Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD)

Hello and welcome to another episode of The Good GP. I am one of your hosts, Christina DeLange, and I would like to begin today's episode by acknowledging the traditional owners of the lands upon which this podcast is recorded. Today's episode is being recorded on the lands of the Turbul and Yagura people, and my guest is joining me from the lands of the Gimoy, Wallabara, Yidinji people. We pay our respects to elders, past, present and emerging.

On today's episode, we will be discussing metabolic dysfunction associated steatotic liver disease, which is a little bit of a mouthful as a lot of our GP listeners may be familiar with its previous term fatty liver disease and I may refer to this as MASLD just as its acronym. It rolls off the tongue a little bit easier. Joining me today to discuss this topic, I have staff specialist hepatologist from Cannes Base Hospital.

Doctor Jonathan Mitchell. John, it's great to have you on the podcast today. Great. See you. John, I've been hustling you for a little bit about this topic. I'm really excited to bring this topic to GPs. I think it's something that I certainly see quite a bit in practice. And I think a lot of the diagnostics and management, especially in uncomplicated disease, can sit in the primary care space. So I think it's really great to be able to have this update for our GP listeners.

I did want to start just setting the scene, I guess, a little bit about what exactly is metabolic dysfunction associated steatotic liver disease. So I guess you did mention the fact that this term has changed over the years. We used to call this non alcoholic fatty liver disease and then it became clear that a significant proportion of people with this condition did consume alcohol at albeit at low levels.

Then metabolic dysfunction associated fatty liver disease, but fatty was deemed to be a barrier to patient engagement and also to research. And now we're at the current iteration. One of the questions that quite often gets asked of me when I do lectures on Massald is is this a liver disease or is this a disease that's best managed by primary care practitioners and GPs?

or metabolic or general physicians. And I think I can firmly say that it's best managed by people that can see the patient holistically and it is not primarily a liver disease. So hepatologists really are dealing with this condition when it leads to liver harm and the complications of advanced liver disease, fibrosis and cirrhosis.

So it is a liver manifestation of a metabolic situation, but most patients with metabolic associated steatotic liver disease will never come to liver harm. But the presence of the disease is a single risk factor for them having harm from other metabolic complications, be they atheromatous complications, hypertension, diabetes, And there isn't really a disease group that is not increased in people who have features of muscles.

So I would emphasize that it's a liver, if you like, indicator on the dashboard of disquiet elsewhere and a sort of pro inflammatory and metabolic dysfunction which has multiple manifestations.

Okay, so let's talk about risk factors then in your experience. What are the most common risk factors and I guess underlying metabolic conditions that can contribute to mastold, as you say? I like that. Thank you. The risk factors are exactly as you'd expect them to be. Excess weight.

And when that excess weight is associated with other metabolic complications, be it dyslipidemia, hypertension, glucose intolerance, the risk of fatty liver disease or steototic liver disease is significantly elevated. one must emphasise that diabetes, hypertension, dyslipidemia do not cause

Fatty liver disease. So although management of those complications and optimizing the management of those complications is paramount, it doesn't lead to an improvement in the liver disease per se. So there are associations, they're not causative conditions. So carrying excess weight, obviously fat distribution, so visceral fat rather than subcutaneous fat, there is an increase.

risk of mastled in people who have a history of other metabolic complications in their family. There is definitely a connection between not so much your weight but the quality of the food that you eat. So there's emerging evidence that ultra processed foods are implicated in a more aggressive phenotype of fatty liver disease. And then there are other sort of subgroups. There is a concept called lean mash or lean massled, which is

someone that has metabolic complications but is not overtly overweight, so you've just got to be a bit careful relying solely on a BMI. And then the other terminology, because hepatologists love of changing terminology every few years because it gives people reason to sit on committees.

is this concept of met ALD, which is very common in that people have both metabolic complications or metabolic reasons to have fatty liberties, but they're also drink it to excess. And that probably constitutes at least fifty percent of the people I see with fatty liver disease in clinic.

Okay, so how can we then as GPs approach the diagnosis of mastold in the primary care setting and what sort of diagnostic testing should we be aware of? So I think it depends on the patient that you're dealing with. If you're dealing with a a patient who's had an ultrasound which shows evidence of steatosis and remember that

a subjective assessment of echo texture, it's not quantitative or objective assessment. But they have normal liver enzymes, then I don't think further investigation of their liver is required. If you really go looking for fatty liver disease in population studies, within Australia between twenty and thirty percent of adults have evidence of fatty liver, but the vast majority of those will never develop fibrotic liver disease.

If you've got a patient who has abnormal liver enzymes and they're consistently abnormal, not just on one measurement, I think obviously you're gonna start off with a sort of pretest probability or presented with a diabetic, overweight patient that doesn't eat particularly well, who has other metabolic risk factors, you're going to pretty much sort of nail that this is schiatotic liver disease from the get go. But you've got to be a little bit careful, especially in young patients.

Having steatotic liver disease does not mean that you are immune from other forms of liver disease and simple screening for hepatitis B, hepatitis C, Wilson's disease in young people and autoimmune liver diseases I think is important. Obviously the pickup rate is pretty low, but I have anecdotes of people with class three obesity who are presented with classic liver enzymes with a raised liver stiffness on fibroscan and lots of metabolic complications, but something didn't quite seem right and

We biopsied that individual and they have primary biliary cholangitis with cirrhosis, with interestingly, on that particular case, no evidence of histological fat in their liver. So you can get caught out. And I think it's important just to s throw that liver screen wide at the outset.

Yeah, I think that's a really great reminder. So John, do you want to just go through exactly what you would consider in a liver screen? You've obviously mentioned some of those conditions. What would you consider in a presentation of someone with LFT derangement if I guess there's a finding of steatotic or steatosis on the ultrasound, but you're just wanting to exclude other causes. What would be your sort of basic liver screen that you would perform?

So I would definitely if you were to pick one test to do, most importantly hepatitis B and C serology, those are the two conditions that it's very important not to miss. Autoimmune screening is normally serum immunoglobulins, ANA, anti mitochondrial antibody and anti smooth muscle antibody. No other autoantibodies are necessary as a general screen. I think it's important to screen people for hemochromatosis.

I would say a considerable number of people with hepatic steatosis or even with metabolic issues without significant liver disease will have hyperferotinemia. And I do have a bug in my ear that I feel that hemochromatosis is one of the most overdiagnosed conditions in Australia. Most of the people that turn up as a compound heterozygo or a are a heterozygote one of the HFE mutations

do not have genetic hemochromatosis, but it is an important condition to screen for. Alpha one antitrypsin, copper studies and seroplasmin in the right patients. So you're not going to be doing those on patients in their seventies. And you've got to have a degree of pragmatism about how far you screen for very rare diseases in the context of a very common condition. And I also add in celiac. screening because that is an under recognized cause of abnormal liver enzymes.

Yeah, that's a great summary. You mentioned a patient case, you know, briefly before someone who ended up having a biopsy. Does every patient with deranged LFTs and likely mastold need a biopsy for confirmation or is the ultrasound finding a negative liver screen for other causes with deranged LFTs? enough for us in primary care setting to make that diagnosis.

Do I reckon out of every hundred people that are referred to me with a diagnosis or a putative diagnosis of mastold, I will maybe biopsy one of those people. And the only real reason to do a liver biopsy is diagnostic uncertainty. So there are some features on the liver screen which are raising the sort of specter of a potential other underlying condition. And the one underlying condition I'm always keen to rule out is autoimmune liver disease, which may require proactive treatment.

But that is the exception rather than the rule. I think it is important to have some assessment of the likelihood of significant fibrosis. So some form of fibrosis assessment is important. Although if you're dealing with an overweight or obese person in their twenties with a negative leverscreen and a bit of a hypertension, maybe some early glucose intolerance.

then you're not going to be seeing hepatic fibrosis in those individuals. So you can be a little bit more relaxed in younger people. And there are several ways to assess hepatic fibrosis in primary care that don't require a referral to a liver clinic. Yeah, great. And I wanted to also just check in around screening. So

You sort of mentioned that like often this will be found on an ultrasound. This may even be an incidental finding. If we did an ultrasound for another reason, it may be the work up for abnormal LFTs on blood tests. Outside of this, is there any evidence for any kind of screening, population type based screening for people at risk of this, or is this purely something that is case finding?

So I think if no one is doing population based screening outside of clinical trials, there is actually a clinical trial running in Cairns at the moment. screening indigenous Australians with diabetes in the diabetic clinic and seeing what the pickup rate for significant liver disease is. I think when you're assessing someone with diabetes or hypertension or dyslipidemia,

If they have completely normal liver enzymes, then I don't think further screening is required. There are always anecdotal, if you like, instances of people with significant liver disease with completely normal liver enzymes, but it's really very unusual in fatty liver disease. So no one is doing population screening. I think if you've just got hepatic steatosis on an ultrasound but no abnormality of liver enzymes, then further assessment is generally not required.

Unless there's something atypical about the patient, it doesn't seem to fit. Patient doesn't have metabolic complications, they're of normal body weight. But generally it's such a common finding that I don't think we can justify overall screening.

Great. Okay. Let's talk then a little bit about management strategies and I guess I really wanted to hone in a little bit on lifestyle interventions, whether there is a role for any pharmacological treatment and also what monitoring is required for patients who've been identified to have metabolic associated steatotic liver disease.

So I think the first thing is to make some form of assessment of the likelihood of hepatic fibrosis. And that can be done easily in primary care. Probably the most accessible and most accurate, widely accessible test is something called the Fib Four, which is available free through NP Calc. And that uses a combination of AST, ALT, platelets and age to give you a likelihood of hepatic fibrosis. And a score of less than one point five five means that hepatic fibrosis.

very unlikely and over three point two five hepatic fibrosis is very likely. That does leave you with a sort of grey area group and you've got to be careful with Fib four and other measurements. in patients at the extremes of the assessment group. So patients of much older age, for example, the accuracy becomes less as people get older. But that's a very, very good screening test.

Commercially available screening tests you can through most of the labs in Australia now actually have something called the enhanced liver fibrosis or ELF test. That does come with a cost to the patient. It is an accurate test at assessing fibrosis, but I don't think it is particularly more advantageous than the free fib four.

There are a number of other tests in clinical trials, including a test called Fib Nine from France, which may be widely available in the future, but at present is an experimental tool. The other ways of assessing, especially that intermediate group is some form of elastography. Now the gold standard for elastography is vibration controlled transient elastography, which we often refer to as fibroscan.

And at the moment, because that doesn't come with an MBS rebate, it's not available outside the public hospital system or a few private gastroenterology practices. It is very accurate, although it does have some issues and people who are very overweight.

you will have had access through a lot of private radiology companies to a technique which is ultrasound based elastography and there are a couple of different modalities that use that, which give you a similar score, something called a liver stiffness measurement.

Now, in the right hands, that's extremely accurate. I would qualify that in saying that a lot of radiology companies have taken this on and not all elastography is the same and When you see an ultrasound report saying the elastography is normal but there are features of cirrhosis that you wonder about the validity of that. So if something doesn't seem right, if your pretest probability doesn't match with the result you're getting on a piece of paper, then question it.

As far as treatments go, there are no licensed pharmacological treatments in Australia for muscles. The hallmark or the backbone of treatment is lifestyle change, and you as general practitioners are much better placed to enact that. I mean, hepatologists are very, very bad at managing metabolic and holistic medical care. Most hepatologists only know

of amylodopen as an antihypertensive, they don't know any of the other ones. I'm being slightly tongue-in-cheek, but you know, these patients do need their dyslipidemia proactively managed and their hypertension managed. So lifestyle change through diet, largely. I always say to patients that unfortunately you're not gonna lose your weight through exercise and certainly not exercise alone, but exercise is important.

advanced muscled clinics worldwide that have enormous financial resources, have exercise physiologists and dietitians and food psychologists and all that sort of thing. Obviously that's not translatable at population level. And we do hand out flyers about Mediterranean style of eating and avoiding ultra processed foods.

We have to be a little bit careful about that sort of middle class tendency to promote olive oil and whole grains and people that find it very difficult to access those types of food.

So I think dietesic referral is important if the patient is struggling. As far as pharmacological agents, you can imagine with the incidence and the prevalence of mastold worldwide that this This condition has been a real target of the pharmaceutical industry for many years, and there have been literally dozens of agents that have made it through to phase two and phase three trials. Some of which have reported some positive results, so some improvement in liver enzymes, some

reduction in liver fibrosis. But when you put all of these agents, these positive outcome agents next to 10% and even 5% weight loss through lifestyle change, they don't actually stack up. So they would be inferior if they were put against that.

Having said that, there are a few agents of particular interest. Of course there's a huge amount of interest in GLP one agonists and similar multi target drugs such as somagalitude and tazepatide, and there's some very interesting data coming out which shows that there are improvements in liver function or liver enzyme elevation and improvements in fibrosis.

But not only in patients that lose significant weight. So some of that positive effect may be independent of the weight loss that results from these drugs. Another agent that is not yet approved in Australia but is approved by the FTI is a drug called Resmetorom, which is

thyroxin beta agonist. I don't expect to see that available in Australia until at least twenty twenty seven, if at all. So the mainstay remains weight loss through dietary change, possibly with additional help from GLP one like drugs.

Okay, so I guess the last question I wanted to talk through was long-term complications and what role can GPs play in this? You've talked a little bit about fibrosis screening. Is there anything else that you think is important in this space? And I also wanted to ask you in terms of frequency of doing fibrosis screening. Obviously we're doing that at diagnosis. You know, how often should we be assessing it from there as well?

So from an elastography point of view, someone is seen in a liver clinic and they have no significant fibrosis on transient elastography or fibroscan, we would normally suggest Depending on their comorbidities and their place in or their time of life, we'd normally suggest a repeat fibre scan after about five years. If someone's got evidence of mild or moderate fibrosis, we may bring that down to the two to three year

interval and obviously people that have got advanced fibrosis but falling shorter cirrhosis will be under a a more regular or shorter interval screening. It also depends on whether or not the patient manages to succeed in their lifestyle changes. So if you've got a patient that did have abnormal liver enzymes, loses fifteen percent of their body weight and then their liver enzymes normalize, then repeated screening with elastography is not required.

the complications of mastold. So only a small proportion of people with hepatic steatosis will develop fibrotic liver disease and only a small proportion of them will develop cirrhosis. And then once you get cirrhosis, of course there are complications of portal hypertension and HCC. So it sounds like a very small number, but when you're dealing with a very large number to start with, that small number becomes significant.

But having said that, the vast majority of people with mastles will not have a liver related event in their lifetime. What they are at increased risk of is pretty much every single disease group, so renal dysfunction, solid organ tumours. hypertension, cardiovascular effects, mental health. There isn't a disease group that is not adversely affected by a metabolic disequilibrium that exists in these patients.

Yeah, which I think is a nice way of bringing it back to the fact that this is an important condition to be picking up and managing in primary care. And if we are able to put that holistic care around patients, then hopefully we can prevent some of these not just the progression of muscle, but also development and progression of so many other metabolic associated conditions as well.

Jonathan, thanks so much for joining me today. It was a really great informative summary. Very appreciative of your time. And hope the listeners enjoyed today's episode. Thank you very much. If you have any questions. Send an email. The content of this podcast represents the opinions of the good GP hosts. The content is aimed at general practitioners working in the Australian context and is not intended to. Any listeners experiencing symptoms or who have concerns?

Yeah. Yeah. We recommend all the signs prior to any clinical decisions.