Causes

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 modifiable risk factors include tobacco smoking, viral co-infection, chronic alcohol consumption, obesity, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, occupational exposures and pollution^[2]. Non-modifiable risk factors of liver cancer include age and sex. Genetic factors also play a role in the progression of liver cancer.

The burden of liver cancer due to different risk factors – alone or in association – varies in different world regions. The Global Burden of Disease Study 2015 showed that 48% of liver cancer cases in Australia are attributable to HBV and HCV. It is estimated that HBV and HCV infections accounted for 10% and 38% of liver cancer cases, respectively.^[3] Smoking and alcohol consumption has also been shown to contribute to Australia’s liver cancer burden.^[3]

See the Tobacco control and Alcohol chapter of the National Cancer Prevention Policy for more information on the link between these risk factors and cancer and recommended policy reforms more broadly.

The proportion of liver cancer attributable to specific factors in Australia is predicted to change from infectious to non-infectious factors over the next few decades. Increasing evidence of the association between obesity, diabetes and NAFLD and liver cancer has led to predictions that up to a third of the future liver cancer burden could be ‘metabolic’.

The International Agency for Research on Cancer first classified chronic HBV and HCV infections as Group 1 carcinogens in 1994^[4]. Chronic viral hepatitis is the leading cause of liver cancer in Australia, with liver cancer incidence reported as 6.5 per 1000 among people with chronic HBV, 30 times higher than the rate in the general Australian population^[5].

Hepatitis B

World Health Organization estimated that 382,104 liver cancer deaths in 2016 were secondary to hepatitis B ^[6]. Worldwide around 2 billion people have been infected with HBV, of whom more than 350 million are chronically infected^[7][8].

HBV is a blood borne virus spread through contact with blood and other body fluids. 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 HBV, while adult exposure leads to chronic infection in only 1–5% of cases^[8][9][10]. People chronically infected during childhood are at a higher risk of liver cancer later in life^[11][12]and their lifetime risk of death from HBV-related liver cancer or cirrhosis is estimated to be 25%^[13].

HBV infection is a notifiable condition in Australia.^[14] In 2017, there were 6,102 notifications of HBV, equating to a rate of 25.0 notifications per 100,000 population ^[15]. The highest rates were reported in the Northern Territory (40.8 per 100,000 population, compared with 29.6 per 100,000 population in NSW, the second highest rate)^[15].

The number of people in Australia living with chronic HBV is estimated to be 233,947 ^[15]. Australian studies indicate the majority of patients with chronic HBV were born overseas, mostly in highly endemic countries of the Asia-Pacific, particularly China and Vietnam ^[16][17].

Chronic HBV infection is considered endemic in Aboriginal and Torres Strait Islander communities. Aboriginal and Torres Strait Islander groups constitute an estimated 11% of Australians living with chronic hepatitis B ^[15]. The prevalence of chronic HBV remains substantially higher among Aboriginal and Torres Strait Islander groups compared to the rest of the population ^[18]. There has been a continued decrease in HBV prevalence in the Indigenous population living in the Northern Territory due to infant vaccination, but also due to other factors, possibly including changes in birthing practices and moving from community to hospital births^[19].

Despite high rates of HBV exposure, men who have sex with men and people who inject drugs have relatively low prevalence of HBV. 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 liver cancer^[20].

Progression to liver cancer

Disease progression and liver cancer development are typically driven by active viral replication and liver cirrhosis^[21][22][23]. Chronic HBV infection can also progress to hepatocellular carcinoma in the absence of cirrhosis^[24].Studies show that people with HBV have a 100-fold increased risk of developing liver cancer ^[25][26].

Factors that have been reported to increase liver cancer 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)^[10].

Hepatitis C

World Health Organization estimated that 115,097 liver cancer deaths in 2016 were secondary to HCV^[6]. Globally, approximately 71 million people are chronically infected with HCV^[6].

In 2017 it was estimated that 182,285 people in Australia were living with chronic HCV, including 36,694 with moderate to severe liver disease^[27]. As this cohort ages, rates of HCV-related cirrhosis, liver failure and liver cancer are projected to further increase^[28].

In Australia, HCV transmission occurs mostly in people with history of injecting through use of unsterile equipment^[27]. The prevalence of HCV in Australia is highest in current and former prisoners^[29] and people born in, or who have spent considerable time in countries where there is a high prevalence of HCV infection^[29].

Aboriginal and Torres Strait Islander Australians carry a disproportionate burden of HCV. They constitute 3% of Australia’s population, but are estimated to account for at least 11% of all newly diagnosed HCV infections in 2017^[27]. It was estimated in 2005 that 22,000 Indigenous people had been exposed to HCV, and 16,000 of those had a chronic HCV infection^[29].

The natural history of HCV is highly variable. In around a quarter of cases (26%) HCV infection is cleared spontaneously^[30]. Treatment regimens (antiviral treatment) for HCV infection achieve a sustained virological response of at least 95%^[31]. Between 60 and 70% of chronically HCV infected people develop chronic liver disease, 20–30% develop cirrhosis^[32] and 1–5% develop liver cancer^[33].

Progression to liver cancer

Studies show the risk of developing liver cancer is increased 15- to 20-fold in people with chronic HCV infection^[34]. HCV increases the risk for liver cancer by inducing fibrosis and eventually, cirrhosis.

Risk factors that increase the progression of liver disease and chances of developing liver cancer 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 ^[13][35][36].

Other risk factors

Fifty-two percent of liver cancer cases are unrelated to either HBV or HCV infection ^[3]. These cases are largely attributable to non-viral risk factors and liver diseases including: alcoholic liver disease, metabolic factors (including NAFLD), genetic haemochromatosis, autoimmune liver disease and other rare, inherited enzyme deficiencies. Some other risk factors act independently, but most are co-factors with HBV or HCV infection.

Tobacco smoking

The International Agency for Research on Cancer (IARC) classified tobacco smoking as a cause of liver cancer ^[37]. Epidemiological studies show tobacco smoking is a risk factor for liver cancer, particularly in patients with liver cirrhosis who also consume alcohol. A meta-analysis showed that smoking increased risk of liver cancer regardless of HBV and HCV infection status^[38].

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

Alcohol

The 2015 Global Burden of Disease Study estimated that 39% of liver cancers in Australia in 2015 were attributable to alcohol consumption^[39]. World Health Organization estimated that 249,989 liver cancer deaths were secondary to alcohol use ^[6]. A review by the World Cancer Research Fund (WCRF) found convincing evidence that consuming three or more alcoholic drinks a day is associated with liver cancer ^[40]. Evidence shows a synergistic effect between heavy consumption of alcohol and HCV infection and, to a lesser extent, HBV infection ^[41]. The combined effects of hepatitis infection and chronic alcohol consumption increase the risk of cirrhosis ^[10]. 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 ^[42].

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 liver cancer risk in people with hepatitis and other causes of cirrhosis^[63][64][65], especially in combination with alcohol use, tobacco smoking and diabetes^[66].

Type 2 diabetes is associated with increased liver cancer incidence and 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].

Liver cancer has been linked to NAFLD, the hepatic manifestation of obesity and related metabolic disorders such as type 2 diabetes. Studies have found an association between NAFLD and liver cancer; patients who are obese and have type 2 diabetes are twice as likely to develop liver cancer compared to non-obese and patients without diabetes^[70][71]. There is also evidence that liver cancer may complicate non-cirrhotic NAFLD with mild or absent fibrosis^[72].

WCRF found convincing evidence that body fatness is associated with increased risk of liver cancer. (WCRF liver 2018) 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].

Liver cancer 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].

Sex

In Australia liver cancer is nearly three times more common in males than females^[43]. This has previously been explained, in part, by the fact that males have a greater incidence of viral hepatitis and alcoholic cirrhosis^[44]. 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^[45].

Age

The risk of liver cancer is 4-fold higher in people aged over 50 years compared with younger individuals^[46]. The extent to which the effect is due to chronological age or is related to longer duration of infection is unclear.

Co-infection

The risk of developing liver cancer is greater in people with HBV/HCV co-infection ^[47][34][48]. In patients with liver cirrhosis, HBV/HCV co-infection is one of the greatest predictors of the development of liver cancer ^[49][50].

Co-infection with HIV increases the risk of liver cancer in people with a chronic HBV or HCV infection^[20] and lowers the age of onset^[51]. Studies have shown that individuals with both HCV and HIV have faster progression to cirrhosis and decompensated liver disease^[10].

Aflatoxin exposure

Aflatoxin (e.g. on mouldy food) is an established risk factor for hepatocellular carcinoma, both independently ^[52] and as a co-factor with chronic HBV infection^[53]. Exposure to dietary aflatoxin (on mouldy food) contributes to high rates of hepatocellular carcinoma in Asia and Africa.

Family history

A family history of liver cancer has been associated with increased liver cancer risk among people infected with HBV (in cohort and case-control studies) and possibly among HCV-infected persons (in case control studies)^[10][54].