Transcript
MIC CAVAZZINI: Welcome to Pomegranate Health from the Royal Australasian College of Physicians. I’m Mic Cavazzini and today I’m going to give you a taste of RACP LIFT 2026. This is a series of in-person events intended to promote Learning, Innovation and Forward Thinking.
The stream called Rapid Fire Clinical Updates does exactly what it says on the tin, bringing together the crème de la crème of clinical leadership and research that the College has to offer. The events don’t just include fascinating seminars but also provide an opportunity for reflective activities with peers that can go towards Category 2 CPD.
Coming up on the 1st of August in Melbourne there will be one based around Respiratory medicine, infectious diseases and critical illness. And on the 20th In Brisbane another one themed around palliative medicine and also population health.
Today’s podcast was recorded at a Rapid Fire event on cardiometabolic and vascular health held in Sydney on 31st March. There were loads of great talks but the one I’m sharing with you didn’t rely too heavily on a data slide show.
It covers everything a generalist needs to know about recognising metabolic dysfunction-associated fatty liver disease. As MAFLD is becoming increasingly common, all physicians need to be aware of it not just hepatologists.
The seminar was presented by Professor Jacob George, Director of the Storr Liver Centre at the Westmead Institute for Medical Research. He has made an immense contribution to the understanding and management of liver disease in over 1300+ academic publications that have been cited more than 90,000 times.
Professor George explains why fatty liver disease is a "canary in the coal mine" for metabolic health more generally, diagnosis using scans and bloods, and use of the FIB-4 index. Also how patients can be stratified and managed for risk of more complex liver disease. Lifestyle interventions are, of course, critical, but there are a few promising pharmacological interventions on hand too.
JACOB GEORGE: So, thanks very much, for inviting me today. I'm going to really talk about MAFLD for the general physician or the cardiologist or the nephrologist. Why should we talk about it? Firstly, I think in the liver literature, we're really saying it shouldn't be CKM, it should be CKLM. And we just submitted a paper to Nature Endocrine Reviews suggesting that it should be CKLM syndromes. The second reason, I guess, is today we've got approval by the TGA for Wegovy or semaglutide 2.4 milligrams for MASH, or the inflammatory form of the disease.
And the last reason is that having an end stage liver disease is probably the most miserable way to die. And most of you cardiologists and renal physicians are making people live longer. So, in the old days, we didn't get much liver disease from fatty liver, because you've got a kilo and a half of organ to play around with. Now that you're fixing their hearts and their kidneys with renal replacement therapy, all these patients are now coming and the peak of MAFLD related liver disease is probably going to be in the next 15 years. And So, you need to know something about this.
MAFLD is a positive definition
Okay, what is MAFLD? So, many of you would have heard non-alcoholic fatty liver disease or NAFLD. The new name for it in Australia that we use is MAFLD or metabolic dysfunction associated fatty liver disease.
The big aspect about this is it's very easy to diagnose. If you've got liver steatosis by whatever technology you want to use, CT scan, ultrasound, blood markers, whatever, and you're overweight or obese, then you've got MAFLD. If you've got diabetes and liver fat, you've got MAFLD. If you've got lean disease, So, you've got a normal BMI by ethnic specific criteria and you've got steatosis, you've got MAFLD.
And so, it's a very simple definition. And the most important aspect is a positive definition. Whereas “non-alcoholic fatty liver disease” said you have to exclude everything else. If you can't think of what it is, it's non-alcoholic fatty liver disease.
What this means is that you could have hep C and MAFLD, can have hep B and MAFLD, can have alcohol-related disease and MAFLD. And that's really the unique strength of a very simple diagnostic term. And so, you don't have to go and do a million other tests, which may be in primary care, you may have to do it. But in specialist care, you could say this patient's got MAFLD, I need to do something about it.
How common are MAFLD and MASH
Okay, So, how common is MAFLD? MAFLD is the fatty liver aspect of it. So, you don't need a biopsy to diagnose it. And the current estimates are 30 % of adults have it. By 2014, the US it's going to be one in two. So, basically, it's very, very prevalent. MASH is metabolic-associated steatohepatitis. In other words, the inflammatory form exactly similar to atherosclerosis, for example, in your blood vessels. And the MASH prevalence is one in 20 of the general population. But if you look at the population with fatty liver disease, then it's about one in five of those people.
The second point to remember is that when you look at patients with MAFLD, we always tend to think of MAFLD in patients who are overweight or obese. But this is looking at data from a paper we published a few years ago. But it doesn't matter from which country you look at one in five patients with MAFLD are actually lean by ethnic-specific [Braemar?] criteria. So, just because someone's looks lean—and this is particularly a case in Asians who don't look like with a BMI of 35 or 40, but they've got truncal obesity and they often have fatty liver disease. And in fact, they tend to have a worse liver prognosis than people with overweight or obese disease.
How do you define metabolic health?
So, I guess this brings us to the question of why we're talking about liver disease. And in many ways, when you look at metabolic disease and metabolic health, the liver is the canary in the coal mine. And so, this is a great article by Sam Klein, and he suggested a definition of what does it mean to be metabolically healthy. And most clinical physicians really look at these basic criteria. I don't have type 2 diabetes. I don't have pre-diabetes.I don't have fatty liver disease or CKD, so, I must be healthy.
But what Sam then goes on to talk about as well, you actually need to be metabolically healthy, you need to have a good cardiometabolic profile, which has a low TGs of less than 1.07, low HDL cholesterols, a good fasting glucose of less than 5.5.
But he says that truly to be metabolically healthy, you really should have no liver fat, either by doing an MRI on the liver or you could do a clamp test, which obviously we don't do. And so, I think if all of you look around yourself and find out how many of you are truly metabolically healthy, the answer would be not many.
OK, So, this is the metabolic dysfunction associated journey that I talk to patients. The first thing that happens is we have adiposity. The next thing that happens is you get liver fat deposition. Then you get intramyocellular lipid. Then you begin to get beta cell dysfunction. And then the patients present with atherogenic dyslipidemia, hypertension, type 2 diabetes, and then end stage liver disease, with— I mean, end stage disease with cardiovascular disease or chronic kidney disease, and that's really the trajectory.
And when I talk to patients, I actually say, you've got past that, you've got past that, you've now got hypertension, you've got now hyperlipidemia, are you waiting for your infarct or your extra hepatic cancer? And when you actually look at liver-related outcomes, why hasn't it got more air time? And this is really the course from fatty liver to HCC, cirrhosis and HCC. So, you can see that the most liver related deaths occur when you've got cirrhosis. So, the DLCD is decompensated chronic liver disease or HCC.
And there are a few HCCs or liver cancers that you can get in the pre-cirrhotic population. But the incidence of liver cancer in pre-cirrhotic is very low so, we don't recommend screening. But as you get fatty liver disease, because it's the canary in the coal mine, what you're seeing is what most patients are going to die from with liver disease is a cardiometabolic death or an extra-hepatic cancer death. So, when you understand that, it's very, very important to really focus on cardiometabolic outcomes and make sure the patient gets their screening for the extra-hepatic cancers.
Mortality and cardiovascular outcomes in patients with T2D
Okay, and this is really a nice study that I give in all my liver talks. This is a study published from Scandinavia in data just as only the Scandinavians could do. They looked at 270,000 Swedish people with type 2 diabetes and essentially they looked at whether these five cardiovascular risk factors at baseline was above or below, and then what they did was they looked at overall risk.
And if you can see in the control population, everything is one. But if you had no cardiovascular risk factors, your HbA1c was less than seven, low LDL, non-smoker, no albuminuria, blood pressure below that number, you have no increased risk of excess mortality. Essentially saying that the most important thing from a liver perspective is really treating to target. Because that's what's actually going to kill the patients except in the future, I guess, with all your treatment for kidney and cardiac disease, we will be getting patients with chronic liver disease.
MAFLD in primary care guideline
So, this is the MAFLD management guidelines that we put forward last year and it's published in the MJA and it's on our website. If you can see that half of all of that work is assessing and managing cardio metabolic risk as per the diabetes, obesity, cardiovascular risk factor calculations. Okay, that should be done on every patient.
And then we think that you should be looking for liver disease because you want to try and capture the patients that might benefit from treatment, particularly now that we've got drugs that may be impacting on the disease. And so, what we suggest is that you can do a FIB-4 index. And it's a very simple test with age, AST, ALT and platelets. And so, as you would expect, as you get older, you get more duration of liver disease. Your platelets drop when you've got more severe liver disease. And at least in DHM, Douglas Hanley-Moir, you can just write FIB-4 on your pathology request form. They'll do it for you. You don't have to use an online calculator. And we're trying, we're very close to getting the RACP to send a letter to all private and public specialties and pathology labs to say, please include a FIB-4 calculator. And then we have a very simple algorithm. If your FIB-4 is less than 1.3, manage them in primary care. If it's more than 2.7, send them to a specialist. If it's in between one of them, between 1.3 and 2.7, then you can try and refer the patient for a fibroscan or a second line test.
And so, the reason why we use that, because the FIB-4 score doesn't cost anything. The laboratory can easily do it for you. If the FIB-4 is less than 1.3, it excludes advanced fibrosis. Patients can be managed in primary care. If it's more than 2.7, you've got a specificity of 91%, but not a great positive predictive value, but those are the patients that need to be referred to a hepatologist.
And this is some longitudinal data done in the US. If you have a persistently low FIB-4, your risk of a liver death is very low. If you've got a number greater than 2.7, your hazards ratio has increased 20-fold, and the risk of a liver death is about 10% over that period of about 20 years.
Current and future therapies for MAFLD / MASH
So, there are some drugs that are being tried. So, it's been a very hot area for clinical trials. All the GLP-1 based drugs, resmetirom and FGF-21 analogs are in clinical trials. Semaglutide was approved by the TGA today. Resmetirom is a thyroid hormone selective liver directed therapy. It's approved in the U.S. Costs $50,000 a year and it's very unlikely to get approved.
In Australia, though the CEO of the resmetirom company actually is an Australian, and So, he does want to get it approved, but I don't fancy the federal government approving it. So, this is the data from the ESSENCE trial. If you thought renal was hard to get patients into, this is only 800 patients. And with our 800 patients, and the reason we can't get people in is you need a biopsy.
MIC CAVAZZINI: I’m just going to step in here to give you some details you’re missing without the slide show. ESSENCE was a trial described in the New England Journal in 2025 with the title “Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.”
The headline finding was resolution of steatohepatitis with no worsening of liver fibrosis. This occurred 63% of patients taking semaglutide, compared to 34% of patients in the placebo arm. When looking at improvement of liver fibrosis, the difference was 37% to 22%.
Another trial published a year prior, also in the NEJM, showed very similar results for resmetirom. This is a first-in-class drug that is an analog of the thyroid hormone, triiodothyronine, stimulating its receptor and increasing lipid metabolism and β-oxidation. This reduces not just hepatic fat but also inflammation and fibrosis.
In the findings from this Phase 3 trial, NASH was resolved in three times as many patients receiving the drug as compared to placebo. For the endpoint of improvement in fibrosis by more than one stage, there were twice as many responders in the resmetirom group and reductions in LDL cholesterol of 16%
Professor George also quickly showed some similar findings from Phase 2 trials of a third experimental drug called efruxifermin. It’s one of several analogues of the human fibroblast growth factor, FGF21. These appear to inhibit activation of the hepatic stellate cells that cause fibrosis and may indirectly reduce liver fat and lipotoxicity.
JACOB GEORGE: So, MASH resolution compared to placebo, you can see is very effective and fibrosis improvement also, there's a delta of about 20%. The phase three trials have actually started. And they're also now doing trials in cirrhosis.
Management algorithm for MAFLD
So, how do we think patients should be managed? And I think it behoves all physicians really to think about doing this. Get your laboratory to do a FIB-4 test. If you're interested enough to do an albumin creatinine ratio, do a FIB-4. If it's less than 1.3, that can be managed in primary care. More than 2.7, you have to refer. In between 1.3 and 2.7, which is about 20 % of a community cohort, then you need to think about a second line test.
So, what is the MAFLD treatment in 2026? It is the canary in the coal mine for metabolic health. GLP-1 based therapies have profound systemic effects on metabolic dysfunction as we've heard throughout today. And MAFLD is a small part of it. And as you know, incretins have now been recommended by WHO, but costs and supply chain issues are a problem. I note that the patent in India for GLP-1 agonist finished about two weeks ago, and the day after there were 40 generics. So, that's actually available. So, it is semaglutide is approved in Australia and we've got more Phase 3 trials on the way. So, I think in the next five years, we'll have two or three medications for this indication.
MIC CAVAZZINI: One feature of the Rapid-Fire Clinical Update events is the case vignettes put to the audience with opportunity for discussion. I’ll just read out with in all its detail the mock case described by Professor George.
Jessica is a 46-year-old female with Type II Diabetes Mellitus and Hypertension which were both diagnosed five years ago. She takes metformin 1g daily and Telmisartan 40mg daily. She consumes no alcohol. Her BMI is 31 kg/m2 and blood pressure on examination today is 145/85 mm/Hg. Her most recent HbA1c was 7.4%.
Bloods tests show a mild elevation of GGT and ALP at 125 and 30U/L respectively. ALT is 55 U/L, AST 40 U/L. She has a platelet count of 175 x109/L, bilirubin is 10 umol/L and her coagulation profile is normal.
Referral for elastography with FibroScan is available which reveals a Median Liver Stiffness of 6.1 kPa (normal <7.0 kPa) with a CAP of 310 (normal <260). CAP is the ‘controlled attenuation parameter’ which comes out of measurements for steatosis by sheer wave elastography.
What would be the next best step in management?
(a) Referral to a clinician with expertise in liver disease
(b) Optimise blood pressure to less than 140/90 and target a HbA1c of less than 7%. Discuss strategies for weight loss and assess for other metabolic risk factors and address these if found (e.g. dyslipidaemia, waist circumference)
(c) Repeat non-invasive testing for fibrosis in 12 months
(d) Reassure her that her blood pressure and HbA1c are within an acceptable range
Those options again:
(a) Referral to hepatologist
(b) Optimise blood pressure and diabetic control
(c) Repeat non-invasive testing for fibrosis in 12 months
(d) Rest easy that bp and glycated haemogolobulin is within an acceptable range
Test your knowledge
JACOB GEORGE: So, HbA1c is 7.4. LFT is mildly abnormal. Platelets, bilirubin, coags normal. Fibroscan is 6.1. What would you do?
The correct answer is B. You know, most of these patients, it's about optimizing metabolic health. It's that small proportion that's got a fibrous scan that's high or a fib four that's high that you need to refer to a liver specialist. And I think all the speakers have emphasized the importance of really treating to target. There's even been studies from China that says, if your blood pressure is 120 on 80 versus 130 on 80, and you lower the blood pressure to 120 on 80, you do better. And similarly, all the PCSK9 kids, they have half the risk of cardiovascular disease. So, very profound impact of cardiometabolic risk reduction for survival. Thank you.
MIC CAVAZZINI: Many thanks to Professor Jacob George for giving his time and immense expertise. At the website racp.edu.au/podcast I’ve included a transcript with relevant citations to help you dig deeper. And at the Medflix video library within elearning you can watch the full video and slides, along with all the other great talks from RACP LIFT.
Professor David Sullivan and Dr Jay Ramanathan also need to be thanked for curating the program for this Rapid Fire Clinical Update on cardiometabolic and vascular health. And a huge shoutout to the RACP Events Team who worked so, hard to pull it all together.
You can see what other clinical themes are coming up from the website racp.edu.au/racp-lift-2026/ and also learn more about the Career Triage conference and an in-depth Conversations formats scheduled towards the end of the year. Remember that while podcasts and lectures get you hours towards CPD Category 1, it’s only by interacting with peers that you can reflect and get feedback for Category 2 credit.
If you’ve got ideas for future podcasts please get in touch with me via the email address podcast@racp.edu.au. And make sure to subscribe So, you don’t miss an episode of Pomegranate Health. A smartphone app like Apple Podcasts, Spotify or Castbox is easiest, but you can also sign up to an email list from our website. And do leave a review or share the podcast with a friend to help us spread the word about RACP learning resources.
This podcast was produced on the lands of the Gadigal clan of the Yura nation. The Royal Australasian College of Physicians. is committed to equitable healthcare for all First Nations People. I’m Mic Cavazzini. Thanks, for listening.