is important to emphasize that unlike Asian and African countries, the contribution of alcohol consumption and NAFLD to the impact of HCC in Europe may be higher . In one study from Germany, among HCC patients who had cirrhosis, 52.2% was attributed to alcohol-related liver disease, whereas HCV- and HBV-related liver disease accounted for 13.7% and 3.6%, respectively. Furthermore, about a quarter of HCC patients in this study were obese while 2 out of 3 were overweight, suggesting a potential role of NAFLD in the development of HCC .
In summary, HCC is an important cancer in Europe with some regional differences. Although HCV may have been the main culprit in the past, it seems that it is being replaced by alcohol-related liver disease and NAFLD.
Compared to the other regions of the world, the incidence of HCC in North America is relatively low . However, these trends have changed and the incidence of HCC in North America seems to be increasing . In 2015, in North America, the age-standardized incidence rate for HCC was 11.6 per 100,000 population in males and 4.3 per 100,000 population in females . These rates are almost one-third of the rates reported from East Asia . Despite this relatively low rates of HCC, the incidence of HCC in the past 2 decades the USA has almost tripled. In fact, HCC is one of the few solid tumors in the USA with increasing incidence [49, 50]. Similarly, deaths from primary liver cancer have been increasing at a faster pace than any other type of cancer in the USA [49, 51, 52]. In fact, in 2012, there were a total of 22,252 deaths due to primary liver cancer in the USA . Of these, 37%, 31%, 9%, and 22% were due to alcohol-related liver disease, HCV infection, HBV infection, and other causes of liver disease, respectively .
The demographics of HCC is influenced by race and ethnicity in the USA. In fact, HCC is twice more common in Asians than in African Americans in the USA, with both groups having higher rates of HCC than Whites . Furthermore, HCV infection and alcohol-related liver disease are still the leading causes of both cirrhosis and HCC in the USA [50, 51], but cases of NAFLD-related HCC are on the rise [54, 55]. In fact, data from SEERS database suggested that NAFLD was the third most common cause of HCC in the USA . Additionally, NAFLD was independently associated with mortality within 1-year of diagnosis in HCC patients .
These data from the USA have important implications. The demographic changes experienced in the past 30 years have brought in immigrants from areas of the world endemic for HBV and possibly HCV. This may partly explain higher rates of HCC in the Asian Americans in the USA, mostly related to vertical transmission of HBV . Additionally, the high prevalence of HCV infection in the African Americans may also be responsible for the relatively higher rates of HCC in this group . In addition to these racial differences in HCC, the high prevalence of HCV infection in the so-called baby boomers who were born between 1945 and 1965 may be partly responsible for the increasing incidence of HCC [56, 57]. This cohort of HCV-infected patients have been infected for over 50 years and are experiencing higher rates of cirrhosis and higher incidence of HCC . Finally, the growing epidemic of obesity and type 2 diabetes has been responsible for a rapid increase in the prevalence of NAFLD in the USA [58, 59]. In this context, NAFLD seems to be poised to become an important cause of HCC in the USA. As noted previously, between 2004 and 2009, there was a 9% annual increase in the number of patients with NAFLD-related HCC . Another study using the same database between 2001 and 2009 showed that, compared to HCV-related HCC, patients with NAFLD-related HCC were more likely to die within 2 years of their diagnosis . Although the exact reasons for this higher mortality are not known, presentation with advanced tumor stage, less surveillance rates, and lower possibility of receiving liver transplantation may be some of reasons .
The epidemiologic picture of HCC in Canada is similar to the USA. In fact, in 2012, a total of 1962 primary liver cancer-related deaths were reported from Canada . Again, 31% of HCC in Canada was due to alcohol-related liver disease, while 34% was due to chronic HCV, 9% due to HBV and 27% due to other causes [18, 60, 61]. This is almost identical rates to those reported from the USA. Furthermore, mortality related to HCC seems to be increasing in Canada. In this context, incidence and mortality of almost 30,000 liver cancer deaths between 1972 and 2006 were assessed in Canada . This study suggested an increase in age-adjusted incidence rates and age-adjusted mortality rates . Similar to the USA, reports from Canada suggest the role of immigration from high-risk areas and its associated high rates of viral hepatitis burden as the main driver of HCC in Canada. In fact, in 2006, almost 20% of population from Canada was born outside of Canada, and Africa and Asia made up 42% of foreign-born population in 2001 . Again, similar to the USA, the global epidemic of obesity may also be affecting Canada and NAFLD may contribute to the burden of HCC in Canada in the future.
Compared to USA and Canada, data about the burden of HCC are quite scarce in the countries of South America. One study from Peru focused on the impacts of HBV vaccination on the burden of HCC . The authors compared the trends in HCC, cirrhosis, and fulminant hepatitis for the time periods of 1960–1990 and 1991–2012. It was shown that the number of deaths attributable to HCC in children and adolescents remained unchanged between the compared time periods, whereas the number of deaths attributable to HCC in adult females decreased significantly . Another study by Petrick et al.  focused on the international trends in liver cancer incidence and reported a rate of 7.0 for Brazil, 4.1 for Colombia and 3.8 for Ecuador, all of which were much lower than the rates seen in East, such as 23.6 in Japan and 28.0 in Thailand. Lastly, a study from the USA focused on the burden of HCC among Hispanic population. It was demonstrated that Hispanic residents of South Texas had experienced the greatest burden of HCC among all ethnic groups . However, it must be noted that there is ongoing need for further studies for the burden of HCC in the countries of South America.
In summary, chronic viral hepatitis B and C have been the main culprit driving HCC in the USA and North America. On the other hand, given the use of highly effective direct acting antiviral agents for HCV and suppressive therapy for HBV, NAFLD and possible alcohol-related liver disease may become the dominant causes of HCC in the USA. Data on South America are scarce, and further studies are needed.
In the last 2 or 3 decades, hepatocellular carcinoma has grown substantially in the Oceania region, as the incidence of the disease has increased by two- to threefold from 1997 to 2007 . In fact, liver cancer has become the fastest increasing cause of cancer death in Australia . Some studies explained that the rising HCC incidence in Australia was partly attributed to the mass migration from the Asia–Pacific region, with the majority of immigrants coming from high-risk HBV-endemic countries . For this reason, a recent study by Wallace et al.  focused on the incidence and survival trends of HCC in Australia, in a time period of more than 3 decades. It was shown that there was a 7.5-fold increase in the incidence of HCC between 1982 and 2014. Waziry et al.  investigated the trends in viral hepatitis-related HCC in Australia between 2000 and 2014 and demonstrated that while the population-level burden of HBV-related HCC was stable, the burden of HCV-related HCC increased markedly. The authors attributed the stable rates in HBV-related HCC to improving HBV antiviral therapy since mid-2000s and the rise in HCV-related HCC to no significant impact of interferon-based treatments for HCV. Unlike Australia, data on specific cancer incidence have been very limited in New Zealand. One study reported that according to New Zealand census-cancer data from 1981 to 2004, the age-standardized incidence rate of HCC was 30.3 per 100.000 in men and 9.8 per 100.000 in women, both of which were higher than the rates in European countries, suggesting that the burden of HCC might be higher in New Zealand compared to Europe .
Disease Burden from Patient Perspective
Health-related quality of life (HRQoL) is an important outcome from the patients’ perspective. In this context, HRQoL is especially important for chronic diseases such as liver disease and its complications such as HCC . In fact, since the longevity of patients with HCC is quite limited, the impact of HCC and its treatment on patients’ HRQoL is of utmost importance . A systematic review by Gandhi et al. demonstrated that among patients who are symptomatic from HCC, the most common symptoms were right upper quadrant pain, weight loss, and anemia . These symptoms had significant negative impact on patients’ functioning and well-being . Additionally, physical, emotional, and functional well-being were significantly affected due to the complications and extrahepatic manifestations of advanced disease . In addition to the underlying HCC, the treatment strategies may also affect patients’ well-being and HRQoL . Although some studies suggest that patients undergoing liver transplantation may have improvement of HRQoL , others reported no significant differences between those who receive a liver transplantation or those who are treated with resection . This may be due to the fact that a large number of HCC patients who undergo liver transplantation or surgical resection may have better preserved liver function and the actual treatment may not substantially affect the disease severity which is the major driver of HRQoL in patients with liver disease.
Finally, it is important to note that some scale of HRQoL, especially fatigue domain, can have important can be used as a prognostic factor for overall survival in patients with HCC [78, 79]. All of these data suggest that HRQoL and other patient-reported outcomes are of utmost importance in patients with HCC and should be included in full disease burden assessments.
Economic Burden of Hepatocellular Carcinoma
As stated above, liver cancer is the only solid organ malignancy with an increasing incidence, and clinicians have been seeing more and more HCC cases both in the inpatient and outpatient setting [70, 71, 72, 73, 74]. Besides its clinical burden, HCC is also responsible for substantial economic burden due to healthcare expenditures. For example, in the USA, a study using National Inpatient Sample database revealed that total inpatient charges related to HCC increased from $1.0 billion in 2005 to $2.0 billion in 2009 . Another study using the same database demonstrated that between 2002 and 2011, despite a decrease in the length of stay and in-hospital mortality rates for HCC patients, the overall inflation-adjusted charges for hospitalizations increased . Similarly, another study using the SEER-Medicare database echoed the aforementioned findings by demonstrating the annual cost of HCC in the USA to be more than $450 million . There are various potential explanations for this economic burden. In this context, a growing number of patients with HCC have a larger number of treatment options (transplantation, resection, loco-regional ablations, “targeted” medications) which could lead to higher healthcare resource utilization . The obstacles to efficient and effective care of patients with HCC include the difficulty of implementing surveillance programs, complicated diagnostic evaluation, limited availability and high cost of potentially curative therapy, and scarcity of specialized multidisciplinary care . Recent reports suggest that treatment of underlying chronic liver disease such as HBV and HCV, in fact, can lead to financial gain in the long term by causing a drop in the incidence of HCC . For example, a recent study from Japan demonstrated that treatment of chronic HCV infection with highly effective direct acting antiviral agents would reduce the number of cases with HCC and increase quality adjusted life years .
In summary, HCC poses substantial and increasing economic burden. Prevention and effective treatment of chronic liver disease as well as early detection and effective treatment of HCC could potentially impact both the clinical outcomes of these patients as well as the economic burden of HCC.
The disease burden of HCC has been an important topic both in the USA and globally. In most cases, the underlying etiologic cause of HCC is apparent and is related to viral hepatitis, alcoholic liver disease, NAFLD, or combination of these liver diseases. These factors along with some other genetic and environmental factors (such as exposure to aflatoxin) may be responsible for significant burden of HCC worldwide.
Currently, HBV is still the leading cause of HCC globally. Although its true impact can only be seen in the long run, the widespread vaccination policies against HBV may be effective in reducing HBV-related HCC. In Europe and the USA, HCV is the main etiologic agent causing HCC. In this context, the recent development of highly effective direct acting antiviral therapies for HCV can potentially reduce the burden of HCV-related HCC. Nevertheless, identification of HCV patients, their linkage to care, and access to these highly effective regimens remain important challenges. Although the rates of alcohol-related liver disease are stable, the epidemic of obesity and type 2 diabetes is driving the increasing prevalence of NAFLD. In this context, NAFLD-related HCC is already considered the third most common cause of HCC in the USA. If these trends continue, NAFLD-related HCC is expected to become the dominant cause of HCC in a number of regions of the world.
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Conflict of interest
Dr. Younossi is a consultant to BMS, Gilead, AbbVie, Intercept, NovoNordisk, Viking, Terns and Quest. All other authors have no conflict of interest to disclose.
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