The Liver Disease 30% of Us Have and Never Feel | Prof Aleksander Krag

0:03You've said before that when you think about liver disease, you don't necessarily think about the statistics. You think about a patient called Henry. Who is Henry and why is this fictional character important to the way that you think about your work? Henry is the key for me, the driver for me, why I do research, why I love to be a clinician, but also know we know research. Henry is a patient that made a big impression on me because Henry had what we today call steatardy liver disease. It's a disease of too much fat in the liver. He's been living that for a long time. We've basically missed it.

0:42He's been under our nose all the time. Then Henry emerges late at the healthcare system with advanced stage liver disease. And sadly, I couldn't save him. He was too sick or he had a cancer. He could not have a liver transplant, but you also have other manifestations of chronic liver disease. So what is my vision here as a researcher and as a clinician? It's basically, I want to change the faith of people like Henry. Because Henry was over 50. He'd been sick for 55. He'd been sick for 15, 20 years in his liver. And I want to see a future where we find Henry 10, 15 years earlier. He identified the causes.

1:21We implement the treatments. We come with the changes in his lifestyle that can change his life. So he had kids. He had a lovely family. It's very sad to say goodbye to him. When could have lived longer, happier? Maybe 20, 30, just like anybody else. So that's why in my mind, the back of the head, I have Henry. So you began your career as a hepatologist and you were seeing people like Henry more towards the end stages of liver disease, whereas now, would it be accurate to say from a research point of view, you're mostly focused on prevention, early detection, early treatment to reduce the number of people that end up in those end stages?

2:04Yeah, that's perfectly correct. It's very interesting as a doctor to have very sick people trying to do something for them. But the truth is really when they're very advanced, the only thing that really matters is in the vitro squad. So that's why I redirected my focus and say, okay, we need to prevent these people to get to this stage. And actually, we already just with biffled behaviors and now with breakthroughs and different types of drugs to try to help all this effort. But how do we find these people at the right time, at the right place in the health care system? How do we give them the right advice, etc.?

2:39So that is, I think, the whole transition where we basically move towards early detection, towards prevention. And both what we call primary prevention, starting from all the way from happening. And if you already have something, liver disease of different severity, what can you actually do to prevent it actually from becoming a clinical problem? I was reading the Lancet seminar that you wrote, and I think this will surprise people in there. You wrote that around 30 % of the global population have steatotic liver disease, and that's something we'll define in a moment here. But is a lot of that 30 % or what amount of that 30 % of people that have steatotic liver disease is undetected?

3:22Could there be someone listening right now who has this and has no idea? Unfortunately, yes. The thing is that this overlaps very much with type 2 diabetes. It overlaps very much with obesity. And the sad thing, I don't know, give it or take, but is that liver disease until very advanced days is asymptomatic. So the issue is as many of these people, they have no idea. And then what happened is exactly what I explained there with Henry. Then at a certain point, they have this sign of advanced days disease. You know, suddenly they have what we call ascites, accumulation of fluid in the stomach that eases up or they're general not feeling well, losing weight, or they have this vomiting blood or infection of the brain, some of these things where it's very advanced.

4:08And that's why we also, in the clinical guidelines, suggested people with some of these risk factors like type 2 diabetes or severe obesity or continuously elevated liver function test, they should actually be assessed for liver disease. In particular now, because we know a lot about it. So we can both do a lot, and I'm sure we'll come back to that, both with behavioral changes, which is really the backbone. And now we also have the first two drugs that has proven effective and approved by the FDA and EMA also, which is really a breakthrough because that has been a search for 20 years to see, okay, can we really do something to revert or prevent this disease from progressing?

4:48And those two drugs at a high level here, what are those? We'll get to that later on in this conversation, but just so people are aware of what they're called. Yeah, one is called Resmederone, Resdifera. The other is Semaglutide, GAP1, I cannot remember the source name in the United States, but it's what's Vigovi, what is the known Nordisk drug that's also used to treat obesity and type 2 diabetes. Both of them had positive phase free trials and were conditionally approved from FDA for the treatment of MASH with significant fibrosis in conjunction with exercise and diet. And just to add some hope up front here at the top of this conversation, if people did find this earlier, as you're saying, and acted on it, whether that's through lifestyle or medications or a combination of both, how reversible is this steatotic liver disease, generally speaking, and what kind of complications could people avoid?

5:50What we've learned, basically, is that in general, these are reversible up to very advanced stages. So when I went to school, and I'm not that old, but then we had an understanding of fibrosis, which is scarring of the liver as something that was not apostatic, that could not be reversed. But as many of the other beliefs we've had and sort of truths, they turn out to be wrong. Fibrosis tissue, scarring tissue, and many other active tissue. and actually mean that it actually can be reverted to make. So even quite advanced stages of disease, we've seen that with hepatitis B and hepatitis C, but also now with steatarsic liver disease.

6:30And that, I think, is really the key to hope. Yes, it's basically, I'll say, never too late. But earlier you go, of course, the easier it is. And then the distance you need to walk to get back to a normal liver is shorter. And the complications for liver disease is that the liver is in many ways, I don't know, I could talk about, I love the liver. It's a fascinating organ. It does thousands of things, but let me not drill into that. But you know, it's a middle of the bloodstream. Most of the proteins in the blood are actually generated by the liver. So many things that make the whole body, everything work is coming from the liver.

7:10But the liver is also a huge organ. It has a very big radiative potential. So you can harm it a lot, both with alcohol, obesity, and many other things and actually regenerates. You know, sometimes when they do surgery, you cut out a chunk of the liver and if it's otherwise a normal liver, it grows out again. It's not happening like that with a finger or if you lose a kidney, it doesn't grow out. So the liver is unique in the body in that sense. But also means the liver has a lot of functions. So it affects a lot. So some of the key things you would see is how people can have symptoms from all over the body.

7:47I use actually when I have my student lectures, then I say, okay, give me one example somewhere in the body where a failing liver cannot be seen. And that means you can have symptoms, yes, from the kidneys, from fluid accumulation in the stomach, in the legs. You can have this, what we call portal hypertension, increased blood pressure, which increases generation of vessels around the cell phone, of course, and you can have vomiting. It can remove, change the cleaning of the blood from the gut so the toxins go to your head and you become completely strange in your head, what we call into philopathy.

8:21And hundreds of other things that are more subtle, but these are some of the dramatic things. And that's what we want to ideally prevent as many people as possible to get to that very advanced stage where you have these symptoms that are dramatic. Because at the same time, you become tired, you become weak. we can come back to that it's also like the liver is also the metabolic supercomputer of the body so if all these things about gluconeogenesis etc if the capacity to all that is lost the body starts to digest itself you start to lose muscle mass etc and that's what we see at advanced stages many of these let's say where we've excess capacity which is very important for for our homeostasis or our biological integrity as a human is sort of lost with this.

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9:54None of this of course replaces your doctor, its information, a more comprehensive view of what's going on inside you so the conversation starts from data rather than guesswork. Check your health the way that I do. Function provides more than 160 lab tests for$1 a day and member pricing on advanced imaging. Join at functionhealth.com forward slash Simon Hill and use the code Simon25 for a$25 credit. So in addition to everything that you just mentioned there, does the liver does it also play a role or does steatotic liver disease increase someone's risk of more common chronic conditions that maybe people hear of or have experienced like having a stroke or a heart attack or developing neurodegenerative disease are there are associations there yeah there's strong associations we just have to be cautious because if you have steatotic liver disease you have higher risk of cardiovascular disease, including Stroh's.

10:54But that's, again, is it the liver that causes, or because they are both driven, they're both very tightly linked to type 2 diabetes, they're tightly linked to hypertension, dyslipidemia, you know, hypercholidosterolemia, and obesity. So some of these shared risk factors. So there we actually have a bit of a discussion in the field. Is this on itself an excess risk? The argument, or many different arguments, but that the liver, when it has this disease, then it cannot just have fat in the liver, but it can also come to inflammation. And inflammation, we know, is not good because then it's a systemic inflammation.

11:31I just working on a wonderful paper that also affects how it affects the fat cells. But, you know, the whole thing then sort of become inflamed. But you have this low-grade inflammation, which we know is also bad for the whole cardiovascular risks cascade. So probably this definitely doesn't help, but it's really tidy. That's also when we should see these people from a more holistic approach. Of course, I'm a liver guy. I love the liver, but I have to be really cautious and aware that of all the other organs that actually share some of the risk factors with what we see with diatonic liver disease.

12:06And also, yeah, I hope you can bring up a little bit there with alcohol because it's really an important factor. And most people in the world, or at least in United States Europe, but also beyond, they drink more of this alcohol. And that's really important activity. Yeah, we need to make sure we do that. And I think in defining steatotic liver disease and the subtypes, that will come out. So my understanding was in 2023, and I think you were involved in this, the field kind of renamed all of this. and NAFLD became MASLD, metabolic dysfunction associated steatotic liver disease, bit of a mouthful.

12:44And then steatotic liver disease, at least the way that I see it, and you can correct me if I'm wrong, it's kind of like this umbrella term. And then underneath this, there is these different subtypes depending on what sort of led to or caused or predisposed that person to developing steatotic liver disease. Can you walk us through that nomenclature and what steatotic liver disease is and what these most common subtypes are? So historically, we called it something else. We call it fatty liver disease, but we want this as liver society to get rid of that. Because fatty in most languages is basically a stigmatizing word.

13:26And then it holds fatty and non-alcoholic. And it's also weird to have, you have a disease and we start to say what it's not. and people who don't drink don't like to have a disease that is called alcoholic. And we acknowledge that. And it's been like that for whatever, 30 years. And then the process started, but very difficult. Actually, a lot of experts all over the world, a lot of fighting, a lot of disagreement because how do we do it? How to make it meaningful? The bottom line is that we in 2023 released from the liver societies. By the time I was president of the European liver societies, it was big, but it was difficult.

14:01Now people love it, but change is hard. So sort of put an umbrella term and say, okay, we could not use fat. So we call it steatosis. And steatosis, that's because steatosis is fat in a medical language. And then liver disease. So say this is sort of the thing. And that is people who have one cardiometabolic risk factor and steatosis in the liver. Steatosis in the liver just means that you have more than 5 % of your liver is with fat. And that you could see with most normally with a bit of whatever imaging, it could be an ultrasound or CT scan. You would also do a biopsy or fibroscan, different types of technologies.

14:41And then you have one of the cardiometabolic risk factors. I mentioned that obesity, type 2 diabetes, hypertension, dyslipidia, et cetera. So that's sort of it. And then the next level is because also there was an appreciation that alcohol is just so important. And alcohol also, if you look at the rates, for instance, United States, how that is actually increasing as a very important driver of transplant morbidity to mortality, how we integrate that. And also that this has an important impact on risk of progression of disease. Alcohol is basically the same as Masol-D, just with, let's say, oil in the fire.

15:20But then we have what we call low-level, and that's the MASH or MESLD, metabolic dysfunction associated with the autotonic liver disease. So let's take that again. That's difficult to remember. We call it MESLD, but metabolic dysfunction, and that's important, and then associated with the autotonic liver disease. But that's what it captures. That's below 20 or 30 grams of alcohol a day. Basically, whatever, depending on US, is 12 grams for one unit of alcohol. place in Europe it's 10 gram but let's say less than two or three units depending on on how you see it and then what I think was important here there's three subcategories there's a one with low alcohol and then there's one we call it intermediary I would not really call it media because it's still harmful alcohol the backspin between these 30 20 and 30 and then 50 and 60 and that's quite a lot that we call a mix because it's really about understanding the drivers of disease.

16:18What is the key driver? And key driver is, of course, also the key focus for the doctor, the key focus for the patient, because that's in the end what will drive the disease forward. And then you have the more than 50 or 60 grams a day that what we call alcohol-related disease. So three subtypes, Maslow B, and the one in the middle, metabolic dysfunction and alcohol, and then the higher one, alcohol. And importantly, I know you want to stop me now because I'm importantly is that iology and human behavior is not linear and that's very important a lot of the research we've done and also just coming out i think important publication in nature reviews also what we did our nl lancid seminar trying to explain that these it's not like when i put you in a box or silo you're there forever you can change and people change that's also mean that Cardiovascular risk factors change less, but they do change and we do treat them.

17:16But alcohol consumption changes over time. So you have to see this as a spectrum where people can move around. And some people actually move quite a lot around between these categories. Okay, so let me recap. I'll throw a few things back to you and let me know if it landed correctly. So the steatonic liver disease, if we just think of that at a high level, that means that there is excess fat inside liver cells. And I think that threshold was 5 % of the overall weight of the liver is fat. Yes. Okay. And then there are these different types depending on what is driving that increased level of fat within the liver.

17:59Would it be accurate to say that of the 30 % of the population that have steatotic liver disease or approximately 30 % is most of that metabolic dysfunction associated with steatotic liver disease? So the kind of old previously non-alcoholic fatty liver disease driven by a combination of things like genes and nutrition and excess calorie consumption, obesity, or is it an even split between that and alcoholic liver disease and the metabolic dysfunction, alcoholic associated liver disease. How do you split up that 30 % across these different subtypes of liver disease? There's one thing I hate to correct you because I worked a lot to the de-stigmatization.

18:45So we don't call it alcoholic. We call it alcohol-associated because it's, again, a stigmatizing word. Many people who drink a lot are very obese. They don't choose it themselves. So we've tried to see this differently. So the split is, that's, again, a very important, interesting, thick discussion. you dig into there. Because if we look at our registries, it looks like the majority is muscle D, you know, the low alcohol. And alcohol and admit ALD are very low. But the problem is, when I ask you, how much do you drink? Or how much did you drink one month ago? It's not so easy to remember. And I'm not sure you necessarily want to tell me, particularly not here in your podcast.

19:29That's the issue. And when we've done some studies, where we did have large population groups of people where we then measured some of the metabolites of albago. There's something called phosphatidyl ethanol, again, peft among friends. So when you break down alcohol, you know, in... Can I explain a little bit physiology? Because it's fascinating. That's what we're here for. Okay. You know, the red barb cells, the one that carries oxygen around the body, they have a membrane. All cells in the body have a membrane. They're made of two lipid layers. These are called phospholipids. One of these phospholipids can change in a certain way when you drink alcohol.

20:07So it's a certain metabolite that you can actually measure with mass spectrometry, liquid chromatography. So you can very specifically target the level of alcohol. And what is interesting, when we look at a large population, and I'm just also here this afternoon, one another manuscript from together with one of my American colleagues, because we measured it also in their samples among patients we thought 100 % sure were a MASS-LD patient. 10 % of them had high levels of this alcohol metabolite. We have in our own cohort, a bigger cohort with 3 ,000 people here in Denmark, in Odense, measured that up to 30 % or actually 38 % of those in the MASS-LD category have this elevated to a level where they actually belong in the MED-ALD or ELD group.

20:57And even more pronounced, if we then go to the med-ALD, you know, the intermediary group there, measure the same, actually more than 50 % of those actually would belong in the ALD group. So that's, again, challenging our thinking. So if we just go to some of these registries, the Enhanced Database, you know, the big US database or UK Biobank, some of these where you have a lot of self-reported, they are probably underestimating the role of alcohol significantly. And that's important because does the doctor then ask about alcohol? Is the patient, all those who listen here, are they aware of the role of alcohol?

21:39That's why this is really an important part of the equation. And also that as our life changes, alcohol can go up and down. Is there a threshold where a certain amount of alcohol, at least at a population level for an individual, becomes problematic from perspective of the liver? And how much of it is the independent effect of alcohol versus the calories that come with it? not easy to answer. Let me first start there with the population. Again, it's again important when we look at population-based knowledge and individual-based knowledge. And actually, when we see the population-based knowledge, if we see the risk, let's say on the x-axis, you have amount of alcohol, or the y-axis, the risk of having advanced stage liver disease is more or less linear.

22:30So that means that that's also why WHO, if you ask WHO this, See, there's no safe limit for alcohol consumption. Basically, my take is that, of course, people, we cannot stop people from drinking, but people should find one not drink alcohol because they think it's healthy. They should drink it cautiously because they enjoy it and know that after a certain threshold, alcohol is actually have a negative effect. And there's a important notion. Again, here, there's a big difference between a male and a female. So where we say if we put them all together, it's more or less linear, but it's actually more linear for a gay, but where females, it takes off.

23:10So the females are when alcohol are much more toxic for alcohol in less. So that's proven numerous times. And that's also why the recommendation there, where we say 20 and 30, the many reasons for that. But that's, again, an important, it tolerates for liver disease, but also for other things, less alcohol as a female aneum. So again, WHO say no semis livis, but that's again, okay. And then you see when does it take off? But now it becomes a little complex here because back to your point there, what is it? Is alcohol itself toxic? Is it the breakdown product? Is it the calories? and I think the best evidence basically we have to understand that it's all of them but it depends also now we add another layer of complexity because alcohol in a lean individual versus an obese or an individual with type 2 diabetes is much more toxic so the risk of developing liver disease if you have high alcohol consumption and type 2 diabetes it may be three to five times higher.

24:20But back to the mechanisms there. So I don't know, do you want to talk a little bit about the mechanisms, how is drive, what's driving? So we have these three, I would say there's three factors. There's this call, it started with the calories. There's a lot of calories in alcohol. That's also why we see a lot of people who have excess alcohol consumption, they are obese or overweight. And that's simply because it's metabolized. Alcohol can blood still will be metabolized to try to glycerize the fat. And that's exactly what goes to the liver. There's not much else in it, and that's how it works.

24:52And of course, that's not very good. And alcohol is also associated with hypertension. It's associated with obesity. It's associated with type 2 diabetes. So all the metabolic components are already there. So that means that is sort of the underlying risk. And then there's a second thing with the breakdown, what's called acetaldehyde, is actually also toxic metabolite that also create inflammation in the liver. Then there is the important thing. I think also what alcohol is doing, it's also affecting the bugs in the gut. So that's also very well proven that actually you have a change. If you add alcohol, we also done studies that are like that and see the behavior of the microbiome is changing.

25:33And another thing, it makes the gut leaky. So basically the barrier between what's going on in the gut and what's going to the liver is being affected by that. It might mean some of these, what we call TAMs and PAMs, something disease or pathogen associated components actually driven to the liver, and that is driving inflammation. And then you have this metabolic, this gut and this direct effect that sort of all together is both driving steatosis. but what is driving the clinical liver disease is then inflammation and in the end it's fibrosis, scarring in the liver because you can have a lot of fit and the liver function quite well but the scarring is what at the end will lead to a decreased or deterioration in liver function and onto a certain threshold where the liver can compensate it more and then you become sick.

26:25What's the typical timeline look like? Let's say someone newly develops more than 5 % of the weight of their liver as fat. What does the progression look like from steatotic liver disease without fibrosis and cirrhosis to developing fibrosis and cirrhosis and having that scarring and inflammation that you're talking about? Yeah. So the good news is basically that's why we say that it sounds a little scary that so many people have fat in the liver. And that's why we would say, no, you have to look for fibrosis because if you have fat in the liver and you have no fibrosis, then your biggest problem is not the liver.

27:03Then you have to look for the obesity. You have to focus on the type 2 diabetes or what we do. So the question is that most of these will never have any liver issues, but there's a fraction of them that will then develop inflammation and start to have fibrosis. And there, the more alcohol you add, the faster they progress. But on average, let's say we have some different types of data. We have it separate them basically in zero fibrosis, grade one, two, three, and four, and four is sort of the advanced status. And we would say that it's a relatively slow progressing disease. And that's, again, a good news.

27:39So if something is discovered, we can do it. We have time, most of the time. But then we see on average, maybe between one stage takes probably a set of years. If you add alcohol, it takes three years. And of course, then there's a lot of variation. There are people who are still trying to understand that people that progress very fast. So all of us see in it, it's really sad and difficult to understand when you have people in the late 20s or 30s that have these disease. But on average, people are alcohol probably around 50, and Maslow-D, when it becomes more advanced, is a little bit older. You mentioned there that most people will not have a liver issue.

28:20So does the excess fat in the liver, does that drive risk of any of those other complications or non-liver disease states It's if the person only has fat and doesn't have the fibrosis and doesn't have cirrhosis and inflammation, is the fat itself problematic? I would say that there's some disagreement among the expert. I myself wrote a paper where I actually argued that we should be cautious overselling the fat alone because it will put too many people, scare too many people. And that's not what we are for. We should not scare people. we should have people where they have relevant risk and that is fibrosis that is where you should be concerned about the liver but of course in a person with fat in the liver alone you have to acknowledge that this is strongly associated with hypertension cardiomyocular risk etc if the fat itself as i also tried to discuss before as an independent additional effect, I think is still under debate.

29:27So if you are otherwise having cardiovascular risk, and then you also have the atonic liver. And the issue is, of course, when 30 % have it, then almost all people with type 2 diabetes, of course, if they're treated well and they have weight loss or GGAP1s, etc., their fat may disappear. But a huge proportion of those will have fat in the liver. But just like if you look in obese people, the majority would also have steatocardial disease or you have mesaline or whatever, depending on the alcohol consumption. We all have the draw. Half a bottle of magnesium that never did anything. A probiotic from two summers ago.

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32:51And are confused, is it the liver just making this fat spontaneously from other substrates? Is it the fat that they're eating in the burger or in the butter? Or is it Is it coming from other fat stores throughout the body? Can you help us understand the origin story here, where that fat kind of originates from? Yeah. So basically, let's say we ingest something. It can be any components of our diet with fat, with proteins, with carbohydrates or alcohol. Anything contains something. and then actually you know when it all goes down to the gut everything is absorbed and at time it's like that everything is boosted to the liver nothing passes the liver so everything you but get into your mouth that's sort of or absorbed in the body goes to the liver and then depending on if you can use the energy or not the body needs to somehow store the energy and ideally that is done also in the fat cells.

33:56But if you have then an excess energy coming in or alcohol, which you cannot burn too much, then what is the liver doing is sort of protecting because you cannot have a circulation which that's floating with fat. So the liver is actually trying to protect the body with holding back the fat, accumulating it in the liver. And then later, of course, this should sort of be trafficked to the fat stores in the adipocytes. So it's basically this situation of a continuous imbalance between how much you can actually handle because you can metabolize it. And then you have an even worse, if you then already have insulin resistance, some of these things make these mechanisms worse.

34:36And we have also the underlying genetic. We have some genetic variants that are very strongly associated with all of the steatotico disease. So both alcohol and null alcohol, actually the same genes, they pop off as rich genes. So we also individually have some susceptibility in our genetic background. Yeah, I was reading about, is it PNPLA3? Yeah, yeah, yeah. There are a few others. PNPLA3 is the most important one. There's also one protective genes and they're actually being developed drugs to try to push both of them. And it's going to be very exciting to see both the protective gene there, if that can be pushed so it can help.

35:16Would that potentially explain or at least partially explain why you can have two individuals who have the same body fatness, body fat percentage, but one of them is storing more fat within the liver compared to the other who is storing more fat subcutaneously? Is it genetics that might explain that? It could be. Again, we know that, again, there's also some beautiful studies that fat on your different place in the body are not the same. Fat in a stomach central obesity is a different types of fat than what you may have subcutaneous on your butt or somewhere else, which is a more healthy bag. back.

35:58And that's also why you see and pointing to your genetic there. If you look at the risk of disease or how fat is composition, there are some famous studies around that. It was published one, I think, many years ago in Lancet, where they have to research exactly one from India and one genetically from UK. And the fat distribution is just differently. And that's also why you see with different genetic backgrounds, their risks are quite different. We also know that for for cardiovascular disease, for BCT, time 2 diabetes, et cetera. So, but the massive signal here, which we also worked a bit quite a lot over to genetics today, I think in most of our patients.

36:36And of course, these, the key risk variants, they pop up all the time, but it's not like they can explain that much. And then you do polygenic risk source, probably to stack a lot of genes and say, okay, how much can we explain? And of course, that is driving a susceptibility and probably also some individual variation that that's again if given that people otherwise have a similar behavior. You mentioned a protective gene. Is that the gene that seems to kind of prevent people from having an increased number of these atherogenic lipids despite having more liver fat? Yeah. So it's interesting that the disease is basically a fibrotic disease, but all the genes, they associate with lipid metabolism, both the protective and at least all the key genes, even though it's still, I think, a little bit incompletely understood exactly how does it work and why the link it is so sure.

37:35But you're right that it's linked to lipid metabolism. You can see how we've done some today, you know, with modern technology, you can look into the lipids, you can measure a thousand lipids in the blood. Isn't that fascinating? We got so many different lipids and they tell a different story also. And you can see the composition of the lipid as liver diseases progresses. And we did an interesting study, both looking at liver tissue and at the circulation. I could see that the composition and the balance between different types of lipids sort of changes during the course of disease. And interestingly, some of the lipids, they sort of disappeared.

38:09The exact biological significance of this, I'm not really sure of. But it's just saying that, yes, what is driving the clinical disease is fibrosis, but steatosis or lipids definitely play a role. We've had a number of guests on this show, cardiologists and lipidologists, talk to us about APOB and APOB containing lipoproteins. Is it typical that as the fat goes up in the liver that HIPO-B, like these VLDL particles tend to go up? Or what does that relationship tend to look like? It's again, the big overlap. And that's again, see what is specifically liver and what is part of a more, let's say metabolic, and not metabolic syndrome, but basically metabolic dysfunction.

38:57And that's why you will see that again, the majority of these, they have different types of dyslipidemia. And that's where Of course, you can do all these, the normal cholesterol, triglyceride, A, B, etc., but digging one layer deeper into different types of lipids and try to see a signal. And what we were also seeing in that study is that these are associated with prognosis, basically outcome, death, and risk of what we call decombinated disease, the time point when it reached a clinical signal. Just coming back to alcohol or in general substances, are there any other substances like medications or recreational drugs that can damage the liver and either lead to steatotic liver disease or if someone has it, worsen it and increase the risk of scarring and fibrosis, cirrhosis, etc.?

39:46Yeah, very important question. So one thing we know, and that has been, again, repeated, Sean, that tobacco smoking cannot explain you the specific mechanism, but it seems to be independently or directly harmful and actually is associated with fibrosis. So that is something we definitely recommend as part of this package of how you can protect your liver. Be careful with smoking. Also associated with a close risk of liver cancer. Then we have the good news for many of us. I don't know what you're drinking there, but coffee is good for the liver. And again, there are many studies over, whatever, 20, 30 years, they all point in the same direction.

40:25For some reason, the coffee is an interesting substance. There's a lot of different things, also lipids, et cetera, in the coffee, but consistently associated with better level outcome, less fat in the liver, et cetera. So coffee, we don't really have any restrictions again. And one thing I want to say then is we're always taught that we should eat a lot of vegetables and a lot of fruits. But one word of caution with fruits, fruits are nice. But remember that fruit, what is it that made a fruit lovely? That is fructose. And how is fructose broken down? That is made into fat, triglycerides in the liver.

41:02So that's again, don't eat a ton of fruits every day because it's definitely not got for your liver and you don't need all that. and it can only lead to that breakdown pathway. And that's when I see something, we have at least my country saying you need whatever six pieces of fruits or vegetables today. And I say, you don't put them all into apples or oranges because it's just too much fructose. Just to kind of softly push back a little bit, let me ask a question on that. Does that matter as much in an individual who is a healthy body weight and is not consuming an excess of calories? Does the conversion of fructose to fat occur more so in the context of someone who has excess calories and the body needs to do something with those as opposed to using that as fuel for energy?

41:50No, no, that's an important point. That's back to my balance I tried to explain before. Can the body handle this? Can the liver handle this? So if this is an excess of what you need or sort of you can process or metabolize, then you have a problem. Otherwise, of course, it's not a problem. Then you sort of, let's say you're very active in your sports or you whatever, do something where you are in a balance and in, let's say, healthy body states. You know, we're also moving a little bit. I was just about saying BMI, but I'm a bit afraid there, again, with the BMI concept because you need to have a healthy body state.

42:25And that's, again, back to this distribution of the fat, the strength of your muscles, because it's so strongly associated with your metabolic health, basically. And on coffee, I wonder if it's caffeine or if it's the polyphenols and the way they're broken down by the microbiome and their metabolites. Do you have any hypotheses or what would you say is most likely the explanation for how coffee could be beneficial for the liver? I don't know. I don't know how many is listening. I'm not sure I know it. Just drink it. I don't have, I don't know. I can guess, but I honestly, I don't know. If it was a single thing, we should have sort of picked it up.

43:04Is the combination of different things in the coffee? There's also been different discussion of different types of coffee. Why is it then there was something with filter coffee versus an espresso? I like espresso better, but for some reason that turned out not to be as strong. And that's a bit sad for some of us that like that kind of coffee. But the truth is, I don't think I have a good explanation. But I can refer to this literature that consistently find this association. And it's, again, the takeaway is that if you like coffee, of course, don't over-exaggerate, but the coffee is at least, there's no evidence that is harmful for the liver.

43:38So if that is important for your quality of life, you should definitely not stop drinking it to increase your liver health. I like coffee too, and I too like espresso, which from my understanding, espresso can, it can increase your blood lipids a little bit. but I think some of that comes down to genetics and what's your overall risk profile. So, you know, that's going to be an individual assessment for people to make. If someone's listening right now and thinking, I'd like to know if I have too much fat inside my liver, can they work that out from non-invasive kind of standard tests, like just a blood test, measuring their waist circumference, let's say measuring their blood pressure, these kind of typical metabolic markers.

44:26Is that enough to give you a kind of high level indication of how you're going here and whether you're at risk of steatotic liver disease or perhaps already there? Yeah. So let me just put two layers before I explain it. So we have the fat, the steatosis is one thing. The second thing we look in, which is the key for the liver person, the risk of having fibrosis, scarring in the liver. And this scarring, basically, we are looking for, at least for the liver phenotype. But for this, let me start with steatosis. So again, these compositions don't really have any symptoms. So when you look at simple blood tests, you cannot really find a single blood test or combination algorithm that can tell a lot about steatosis.

45:12That doesn't stick. Also the same with inflammation. But we have combinations of blood tests. We have what we call FIG4, fibrosis 4 index, which is recommended in all the guidelines and different other algorithms that works in a similar way, which is what should be taken at the general practitioner or the diabetes obesity clinic as sort of seeing, are you somebody who should have a confirmatory test? So basically, simple blood tests cannot really detect steatosis. So what is the go-to is where we often see it is that a lot of people will have an ultrasonography for whatever reason. You know, people have stomach ache for this, that reason, and then you see a whitening of the liver.

45:54And that is then the indication that we have or have a CT scan for some other reason or also the cup value on the FIPR scan. So if you already have a FIPR scan or having a FIPR scan, that can sort of track it. But the good news is that from a liver perspective, the important thing is fibrosis. That is what you should prevent from progressing. And that's where the direction of the treatment is to prevent fibrosis. So it's more important for finding fibrosis than steatosis alone. How common would it be for someone to have normal HbA1c, normal triglycerides, normal blood pressure, normal ApoB, normal waist circumference, normal liver function tests, but have fibrosis?

46:38That's rare. That would be called a lean mesh or very young people with very high alcohol consumption. Just one important point there, back to your point, which I think is, I forgot to say, the one clinical parameter, and again, we studied that in big populations where one with 5 ,000 people, we were looked into this. The abdominal parameter is very important. So that as a single measure, if you want to measure one measure, you can also do at home and anybody can do that is strongly associated. Then it's because that's, again, the central obesity, the unhealthy obesity that is strongly associated with liver disease.

47:17So if you should choose one very simple parameter to risk assess, then start with the abdominal perimeter. Is abdominal perimeter different to waist circumference or is that the same measurement? Yes, the modern thing that then you have hip ratio or you have the waist height ratio. I think the point here is that the central obesity, the abdominal obesity is just a completely different types of unhealthy metabolism than if you have. And that's why there's this discussion among the obesity medicine, the definition of how do we define overweight obesity and the whole thing about body mass, you know, because the whole thing with people with a lot of muscles.

47:58They can basically be healthy, but technically obese. And also if you have women with whatever different body distribution that may also technically be obese, but have a completely healthy metabolism because the fat is sort of distributed in a much healthier way and you can have relatively lean people within arm to leg and have central obesity, which is a very bad way of having distributed fat. So is there a reference chart or resource that I could put into the show notes that explains how to measure abdominal diameter and what the normal kind of healthy reference range would be for gender and age?

48:34Yes, there is. I cannot find a note by heart, but there should be plenty out there. There's an also important notion that there's some genetic difference. So it's different from patients than from Caucasians. So again, when you put it out, make sure you have this both for with the Asian because there is basically lower. These people are smaller and as you know. Cool. Okay. I'll do my best to find that and put that into the show notes. So I'm sure there will be from some of the obesity societies or cardiology societies, there must be some with a reference. But I think they would adjust this for the race.

49:09So coming back to scanning, who is actually a good candidate for scanning to measure the stiffness and to measure fat content beyond these just blood biomarkers and measuring their waist circumference? And in addition to that, I'd like to clear up some of this terminology, ultrasound, fibrous scan, elastography. I think these terms often get used interchangeably and are confusing, even for me. Ultrasonography is an image that's what is done, I think, in any clinic in the world where you have an imaging. You basically send a sound signal in, you get a mirror back, and then you can see a lot of things.

49:48So what is different in an elastography? Elastography means where you measure stiffness. Some colleagues, it's sold under the name of Fibroscan, but there are many other machines that can also do it that sort of measure the stiffness of the tissue originally it was developed to measure stiffness of a cheese in france if it was mature or not but then it turns out yeah that's a great story actually repurposing and then finally this because it at a distance you don't want to open the cheese and you still want to know how how soft it was inside and that turns out to call it very well to see what what you have and that's a stiffness and that you can measure basically by this, an image bay and also sound machine, but also an MRI, elastography, that's more advanced, more precise, but also more or less accessible.

50:35So these are the machines we use. If we have a person that is, you have a high risk of suspicion, I'll come back to that. And then you have this V4 or another index marker or circulating marker, then you go to a confirmatory test. And that could then be elastography or an ELF test enhanced liver fibrosis test. I see. So Fib4, that's a quick assessment. That's age, some liver function tests and platelet count. And that gives you a quick idea as to is someone at risk of fibrosis. And then you move on to these kind of more in-depth, accurate investigations to give you a clear idea of what's going on in the liver and is there scarring and stiffness.

51:18Yeah. And the population we are looking at, it's the question is who should be screened. We just did and published earlier this year in Lancet, it screened 30 ,000 people in Europe just to take the population. And I don't think there's evidence to do it for everybody because the prevalence is simply too low. But if you then crack down the data, and we also recently published again, to trying to look into different things, and that's also aligned with the guidelines. So now I'm talking about the latest evidence, so maybe we'll go a little bit beyond the guideline, but this is my personal interpretation of it.

51:50But of course, people with type 2 diabetes, they should be there. We agree. And grade 3, obesity. But what we can see is also then when you add the risk factors. If you both have obesity, you have type 2 diabetes, and you also have elevated liver function test. okay then you definitely should but when you have less of these or one of these the risk is simply lower and then that is sort of the metabolic component and then you have the alcohol component also so alcohol is again important to come in and also for people themselves to consider how significant is my alcohol consumption and also for the for the doctor and then don't forget this test there i mentioned where you can actually get a better reflection of it and it's not just to to try to accuse people of cheating, but it's difficult to remember.

52:38And then you get a sort of a starting point for that. Forgive me if I miss this, but just to really underscore this for people, when there is increased stiffness within the liver, there's scarring and fibrosis or cirrhosis, how does that actually change the liver function? What's the inherent problem with that? So I earlier talked about how many things the liver do, and then you will start to see that some of these key functions the liver is doing to maintain homeostasis in the body is falling apart or not working. So that's one thing. Another thing is that a lot of blood, I told you also, all the food that goes in when it's digested, we have acid recirculating the blood into the blood and all flows through the liver.

53:23But the problem is the time normally the liver super softens with all lovely sorts, it all passes through there into this metabolic supercomputer. But then if that is changed to scarring, to fibrosis, which is basically in that sense not helping any of these processes, just making it more difficult, then the blood cannot go through. Then you get what you get portohypertension, hypertension in that blood vessel there. And that is changing a lot. That would cause this accumulation of fluid between the gods. This increased pressure can then redirect some of the blood to make some big varices in the esophagus and you can vomit blood.

54:03It can again make this issue that the shunting, that the blood cannot go through the liver, it just runs all the way. And then you have some of these tubs into there coming out of the gut that's also becoming more leaky. You have bad things coming from the microbes that go into the brain and that will make this encephalopathy. So that is sort of the key symptoms. But then at the same times, you can also see with people's eyes, the liver is also excreting a lot of things. So the yellow, did you know people can become jaundice because the ability of the liver to conjugate the breakdown of the red blood cells can be reduced.

54:38And then you have sort of the income funeral, so people can have jaundice. You can also see the factors that calculate the blood is also produced in the liver. So people's ability to coagulate or hypercoagulate, so there can be disturbances in the circulation system. You could have people who get tremosis or they get bleedings or you can see also the skin, they will get a lot of arachemosis or similar things. We talk a lot on this show about important biomarkers like ApoB and blood pressure, VO2 max, et cetera. Here's one that most men have never measured, sperm health. Possibly the only biomarker that nobody volunteers at dinner.

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57:51You get 30 days to try it at home and return it if you don't love it. Again, that's code theproof at eightsleep.com forward slash the proof. On your point about screening people that have type 2 diabetes with obesity in particular, does this knowledge of understanding if someone has fibrosis does that change the interventions that would be recommended to that person does it add some extra information is that could bring us back to res metaram or other specific medications that act on the liver that someone with obesity and type 2 diabetes without fibrosis may not be recommended yes that's what is changing now of Of course, when we see this or have this, you have the metabolic part.

58:38You need to make sure that all metabolic components are well treated. You need also to target obesity, type 2 diabetes, because all these are sort of synergetic factors. And you need also to target alcohol. And then if you have, there's a little bit of recommendation. So I don't want to discuss exactly the threshold for when treatment. But a certain threshold where you have significant or advanced fibrosis, also depending on the reimbursement system. And so it's more important to let people get this assessment and then see what's available around me. But then that is the threshold where you say, no, now you can have some specific treatment that can prevent or reverse this fibrogenesis, basically the progression of liver disease where you already have something that is significant fibrosis.

59:22And that's where both semaglutide and resmedirone comes in as two different drugs with two different mechanisms of backshits. And we spoke about this at the top, but when you say reverse, what is possible? And does it matter how long this person has had excess fat and inflammation and scarring? Or does it matter how much of the liver is damaged? What's possible? Yeah, that's a good point. So let's take them one by one. So steatosis alone is very dynamic. People go out and drink a lot for a few days or something. You can have steatosis in the liver. If you then stop, it goes away. People with obesity that are treated, steatosis go away.

1:00:06And that can go away pretty quickly. So that is the most dynamic group. And then you have the second one is inflammation. Okay, that takes a little bit more different types of cells that are activated. That is also perversal. Then you have the third component, which is fibrosis, basically the extracellular matrix. So fibrosis is different types of collagen, collagids, some long filament that is accumulating between the cell, extracellular matrix, it's called. So that is more static. But we know, and again, that it is reversible to a very, very large extent. In some people, all to the most advanced states of disease.

1:00:44But there's also a situation where, and that is again incomplete, when is it too far? There's some mechanism of how these collagen can cross-link in a way so they're more difficult to activate. But at least up to the age of cirrhosis and also decompensated cirrhosis, we're actually having, introducing the new concept of recompensation, very advanced disease that actually come back. If we remove the etiological factor, many can actually come back. So I would say in principle, there's no upper limit of when there is hope or something can be done. There are different drugs that are tolerated or approved for different past in severity of the disease.

1:01:27But the way of actually trying to intervene in the right place will always have an impact, a positive impact on the prognosis. And in terms of achieving that reversal, if you think about the clinical studies, the kind of body of evidence that we have looking at interventions and remission or reversal, if you had to rank them, diet, exercise, cutting alcohol, GLP-1s, res metaram, bariatric surgery, all these different things, what would you say is most important down to least important or still important but less in terms of the recovery? of magnitude. It really depends also, if I look at the individual patient, it really also depends on who is sitting in front of you.

1:02:12What is their phenotype? What is their history? What is their also personal, social, financial resources? There are people who can do incredible thing when they're motivated. We did a big study with a lot of people, a cestica, that's some years ago before we had all these drugs and all the things, told them about the liver disease. And there was an incredible ability to change behavior, both reduce alcohol, induce, change diet and increase exercise. And then there's a part of the population where this, for various reasons, is not so easy. And also saying that the drugs are approved, but also test in conjunction with advice, let's say best practice around exercise and diet.

1:02:54So I think anything cannot stand alone, but it also depends what is the phenotype? If the patient then have, let's say you start off with severe obesity or type 2 diabetes, okay, then it would make sense to start off with a GLP-1 because then they also lose weight, you know. And if that does not work or you have another or you don't tolerate that, okay, then you may want to start with resmenarone. So that's where it becomes, I think, a little bit more advanced. And you really need to take the patient's, yes, the access to the drug, the phenotype, the tolerability, and also there's the ability to do the behavioral change themselves.

1:03:35And some can be more or less successful with that. And also if people are a little bit older, they might have some arthrosis in the knees or the hips or whatever. There's a limit to how much exercise you can push these people to. Yes, we ask them to talk to dieticians, but how good are at following the diet, et cetera. And there are areas in many where it's difficult actually to get what we call food swamps, you know, where it's difficult to, or food deserts, where it's difficult to get healthy food. And if you don't acknowledge that the patient's integrated situation, it's more difficult to give, I think, the appropriate care that will benefit that individual most.

1:04:13So that's the holistic. We try to be holistic, even it's not always so easy. Have many of the GLP-1 trials measured liver outcomes? Of course, they've measured kind of total weight loss, but are there many that have looked at what's happening inside the liver? And do we understand GLP-1s affecting the liver just through the weight loss, or are there any direct mechanisms that could be occurring? For a long time, it was believed that there was no receptors in the liver for GLP-1s, And it was an indirect effect. And what we're seeing was a consequence of all the other positive metabolic effect. But there's actually been now more publication and even famous from Daniel Droghne.

1:04:54You know, some of these people really were super pioneers. So they have some fun, some receptors in the sinusoidal endothelial cells and seems to be linking that to the mechanisms and are directly all to the antiphibrated effect. Because to be true, you know, the first study on semaglutide, the phase two study, there was effect on steatosis it disappeared there was effect on inflammation it produced significantly but the effect on fibrosis was a little bore we see so we were not sure and then the phase three trial comes and then you see if you then go up to a thousand people and 72 weeks of treatment you suddenly see there's a significant reduction also in fibrosis and that was to many of us to say wow this is great news but how is this happening and that's why okay there's an indirect you sort of shut off some of the things that is pushing it because it's diabetes, it's hypertension, and it's, of course, obesity, but also this liver-directed effect.

1:05:52So, there's been a number publications, some associated with the company, some not, but of course, the company has a lot of the data seeing, can we see liver effect independent of weight loss? And I think, to me, the evidence is quite convincing that there are, and also particular now with these receptors there, that there are some direct effects. That's good news because we have a lot of the GLP-1s. We have another of the Juul, Tribble, Akinist. A lot of this whole space is coming. Now, it's again, also see all these drugs that it will be soon. And that's also why this awareness is important.

1:06:29We will more or less, as hepatologists, be like treating type 2 diabetes. They don't give up until they reach their target or treating hypertension because you have one, two, three, four, five drugs. and that's really good news. So resmediron is a completely different drug. So in people with MASH, there's a hyperfibridism in the liver. So that's where resmediron is sort of a liver, works in the liver, it's tied up in the liver and sort of reverses this hyperfibridism in the liver. It's a quite distinct mechanism working only in the liver. So that is and exerts its antifibrotic effect there. So it also has some effect on the lipids.

1:07:10It does not have effect on weight and also no big surprise because it does not really work along these lines and also not on glycemic control. So that's why these drugs are quite differently. And we probably see both trials and also in the clinic that these can, when needed, be combined. There's a whole new class of drugs, which is also coming, the FGF21 analogs, which I think also brings a lot of hope because some of these we recently saw signals that even in advance in stages with cirrhosis there's a reversal of cirrhosis i say oh my god this is really kind of a breakthrough that you see suddenly okay can we with drugs move people down from let's say a very dangerous place to a less dangerous place and then it sort of spreads out so now you have is not comparable to the obesity.

1:08:02You know, obesity, you have 40 whatever different acids, but here you still have a lot and a lot of phase three trials. And you see all these foster phase three trials, people have now sort of find out how does this work? What is kind of the disease? What kind of mechanism? What kind of drugs are likely to work? So I'm quite enthusiastic there that when there's so many players, it's very likely that we will be able for the individual patients sooner or later to find something that they can all tolerate and they can all will benefit them. What was the name of those analogs? FGF 21, fibroblast growth factor one.

1:08:39So there are different assets being developed by a bit different of the big companies now entering phase three, which has shown again the strongest. I think at least now it's a phase two signal. So we have to be a little bit careful because the signal we've seen in phase three, which which is semaglutide and resmederone, but seems again and again, the signal on cirrhosis, which is quite, I think, brings a lot of optimism to this and also to some of the other similar molecules. Okay. So that's some of the drugs, obviously reducing alcohol or not starting alcohol consumption if you don't already drink, exercising.

1:09:21From a diet nutrition perspective, is there a dietary pattern? No, it was just actually, there are now started to be, where many of the drug trials have been focused very much on the MASTLD. No, but now they're more and more doing in MED-ALD and ALD. And actually, it's a very exciting trial we look forward to present at the upcoming liver meeting in November, the first trial actually with various components, including semaglutide on alcohol-related liver disease. And that's a very interesting thing, because there's been a lot of observational studies that suggest that both the FGF21s, but also GLP-1s, they don't just work in the liver.

1:09:59They also process the blood-brain barrier. GLP-1s definitely do. FGF21, depending on the molecule size. But that means they affect the reward system. And that associated with reduced alcohol intake, et cetera. So how does it work in that? And that is, I think, a very exciting development. But let's jump to the behavioral things. That could be really promising when you think about the fact that for those individuals, it's both excess calories often and alcohol contributing to the changes in the liver. So if the drug is able to reduce calorie intake and also help someone reduce their intake of alcohol, it could be beneficial for the liver from multiple kind of pathways.

1:10:43In conjunction with alcohol, it's important to acknowledge that if all the alcohol that is sold is also consumed, the average American and European drink more than two units a day. And that's quite a lot, given that there's actually, whatever, 10, 20 % that does not drink at all. So alcohol is always, I think, an important component. And what about dietary pattern? In terms of the evidence we have. Is there a dietary pattern that you'd say kind of stands out or a general kind of way of eating that would be best for reducing fat within the liver? Let's say the guidelines recommend whatever Mediterranean diet.

1:11:22How strong is the advice around that? And I know the American guidelines for diet sort of reversed some of these things a little bit relative to protein, meats, et cetera. Let's not open that discussion. And then there's calorie restriction. We know calories restriction can make people lose weight, but we also know it's super, super difficult to maintain. We did a randomized study some years back where we tried to do a low-carb, high-fat versus a standard diabetes diet and actually found that a low-carb, high-fat actually increased or reduced the fat in the liver. So if you can maintain some kind of these diets, many of these will be associated with improved outcome.

1:12:02But the learning also in our study, yes, when they were in the study, they had reduced weight, even they were not supposed to, but both of them did. They had better glycemic control. They had better liver phenotype. But the problem is when you fall out of the study and you don't have a dietitian to follow you, you sort of fall back. And that's what we repeatedly see in some of these weight loss. But the standard recommendation is basically these, what you would call a Mediterranean diet. But I would say that if people can maintain their calories, and then I think also the interaction, which is also something we know a lot more about, which I think is super exciting and important, is the crosstalk between the liver and the fat cells, between the liver and the muscles, between the muscles and the brain.

1:12:42And all these talk together. And it's important. That's why physical exercise and doing these, now we all have something that can track how many steps we take. And I would say any exercises, as much as you can, is really, really important and also associated with well-being. So finding a way of eating a diet that essentially at an individual level makes you feel full on less calories so you can maintain a healthy body weight, that's like the most important thing. That's interesting about your low-carb, high-fat trial. Is there any evidence that you've seen that suggests the type of fat that we eat independent of calories affects liver fat?

1:13:23I've seen some research suggesting that maybe saturated fats might act differently to unsaturated fats on the liver. Is that something that is important in the scheme of all of the contributors to liver fat? What's the magnitude of that effect? I'm not completely sure. We have all these associations and you say, okay, we have a fat that comes from different types of nuts. You know we're better than something else. what is the really the compelling evidence for some of these things i'm a little bit of more of a pragmatic person so i would say that it's more a la carte i want to discuss and that's back to the individual patients how can i help these patients given their situation and given their preference and that's also what we saw in their trial some people did very well on it they really felt good they took it as a challenge they kept it up and some it was really difficult it was difficult to shop, it was difficult to change their recipes, whatever.

1:14:22So I think the goal is to then reduce weight or basically have a balance between what your body uses and what you consume. That is the realistic. We can set goals. Sometimes in the guideline, we read goals that are so high, but they're difficult to reach for a lot of the people. And that's again back to the exercise. Yes, it's wonderful if you have a person that can do a lot of exercise, whatever, several hours a week and high intensity, do all the things. But the fact is that a lot of these people that are whatever, let's say they're mid-60s, they've been a beast for the last 30 years, you don't get them out running whatever, three, four miles more.

1:15:01You know, that's unrealistic. So how do you actually get them to swim? How do you actually get them to walk? Do they want a dog or something like that where you can work with them or a bike or stuff like that. I've been using WHOOP for over six years and I can confidently say it keeps me on track when it comes to my sleep and exercise routines. The next generation of WHOOP isn't just tracking your workouts. It's monitoring your sleep quality, your recovery state and even giving you insights into your biological age. No screen, no distractions, just continuous data on what your body actually needs.

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1:16:13Don't you think, though, that the individual needs to make the decision of what's realistic or not, and we should just give them the information, and then as long as they have the information, they can kind of decide what is going to be right for them and what they can adhere to? Fully agree. We're here to help them. So at least I try to, but also support them because it's difficult. It's difficult to have a disease. They are afraid, of course. They have something, another, let's say, disease, if it's driven by the metabolic component, alcohol component, also things that are difficult to get out of.

1:16:49But I fully agree. You need to see these are the opportunities we have. Which one are most likely to be successful with you? And then you take it from there because otherwise you are sort of made for failure. From a kind of society perspective here, if we zoom out, the Lancet Commission, and I think what you've put forward today suggests that you believe a large share of liver disease is preventable. What are the levers across a population level? If we're thinking about policymaking or changes to the environment in some way, shape or form, what do you think would need to take place to really get right down to the root cause of these different variations of steatotic liver disease that you've described today?

1:17:31Yeah, it's a sad fact, but in theory, these diseases that kill so many people are 100 % preventable because we know what causes them and it's associated with our behavior. And that's why we, again, in the East Lancet Commission, there has various recommendations and can actually map how many deaths we will prevent if we increase the price of alcohol. If you change the marketing, there's a reason why there's marketing for alcohol. That's because it works. People drink more. What is a legal age of alcohol? It's 16 years in my country. I think it's not right. And should you allow marketing of unhealthy foods, ultra processed foods towards kids when you know this is just as addictive as many other things?

1:18:17So there are some of these things associated with where we can actually do a lot as a society community. For instance, my country now we're discussing, I hope they will succeed, that they will remove the VAT from vegetables. Wow, would that be then utterly because some of the reasons healthy food is often more expensive than unhealthy food. And the levers are there. The data are there to support it. So we know that at the population level, we need to drink less alcohol. We need to reduce the ultra-processed food. We also need the overall calories. But you know, if you add salt or sugar to anything, a lot of people will eat it because our brains are sort of made like that.

1:18:57We need salt and sugar. And some of these companies use it. And the issue here is on the one side, we have those that are supposed to protect citizens. We have all of our researchers and doctors who want to do it. And then, of course, you have a lot of people, a lot of big industries that earn their money, their profit. OK, the more alcohol sold, the more unhealthy food sold, the better the profit of the company. And they have a big lobby industry. And that is sort of the battle. Where is it? And that's the story where I think, no, you can not just put this to the individual's choice. Nobody choose to drink 20 units a day.

1:19:34Nobody choose to have a BMI of 40. They wish a different life. And there, I think, for the policy and the whole point of the Easy Lancer Commission. Now, we need to push to politicians. We know how it works. We know what to do. So it's basically up to them to see, OK, do you want to do something or should we just leave it as it is with the consequences? it hasn't it yeah i always find it bewildering that the a lot of the professional sporting codes at least in australia and other parts of the world the biggest sponsors are often alcohol companies and fast food companies and gambling companies and this is where a lot of children are exposed to that marketing from a very early age because they they go and watch the sport and these are their idols i fully agree and that's something where some of these countries go and Okay, no, we don't want to associate.

1:20:26Sport is something we do because it's healthy, because it's fun. It should not be associated with something we know in the end will cost a lot of these people's life or make them premature. So that's, again, something that should be kind of easy. But it's the same all over the world that this is going on. And these marketing machines and companies are very influential also at the political level. Totally. Let's bring this back to Henry where we started this conversation and we'll leave people with something very practical. So let's imagine that someone listening is in their 30s or 40s. And maybe this is Henry earlier in his life, a little bit earlier.

1:21:03And they feel fine. They're listening to this conversation. They feel fine. But they are in the typical, let's say, Aussie or British culture and many other parts around the world where they finish work. and you might go to the pub and have a couple of drinks maybe across the week. They're drinking 12, 20 drinks over that week. They're moderately overweight. They're listening. They have no idea how their liver is doing, but they're interested by what you're saying. Is there something that you would recommend them to do this week, next week as a starting point to just understand where their liver health is that?

1:21:43So I think number one, I think it's important to consider how much you drink. You're good to count it. And also acknowledge that there is a strong association between health and amount of alcohol. And also feel, do you have alcohol use disorder? Do you drink because you cannot or because you don't feel well if you don't? Okay, that's a different issue. Then you need help. But also if you drink and you can basically reduce drinking alcohol every day, why not give the liver a break? So give the liver a break for a few of the days because that will reduce the calories. And most people like to be lose a few kilos.

1:22:17But otherwise, if you worry about the liver and particularly if you have overweight or also come to a place with type 2 diabetes like Henry, you need to, when you go for your general practitioner and you anyway have checkup for your type 2 diabetes, your obesity, ask for the liver. Ask for a FIB4 and see, okay, do I have, because you could be one of those that then needs to be looked for. And in the end of the day, you have some of these treatments that is now approved and prevent what's happening from Henry. That's my dream, basically. Wonderful. Well, thank you so much for being with us today, Dr.

1:22:52Kraag. We're very grateful to have your time and grateful for your contribution to science and this really important aspect of human health. So I've really enjoyed this conversation. You're welcome to come back and join me anytime. I know you're working on a lot of interesting projects and new research. So perhaps when some of those things come out, you can come back and we can do a round two. That would be lovely. There you have it, friends. I hope you enjoyed this episode. If you did and want to stay up to date with future episodes, be sure to hit that subscribe button on YouTube and follow on Apple or Spotify.

1:23:27Finally, thank you for showing up and the effort that you're making to take control of your health. I look forward to hanging out with you again in the next episode.