Further information

You can explore the latest advances in hepatocellular carcinoma through our curated list of recent publications.

What is MAFLD?

‘Metabolic associated fatty liver disease (MAFLD)’ is the name given to fatty liver disease that is caused by metabolic dysfunction.¹

The term was suggested in 2020 to replace the name ‘non-alcoholic fatty liver disease (NAFLD)’.¹ It’s generally felt that MAFLD better reflects the disease process.¹

Unlike NAFLD, MAFLD has specific diagnostic criteria.² MAFLD can also coexist with other liver diseases, including alcoholic liver disease and viral hepatitis.²

Who is at risk of MAFLD?

MALFD affects 25% of Australian adults and many children.² Anyone with metabolic abnormalities is at risk of developing MAFLD.

With the increasing rates of obesity seen in Australia, it’s unsurprising to discover that the results of a recent modelling study show that rates of MAFLD will increase substantially in the next 10 years.³

How is MAFLD diagnosed?

The change in name to MAFLD was also accompanied by a change in the diagnostic criteria.¹

The diagnosis of MAFLD is based on the presence of hepatic steatosis AND:

• type 2 diabetes mellitus; OR
• obesity; OR
• metabolic dysregulation.⁴

Metabolic dysregulation is defined as the presence of at least two of the following metabolic risk factors.

• Waist circumference ≥ 102/88 cm in Caucasian men/women or ≥ 90/80 cm in Asian men/women.
• Blood pressure ≥ 130/85 mmHg (or antihypertensive medication).
• Plasma triglycerides ≥ 150 mg/dl (or triglyceride-lowering medication).
• Plasma high-density lipoprotein (HDL) cholesterol < 40 mg/dl for men and < 50 mg/dl for women (or lipid-lowering medication).
• Pre-diabetes.
• Homeostasis model assessment of insulin resistance score >2.5.  Plasma high-sensitivity C-reactive protein (CRP) level > 2 mg/L.⁴

How is MAFLD managed?

The cornerstone of MAFLD management is lifestyle modification. This includes:

• dietary change;
• weight loss;
• structured exercise intervention;
• diabetes control;
• quitting smoking; and
• limiting or stopping alcohol intake.

Treatments to target risk factors such as hypertension and dyslipidaemia are also essential.²

Most patients with MAFLD are able to be successfully managed in primary care.² However, patients with stage 2–4 fibrosis should be referred to a specialist.²

At least one in 10 people with MAFLD will develop liver fibrosis over time if it’s not adequately treated.² This in turn can progress to cirrhosis and liver failure or liver cancer.²

How does MAFLD progress to liver cancer?

Once a diagnosis of MAFLD is made, the next step is to assess the stage of fibrosis. Fibrosis is the most important predictor of liver-related morbidity and mortality in patients. Those with cirrhosis have the highest risk.²

The good news is that fibrosis progression in MAFLD is slow. Most patients with MAFLD will die from cardiovascular disease or extrahepatic cancer. However, liver cancer can develop in patients with more advanced fibrosis.²

It’s predicted that in the next 10 years, MAFLD will become the leading cause of liver transplantation in Australia.³ This will occur even if rates of obesity in Australia stabilise.

Note: In this article, the term MAFLD is used even when the terms NASH or NAFLD have been used in the original publication.

How common is liver cancer in Australia?

In Australia, both the incidence and mortality rates of hepatocellular carcinoma (HCC) have been increasing over several decades, and the overall 5-year survival rate currently sits at about 23%.^1,2,3

The increasing rates of HCC in Australia are thought to reflect:^2,4

• revised diagnostic criteria;
• an increased at-risk population due to migration; and
• a rise in metabolic dysfunction-associated fatty liver disease due to rising obesity rates.

You can find out more about liver cancer epidemiology here.

Who’s at increased risk of liver cancer?

We know that patients at risk of hepatocellular carcinoma are those with:⁴

• liver cirrhosis;
• chronic hepatitis B or hepatitis C infection;
• alcohol-related liver disease (ARLD); and
• metabolic dysfunction-associated fatty liver disease (MAFLD).

People with cirrhosis make up 85% to 90% of those diagnosed with HCC.¹

HCC is also disproportionately high among Aboriginal and/or Torres Strait Islander people and migrants to Australia from countries where viral hepatitis is endemic.⁴

Why is liver cancer surveillance so important?

Low 5-year survival rates in people with liver cancer are related to many patients being diagnosed with late-stage disease.⁴ Surveillance of our at-risk patients aims to detect HCC early, when curative treatment is still possible.⁴

HCC surveillance programs aim to improve the rates of early detection and curative treatment of HCC, as well as overall survival in people with cirrhosis.⁴

Who should be tested and what tests are needed for people at risk of liver cancer?

Liver ultrasound is the current standard of care for HCC surveillance – in general, testing should be done every 6 months in people at high risk of liver cancer.⁴

A blood test looking for the tumour biomarker alpha-fetoprotein (AFP) can be used in addition to ultrasound to help improve detection rates.^2,4

HCC surveillance in people with cirrhosis

Surveillance should be offered to people with cirrhosis who are:

• willing to have an HCC diagnosis made and consider treatment if HCC is diagnosed;and
• suitable – well enough to receive HCC treatment and with a life expectancy greater than 6 months.⁴

HCC surveillance in people without cirrhosis

Surveillance is also recommended for some people with chronic hepatitis B (HBV) infection without cirrhosis. Factors such as age, ethnicity and family history also need to be considered in these patients.

According to Cancer Council Australia Guidelines, surveillance is generally recommended for the following people with chronic HPV infection without cirrhosis:^2,4

• Asian or Pacific background men aged 40 years or older
• Asian or Pacific background women aged 50 years or older
• Sub-Saharan African people aged 20 years or older
• Aboriginal and/or Torres Strait Islander people aged 50 years or older
• Aboriginal and/or Torres Strait Islander people with a family history of HCC
• Anyone aged 40 years or older with a family history of HCC

See the Cancer Council Guidelines for more detailed information on HCC surveillance.^1,4

Risk assessment for surveillance

Before surveillance is offered, it’s best to perform an individual risk assessment and discuss the risks and benefits with your patient. It’s important to ensure that they are willing to participate in ongoing surveillance.⁴

Patient factors that need to be considered include:⁴

• age;
• family history of HCC;
• individual risk factors;
• ethnocultural group/region of birth;
• comorbidities;
• functioning (ECOG performance status scale); and
• liver-related health status.

Future considerations for surveillance testing

Unfortunately, there are some barriers to surveillance uptake.² The effectiveness of HCC surveillance can also be impacted by the limitations of the current tests and under-recognition of patients at risk.²

In 2023, the Cancer Council and Daffodil Centre published a report called ‘ Roadmap to Liver Cancer Control in Australia’. This document outlines priority actions for targeted screening for advanced liver disease and HCC surveillance.⁵

One of the priority actions identified for primary care is improved systems for surveillance, including patient recall and abnormal-results notification systems.⁵

Future improvements in HCC surveillance may also be achieved with prediction models that identify patients at risk of HCC, and the use of serum biomarkers as an alternative to ultrasound-based HCC surveillance.²

What causes hepatocellular carcinoma?

Historically, the main cause of liver cirrhosis was hepatitis B and hepatitis C infections.²
However, the impact of these infections is declining due to both effective hepatitis B and C treatments and hepatitis B vaccination in newborns.²

Unfortunately, this decrease in viral risk factors for HCC is offset by an increase in metabolic risk factors.^2,3 These include obesity, type 2 diabetes, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD).^2,3 Alcohol abuse is another common risk factor for the development of HCC.^2,3

How common is hepatocellular carcinoma in Australia?

The incidence of hepatocellular carcinoma (HCC) in Australia has been on the rise over the past few decades.⁴

Between 1982 and 2014, rates of HCC increased from 1.38 cases per 100,000 to 4.96 cases per 100,000.⁵

Between 1982 and 2019, the incidence of liver cancer (and thyroid cancer) increased more than for any other cancers in Australia.⁴

Who is most affected by hepatocellular carcinoma?

HCC typically affects those people who are genetic susceptible and exposed to HCC risk factors, in the presence of liver cirrhosis.¹

Sex

While the increase in HCC rates has been seen in both men and women, men are more likely to develop HCC than women.

The risk of an Australian male developing HCC is 1 in 70 (1.4%) compared to that for an Australian female, whose risk is 1 in 195 (0.51%).⁶

Age

In Australia, your chance of developing HCC increases with age. It’s estimated that you have a 1 in 103 (or 0.97%) risk of being diagnosed with liver cancer by the age of 85 years.⁶

Location

Globally, the burden of liver cancer has shifted from the low sociodemographic regions to higher sociodemographic regions. This reflects the transition from viral to nonviral causes of HCC.

However, in Australia, people living in the lowest socio-economic areas are still 58% more likely to be diagnosed with liver cancer and 61% more likely to die from liver cancer than those living in the highest socio-economic areas.⁴

HCC in Aboriginal and/or Torres Strait Islander people

HCC in Australia affects both Indigenous and non-Indigenous people, however there are significant differences in the epidemiology and outcomes between both groups of people.

Indigenous Australians typically develop HCC at a younger age and are more likely to be female, live rurally, have a lower socioeconomic status and a higher comorbidity burden than non-Indigenous people with HCC.⁷ Indigenous Australians with HCC are also more likely to misuse alcohol and have hepatitis B and/or diabetes.⁷
The survival rate for Indigenous Australians with HCC is also poorer compared to that for non-Indigenous Australians. However, this association becomes weaker after adjusting for other factors.⁷

Deaths from hepatocellular carcinoma

HCC is a leading cause of cancer‐related death worldwide and the rates are also increasing in Australia.8 This is in part due to the increasing incidence of liver cancer.⁴

In 2023, the number of deaths from liver cancer, were estimated to be 2,545:

• 871 (34.2%) in females; and
• 1,674 (65.48%) in males.⁶

The latest figures show that HCC accounts for about 5% of all deaths from cancer.^6,8

In 2021, liver cancer was the seventh most common cause of cancer death in Australia.⁶ The highest death rates from HCC are seen in the Northern Territory, Victoria and New South Wales.⁹

What is the survival rate for people with hepatocellular carcinoma?

In Australia, the average life expectancy after diagnosis of HCC is now about one year.10 While this has improved from just over 2 months in 1982,¹⁰ HCC remains a low-survival cancer, with the 5-year survival rate reported to be around 23%.⁶

Notably, HCC is the only low-survival cancer that is rapidly increasing in incidence in Australia.⁸

This data highlights the need for increased surveillance for HCC, which will help increase rates of early diagnosis and in turn improve treatment outcomes. Surveillance [3] is essential as HCC generally remains asymptomatic until it is very advanced.

Further information

If you want to learn more about the epidemiology of HCC, we recommend the following resources:

Liver Cancer in Australia statistics [4]
Cancer Australia presents the most recent data from the Australian Institute of Health and Welfare.

Australian Cancer Atlas[5]

This interactive atlas allows you to visualise the burden of HCC across Australia. It is a collaboration between Cancer Council Queensland, Queensland University of Technology, and the Cooperative Research Centre for Spatial Information.

Notes

We note that much of the data reported here is for liver cancer (ICD10 C22) which includes both hepatocellular carcinoma and cholangiocarcinoma. However, hepatocellular carcinoma (HCC), is responsible for most liver cancer diagnoses and deaths.² As such, the terms liver cancer and HCC have been used interchangeably on this page.

Why don’t patients get tested?

Why might our patients miss out on HCC surveillance testing? Some of the reasons for missed tests and non-adherence with appointments are similar to any screening tests, such as other commitments (including family and work) and other health priorities. ⁴ Another patient factor at play is poor health literacy.⁴

But suboptimal surveillance uptake is not just down to our patients – it’s thought to be due to a combination of clinical and system-level barriers. ²

Clinician factors that can contribute to reduced patient participation in liver cancer surveillance programs include limited consultation time, competing clinical concerns and not being up-to-date with surveillance recommendations.²[5]

Other barriers^[6] to liver cancer surveillance testing

The uptake of HCC surveillance testing may also be affected by some bigger-picture issues, such as misinformation and language barriers.¹

People living in rural and remote areas of Australia may have limited access to quality ultrasound testing. This means they need to travel and pay for travel costs and accommodation, which can be a further barrier to testing.¹

It’s also known that race and socio-economic status can further affect our patients’ participation in surveillance programs.²

People living in rural and remote areas of Australia may have limited access to quality ultrasound testing. This means they need to travel and pay for travel costs and accommodation, which can be a further barrier to testing.¹

It’s also known that race and socio-economic status can further affect our patients’ participation in surveillance programs.²

Evidence review: Do at-risk patients take part in HCC surveillance programs?

A 2017 Australian retrospective study examined participation in, and adherence to, HCC surveillance. The study looked at patients with chronic hepatitis B who attended a community health centre that was supported by the Integrated Hepatitis B Service.⁴

The overall surveillance participation rate was 75%, and of the 67 patients who underwent HCC surveillance, adherence was considered:
● good in 18 patients (27%);
● suboptimal in 29 patients (43%); and
● poor in 20 patients (30%).

(Good adherence was defined as an average of ≥1 ultrasound every 7 months; suboptimal was an average of ≥1 but <2 scans every 14 months and poor was an average of <1 scan every 14 months.)

How can we improve liver cancer surveillance participation and adherence?

Factors associated with improved HCC surveillance include frequency of clinic visits and specialist service involvement, as well as higher socioeconomic status.⁴

A centralised HCC surveillance program, similar to that used in countries such as Japan and South Korea, may help deliver improved and more equitable care.² The Japanese surveillance program includes free hepatitis testing and surveillance, dedicated educators and public awareness campaigns.

Other strategies that should be considered are clinician education, patient recall systems, nurse-led clinics and outreach invitations.²

Optimising primary care patient recall and abnormal results notification systems are priority actions identified by the 2023 Roadmap to Liver Cancer Control Australia[7].⁵[8]. This can be done by working with your medical practice software provider to set reminders.

What measures are needed to help at-risk Indigenous Australians?

The higher incidence of HCC and poor survival rates among Aboriginal and/or Torres Strait Islander people with HCC may stem from:²
● reduced access to testing;
● socio-environmental inequalities;
● cultural barriers; and
● distrust in the health care system.

While the use of mobile liver clinics in remote Indigenous communities has led to improved rates of HCC surveillance,⁶ further improving outcomes for Indigenous Australians with HCC poses an enormous challenge.⁶

The link between social determinants of health and the high rates of HCC and mortality suggests that to be successful, interventions will need to also involve public health measures that both reduce social disadvantage and improve access to care.⁶

Where can I find educational materials on liver disease?

The Liver Foundation[9] has information for both patients and health professionals[10], including:
● GP information[11];
● nurse information[12]; and
● patient information[13].

ThinkGP[AD14] also has information for GPs on liver disease[AD15], which qualifies as CPD hours for educational activities.

What are some of the barriers to ultrasound surveillance?

For patients, some of the problems with ultrasound-based liver cancer surveillance include access to a clinic with an ultrasound machine, travel times and costs, as well as the inconvenience of attending appointments (1, 2). For clinicians, there may be differences in how the ultrasound is reported between sonographers (inter-observer variability) (1, 2).

What are the advantages of specific blood-based biomarkers over ultrasound alone?

Blood-based biomarker surveillance only requires a simple blood test. The risk of liver cancer is assessed using clinical scores, removing the need for ultrasound altogether (1, 2). Biomarker based surveillance may make it easier for patients to participate in liver cancer surveillance (1).

So, what blood-based biomarkers are currently used for liver cancer surveillance?

AFP is a blood-based biomarker currently used in hepatocellular carcinoma (HCC) surveillance in Australia (1). AFP tests are subsidised through the Medicare Benefits Schedule (MBS) for detecting and monitoring hepatic tumours (3). However, AFP use has been limited by its low sensitivity and suboptimal specificity (3).

While AFP is not used as a stand-alone surveillance test, it can help improve the detection of early-stage HCC when used together with ultrasound (1, 2).

What emerging biomarkers may be used for surveillance in the future?

There are two biomarkers showing promise for HCC surveillance, both of which are highly specific for the diagnosis of HCC (1):

• lens culinaris agglutinin-reactive fraction of AFP (alpha-fetoprotein L3 or AFP-L3); and
• des-gamma-carboxy prothrombin (DCP) (1).

Levels of these biomarkers are assessed using a simple blood test. The results of this blood test are used along with patient information to assess the risk of HCC. Two methods have been developed to calculate a clinical score, these are called GALAD and GAAD (1).

Both of these scores are still undergoing evaluation to check they have sufficient sensitivity and specificity (2). They are yet to be incorporated into clinical guidelines, or be subsidised by the MBS (3). If validated, the future use of non-invasive biomarkers for liver cancer surveillance holds promise, as it may allow for point-of-care testing with objective results (2).

GALAD

A serum biomarker-based model called GALAD can be used to predict the probability of HCC
in people with chronic liver disease (cirrhosis or chronic hepatitis B) (3).

GAAD

Another clinical score using biomarkers is the GAAD score.

Further information

For a more in-depth discussion of blood-based biomarkers in HCC surveillance, see the Research Review Educational Series: Hepatocellular carcinoma surveillance and the emerging role of biomarker-based models (2023).