Simple, non-invasive tests now allow GPs to identify those at risk earlier and intensify prevention…

Roughly one in three adults are estimated to have hepatic steatosis, most often driven by metabolic dysfunction rather than alcohol.

For many, the liver will never progress to decompensation, but a substantial proportion will develop advanced fibrosis, and an even larger group will experience premature cardiovascular disease and non-liver cancers.

In this context, fatty liver is less about mildly abnormal liver function tests (LFT) and more about early cardiometabolic risk detection and fibrosis risk stratification.

Simple, non-invasive tools now allow GPs to identify the small subgroup at risk of advanced liver disease while using fatty liver as an early warning sign to intensify cardiovascular prevention.

At the same time, terminology has shifted, non-invasive testing has become more accessible, and pharmacotherapy for metabolic disease is evolving rapidly.

What has changed?

Of the 5–6 million people in Australia with hepatic steatosis, around 1.5 million develop significant hepatic inflammation, more than a million may already have advanced fibrosis, and around 150,000 are living with, often undiagnosed, cirrhosis.

This has worsened in the last 20-30 years as caloric intake and sedentary lifestyles have increased.

These lifestyle changes have led to expanding white adipose tissue and insulin resistance. Insulin resistance increases the flux of fatty acids from adipose tissue into the circulation and promotes de novo lipogenesis in the liver. A significant proportion of the fat in a fatty liver is therefore synthesised within the liver itself.

Fibrosis as the key prognostic driver

Histologically, steatosis is graded from 0 to 3 based on the proportion of hepatocytes containing fat, but from a clinical standpoint, fibrosis rather than fat content is the key determinant of prognosis.

Long-term follow-up of biopsy-proven fatty liver cohorts consistently shows that patients with no or minimal fibrosis have survival similar to individuals without fatty liver. However, once fibrosis progresses to stage F2, F3 and finally F4 (cirrhosis), overall survival drops sharply.

The accumulation of fibrosis drives liver outcomes such as decompensation, hepatocellular carcinoma and liver-related death. This is why guidance recommends that all people with metabolic dysfunction-associated fatty liver disease undergo non-invasive assessment of fibrosis.

Cardiovascular disease and non-liver cancer

Although fibrosis progression and cirrhosis are important, most people with fatty liver will ultimately die from cardiovascular disease or non-liver cancers rather than liver-related causes. Large cohort studies show that individuals with fatty liver have a substantially higher risk of cardiovascular events and non-liver malignancy, and that these outcomes occur at younger ages than in the general population.

In one study of more than 13,000 people with fatty liver and a median age of 56, almost 30% had died by 15 years’ follow-up. The leading causes of death were cardiovascular disease and non-liver cancers. These are common in the general population, but they occur more frequently and earlier in people with fatty liver.

Subclinical coronary artery disease is very common in this group.

When patients with fatty liver are carefully assessed, up to 40% have evidence of coronary atherosclerosis before symptoms develop.

Increased adiposity, physical inactivity, unhealthy diet, smoking, hypertension, dyslipidaemia and hyperglycaemia are modifiable risk factors that drive both fatty liver and atherosclerotic disease.

Steatosis often appears 10–20 years before the first cardiac event, providing a long window for early intervention. Incidental fatty liver should therefore be considered a cardiovascular risk signal and an opportunity to reassess global cardiometabolic risk and escalate prevention.

Rethinking “normal” liver function tests

Laboratory reference ranges for ALT often list an upper limit of around 45–50 IU/L. However, when ALT values are examined against long-term mortality across very large populations, people with ALT at the upper end of this range have a markedly higher mortality than those with ALT around 15–20 IU/L.

This is likely because around one-third of adults have fatty liver, population-based reference ranges inevitably include many individuals with undiagnosed metabolic liver disease. A “normal” ALT does not reliably exclude pathology. Conversely, a high-normal ALT should not be interpreted as reassuring in a patient with clear metabolic risk factors.

Evolving terminology

Terminology has evolved as our understanding of fatty liver has improved.

Historically, NAFLD (non-alcoholic fatty liver disease) was defined by the presence of steatosis on imaging or histology and the absence of other causes such as significant alcohol consumption, chronic hepatitis C or certain drugs. This is a diagnosis of exclusion and does not reflect the underlying mechanism, which is metabolic dysfunction for most patients.

The term MAFLD (metabolic dysfunction-associated fatty liver disease) reframes this as a positive diagnosis. A person is considered to have MAFLD if they have hepatic steatosis plus either overweight or obesity, type 2 diabetes, or at least two features of metabolic syndrome. Alcohol use or viral hepatitis can coexist; they no longer exclude the diagnosis and may in fact accelerate fibrosis when present together.

More recently, the term MASLD (metabolic dysfunction-associated steatotic liver disease) has been introduced internationally, largely to replace the word “fatty” with “steatotic” and to further refine cardiometabolic risk criteria. The key message is that steatosis in the setting of metabolic dysfunction identifies a group at higher risk of both liver-related and extrahepatic complications.

Practice tip: The exact label matters less than the principle that steatosis plus metabolic dysfunction marks a higher-risk patient.

Who should be screened?

Screening the general population for fatty liver or fibrosis is impractical. In an unselected community, the prevalence of advanced fibrosis is likely around 1%. However, the prevalence increases substantially in people with metabolic risk factors.

Individuals at higher risk of advanced fibrosis include those with type 2 diabetes, overweight or obesity, metabolic syndrome, known fatty liver disease or other chronic liver conditions such as alcohol excess or viral hepatitis. In these groups, advanced fibrosis may be present in 5–7% of patients, and this risk can be further enriched by using a simple score such as FIB-4.

Confirming steatosis with ultrasound

For high-risk patients, ultrasound is recommended as the initial investigation to detect hepatic steatosis. In fatty liver, the liver appears more echogenic or “bright” compared with the adjacent kidney. In a normal liver, the echogenicity of liver and kidney is similar.

If a high-risk patient has steatosis on ultrasound and clear metabolic risk factors, they can reasonably be regarded as having MAFLD (or MASLD) and should proceed to assessment of both cardiovascular risk and fibrosis.

Assessing cardiovascular and metabolic risk

Once MAFLD is identified, cardiometabolic risk assessment should be systematic. This includes weight and adiposity pattern, glycaemic control, blood pressure, lipids, smoking status and common comorbidities such as obstructive sleep apnoea and osteoarthritis, which can limit activity and weight loss efforts. Standard absolute cardiovascular risk calculators remain useful to guide intensity of management.

Statins are safe in patients with fatty liver, including those with mildly abnormal LFTs and even in cirrhosis. Beyond cardiovascular protection, they may also have favourable hepatic effects, including potential anti-fibrotic actions, reduced risk of hepatocellular carcinoma and lower portal pressure.

Assessing fibrosis in primary care using FIB-4

The FIB-4 score is a simple, non-invasive calculation based on age, AST, ALT and platelet count. In primary care, it functions primarily as a rule-out tool for advanced fibrosis, allowing most patients to be safely managed in general practice while identifying a smaller group who need further testing or referral.

A FIB-4 <1.3 is reassuring. In longitudinal cohorts, patients who remain below this threshold have an extremely low risk of severe liver-related events (<1%). These patients can usually be managed in primary care with repeat FIB-4 every 2–3 years, alongside routine cardiometabolic risk management.

A FIB-4 ≥1.3 signals a higher probability that significant fibrosis may already be present. In primary care cohorts, higher FIB-4 scores also predict major cardiovascular events, sometimes more strongly than traditional risk factors, reinforcing the need to treat this as a systemic risk marker rather than a liver-only issue.

Practice tip: Even a single high-risk FIB-4 result is associated with a markedly increased risk of severe liver outcomes over time.

For patients with an indeterminate or high FIB-4 (≥1.3), the next step is a second-tier non-invasive test. Transient elastography (FibroScan) is the preferred option where available. It provides a quick, painless bedside measure of liver stiffness that correlates with fibrosis stage and helps distinguish those with advanced disease. Where FibroScan access is limited, serum fibrosis panels such as ELF can be used, but these are proprietary tests that typically cost in the order of a few hundred dollars and may not be reimbursed, so cost and access can be significant barriers. An alternative is to refer patients with clearly elevated or indeterminate FIB-4 to a hepatology or liver clinic, where elastography and other investigations are routinely available.

Stepwise approach for clinical practice:

• identify high-risk adults (type 2 diabetes, obesity, metabolic syndrome, known steatosis or other chronic liver disease)
• confirm steatosis with ultrasound
• calculate and document FIB-4
• manage those with FIB-4 <1.3 in primary care with repeat testing every two to three years, and
• arrange FibroScan, other non-invasive fibrosis testing or specialist review for those with FIB-4 ≥1.3.

Practice tip: Build FIB-4 into the routine work-up of adults with MAFLD or metabolic risk factors, using an online or smartphone calculator during the consultation to quickly decide who can safely stay in primary care and who needs FibroScan or specialist input.

Management: weight loss and evolving metabolic therapies

Weight reduction and optimising metabolic health is the cornerstone of MAFLD management. Even relatively modest weight loss has significant hepatic benefits.

A reduction of more than 5% of body weight is usually sufficient to meaningfully reduce liver fat, while weight loss of 7–10% or more is associated with regression of fibrosis in many patients.

Alongside lifestyle advice, there has been a rapid evolution in metabolic pharmacotherapy. Incretin-based therapies such as semaglutide and tirzepatide have been shown in phase 2/3 trials to induce resolution of MASH without worsening of fibrosis in approximately 50–63% of treated patients, with ≥1-stage fibrosis improvement achieved in around 37–55% of patients.

Newer agents are being explored in clinical trials, with FGF21 analogues such as efruxifermin demonstrating even more striking effects in advanced disease. For example, reversal of cirrhosis occurred in about 39% of 46 people with established cirrhosis who took the 50mg dose of efuxifermin and 29% of the 41 patients on the 28mg dose— –compared with 15% of 47 placebo-treated patients in a phase 2b RCT published in the New England Journal of Medicine last year.

Key takeaways

• In adults with type 2 diabetes, obesity or metabolic syndrome, screen for fatty liver and fibrosis using ultrasound (steatosis) and FIB-4 (fibrosis risk).
• Focus on fibrosis stage rather than fat load, as it predicts liver outcomes and need for further tests or referral.
• Treat fatty liver as a cardiovascular and cancer risk marker and intensify overall cardiometabolic risk management.
• Use FIB-4 (<1.3 vs ≥1.3) to decide who can stay in primary care and who needs FibroScan, further non-invasive tests or specialist review.
• Target ≥5% weight loss to reduce steatosis and 7–10%+ to improve fibrosis, and use statins and metabolic therapies as appropriate.