Metabolic dysfunction–associated fatty liver disease: an update

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Metabolic dysfunction is a common underlying mechanism of much of chronic disease in Australia. The focus has classically been on blood sugar and lipids. However, a recent update article in Australian Prescriber is encouraging healthcare practitioners to also consider the metabolic dysfunction associated with fatty liver. MAFLD [metabolic dysfunction–associated fatty liver disease], previously known just as fatty liver, but also MASH [metabolic dysfunction–associated steatohepatitis] and internationally called MASLD [metabolic dysfunction–associated steatotic liver disease], is incredibly common, affecting about a third of Australian adults. In 2025, the Gastroenterological Society of Australia published a consensus statement, highlighting the major role for primary care in prevention, early detection, as well as the management and monitoring of MAFLD.

I'm Dr Laura Beaton, a GP in Melbourne and your host for today. I'm joined by hepatology research fellow, Dr Richard O'Halloran, who works at the WA Liver Transplant Unit. Richard has joined me to talk through the article he wrote with colleagues on this very topic for Australian Prescriber. Thanks for coming on the show, Richard.

Thanks, Laura. Really happy to be here.

Can we go back to the basics and define what MAFLD is and also by contrast what it isn't?

Yeah, of course. So MAFLD is hepatic steatosis, so that's fat accumulation in liver cells or hepatocytes. And that's defined by whether you see that on imaging or if you get a liver biopsy. And as you pointed out, it's linked with that metabolic dysfunction, metabolic dysregulation that drives that. So we see it in people with metabolic risk factors.

Why did the nomenclature change so many times?

Yeah, exactly. It does cause some confusion. So it used to be called non-alcoholic fatty liver disease, so NAFLD. You'll see that terminology still used in a number of resources. The reason it changed is because that then really excluded anyone who consumed any kind of alcohol intake from being defined by this. But of course, as any health practitioner would know, just because someone drinks alcohol doesn't mean they can't also have metabolic risk factors for progressive liver disease. In fact, we see a number of people with multiple reasons for having liver disease. So it's important that those people with metabolic risk factors, so type 2 diabetes, obesity, and others that they're captured in data, but also that any management plan accounts for that as well.

And what about the international move to call it steatotic liver disease rather than fatty liver disease?

So that change has been proposed. As you've pointed out, MAFLD is more commonly accepted within Australia, but MASLD is also used internationally. The rationale there was that that further mitigates the stigma of the term fatty liver disease, but the rationale in Australia, I think for keeping the current terminology is ease of understanding, a lot of consumer groups have accepted that term as well, but they are used interchangeably.

It's hard for me to describe steatosis to a patient without using the word fatty. So I do wonder how much more acceptable it is to patients.

Exactly.

What do we know about how and why MAFLD occurs?

The exact mechanism is not well understood, but we know what's required. So you need metabolic dysfunction and insulin resistance as the upstream drivers, and then that fat accumulation in the cells. That mediates cytokines, inflammatory mediators, all the sort of bad things to then cause damage to the hepatocytes, the liver cells. It's quite a similar process to what we see in kidney disease and cardiac disease from similar pathways from oxidative stress and fibrotic pathways. And so that's the reason why we know that it's pathophysiologically related to a lot of other metabolic disorders, cardiovascular and CKD [chronic kidney disease] amongst them.

And this process of inflammation is slow, right, compared to other liver conditions, which might be really quite rapid?

Yeah. So I think for most people it is. To go from having no or minimal fibrosis to getting advanced fibrosis, which is associated with all the bad complications, the median time for that is 10 years. But a small group, so about up to 1 in 6, that process can happen in less than 5 years. So for the vast majority of people, they won't progress rapidly, but a small subgroup can. It's about 5% of people with MAFLD that progress to advanced fibrosis. So it's a small group, but given it's a condition that affects about a third of adult Australians, those numbers add up.

And I guess it's that small subgroup who we hope to pick up with our regular monitoring, which we'll come to a little bit later on. And you mentioned, of course, this is a condition of metabolic dysfunction. As a GP, I'm really interested in prevention and early detection. I wanted to ask you, do we think MAFLD is kind of a really sensitive early sign of metabolic dysfunction or does it kind of start at the same time as the insulin resistance and glucose impairment? Or is that actually happening first? Do we know?

I think it's a bidirectional association. So people with MAFLD are more likely, even if at baseline they don't have diabetes, they're more likely to go on and develop type 2 diabetes. But conversely, over 50% of adults with type 2 diabetes or obesity, or at least 2 metabolic risk factors will have MAFLD if you assess them. So it is that bidirectional relationship. In terms of what causes what, we obviously know a lot of this, it's that relationship and that interaction of risk factors that causes disease progression.

And speaking of assessment, this is an asymptomatic condition, certainly at the start. Who should we be assessing?

So it's exactly those people, so adults who have got type 2 diabetes, obesity, or at least 2 metabolic risk factors. So things like hypertension, high cholesterol, being overweight, insulin resistance, prediabetes. And in those people, the thinking is that we should be doing a liver ultrasound as a first-line test to look for evidence of fat accumulation or hepatic steatosis.

And before we move to the specific nuances of what liver ultrasounds we have access to or what we order, I'm actually interested in that scenario where we get incidentally detected deranged LFTs [liver function tests]. Do you suggest we start thinking about MAFLD for everybody or really only if there's metabolic risk factors present?

So I think that certainly is a really good prompt. And obviously in primary care, that's a very common situation to encounter. I think in those people, you do want to think about what metabolic risk factors they have, whether they're at risk of having MAFLD, but also you're thinking about alcohol history, what medications might predispose people to have abnormal liver function tests, and whether they've got risk factors for things like hepatitis B or hepatitis C and other conditions.

In the article, there's a very handy table thinking about for deranged LFTs and working up for MAFLD, what are the other things we should consider? Because not always do we have these things in the front of our mind as a generalist specialty, so it's really helpful to be able to have those tables to come back to.

Yeah. In terms of some common things to look at, if it's chronic, then things like autoimmune condition and iron studies and so on are also important. But I guess in the interest of keeping it simple, as you said, the table's quite a useful guide for what to think about and when based on if you get abnormal liver function tests.

And going back to some practicalities, if we are considering MAFLD and we do need to order a liver ultrasound to look at potential fibrosis, what kind of ultrasounds can we get in the community setting and which are the ones that are available only in the public hospitals?

Yeah. So just as a first-line test to look for presence of fat, that's just a plain liver ultrasound. It's a simple test, it's accessible, it's relatively inexpensive, and it's got good diagnostic performance. So 82% sensitivity and 80% specificity for picking up fat accumulation or hepatic steatosis compared to liver biopsy. So it's a very good test for picking that up.

Okay. Well, given that it sounds like MAFLD might be case finding, once we find someone who we think is affected, how do we then risk stratify them into who needs really close surveillance, who needs kind of more intermediate surveillance or further workup, and who needs to be sent to see someone like you pretty quickly?

So I think as we touched on briefly before, looking for some of those other causes for fatty liver, whether that's an alcohol history, some medications, steroids, methotrexate, for example, and also some other causes for liver function test derangement, but really the important thing once you know someone has steatosis is to think about whether they have liver fibrosis. So we're trying to find that small group that will go on to have advanced liver disease. The best way to do that, the test that we recommend is what's called the FIB-4 [fibrosis-4] index. So that's a composite measure of a few really common metrics that we're already going to have. So age, AST [aspartate aminotransferase], ALT [alanine aminotransferase], and platelets. So very easy to perform in a primary care setting. You can request a FIB-4 when you do a blood test, but there's also a lot of really easy to access online calculators where you can plug in those 4 details and get a really quick score.

Of course, every tester score has its limitations. When thinking about interpreting a FIB-4, are there some groups that we need to not use it in?

Yeah. So it's a little bit less accurate in younger people, so we don't recommend it in under 35s. In over 65s, there's a slightly higher cut-off score. And then because it uses platelets, sometimes if you've got another reason for low platelet count, that can affect the score as well.

And thank you again for including in your article a really handy flow chart as well. It makes common sense when you think using something, a FIB-4, stratified into low risk, advice and monitor. I would remind all of our GPs, our excellent reminder systems. And then of course, higher score, high risk, need specialist review. But in that intermediate group, what can we order to help further stratify that intermediate group?

So this is a little bit more challenging to provide direct guidance just because it really depends on your local area, different states and jurisdictions and whether you're local or country and some have different resources available. But we tend to recommend if you've got that intermediate score, so between 1.3 and 2.7. And again, the flow chart that you mentioned is really good, just reminding, because I certainly forget some of these cut-offs for all sorts of things as well, but that's when you can do a second-line test, so elastography. Ultrasound providers often will do elastography at the same time. There's also FibroScan, although that can be sometimes more challenging to access outside of a specialist setting. And then there's other direct serum blood tests. So for example, in Western Australia, we use something called a Hepascore, but there's a number of others that can be used as well.

Now let's move on to management. And I guess it will surprise nobody that given the underlying mechanism of this condition, most of the management has been focused on reducing the risk factors for metabolic dysfunction. I know at the time of writing your article, there were no drugs specifically approved in Australia for MAFLD, but I guess very timely for this podcast, in early April 2026, the TGA [Therapeutic Goods Administration] announced semaglutide was provisionally registered for MAFLD with fibrosis stage 2 to 3. But of course, that's high cost, not on the PBS [Pharmaceutical Benefits Scheme]. So let's actually talk through what we should be practically recommending that isn't going to cost people a huge amount of money.

So I think a lot of it is managing those health risk behaviours and comorbidities. One of the things that has the best evidence is weight loss. So all the things that go into achieving that, you touched on pharmacotherapy, but obviously a lot of it is about lifestyle, diet, physical activity and so on. And monitoring that as well is clearly really important. But in those that achieve at least 10% loss of body weight, there is good evidence that they have improved histological outcomes. That is, you can see evidence of improvement in liver biopsy samples when we've done that. And that includes achieving that through measures such as even bariatric surgery. Similarly, you're monitoring for those associated comorbidities. So in those with type 2 diabetes, managing that's important, but in those without, it's also important to continue to assess for that. There are other comorbidities associated with all metabolic diseases, chronic kidney disease, sleep apnea.

But I think what's quite important as well, and those that don't have advanced fibrosis, so they've got a normal FIB-4, it's good to just remember that that's something to keep an eye on every, say, 2 to 3 years as well. So repeating the FIB-4 and embedding that into routine practice is something that we think would be really helpful for people with MAFLD.

And primary care talking to people about health promotion and their health behaviours is pretty common work, but of course we know behaviour changes is one of the hardest things to do. So it's a little bit of encouragement to all of us to continue to work at this because we know it has a great efficacy where we can do it in a tailored way.

Absolutely.

Even though we're talking quite a lot about the liver today, it was actually quite interesting to read that modifying these common risk factors is extra critical because of the shared risk factors for cardiovascular disease, which is in fact the most common cause of death with MAFLD, not actually cirrhosis or HCC [hepatocellular carcinoma].

Yeah. I mean, certainly one of the most common things I can do in a specialty liver clinic in terms of managing someone's long-term health is doing a cardiovascular risk assessment, which clearly is bread and butter primary care work, but someone who needs a statin because they've got a raised cholesterol and a raised cardiovascular risk score, sometimes people get concerned about starting statins in liver disease, but if it's indicated and if they don't have decompensated cirrhosis, it's very safe to do so.

That's great to hear. I think sometimes practitioners or patients are often really cautious to use statins in MAFLD. When do we start considering things like HCC surveillance?

So in people with liver cirrhosis, the annual risk of developing a liver cancer is somewhere between 3 and 5%. So in people with cirrhosis, we recommend 6-monthly liver ultrasound, and we can supplement that with an alpha fetoprotein blood test as well, which increases sensitivity. In people that don't have cirrhosis, the risk is very low. It's less than 0.05% in a 12-month period, so surveillance in that group is not routinely recommended. And again, coming back to why it's so important to identify that group with cirrhosis, with advanced fibrosis, because surveilling with liver ultrasound for HCC is so important in that group.

Richard, as we come close to the end of our podcast today, I wonder if there are any things in the medication pipeline that you wanted to flag to our listeners, even though they may not be available now, some promising areas of therapeutics.

It's quite a dynamic landscape. So there's no drugs that are routinely used for MAFLD in Australia and any that are usually reserved for high-risk patients or in a clinical trial setting. But as you pointed out, semaglutide's just received TGA approval. It's already used off label in some settings in people that have another indication for its use. And then there's a few other medications that have got good evidence for improved liver outcome. There's one of efruxifermin, which is an FGF21 [fibroblast growth factor 21] analogue, and also resmetirom, which has got approval in a US setting on the FDA [Food and Drug Administration]. Again, these are for people that have got at least moderate liver fibrosis, so it's not routinely used for people just with no or minimal fibrosis, but more in people with more fibrosis.

That's interesting to have a bit of a think about, but of course, the vast majority of people with MAFLD are in that milder group and in the care of us in primary care.

Very much watch this space, Laura, with that.

Thanks, Richard, for the discussion today. It is a really timely reminder to consider the liver when we're thinking about metabolic dysfunction. And of course, again, a huge plug to all the healthcare practitioners who are working to move people to improve their health behaviours.

Thanks so much, Laura. It's been great to chat.

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