Causes

From National Cancer Control Policy
Liver cancer > Causes


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Causes

The major risk factors for liver cancer are well known. The most important risk factors for liver cancer are hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Together, HBV and HCV infections account for an estimated 71% of cases of liver cancers globally[1]. Other risk factors include sex, age, viral co-infection, chronic alcohol consumption, obesity, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes and tobacco smoking. Genetic factors also play a role in the progression of hepatocellular carcinoma.

Hepatocellular carcinoma is the most common liver cancer. The burden of hepatocellular carcinoma due to different risk factors – alone or in association – varies in different world regions. HBV infection is more prevalent than HCV infection in most Asian and African countries; thus about 60% of hepatocellular carcinoma cases are attributable to HBV infection. The reverse occurs in Europe and the US, where 50–60% of hepatocellular carcinoma is attributable to HCV, 10–15% to HBV, and 30–35% to neither[2]. Within Europe, the HBV-attributable proportion of hepatocellular carcinoma is highly variable, reflecting different levels of HBV prevalence[2].

The proportion of hepatocellular carcinoma attributable to specific factors is predicted to change over the next few decades. HBV-related hepatocellular carcinoma should decline in countries with universal infant hepatitis B vaccination programs (including Australia), although the burden from currently infected individuals and infected immigrants is expected to persist for many years. In the developed world, a growing proportion of liver cancers are attributable to non-viral factors, particularly obesity-related liver diseases such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Increasing evidence of the association between obesity, diabetes and NAFLD and hepatocellular carcinoma has led to predictions that up to a third of the future hepatocellular carcinoma burden could be ‘metabolic’.

See below for data on the proportion of hepatocellular carcinoma cases associated with hepatitis in Australia.

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Hepatitis viruses and cancer

Hepatitis viruses are blood-borne and sexually-transmitted. They cause acute infection (newly acquired) and/or chronic infection (persisting for more than six months) and inflammation of the liver. HBV and HCV are major causes of severe illness and death globally, responsible for an estimated 4.5% of all new cancers – and nearly 80% of liver cancers – worldwide in 2008[3]. Globally, chronic HBV infection accounts for approximately half of all cases, and virtually all childhood cases, of hepatocellular carcinoma[2]. Hepatitis D virus, which depends on HBV co-infection for transmission, is a less common risk factor for hepatocellular carcinoma[4][5].

The International Agency for Research on Cancer first classified chronic HBV and HCV infections as Group 1 carcinogens in 1994[6]. The precise molecular mechanisms for the development of hepatocellular carcinoma due to HBV and HCV are unknown, but both persistent viral replication, and ongoing liver damage and regenerative activity (clinically manifest by the development of cirrhosis) are part of the causal path. Cirrhosis (secondary to chronic necroinflammation) is found in 70–90% of patients with hepatocellular carcinoma[7].

Chronic viral hepatitis is the leading cause of hepatocellular carcinoma in Australia, with hepatocellular carcinoma incidence reported as 6.5 per 1000 among people with chronic hepatitis B, 30 times higher than the rate in the general Australian population[8]. Precise information regarding the number of cases of hepatitis related hepatocellular carcinoma Australia-wide is not available, however smaller state-based studies have provided some indication of the number. A longitudinal study in NSW using data linkage found that of 2072 cases of hepatocellular carcinoma identified from 1990 to 2002, 323 (15.6%) were linked to HBV infection, 267 (12.9%) to HCV infection, and 18 (0.8%) to HBV/HCV co-infection[9]. A smaller NSW study of 151 people presenting at hospitals with hepatocellular carcinoma found that 41% had chronic HBV infection and 26% had chronic HCV infection, this included 8% who were co-infected with both viruses[10]. A Victorian study of 215 people with hepatocellular carcinoma reported that approximately 38% of patients presented with hepatitis C and 19% of with hepatitis B[11]. The study hospital predominantly serves one of the lowest HBV prevalence areas of Melbourne which is reflected in the low proportion of cases associated with HBV.

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Hepatitis B

Worldwide around 2 billion people have been infected with HBV, of whom more than 350 million are chronically infected[12]. About 600,000 people die annually as a result of HBV infection[12]. The Global Burden of Disease study reported that 341,000 people died of HBV-related liver cancer in 2010[1].

Transmission

HBV replicates almost exclusively in the liver but very high concentrations of virus are released into the blood, so that most tissues and body fluids are infectious. Transmission occurs through percutaneous or mucous membrane contact with infected blood or body fluids including serum, semen or saliva.

Transmission routes generally are described as:

  • vertical – from mother to infant at or around birth; or
  • horizontal – through unprotected sexual contact; unsafe sharing of injecting drug equipment; household contact between children and adults or other children; or in healthcare settings, from exposure to contaminated equipment, blood products or body tissue/fluids.

Vertical transmission is the major mode of transmission globally. Active or chronic HBV infection and presence of HBeAg (indicating higher levels of viral replication) at the time of pregnancy leads to a 90% chance of infection of the newborn infant[13]. In Australia, vertical transmission is associated with very high maternal HBV DNA levels[14].

In areas that have a low incidence of hepatocellular carcinoma, infection usually occurs in adulthood, through sexual contact and sharing of unsterile injecting equipment. Horizontal transmission can also occur through the use of shared objects, such as razor blades, where the virus has been shown to persist for up to one week[15][16]. Horizontal transmission risk decreases with increasing age, as such the risk of horizontal transmission is increased in children compared with adults.

The Australian Red Cross Blood Service introduced screening of donations for HBV in 1971 to prevent transmission of the virus through blood transfusion.

Natural history

The natural history of HBV infection is largely dependent on the age when a person was exposed to the virus.

An estimated 95% of infants infected through perinatal exposure develop chronic hepatitis B, while adult exposure leads to chronic infection in only 1–5% of cases[17][13][2]. People chronically infected during childhood are at higher risk of cirrhosis, decompensated liver disease and hepatocellular carcinoma later in life[18][19]. Their lifetime risk of death from HBV-related hepatocellular carcinoma or cirrhosis is estimated to be 25%[20].

Chronic hepatitis B occurs when the immune response fails to clear acute infection. Markers of chronic HBV infection are the persistence of hepatitis B surface antigen (HBsAg), with or without HBeAg, for more than six months after initial infection. This is further determined by the presence of HBV DNA in the blood. Up to 30% of cases of chronic HBV infection progress to cirrhosis[21][22].

Progression to hepatocellular carcinoma

Disease progression and hepatocellular carcinoma development are typically driven by active viral replication – indicated by high serum alanine aminotransferases, high HBV DNA levels and persistently positive HBeAg – and liver cirrhosis[23][24][25]. Chronic HBV infection can also progress to hepatocellular carcinoma in the absence of cirrhosis[26].

Prospective cohort studies show people with chronic hepatitis B have a five- to 100-fold increased risk of developing hepatocellular carcinoma. Meta-analysis of case control and cross-sectional studies indicates that the lifetime relative risk for hepatocellular carcinoma is 15–20 among HBsAg-positive individuals, compared with HBsAg-negative individuals[2].

Factors that have been reported to increase hepatocellular carcinoma risk among people infected with HBV include demographic (male sex, older age, Asian or African ancestry, family history of hepatocellular carcinoma), viral (higher levels of HBV replication, HBV genotype, longer duration of infection, or co-infection with HCV, HIV or hepatitis D virus), clinical (cirrhosis), and environmental factors (exposure to aflatoxin, heavy intake of alcohol or tobacco)[2].

Hepatitis B in Australia

Estimates of the number of people in Australia living with chronic hepatitis B range from 209,000 to 218,567[27][28].

HBV infection is a notifiable condition in Australia. Hepatitis B notifications are classified as either ‘newly acquired’ (infection acquired within 24 months prior to diagnosis) or ‘unspecified’ (infection acquired more than 24 months prior to diagnosis or not able to be specified)[29]. Classification is primarily based on serological evidence or evidence of a previously negative test within the 24 months prior to diagnosis.

In 2009, there were 7,345 notifications of hepatitis B (both newly acquired and unspecified), equating to a rate of 33.6 notifications per 100,000 population[29]. The highest rates were reported in the Northern Territory (69.4 per 100,000 population, compared with 37.8 per 100,000 population in NSW, the second highest rate)[29].

The reported rate of newly acquired infections in 2009 (1.1 per 100,000 population) was the lowest since 1999, following a peak of 2.1 notifications per 100,000 population between 2000 and 2001[29].

Populations groups at high risk

Australian population groups at higher risk of HBV infection are:

  • migrants from highly endemic regions;
  • Aboriginal and Torres Strait Islander peoples;
  • children born to women infected with HBV;
  • men who have sex with men;
  • people who inject drugs;
  • sex workers;
  • partners and other intimate and household contacts of people with HBV infection;
  • people in custodial settings;
  • people with HIV or HCV or both;
  • healthcare workers and emergency services workers;
  • people travelling to and from high prevalence countries, particularly those visiting families and friends in their country of origin; and
  • vulnerable populations, including the homeless and people with mental illness[30].

Australian studies indicate the large majority of patients with chronic hepatitis B were born overseas, mostly in highly endemic countries of the Asia-Pacific, particularly China and Vietnam[31][16][28]. A recent linkage study found that 70% of HBV-related hepatocellular carcinoma cases were in Asian-born residents[9]. According to population-based sero surveys in countries of birth and immigration patterns, the burden of HBV-related hepatocellular carcinoma among Asia-Pacific born Australians is projected to increase further during the next two decades[32].

Individuals migrating from high prevalence countries are generally considered to have the same rates of infection as that of their birth country[33]. Subsequent generations show a declining infection rate irrespective of vaccination[34], although Australian-born children of parents from hepatitis B endemic regions are at increased risk of acquiring hepatitis infection, either perinatally or through horizontal transmission.

Chronic HBV infection is considered endemic in Aboriginal and Torres Strait Islander communities. While Aboriginal and Torres Strait Islander peoples represent 2.5% of the Australian population[35], they constitute an estimated 16% of Australians living with chronic hepatitis B[31]. Antenatal seroprevalence studies in the Northern Territory have found a current infection prevalence of 3.7–5.5%[36][37]. Studies in the mid-1990s indicated that up to 25% of rural Aboriginal populations were HBsAg positive[38][31]. Earlier studies of Aboriginal schoolchildren in the NT showed nearly 47% had serological markers of HBV infection, suggesting transmission of the infection occurs at an early age, including in schools[39].

Despite high rates of hepatitis B exposure, men who have sex with men and people who inject drugs have relatively low rates of chronic hepatitis B, because most contract the virus as adults or adolescents and therefore more likely to clear the virus than people infected in infancy. However, many people in these groups who are infected with HBV are co-infected with HCV and/or HIV (due to shared transmission routes), increasing their risk of liver damage and hepatocellular carcinoma[40] (see below).

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Hepatitis C

Globally, between 130 million and 170 million people are chronically infected with HCV, and more than 350,000 people are estimated to die from HCV-related liver diseases each year[12]. The Global Burden of Disease study reported that 195,700 people died of HCV-related liver cancer in 2010[1].

Transmission

In Australia, HCV transmission occurs mostly among people with a recent history of injecting drug use, through use of unsterile injecting drug equipment[27]. About 80% of Australians with chronic HCV were infected through sharing or re-using unsterile injecting drug equipment such as needles and syringes[41]. A small number of people have been infected with HCV through unsterile tattooing, or body piercing procedures, or through transfusion of infected blood or blood products before 1990.

The risk of transmitting HCV to a baby during pregnancy or childbirth is low, at around 3-6%[42][43].

Hepatitis C is not classified as a sexually transmitted infection, but there is a small risk of transmission during sexual intercourse (if there is blood present during sex). Men who have sex with men who also have HIV are at higher risk of HCV transmission[44].

The Australian Red Cross Blood Service introduced screening of donations for HCV antibodies in 1990 and for HCV RNA in 2000 to prevent transmission of the virus through blood transfusion.

Natural history

The natural history of HCV is highly variable. In around a quarter of cases (26%) HCV infection is cleared spontaneously[45]. Treatment regimens for HCV infection achieve clearance in approximately up to 75% of cases[46][47][48][49]. Despite the efficacy of treatment, up to 80-86% of adults infected with HCV progress to chronic infection[50][51]. This is largely because spontaneous elimination is uncommon, and as many people may remain asymptomatic they do not seek treatment. About 80% of people infected with HCV exhibit no symptoms.

The presence of antibodies against HCV (anti-HCV) indicates that a person is or has been infected. HCV RNA testing is most commonly used to confirm HCV infection. Diagnosis of chronic infection diagnosis is made when anti-HCV is present for more than six months.

Between 60 and 70% of chronically HCV infected people develop chronic liver disease, 20–30% develop cirrhosis[52] and 1–5% develop hepatocellular carcinoma[53].

Progression to hepatocellular carcinoma

Cross-sectional and case-control studies show the risk of developing hepatocellular carcinoma is increased 15- to 20-fold in people with chronic HCV infection[54]. HCV increases the risk for hepatocellular carcinoma by inducing fibrosis and eventually, cirrhosis. The likely mechanism is chronic necroinflammation, cellular regeneration and fibrosis that predisposes to genomic damage[50].

Risk factors that increase the progression of liver disease and chances of developing hepatocellular carcinoma in a person with chronic HCV include being male, older age, alcohol use, longer duration of infection, co-infection with HBV or HIV, comorbidities (type 2 diabetes, obesity, steatosis), older age and cigarette smoking[20][55][56].

Hepatitis C in Australia

In 2011 it was estimated that 226,700 people in Australia were living with chronic hepatitis C, including 49,500 with moderate to severe liver disease[27]. As these people age, rates of HCV-related cirrhosis, liver failure and hepatocellular carcinoma are projected to further increase [41].

Populations groups at high risk

Australian population groups at higher risk of HCV infection include:

  • people who inject drugs;
  • people in, or who have been in, custodial settings;
  • people who received organs, tissues, blood or blood products before February 1990 in Australia (or at any time in countries where mandatory screening does not occur);
  • people with tattoos or skin piercings (if procedure was unsterile);
  • people born in countries with high hepatitis C prevalence;
  • Aboriginal and Torres Strait Islander peoples;
  • men who have sex with men, particularly those with HIV;
  • infants born to mothers with detectable HCV at the time of delivery; and
  • healthcare workers and others at risk of needle-stick injuries or accidental exposures to infected blood or blood products[57].

More than 80% of existing and almost 90% of all new HCV infections are diagnosed in people with a history of injecting drug use[41].

HCV prevalence in Australia is highest in current and former prisoners, with an estimated one in three male inmates, and two in three female inmates being HCV positive[58]. Increased transmission in custodial settings is mainly attributed to a high number of inmates previously infected with HCV, and the sharing of unsterile injecting drug, tattooing and body piercing equipment in these settings.

People born in, or who have spent considerable time in countries where there is a high prevalence of HCV infection have an increased risk of infection. It has been estimated that nearly 11% of people in Australia with a current or previous HCV infection are immigrants from countries where HCV is prevalent or endemic, who have subsequently migrated to Australia[59].

Aboriginal and Torres Strait Islander people carry a disproportionate burden of hepatitis C. They constitute 2.5% of Australia’s population[35], but are estimated to account for 8.3% of all HCV diagnoses. It was estimated in 2005 that 22,000 Aboriginal and Torres Strait Islander people had been exposed to HCV, and 16,000 of those had a chronic HCV infection[59].

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Non-viral liver diseases

A significant proportion of hepatocellular carcinoma cases are unrelated to either HBV or HCV infection. These cases are largely attributable to non-viral liver diseases including alcoholic liver disease, cirrhosis related to metabolic factors, genetic hemochromatosis, autoimmune liver disease and other rare, inherited enzyme deficiencies.

Alcohol

A recent review by WCRF found convincing evidence that consuming three or more alcoholic drinks a day can cause liver cancer[60]. Evidence shows a synergistic effect between heavy ingestion of alcohol and HCV infection and, to a lesser extent, HBV infection[61]. The combined effects of hepatitis infection and chronic alcohol consumption increase the risk of cirrhosis[2]. A systematic review of 133 studies found that alcoholics with HCV infection are at increased risk of developing liver disease compared with non-alcoholics - with or without HCV infection[62].

The Global Burden of Disease study reported that 149,000 people died of alcohol-related liver cancer in 2010[1].

For more information about the link between alcohol consumption and cancer, see the Alcohol chapter of the National Cancer Prevention Policy.

Metabolic factors

There is growing evidence that the metabolic factors of obesity and type 2 diabetes independently increase hepatocellular carcinoma risk in people with hepatitis and other causes of cirrhosis[63][64][65], especially in combination with alcohol use, tobacco smoking and diabetes[66]. A large Taiwanese population-based study found the presence of both type 2 diabetes and obesity independently increased hepatocellular carcinoma risk 265-fold (in the case of HBV) and 135-fold (in the case of HCV)[67].

Type 2 diabetes is associated with increased hepatocellular carcinoma incidence and hepatocellular carcinoma mortality, independent of geographic location, alcohol consumption, cirrhosis, or infection with HBV or HCV[68]. The increased risk for people with type 2 diabetes is thought to be a result of hepatic injury, fibrosis, and eventual cirrhosis resulting from fatty liver disease[69].

Hepatocellular carcinoma has been linked to NAFLD, the hepatic manifestation of obesity and related metabolic disorders such as type 2 diabetes. Several population-based cohort and case-control studies have shown an association between NAFLD and hepatocellular carcinoma by showing that patients who are obese and have type 2 diabetes are twice as likely to develop hepatocellular carcinoma compared to non-obese and non-diabetic patients[70][71]. There is also evidence that hepatocellular carcinoma may complicate non-cirrhotic NAFLD with mild or absent fibrosis[72].

For more information on the link between cancer and obesity/overweight see the Overweight and obesity, physical inactivity and nutrition chapter of the National Cancer Prevention Policy.

Haemochromatosis

Haemochromatosis is an important cause of liver disease in Australia and New Zealand[73]. Haemochromatosis is a common genetic disorder in people of Anglo-Celtic origin, with an estimated frequency in Australia of 1:300[74].

Hepatocellular carcinoma has been reported to develop in about 30% of people with untreated cirrhosis due to haemochromatosis[75].

Recent studies indicate that the presence of diabetes in people with haemochromatosis increases the risk of liver injury and the severity of hepatic fibrosis[76].

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Other risk factors

Several other factors that increase the risk of primary liver cancer have been identified. Some act independently, but most are co-factors with HBV or HCV infection.

Sex

In Australia liver cancer is nearly three times more common in males than females[77]. This has previously been explained, in part, by the fact that males have a greater incidence of viral hepatitis and alcoholic cirrhosis[78]. However, men’s increased risk remains after adjusting for these factors. The differences in gender distribution may reflect variations in hepatitis natural history between women and men: women are less likely to maintain persistent HBV infection than men, or to develop hepatocellular carcinoma if they remain infected through middle age. Some studies have associated increased hepatocellular carcinoma risk with high serum levels of testosterone[79].

Age

The risk of hepatocellular carcinoma is fourfold higher in people aged over 50 years compared with younger individuals[80]. It is unclear whether the effect is due to age, or is related to longer duration of infection. A longitudinal study showed HBsAg seroclearance before the age of 50 was associated with a lower risk of hepatocellular carcinoma development and a lower risk of fibrosis compared with HBsAg seroclearance in people aged over 50[81].

Co-infection

People with HBV/HCV co-infection have more severe liver disease, are more likely to develop cirrhosis with decompensation, and have an increased risk of developing hepatocellular carcinoma than individuals with HCV or HBV alone. An Australian study describing cancer incidence in people with HBV infection, HCV infection or both found the risk of liver-related death was highest in those with co-infections[82].

However, a recently updated meta-analysis of 59 studies that assessed HBV/HCV co-infection reported a subadditive effect based on more recent studies (2000–2009), where HBV and HCV infection were not common[83]. This has led to suggestions that infection with one virus might inhibit infection with the other[2].

Co-infection with HIV increases the risk of hepatocellular carcinoma in people with a chronic HBV or HCV infection[40] and lowers the age of onset[84]. Studies have shown that individuals with both HCV and HIV have faster progression to cirrhosis and decompensated liver disease[2].

Aflatoxin exposure

Aflatoxin (e.g. on mouldy food) is an established risk factor for hepatocellular carcinoma, both independently and as a co-factor with chronic HBV infection[85]. Exposure to dietary aflatoxin (on mouldy food) contributes to high rates of hepatocellular carcinoma in Asia and Africa. Studies in China have shown that individuals infected with HBV who excrete aflatoxin metabolites in urine have a 60-fold increased risk of developing hepatocellular carcinoma[86]. Preventing HBV-related hepatocellular carcinoma would reduce the impact of aflatoxin on hepatocellular carcinoma risk[2].

Tobacco smoking

Epidemiological studies show tobacco smoking is hepatocellular carcinoma risk factor, particularly in patients with liver cirrhosis who also consume alcohol.

A recent meta-analysis showed a more than additive interaction between HBV infection and cigarette smoking, and a more than multiplicative interaction between HCV infection and cigarette smoking[87].

See the Tobacco control chapter of the National Cancer Prevention Policy for more information.

Family history

A family history of liver cancer has been associated with increased hepatocellular carcinoma risk among people infected with HBV (in cohort and case-control studies) and possibly among HCV-infected persons (in case control studies)[2].

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